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Library of Congress Cataloging-in-Publication Data

Holt, Richard I. G.

Essential endocrinology and diabetes. - 6th ed. / Richard I.G. Holt, Neil A. Hanley.

p. ; cm. -

(Essentials)

Includes bibliographical references and index.

ISBN-13: 978-1-4443-3004-5 (pbk. : alk. paper)

ISBN-10: 1-4443-3004-7 (pbk. : alk. paper)

1. Endocrinology-Case studies.

2. Diabetes-Case studies. I. Hanley,

Neil A. II. Title. III. Series: Essentials (Wiley-Blackwell)

[DNLM:

1. Endocrine Glands-physiology.

2. Diabetes Mellitus.

3. Endocrine System Diseases.

4. Hormones-

physiology. WK 100]

RC648.H65 2012

616.4-dc23

2011024249

A catalogue record for this book is available from the British Library.

Set in 10 on 12 pt Adobe Garamond Pro by Toppan Best-set Premedia Limited

2012

Preface

There have been significant advances and developments in the 4 years since we wrote

the last edition. Consequently, many areas of the book have required substantial updating

and extensive re-writing. Nevertheless, the structure of the book has remained similar

to the last edition, which seemed popular around the world.

The first part strives to create a knowledgeable reader prepared for the clinical sec-

tions. Recognizing that many students now come to medicine from non-scientific

backgrounds, we have tried to limit assumptions on prior knowledge. For instance, the

concept of negative feedback regulation, covered in Chapter 1, is mandatory for under-

standing almost all endocrine physiology and is vital for the interpretation of many

clinical tests. Similarly, molecular diagnostics has advanced far beyond the historical

development of immunoassays. New modalities, such as molecular genetics, mass spec-

trometry and sophisticated imaging, are already standard practice and it is important

that aspiring clinicians, as well as scientists, appreciate their methodology, application

and limitations. The second part retains a largely organ-based approach. The introduc-

tory basic science in these chapters aims to be concise yet sufficient to understand,

diagnose and manage the associated clinical disorders. The chapter on endocrine neo-

plasia, including hormone-secreting tumours of the gut, has been expanded in recogni-

tion of the increasing array of hormones discovered from the pancreas and gastrointestinal

tract. In previous editions these hormones have lacked attention. However, many of

them are now emerging as key regulators that are exploited in new therapies. For

instance, augmentation of glucagon-like peptide 1 signalling is an effective treatment for

diabetes. The third part on diabetes and obesity was entirely new in the last edition and

these chapters have undergone the greatest change here. Over the last 4 years we have

seen significant advances in the treatment of type 2 diabetes such as the new incretin-

based therapies and the withdrawal of other treatments due to safety concerns. Clinical

algorithms have also changed and these have been updated.

The textbook aims to bridge the gap from basic science training, through clinical train-

ing, to the knowledge required for the early postgraduate years and specialist training. The

text goes beyond core undergraduate medical education. Learning objectives, boxes, and

concluding ‘key points’ aim to emphasize the major topics. There is hopefully useful detail

for more advanced clinicians who, like the authors, enjoy trying to interpret clinical medi-

cine scientifically, but for whom memory occasionally fails. Although the structure of the

book is largely unchanged from the previous edition, readers of the old edition will recog-

nize welcome developments. For the first time, the book is in full colour, which has allowed

us to include colour photographs in the relevant chapter. We have introduced recap and

cross-reference guides at the beginning of each of the clinical chapters to help the reader

find important information in other parts of the book more easily. The case histories that

were introduced in the last edition proved to be a success and these have been expanded to

provide greater opportunity to put theory into practice.

We have brought our clinical and research experiences together to create this book.

While it has been a truly collaborative venture and the book is designed to read as a

whole, inevitably one of us has taken a lead with each chapter depending on our own

interests. As such, NAH was responsible for writing Part 1 and Part 2, while RIGH was

responsible for Part 3.

List of abbreviations

5-HIAA

5-hydroxyindoleacetic acid

gas chromatography

5-HT

5-hydroxytryptophan

GDM

gestational diabetes

αMSH

α-melanocyte stimulating hormone

GFR

glomerular filtration rate

ACTH

adrenocorticotrophic hormone

growth hormone (somatotrophin)

ADH

vasopressin/antidiuretic hormone

GHR

GH receptor

AFP

α-fetoprotein

GHRH

growth hormone-releasing hormone

AGE

advanced glycation end-product

glycaemic index

AGRP

Agouti-related protein

GIP

glucose-dependent insulinotrophic

angiotensin I

peptide (gastric inhibitory peptide)

AII

angiotensin II

GLUT

glucose transporter

ALS

acid labile subunit

GnRH

gonadotrophin-releasing hormone

AMH

anti-Müllerian hormone

GPCR

guanine-protein coupled receptor

androgen receptor

glucocorticoid receptor

APS-1

type 1 autoimmune polyglandular

Grb2

type 2 growth factor receptor-bound

syndrome

protein

APS-2

type 2 autoimmune polyglandular

hCG

human chorionic gonadotrophin

syndrome

hMG

human menopausal gonadotrophin

CAH

congenital adrenal hyperplasia

HMGCoA

hydroxymethylglutaryl coenzyme A

cAMP

cyclic adenosine monophosphate

HNF

hepatocyte nuclear factor

CBG

cortisol binding globulin

HPLC

high performance liquid

cGMP

guanosine monophosphate

chromatography

CRE

cAMP response element

HRE

hormone response element

CREB

cAMP response element-binding

HRT

hormone replacement therapy

protein

ICSI

intracytoplasmic sperm injection

CNS

central nervous system

IDDM

insulin-dependent diabetes mellitus

CRH

corticotrophin-releasing hormone

IFG

impaired fasting glycaemia

CSF

cerebrospinal fluid

IFMA

immunofluorometric assay

computed tomography

IGF

insulin-like growth factor

CVD

cardiovascular disease

IGFBP

IGF-binding protein

DAG

diacylglycerol

IGT

impaired glucose tolerance

DEXA

dual energy X-ray absorptiometry

inositol phosphate

DHEA

dehydroepiandrosterone

IPF

insulin promoter factor

DHT

5α-dihydrotestosterone

insulin receptor

diabetes insipidus

IRMA

intraretinal microvascular

EGF

epidermal growth factor

abnormalities (Chapter 14)

EPO

erythropoietin

IRMA

immunoradiometric assay

oestrogen receptor

(Chapter 4)

FFA

free fatty acid

IRS

insulin receptor substrate

FGF

fibroblast growth factor

IVF

in vitro fertilization

FIA

fluoroimmunoassay

JAK

Janus-associated kinase

FISH

fluorescence in situ hybridization

LDL

low-density lipoprotein

FSH

follicle-stimulating hormone

luteinizing hormone

fT₃

free tri-iodothyronine

MAO

monoamine oxidase

fT₄

free thyroxine

MAPK

mitogen-activated protein kinase

How to get the best out of your textbook / xiii

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Features contained within your textbook

CHAPTER 1

Overview of

endocrinology

 Every chapter has its own chapter-opening page that

311

offers a list of key topics and learning objectives

CHAPTER 14

Key topics

pertaining to the chapter

■ A brief history of endocrinology and diabetes

Complications of

■

The role of hormones

■ Classification of hormones

■ Organization and control of endocrine organs

diabetes

■ Endocrine disorders

■ Key points

Learning objectives

Key topics

■ Microvascular complications

312

Throughout your textbook you will find this

■ To be able to define endocrinology

■ Macrovascular disease

330

■ To understand what endocrinology is as a basic science and

■ Cancer

334

a clinical specialty

■ To appreciate the history of endocrinology

■ Psychological complications

334

icon which points you to cases with

■ To understand the classification of hormones into peptides,

■ How diabetes care can reduce complications

335

steroids and amino acid derivatives

■ Diabetes and pregnancy

336

self-test questions. You will find the

■ To understand the principle of feedback mechanisms that

■ Social aspects of diabetes

339

regulate hormone production

■ Key points

340

This chapter details some of the history to endocrinology anddiabetes, and introduces basic principles that underpin the

■ Answers to case histories

340

answers at the end of each chapter.

subsequent chapters

Learning objectives

■ To discuss the causes of microvascular and macrovascular

complications

■ To understand the importance of screening for complications

■ To understand the strategies to prevent and treat

complications

■ To discuss diabetes in pregnancy

You will also find a helpful list of key points

■ To understand the psychosocial aspects of diabetes

Essential Endocrinology and Diabetes, Sixth Edition. Richard IG Holt, Neil A Hanley.

This chapter discusses the microvascular and macrovascular

psychosocial aspects of diabetes

complications of diabetes, diabetes in pregnancy and

at the end of each chapter which give a

quick summary of important principles.

Essential Endocrinology and Diabetes, Sixth Edition. Richard IG Holt, Neil A Hanley.

xiv

/ How to get the best out of your textbook

102 / Chapter 6: The adrenal gland

Chapter 6: The adrenal gland / 103

 Your textbook is full of useful photographs,

Figure 6.2 Section throughthe adrenal cortex. (a) The

(a)

(b)

17α-hydroxylase

17,20-lyase

Sulphotransferase

illustrations and tables. The Desktop Edition

blood vessels run from outer

Capsule

Smooth endoplasmic reticulum

(CYP17A1)

(SULT2A1)

capsule to medullary venule.

(b) A zona fasciculata cell with

Zona

glomerulosa

Cholesterol

version of your textbook will allow you to

large lipid droplets, extensive

Capillary

cleavage (CYP11A1)

Cholesterol side chain

smooth endoplasmic

Pregnenolone

17a-hydroxy-

Dehydroepi-

DHEAsulphate

reticulum and mitochondria.

Zona

fasciculata

3β-hydroxysteroid

pregnenolone

androsterone(DHEA)

(DHEAS)

copy and paste any photograph or illustration

Lipid droplets Mitochondria

(HSD3B2)

dehydrogenase

Progesterone

17a-hydroxy-progesterone

Androstenedione

21-hydroxylase

into assignments, presentations and your

Zona

reticularis

(CYP21A2)

Deoxy-

corticosterone

11-deoxycortisol

own notes.

(CYP11B2)

11β-hydroxylase

(CYP11B1)

11β-hydroxylase

Medulla

Corticosterone

Cortisol



Venule

(CYP11B2)

18-hydroxylase

18-hydroxy-

corticosterone

(CYP11B2)

Aldosterone synthase

Box 6.2 Zones of the adult adrenal

used as a test of glucocorticoid excess (UFC is ∼1%

Aldosterone

cortex and their steroid hormone

of cortisol production by the adrenal glands).Measuring salivary cortisol similarly avoids issues

secretion

with uctuating serum CBG.

Figure 6.3 Biosynthesis of adrenocortical steroid hormones. HSD3B activity in the adrenal cortex a

• Zona glomerulosa, nests of closely packed

the type 2 isoform. The three steps from deoxycorticosterone to aldosterone are catalyzed by the s

252 / Chapter 11: Overview of diabetes

Chapter 11: Overview of diabetes / 253

layer; secretes aldosterone

small cells creating the thinnest, outermost

Regulation of cortisol biosynthesis and

CYP11B2 (also see Figure 2.6).

• Zona fasciculata, larger cells in columns

adrenal axis

secretion - the hypothalamic-pituitary-

making up ∼three-quarters of the cortex;

e major regulation of the adrenal cortex

Box 6.3 Adrenocortical steroidogenesis can be summarized into a f

Table 11.6 Insulin actions on carbohydrate metabolism

secretes cortisol and some sex steroid

comes from the anterior pituitary, via the produc-

key steps

Action

Mechanism

Glucose

Sorbitol route

Fructose

precursors

tion and circulation of adrenocorticotrophic hor-

• Transport of cholesterol into the

cortisol or sex steroid precursor.

Increases glucose uptake

Translocation of glucose transporter (GLUT)-4 to the cell surface

• Zona reticularis, ‘net-like’ arrangements ofinnermost cells, formed at 6-8 years to

mone (ACTH), a cleavage product of the pro-

mitochondrion by the steroid acute

CYP17A1 is absent from the zon

into cells

Glucose-6- P

Glucose-1- P

Glycogen

herald a poorly understood change called

opiomelanocortin (POMC) gene (review Chapter 5).In turn, ACTH is regulated by corticotrophin-

regulatory (StAR) protein

glomerulosa

Increases glycogen synthesis

Activates glycogen synthase by dephosphorylation

‘adrenarche’; secretes sex steroid

releasing hormone (CRH) from the hypothalamus

• The rate-limiting removal of the cholesterol

°^{Early action of HSD3B2 steers s}

Inhibits glycogen breakdown

Inactivates glycogen phosphorylase and its activating kinase by

UDP-Glucose

precursors and some cortisol

(Figure 6.4). By binding to cell-surface receptors

side chain by CYP11A1

• Shuttling intermediaries between

precursors away from the sex stprecursors towards aldosterone

dephosphorylation

Glycolytic-

Pentose

Glucuronate-

Glycoprotein

and activating cAMP second messenger pathways,

mitochondria and endoplasmic reticulum for

• The presence and activity of CYP1

Inhibits gluconeogenesis

Dephosphorylation of pyruvate kinase and 2,6-biphosphate kinase

gluconeogenic

phosphate

xylulose

Mucopoly-

ACTH increases ux through the pathway from

further enzymatic modification

zona glomerulosa permitting aldos

Increases glycolysis

Dephosphorylation of pyruvate kinase and 2,6-biphosphate kinase

pathways

α-Glycero- P

pathway

saccharide

cortisol measurement; an important clinical issue.Like thyroid hormones, it is only the free compo-

cholesterol to cortisol, particularly at the rate-limiting step catalyzed by CYP11A1. is happens

• Action of two key enzymes at branch

synthesis

Lactate

Pyruvate

Ribose-5- P

Nucleotides

nent that enters target cells.

e free component

acutely such that a rise in ACTH increases cortisol

points:

• The presence and activity of CYP1

CoA

Converts pyruvate to acetyl

dehydrogenase

Activates the intramitochondrial enzyme complex pyruvate

NADPH

NADP⁺

RNA and DNA

also passes into urine - ‘urinary free cortisol’ (UFC)

levels within

5 min. Cortisol provides feedback

°^{CYP17A1 prevents the biosynthesis of}

aldosterone and commits a steroid to

allowing cortisol production

fasciculata (and less so the reticul

α-Glycero- P

– where its collection and assay over 24 h has been

to the anterior pituitary and hypothalamus to

phosphorylation and dephosphorylation of the

lism by the pentose phosphate pathway provides

acid cycle

Tricarboxylic

CoA

Acetyl

Lipid

synthesis

Triglycerides

enzymes controlling glycogenolysis and glycogen

nicotinamide adenine dinucleotide phosphate

ATP

synthesis (Figure 11.12). e rate-limiting enzymesare the catabolic enzyme glycogen phosphorylase

synthesis.

(NADPH), which is needed for fatty acid

Protein

degradation

Aminoacids

^NH3

Ureacycle

Urea

and the anabolic enzyme glycogen synthase. Insulin

increases glycogen synthesis by activating glycogen

Triglyceride synthesis is stimulated by ester-

ication of glycerol phosphate, while triglyceride

synthase, while inhibiting glycogenolysis by

dephosphorylating glycogen phosphorylase kinase.

breakdown is suppressed by dephosphorylation of

hormone-sensitive lipase.

Figure 11.12 Inter-relationships among alternative

routes of glucose metabolism. The central role of

reversibility of certain reaction sequences implied

by double-headed arrows is not necessarily

Glycolysis is stimulated and gluconeogenesis inhib-

ited by dephosphorylation of pyruvate kinase (PK)

Cholesterol synthesis is increased by activation

and dephosphorylation of hydroxymethylglutaryl

glucose in carbohydrate, fat and protein metabolism

is summarized. The principal metabolic pathways

intended to suggest that the same enzymes are

involved in both the forward and reverse

and 2,6-biphosphate kinase. Insulin also enhances

co-enzyme A (HMGCoA) reductase, while choles-

are shown enclosed in boxes in order to simplify

the diagram; some key intermediates and products

reactions. The principal reversible pathways that

are activated during fasting are marked with heavy

the irreversible conversion of pyruvate to acetyl

CoA by activation of the intramitochondrial enzyme

terol ester breakdown appears to be inhibited

by dephosphorylation of cholesterol esterase.

of metabolic interconversions are shown. The

arrows.

complex pyruvate dehydrogenase. Acetyl CoA

Phospholipid metabolism is also inuenced by

may then be directly oxidized via the tricarboxylicacid (Krebs’) cycle, or used for fatty acid synthesis

insulin.

(Figure 11.13).

Protein metabolism

Lipid metabolism

Insulin stimulates the uptake of amino acid intocells and promotes protein synthesis in a range of

Insulin increases the rate of lipogenesis in several

tissues.

ere are eects on the transcription of

Table 11.7 Insulin actions on fatty acid metabolism

the formation and storage of triglyceride.

ways in adipose tissue and liver, and controls

specic mRNA, as well as their translation intoproteins on the ribosomes (review Chapter 2 and

Action

Mechanism

critical step in lipogenesis is the activation of the

Figure 2.2). Examples of enhanced mRNA tran-

Releases fatty acids from circulating

chylomicrons or very low-density lipoproteins

Activates lipoprotein lipase

insulin-sensitive lipoprotein lipase in the capillaries.Fatty acids are then released from circulating

scription include glucokinase and fatty acid syn-thase. By contrast, insulin decreases mRNA

Increases fatty acid synthesis

Activates acetyl CoA carboxylase

chylomicrons or very low-density lipoproteins

encoding liver enzymes such as carbamoyl phos-

Suppresses fatty acid oxidation

Inhibits carnitine acyltransferase

and taken up into the adipose tissue. Fatty acidsynthesis is increased by activation and increased

phate synthetase, which is a key enzyme in the ureacycle. However, the major action of insulin on

Increases triglyceride synthesis

Stimulates esterification of glycerol phosphate

phosphorylation of acetyl CoA carboxylase, whilefat oxidation is suppressed by inhibition of carnitine

protein metabolism is to inhibit the breakdown ofproteins (Figure 11.14). In this way it acts synergis-

Inhibits triglyceride breakdown

Dephosphorylates hormone-sensitive lipase

Cross-reference

acyltransferase

(Table

11.7). Lipogenesis is also

tically with GH and insulin-like growth factor I

Increases cholesterol synthesis

Activates and dephosphorylates HMGCoA reductase

facilitated by glucose uptake, because its metabo-

(IGF-I) to increase protein anabolism.

Inhibits cholesterol ester breakdown

Dephosphorylates cholesterol esterase

The development of the parathyroid and parafollicular

C-cells is described alongside the thyroid in Chapter 8

Tumours of the parathyroid glands are an important

component of multiple endocrine neoplasia, covered in

Chapter 10

Other hormones such as cortisol (see Chapter 6) and sex

 At the beginning of some chapters you will also find

hormones (see Chapter 7) affect mineralization of the

bones

cross-references which make it easy to locate related

information quickly and efficiently.

We hope you enjoy using your new textbook. Good luck with your studies!

4 / Chapter 1: Overview of endocrinology

An organism comprised of a single or a few cells

A brief history of endocrinology

analyzes and responds to its external environment

and diabetes

with relative ease. No cell is more than a short dif-

fusion distance from the outside world or its neigh-

The term ‘hormone’, derived from the Greek word

bours, allowing a constancy of internal environment

‘hormaein’ meaning ‘to arouse’ or ‘to excite’, was

(‘homeostasis’). This simplicity has been lost with

first used in

1905 by Sir Ernest Starling in his

the evolution of more complex, larger, multicellular

Croonian Lecture to the Royal College of Physicians;

organisms. Simple diffusion has become inadequate

in larger animal species where functions localize to

specific organs. In humans, there are ∼10¹⁴ cells of

(a) Endocrine

(b) Autocrine (A) and

200 or more different types. With this compart-

Paracrine (P)

mentalized division of purpose comes the need for

Hormone

Target cell

effective communication to disseminate informa-

tion throughout the whole organism - only a few

cells face the outside world, yet all respond to it.

Two communication systems facilitate this: the

endocrine and nervous systems (Box 1.1).

Local hormone

Blood vessel

The specialized ductless glands and tissues of the

endocrine system release chemical messengers

hormones - into the extracellular space, from where

(d) Neurotransmitter

they enter the bloodstream. It is this blood-borne

transit that defines endocrinology; however, the

Nerve cell

Neurone

principles are similar for hormone action on a

neighbouring cell (‘paracrinology’) or, indeed, itself

(‘auto- or intra-crinology’) (Figure 1.1).

Axon

The nervous and endocrine systems interact.

Endocrine glands are under both nervous and hor-

Axon

Neurone

monal control, while the central nervous system is

terminal

affected by multiple hormonal stimuli - features

Neurotransmitter

reflected by the composite science of neuroendo-

crinology (Figure 1.1).

Blood vessel

Target cell

Figure 1.1 Cells that secrete regulatory substances to

communicate with their target cells and organs. (a)

Endocrine. Cells secrete hormone into the blood

vessel, where it is carried, potentially over large

distances, to its target cell. (b) Autocrine (A): hormones

Box 1.1 Functions of the

such as insulin-like growth factors can act on the cell

endocrine and nervous systems,

that produces them, representing autocrine control.

the two main communication

Paracrine (P): cells secrete hormone that acts on

nearby cells (e.g. glucagon and somatostatin act on

systems

adjacent β-cells within the pancreatic islet to influence

• To monitor internal and

insulin secretion). (c) Stimulated neuroendocrine cells

external environments

secrete hormone (e.g. the hypothalamic hormones that

maintain

• To allow appropriate

regulate the anterior pituitary) from axonic terminals

homeostasis

adaptive changes

into the bloodstream. (d) Neurotransmitter cells secrete

substances from axonic terminals to activate adjacent

• To communicate via

}

neurones.

chemical messengers

Chapter 1: Overview of endocrinology / 5

however, the specialty is built on foundations that

crine syndromes. Since then, our understanding has

are far older. Aristotle described the pituitary, while

advanced through:

the associated condition, gigantism, due to excess

growth hormone (GH), was referred to in the Old

• Successful

quantification

circulating

Testament, two millennia or so before the 19th

hormones

century recognition of the gland’s anterior and pos-

• Pathophysiological identification of endocrine

terior components by Rathke, and Pierre Marie’s

dysfunction

connection of GH-secreting pituitary tumours to

• Molecular genetic diagnoses

acromegaly.

• Molecular unravelling of complex hormone

Diabetes was recognized by the ancient

action.

Egyptians. Areteus later described the disorder in

the second century ad as ‘a melting down of flesh

Some of the landmarks from the last 100 years

and limbs into urine’ - diabetes comes from the

are shown in Box 1.2, and those researchers who

Greek word meaning siphon. The pancreas was only

have been awarded the Nobel Prize for Medicine,

implicated relatively recently when Minkowski real-

Physiology or Chemistry for discoveries that have

ized in 1889 that the organ’s removal in dogs mim-

advanced endocrinology and diabetes are listed in

icked diabetes in humans.

Table 1.1.

The roots of reproductive endocrinology are

Traditionally, endocrinology has centred on spe-

equally long. The Bible refers to eunuchs and

cialized hormone-secreting organs

(Figure

1.2),

Hippocrates recognized that mumps could result in

largely built on the ‘endocrine postulates’ of Edward

sterility. Oophorectomy in sows and camels was

Doisy (Box 1.3). While the focus of this textbook

used to increase strength and growth in ancient

remains with these organs, many tissues display

Egypt. The association with technology is also long-

appreciable degrees of hormone biosynthesis, and,

standing. For instance, it took the microscope in the

equally relevant, modulate hormone action. All

17th century for Leeuwenhoek to visualize sperma-

aspects are important for a complete appreciation

tozoa and later, in the 19th century, for the mam-

of endocrinology and its significance.

malian ovum to be discovered in the Graafian

follicle.

The role of hormones

During the last

500 years, other endocrine

organs and axes have been identified and character-

Hormones are synthesized by specialized cells

ized. In

1564, Bartolommeo Eustacio noted the

(Table 1.2), which may exist as distinct endocrine

presence of the adrenal glands. Almost 300 years

glands or be located as single cells within other

later (1855), Thomas Addison, one of the forefa-

organs, such as the gastrointestinal tract. The chap-

thers of clinical endocrinology, described the con-

ters in Part 2 are largely organized on this anatomi-

sequences of their inadequacy. Catecholamines were

cal basis.

identified at the turn of the 19th century, in parallel

Endocrinology is defined by the secretion of

with Oliver and Schaffer’s discovery that these

hormones into the bloodstream; however, autocrine

adrenomedullary substances raise blood pressure.

or paracrine actions are also important, often mod-

This followed shortly after the clinical features of

ulating the hormone-secreting cell type. Hormones

myxoedema were linked to the thyroid gland, when,

act by binding to specific receptors, either on the

in 1891, physicians in Newcastle treated hypothy-

surface of or inside the target cell, to initiate a

roidism with sheep thyroid extract. This was an

cascade of intracellular reactions, which frequently

important landmark, but long after the ancient

amplifies the original stimulus and generates a final

Chinese recognized that seaweed, as a source of

response. These responses are altered in hormone

iodine, held valuable properties in treating ‘goitre’,

deficiency and excess: for instance, GH deficiency

swelling of the thyroid gland.

leads to short stature in children, while excess

Early clinical endocrinology and diabetes tended

causes over-growth (either gigantism or acromegaly;

to recognize and describe the features of the endo-

Chapter 5).

6 / Chapter 1: Overview of endocrinology

Box 1.2 Some landmarks in endocrinology over the last 100 years or so

1905

First use of the term ‘hormone’ by Starling in the Croonian Lecture at the Royal

College of Physicians

1909

Cushing removed part of the pituitary and saw improvement in acromegaly

1914

Kendall isolated an iodine-containing substance from the thyroid

1921

Banting and Best extracted insulin from islet cells of dog pancreas and used it to

lower blood sugar

Early 1930s

Pitt-Rivers and Harrington determined the structure of the thyroid hormone,

thyroxine

1935-40

Crystallization of testosterone

1935-40

Identification of oestrogen and progesterone

1940s

Harris recognized the relationship between the hypothalamus and anterior pituitary

in the ‘portal-vessel chemotransmitter hypothesis’

1952

Gross and Pitt-Rivers identified tri-iodothyronine in human serum

1955

The Schally and Guillemin laboratories showed that extracts of hypothalamus

stimulated adrenocorticotrophic hormone (ACTH) release

1956

Doniach, Roitt and Campbell associated antithyroid antibodies with some forms of

hypothyroidism - the first description of an autoimmune phenomenon

1950s

Adams and Purves identified thyroid stimulatory auto-antibodies

Gonadectomy and transplantation experiments by Jost led to the discovery of the

role for testosterone in rabbit sexual development

1955

Sanger reported the primary structure of insulin

1957

Growth hormone was used to treat short stature in patients

1966

First transplant of human pancreas to treat type 1 diabetes by Kelly, Lillehei, Goetz

and Merkel at the University of Minnesota

1969

Hodgkin reported the three-dimensional crystallographic structure of insulin

1969-71

Discovery of thyrotrophin-releasing hormone (TRH) and gonadotrophin-releasing

hormone (GnRH) by Schally’s and Guillemin’s groups

1973

Discovery of somatostatin by the group of Guillemin

1981-2

Discovery of corticotrophin-releasing hormone (CRH) and growth hormone-

releasing hormone (GHRH) by Vale

1994

Identification of leptin by Friedman and colleagues

1994

First transplantation of pancreatic islets to treat type 1 diabetes by Pipeleers and

colleagues in Belgium

1999

Discovery of ghrelin by Kangawa and colleagues

1999

Sequencing of the human genome - publication of the DNA code for

chromosome 22

2000

Advanced islet transplantation using modified immunosuppression by Shapiro and

colleagues to treat type 1 diabetes

Thyroid hormone acts on many, if not all, of the

its role in the survival and growth of many cell types

200 plus cell types in the body. The basal metabolic

in laboratory culture. In contrast, other hormones

rate increases if it is present in excess and declines

may act only on one tissue. Thyroid-stimulating

if there is a deficiency (see Chapter 8). Similarly,

hormone

(TSH), adrenocorticotrophic hormone

insulin acts on most tissues, implying its receptors are

(ACTH) and the gonadotrophins are secreted by

widespread. Its importance is also underlined by

the anterior pituitary and have specific target tissues

Chapter 1: Overview of endocrinology / 7

Table 1.1 Nobel prize winners for discoveries relevant to endocrinology and diabetes

Year

Prize winner(s)

For work on . . . 

1909

Emil Theodor Kocher

Physiology, pathology and surgery of the thyroid

gland

1923

Frederick Grant Banting and John James

Discovery of insulin

Richard Macleod

1928

Adolf Otto Reinhold Windhaus

Constitution of the sterols and their connection

with the vitamins

1939

Adolf Friedrich and Johann Butenandt

Sex hormones

1943

George de Hevesy

Use of isotopes as tracers in the study of chemical

processes

1946

James Batcheller Summer, John Howard

Discovery that enzymes can be crystallized and

Northrop and Wendell Meredith Stanley

prepared in a pure form

1947

Carl Ferdinand Cori, Getty Theresa Cori

Discovery of the course of the catalytic conversion

(neé Radnitz) and Bernardo Alberto

of glycogen

Houssay

1950

Edwin Calvin Kendall, Tadeus Reichstein

Discoveries relating to the hormones of the

and Philip Showalter Hench

adrenal cortex, their structure and biological

effects

1955

Vincent du Vigneaud

Biochemically important sulphur compounds,

especially for the first synthesis of a polypeptide

hormone

1958

Frederick Sanger

Structures of proteins, especially that of insulin

1964

Konrad Bloch and Feodor Lynen

Discoveries concerning the mechanism and

regulation of cholesterol and fatty acid metabolism

1966

Charles Brenton Huggins

Discoveries concerning hormonal treatment of

prostatic cancer

1969

Derek HR Barton and Odd Hassel

Development of the concept of conformation and

its application in chemistry

1970

Bernard Katz, Ulf von Euler and Julius

Discoveries concerning the humoral transmitters in

Axelrod

the nerve terminals and the mechanism for their

storage, release and inactivation

1971

Earl W Sutherland Jr

Discoveries concerning the mechanisms of the

action of hormones

1977

Roger Guillemin, Andrew V Schally and

Discoveries concerning peptide hormones in the

Rosalyn Yalow

production in the brain and the development of

radioimmunoassay from peptide hormones

1979

Allan M Cormack and Godfrey N

Development of computer-assisted tomography

Hounsfield

(Continued)

8 / Chapter 1: Overview of endocrinology

Table 1.1 (Continued )

Year Prize winner(s)

For work on . . . 

1982

Sune K Bergström, Bengt I Samuelson

Discoveries concerning prostaglandins and related

and John R Vane

biologically active substances

1985

Michael S Brown and Joseph L Goldstein Discoveries concerning the regulation of

cholesterol metabolism

1986

Stanley Cohen and Rita Levi-Montalcini

Discoveries of growth factors

1992

Edmond H Fischer and Edwin G Krebs

Discoveries concerning reversible protein

phosphorylation as a biological regulatory

mechanism

1994

Alfred G Gilman and Martin Rodbell

Discovery of G-proteins and the role of these

proteins in signal transduction in cells

2003

Peter Agre and Roderick MacKinnon

Discovery of water channels, and the structural

and mechanistic studies of ion channels

2003

Paul Lauterbur and Sir Peter Mansfield

Discoveries concerning magnetic resonance

imaging

2010

Robert G Edwards

Development of in vitro fertilization

– the thyroid gland, the adrenal cortex and the

Some peptide hormones have complex tertiary

gonads, respectively (Table 1.2).

structures or are comprised of more than one

peptide chain. Oxytocin and vasopressin, the two

posterior pituitary hormones, have ring structures

linked by disulphide bridges. Despite being remark-

Classification of hormones

ably similar in structure, they have very different

There are three major groups of hormones accord-

physiological roles (Figure 1.3). Insulin consists of

ing to their biochemistry

(Box 1.4). Peptide or

α- and β-chains linked by disulphide bonds. Like

protein hormones are synthesized like any other

several hormones, it is synthesized as an inactive

cellular protein. Amino acid-derived and steroid

precursor that requires modification prior to release

hormones originate from a cascade of biochemical

and activity. To some extent this regulation protects

reactions catalyzed by a series of intracellular

the synthesizing cell from being overwhelmed by its

enzymes.

own hormone action. The gonadotrophins, follicle-

stimulating hormone (FSH) and LH, TSH and

human chorionic gonadotrophin (hCG) also have

Peptide hormones

two chains. However, these α- and β-subunits are

The majority of hormones are peptides and range

synthesized quite separately, from separate genes.

in size from very small, only three amino acids

The α-subunit is common; the distinctive β-subunit

[thyrotrophin-releasing hormone (TRH)], to small

of each confers biological specificity.

proteins of over 200 amino acids, such as TSH or

luteinizing hormone (LH). Some peptide hormones

Amino acid derivatives

are secreted directly, but most are stored in granules,

the release from which is commonly controlled

These hormones are small water-soluble com-

by another hormone, as part of a cascade, or by

pounds. Melatonin is derived from tryptophan,

innervation.

whereas tyrosine derivatives include thyroid hor-

Chapter 1: Overview of endocrinology / 9

Box 1.3 The ‘Endocrine

Pituitary gland:

Hypothalamus

Postulates’: Edward Doisy,

anterior and

and median

posterior

eminence

St Louis University School of

Medicine, USA, 1936

Four parathyroid

Thyroid

glands

• The gland must secrete something (an

gland

‘internal secretion’)

• Methods of detecting the secretion must

be available

• Purified hormone must be obtained from

gland extracts

• The pure hormone must be isolated, its

structure determined and synthesized

To this could be added:

Two adrenal

Stomach

• The hormone must act on specific target

glands: cortex

Kidney

cells via a receptor such that excess or

and medulla

Pancreas:

deficiency results in a specific phenotype

Duodenum

Islets of

Langerhans

Two ovaries

stituent of the cell membrane. Produced by the

(o)

adrenal cortex, gonad and placenta, steroid hor-

Two testes

mones are insoluble in water and largely circulate

(o)

bound to plasma proteins.

Organization and control of

Figure 1.2 The sites of the principal endocrine

endocrine organs

glands. The stomach, kidneys and duodenum are

The synthesis and release of hormones is regulated

also shown. Not shown, scattered cells within the

by control systems, similar to those used in engineer-

gastrointestinal tract secrete hormones.

ing. These mechanisms ensure that hormone signals

can be limited in amplitude and duration. Central

to the regulation of many endocrine organs is the

mones, catecholamines, and dopamine, which

anterior pituitary gland, which, in turn, is controlled

regulates prolactin secretion in the anterior pitui-

by a number of hormones and factors released from

tary. The catecholamines from the adrenal medulla,

specialized hypothalamic neurones (see Chapter 5).

epinephrine

(adrenaline) and norepinephrine

Thus, major endocrine axes comprise the hypotha-

(noradrenaline), are also sympathetic neurotrans-

lamus, anterior pituitary and end organ, such as the

mitters, emphasizing the close relationship between

adrenal cortex, thyroid, testis or ovary. An under-

the nervous and endocrine systems (see Figure 1.2).

standing of these control mechanisms is crucial for

Like peptide hormones, they are stored in granules

appreciating both regulation of many endocrine

prior to release.

systems and their clinical investigation.

Steroid hormones

Simple control

Steroid hormones are lipid-soluble molecules

An elementary control system is one in which the

derived from cholesterol, which is itself a basic con-

signal itself is limited, either in magnitude or

Chapter 1: Overview of endocrinology / 11

Table 1.2 (Continued)

Gland

Hormone

Molecular characteristics

Liver

Insulin-like growth factor I (IGF-I)

Protein

Ovary

Oestrogens

Steroid

Progesterone

Steroid

Testis

Testosterone

Steroid

* The distinction between peptide and protein is somewhat arbitrary. Shorter than 50 amino acids is termed a peptide in this

table.

^† The list is not exhaustive for the gastrointestinal tract and the pancreas (see Chapter 11).

Figure 1.3 The structures of

Vasopressin

regulates water excretion

vasopressin and oxytocin are

remarkably similar, yet the

Cys - Tyr - Phe - Gln - Asn - Cys - Pro - Arg - Gly (NH₂)

physiological effects of the two

hormones differ profoundly.

Oxytocin

uterine contraction

Cys - Tyr - IIe - Gln - Asn - Cys - Pro - Leu - Gly (NH₂)

in enzymology, the product frequently inhibits

Box 1.4 Major hormone groups

further progress of the catalyzed reaction. In endo-

crinology, a hormone may act on its target cell to

• Peptides and proteins

stimulate a response

(often secretion of another

• Amino acid derivatives

hormone) that then inhibits production of the first

• Steroids

hormone (Figure 1.4a). Hormone secretion may also

be regulated by metabolic processes. For instance,

duration, so as to induce only a transient response.

the pancreatic β-cell makes insulin in response to

Certain neural impulses are of this type. Refinement

high ambient glucose. The effect is to lower glucose,

allows discrimination of a positive signal from

which, in turn, inhibits further insulin production.

background ‘noise’ to ensure that the target cell

The hypothalamic-anterior pituitary-end organ

cannot or does not respond below a certain thresh-

axes are a more complex extension of this model.

old level. An example is the pulsatile release of

The hypothalamic hormone [e.g. corticotrophin-

gonadotrophin-releasing hormone

(GnRH) from

releasing hormone

(CRH)] stimulates release of

the hypothalamus.

anterior pituitary hormone (e.g. ACTH) to increase

peripheral hormone production

(e.g. cortisol),

which then feeds back on the anterior pituitary and

Negative feedback

hypothalamus to reduce the original secretions.

Negative feedback is the commonest form of regula-

Figure 1.4b illustrates the anterior pituitary and end-

tion used by many biological systems. For example,

organ components of this model.

12 / Chapter 1: Overview of endocrinology

(a)

(b)

Endocrine

organ

Hormone

Response

Hormone 1

Hormone 2

Target

tissue

endocrine

tissue

organ

Response

Figure 1.4 Two models of feedback regulating

produces hormone 1, which acts on a second

hormone synthesis. (a) The endocrine organ releases

endocrine gland to release hormone 2. In turn,

a hormone, which acts on the target tissue to

hormone 2 acts dually on the target tissue to induce

stimulate a response. The response usually feeds

a response and feeds back negatively onto the

back to inhibit ( - ) the endocrine organ to decrease

original endocrine organ to inhibit further release of

further supply of the hormone. Occasionally, the

hormone 1. This model is illustrative of the axes

feedback can act to enhance the hormone secretion

between the anterior pituitary and the peripheral

( + , positive feedback). (b) The endocrine organ

end-organ targets.

Positive feedback

establish positive feedback that is only terminated

by delivery of the baby. The role of oxytocin in the

Under certain, more unusual, circumstances,

suckling-milk ejection reflex is similar - a positive

hormone feedback enhances, rather than inhibits,

feedback loop that is only broken by cessation of

the initial response. This is called positive feedback

the baby’s suckling.

(an example is shown alongside the more usual

negative feedback in Figure 1.4a). This is intrinsi-

Inhibitory control

cally unstable. However, in some biological systems

it can be transiently beneficial: for instance, the

The secretion of some hormones is under inhibitory

action of oestrogen on the pituitary gland to induce

as well as stimulatory control. Somatostatin, a

the ovulatory surge of LH and FSH (see Chapter

hypothalamic hormone, prevents the secretion of

7); or during childbirth, stretch receptors in the

GH, such that when somatostatin secretion is dim

distended vagina and nerves to the brain stimulate

inished, GH secretion is enhanced. Prolactin is

oxytocin release. This hormone causes the uterus to

similarly controlled, under tonic inhibition from

contract, further activating the stretch receptors to

dopamine.

Chapter 1: Overview of endocrinology / 13

genetic defect. For example, in congenital adrenal

Box 1.5 Endocrine cycles

hyperplasia, the lack of

21-hydroxylase causes

Circadian = 24-h cycle

failure to synthesize cortisol (see Chapter 6). Other

• Circa = about, dies = day

pathways remain intact, leading to excess produc-

tion of sex steroids that can masculinize aspects of

Ultradian < 24-h cycle

the female body. Endocrine disorders may also arise

• E.g. GnRH release

from abnormalities in hormone receptors or down-

stream signalling pathways. The commonest

Infradian > 24-h cycle

example is type 2 diabetes, which arises in part from

• E.g. menstrual cycle

resistance to insulin action in target tissues

(see

Chapter 13).

For those endocrine glands under regulation by

the hypothalamus and anterior pituitary, disorders

Endocrine rhythms

can also be categorized according to site. Disease in

Many of the body’s activities show periodic or cyclical

the end organ is termed ‘primary’. When the end

changes (Box 1.5). Control of these rhythms com-

organ is affected downstream of a problem in the

monly arises from the nervous system, e.g. the hypoth-

anterior pituitary (either underactivity or overactiv-

alamus. Some appear independent of the environment,

ity), it is secondary, while in tertiary disease, the

whereas others are coordinated and ‘entrained’ by

pathology resides in the hypothalamus.

external cues

(e.g. the

24-h light/dark cycle that

Like in other specialties, tumourigenesis impacts

becomes temporarily disrupted in jetlag). Cortisol

on clinical endocrinology. Most commonly, these

secretion is maximal between 0400h and 0800h as we

tumours are sporadic and benign, but they may

awaken and minimal as we retire to bed. In contrast,

oversecrete hormones, and are described in the

GH and prolactin are secreted maximally ∼1 h after

appropriate organ-specific chapters in Part

falling asleep. Clinically, this knowledge of endocrine

However, endocrine tumourigenesis may also form

rhythms is important as investigation must be refer-

part of recognized multiorgan clinical syndromes.

enced according to hour-by-hour and day-to-day vari-

These are described in Chapter 10.

ability. Otherwise, such laboratory tests may be invalid

or, indeed, misleading.

Key points

• Endocrinology is the study of hormones

Endocrine disorders

and forms one of the body’s major

The chapters in Part 2 largely focus on organ-

communication systems

specific endocrinology and associated endocrine

• A hormone is a chemical messenger,

disorders. Diabetes in Part 3, incorporating obesity,

commonly distributed via the circulation,

has now become its own specialized branch of endo-

that elicits specific effects by binding to a

crinology. Nevertheless, it is possible to regard all

receptor on or inside target cells

endocrine abnormalities as disordered, too much or

• The three major types of hormones are

too little production of hormone. Some clinical fea-

peptides, and the derivatives of amino

tures can occur because of compensatory over-

acids and cholesterol

production of hormones. For example, Addison

• Negative and, occasionally, positive

disease is a deficiency of cortisol from the adrenal

feedback, and cyclical mechanisms

cortex (see Chapter 6), which reduces negative feed-

operate to regulate hormone production,

back on ACTH production at the anterior pituitary.

commonly as part of complex multiorgan

ACTH rises and stimulates melanocytes in the

systems or axes

skin to increase pigmentation - a cardinal sign of

• Clinical endocrine disorders usually arise

Addison disease.

through too much, too little or disordered

Imbalanced hormone production may occur

hormone production

when a particular enzyme is missing because of a

Chapter 2: Cell biology and hormone synthesis / 15

This chapter introduces five major themes: chromo-

cell surface act as receptors that initiate intracellular

somes and DNA; protein (and peptide) hormone

signalling, which in turn is reliant on proteins that

synthesis; hormones derived from amino acids;

function as enzymes. Eventually, signalling infor-

steroid hormones and vitamin D; and hormone

mation reaches the nucleus and the proteins within

transport in the circulation. How hormones exert

it, called transcription factors. These latter proteins

their actions is covered in Chapter 3.

bind or release themselves from areas of DNA

The human genome is made up of deoxyribo-

around genes to determine whether a gene is

nucleic acid (DNA), assembled into 46 chromo-

switched on

(‘expressed’, when mRNA is tran-

somes, and resides in the nucleus (Box 2.1). The

scribed) or silenced.

DNA contains the ‘blueprints’, called genes, for

synthesizing proteins. There are approximately

30,000 human genes. Each gene serves as the tem-

Chromosomes, mitosis

plate for generating many copies of messenger ribo-

and meiosis

nucleic acid

(mRNA) by a process called gene

expression that amplifies the information contained

Genomic DNA in most human cells is packaged

in a single gene into the building blocks for many

into chromosomes by being wrapped around pro-

replica proteins. Specific proteins define the pheno-

teins called histones - the DNA-histone complex

type of a particular cell type (e.g. a thyroid cell that

is referred to as chromatin. There are

22 pairs

synthesizes thyroid hormone); more commonplace

of ‘autosomes’ and two sex chromosomes - two Xs

proteins carry out basic functions, e.g. the meta-

in females, one X and a Y in males. This composi-

bolic processes common to all cells. Proteins on the

tion makes females

46,XX and males

46,XY.

Distinct chromosomes are only apparent when they

are lined up in preparation for cell division, either

‘mitosis’ or ‘meiosis’ (Figure 2.1). Mitosis generates

Box 2.1 The structure of DNA

two daughter cells, each with a full complement

46 chromosomes, and occurs

∼10¹⁷ times

• A molecule of deoxyribose (a 5-carbon

during human life. Meiosis creates the gametes (i.e.

sugar) is linked covalently to one of two

spermatozoan or ovum), each with 23 chromo-

types of nitrogenous bases:

somes so that full diploid status is reconstituted at

° Purine - adenine (A) or guanine (G)

fertilization.

° Pyrimidine - thymine (T) or cytosine (C)

Several chromosomal abnormalities can result in

° The base plus the sugar is termed a

endocrinopathy. During meiosis, if a chromosome

‘nucleoside’, e.g. adenosine

fails to separate properly from its partner or if

• The addition of a phosphate group to a

migration is delayed, a gamete might result that

nucleoside creates a nucleotide, e.g.

lacks a chromosome or has too many. Thus, it is

adenosine mono-, di- or tri-phosphate

easy to appreciate Turner syndrome (45,XO), where

(according to how many phosphate

one sex chromosome is missing; or Klinefelter syn-

groups have been added)

drome

(47,XXY), where there is an extra X.

• Phosphodiester bonds polymerize the

Similarly, breaks and rejoining across or within

nucleotides into a single strand of DNA

chromosomes produce unusual ‘derivative’ chromo-

• Two strands, running in opposite

somes or ones with duplicated or deleted regions

directions, 5 prime (5′; upstream) to 3′

(see Figure 4.4). If such events occur close to genes,

(downstream) assemble as a double helix:

function can be disrupted, e.g. congenital loss of a

° Hydrogen bonds form between the

hormone. Duplication can be equally significant;

strands, between the base pairs A-T and

on the X chromosome, a double dose of a region

G-C

that includes the dosage-sensitive sex reversal, adrenal

• ∼3 billion base pairs comprise the human

hypoplasia critical region gene

1 (DAX1) causes

genome

female development in a 46,XY fetus.

16 / Chapter 2: Cell biology and hormone synthesis

Mitosis: retains the full complement of 46 chromosomes to generate two diploid daughter cells

(a)

Prophase

Interphase

Nuclear membrane

Spindle formation

Prometaphase

Chromosomes condense

Nucleolus visible

Nuclear membrane dissolves

No chromosomes

Chromosomes migrate centrally

DNA synthesis (‘S’ phase)

Metaphase

Chromosomes centrally

positioned at ‘metaphase

plate’

‘M’ phase

Anaphase

Chromatids separate as

centromere splits

Cytokinesis

Cell divides into

Telophase

two daughter cells

Chromosomes separate to each pole and start to decondense

Nuclear membrane reforms

Cytoplasm starts to divide

Figure 2.1 Cell division. Prior to mitosis and meiosis

critical aspect of genetic diversity. The two sister

the cell undergoes a period of DNA synthesis (‘S’

chromatids do not separate, so that the secondary

phase) so that the normal diploid status of DNA (2n)

oocyte and spermatocytes each contains 2n

temporarily becomes 4n. (a) The stages of mitosis

quantities of DNA. During the second stage of

result in each daughter cell containing diploid 2n

meiosis, separation of the chromatids results in

quantities of DNA. (b, opposite) Meiosis is split into

haploid cells (n). In males, meiosis is an equal

two stages, each of which comprises prophase,

process resulting in four spermatids. In contrast, in

prometaphase, metaphase, anaphase and

females, only one ovum is produced from a primary

telophase. During prophase of meiosis I, the

oocyte, smaller polar bodies being extruded at both

maternally and paternally derived chromosomes

stages of meiosis.

align to allow crossing over (‘recombination’), a

base pairs. Transcription factors bind to these

Making a protein or peptide

elements either to promote (i.e. turn on) or to repress

hormone

(i.e. turn off ) the production of mRNA by RNA

polymerase, the enzyme that ‘reads’ the DNA code.

Gene transcription and its regulation

Commonly, the signal that recruits RNA polymerase

The production of mRNA from a gene is called tran-

to the DNA occurs at a ‘TATA’ box, a short run of

scription. Within most genes, the stretches of DNA

adenosines and thymidines, ∼30 base pairs upstream

that encode protein, called exons, are separated by

of exon 1 (Figure 2.2) or an area rich in G and C

variable lengths of non-coding DNA called introns

residues.

(Figure 2.2). Upstream of the first exon is the 5′ flank-

Superimposed on this, gene expression can be

ing region of the gene, which contains multiple

further increased or diminished by more cell- or

promoter elements, usually within a few hundred

tissue-specific transcription factors potentially

Chapter 2: Cell biology and hormone synthesis / 17

(b) Meiosis: halves the chromosomal complement to generate haploid daughter cells each with 23 chromosomes

Mitotic division of the diploid (2n) germ cells;

Female

Male

oogonia (ovary) and spermatogonia (testis)

DNA synthesis (4n)

Primary oocyte

in differentiated cells

Primary spermatocyte

First polar

Meiosis I

body

Secondary oocyte

2n DNA cells

Secondary spermatocytes

Meiosis II

Second polar

body

Mature ovum

Haploid (n) cells

Spermatids

Figure 2.1 (Continued)

binding to more distant stretches of DNA (either

modifications to histones such that gene expression

‘enhancer’ or ‘repressor’ elements). For instance, the

varies according to which parent the particular

transcription factor, steroidogenic factor-1 (SF-1),

chromosome came from.

turns on many genes specific to the adrenal cortex

RNA contains ribose sugar moieties rather than

and gonad; when SF-1 is absent, both organs fail to

deoxyribose. RNA polymerase ‘sticks’ ribonucle-

form. These alterations to expression are dependent

otides together to generate a single strand of mRNA

on the exact DNA sequence recognized by specific

that correlates to the DNA code of the gene, except

proteins. There is another layer of complexity gov-

that in place of thymidine, a very similar nucleoside,

erning how genes are expressed. Epigenetics is the

uridine, is incorporated. The initial mRNA strand

study of how gene expression is regulated by mecha-

(pre-mRNA) is processed so that intronic gene

nisms beyond the precise DNA sequence, e.g. by

regions are excluded and only the exonic sequences

methylation of the DNA around genes, which tends

are ‘spliced’ together. Not all exonic regions encode

to silence expression; or by modifications to his-

protein; stretches at either end constitute the 5′ and

tones, such as acetylation or methylation, which

3′ untranslated regions (UTRs) (Figure 2.2). Within

alter the chromatin structure and make stretches of

the 3′ UTR, mRNA transcription is terminated by

DNA containing genes accessible or inaccessible to

a specific purine-rich motif, the polyadenylation

transcription factors. Acetylation tends to open up

signal, ∼20 base pairs upstream of where the mRNA

the structure, facilitating gene expression, whereas

gains a stretch of adenosine residues. This poly-A

methylation tends to close it down, silencing tran-

tail provides stability as the mRNA is moved from

scription. Genomic imprinting is an epigenetic

the nucleus to the cytoplasm for translation into

phenomenon involving DNA methylation and

protein.

18 / Chapter 2: Cell biology and hormone synthesis

5’ flanking region

Intron 1

Intron 2

3’ flanking region

TATA

Gene (DNA)

Exon 1

Exon 2

Exon 3

Enhancer

Repressor

element

Basal promoter

element

Stop

PolyA

codon signal

Pre-mRNA

Exon 1

Exon 2

Exon 3

AAAAAA

Intron 1

Intron 2

5’ UTR

3’ UTR

Spliced mRNA

Exon 1

Exon 2

Exon 3

AAAAAA

Start codon (AUG)

Stop

codon

Exon 1

Exon 2

Ex3

Peptide

Met

Figure 2.2 Schematic representation of a gene, transcription and translation. In this example, the gene

comprises three exons with an enhancer element in the 5′ flanking region and a repressor element in the 3′

flanking region. UTR, untranslated region. Met, methionine (encoded by the start codon).

Translation into protein

possible to appreciate how mutations

(sequence

errors) in the genomic DNA lead to a miscoded,

mRNA is transported to the ribosomes, where

and consequently malfunctional, protein (Box 2.2).

protein synthesis occurs by translation

(Figure

An entire gene may be missing

(‘deleted’) or

2.3a). The ribosomes are attached to the outside of

duplicated. An erroneous base pair in the promoter

the endoplasmic reticulum (ER), leading to the

region may impair a critical transcription factor

description of rough ER.

from binding. A similar error in an exonic coding

The ribosome is an RNA-protein complex

sequence might translate a different amino acid

that

‘reads’ the mRNA sequence. On the first

or even create a premature stop codon. Small

occasion that sequential A-U-G nucleotides are

deletions or insertions of one or two base pairs

encountered (corresponding to ATG in the genomic

throw the whole triplet code out of frame. A muta-

DNA), translation starts

(see Figure

2.2). From

tion at the boundary between an intron and an

this point, every three nucleotides represent an

exon can prevent splicing so that the intron becomes

amino acid. This nucleotide triplet is called a codon,

included in the mature mRNA. All of these

AUG being a start codon that specifies the amino

events affect endocrinology either as congenital

acid methionine. Similarly, translation continues

defects (i.e. during early development so that the

until a ‘stop’ codon is encountered (UAA, UGA or

fault is present in the genome of many cells) or as

UAG).

acquired abnormalities later in life, potentially pre-

By understanding these normal events of gene

disposing to the formation of an endocrine tumour

transcription and protein translation, it becomes

(see Chapter 10).

Chapter 2: Cell biology and hormone synthesis / 19

(a) Peptide hormone synthesis

(b) Steroid hormone synthesis

Nucleus

Mitochondrion

Rough

Mitochondrion

endoplasmic

mRNA

reticulum

Cholesterol

Lysosome

Lipid droplet

Golgi complex

Smooth

endoplasmic

reticulum

Secretory

granules

Secretion

Microtubules

Lysosome

Exocytosis

Golgi complex

of granule

Microfilaments

Capillary

Figure 2.3 (a) Peptide hormone-synthesizing and (b) steroid hormone-synthesizing cells. In (b) cholesterol

enters the cell via the low-density lipoprotein receptor which is internalized.

Post-translational modification

important

(Figure

2.4). The precursor peptide,

of peptides

called a pre-prohormone, carries a lipophilic signal

peptide at the amino terminus. This sequence is

Some polypeptides can function as hormones after

recognized by channel proteins so that the imma-

little more than removal of the starting methionine,

ture peptide can cross the ER membrane. Once

e.g. thyrotrophin-releasing hormone (TRH), which

inside the ER, the signal peptide is excised in prepa-

consists of only three amino acids. Others undergo

ration for other post-translational changes (Figure

further modification or potentially fold together as

2.4a-d).

different subunits of a hormone, e.g. luteinizing

Disulphide bridges are formed in certain pro-

hormone (LH). Peptides with any degree of com-

teins (e.g. growth hormone or insulin; Figure 2.4a

plexity fold into three-dimensional structures,

and c). Certain carbohydrates may be added to form

which may contain helical or pleated domains.

glycoproteins

(Figure

2.4d). Some prohormones

These shapes provide stability and affect how one

(e.g. pro-opiomelanocortin and proglucagon) need

protein interacts with another (e.g. how a hormone

processing to give rise to several final products,

might bind to its receptor).

whereas others are assembled as a combination of

For hormones that require secretion out of the

distinct peptide chains, each synthesized from differ-

cell, additional modifications are common and

ent genes, e.g. thyroid-stimulating hormone (TSH).

20 / Chapter 2: Cell biology and hormone synthesis

Box 2.2 Genetic, genomic and

Box 2.3 Role of post-translational

epigenetic abnormalities that can

modifications

result in endocrinopathy

Post-translational modifications are important

Abnormalities in DNA (genetic)

so that:

• Base substitution - swapping different

• Great diversity of hormone action is

nucleotides

generated from a more limited range of

• Insertion or deletion - alters frame if exonic

encoding genes

and not a multiple of three

• Active hormone is saved for its intended

site of action

Chromosomal abnormalities (genomic)

• The synthesizing cell is protected from a

• Numerical - three copies as in Down

barrage of its own hormone action

syndrome (trisomy 21)

• Structural:

ules. Movement of these vesicles to a position near

° Inversions - region of a chromosome is

the cell membrane is influenced by two types of

turned upside down

filamentous structure: microtubules and microfila-

° Translocations - regions swapped

ments (see Figure 2.3a). Secretion of the stored

between chromosomes

hormone tends to be rapid but only occurs after

° Duplications - region of a chromosome

appropriate stimulation of the cell. Whether this

is present twice

is hormonal, neuronal or nutritional, it usually

° Deletions - region of a chromosome is

involves a change in cell permeability to calcium

excised and lost

ions. These divalent metal ions are required for

interaction between the vesicle and plasma mem-

Imprinting abnormalities (epigenetic)

brane, and for the activation of enzymes, microfila-

• Methylation - altered methylation changing

ments and microtubules. The secretory process is

local gene expression, such as Beckwith-

called exocytosis (see Figure 2.3a). The membrane

Wiedemann syndrome with neonatal

of the storage granule fuses with the cell membrane

hypoglycaemia or transient neonatal

at the same time as vesicular endopeptidases are

diabetes associated with overexpression of

activated so that active hormone is expelled into the

the gene called ZAC

extracellular space from where it enters the blood

• Structural chromosomal abnormalities (as

vessels. The vesicle membrane is then recycled

above) can also cause imprinting errors

within the cell.

The completed protein is then packaged into

membrane-bound vesicles, which may contain spe-

Making a hormone derived from

cific ‘endopeptidases’. These enzymes are responsi-

amino acids or cholesterol

ble for final hormone activation

- cleaving the

In addition to peptides or proteins, hormones can

‘pro-’portion of the protein chain, as occurs with

also be synthesized by sequential enzymatic modi-

the release of C-peptide and insulin (Figure 2.4c).

fication of the amino acids tyrosine and tryptophan,

Such post-translational modifications are essential

or of cholesterol.

stages in hormone synthesis (Box 2.3).

Enzyme action and cascades

Storage and secretion of

peptide hormones

Enzymes can be divided into classes according to the

Endocrine cells usually store newly synthesized

reactions that they catalyze (Table 2.1). In endocrinol-

peptide hormone in small vesicles or secretory gran-

ogy, they frequently operate in cascades where the

Chapter 2: Cell biology and hormone synthesis / 21

Signal

Hormone-encoding

sequence

AAAA

mRNA

Translation on ribosomes attached to the outer

membrane of the endoplasmic reticulum, cleavage of

the signal ('pre-') sequence, potential glycosylation

±CHO

Endoplasmic

reticulum

Signal peptide

Hormone

CHO

Alpha

Mature hormone or

Polyprotein

Pro-hormone

CHO

Orientation

Beta

Multiple

Separate genes for alpha

Pro-hormone

of functional

processing

peptides

and beta subunits

Disulphide bond

formation and/or

Golgi

Subunit

cleavage of amino-

assembly

terminal pro-hormone

S S

(± further

sequence

Secretory

glycosylation)

granules

Cleavage

CHO

Alpha

Secreted

S S

+ C-peptide

Beta

hormone

S S

CHO

Growth hormone or

Pro-opiomelanocortin,

Insulin

Thyrotrophin, gonadotrophins,

parathyroid hormone

glucagon, somatostatin

human chorionic gonadotrophin

Examples

and calcitonin precursors

(a)

(b)

(c)

(d)

Figure 2.4 Post-translational modifications of

of insulin requires folding of the peptide and the

peptide hormones. Four types are shown. (a) Simple

formation of disulphide bonds. The active molecule is

changes such as removal of the amino terminal

created by hydrolytic removal of a connecting

‘pro-’extension prior to secretion (e.g. parathyroid

(C)-peptide, i.e. proinsulin gives rise to insulin plus

hormone) or the addition of intra-chain disulphide

C-peptide in equimolar proportion. (d) Synthesis of

bonds (e.g. growth hormone). (b) Multiple

larger protein hormones (e.g. thyroid-stimulating

processing of a ‘polyprotein’ into a number of

hormone, luteinizing hormone, follicle-stimulating

different peptide hormones (e.g. pro-

hormone and human chorionic gonadotrophin) from

opiomelanocortin can give rise to

two separate peptides that complex together. The four

adrenocorticotrophic hormone plus melanocyte-

hormones share the same α-subunit with a hormone-

stimulating hormone and β-endorphin). (c) Synthesis

specific β-subunit.

product of one reaction serves as the substrate for

where to the enzyme and function as co-factors,

the next. Most simplistically, enzyme action is achieved

adding more complex regulation to the biochemical

by protein-protein interaction between the sub

reaction.

strate and the enzyme at the latter’s

‘active site’.

Patients can present with many endocrine syn-

This causes a modification to the substrate to form

dromes because of loss of enzyme function. For

a product which no longer binds to the active site and

instance, gene mutation might lead to substitution

is thus released. Other macromolecules bind else-

of an amino acid at a key position of an enzyme’s

22 / Chapter 2: Cell biology and hormone synthesis

Table 2.1 Definition and classification of enzymes

Definition

An enzyme is a biological macromolecule - most frequently a protein - that catalyzes a biochemical

reaction

Catalysis increases the rate of reaction, e.g. the disappearance of substrate and generation of product

Enzyme action is critical for the synthesis of hormones derived from amino acids and cholesterol

Classification

Enzyme

Catalytic function

Example (and relevance)

Hydrolases

Cleavage of a bond by the

Cytochrome P450 11A1/cholesterol side-chain

addition of water

cleavage (CYP11A1; early step in steroid hormone

biosynthesis)

Lyases

Removal of a group to form a

Cytochrome P450 17α-hydroxylase/17-20 lyase

double bond or addition of a

(CYP17A1; step in synthesis of steroid hormones

group to a double bond

other than aldosterone)

Isomerases

Intramolecular rearrangments

3β-hydroxysteroid dehydrogenase/delta 4,5

isomerase isoforms (HSD3B; step in synthesis of all

major steroid hormones)

Oxidoreductase Oxidation and reduction

11β-hydroxysteroid dehydrogenase isoforms

(HSD11B; inter-conversion of cortisol and cortisone)

Ligases or

Joins two molecules together

Thyroid peroxidase (TPO; step in synthesis of

synthases

thyroid hormone)

Transferases

Transfer of a molecular group

Phenol ethanolamine N-methyl transferase (PNMT;

from substrate to product

conversion of norepinephrine to epinephrine)

active site. The three-dimensional structure might

Box 2.4 Hormones derived from

be affected so significantly that the substrate may

tyrosine

no longer convert to product. In the enzyme cascade

that synthesizes cortisol, this causes various forms

• Thyroid hormones: sequential addition of

of congenital adrenal hyperplasia

(CAH)

(see

iodine and coupling of two tyrosines

Chapter 6). Understanding the biochemical cascade

together (see Chapter 8)

allows accurate diagnosis as the substrate builds up

• Adrenomedullary hormones: hydroxylation

in the circulation and its excess can be measured,

steps and decarboxylation to form

e.g. by immunoassay or mass spectrometry (see

dopamine and catecholamines (see

Chapter 4).

Chapter 6)

• Hypothalamic dopamine formed by

hydroxylation and decarboxylation (see

Synthesizing hormones derived

Chapter 5)

from amino acids

The amino acid tyrosine can be modified by sequen-

Chapter 6 (Figure 6.11) and for thyroid hormones

tial enzyme action to give rise to several hormones

in Chapter 8 (Figures 8.3 and 8.4). Melatonin,

(Box

2.4). The precise synthetic pathways for

important in endocrine circadian rhythms with a

dopamine and catecholamines are described in

new link to type 2 diabetes (see Chapter 5), is gener-

Chapter 2: Cell biology and hormone synthesis / 23

ated from the amino acid tryptophan via synthesis

In steroidogenic cells, cholesterol is largely

of the neurotransmitter serotonin.

deposited as esters in large lipid-filled vesicles (see

Figure

2.3b). Upon stimulation, cholesterol is

released from its stores and transported into the

Synthesizing hormones derived from

mitochondria, a process that is facilitated by

cholesterol

the steroid acute regulatory (StAR) protein in the

Steroid hormones are generated by enzyme cascades

adrenal and gonad and by the related protein, start

that modify the four-carbon ring structure of cho-

domain containing 3 (STARD3), in the placenta.

lesterol

(see Figure 2.6). The precise sequence of

The first step in the synthesis of a steroid hormone

enzymes determines which steroids are generated as

is the rate-limiting conversion of cholesterol to preg-

the final product (Box 2.4). In addition to making

nenolone. Pregnenolone then undergoes a range of

steroid hormones, cholesterol is a critical building

further enzymatic modifications in the mitochon-

block of all mammalian cell membranes and the

dria or the ER to make active steroid hormones.

starting point for synthesizing vitamin D, which

functions, and can be classified, as a hormone (see

Nomenclature of steroidogenic pathways

Chapter 9). Cholesterol is acquired in approxi-

mately equal measure from the diet and de novo

Figure 2.6 shows a generic representation of human

synthesis (mostly in the liver; Box 2.5). From the

steroid hormone biosynthesis. Many of the enzymes

diet, cholesterol is delivered to cells as a complex

that catalyze steps in these pathways are encoded by

with low-density lipoprotein

(LDL-cholesterol).

the cytochrome P450 (CYP) family of related genes

Intracellular uptake is via the cell-surface LDL

that is also critical for hepatic detoxification of

receptor and endocytosis (see Figure 2.3b). De novo

drugs. Some of the enzymes are important in both

biosynthesis commences with co-enzyme A (CoA),

the adrenal cortex and gonad

(e.g. CYP11A1),

itself synthesized from pantothenate, cysteine and

whereas others are restricted and thus create the

adenosine, and proceeds via hydroxymethylglutaryl

distinct steroid profiles of each tissue (e.g. CYP21A2,

co-enzyme A

(HMGCoA) and mevalonic acid

needed for cortisol and aldosterone biosynthesis, is

(Figure 2.5). The rate-limiting step is the reduction

very largely limited to the adrenal cortex).

of HMGCoA by the enzyme HMGCoA reductase.

Historically, the enzymes have been named

Pharmacological inhibition of this enzyme to treat

according to function (e.g. hydroxylation) at a spe-

hypercholesterolaemia and lessen cardiovascular

cific carbon atom, with a Greek letter indicating

disease has led to the most widely prescribed drug

orientation above or below the four-carbon ring

family in the world (the ‘statins’) and the award of

structure (e.g. 17α-hydroxylase attaches a hydroxyl

the Nobel Prize to Michael Brown and Joseph

group in the alpha position to carbon 17; Figure 2.6).

Goldstein (see Table 1.2).

The common names used for steroids also

adhere to a loose convention. The suffix -ol indi-

cates an important hydroxyl group, as in cholesterol

Box 2.5 Hormones derived from

or cortisol, whereas the suffix

-one indicates an

cholesterol

important ketone group (testosterone). The extra

presence of -di, as in -diol (oestradiol) or -dione

Cholesterol derived from the diet and de

(androstenedione), reflects two of these groups,

novo synthesis used to synthesize:

respectively;

‘-ene’

(androstenedione) within the

• Vitamin D (see Chapter 10)

name indicates a significant double bond in the

• Steroid hormones:

steroid nucleus.

° Adrenal cortex: aldosterone, cortisol and

sex steroid precursors (see Chapter 6)

° Testis: testosterone (see Chapter 7)

Storage of steroid hormones

° Ovary and placenta: oestrogens and

Unlike cells making peptide hormones, most

progesterone (see Chapter 7)

steroid-secreting cells do not store hormones but

24 / Chapter 2: Cell biology and hormone synthesis

Acetyl CoA

Acetoacetyl CoA

HMG-CoA synthase

3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)

HMG-CoA reductase

Mevalonic acid

Mevalonate kinase

Mevalonate-5-phosphate

Phosphomevalonate kinase

Mevalonate-5-pyrophosphate

decarboxylase

Isopentenyl-5-pyrophosphate (PP)

Geranyl PP

Farnesyl PP synthase

Farnesyl PP

Squalene synthase

Squalene

A series of 21 reactions

CHOLESTEROL

Figure 2.5 Synthesis of cholesterol. Step is catalyzed by the enzyme thiolase; otherwise the enzymes are

shown to the right of the cascade. The individual steps between squalene and cholesterol have been omitted.

synthesize them as required. As a consequence,

as for thyroid hormones

[thyroxine-binding

there is a slower onset of action for steroid hor-

globulin (TBG)]. Many hormones also loosely asso-

mones following the initial stimulation of the ster-

ciate with other circulating proteins, especially

oidogenic organ.

albumin.

The equilibrium between protein-bound and

unbound (‘free’) hormone determines activity, as

Hormone transport

only free hormone readily diffuses into tissues. This

Most peptide hormones are hydrophilic, so they

is relevant to many hormone assays where total

generally circulate free in the bloodstream with little

hormone is measured. Results may be markedly

or no association with serum proteins. In contrast,

altered by changes in the concentration of binding

steroid hormones and thyroid hormones circulate

protein, but the change in free hormone concentra-

bound to proteins because, like cholesterol, they

tion may be very small and biological activity

are hydrophobic. There are relatively specific

remains unaltered. For instance, women on the

transport proteins for many of the steroid hor-

combined oral contraceptive pill have raised serum

mones, e.g. cortisol-binding globulin (CBG) and

CBG and increased total cortisol; however, free cor-

sex hormone-binding globulin

(SHBG), as well

tisol is unaltered.

28 / Chapter 3: Molecular basis of hormone action

Hormones act by binding to receptors. There are

Stage 1: Binding of hormone to

two superfamilies of hormone receptor: the cell-

receptor

surface receptors and nuclear receptors, named

Historically, hormone-receptor interactions

(Box

according to their site of action, and which display

3.2) have been characterized using radiolabelled

characteristic features (Figure 3.1 and Box 3.1).

hormones and isolated preparations of receptors to

define two properties:

Cell-surface receptors

• The hormone-receptor interaction is saturable

Cell-surface receptors comprise three components,

(Figure 3.3)

each with characteristic structural features that

• The hormone-receptor interaction is reversible

reflect their location and function (Figure 3.2).

(Figure 3.4).

Hormone receptors

Superfamilies

Cell-surface receptors

Nuclear receptors

Groups

Linked to TK

Linked to G proteins

Subgroups

Adenylate

PLC

cyclase

Growth factor receptors

e.g.

TRH

e.g. TRH

with intrinsic TK

GnRH

TSH

Somatostatin

e.g. Insulin

TSH

IGF-I

FSH

Cytokine receptors

ACTH

FSH

which recruit TK

Vasopressin

Oxytocin

Catecholamines

Vasopressin

e.g. Growth hormone

Glucagon

Angiotensin II

Prolactin

PTH

Ca²⁺

Leptin

PTHrP

Calcitonin

PGE₂

PTH

GHRH

PTHrP

Orphan and

Metabolites

Steroid/thyroid

Vitamin

variant

e.g. peroxisome

hormone

e.g. calcitriol

proliferator-activated

receptors (PPARs)

Figure 3.1 The different classes of hormone receptor.

stimulating hormone; LH, luteinizing hormone; FSH,

Some cell-surface receptors, e.g. the parathyroid

follicle-stimulating hormone; ACTH,

hormone (PTH) receptor, can link to different

adrenocorticotrophic hormone; PTHrP, parathyroid

G-proteins, which couple to either adenylate cyclase

hormone-related peptide; PGE₂, prostaglandin E₂;

or phospholipase C (PLC). TK, tyrosine kinase; TRH,

GHRH, growth hormone releasing hormone; IGF-I,

thyrotrophin-releasing hormone; GnRH,

insulin-like growth factor I.

gonadotrophin-releasing hormone; TSH, thyroid-

Chapter 3: Molecular basis of hormone action / 29

Box 3.1 Some basic facts about hormone receptors

• Tissue distribution of receptor determines

Hormone receptor superfamilies

the scope of hormone action:

• Water-soluble hormones (e.g. peptide

° Thyroid-stimulating hormone (TSH)

hormones):

receptor largely limited to thyroid, therefore

° Plasma membrane is impenetrable

TSH action restricted to the thyroid

° Cell-surface receptors transduce signal

° Thyroid hormone receptor is widespread,

through membrane

therefore thyroid hormone action is diverse

° Activate intracellular signalling pathways

• Binding of hormone induces a

° Fast responses (seconds) as well as slow

conformational change in the receptor that

ones

initiates downstream signalling

• Lipid-soluble hormones (e.g. steroid and

• Downstream signalling differs across cell

thyroid hormones):

types to produce potentially diverse

° Pass through plasma membrane

hormonal effects

° Receptors function as transcription factors

• Control is exerted through the constant

in the nucleus

synthesis, degradation and localization of

° Activate or repress gene expression

hormone receptors - most target cells have

° Tend to be relatively slow responses

2000-100,000 receptors for a particular

(hours-days)

hormone

NH₂

Extracellular domain

(hormone binding)

Hydrophobic transmembrane

Plasma membrane

domain

Cytoplasmic domain

(initiates intracellular signalling)

COOH

Figure 3.2 A membrane-spanning cell-surface

fragments of the thyroid-stimulating hormone receptor

receptor. The hormone acts as ligand. The ligand-

may be immunogenic for antibody formation in

binding pocket in the extracellular domain is

autoimmune thyroid disease. The α-helical membrane-

comparatively rich in cysteine residues that form

spanning domain is rich in hydrophobic and

internal disulphide bonds and repeated loops to

uncharged amino acids. The C-terminal cytoplasmic

ensure correct folding. For some hormones, e.g.

domain either contains, or links to, separate catalytic

growth hormone, this extracellular domain can

systems, which initiate the intracellular signals after

circulate as a potential binding protein. Circulating

hormone binding.

30 / Chapter 3: Molecular basis of hormone action

Maximum saturation

Half-maximal saturation

Add excess

unlabelled

K_D

hormone

Increasing concentration of labelled hormone

Time of incubation

Figure 3.4 Hormone-receptor interactions are

Figure 3.3 Hormone-receptor systems are

reversible. Constant amounts of labelled hormone

saturable. Increasing amounts of labelled hormone

and receptors are incubated together for different

are incubated with a constant amount of receptor.

times. The bound label increases with time until it

The amount of bound labelled hormone increases as

reaches a plateau, when the bound and free

more is added until the system is saturated. At this

hormone have reached a dynamic equilibrium. In a

point, further addition fails to increase the amount

dynamic equilibrium, hormone continually associates

bound to receptors. The concentration of hormone

and dissociates from its receptor. By adding excess

that is required for half-maximal saturation of the

unlabelled hormone, competition with the labelled

receptors is equal to the dissociation constant (K_D)

hormone is established for access to the receptors.

of the hormone-receptor interaction.

Consequently, the amount of bound labelled

hormone decreases with extended incubation

(dashed line).

ment can allow estimation of the number of

Box 3.2 Binding characteristics of

hormone receptors present on each target cell.

hormone receptors

• High affinity: hormones circulate at low

Stage 2: Signal transduction

concentrations - receptors are like

‘capture systems’

When a hormone binds to a cell-surface receptor,

• Reversible binding: one reason for the

the cascade of cytoplasmic responses is mediated

transient nature of endocrine responses

through protein phosphorylation by kinase enzymes

• Specificity: receptors distinguish between

or the generation of ‘second messengers’ via cou-

closely related molecular structures

pling to guanine (‘G’) proteins. Signalling through

either process amplifies the hormone response as

many protein phosphorylation events or second

messenger molecules are produced for each

Using methodology similar to that for immu-

hormone-receptor interaction. They also distin-

noassays

(see Chapter

4), constant amounts of

guish the two major groups of cell-surface receptor:

labelled hormone and receptor preparations can

tyrosine kinase receptors and G-protein-coupled

be incubated with increasing, known amounts of

receptors (Figure 3.1 and Box 3.3).

unlabelled hormone for a specified time. Separating

Protein phosphorylation is a key molecular

and measuring the receptor-bound labelled fraction

switch. Approximately 10% of proteins are phos-

allows curves to be plotted and mathematical mod-

phorylated at any given time in a mammalian cell.

elling of the hormone (H)-receptor (R) interac

The phosphate group is donated from ATP during

tion; e.g. whether it is conforms to the equation

catalysis by the ‘kinase’ enzyme. It is accepted by

H + R  HR. Ultimately, these types of experi-

the polar hydroxyl group of serine, threonine or

Chapter 3: Molecular basis of hormone action / 31

Receptors with intrinsic tyrosine

Box 3.3 Categories of cell-surface

kinase activity

receptors

Intrinsic TK receptors autophosphorylate upon

Tyrosine kinase receptors

binding of the appropriate hormone. This group

• Signal via phosphorylation of the amino

includes the receptor for insulin and those for

acid, tyrosine

epidermal growth factor (EGF), fibroblast growth

factor

(FGF) and insulin-like growth factor I

G-protein-coupled receptors

(IGF-I). The EGF and FGF receptors exist as mon-

• Activate or inhibit adenylate cyclase and/or

omers that dimerize upon hormone binding to acti-

phospholipase C (PLC)

vate tyrosine phosphorylation. Those for insulin

• Signal via second messengers: cyclic

and IGF-I exist in their unoccupied state as pre-

adenosine monophosphate (cAMP),

formed dimers. The signalling pathways for all these

), diacylglycerol

inositol triphosphate (IP₃

receptors are heavily involved in cell growth and

(DAG) and intracellular calcium

proliferation.

• Signal via phosphorylation of serine and

threonine amino acids

Insulin signalling pathways

The dimerized insulin receptor (IR) is composed of

two α- and two β-subunits linked by a series

of disulphide bridges (Figure 3.6; see Chapter 11).

tyrosine (Figure 3.5a) and causes a conformational

The earliest response to insulin binding is autophos-

change in the three-dimensional shape of the

phorylation of the cytosolic domains of the β-

protein (Figure 3.5b). In many signalling pathways,

subunit. The activated receptor then phosphorylates

the phosphorylated protein can also act as a kinase

two key intermediaries, insulin receptor substrate

and phosphorylate the next protein in the sequence.

(IRS) 1 or 2, which are thought to be essential for

In this way, a phosphorylation cascade is generated,

almost all biological actions of insulin. IRS1 has

which relays and amplifies the intracellular signal

many potential tyrosine phosphorylation sites, at

generated by the hormone binding to its receptor

least eight of which are phosphorylated by the acti-

(Figure 3.5c).

vated IR.

Multiple phosphorylation of IRS1 or 2 leads to

the docking of several proteins with SH2 domains,

Tyrosine kinase receptors

and the activation of divergent intracellular signal-

Phosphorylation of tyrosine kinase (TK) receptors

ling. For example, docking of phosphatidylinositol-

can occur through:

3-kinase (PI3-kinase) leads to deployment of the

glucose transporter (GLUT) family members. For

• Intrinsic TK activity located in the cytosolic

instance, in adipose tissue and muscle, GLUT-4

domain of the receptor; or

translocates from intracellular vesicles to the cell

• Separate TKs recruited after receptor activation

membrane, allowing glucose uptake into the cell.

(see Figure 3.1).

The mitogenic effects of insulin are mediated via a

By either mechanism, conformational change

different intracellular pathway. Activated IRS1

induced by phosphorylation creates ‘docking’ sites

docks with the SH2/SH3 domains of the type 2

for other proteins. Frequently, this occurs via con-

growth factor receptor-bound (Grb2) protein. This

served motifs within the target protein, known as

adaptor protein links IRS1 to the son of sevenless

‘SH2’ or ‘SH3’ domains. These domains may be

(SoS) protein and, ultimately, to activation of the

involved in the activation of downstream kinases or

mitogen-activated protein kinase (MAPK) pathway,

they may stabilize other signalling proteins within

leading to gene expression that promotes mitosis

a phosphorylation cascade.

and growth.

Chapter 3: Molecular basis of hormone action / 33

Receptor structure. Disulphide bridges (S-S)

Insulin binding. Insulin

binding to the

link the α-subunits of the insulin receptor

α-subunits results in autophosphorylation

to one another and also to two identical

P of the intracellular domains of the

β-subunits, which span the plasma

β-subunits by the intrinsic tyrosine

membrane

kinase activity (

)

Links to the MAPK pathway. Grb2 links

Activation of IRS1 or IRS2.

IRS1 to the GDP/GTP exchange protein, SoS.

Autophosphorylation of the

The Grb2-Sos complex is

intracellular domains of the

brought into proximity of

receptor causes docking of

the small G-protein, Ras,

IRS1 or IRS2, which can then

located in the plasma

be activated by tyrosine

membrane. Translocation of

P P

phosphorylation P

Grb2-Sos triggers Ras by the

exchange of GTP for GDP.

The serine/threonine kinase

enzyme, Raf, activates a

tyrosine/serine/threonine

IRS1

IRS1/2

kinase enzyme (MEK).

MEK activates MAPK.

PI3

MAPK is multifunctional

kinase

and modulates cell

Glycogen

proliferation,

Glucose

synthase

differentiation and

trans-

activation

function.

Ras

porter

trans-

location

MAPK

PI3 kinase pathway.

IRS1 or IRS2 can activate

the PI3 kinase pathway,

which, in particular,

enhances glucose

transport

Glucose

uptake

Figure 3.6 The insulin receptor and some of its

protein (Grb2) can be stimulated independently of

signalling pathways. The number of insulin receptors

insulin receptor substrate 1 (IRS1). MAPK, mitogen-

on target cells varies, commonly from 100 to 200,000,

activated protein kinase; PI3 kinase,

with adipocytes and hepatocytes expressing the

phosphatidylinositol-3-kinase; SoS, son of sevenless

highest numbers. Not all insulin-signalling pathways

protein; I, insulin.

are shown, e.g. type 2 growth factor receptor-bound

These molecular events lie at the heart of

Receptors that recruit tyrosine

insulin’s clinical action (see Part 3). Defects in the

kinase activity

signalling pathway can result in resistance to insulin

action either as rare monogenic syndromes (Box

The sub-family of receptors that bind growth

3.4) or as a considerable part of the type 2 diabetes

hormone (GH) and prolactin (PRL) includes those

phenotype (see Chapters 11 and 13).

for numerous cytokines and the hormones leptin

34 / Chapter 3: Molecular basis of hormone action

cytoplasmic regions and signal transduction.

Box 3.4 Defects in the insulin

Discovery of this phenomenon has been utilized in

signalling pathways and ‘insulin

drug design to combat excessive GH action in

resistance’ syndromes

acromegaly (Figure 3.7). The EPO receptor also

forms homodimers, i.e. two identical receptors bind

Over 50 mutations have been reported in the

together. The cytokine receptors tend to form het-

insulin receptor (IR) that impair glucose

erodimers with diverse partner proteins.

metabolism and raise serum insulin (‘insulin

Activation of the hormone receptor rapidly

resistance’). Historically, these have been

recruits one of four members of the ‘Janus-associated

discovered as different congenital

kinase’ (JAK) family of TKs (Figure 3.8), so named

syndromes; however, the advance of

after the two-faced Roman deity, Janus, because of

molecular genetics has unified these

distinctive, tandem kinase domains at their carboxy-

diagnoses as a phenotypic spectrum

terminals. GH, PRL and EPO receptor dimeriza-

according to the severity of IR inactivation.

tion brings together JAK2 molecules that become

Patients with milder insulin resistance and

phosphorylated. The major downstream substrates

less affected IR signalling are usually only

of JAK are the STAT family of proteins (hence the

diagnosed at puberty, whereas what was

term ‘JAK-STAT’ signalling; Figure 3.8). The name

known as ‘Leprachaunism’, with an effective

STAT comes from dual function: signal transduc-

absence of functional IR, manifests as severe

tion, located in the cytoplasm, and nuclear activa-

intrauterine growth retardation. These latter

tion of transcription. Both activities rely on

patients rarely survive beyond the first year of

phosphorylation by JAK (Figure 3.8). Phosphorylated

life. Interestingly, the IR gene is seemingly

STAT proteins dissociate from the occupied

normal in most patients with milder

receptor-kinase complex and, themselves, dimerize

congenital insulin resistance, suggestive of

to gain access to the nucleus. There, they activate

abnormalities in other components of insulin

target genes, commonly those that regulate prolif-

signalling pathways. Indeed, some of these

eration or the differentiation status of the target cell.

monogenic causes of insulin resistance have

One of the major targets of GH is the IGF-I gene

now been discovered. Impaired insulin

(Box 3.5). JAK signalling does not focus exclusively

signalling is also a very significant

on STAT. The GH receptor (GHR) also signals

component of type 2 diabetes (see Chapters

through MAPK and PI3-kinase pathways. This

11 and 13).

overlap may account for some of the rapid meta-

bolic effects of GH (Figure 3.8).

Defects in the GH signalling pathway can result

in rare syndromes of resistance to GH action (Box

and erythropoietin (EPO). The basic receptor com-

3.6 and Figure 3.9).

position, shown in Figure

3.2, contains major

homology between family members in the extracel-

lular domain.

G-protein-coupled receptors

The commonest subset of cell-surface receptors

Growth hormone and prolactin signalling

(>140 members) couple to G-proteins at the inner

pathways - the Janus family of tyrosine

surface of the cell membrane, leading to the genera-

kinases

tion of intracellular second messengers such as

adenosine-3′,

5′-cyclic monophosphate

(cyclic

Similar mechanisms govern GH and PRL receptor

AMP or cAMP), diacylglycerol (DAG) and inositol

binding and signal transduction. Two different sites

triphosphate

(IP₃). In addition to hormones,

on the hormone are capable of binding receptors

G-protein-coupled receptors (GPCRs) also exist for

that dimerize. The hormone-dimerized receptor

glutamate, thrombin, odourants and the visual

interaction leads to conformational change in the

transduction of light.

36 / Chapter 3: Molecular basis of hormone action

GH binding. Binding of growth

JAK2 binding to 'Box 1'. JAK2 binds to the

hormone to the dimerized

juxtamembrane region of the intracellular

receptor recruits the

domains of the receptor, known as Box 1 (

)

cytoplasmic tyrosine kinase, JAK2

STATs. Activated JAK2

phosphorylates tyrosines on

STATs. These form dimers

and undergo translocation

into the nucleus, where they

P P

act as transcriptional

regulatory proteins

STAT

IRS1/2

PI3

STAT

kinase

MAPK

Rapid

metabolic effects

NUCLEUS:

Gene

regulation

MAPK pathway. The

(e.g. SRE, c-fos)

PI3 kinase pathway. The

intermediate steps leading

intermediate steps, whereby

to MAPK activation by GH

IRS1 and IRS2 recruit the p85

are similar to those shown

subunit of PI3 kinase, are the

for insulin in Figure 3.6

same as for insulin, and are

responsible for some of the

rapid metabolic effects of GH

Figure 3.8 Growth hormone (GH) receptor and its

regulatory elements that mediate the induction of

signalling pathways. The receptor recruits tyrosine

target genes, such as c-fos. STAT, signal transduction

kinase (TK) activity from Janus-associated kinase 2

and activation of transcription protein; PI3 kinase,

(JAK2). Serum response elements (SREs) are

phosphatidylinositol-3-kinase; IRS, insulin receptor

mitogen-activated protein kinase (MAPK)-responsive

substrate.

from the cleavage of phosphate from GTP. This

second messenger systems (Figure 3.12). In part,

regenerates Gα-GDP, which no longer associates

this promiscuity can be attributed to the degree of

with adenylate cyclase or PLC, thus switching off

hormonal stimulation or activation of different

the cascade and recycling the Gα-GDP back to the

receptor sub-types. For instance, at low concentra-

start.

tions, TSH, calcitonin and LH receptors associate

There are over 20 isoforms of the Gα subunit

with G_sα to activate adenylate cyclase, whereas

that may be grouped into four major sub-families

higher concentrations recruit G_qα to activate PLC.

(Box 3.7). These are involved differentially with the

Calcitonin receptor sub-types are differentially

various hormone receptor signalling pathways

expressed according to the stage of the cell cycle.

(Table 3.1). More than half of GPCRs can interact

Defects in the G-protein signalling pathways can

with different Gα subunits and thus signal through

result in many endocrine disorders (Box 3.8; Figures

contrasting, and sometimes opposing, intracellular

3.13 and 3.14).

Chapter 3: Molecular basis of hormone action / 37

Box 3.6 Defects in growth

hormone signalling pathways and

growth hormone resistance

syndromes

Severe resistance to GH, mainly secondary

to mutations in the GH receptor that

commonly affect the hormone-binding

domain, is characterized by grossly impaired

growth and is termed Laron syndrome,

eponymously named after it was first

reported by Laron in 1966 (Figure 3.9). It is

an autosomal recessive disorder with a

variable phenotype typified by normal or

raised circulating GH and low levels of serum

IGF-I.

For other patients, no GHR mutations have

been identified, implicating genes that

Figure 3.9 Laron syndrome showing truncal obesity.

encode downstream components or related

This boy presented aged 10.4 years but with a

aspects of GH signalling. For instance,

height of 95 cm - equivalent to that of a 3-year-old.

defects in the IGF-I gene have been

In addition to truncal obesity, there is a very small

penis. These features could represent severe growth

associated with severe intrauterine growth

hormone (GH) deficiency. However, serum GH levels

retardation, mild mental retardation,

were elevated with undetectable insulin-like growth

sensorineural deafness and postnatal growth

factor I (IGF-I) indicative of GH resistance. Laron

failure.

syndrome was diagnosed due to an inactivating

mutation of the gene encoding the GH receptor.

Other clinical features include a prominent forehead,

depressed nasal bridge and under-development of

the mandible.

Second messenger pathways

Cyclic adenosine monophosphate

Activation of membrane-bound adenylate cyclase

phorylation by PKA in a negative feedback loop.

catalyzes the conversion of ATP to the potent

PDEs rapidly hydrolyze cAMP to the inactive 5′-

second messenger cAMP (see Figure 3.11). cAMP

AMP. In addition, activated PKA can phosphorylate

interacts with protein kinase A (PKA) to unmask

serine and threonine residues of the GPCR to cause

its catalytic site, which phosphorylates serine and

receptor desensitization.

threonine residues on a transcription factor called

cAMP response element binding protein (CREB)

Diacylglycerol and Ca2+

(Figure

3.15). CREB then translocates to the

nucleus where it binds to a short palindromic

Signalling from hormones, such as TRH, GnRH

sequence in the regulatory regions of cAMP-

and oxytocin, recruits G-protein complexes con-

regulated genes. This signalling pathway controls

taining the Gqα subunit. This activates membrane-

major metabolic pathways, including those for

associated PLC, which catalyzes the conversion of

lipolysis, glycogenolysis and steroidogenesis.

PI 4,5-bisphosphate (PIP₂) to DAG and IP₃ (Figures

The cAMP response is terminated by a large

3.11 and 3.16). IP₃ stimulates the transient release

family of phosphodiesterases (PDEs), which can be

of calcium from the endoplasmic reticulum to acti-

activated by a variety of systems, including phos-

vate several calcium-sensitive enzymes, including

38 / Chapter 3: Molecular basis of hormone action

NH₂

Vacant receptor

'Resting'

G-protein adenylate

Adenosine-3',5'-cyclic

cyclase

monophosphate

Plasma

membrane

CH₂

CH₂.O.CO.R₁

CH.O.CO.R₂

CH₂.OH

GDP

Diacylglycerol (DAG)

+ Hormone (

)

CH₂.O.CO.R₁

CH.O.CO.R₂

OH OH

GDP

GTP

released

Phosphatidylinositol (PI)

Inositol-1,4,5-tris

GDP

binds

phosphate (IP₃)

+ Conformational

change

Figure 3.11 Second messengers that mediate

G-protein-coupled receptor signalling. The symbol P

is the abbreviation for a phosphate group. Carbon

atoms are numbered in their ring position. R₁ and R₂

represent fatty acid chains.

GTP

Box 3.7 Sub-families of Gα protein

ATP cAMP

subunits

Figure 3.10 G-protein-coupled receptors. The

• G_sα: activates adenylate cyclase

extracellular domain is ligand specific and, hence,

• G_iα: inhibits adenylate cyclase

less conserved across family members (e.g. only

• G_qα: activates PLC

35-45% for the TSH, LH and FSH receptors). The

• G_oα: activates ion channels

transmembrane domain has a characteristic

heptahelical structure, most of which is embedded in

the cell membrane and provides a hydrophobic

isoforms of protein kinase C (PKC), and proteins

core. Conserved cysteine residues can form a

like calmodulin (Figure 3.16). Calcium ions also

disulphide bridge between the second and third

activate cytosolic guanylate cyclase, an enzyme that

extracellular loops. The cytoplasmic domain links the

catalyzes the formation of cyclic guanosine mono-

receptor to the signal-transducing G-proteins and, in

this example, is linked to membrane-bound

phosphate (cGMP). The effects of atrial natriuretic

adenylate cyclase. The activation of adenylate

peptide are mediated by receptors linked to guan-

cyclase is depicted by the conversion of C to C*.

ylate cyclase.

The major target of DAG signalling is PKC,

which activates phospholipase A₂ to liberate arachi-

donic acid from phospholipids and generate potent

eicosanoids, including thromboxanes, leucotrienes,

40 / Chapter 3: Molecular basis of hormone action

lipoxins and prostaglandins (Figure 3.17). The latter

Box 3.8 Defects in the G-protein-

are well-recognized paracrine and autocrine media-

coupled receptor/G-protein

tors capable of amplifying or prolonging a response

signalling pathways

to a hormonal stimulus.

Several endocrinopathies occur because of

activating or inactivating mutations in genes

encoding GPCRs or G-proteins coupled to

Nuclear receptors

them. Activating mutations cause constitutive

The second superfamily of hormone receptor is

overactivity; inactivating mutations cause

the nuclear receptors, which are classified by their

hormone resistance syndromes characterized

ligands, small lipophilic molecules that diffuse

by high circulating hormone levels but

across the plasma membrane of target cells. Once

diminished hormone action.

ligand bound, the receptors typically bind DNA

Gain of function

and function as transcription factors (Figure 3.18).

• LH receptor: male precocious puberty

This need for transcription and translation to elicit

(Figure 3.13)

an effect means that biological responses of nuclear

• TSH receptor: ‘toxic’ thyroid adenomas

receptors are relatively slow compared to cell-surface

• G_sα: McCune-Albright syndrome (Figure

receptor signalling.

3.14), some cases of acromegaly and

Distinct regions of nuclear receptors can be

some autonomous thyroid nodules

identified, for which evolutionary conservation can

be as high as 60-90%, i.e. the receptors are structur-

Loss of function

ally related (Figure 3.19). For one sub-group of the

• V2 receptor: nephrogenic diabetes

superfamily, no endogenous ligand has been identi-

insipidus (high vasopressin)

fied and they are termed ‘orphan’ nuclear receptors.

• TSH receptor: resistance to TSH (high

In addition, some variant receptors have atypical

TSH)

DNA-binding domains and potentially function via

• G_sα: pseudohypoparathyroidism (see

indirect interaction with the genome. All the differ-

Figure 9.9) and Albright hereditary

ent types are associated with endocrinopathies,

osteodystrophy

usually due to loss of function.

(a)

(b)

Figure 3.14 McCune-Albright syndrome. At 6 years of

premature breast development. In some cases,

age, this girl presented with breast development and

constitutive overactivity can manifest in bones

vaginal bleeding in the absence of gonadotrophins.

(causing ‘fibrous dysplasia’), the adrenal cortex

An activating mutation in G_sα had created

(Cushing syndrome) and the thyroid (thyrotoxicosis).

independence from melanocyte-stimulating hormone

From Brook’s Clinical Pediatric Endocrinology, Sixth

(MSH) causing skin pigmentation (‘café-au-lait’ spots)

Edition, Charles G. D. Brook, Peter E. Clayton,

and similar constitutive activation in the ovary (i.e.

Rosalind S. Brown, Eds. Blackwell Publishing

independence from gonadotrophins), giving rise to

Limited. 2009.

Chapter 3: Molecular basis of hormone action / 41

at much higher concentrations than aldosterone,

Inactive kinase

cAMP cAMP / Regulating Active

might saturate the MR, causing inappropriate

tetramer

subunit complex kinase

overactivity. Accordingly, impaired function of

HSD11B2 leads to hypertension and hypokalaemia

in the syndrome of

‘apparent mineralocorticoid

excess’.

Catalyzes

phosphorylation

of CREB

Nuclear localization, DNA binding and

transcriptional activation

In their resting state, unbound steroid hormone

RNA POL

receptors associate with heat-shock proteins, which

Target gene

obscure the DNA-binding domain, so that they

CRE

are considered incapable of binding the genome.

Steroid binding causes conformational change and

Figure 3.15 The activation of protein kinase A, a

dissociation of the heat-shock proteins. This reveals

cAMP-dependent protein kinase. The four-subunit

two polypeptide loops stabilized by zinc ions,

complex is inactive. When cAMP binds to the

regulatory subunits (red), dissociation occurs so that

known as zinc fingers. Once two steroid receptors

the active kinase subunits (blue) are released to

have dimerized, these motifs bind to target DNA at

catalyze the phosphorylation of the cAMP response

the specific hormone response element

(HRE)

element-binding protein (CREB). This activates CREB

(Figure 3.20).

(

 → 

) so that it can bind to its DNA target, the

The unliganded thyroid hormone receptor (TR)

cAMP response element (CRE), to switch on

is located in the nucleus bound to DNA at the

transcription of cAMP-inducible genes. RNA POL,

thyroid hormone response element

(TRE). In

RNA polymerase.

the absence of hormone, the TR dimerizes with the

retinoid X receptor and tends to recruit nuclear

proteins that inhibit transcription (co-repressors).

The receptors predominantly reside in the

The binding of thyroid hormone leads to dissocia-

nucleus, although increasingly nuclear import and

tion of these factors, the recruitment of transcrip-

export appears to be an important regulatory

tional co-activators, and a sequence of events

mechanism, controlling access of the nuclear recep-

recruiting DNA-dependent RNA polymerase

tor to target gene DNA. This shuttling has been

leading to transcription (Figure 3.20 and review

long recognized for the glucocorticoid receptor

Figure 2.2).

(Figure 3.18).

Resistance syndromes for nuclear receptors

are similar to those for cell-surface receptors.

Target cell conversion of hormones

Inactivating mutations lead to loss of receptor func-

destined for nuclear receptors

tion, such as reduced hormone binding or impaired

receptor dimerization, loss of hormone action, for

In many instances, the ligand for the nuclear recep-

instance decreased binding to the HRE, and, char-

tor undergoes enzymatic modification within the

acteristically, raised circulating hormone levels

target cell. This converts the circulating hormone

(Table 3.3).

into a more or less potent metabolite prior to

receptor binding (Table 3.2). For instance, cortisol

is metabolized to cortisone by type 2 11β-hydro

Orphan nuclear receptors and variant

xysteroid dehydrogenase

(HSD11B2). In kidney

nuclear receptors

tubular cells, this inactivation preserves aldosterone

action at the mineralocorticoid receptor

(MR).

Some orphan and variant receptors play very

Without this, cortisol, present in the circulation

important roles in endocrinology. For instance,

Chapter 3: Molecular basis of hormone action / 43

Membrane phospholipid

O CH₂

O CH

CH₂

O^-

Phospholipase A₂

COOH

Arachidonic acid

COOH

PGE₂

OH OH

Figure 3.17 Eicosanoid signalling. Arachidonic acid,

types and exert paracrine and autocrine actions (e.g.

released by phospholipase A₂, is the rate-limiting

the inflammatory response and contraction of uterine

precursor for generating eicosanoid signalling

smooth muscle). Their circulating half-life is short

molecules by cyclo-oxygenase (COX) and

(3-10 min). Aspirin inhibits prostaglandin production

lipoxygenase pathways. This example produces

at sites of inflammation. There are different forms of

prostaglandin E₂ (PGE₂) but there are at least 16

COX; inhibitors of COX-2 are also used as

prostaglandins - structurally related, 20-carbon, fatty

anti-inflammatory agents.

acid derivatives. They are released from many cell

Endocrine transcription factors

show reduced, or absent, levels of these hormones,

causing short stature, and are at risk of congenital

Although distinct from the nuclear receptor super-

secondary hypothyroidism with severe learning

family, other transcription factors play critical

disability.

roles in the endocrine system, both during its

The development of the pancreas and, in partic-

development and in regulating its differentiated

ular, the specification and function of β-cells relies

function (Table 3.4). This is important to the endo-

on several transcription factors. Pancreas duodenal

crinologist because inactivating mutations in the

homeobox factor 1 [PDX1, also called insulin pro-

transcription factors can be a cause of endocrine

moter factor 1 (IPF1)] and several members of the

pathology, particularly in the paediatric clinic,

hepatocyte nuclear factor (HNF) family are critical

where molecular genetics can increasingly provide

in this regard; inactivating mutations have been

precise diagnostic answers

(see Chapter

4). For

identified, which cause monogenic diabetes mellitus

instance, in the pituitary, pituitary-specific tran-

at an early age, called maturity-onset diabetes of the

scription factor 1 (PIT1) regulates the expression of

young (MODY) (see Table 11.3). Potentially, these

genes encoding GH, PRL and the β-subunit of

patients never accrue a normal number of β-cells,

TSH. Patients with inactivating PIT1 mutations

which also fail to function properly.

Chapter 3: Molecular basis of hormone action / 45

Mineralocorticoid

Progesterone

Androgen

Glucocorticoid

Oestrogen

Calcitriol

Retinoic acid

Tri-iodothyronine

Highly conserved, DNA-binding domain, comprised of two zinc fingers

Specific hormone-binding domain, which forms a hydrophobic pocket

C-terminus ‘AF2’ region, which recruits the nuclear components for

transcriptional activation

Variable N-terminal domain

Figure 3.19 The nuclear hormone receptor superfamily. The receptors, named according to their ligands

(shown to the right), range in size from 395 to 984 amino acids.

Table 3.2 Potential modifications of hormones, their precursors and metabolites within the cell

prior to nuclear receptor action

Modification that increases activity

Modification that decreases activity

Deiodination of thyroxine (T₄) to tri-iodothyronine

Inactivation of T₄ and T₃ by the formation of reverse

(T₃) by type 1 and type 2 selenodeiodinase (see

T₃ and di-iodothyronine (T₂) by type 3

Figure 8.6)

selenodeiodinase (see Figure 8.6)

Reduction of testosterone to dihydrotestosterone

Loss of androgenic activity by conversion of

(DHT) by 5α-reductase (see Figure 7.7); gain of

testosterone to oestradiol by the action of

oestrogenic activity by conversion of

aromatase (CYP19; see Figure 2.6)

testosterone to oestradiol by the action of

aromatase (CYP19; see Figure 2.6)

Conversion of 25-hydroxyvitamin D to

1,25-dihydroxyvitamin D (calcitriol) by 1α-

24,25-dihydroxyvitamin D or the inactivation of

hydroxylase (see Figure 9.2)

1,25-dihydroxyvitamin D to 1,24,25-trihydroxyvitamin

D by 24α-hydroxylase (see Figure 9.2)

Generation of cortisol from cortisone by type

Inactivation of cortisol to cortisone by Type 2

1 11β-hydroxysteroid dehydrogenase (HSD11B1;

11β-hydroxysteroid dehydrogenase (HSD11B2; see

see Figure 6.4)

Figure 6.4)

The biological importance of these modifying enzymes is exemplified by rare mutations in the genes that encode them,

presenting with endocrine overactivity or underactivity.

Chapter 4: Investigations in endocrinology and diabetes / 49

All specialties have been advanced by methods

Box 4.1 The specifics of sample

to aid diagnosis, and monitor and assess treat

collection are mandatory

ment. Investigation in endocrinology and diabetes

remains centred on laboratory assays that determine

Containers for investigation of blood

the concentration of hormones and metabolites

• Lithium heparin: most hormones

usually in blood. The first challenge is correct col

• Fluoride oxalate: glucose

lection; for some investigations, prior fasting is

• Di-potassium EDTA: tests requiring DNA

important. Appropriate conditions or preservatives

isolation

are mandatory (Box 4.1). In addition to clinical

Peptide hormones and catecholamines

biochemistry

(also called chemical pathology),

tend to be less stable than other hormones

molecular genetics and cytogenetics are routine

and need prompt delivery to the laboratory

investigations to provide personalized genetic diag

on ice

noses that predict the course of some endocrine

disorders

(e.g. multiple endocrine neoplasia; see

Samples for which prior fasting may be

Chapter 10).

required

Outside of the laboratory, clinical investigation

• Glucose

draws heavily upon expertise in radiology and

• Lipids

nuclear medicine. Some investigations are highly

• Calcium

specific (e.g. visual fields for pituitary tumours or

retinal screening for diabetes) and these are covered

Hormones that may require 9 am collection

in later topic-specific chapters.

• Cortisol

• Testosterone

Containers for investigation of urine

Laboratory assay platforms

• Acid: calcium, 5-hydroxyindoleacetic acid

(5-HIAA), catecholamines

• No acid/simple preservative: urinary free

Immunoassays

cortisol

Hormones (and other metabolites) are most com

monly measured by immunoassay, although increas

ingly mass spectrometry is used

(see below).

Immunoassays, introduced in the 1960s, are suffi

ciently sensitive, precise and hormone specific

for routine application in clinical biochemistry.

To set up a calibration or standard curve for the

Bioassays, which measure physiological responses

immunoassay, a constant amount of antibody is

induced by a stimulus, are near obsolete in clinical

added to a series of tubes with increasing, known

practice.

amounts of a reference preparation, in this example

Immunoassay is a broad term for one of two

GH (Figure 4.1). This reaction is reversible with the

different techniques: true immunoassay and immu

antigen and antibody continuously associating and

nometric assay. Both forms are based on the

dissociating; however, after incubation, equilibrium

hormone to be measured being antigenic and bound

is reached when tubes with more GH generate more

by specific antibodies to form an antibody-antigen

bound complex. Measurement of the amount of

complex. Both forms of immunoassay also employ

bound complex (e.g. in terms of fluorescence or

a label, historically a radioactive isotope [e.g. iodine-

radioactivity) can thus be related to the quantity of

125 (I¹²⁵)], but commonly now a fluorescent tracer,

GH that was originally added. This allows a calibra

to generate a quantitative signal. Both assays also

tion curve to be plotted, against which the same

rely on comparison of the patient sample with

process can now deduce the GH concentration in

known concentrations of a reference compound.

a patient sample.

50 / Chapter 4: Investigations in endocrinology and diabetes

Zero GH

+2 GH

+4 GH

Anti-GH

Zero GH

+4 GH

Labelled second anti-GH

Incubate

Add excess labelled second anti-GH

+ excess

Separate antibody-bound complex

Anti-GH

Figure 4.1 The basics of immunoassay are shown

Calibration curve

for growth hormone (GH; see text for details). For

clarity, in Figures 4.1-4.3 only small numbers of

Tube 1

Tube 2

Counts from

Tube 2

hormone molecules and antibodies are shown; in

sample tube

practice, numbers are in the order of 10⁸-10¹³.

hGH in

Tube 1

sample

Count bound

tube

fraction

Standard GH

Immunometric assays - the sandwich

assays

Figure 4.2 The basics of an immunometric assay for

growth hormone (GH; also see text). As in Figure 4.1, in

In the immunometric assay (shown for GH in

practice large numbers of molecules are present for each

Figure 4.2), a constant amount of antibody is added

reagent and the incubation of the first and second

to each tube with increasing, known amounts of

antibodies is usually simultaneous. Because the hormone

reference preparation. After incubation, the amount

is bound between the two antibodies in the triple complex

of GH bound to the antibody is detected by adding

(

), this assay is sometimes referred to as a sandwich

an excess of a second labelled antibody to all tubes.

assay. Separation of the complex from the excess

The second antibody is directed against a different

labelled second antibody is usually achieved physically,

antigenic site on GH from the first antibody to

e.g. by precipitation and centrifugation (the supernatant

form a triple complex sandwiching GH between the

contains the unbound antibody and is discarded). This

two antibodies. Any unbound antibody is removed,

leaves the bound labelled second antibody to be

leaving the amount of triple complex to be deter

quantified by counting radioactivity or measuring

fluorescence. The low measurement from the ‘zero’ tube,

mined by quantifying the bound label (e.g. fluores

Tube 1, and the higher value from Tube 2 are plotted on

cence or radioactivity). This emission is plotted for

the calibration curve. Tube 1 is not zero because of minor

increasing, known amounts of reference compound

non-specific antibody binding. The calibration line is also

to generate a calibration curve (Figure 4.2). In prac

curved, rather than straight, because of the reversible

tice, five to eight concentrations of hormone

nature of the interaction between antibodies and their

standard are used to generate a precise calibration

antigens. In practice, five to eight calibration points are

used to construct the curve.

curve, against which patient samples can be inter

Chapter 4: Investigations in endocrinology and diabetes / 51

polated. The immunometric assay is suitable only

Anti-T₄

Labelled T₄

when the hormone to be measured permits discrete

Zero tube

+T₄

binding of two antibodies. This would not work

Unlabelled T4 standard

+12

for small hormones such as thyroxine (T₄) or tri-

iodothyronine

(T₃), for which the competitive-

binding immunoassay system must be used.

Incubate

Immunoassays - the competitive-binding

assays

In the competitive-binding immunoassay (shown

for T₄ in Figure 4.3), constant amounts of antibody

and labelled antigen are added to each tube. A ‘zero’

Separate antibody-bound complex

tube is set up that contains labelled T₄, as well as a

tube that also includes a known amount of unla

belled standard T₄. Incubation allows the antigen-

antibody complex to form. Since the zero tube

contains twice as much labelled T₄ as antibody, half

of the labelled hormone will be bound and the other

Tube 1

Tube 2

half will remain free (i.e. in excess). In the other

Calibration curve

tube, unlabelled and labelled T₄ compete for the

Tube 1

limited opportunity to bind antibody. The total

Counts from

sample tube

antibody-bound T₄ is separated (e.g. by precipita

tion) and the label measured (e.g. by fluorescence

Tube 2

or radioactivity). There will be less signal from the

Count bound

second tube because of competition from the unla

fraction

T4 in sample tube

belled T₄; the decrease will be a function of the

Standard T₄

amount of unlabelled T₄ added, i.e. the signal

decreases as the amount of unlabelled T₄ increases,

Figure 4.3 The basics of an immunoassay for

allowing the construction of a calibration curve

thyroxine (T4; also see text). As in Figure 4.1, in

(Figure 4.3). For clinical use, standard T₄ is replaced

practice large numbers of molecules are present for

by the patient sample, with all other assay condi

each reagent. Under the conditions shown, the

tions kept the same. As for immunometric assays, a

competition between equal amounts of labelled and

five to eight point calibration curve offers sufficient

unlabelled T₄ in Tube 2 will be such that, on average,

precision for patient samples to be interpolated.

50% of the antibody binding sites will be occupied

by labelled T₄. Because of competition between

labelled and unlabelled hormone for a limited

Analytical methods linked to mass

amount of antibody, this type of immunoassay is

spectrometry

sometimes called a ‘competitive-binding’ assay. After

removing unbound label (as in Figure 4.2 legend),

In some situations, immunoassays are unreliable

the fluorescent or radioactive bound fraction is

or unavailable, commonly because antibodies lack

quantified and a calibration curve constructed. In

sufficient specificity, or there are difficulties with

practice, five to eight calibration points are used to

measurements at low concentrations (e.g. serum

construct the curve.

testosterone in women). This leads to differences in

measurements across different assay platforms that

inhibit the development of internationally agreed

standards for diagnosis and care. For some steroid

or peptide hormones, or metabolic intermediaries,

mass spectrometry (MS) is becoming increasing

52 / Chapter 4: Investigations in endocrinology and diabetes

helpful. It is applied either by itself or, for increased

because they circulate in a variety of slightly different

ability to resolve and measure substances, in tandem

forms (‘microheterogeneity’). In this scenario, inter

(MS/MS) or downstream of liquid chromatography

national reference preparations are agreed, with

(LC/MS) or gas chromatography (GC/MS). These

potency expressed in ‘units’ (U) and their subdivisions

approaches provide definitive identification of the

[e.g. milliunits (mU)]. Potency is assigned after large

relevant hormone or compound according to its

collaborative trials involving many laboratories world

chemical and physical characteristics, e.g. par

wide using a range of assay platforms and physical

ticularly useful for the unequivocal detection of

analytical techniques. Patient results are then expressed

performance-enhancing agents in sport.

relative to the reference data.

GC allows separation of vaporized molecules

according to their chemical structure. For a sample

Static and dynamic testing

loaded on a GC column, different components exit

the column and pass to the mass spectrometer at

Most of endocrinology testing is ‘static’; the meas

different times. MS ionizes compounds to charge

urement of hormones and metabolites as they

them, after which the spectrometer measures mass

circulate at any one time. However, rhythmical,

and charge during passage through an electromag

pulsatile or variable hormone secretion makes inter

netic field. This gives a characteristic mass-to-charge

pretation of single random samples meaningless or

ratio for any one substance. As with immunoassays,

misleading (see Chapter 1). For some hormones,

patient samples can be judged against the perform

such as GH, a clinical impression can be gained

ance of precisely known standards. LC/MS is similar

from a series of six to eight measurements during

to GC/MS; however, the initial separation is per

the course of a day. Alternatively, dynamic testing

formed in the liquid rather than the gaseous phase.

can be necessary where, based on understanding

normal physiology, responses are measured follow

ing a stimulus. This might be metabolic, such as

Enzymatic assays

insulin-induced hypoglycaemia to study the

Some metabolites are assayed enzymatically, fre

expected rise in serum GH and cortisol (see Chapter

quently using dye substrates that are catalyzed to

5), or the administration of glucose during a glucose

products that are coloured or fluoresce. By incorpo

tolerance test to diagnose diabetes (see Chapter 11).

rating known standards, the amount of colour or

Alternatively, the stimulus might be hormonal, such

fluorescence can be used for precise quantification.

as injecting adrenocorticotrophic hormone (ACTH;

For example, glycated haemoglobin

(HbA_1c), a

the anterior pituitary hormone) to measure secre

measure of long-term diabetes control (see Chapter

tion of cortisol (the adrenocortical hormone). In

11) can be measured in an enzymatic assay as well

this sense, fasting measurements, as required for

as by immunoassay and chromatography/MS

serum lipids or commonly for glucose, could be

approaches. Serum glucose can be measured by oxi

viewed as dynamic, where fasting is the stimulus.

dation to generate a product that interacts with a

Dynamic tests can be split into two categories:

dye to generate colour or fluorescence in an enzy

provocative ones to interrogate suspected inade

matic assay.

quate function; or suppression tests, taking advan

tage of negative feedback to investigate potential

overactivity

(Box

4.2). For instance, ACTH is

Reference ranges

injected to see if cortisol secretion rises in suspected

Typical adult reference ranges are listed for a number

adrenocortical inadequacy

(Addison disease; see

of hormones in Table 4.1. Whenever possible, hor

Chapter 6); whereas dexamethasone, a potent syn

mones are measured in molar units (e.g. pmol/L) or

thetic glucocorticoid, is given to see if pituitary

mass units (e.g. ng/L). However, this is not possible for

ACTH and consequently cortisol secretion is

complex hormones such as the glycoproteins thyroid-

appropriately diminished. If it is not, it implies that

stimulating hormone (TSH), luteinizing hormone

the adrenal cortex is overactive (Cushing syndrome;

(LH) and follicle-stimulating hormone

(FSH),

see Chapter 6).

Chapter 4: Investigations in endocrinology and diabetes / 55

Table 4.1 (Continued)

Adult reference hormone

Range

Units

Range

Unit

Early follicular phase

70-600

pmol/L

19-160

pg/mL

Mid-cycle

700-1900

pmol/L

188-371

pg/mL

Luteal phase

300-1250

pmol/L

81-337

pg/mL

Pancreatic polypetide (fasting)

0-100

pmol/L

0-418.5

pg/mL

Parathyroid hormone (PTH)

0-4.4

pmol/L

0-41.5

pg/mL

Prolactin

80-500

mU/L

3.8-23.6

ng/mL

Progesterone (day 21, luteal phase)

>30

nmol/L

>9.4

ng/mL

Renin (am; out of bed for 2 h; seated

2-30

mU/L

0.9-13.6

pg/mL

5-15 min)^ag

Sex hormone-binding globulin

Females

40-120

nmol/L

Males

20-60

nmol/L

Somatostatin (fasting)

0-150

pmol/L

0-245

pg/mL

Testosterone

Males

8-35

nmol/L

230-1000

ng/mL

Females

0.7-3.0

nmol/L

20-85

ng/mL

Thyroglobulin

1.5-30

pmol/L

1-20

µg/L

Thyroid-stimulating hormone (TSH)

0.3-5.0

mU/L

Thyroxine, free (fT₄)

9-23

pmol/L

0.7-1.8

ng/dL

Tri-iodothyronine, free (fT₃)

3.1-7.7

pmol/L

0.2-0.5

ng/dL

Vasoactive intestinal polypeptide

0-30

pmol/L

102

pg/mL

(fasting)

Vitamin D (25-OH-cholecalciferol)

4-40

nmol/L

1.6-16

ng/mL

Vitamin D (1,25-OH-cholecalciferol)

48-110

pmol/L

20-45.8

pg/mL

Ranges shown are for serum unless otherwise stated. Ranges vary slightly between laboratories due to differences in the

methods employed. These examples are only intended to be illustrative and readers should check with their local

laboratories.

^aMost informative as part of the aldosterone:renin ratio (see Chapter 6).

^bAge-dependent. Low values indicate poor ovarian reserve.

^cSalivary assays are variable and require establishment of local normal ranges.

^dGreater suppression from glucose load can be demonstrated using newer more sensitive immunoradiometric or

chemiluminescent assays.

^eThe World Health Organization and the American Diabetes Association have endorsed HbA_1c for the diagnosis of diabetes

above or equal to these values.

^fIGF-I values are approximate as age- and sex-adjusted ranges are required.

^gRenin is also measured as ‘plasma renin activity’ when 1 mU/L equates to 1.56 pmol/L/min (0.12 ng/mL/h).

56 / Chapter 4: Investigations in endocrinology and diabetes

fluorescence in situ hybridization

(FISH) allows

Box 4.2 Dynamic investigation in

assessment of duplications, deletions or transloca

endocrinology

tions on a smaller scale. For instance, a locus for

congenital hypoparathyroidism, as part of DiGeorge

• If underactivity suspected: try to stimulate it

syndrome, exists on the long arm of chromosome

• If overactivity suspected: try to suppress it

22 (22q). FISH utilizes the principle that comple

mentary DNA sequences will hybridize together by

hydrogen bonding. Stretches of DNA from the

region of interest are fluorescently labelled and

hybridized to the patient’s DNA. The fluorescence

Cell and molecular biology as

is visible as a dot on each sister chromatid of

diagnostic tools

each relevant chromosome (Figure 4.4). Therefore,

normal autosomal copy number is viewed as two

pairs of two dots; one pair indicates a deletion; and

Karyotype

three pairs indicate either duplication or potentially

Karyotype refers to the number and microscopic

a translocation breakpoint (where the probe detects

appearance of chromosomes arrested at metaphase

(see Chapter 2). The word also describes the com

plement of chromosomes within an individual’s

cells, i.e. the normal karyotype for females is 46,XX

and for males is 46,XY. A karyogram is the reorgan

ized depiction of metaphase chromosomes as pairs

in ascending number order. An abnormal total

number of chromosomes is called aneuploidy

(common in malignant tumours). More detail

comes from Giemsa (G) staining of metaphase

chromosomes, where each chromosome can be

identified by its particular staining pattern, called

‘G-banding’.

Ascertaining the karyotype can be useful in con

genital endocrinopathy, such as genital ambiguity

(i.e. is it 46,XX or 46,XY?), or if there is concern

over Turner syndrome (45,XO) or Klinefelter syn

drome (47,XXY) (see Chapter 7). G-banding allows

experienced cytogeneticists to resolve chromosomal

deletions, duplications or translocations (when frag

ments are swapped between two chromosomes) to

within a few megabases. Sometimes, there is evi

Figure 4.4 Fluorescent in situ hybridization in a

dence of mosaicism when cells from the same

patient with congenital hypoparathyroidism due to

person show more than one karyotype. This implies

DiGeorge syndrome causing hypocalcaemia and

that something went wrong downstream of the first

congenital heart disease. Metaphase chromosomes

cell division such that some cell lineages have a

were hybridized with a fluorescent probe from

normal karyotype while others are abnormal.

chromosome 22q11. The two bright dots indicate

hybridization on the sister chromatids of the normal

chromosome 22. The arrow points to the other

Fluorescence in situ hybridization

chromosome 22 that lacks signal, indicating a

deletion. Images kindly provided by Professor David

When a syndrome is suspected, for which the causa

Wilson, University of Southampton.

tive gene or locus (genomic position) is known,

Chapter 4: Investigations in endocrinology and diabetes / 57

sequence either side of the breakpoint on different

multiple endocrine neoplasia (MEN2; see Chapter

chromosomes).

10) have never been associated with phaeochromo

cytoma, normally one of the commonest features of

MEN2. However, other RET mutations predict

medullary carcinoma of the thyroid at a very young

Genome-wide microarray-based

age, thus instructing when total thyroidectomy

technology

is needed. Genetically defining certain forms of

Applying the principles of FISH on a genome-wide

monogenic diabetes is now dictating choice of

scale in a microarray format is called ‘array com

therapy (see Case history 11.3).

parative genomic hybridization’ (array CGH). Short

Polymerase chain reaction (PCR) and sequenc

stretches of the genome are printed as thousands of

ing is used to identify a mutation in a specific gene

microscopic spots on a glass slide (the ‘microarray’).

(Figure 4.5). Using DNA isolated from the patient’s

The patient’s genomic DNA is fluorescently labelled

white blood cells, PCR amplifies the exons of the

and hybridized to the spots on the slide. According

gene of interest in a reaction catalyzed by bacterial

to the strength of the fluorescent signal, microdele

DNA polymerases that withstand high temperature

tions or duplications anywhere in the whole genome

(>90°C). These enzymes originate from microor

can be detected in one experiment with a resolution

ganisms that replicate in hot springs. A second

of several kilobases.

modified PCR reaction provides the base pair

Single nucleotide polymorphism (SNP) arrays

sequence of the DNA, demonstrating whether or

are being used similarly. Spread across the entire

not the gene is mutated.

genome, there are millions of very subtle variations

Since sequencing the human genome in the last

(polymorphisms) at specific nucleotides between

decade, technology has advanced enormously,

different individuals. On SNP arrays, the spots on

greatly bringing down cost. What was once achieved

the glass slide represent the different sequences at

by cutting-edge multi-million pound international

each SNP. As an individual’s paired chromosomes

consortia is now possible within an individual labo

come one from each parent, this means that at any

ratory in a matter days or weeks for a few thousand

one SNP, there are often two different sequences

pounds. In addition to ethical implications of

(one from the mother, one from the father; this is

holding these whole genome datasets, the bioinfor

called heterozygosity). Across stretches of DNA,

matics required for their analysis is massive.

SNP arrays can identify regions showing ‘loss of

Nevertheless, by ‘next generation sequencing’ on

heterozygosity’

(i.e. there is no variation in the

‘exome’ arrays (i.e. all exons of nearly all genes),

signal), which is indicative of deletion of either the

defining a patient’s genome is fast becoming a diag

maternal or paternal copy, or altered ratio of signals

nostic reality.

indicative of duplication.

Imaging in endocrinology

Diagnosing mutations in single genes by

polymerase chain reaction and

sequencing

Ultrasound

With the discovery of disease-causing genes in

Ultrasound travels as sound waves beyond the range

monogenic disorders (i.e. a single gene is at fault),

of human hearing and, according to the surface

genetic testing is expanding rapidly into clinical

encountered, is reflected back towards the emitting

endocrinology and diabetes. Increasingly precise

source

(the ultrasound probe). Different tissues

prediction is becoming possible from correlating

have different reflective properties. By knowing the

genotype (i.e. the gene and the position in a gene

speed of the waves and the time between emission

that a specific mutation lies) and phenotype (i.e. the

and detection, the distance between the reflective

clinical course of a patient). For instance, certain

surfaces and the source can be calculated. These

mutations in the RET proto-oncogene in type 2

data allow a two-dimensional image to be generated

Chapter 4: Investigations in endocrinology and diabetes / 59

Figure 4.6 Ultrasound of a polycystic ovary. The

Figure 4.7 Abdominal computed tomography (CT)

presence of multiple small cysts (one shown by the

with contrast. This patient presented with Cushing

arrow) is consistent with, but not required for, the

syndrome (see Figure 6.9). The right adrenal mass

diagnosis of polycystic ovarian syndrome (see

on the CT (arrow) was a cortisol-secreting adenoma.

Chapter 7). Ultrasound does help to exclude the

single mass of an androgen-secreting tumour (see

Chapter 7). Image kindly provided by Dr Sue

Ingamells, University of Southampton.

patient lies on a table that slides through a motor

ized ring, which rotates and emits X-rays. Data are

(Figure 4.6). The major advantage of ultrasound is

acquired on penetration from different angles (i.e.

its simplicity, safety and non-invasiveness. Machines

as if multiple plain X-rays had been taken), which

are portable. It is helpful as an initial imaging inves

are then constructed by computer into a single

tigation of many endocrine organs. For instance,

transverse ‘slice’ through the body (Figure 4.7). The

the thyroid has a characteristic appearance in Graves

brain is encased by the skull, hence its imaging by

disease because of its increased vascularity

(see

CT is limited.

Chapter 8). The ovaries can be delineated transab

In comparison to CT, MRI does not rely on

dominally, or with specific consent, transvaginally,

X-rays and is particularly useful at imaging intrac

when the shorter distance between probe and ovary

ranial structures, such as the pituitary (Figure 4.8).

and fewer reflective surfaces create higher resolution

It is also very useful for screening purposes when a

images (Figure 4.6).

patient will need life-long monitoring, e.g. to assess

tumour formation in MEN. Repeat CT would

provide a large cumulative radiation dose, itself a

Computed tomography and magnetic

risk factor for tumour formation, which is avoided

resonance imaging

by MRI. The key components of MRI are magnets.

Computed tomography (CT) and magnetic reso

At their centre is a hollow tube, into which the

nance imaging (MRI) provide excellent depiction

patient passes on a horizontal table. Once inside the

of the body’s internal organs and tissues. The prin

tube, the patient is in a very strong magnetic field

ciple of CT is the same as for X-ray. X-rays pass

(this is the reason why MRI is dangerous to patients

differently through the various organs and tissues of

with metallic implants such as pacemakers or aneu

the body. For instance, bone is not penetrated very

rysm clips). Within the magnetic field, some of the

well so a plain X-ray image is obtained as if the

body’s hydrogen atoms resonate after absorbing

skeleton has cast a shadow. In CT scanning, the

energy from a pulse of radio waves. Once the pulse

Chapter 4: Investigations in endocrinology and diabetes / 61

population after ∼40 years. In a patient with hyper

a phaeochromocytoma from other tumours (Figure

tension, it would be important to distinguish these

4.9). At higher doses, it can even be used as targeted

from a phaeochromocytoma that could be the

therapy, when instead of marking cells, it kills them.

curable cause of elevated blood pressure (see Chapter

I123 or technetium-99m pertechnetate can also be

6). Uptake markers (or ‘tracers’) specific to a par

used to delineate different causes of hyperthy

ticular cell type can provide valuable clues. For

roidism (see Chapter 8) when taken up by the

instance, meta-iodobenzylguanidine (mIBG) acts as

thyroid gland. In Graves disease, the uptake is

an analogue of norepinephrine and is taken up by

homogeneous; with a solitary ‘toxic’ adenoma, the

adrenal medulla cells. When labelled with radioac

uptake is restricted to the relevant nodule.

tive iodine-123 (I¹²³) it can be used to distinguish

Key points

• Diagnosing or excluding endocrine

disorders relies on measuring the

concentration of hormones and

metabolites

• Immunoassays provide accurate, reliable

laboratory measurement of many

hormones and metabolites

• Techniques involving mass spectrometry

are increasingly being used to measure

hormones and metabolites

• Cellular and molecular biology can

increasingly provide patient-specific

diagnoses of congenital disorders or

endocrine neoplasia syndromes;

information that can predict and influence

patient outcome and management

• Imaging investigations localize endocrine

disorders and assist surgical intervention

• ‘Incidentalomas’ are common and

conscientious effort is needed to

correlate a biochemical endocrine

abnormality to a tumour identified on

Figure 4.9 mIBG uptake by a phaeochromocytoma.

imaging

A whole body I¹²³ mIBG scan with imaging from the

front and back shows a right phaeochromocytoma

with pulmonary and bony metastases. This imaging

is helpful to investigate potential metastatic disease

prior to adrenalectomy. Image kindly provided by Dr

Val Lewington, Royal Marsden Hospital.

66 / Chapter 5: The hypothalamus and pituitary gland

To recap

■ Hormone production from the hypothalamus and pituitary gland is highly dependent upon

negative feedback from the relevant endocrine end-organs. The principles underlying this

and dynamic testing are introduced in Chapters 1 and 4 respectively

■ Hormones from the hypothalamus and pituitary gland are peptides; review their synthesis

and modes of action in Chapters 2 and 3

Cross-reference

■ The hypothalamus and anterior pituitary function to regulate several endocrine end-organs:

the adrenal cortex (see Chapter 6), ovary and testis (see Chapter 7), and thyroid (see

Chapter 8)

■ Oxytocin is described here as a hormone from the posterior pituitary; its major function is to

regulate birth and breast-feeding (see Chapter 7)

■ The hypothalamus regulates appetite, which is also covered in Chapter 15 on obesity

■ The hypothalamus plays critical roles in sensing hypoglycaemia, a major side-effect from

insulin therapy in type 1 diabetes (see Chapter 12)

The hypothalamus and pituitary gland are critical

Embryology and anatomy

for integrating the function of the central nervous

and endocrine systems. The hypothalamus receives

The pituitary develops as two independent struc-

diverse endocrine inputs and signals to affect proc-

tures (anterior and posterior) from very different

esses such as appetite, body temperature and circa-

starting points (Figure 5.1). The anterior pituitary

dian rhythms. It intimately regulates the pituitary

(also known as the adenohypophysis) is derived

gland’s hormone secretion in a series of intercon-

from the epithelial lining of the roof of the mouth.

nected axes with endocrine end-organs, including

These cells are part of the foregut endoderm that

the adrenal cortex, thyroid, testis and ovary. Each

goes on to form the pharynx, respiratory tract,

of the pituitary hormones is described in turn; the

thyroid, pancreas, liver and intestine as far as the

associated clinical disorders secondary to hormone

proximal duodenum. In the mouth, proliferating

excess or deficiency are mentioned here, or, where

epithelial cells fold upwards as Rathke’s pouch and

the phenotype is a consequence of the end-organ

eventually detach from the oral lining prior to

hormone, in the relevant end-organ chapter. For

closure of the bony palate. At the same time, central

example, Chapter 6 describes the consequences of

nervous system (CNS) cells proliferate in the floor

excess cortisol from the adrenal cortex in Cushing

of the third ventricle (a region called the infundibu-

disease, even though the primary pathology is exces-

lum) and migrate downwards to form the posterior

sive adrenocorticotrophic hormone (ACTH) from

pituitary (also known as the neurohypophysis). The

an anterior pituitary corticotroph adenoma. The

downward movement creates the stalk of the pitui-

concluding section of this chapter describes the loss

tary, below which the anterior and posterior com-

of multiple pituitary hormones (‘hypopituitarism’).

ponents become apposed within the bony casing of

The structural consequences of pituitary tumours

the pituitary fossa (also called the sella turcica, part

follow the description of pituitary anatomy and its

of the sphenoid bone) (Figure 5.2). Sometimes,

surrounding landmarks.

remnants of Rathke’s pouch result in fluid-filled

Chapter 5: The hypothalamus and pituitary gland / 67

Pituitary tumours as

space-occupying lesions

The commonest space-occupying lesions in the

pituitary fossa are benign adenomas. If arising from

endocrine cell types, the patient may present with

features of the relevant hormone excess. These syn-

dromes are dealt with later on. Here, we consider

the physical consequences of pituitary tumours.

Given the confined nature of the pituitary fossa and

Figure 5.1 The human pituitary gland forms at ∼8

surrounding important structures (Box 5.1), knowl-

weeks of development. The boxed region is

edge of anatomy is important.

enlarged to the right. The arrows show the

respective migration of the cells that form the

anterior (AP) and posterior pituitary (PP). III, third

Non-functioning adenomas

ventricle; h, hypothalamus; rp, Rathke’s pouch; s,

The commonest pituitary adenoma does not secrete

sphenoid bone; t, tongue; *, oral cavity.

known active hormones and is termed a ‘non-

functioning’ adenoma. Foci of pituitary adenoma

are recognized in up to 20% of post-mortem exami-

nations. The reason for this incredibly high rate of

benign tumour formation is unclear; attention has

cysts that, like pituitary tumours, cause detrimental

fallen on the pituitary’s unusual location where it

effects from local pressure (see next section).

receives privileged access to high concentrations of

Above the pituitary, clusters of neurosecretory

hormones and growth factors directly from the

cells form the various hypothalamic nuclei (Figure

hypothalamus. Molecular genetics has also advanced

5.2); hormones secreted from these cells regulate

understanding. For instance, ∼40% of GH-secreting

hormones released from the pituitary (Table 5.1).

adenomas contain a mutation in G_sα

(review

Other functions include the control of temperature

G-protein-coupled receptor signalling in Chapter

and appetite.

3). Despite this high rate of tumour initiation,

The anterior component forms three-quarters of

pituitary carcinoma is exceptionally rare.

the adult pituitary weight (∼0.5 g), which doubles

The distinction between microadenoma and

during pregnancy and puberty. Hypothalamic hor-

macroadenoma (Box 5.1; diameter < or >1 cm) is

mones released into the capillary plexus at the

arbitrary and in part reflects historical resolution of

median eminence flow down the portal veins to the

imaging techniques. Magnetic resonance imaging

anterior pituitary (Figure 5.2). In turn, this stimu-

(MRI) is now the investigation of choice for

lates specific anterior pituitary cell types to secrete

visualizing the pituitary gland (see Figure 4.8) and

their own hormones from storage granules.

is capable of resolving tumours of a few millimetres

The posterior pituitary receives hormone-

in diameter.

containing granules transported down the hypotha-

Tumours restricted to the pituitary fossa may

lamic neurones continually at a rate of 8 mm/h.

compress nearby cells and cause various forms of

Upon stimulation, these hormones are released

hypopituitarism (i.e. deficiency of one or more, or

from the nerve terminals into the adjacent

all pituitary hormones). Adenomas can also expand

fenestrated capillaries. Thus, the posterior pituitary

beyond the pituitary fossa, eroding the sella turcica,

functions largely as a store. Consequently, as some

and bulge in all directions (see Box 5.1; Figure 4.8).

of the vasopressin fibres terminate in the median

Upward growth can compress the optic chiasm

eminence of the hypothalamus

(Figure

5.2), a

where the optic nerves cross, relaying information

patient with destruction of the posterior pituitary

from the eyes to the visual cortex. This creates a

commonly recovers vasopressin function.

characteristic defect, where the first fibres to be

68 / Chapter 5: The hypothalamus and pituitary gland

Paraventricular nuclei

Supraoptic nuclei

Arcuate and other

Optic chiasm

nuclei

Primary capillary plexus

Superior hypophyseal

artery

Median eminence

Pituitary stalk

Hypophyseal portal

Supraoptic -

vessels

hypothalamic tract

Anterior pituitary

Posterior pituitary

Hormone-secreting

cells

Capillaries

Efferent veins

draining into the

inferior petrosal

sinuses on left and

Inferior hypophyseal

right

artery

Figure 5.2 Highly simplified structure of the

into the inferior petrosal sinuses from where

hypothalamus and its neural and vascular connections

hormone sampling can be conducted to assess

with the pituitary. The superior hypophyseal artery

Cushing syndrome (see Chapter 6). The axons from

branches to form the primary capillary plexus in the

the arcuate and other nuclei terminate close to the

median eminence and the upper part of the pituitary

primary capillary plexus. Axons of the supraoptic

stalk. From the primary plexus arise the hypophyseal

and paraventricular nuclei traverse the pituitary stalk

portal vessels, which terminate in the anterior pituitary

and terminate close to the capillaries of the inferior

to form a secondary plexus of sinusoidal capillaries

hypophyseal artery, which supplies the posterior

supplying the hormone-secreting anterior pituitary cell

pituitary. The entire pituitary gland is encased in the

types. Efferent veins drain from the anterior pituitary

bony sella turcica.

affected are those crossing over (‘decussating’) from

patients may present having already lost significant

the inner portions of the retina. This leads to a

vision. A striking presentation is a road traffic acci-

bitemporal visual field loss, commonly as a hemi-

dent where cars or pedestrians coming from either

anopia (the peripheral half of each visual field is

side were unappreciated.

lost). Figure

5.3 shows a more subtle defect.

Lateral extension into the cavernous sinus can

Sometimes the upper fields are lost first because the

cause ophthalmoplegia (paralysis of eye movement)

lower nerves are affected first by pressure from

from pressure on any of the three cranial nerves

below. Visual field loss progresses insidiously and

innervating the extraocular muscles of the eye

Chapter 5: The hypothalamus and pituitary gland / 69

Table 5.1 Summary of anatomy and function of the hypothalamic nuclei

Nuclei

Function

Medial

Supraoptic

Paraventricular (PVN)

Secretes vasopressin and oxytocin; large neurones

pass through the pituitary stalk as the ‘supraoptic-

hypothalamic tract’ to the posterior pituitary where

the nerve terminals contain storage granules

Secretes corticotrophin-releasing hormone (CRH)

Supraoptic (SON)

Vasopressin and oxytocin secretion (like PVN)

Suprachiasmatic (SCN)

Biological clock functions (e.g. wake-sleep cycle);

receives input from retina

Tuberal

Ventromedial (VMN)

Satiety; lesions cause overeating (‘hyperphagia’)

Mood

Arcuate

Secretes multiple releasing hormones, somatostatin

and dopamine from nerve terminals in the median

eminence into capillary network for delivery to the

anterior pituitary; overlapping function with PVN and

other nuclei

Mammillary

No known endocrine function; role in memory

Posterior

Thermoregulation

Blood pressure

Lateral

Hunger; lesions cause anorexia

Thirst

Hormone axes and functions are detailed in the relevant sections of this chapter and later organ-specific chapters. Not all

nuclei play endocrine roles and some functions remain incompletely understood. However, general appreciation of the

diverse function is important as disruption (e.g. from space-occupying lesions or radiation damage) can have pronounced

effects for patients attending endocrinology clinics.

(Table 5.2). Involvement of each nerve can give rise

the internal carotid artery in the cavernous sinus,

to characteristic forms of diplopia (double vision),

after which restricted access and the dangers of

exacerbated by looking away from the action of the

operating around major vessels makes curative

paralyzed muscle. Laterally, tumour can also envelop

surgery impossible.

Case history 5.1

A 65-year-old man had attended the optician for new reading glasses when a routine

assessment revealed loss of the entire lateral half of the visual fields on both sides.

What is the precise description for this visual deficit?

What is the likely cause?

How would it be best imaged?

If imaging of the pituitary gland is abnormal, why should this person be referred urgently to

an endocrinologist?

Answers, see p. 96

70 / Chapter 5: The hypothalamus and pituitary gland

epithelial cells that lined Rathke’s pouch and can

Box 5.1 Pituitary tumours

cause coincident diabetes insipidus (deficiency of

Two issues must be considered:

vasopressin, see later).

• Potential hormone excess from the tumour

cell type (see following sections)

• Physical pressure on local structures and

Treating pituitary tumours

other pituitary cell types:

Pharmacological treatment is available for some

° Cranial nerve palsies (see below and

Table 5.2)

hormone-secreting tumours (see sections on growth

hormone and prolactin). For all others, and where

° Loss of pituitary hormones, either

individually or in combination, causing

drug treatment proves inadequate, there are three

hypopituitarism (see later sections)

choices (Box 5.2).

Compression of the optic chiasm is a neurosur-

gical emergency. Even profound visual loss can

Local anatomy at risk from expanding pituitary

recover quickly by relieving pressure on the chiasm.

tumours

In this scenario, surgery is advantageous over radio-

• Superiorly - optic chiasm:

therapy, which is less invasive, but would damage

° Compression causes loss of vision

optic neurones, can take up to 10 years for its com-

(commonly bitemporal; Figure 5.3)

plete effect, mildly increases the risk of cerebrovas-

• Laterally - cavernous sinuses:

cular ischaemic events and frequently results in

° Compression of cranial nerves III, IV and

hypopituitarism because of the death of other

VI (Table 5.2)

hormone-secreting cell types.

° Encasing of the internal carotid artery;

does no harm but prevents curative

surgery

• Antero-inferiorly - sphenoid sinus (the

The hypothalamus

route for transsphenoidal surgery):

The hypothalamus is a critical part of the brain

° Cerebrospinal fluid (CSF) rhinorrhoea

linking diverse aspects of the endocrine system to

secondary to tumour erosion is rare

the CNS and vice versa in health and disease. For

example, depression is associated with altered func-

Categorization of tumour size

tion of the hypothalamic-anterior pituitary adreno-

• >1 cm diameter = macroadenoma

cortical axis. In many situations it functions as a

• <1 cm diameter = microadenoma

rheostat

(e.g. like the thermostat on a heating

system), regulating the stimulation or suppression

of a variety of processes such as hunger or thirst. It

Other more generalized symptoms of pituitary

lies below the thalamus and above the pituitary

masses include headache (especially frontal/retro-

gland as a series of nuclei categorized anatomically

orbital) from stretching of the meninges or obstruc-

as medial (plus subdivisions) and lateral (see Table

tion to CSF drainage. Very rarely, tumours extend

5.1). Many of the nuclei interact with peripheral

anteriorly through the sphenoid sinus to cause CSF

endocrine organs either dependent on or independ-

leakage through the nose (‘CSF rhinorrhoea’).

ent of the hormone axes of the anterior pituitary

Not all pituitary masses are adenomas. The dif-

(see next section). The hypothalamic role in appe-

ferential diagnosis includes metastasis, meningi-

tite control is covered in Chapter

15. It is also

oma, lymphoma, sarcoid, histiocytosis, or an

involved in the body’s counter-regulatory hormone

unusual tumour called a craniopharyngioma that

response to hypoglycaemia (Chapter 12).

more commonly presents to the paediatric endo-

The hypothalamus is responsible for tempera-

crinologist. Histologically, this tumour is benign,

ture control and the regulation of several circadian

but it is still invasive. It most likely arises from the

rhythms and ‘biological clock’ functions (e.g. the

72 / Chapter 5: The hypothalamus and pituitary gland

Box 5.2 Summary of non-pharmacological treatment of pituitary tumours

Observation

• Transfrontal surgery:

• Repeat MRI and monitor anterior pituitary

° Less common but can be considered for

hormone function:

particularly large tumours

° Increasingly common as ‘incidentalomas’

are discovered on MRI performed for

Radiotherapy

headaches and other CNS symptoms and

• External beam radiotherapy:

signs

° Three beams at different angles are

° Can be sensible for tumours not

focused on the tumour region, but

compressing the optic chiasm

avoiding the optic chiasm

° Common second-line modality when

Surgery

tumours re-grow after surgery

• Transsphenoidal surgery:

• Stereotactic radiotherapy:

° From behind the upper lip or via the nose,

° Many beams at different angles produce a

the sphenoid sinus is crossed and the

very high dose at a precise focal point

pituitary accessed via making a window in

° Considered for very discrete tumours in

the sella turcica

an attempt to retain surrounding pituitary

° Used for emergency decompression of

function

the optic chiasm (except for prolactinomas

° Not used as the first-line radiotherapy

– see later)

treatment

then regulate vasopressin secretion (see section on

test of anterior pituitary function, e.g. to assess the

the posterior pituitary) and the sensation of thirst.

magnitude and speed of rise in thyroid-stimulating

hormone (TSH) concentration in response to intra-

venous TRH.

Regulation of hypothalamic and anterior pitui-

The hypothalamic-anterior

tary hormone release can be complex. Axis-specific

pituitary hormone axes

and associated clinical details are given in the rele-

There is a special relationship between an anterior

vant ‘end-organ’ chapters on the adrenal cortex,

pituitary cell type, its hypothalamic regulator(s) and

testis, ovary and thyroid. Generally, the common

its secreted hormone(s), which in several instances

basic principle of negative feedback can be used to

goes on to regulate major endocrine end-organs

make biochemical diagnoses in the clinic (Figure

(Table 5.3).

5.4 and review Chapter 1). Negative feedback influ-

Hypothalamic-releasing hormones are mostly

ences transcription and translation of hormone-

small peptides with pulsatile secretion and short

encoding genes, the release of stored hormone

circulating half-lives. In vivo action is very fast via

granules and the number of receptors on the target

specific anterior pituitary cell-surface G-protein-

cell. For example, increased thyroid hormone

coupled receptors linked to second messenger path-

reduces TRH production, the number of TRH

ways (review Chapter 3). Hypothalamic hormones

receptors on anterior pituitary thyrotrophs and

may also be inhibitory; e.g. the actions of growth

TSH production. Low thyroid hormone concentra-

hormone-releasing hormone (GHRH) on soma-

tion has the opposite effects. This means that serum

totrophs and thyrothrophin-releasing hormone

hormone concentrations from the end-organ, the

(TRH) on lactotrophs are inhibited by the hor-

hypothalamus (rarely measured) and anterior pitui-

mones somatostatin and dopamine respectively.

tary (frequently or always measured) can be used to

Clinically, hypothalamic hormones are rarely meas-

diagnose if and where a clinical problem lies in the

ured, although they can be injected as an infrequent

axis. For instance, lack of thyroid hormone because

Chapter 5: The hypothalamus and pituitary gland / 73

Table 5.3 Hormone-secreting cell types of the anterior pituitary

Anterior pituitary Hormone secreted

Size (number

Target organ

Hypothalamic

cell type

of amino

regulator (+

acids)

or - effect)

Somatotroph

Growth hormone

191

Diverse

GH-releasing hormone

(GH)

(GHRH, +) and

somatostatin (SS, -)

Lactotroph

Prolactin (PRL)

199

Breast

Dopamine (-) and

thyrotrophin-releasing

hormone (TRH, +)

Corticotroph

Adrenocorticotrophic

Adrenal cortex Corticotrophin-

hormone (ACTH)

releasing hormone

(CRH, +)

Thyrotroph

Thyroid-stimulating

204

Thyroid

TRH (+)

hormone (TSH)

Gonadotroph

Follicle-stimulating

Both 204

Ovary or testis Gonadotrophin-

hormone (FSH) and

releasing hormone

luteinizing hormone

(GnRH, +)

(LH)

of primary hypothyroidism (i.e. underactivity ema-

such as psychological stress, exercise and tempera-

nating from the thyroid) results in raised TSH (and

ture, are mediated in this way. Several anterior pitui-

TRH); low thyroid hormone with low or normal

tary hormones exhibit a circadian rhythm, the

TSH indicates hypothalamic or anterior pituitary

regulation of which probably involves the suprachi-

disease

(tertiary or secondary hypothyroidism,

asmatic nucleus and the pineal gland. In mammals,

although a distinction between the two is rarely

the pineal gland appears to transduce neural infor

made). The principle is the same for the other

mation on the day/night light cycle from the retina

hormone axes.

into a circadian rhythm of melatonin secretion.

Pulsatility of hypothalamic hormone release

These poorly understood phenomena appear

can also affect anterior pituitary responsiveness.

increasingly important: for instance, the type B

Constant

gonadotrophin-releasing

hormone

receptor for melatonin has recently been associated

(GnRH) desensitizes the gonadotroph, leading to

with risk of type 2 diabetes; and shift workers have

loss of luteinizing hormone

(LH) and follicle-

disturbed endocrinology with increased mortality

stimulating hormone (FSH) secretion, and, conse-

and morbidity.

quently, testicular or ovarian quiescence. Thus,

continuous intravenous GnRH can be used as a

contraceptive or as pharmacological castration in

The anterior pituitary hormones

hormone-dependent prostrate or breast cancer. In

contrast, pulses of GnRH every 90 min can be used

Growth hormone

to restore fertility in patients with hypothalamic

dysfunction.

GH is the most abundant hormone of the adult

In addition to autonomous regulation, transient

anterior pituitary, secreted by the somatotrophs,

neural inputs from higher centres modulate

which account for up to 10% of the pituitary’s dry

endocrine axes via the hypothalamus. Several

weight. The major form of human GH is a protein

endocrine responses to environmental changes,

of 191 amino acids, two disulphide bridges and a

74 / Chapter 5: The hypothalamus and pituitary gland

IGF-I is produced in many tissues, including large

Input from

amounts in the liver. In turn, the actions of IGF-I

higher centres

+ or -

are regulated by a family of at least six highly

+ or -

specific IGF-binding proteins

(IGFBPs). Most

Hypothalamus

(> 95%) serum IGF-I is bound in a complex with

IGFBP-3 and a protein called acid labile subunit

(ALS). The production of IGFBP-3 and ALS is also

Releasing hormone

increased by GH.

+ or -

Metabolic actions

pituitary

Intermediate metabolism

The direct metabolic effects of GH tend to syner-

gize with cortisol and generally antagonize insulin,

Anterior pituitary

giving rise to the ‘diabetogenic’ properties of excess

hormone

GH. GH leads to a stimulation of lipolysis and

increases fasting free fatty acid

(FFA) concentra-

Target gland

tions. During times of fasting or energy restriction,

hormone

this lipolytic effect of GH is enhanced, while the

effect is suppressed by co-administration of food or

Figure 5.4 Endocrine feedback circuits. The

glucose. In the long term, and important clinically,

diagram shows interactions between higher brain

GH leads to a reduction in fat mass.

centres, the hypothalamus, anterior pituitary and

GH and IGF-I both have roles in normal

peripheral endocrine glands. The controlling factors

glucose homeostasis. GH increases fasting hepatic

can be stimulatory ( + ) or inhibitory ( - ). Three

glucose output, by increasing hepatic gluconeogen-

feedback loops are shown: from anterior pituitary

esis and glycogenolysis, and decreases peripheral

to hypothalamus; from the end-organ to the

glucose utilization through the inhibition of glyco-

anterior pituitary; and

from the end-organ to the

gen synthesis and glucose oxidation. These effects

hypothalamus.

are antagonistic to those of insulin and acute reduc-

tions in GH secretion are associated with enhanced

insulin sensitivity. Longer term reductions in GH

are associated with the development of insulin

resistance in association with changes in body com-

molecular weight of 22 kDa, although there are

position. In contrast to GH, IGF-I, as suggested by

other minor variants. The structure of GH is species

its name, acts like insulin to lower blood glucose by

specific. Human GH differs markedly from that of

stimulating peripheral glucose uptake, glycolysis

non-primates. This is thought to reflect the dra-

and glycogen synthesis, while having a minimal

matic evolution of the GH/PRL gene family with

effect on hepatic glucose production.

the appearance of primates. One practical conse-

quence is the obligatory use of human GH, now

Energy expenditure

produced recombinantly, to treat children and

GH causes an increase in basal metabolic rate

adults with GH deficiency.

through a number of mechanisms, including an

increase in lean body mass, increased FFA oxidation

Effects

and enhanced peripheral tri-iodothyronine produc-

tion (see Chapter 8).

The net actions of GH are both metabolic and

anabolic (Figure 5.5). The latter are mediated pre-

dominantly through the generation of the mitogenic

Anabolic actions

polypeptide insulin-like growth factor I (IGF-I),

GH output increases with size to sustain growth

which acts either locally or in an endocrine manner.

during childhood. An individual destined to become

Chapter 5: The hypothalamus and pituitary gland / 75

Exercise

Sleep

Stress

DIRECT EFFECTS

Liver: gluconeogenesis and glycogenolysis

Hypothalamus

Adipose: lipolysis

Muscle: glycogenolysis and inhibition of glycogen synthesis

GHRH

Somatostatin

Cartilage / Bone: chondrocyte and osteoblast differentiation

Energy expenditure: increased

Ghrelin

Pituitary

(mainly from

the stomach)

Liver

IGF-I

Growth: long bones at epiphyseal plate

Muscle (and periphery): glucose uptake,

glycolysis, glycogen synthesis

Figure 5.5 Summary of the regulation and effects of growth hormone (GH). Some of the anabolic effects of GH

are mediated by local production of IGF-I acting in an autocrine or paracrine manner. In addition to the feedback

loops shown, glucagon and free fatty acids decrease GH secretion by increasing somatostatin release. GHRH,

growth hormone-releasing hormone; IGF-I, insulin-like growth factor I.

tall secretes GH at higher circulating concentrations

profound effects on bone turnover. It is likely that

than smaller peers. The consequence is faster than

these effects are largely indirect, as serum IGF-I

average growth and, year-by-year, height gain. There

correlates well with estimates of bone mineral

is a marked rise in circulating GH levels at puberty.

density. In addition, GH and IGF-I may modify

The anabolic effects of GH on protein metabo-

intestinal calcium absorption and serum levels of

lism are mainly mediated by IGF-I. This promotes

active vitamin D (see Chapter 9).

growth of long bones at the epiphyseal plates, where

Acute administration of GH modestly stimu-

there are actively proliferating cartilage cells. This

lates muscle and whole-body protein synthesis,

‘growth spurt’ at and following puberty ceases once

leading to nitrogen retention and increased lean

the epiphyses of the long bones fuse at the end of

body mass. The converse effects are seen with

adolescence - the reason why too much GH after

decline in GH secretion with ageing, features of

this time leads to the progressively dysmorphic

which can be partially reversed by GH administra-

growth of acromegaly compared to the proportion-

tion. As well as GH, IGF-I concentration also

ate growth of gigantism (see Box 5.4). GH also has

declines with advancing age. Accordingly, age- and

76 / Chapter 5: The hypothalamus and pituitary gland

sex-matched normal ranges are necessary for the

appropriate interpretation of serum IGF-I assays.

Without these details, there is a risk of incorrectly

diagnosing overactivity or underactivity of the GH-

IGF-I axis.

Sodium and water homeostasis

The mechanisms enabling the body to regulate

008

sodium and water homeostasis are complex.

Clock time

Although incompletely understood, there is evi-

Figure 5.6 A 24-h profile of serum growth hormone

dence that GH induces sodium and fluid retention,

(GH) in a normal 7-year-old child. Irregular pulses

possibly by increasing glomerular filtration rate.

occur, which are greatest during sleep.

The main clinical implication of this phenomenon

is the side-effect of swollen hands or feet or pitting

oedema reported by adults receiving GH replace-

ment therapy or with acromegaly.

Box 5.3 Assessing the GH-IGF-I

axis

Mechanism of action of GH and IGFs

• GH release is pulsatile (Figure 5.6):

GH signals within the cell via the JAK-STAT

° Random serum GH is a poor marker of

pathway (see Figures 3.7 and 3.8). GH receptors

clinical GH status

have been detected within the first year of life in all

° Either dynamic testing (see later) or a

known target tissues. The number of receptors in a

series of serum measurements is

target tissue

(e.g. the liver) is changed both by

needed

peripheral factors, such as sex hormones, and down-

• Circulating IGF-I concentration is relatively

regulated by GH itself. As suggested by the name,

constant:

the indirect effects of GH via IGF-I are often

° Random serum IGF-I is a useful marker

‘insulin-like’. They can be antagonized by cortisol

of clinical GH status

and are mediated intracellularly by pathways very

similar to those for insulin signalling

(review

Chapter 3 and Figure 3.6).

Instead, regulation of GH production comes from

the dynamic, opposing interplay between hypotha-

Growth hormone regulation

lamic GHRH (a positive influence) and somato

Input from the hypothalamus and higher

statin

(negative) (see Figure 5.5). GH pulses are

brain centres

virtually simultaneous with peaks of GHRH and

GH secretion is stimulated by sleep and exercise and

low somatostatin secretion; conversely, GH falls

inhibited by food ingestion. During deep sleep,

as somatostatin concentration rises. The pulsatile

bursts of secretion occur every 1-2 h (Figure 5.6).

release of GH and its relatively short half-life of

Stress (e.g. excitement, cold, anaesthesia, surgery or

∼15 min mean that random serum measurements are

haemorrhage) produces a rapid increase in serum

usually barely detectable [<0.4 ng/mL (<1 mU/L)].

GH. Although negative feedback has been proposed

A circulating GH-binding protein slightly increases

for IGF-I (see Figure 5.5), the GH axis lacks a single

the half-life, but its physiological significance is

end-organ secreting a hormone with a clear negative

unclear. This intermittent nature of circulating GH,

feedback role. Contrast this with cortisol from the

compared to reasonably constant levels of serum

adrenal cortex, which suppresses corticotrophic-

IGF-I, is important in assessing clinical GH status

releasing hormone (CRH) and ACTH secretion.

(Box 5.3).

Chapter 5: The hypothalamus and pituitary gland / 77

Input from other hypothalamic-anterior

insulin secretion rises, which suppresses lipolysis. As

pituitary-end-organ axes

the individual moves back into the fasting state,

GH production from somatotrophs is dependent

FFA concentrations fall, GH secretion returns and

upon an adequate supply of thyroid hormone,

falling insulin concentration removes the brake on

which explains why hypothyroid children suffer

lipolysis. Longer periods of fasting and chronic mal-

from stunted growth. Glucocorticoids, as either

nutrition are associated with increased amplitude

endogenous cortisol or synthetic steroids given for

and frequency of GH secretion. In contrast, obesity

inflammatory disorders such as asthma or rheuma-

is associated with increased GH clearance and

toid arthritis, suppress GH secretion. Children with

reduced GH secretion. The metabolic regulation of

Cushing syndrome stop growing. By contrast, oes-

GH secretion is utilized clinically in the oral glucose

trogens sensitize the pituitary to the action of

tolerance test (OGTT) and insulin tolerance test

GHRH, so that basal and stimulated GH concen-

(ITT) for assessment of GH status (Figure 5.7 and

trations are slightly higher in women and rise earlier

Table 5.4).

during female puberty.

Clinical disorders

Metabolic regulation

Growth hormone excess - acromegaly and

In addition to the regulation of GH by hypotha-

gigantism

lamic GHRH and somatostatin, ghrelin is secreted

GH excess is rare, affecting approximately 60 people

mainly by the stomach and acts as a potent GH

per million (Box 5.4). It most commonly arises

secretagogue. It also stimulates hunger, acting oppo-

from tumours of the pituitary somatotroph. In line

sitely from leptin (see Chapter 15).

with all pituitary tumours, these are virtually always

FFA and GH form a negative feedback loop;

benign adenomas rather than carcinomas.

GH induces lipolysis and a rise in FFA, which, in

turn, inhibits further GH secretion by increasing

Symptoms and signs

somatostatin. FFA also increases following a meal

The phenotypic appearance of excessive bone

and GH release is inhibited at the same time as

growth differs depending on whether the patient

(a)

(b)

Normal

Partial

deficiency

Hours

Glucose

Insulin

Figure 5.7 Dynamic tests of growth hormone (GH)

glucose, which stimulates GH release in normal

status. (a) In an oral glucose tolerance test (OGTT)

subjects. This response is blunted in partial GH

GH release is normally suppressed, although it can

deficiency and lacking in patients with complete

rebound as blood glucose returns to normal (as

deficiency; it is also diminished in some people with

shown at 2-3 h). In acromegaly, GH release does not

longstanding type 1 diabetes. The precise diagnostic

suppress and may even rise paradoxically. (b) In an

values are shown in Table 5.4.

insulin tolerance test (ITT), insulin reduces blood

78 / Chapter 5: The hypothalamus and pituitary gland

Table 5.4 Dynamic tests of growth hormone (GH) status

Test

Results

75 g oral glucose tolerance test (OGTT)

Rapid suppression of GH secretion to a nadir of

<0.3 ng/mL (<0.8 mU/L) if normal

Remains high in acromegaly or gigantism

Insulin tolerance test (ITT) [serum glucose

Stimulation of GH secretion:

≤2.2 mmol/L (40 mg/dL)]

>6.7 ng/mL (>17 mU/L), normal

3-6.7 ng/mL (~8-17 mU/L), partial deficiency

<3 ng/mL (<8 mU/L), severe GH deficiency

Amino acid infusion

Stimulation of GH secretion

(commonly arginine)

(useful in patients where insulin-induced

hypoglycaemia is undesirable, e.g. in children)

diagnosis (Box 5.5 and Case history 5.1). Making

Box 5.4 Growth hormone excess:

the diagnosis is important as acromegaly increases

a constellation of signs and

mortality two- to three-fold, mainly because of its

symptoms caused by bony and

cardiovascular complications.

soft tissue overgrowth, and

Inspection of the patient will usually reveal

metabolic disturbance

many of the features of bony and soft tissue over-

growth (Figure 5.8). However, examination should

• Gigantism: occurs prior to epiphyseal

also include the cardiovascular system as blood pres-

closure and causes relatively proportionate

sure might be increased and there might be signs of

increased stature

congestive cardiac failure (e.g. ankle oedema, basal

• Acromegaly: occurs after epiphyseal

lung crepitations).

closure and causes progressive, cosmetic

disfigurement because of disproportionate

growth

Investigation and diagnosis

Three approaches can diagnose GH excess: serum

IGF-I measurement elevated above the age- and

presents prior to or after epiphyseal fusion. Before

sex-adjusted normal range; repeatedly detectable

epiphyseal fusion, the excess GH promotes increased

GH in a series of serum measurements illustrating

linear velocity, which remains relatively proportion-

autonomous production rather than the normal

ate and results in extremely tall final stature - well

pulsatile secretion; and failure for GH to suppress

over 2 m. Gigantism is relatively easy to recognize.

[remaining >0.3 ng/mL (>0.8 mU/L) using newer

After epiphyseal fusion, linear growth is no longer

immunoradiometric or chemiluscent assays follow-

possible, leading to disproportionate growth and

ing 75 g oral glucose (OGTT; Figure 5.7 and Table

the features of acromegaly (Figure 5.8). A patient

5.4)]. In all but exceptionally rare ectopic GHRH

with a GH-secreting adenoma that started before

secretion, the cause is a GH-secreting pituitary

puberty and only presents after epiphyseal fusion

adenoma. By MRI these tumours are usually greater

will carry features of both phenotypes. In isolation,

than 1 cm in diameter (i.e. a macroadenoma) and

acromegaly is more difficult to diagnose. The fea-

may have extended and eroded beyond the pituitary

tures are insidious, frequently causing a 10-year gap

fossa at the time of diagnosis (see earlier anatomical

between the retrospective onset of symptoms and

complications of pituitary tumours).

80 / Chapter 5: The hypothalamus and pituitary gland

If the tumour is accessible in its entirety, trans-

Box 5.5 Symptoms and signs of

sphenoidal surgery can be curative. Serum GH

growth hormone excess

falls promptly if successful; if it remains elevated,

some neurosurgeons will re-operate straight away.

Musculoskeletal (acromegaly unless

If surgery is not curative (the goal may have been

indicated)

only to debulk an extensive tumour), medical

• Increased stature (gigantism)

therapy is possible. Normal somatotrophs respond

• Protruding mandible (‘prognathia’), teeth

to somatostatin via specific cell-surface receptors by

separation on lower jaw

reducing GH secretion. Most GH-secreting adeno-

• Big tongue (‘macroglossia’)

mas retain this feature to some extent so that they

• Enlarged forehead (‘frontal bossing’)

can be treated by potent somatostatin analogues

• Large hands and feet (carpal tunnel

delivered by monthly intramuscular injection. If

syndrome, tight rings, increasing shoe

these fail, dopamine agonists

(see treatment of

size)

prolactinomas later) can sometimes be helpful,

• Osteoarthritis from abnormal joint

especially if the tumour co-secretes prolactin.

Pegvisomant antagonizes GH action at the GH

receptor. Although this is a beautiful example of

Cardiovascular

drug design (see Figure 3.7), it remains prohibi-

• Dilated cardiomyopathy, cardiomegaly,

tively expensive for many patients in the UK and

cardiac failure

other countries.

• Hypertension

A common management pathway sees a patient

treated with a somatostatin analogue if trans-

Metabolic

sphenoidal surgery is not curative. If this still fails

• Impaired glucose tolerance or potentially

to achieve normal GH status [e.g. normal serum

secondary diabetes (see Chapter 11)

IGF-I, nadir GH

<0.3 ng/mL

(<0.8 mU/L) on

OGTT], external beam radiotherapy can be admin-

Skin

istered. Hypopituitarism is common after radio-

• Irritating, thickened, greasy (increased

therapy, requiring attentive follow-up; however,

sebum production)

once radiotherapy has been effective (e.g. IGF-I in

• Excessive sweating

the age- and sex-adjusted normal range), somatosta-

tin analogue therapy can be withdrawn.

General

There is much debate over whether GH pro-

• Headaches

motes bowel tumour formation and/or growth.

• Tiredness, often very disabling lowering

Colonoscopy, at least once at diagnosis, can be con-

quality of life and ability to work

sidered to look for colonic polyps with malignant

potential. Long-term surveillance is contentious,

Local tumour effects

but may have a role in patients who are not cured

• See earlier section on anatomy and

by the above modalities, i.e. where there is ongoing

pituitary space-occupying lesions

GH excess.

Treatment

Growth hormone deficiency

Restoring normal GH status returns age-adjusted

Like GH excess, insufficient GH presents differ-

mortality to normal. The goal is a normal age-

ently at different times of life. Prior to final height,

adjusted serum IGF-I and GH nadir on glucose

it comes to the attention of the paediatric endo-

loading of less than 0.3 ng/mL (0.8 mU/L). This is

crinologist as failure to grow (‘falling off ’ height

sometimes very difficult to achieve. There are several

centile charts; Figure 5.9). In adulthood, it presents

options (Table 5.5).

insidiously, often in conjunction with other pitui-

Chapter 5: The hypothalamus and pituitary gland / 81

Table 5.5 Treatments of acromegaly

Advantages

Disadvantages

Transsphenoidal surgery - common first-line

Rapid effect

Invasive and requires general anaesthetic

Can restore vision in optic nerve

Non-curative for large, extrasellar tumours

compression

Might be curative if complete resection

May cause hypopituitarism by damage to other cell types

Somatostatin analogue drugs - lower growth hormone (GH)

Non-invasive

Monthly intramuscular injection (most commonly)

May shrink large extrasellar tumours

Expensive, may lower chance of curative surgery for

intrapituitary lesions

Decreases GH in ∼60% of patients

Gastrointestinal side-effects (commonly diarrhoea)

Unlikely to be curative, i.e. continuous therapy needed

Radiotherapy - a good second or third line

Non-invasive

Slow to act - may take up to 10 years

Likely to shrink tumour and reduce GH

Likely to cause hypopituitarism by destroying other pituitary

levels

cell types

Might be curative

Mildly increases risk of cerebrovascular disease

Case history 5.2

A 40-year-old woman had attended her family doctor for a cervical smear. She saw a new

doctor, her previous doctor having known her since childhood. The new doctor was concerned

by the patient’s coarse facial appearance and asked some questions. The woman was

surprised to be asked about her shoe size but confirmed that most of her shoes were now a

size larger than 10 years ago.

What diagnosis is being considered?

What other questions should be asked?

What specific features of the examination should be sought?

What tests would confirm the doctor’s suspicion?

Answers, see p. 97

tary hormone deficiencies following surgery or

most likely a non-functioning adenoma. Other

radiotherapy to the anterior pituitary (Box 5.6).

childhood causes include congenital deficiency

Any pituitary space-occupying lesion can cause

(Figure 3.9; review Box 3.6) or cranial irradiation

loss of somatotrophs and GH deficiency. In child-

for CNS tumours or haematological malignancy. In

hood, this may be a craniopharyngioma; in adults,

adults, loss of GH secretion is part of physiological

82 / Chapter 5: The hypothalamus and pituitary gland

190

Box 5.6 Symptoms and signs of

180

growth hormone deficiency

170

• Decreased stature/cessation of growth

160

(childhood)

150

• Decreased exercise tolerance

140

• Decreased muscle mass and strength

130

• Increased body fat/decreased lean body

120

mass

110

• Centripetal fat distribution, increased

waist:hip ratio

100

• Hypertension and ischaemic heart disease

• Decreased left ventricular mass

• Dyslipidaemia [increased low-density

Growth

lipoprotein (LDL)-cholesterol]

hormone

• Osteoporosis

• Poor quality of life

1 2 3 4 5 6 7 8 910111213141516171819

Age (years)

Figure 5.9 Short stature due to growth hormone

ous injection of recombinant GH (oral peptides

(GH) deficiency and the effect of GH replacement.

would be degraded in the intestine). In children

The height of a girl is shown compared to the

with true GH deficiency, this results in a spectacular

reference growth charts, where the population is split

clinical effect, with a small child growing slowly

into centiles (i.e. 50% of girls’ heights lie below the

into a normally sized adult. It is also used by

50th centile line, 5% below the 5th, etc.). Her height

paediatric endocrinologists to treat short stature

for chronological age (•) is greatly reduced, but

of other causes

(e.g. Turner syndrome/45,XO).

skeletal maturity (or bone age) is also delayed. As a

Administration of GH in adequate dose will make

consequence, height plotted for bone age (•) falls

any child grow more quickly in the short term, but

within the centiles of normality. Bone age is

does not necessarily increase final height.

determined by radiological examination of the left

hand. Comparison is made with standard radiographs

The benefit of treatment in adulthood remains

to assess skeletal maturity. Serum GH was

contentious amongst clinicians as improvements

undetectable in a basal sample and no secretion

for individual patients can be minimal. Treatment

could be elicited by dynamic testing. Secretion of

is also relatively expensive and invasive; thus, it

other anterior pituitary hormones was normal. After

is important to demonstrate clear patient benefit

GH replacement was initiated, there was rapid

from GH replacement. At present, UK guidelines

catch-up of both height and skeletal maturity. M

include a quality-of-life questionnaire generating

and F represent maternal and paternal height

an Assessment of Growth Hormone Deficiency in

respectively.

Adults (AGHDA) score and clear biochemical evi-

dence of GH deficiency (see Table 5.4). From the

clinician’s perspective, improvement in fasting lipid

ageing and may be partly responsible for some of

analysis would also be persuasive for continuing

the changes in body composition associated with

replacement therapy. In clinical trials, studies have

ageing, but does not usually produce obvious clini-

reported extensive benefits:

cal symptoms.

If GH is lacking, try to stimulate it; lack of GH

• Improvements in fat mass

is diagnosed by stimulation testing alongside iden-

• Decreased waist-to-hip ratio and lower visceral fat

tifying a low serum IGF-I value (see Figure 5.7

• Increased lean body mass

and Table 5.4). It is treated by the daily subcutane-

• Increased bone mineral density

Chapter 5: The hypothalamus and pituitary gland / 83

• Increased muscle mass and strength

signals through specific receptors that dimerize and

• Increased maximal exercise performance

recruit tyrosine kinase signalling pathways (review

• Increased VO₂max, maximum power output,

Chapter 3 and Figure 3.8).

maximum heart rate and anaerobic threshold

• Increased left ventricular mass, stroke volume,

cardiac output and resting heart rate with decreased

Regulation of production

diastolic blood pressure

The principles and features of PRL regulation are

• Increased red cell mass

similar to those of GH. PRL from lactotrophs is

• Increased emotional reaction and improved social

under tonic inhibition by dopamine, with TRH

isolation scores

providing a stimulatory input (Figure 5.10). Stress

• Increased perceived quality of life

increases serum PRL. Although the peaks are not as

• Increased self-esteem

discrete as for GH, PRL is also released episodically

• Decreased sleep requirement

with highest levels during sleep. The most profound

changes in serum PRL occur during pregnancy and

Prolactin

lactation. The concentration increases progressively,

up to 10-fold, through pregnancy, possibly in part

Human prolactin (PRL) is secreted by the lac-

because of rising oestrogen levels. It remains elevated

totroph cells in the anterior pituitary and comprises

during lactation under the stimulus of suckling, an

199 amino acids with three disulphide bonds. By

example of a positive feedback loop: prolactin stimu-

weight, outside of pregnancy or breast-feeding, the

lates milk production, consumed by suckling, which

PRL content of the normal human pituitary gland

in turn by a neural reflex stimulates further prolactin

is ∼1% that of GH.

release. The loop is only broken once the baby stops

suckling.

Effects and mechanism of action

Prolactin plays some role in stimulating growth of

Clinical disorders

the alveolar component of breast tissue during ado-

lescence. However, its major action is to stimulate

Hyperprolactinaemia

breast milk production (lactation) (Figure 5.10; also

Symptoms and signs

see the endocrinology of pregnancy in Chapter 7,

Increased serum PRL causes oligomenorrhoea or

Box 7.16). Following childbirth and the consequent

secondary amenorrhoea (see Box 7.17), or sub-

decrease in maternal serum oestrogen and proges-

fertility in women of reproductive age by inhibiting

terone, PRL in the presence of cortisol initiates and

the normal pulsatile secretion of LH and FSH, and

maintains lactation. Its loss results in the immediate

the mid-cycle LH surge, leading to anovulation.

cessation of milk secretion. PRL also inhibits syn-

When present, inappropriate breast milk produc-

thesis and release of LH and FSH by the anterior

tion (galactorrhoea) is striking. Hyperprolactinaemia

pituitary gonadotrophs. This causes a physiological

occurs with sufficient frequency to be relevant to

secondary amenorrhoea (see Box 7.17) that acts as

the primary care physician. The underlying cause is

a natural contraceptive in the post-partum period.

commonly a microprolactinoma. Other causes are

In birds, the hormone stimulates nest-building

listed in Box 5.7 (Case history 5.3).

activity and crop-milk production; in reptiles,

In contrast, men and post-menopausal women

amphibians and some fish, it acts as an osmoregula-

tend to present later when the underlying pathology

tor. These wider functions and the conservation of

is more likely to be a larger macroadenoma, and

PRL-like molecules across species have led to other

presenting symptoms and signs may reflect the con-

actions being attributed to PRL in both male and

sequences of a space-occupying lesion (see Box 5.1).

female humans. However, for many of these pro-

Men with hyperprolactinaemia may also present

posed functions, the physiological significance

with gynaecomastia or features of secondary hypog-

remains unclear

(Figure

5.10). Like GH, PRL

onadism (see Box 7.10).

84 / Chapter 5: The hypothalamus and pituitary gland

Sleep

Suckling

Stress

stimulus

Hypothalamus

TRH

Dopamine

pituitary

Prolactin

Mammary gland

Other effects

Major

Suppression of LH and FSH production

Potential or minor

Regulation of lymphocytes

Osmoregulation

Maintenance of the corpus luteum in the ovary

Steroidogenesis in testis and ovary

Stimulates development

Epithelial cell proliferation

Initiates and maintains lactation

Synthesis of casein and lactalbumin

Synthesis of lactose

Synthesis of free fatty acids

Synergized by glucocorticoids

Inhibited by oestrogen and progesterone

Figure 5.10 Summary of the regulation and effects of prolactin. For the influences on the hypothalamus,

the + and - symbols reflect their net effect on prolactin secretion. The bold arrow for dopamine reflects its

predominance as a regulatory factor compared to thyrotrophin releasing hormone (TRH). LH, luteinizing

hormone; FSH, follicle stimulating hormone.

Investigation and diagnosis

apart the differential diagnosis when serum PRL is

Diagnosing hyperprolactinaemia requires several

repeatedly above the normal range [i.e. >∼500 mU/L

blood samples to avoid the risk of raised PRL sec-

(∼25 ng/mL)] (Box 5.7).

ondary to stress from a single painful venesection

The exclusion of pregnancy is mandatory to

leading to a false diagnosis. Also, on occasion, large

avoid further unnecessary investigation. Otherwise,

forms of PRL, called macroprolactin

(do not

the extent of the raised prolactin concentration gives

confuse the word with macroprolactinoma), are

a clue to the underlying diagnosis. PRL secretion

detected by some PRL assays. Although inactive

from microprolactinomas and macroprolactinomas

biologically, macroPRL creates the false impression

forms a continuum above the upper limit of the

of hyperprolactinaemia. If suspected, additional

normal range. However, when PRL is only relatively

laboratory methods can remove it from the assay.

modestly increased [500-2000 mU/L (∼25-100 ng/

These issues aside, the major challenge is to tease

mL)], other diagnoses need consideration, such as

Chapter 5: The hypothalamus and pituitary gland / 85

tor antagonists used as antiemetics) can increase

Box 5.7 Hyperprolactinaemia

serum PRL and cause galactorrhoea.

Commonly presents in women with

Having excluded other causes, the aetiology is

amenorrhoea ± galactorrhoea

likely to be a pituitary tumour, most frequently a

Confirm hyperprolactinaemia on several

microprolactinoma, which is the commonest sce-

stress-free blood tests

nario in women of reproductive age. With pituitary

pathology, especially larger macroprolactinomas,

Differential diagnosis

other anterior pituitary axes need to be assessed as

• Pregnancy

they may be underactive. On occasion, acromegaly

• Prolactin moderately raised [500-

may be suspected as some pituitary tumours can

2000 mU/L (∼25-100 ng/mL)]:

secrete both GH and PRL, possibly reflecting the

shared developmental origin of the somatotroph and

° Primary hypothyroidism (↑ TRH drive to

PRL secretion)

lactotroph. There is also the possibility of stalk dis-

connection syndrome where a pituitary tumour

° Stress

(especially if superiorly positioned), previous surgery

° Drug treatment [e.g. dopamine receptor

antagonists antiemetics, antipsychotics,

or trauma can block hypothalamic dopaminergic

antidepressants, certain

neurones from reaching the lactotrophs, causing a

antihypertensives (α-methyldopa,

mild rise in PRL. However, serum PRL concentra-

reserpine), opioids and H₂ antagonists]

tion above 2000 mU/L (∼100 ng/mL) most likely

indicates a prolactinoma. Thereafter, serum levels

° Chronic renal failure (reduced clearance)

and cirrhosis

tend to correlate with size and can exceed

100,000 mU/L (∼5000 ng/mL) in large tumours.

° Idiopathic (PRL levels frequently return

to normal)

MRI will delineate the size of the pituitary tumour

and any impact on the surrounding structures.

° Stalk disconnection

Where there is extensive growth close to the optic

° Acromegaly

chiasm, formal visual field assessment is very

° Chest wall injury

important.

° Nipple stimulation

• High prolactin [>3000 mU/L (>∼150 ng/mL)]:

° Microprolactinoma

• Very high prolactin [>6000 mU/L (>∼300 ng/

Treatment

mL)]:

The major reasons for treating hyperprolactinae-

mia are to prevent inappropriate lactation, restore

° Macroprolactinoma

fertility and prevent bone demineralization from

Treatment

inadequate oestrogen in women or testosterone in

• Dopamine agonist (e.g. cabergoline)

men (see Chapter 7).

• Surgery and radiotherapy rarely needed

Treatment is by cause. If secondary to offending

drugs, these should be withdrawn or changed wher-

ever possible. This is frequently difficult with antip-

primary hypothyroidism causing inadequate feed-

sychotic medication and treatment changes should

back of thyroid hormone on TRH, raised TRH and

be discussed with the mental health team. Primary

lactotroph (as well as thyrotroph) stimulation. Renal

hypothyroidism is treated with thyroxine.

disease can compromise clearance, slightly elevating

Prolactinomas are exquisitely sensitive to

circulating PRL levels. Therefore, serum urea and

dopamine agonists. Therefore, prolactinomas of all

electrolyte assays, and tests for pregnancy and thyroid

sizes should be treated with medical therapy in the

function should be performed.

first instance, even in the presence of optic chiasm

A drug history is important as some pharmaco-

compression and visual field loss. Surgery and/or

logical agents can stimulate PRL release. For

radiotherapy are only very rarely required. Upon

example, any drug that inhibits dopamine synthesis

dopamine agonist treatment, PRL falls, tumour

(e.g. l-methyldopa) or action (e.g. dopamine recep-

cells shrink quickly and sight is commonly restored.

86 / Chapter 5: The hypothalamus and pituitary gland

Historically, bromocriptine has been used; however,

Case history 5.3

it is frequently associated with nausea because of its

action on other dopamine receptor sub-types. Better

A 16-year-old girl was referred to the

alternatives now include cabergoline, taken orally,

gynaecologist with a history of primary

usually twice weekly. By treating for 5 years, the

amenorrhoea, tiredness and poor growth.

majority of microprolactinomas are cured, i.e. PRL

She was receiving no medication. She

remains in the normal range permanently after

was not sexually active. She was short.

withdrawal of therapy. This is not true of large

Investigations showed raised PRL

macroprolactinomas, which are more likely to

[2000 mU/L (∼100 ng/mL)] and MRI

require on-going treatment. In recent years, there

revealed an enlarged pituitary. Her renal

has been concern over drugs derived from ergot

function was normal. A diagnosis of

alkaloids, like cabergoline, causing sclerotic heart

prolactinoma was made and she was

valve pathology. However, the data emanate from

treated with cabergoline. She started to

use in Parkinson disease at much higher dose than

have periods but did not grow. Repeat

commonly prescribed for hyperprolactinaemia (e.g.

imaging of her pituitary showed no

cabergoline 250 µg twice weekly).

change. At this point she was referred to

The management of prolactinomas in preg-

the endocrinologist who performed further

nancy can potentially be difficult. Although there is

investigations and realized that the initial

little evidence of a teratogenic effect, dopamine

diagnosis was wrong. Her treatment was

agonists are usually stopped. However, the lac-

altered and she started to grow. Her

totroph population normally increases significantly

pubertal development continued and,

during pregnancy and there is a risk of excessive

furthermore, there was complete

tumour growth, especially from macroadenomas.

resolution of the abnormality on MRI.

Headaches and visual disturbance are very impor-

tant symptoms. One strategy is to conduct visual

What are the possible causes of

field analyses in each trimester. In addition, within

hyperprolactinaemia?

a specialist setting, observing serum PRL measure-

What investigation made the diagnosis?

ments broadly commensurate with the stage of

Why did the pituitary enlargement on MRI

pregnancy is reassuring that very large tumour

regress with treatment?

growth has not occurred. If necessary, MRI and

potential reinstitution of dopamine agonist therapy

Answers, see p. 97

can be considered.

Breast cancer

Epidemiological studies have linked higher levels

Adrenocorticotrophic hormone

of PRL with increased risk of breast cancer, treat-

ACTH is a short peptide of

39 amino acids.

ment failure and worse survival, but whether thera-

Residues

1-24 are highly conserved and confer

peutic lowering of PRL alters these outcomes is

full activity, such that synthetic ACTH(1-24)

unknown.

is used clinically to test adrenocortical function

(see Chapter

6). ACTH comes from the pro-

Hypoprolactinaemia

opiomelanocortin gene (POMC), which encodes the

Low serum prolactin from loss of lactotrophs in

POMC protein that is cleaved enzymatically into

hypopituitarism has no known clinical consequence

many potential products

(Figure

5.11). These

beyond failure of lactation and thus inability to

include several forms of melanocyte-stimulating

breast-feed. This demonstrates the questionable sig-

hormone (MSH) and β-endorphin with morphine-

nificance of PRL in humans other than on lactation

like activities that may inhibit pain signals to the

and gonadotrophin production.

brain. The enzyme that cleaves POMC to yield

Chapter 5: The hypothalamus and pituitary gland / 87

Signal

Figure 5.11 The cleavage of pro-

peptide Pre-pro-opiomelanocortin

opiomelanocortin (POMC).

Adrenocorticotrophic hormone (ACTH)

prior to and after cleavage is shown in

red. Dark blue areas represent different

forms of melanocyte-stimulating

Pro-opiomelanocortin (POMC, 1-265; MW 31,000)

hormone (MSH). The number of amino

acids in each peptide unit is shown in

parentheses. LPH, lipotrophic hormone;

N-POMC, the amino-terminal sequence

of POMC. MW, molecular weight in

Pro-ACTH; MW 22,000

β-LPH (1-93)

kilodaltons.

γ-LPH

β-endorphin

Pro-γ-MSH

ACTH

(1-60)

(1-31)

(1-39)

Joining

N-POMC (1-76)

peptide α-MSH

β-MSH

(1-13)

(1-18)

N-POMC

γ-MSH

(1-48)

(1-28)

ACTH is called prohormone convertase 1/3 (offi-

adrenocortical insufficiency (see below and Chapter

cially abbreviated as PCSK1), which also catalyzes

6). The cleavage of POMC by PC1/3 to generate

the cleavage of insulin and C-peptide from proin-

ACTH is also important in hypothalamic neurones

sulin in pancreatic β-cells (see Chapter 11).

as its failure is a rare monogenic cause of obesity

(see Chapter 15).

Effects and mechanism of action

Regulation of production

The major clinical action of ACTH is at the

adrenal cortex, where it stimulates several of the

ACTH production is stimulated by CRH from the

enzymatic reactions that convert cholesterol to

hypothalamus and inhibited by cortisol from the

either cortisol or adrenal sex steroid precursors (see

adrenal cortex in a negative feedback loop. Specific

Chapter 6). The hormone acts on the adrenocorti-

details of axis regulation and its circadian rhythm

cal cell surface via a specific G-protein-coupled

are discussed in Chapter

(see Figure

6.4).

receptor, the type 2 melanocortin receptor (MC2R),

Vasopressin potentiates CRH action and may

to increase intracellular levels of cAMP

(review

be particularly important during fetal life. Like

Chapter 3). ACTH also binds the MC1R in the

PRL and GH, ACTH (and consequently cortisol)

skin to cause pigmentation; a feature that acts as a

rises with stress, mediated by neural inputs from

surrogate marker of corticotroph overactivity in

other parts of the brain. This includes stress from

88 / Chapter 5: The hypothalamus and pituitary gland

hypoglycaemia, such that insulin administration to

tisol in primary hypoadrenalism. Increased POMC

lower serum glucose is a clinical test of corticotroph

expression leads to raised levels of ACTH and char-

function and potential ACTH deficiency

(see

acteristic hyperpigmentation of the skin, especially

‘insulin tolerance test’ in the next section).

in unusual places like scars, skin creases and inside

the mouth (see Figure 5.11).

Clinical disorders

ACTH deficiency

Excess ACTH and Cushing disease

In ACTH deficiency, biosynthesis of cortisol (and

An excess of cortisol is called Cushing syndrome

sex steroid precursors) by the adrenal cortex is lost,

(see Chapter

6). When secondary to too much

causing secondary hypoadrenalism (see Chapter 6).

ACTH from a corticotroph adenoma, the disorder

Historically, the diagnosis of hypoadrenalism as a

is called Cushing disease, after Harvey Cushing who

result of pituitary dysfunction has been made using

described the original disorder. The corticotroph

the ITT (see GH deficiency earlier; Table 5.4).

overactivity stimulates adrenal cortices bilaterally,

Insulin is injected to produce hypoglycaemia [blood

which become enlarged, and cortisol increases to

glucose <2.2 mmol/L (<40 mg/dL)], which, under

pathological levels. Clinically, the challenge is to

normal circumstances, stimulates a large stress

recognize and diagnose glucocorticoid excess (i.e.

response, and a prompt rise in ACTH and thus

Cushing syndrome); then to decipher whether the

cortisol. The test is unpleasant and not without

source is adrenal in origin (e.g. an adrenocortical

danger, requiring continuous medical supervision.

adenoma; see Figure

4.7) or due to too much

It is contraindicated in patients with cardiovascular

ACTH from either the anterior pituitary (Cushing

disease. The ITT is still used as it allows simultane-

disease) or secreted ectopically from rare tumours,

ous assessment of both ACTH and GH responses.

such as small cell carcinoma of the lung (see Table

However, ACTH deficiency for longer than a

10.6). The tests, approach and treatment are

few months leads to atrophy of the adrenal

described in Chapter 6.

cortex, which can also be revealed by an inadequate

In Cushing disease, the negative feedback from

cortisol response to synthetic ACTH(1-24) (see

cortisol is unable to control ACTH secretion;

Chapter 6). This latter test, which is easier to

however, it still exerts some effect. In particularly

perform, may fail to diagnose recent corticotroph

difficult operative cases and where pituitary radio-

underactivity where the adrenal cortex has started

therapy has failed, a last resort is to remove the

to fail but can still respond to pharmacological

adrenal glands to solve the problem of excess

stimulation.

cortisol. On occasion, this ultimate removal of

negative feedback causes uncontrolled invasive

growth of the corticotroph adenoma and is called

Thyroid-stimulating hormone

Nelson syndrome.

TSH is a glycoprotein composed of two subunits

Interestingly, some non-functioning adenomas

(α and β; see Figure 2.4). The α-subunit is shared

with no recognizable hormone secretion, when

by TSH, LH and FSH, with hormone specificity

removed, display cellular immunoreactivity for

conferred by different, distinctive β-subunits. TSH

ACTH. These tumours pursue a slightly more

is synthesized in the thyrotrophs, which constitute

aggressive course of recurrence and re-growth,

∼10% of the cells in the anterior pituitary.

requiring close surveillance with MRI and consid-

eration of radiotherapy (see Box 5.2).

Effects and mechanism of action

Excess ACTH as a result of adrenocortical

TSH is the major physiological regulator of the

insufficiency

thyroid gland, stimulating the biosynthesis and

Increased corticotroph activity is a physiological

secretion of thyroid hormones (see Chapter 8). The

response to diminished negative feedback from cor-

hormone acts on the thyroid follicular cell surface

Chapter 5: The hypothalamus and pituitary gland / 89

via its specific cell-surface G-protein-coupled

individualized β-subunit. Variation of the carbohy-

receptor to increase intracellular cAMP levels

drate post-translational modification (i.e. the ‘glyco-’

(review Chapter 3; see Figure 8.4).

part; review Chapter 3) leads to substantial subtle

variation (microheterogeneity).

Regulation of production

Effects and mechanism of action

TSH production is stimulated by TRH and acts to

stimulate the biosynthesis and release of thyroid

LH and FSH regulate gonadal function in males

hormones - thyroxine (T₄) and tri-iodothyronine

(testosterone biosynthesis and spermatogenesis in

(T₃). Basal TSH secretion depends on tonic TRH

the testis) and females (oestrogen and progesterone

release; rare hypothalamic lesions or transection of

biosynthesis in the ovary, and the menstrual cycle).

the pituitary stalk result in TSH deficiency and

All of these complex functions are described in

subsequent hypothyroidism. Negative feedback by

detail in Chapter 7. Both hormones act through

thyroid hormone at the anterior pituitary decreases

cell-surface G-protein-coupled receptors linked to

the effectiveness of TRH, in part by reducing TRH

cAMP second messenger signalling.

receptor number on the cell surface of the thyro-

trophs. Somatostatin also inhibits TSH secretion

from the anterior pituitary.

Regulation of production

The production of gonadotrophins is stimulated

Clinical disorders

by the hypothalamic

10-amino acid hormone,

GnRH, which binds to its G-protein-coupled

Excess TSH

receptor on the cell surface of the gonadotroph and

Excess TSH is almost always a normal compensa-

is linked to cAMP second messenger signalling.

tion to thyroid underactivity and is used as a screen

Factors such as stress and prolactin act negatively

for hypothyroidism in newborn babies (see Chapter

(see Figure 5.10). Like the hypothalamic-anterior

8). Tumours that secrete TSH (‘TSHomas’) are very

pituitary axes regulating the adrenal cortex and

rare. They are usually sporadic macroadenomas and

thyroid, hormones secreted by the testis and ovary

present with hyperthyroidism with inappropriately

(steroid sex hormones and inhibins) exert negative

detectable TSH. The serum α-subunit is usually

feedback on the production of both GnRH and

raised. The differential diagnosis is thyroid hormone

gonadotrophins (see Chapter 7, Figures 7.8 and

resistance syndrome as a result of mutations in the

7.12).

thyroid hormone receptor. The latter condition is

usually inherited and may be identified by the

family history and genetic testing.

Clinical disorders

Excess gonadotrophins

TSH deficiency

Increased levels of both gonadotrophins almost

Any condition resulting in hypopituitarism

(see

always reflect loss of negative feedback from the

later) can cause TSH deficiency and clinical

testis or ovary. Usually, primary testicular or ovarian

hypothyroidism (see Chapter 8).

failure yields serum LH and FSH levels several fold

higher than the upper limit of normal. The com-

monest cause of this gonadotrophin overactivity is

Gonadotrophins - luteinizing hormone

physiological after the menopause when ovarian

and follicle-stimulating hormone

depletion of ova ends cyclical hormone production

LH and FSH are secreted from the gonadotrophs,

in women. Excess gonadotrophin secondary to

which make up 10-15% of cells in the anterior

increased GnRH stimulation is rare. In contrast,

pituitary. As for TSH, the glycoproteins LH and

inappropriately timed rather than excessive

FSH are composed of a common α-subunit and

production causes central precocious puberty (see

90 / Chapter 5: The hypothalamus and pituitary gland

Chapter 7). A pituitary adenoma secreting func-

Box 5.8 Hypogonadotrophic

tional LH or FSH is incredibly rare. Commonly,

hypogonadism

however, non-functioning pituitary adenomas may

stain by immunohistochemistry for the α-subunit,

Low or

‘

’

perhaps giving an indication of the developmental

symptoms, signs and biochemistry

lineage, but little else.

= hypogonadotrophic hypogonadism

Deficiency of the gonadotrophins

During childhood, it is normal for the gonado-

trophins to be low and relatively unresponsive to

pituitary hormones and, potentially, those of the

GnRH; however, continued gonadotroph inactivity

posterior pituitary (see next section). This is termed

will delay puberty (see Chapter 7). This can be

‘hypopituitarism’ and when all hormones are inad-

tested by GnRH stimulation when serum LH and

equate, ‘panhypopituitarism’. In adult endocrinol-

FSH are measured 30 and 60 min later. A normal

ogy, hypopituitarism is most commonly encountered

response is a two- to three-fold increase from

as a result of compression from non-functioning

basal serum levels. After puberty, loss of gonado-

pituitary adenomas or their treatment by surgery or

trophins causes secondary hypogonadism. In

radiotherapy. In paediatric practice, congenital

women, this is very common at some stage of the

absence or malformation of the pituitary gland, or

reproductive years as cyclical gonadotrophin secre-

inactivating mutations affecting the synthesis of a

tion is very vulnerable to

‘stress’, such as major

particular hormone are more relevant.

exercise (e.g. marathon running), excessive dieting

Clinical issues relating to the lack of individual

or, most commonly, emotional anxiety of relatively

anterior pituitary hormones are covered in preced-

minor proportions. A rise in prolactin levels is also

ing sections. The clinical approach to hypopituitar-

sufficient to suppress LH and FSH production

ism where multiple hormones may be missing is

(see earlier). Several syndromes from mutations

brought together here and in Box

5.9. Each

in any one of a number of genes also result in loss

hormone that is potentially missing and its conse-

of gonadotrophins because of absent GnRH.

quences demands consideration. History taking and

Kallman syndrome is a combination of absent

examination need to include all the features of

GnRH-secreting neurones and lack of smell

hormone deficiency described in each of the preced-

(anosmia).

ing sections, e.g. hypogonadism, hypothyroidism

Clinically, it is important to realize that, in the

and hypoadrenalism. For instance, diagnosing defi-

face of significant hypogonadal symptoms and

ciency of LH and FSH, but missing concomitant

signs, and low levels of sex hormones, gonado-

ACTH deficiency might lead to a patient’s death

trophins within the normal range are inappropri-

from hypoadrenalism

(see Chapter

6 and Case

ately low. In women, where significant fluctuation

history 5.4).

of gonadotrophins accompanies the normal men-

Mutations in several genes cause pituitary hypo-

strual cycle, this can be more difficult to identify. It

plasia (Box 5.9). Those responsible for early forma-

tends to manifest as amenorrhoea with low or unde-

tion of the pituitary gland tend to cause broader loss

tectable serum oestrogen. In both sexes the disorder

of anterior pituitary cell types and can include mal-

is described as ‘hypogonadotrophic hypogonadism’

formation of other nearby structures (e.g. absent

(Box 5.8; see Chapter 7).

corpus callosum and optic nerve underdevelopment

in septo-optic dysplasia due to HESX1 mutations).

In contrast to the other lineages, isolated TSH defi-

Hypopituitarism

ciency is rarely a problem. Because corticotrophs are

Syndromes of pituitary hormone excess tend to be

set aside relatively early during anterior pituitary

restricted to one particular hormone. In contrast,

differentiation, ACTH tends to be spared in cases

deficiency commonly affects several of the anterior

of congenital hypopituitarism. However, isolated

Chapter 5: The hypothalamus and pituitary gland / 91

datory to replace missing cortisol using hydrocorti-

Box 5.9 Hypopituitarism

sone (see Chapter 6) and thyroid hormone using

Clinical suspicion requires investigation of all

thyroxine (see Chapter 8). Depending on age and

the hormone axes

sex, gonadal hormones (in men and pre-menopausal

women; see Chapter 7) and GH (during childhood,

Pituitary destruction

adolescence and in some adults; see earlier) may also

• Adenoma or other tumours

be appropriate.

(craniopharyngioma, meningioma,

metastasis)

• Previous surgery

Case history 5.4

• Radiotherapy

• Infarction

A patient has been diagnosed with

Congenital pituitary disorders

acromegaly and referred to an

• Pituitary hypoplasia or aplasia

endocrinologist. Visual field assessment

° E.g. mutations in POU1F1, PROP1,

reveals bitemporal hemianopia. MRI

HESX1, LHX2

demonstrates a large pituitary mass

° Mutations in TPIT tend to affect only the

extending to and compressing the optic

corticotroph lineage

chiasm. Serum PRL was 1200 mU/L

(57 ng/mL), TSH was undetectable, fT₄

Others

was 5.3 pmol/L (0.4 ng/dL) and an ACTH

• Impaired secretion of hypothalamic

stimulation test gave a serum cortisol

hormones (e.g. loss of GnRH neurones in

value at 30 min of 305 nmol/L (10.9 µg/dL).

Kallman syndrome; see Chapter 7)

• Disconnection of the hypothalamic-

What do these biochemistry results

pituitary axis (e.g. stalk tumour, trauma or

indicate?

infection)

What urgent treatments are needed and

in what order?

ACTH deficiency is caused by inactivating muta-

Answers, see p. 97

tions in TPIT.

In adults, the hypothalamic-pituitary axes are

particularly vulnerable to irradiation. Loss of pitui-

tary hormones, especially GH, can become almost

Hormones of the posterior

inevitable after cranial radiotherapy, but may take

pituitary

up to 10 years to manifest. In contrast, gonado-

trophin secretion is particularly vulnerable to

The two hormones synthesized in the hypothala-

trauma such as surgery. Infarction of the pituitary

mus and released from the posterior pituitary are

is rare, although one well-described condition,

oxytocin and vasopressin (see Table 5.1). Although

Sheehan syndrome, reflects hypotension following

structurally similar, being composed of nine amino

major post-partum haemorrhage. The sudden vas-

acids, they have markedly different physiological

cular insufficiency to a hypertrophied gland (i.e.

roles (review Figure 1.3).

following pregnancy) leads to sudden death of pitu-

itary tissue. Major headache and the symptoms and

Vasopressin

signs of sudden hormone loss (e.g. failure of lacta-

tion, hypoadrenalism) are clues.

Clinically, vasopressin is also known as ‘antidiuretic

Having defined which hormone axes are under-

hormone’ (ADH) and has also been called ‘arginine

active, replacement of the appropriate hormones

vasopressin’. The biology of vasopressin is summa-

needs consideration. In hypopituitarism, it is man-

rized in Box 5.10.

92 / Chapter 5: The hypothalamus and pituitary gland

Box 5.10 Summary of vasopressin

Box 5.11 Regulation of

biology

vasopressin

Physiology

Serum osmolality (S_OSM)

• Circulates largely unbound  rapidly

• High (e.g. dehydration)  increased

metabolized in the liver and filtered by the

vasopressin release  increased water

kidney  t_1/2 ∼15 min

retention  decreased S_OSM

• Low (e.g. water intoxication)  decreased

Function

vasopressin release  decreased water

• Regulates water excretion by the kidney

retention  increased S_OSM

- its main action at normal circulating

vasopressin levels:

Volume

° Acts on the distal convoluted tubule 

• Fall in blood volume ≥8% (e.g.

increased permeability to water  water

haemorrhage)  increased vasopressin

resorption  increased urine

release  vasoconstriction

concentration

O₂ and CO₂ tension

• Potent vasoconstrictor

• Decreased arterial O₂ partial pressure

Cellular mechanism of action

(P_aO₂)  increased vasopressin release

• Distinct cell-surface G-protein-coupled

• Increased arterial CO₂ partial pressure

receptor (V) sub-types and second

(P_aCO₂)  increased vasopressin release

messengers:

° V1 (two further sub-types) 

as an additional stimulus for ACTH release from

phosphatidylinositol (PI) metabolism and

corticotrophs.

raised intracellular Ca²⁺  vascular

smooth muscle contraction

° V2  cAMP  renal water excretion

Regulation of production

(receptor antagonized by ‘vaptan’ class

of drugs)

The main physiological regulator of vasopressin

release is serum osmolality detected by osmorecep-

tors in the hypothalamus (see earlier for functions

of the hypothalamus). Circulating volume is

Effects and mechanism of action

detected by baroreceptors in the carotid sinus and

In the kidney, the presence of vasopressin and the

aortic arch, and by plasma volume receptors in the

high osmolality of the renal interstitium lead to

left atrium.

water movement out of the final section of the distal

In addition to the factors listed in Box 5.11,

convoluted tubule along the osmotic gradient. The

angiotensin II, epinephrine, cortisol and the female

effect can be truly remarkable. For example, a child

sex steroids, oestrogen and progesterone, can also

weighing 30 kg needs to excrete a solute load of

modulate vasopressin release. The latter may explain

∼800 mOsm in 24 h: at its most dilute (∼50 mOsm/

the fluid retention that can occur in the latter part

kg), this load requires 16 L of urine; under maximal

of the menstrual cycle. As with other hypothalamic

vasopressin stimulation, it can be achieved with

hormones, the CNS plays an important part in the

little over 700 mL (∼1100 mOsm/kg).

regulation of vasopressin. Pain and trauma associated

Vasopressin is a potent vasoconstrictor and has

with surgery cause a marked increase in the circulat-

been utilized either directly or in synthetic analogue

ing vasopressin concentration, as do nausea and

form to achieve haemostasis, e.g. in severe gastroin-

vomiting. The activity of the neurohypophyseal

testinal bleeding or post-partum haemorrhage. It

system is also influenced by environmental tempera-

also acts on vascular tone at normal physiological

ture; a rise in temperature stimulates vasopressin

levels. During fetal development, vasopressin serves

release prior to any change in plasma osmolality.

Chapter 5: The hypothalamus and pituitary gland / 93

Clinical disorders

a feature because free water is evenly distributed

across all body compartments.

Excess vasopressin/syndrome of

inappropriate antidiuretic hormone

The syndrome of inappropriate ADH (SIADH)

Investigation, diagnosis and treatment

refers to the release of vasopressin when normal

The cardinal features of SIADH are low serum

regulatory mechanisms should restrict its secretion

osmolality, hyponatraemia and inappropriately high

into the circulation (Case history 5.5). This is a

urine osmolality. Other common causes of hyponat-

difficult and dangerous clinical situation (Box 5.12)

raemia, especially in the elderly, are congestive

where hyponatraemia and low osmolality can cause

cardiac failure and diuretic use. In SIADH, identi-

irreversible brain damage and death.

fying the underlying cause is important (Box 5.12).

Vaptans are new non-peptide drugs that can be

given orally in chronic SIADH. They antagonize

Symptoms and signs

the V₂ receptor lowering the number of aquaporin

Headache and apathy progress to nausea, vomiting,

water channels in the renal collecting duct thus

abnormal neurological signs and impaired con-

reducing water re-absorption from the urine.

sciousness. In very severe cases, there may be coma,

convulsions and death. Generalized oedema is not

Case history 5.5

Box 5.12 Excess

vasopressin/SIADH

A 74-year-old man presented to the

emergency medical service with a 2-week

Definition

history of a cough productive of bloody

• Hyponatraemia + low serum osmolality

green sputum, fever, shortness of breath

(<270 mOsm/kg) + inappropriately high

and pleuritic chest pain. He was a life-long

urine osmolality

smoker. Serum sodium was 124 mmol/L

(124 mEq/L), potassium 3.6 mmol/L

Causes

(3.6 mEq/L), urea 2.7 mmol/L (∼7.6 mg/dL)

• Tumours (e.g. small cell cancer of the

and creatinine 73 µmol/L (∼0.8 mg/dL).

lung)

Serum osmolality was 258 mOsm/kg and

• Any brain disorders (trauma, infection,

urine osmolality was 560 mOsm/kg.

tumour)

• Pneumonia

What is the most likely endocrine cause

• Cytotoxic therapy (chemotherapy or

for the hyponatraemia and what acute

radiotherapy)

condition underlies it?

• Narcotics and analgesics

What measures might be taken to rectify

• Hypothyroidism

the situation?

• Hypoadrenalism

What further investigations might be

considered?

Treatment

• Identify and treat underlying cause where

Answers, see p. 97

possible

• Restrict fluid intake (up to 1 L/day) and

replace sodium lost in the urine

• Vaptans act as V₂ receptor antagonists

Deficiency of vasopressin/diabetes

• Demeclocycline may induce partial

insipidus

diabetes insipidus (see below) but it is less

Even when damage to the posterior pituitary occurs,

commonly used now

vasopressin or oxytocin deficiency commonly does

94 / Chapter 5: The hypothalamus and pituitary gland

not arise so long as the hypothalamic neurones that

treat effectively. In the latter, the high urine flow

transport the hormones remain intact (see earlier

rate tends to dilute the solutes that create the

anatomy section). When deficiency of vasopressin

counter-current exchange mechanism in the renal

or its action does occur, it results in diabetes insip-

parenchyma such that the kidney loses its ability to

idus (DI). Deficiency of vasopressin production by

concentrate urine.

the hypothalamus and posterior pituitary is termed

‘cranial DI’, whereas deficient action at the V₂

receptor causes ‘nephrogenic DI’ (Table 5.6). In the

Case history 5.6

former, the vast majority of vasopressin production

needs to be lost (≥90%) before water balance is

A 58-year-old woman was referred by her

necessarily affected. The term DI stems from when

family doctor because of complaints of

physicians used to taste urine and contrast it with

passing urine every hour during both the

the sweet urine of diabetes mellitus.

day and night. Nothing else was

volunteered in the history and the doctor

Symptoms and signs

had excluded diabetes mellitus. The

Patients with DI pass extremely large and frequent

patient had browsed the internet and felt

volumes of low osmolality urine (potentially 20 L in

she had diabetes insipidus. Serum sodium

24 h). This polyuria and passing urine at night (noc-

was 135 mmol/L (135 mEq/L), potassium

turia) demonstrate that in DI the patient is unable

4.5 mmol/L (4.5 mEq/L), urea 4.3 mmol/L

to reduce urine flow. Clinically, problems only tend

(∼12.0 mg/dL) and creatinine 93 µmol/L

to arise when the patient also lacks sensation of

(∼1.1 mg/dL).

thirst or is deprived of water, when plasma osmolal-

ity rises.

What other aspects of the history need

direct questioning?

What test(s) is appropriate to confirm or

Investigation and diagnosis

refute a diagnosis of diabetes

Some centres have access to a vasopressin immu-

insipidus?

noassay, which allows the diagnosis to be made by

If diabetes insipidus is confirmed, in

monitoring serum vasopressin concentration after

which two sites might the pathology

an infusion of hypertonic saline. Most endocrinolo-

lie?

gists still rely on the water deprivation test and the

use of the vasopressin analogue, desmopressin

Answers, see p. 97

(Table 5.6).

Treatment

Oxytocin

Having diagnosed DI, it remains important to con-

sider and investigate the underlying cause, which

The major roles of oxytocin are during birth and

may be curable. Otherwise management of DI relies

breast-feeding (see Chapter 7). It is also emerging

on intact thirst and access to adequate fluid. For

as a brain neurotransmitter with roles in modulat-

cranial DI, replacement of vasopressin is all that is

ing behaviour and overeating.

required. Desmopressin, either by intranasal spray,

tablet or injection, is a synthetic analogue that acts

Effects and mechanism of action

predominantly on the V₂ receptor and therefore has

minimal hypertensive side-effects. Desmopressin is

Oxytocin has two main sites of action: the uterus

sometimes also used in normal children who suffer

and the mammary gland. It is the hormone of par-

from nocturnal enuresis (bed-wetting). Nephrogenic

turition, literally meaning ‘quick birth’. It increases

DI and psychogenic polydipsia can be harder to

the contraction of the myometrium during labour

96 / Chapter 5: The hypothalamus and pituitary gland

causing expulsion of the fetus and the placenta. In

causes release of oxytocin and leads to ejection of

this role progesterone appears to antagonize and

milk. Even the sight and sound of an infant can

oestrogen potentiate the uterine response to oxy-

stimulate milk ejection. Stimulation of oxytocin

tocin. Post-partum in the mammary gland, oxy-

secretion ceases once the baby stops suckling.

tocin causes contraction of the myoepithelial cells

surrounding the alveoli and ducts to expel milk

Clinical disorders

from the breast.

Like vasopressin, oxytocin circulates largely

Endocrine syndromes of oxytocin excess and defi-

unbound and so is removed rapidly by the kidney

ciency have not been described. However, increased

(t_1/2

∼5 min). Outside parturition and breast-

oxytocin appears to improve behaviour in autism

feeding, it circulates in very low concentrations and

spectrum disorder.

is normally undetectable in the blood. Oxytocin

binds to its cell-surface G-protein-coupled receptor

and signals intracellularly via phosphatidylinositol

Key points

metabolism and calcium (review Figure 3.16).

• GH, PRL, ACTH, FSH, LH and TSH are

Regulation of production

the major hormones of the anterior

pituitary

The movement of the fetus down the birth canal is

• Oxytocin and vasopressin are the major

an example of positive feedback in endocrinology

hormones of the posterior pituitary

(review Chapter 1). Oxytocin stimulates uterine

• Pituitary tumours, especially non-

muscular contraction which moves the fetus into

functioning adenomas, are very common

the distending vagina, which in turn sends neural

• Hormone overactivity secondary to

inputs back to the brain to enhance oxytocin secre-

tumour formation can cause well-

tion. This positive feedback loop is only broken

recognized endocrine syndromes

once the fetus is expelled. Other factors, such as the

• Always consider local structural damage

fall in progesterone and the presence of oestrogen,

and compression from pituitary tumours

may play a minor part in regulating oxytocin release.

• Underactivity of the anterior pituitary

Similarly, positive feedback regulates oxytocin

tends to affect multiple hormones

release during breast-feeding. Suckling of the nipple

Answers to case histories

Case history 5.1

If a pituitary space-occupying lesion is

detected, the patient should be referred

The patient has bitemporal hemianopia. This

urgently to an endocrinologist for two

is caused by loss of function of optic nerve

reasons: first, a prolactinoma will almost

fibres; the only point where pressure can

certainly shrink with dopamine agonist

cause this distribution of visual field loss is at

therapy with restoration of vision (see clinical

the optic chiasm.

section on prolactin); and second, with

The most likely pathology at this location

pituitary tumours, it is critical to think of what

is upward growth of a pituitary tumour.

hormone function may have been lost by

The best imaging modality is MRI. In an

local pressure on pituitary cell types. Most

emergency setting, CT can be useful, but the

importantly, the patient may be hypoadrenal

resolution from MRI is much better for

because of loss of ACTH secretion (see

intracranial structures.

Chapter 6) and hypothyroid (see Chapter 8)

Chapter 5: The hypothalamus and pituitary gland / 97

from TSH deficiency. In an emergency

represent co-secretion of PRL by the tumour.

setting (e.g. if the patient has presented

It is more likely to indicate a small degree of

unconscious and hypotensive and a large

stalk disconnection.

pituitary mass has been detected),

The patient should be placed on daily

hydrocortisone should be administered

hydrocortisone, then thyroid hormone, and

intravenously.

programmed for urgent transsphenoidal

surgery to debulk the tumour and relieve

Case history 5.2

pressure on the optic chiasm. Vision might

be permanently lost if surgery is delayed.

The diagnosis under consideration is

Surgery is highly unlikely to be curative and

acromegaly. Its insidious nature means that

suitable secondary treatments include

those who know the patient well frequently

somatostatin analogues and/or radiotherapy.

miss it.

Questions should address symptoms and

Case history 5.5

signs relating to GH excess (see Box 5.5). In

addition, are there any symptoms or signs

The man has SIADH. Although Addison

from loss of other pituitary hormones (e.g.

disease might be considered in view of the

hypoadrenalism or hypothyroidism) or a

hyponatraemia, the plasma osmolality is low.

local mass effect? A sensitive question would

The SIADH is secondary to pneumonia,

interrogate potential loss of the menstrual

although an underlying lung malignancy

cycle. Facial photographs should be sought

cannot be excluded as a contributory factor.

from the previous 10-20 years.

After taking samples of sputum and blood

In addition to the features listed in Box 5.5,

for microbiology, antibiotics should be

examination should look for potential visual

started and fluid intake restricted to ∼1 L over

field defects or diplopia.

the next 24 h with close attention paid to

Serum IGF-I should be measured. A 75g

urine output and haemodynamic status, e.g.

OGTT should be considered or a serum GH

pulse and blood pressure. Tachycardia and

day series conducted.

hypotension would argue for high-

dependency care.

Case history 5.3

Other investigations directly related to his

The differential diagnosis of

symptoms include arterial blood gas

hyperprolactinaemia is given in Box 5.7. The

assessment (with oxygen given if the patient

presence of poor growth and tiredness

is hypoxic), chest X-ray and sputum analysis

suggests hypothyroidism.

for tuberculosis and malignancy.

A thyroid function test showed a markedly

In this case, fever settled rapidly with

raised serum TSH with low T₄.

antibiotics, the patient remained

The lack of thyroid hormone feedback to

haemodynamically stable, serum sodium

the pituitary had led to an increase in TRH

rose within 12 h to 132 mmol/L (132 mEq/L)

which, in turn, had promoted growth of

and, on continuing the same management,

lactotrophs. Once this stimulus was

normalized 36 h later. Other symptoms

removed by restoration of thyroxine negative

gradually improved. No evidence was

feedback on TRH, the pituitary enlargement

obtained for lung malignancy and

regressed.

electrolytes were normal at discharge.

Case history 5.4

Case history 5.6

The patient has secondary hypothyroidism

The history needs to focus on the CNS for

and hypoadrenalism from the pituitary mass.

previous trauma or infection and specific

The PRL is minimally raised but is unlikely to

symptoms such as headache. Questions

100 / Chapter 6: The adrenal gland

To recap

■ As preparation for understanding the role of the adrenal gland, review the synthesis of steroid

hormones and hormones derived from tyrosine described in Chapter 2

■ To understand the effects of hormones from the adrenal gland, begin by reviewing hormone

action, especially that of steroid hormones, described in Chapter 3

Cross-reference

■ The adrenal cortex is regulated by the anterior pituitary corticotroph such that the body’s

cortisol status reflects whether the corticotroph is physiologically normal, underactive or

overactive (see Chapter 5)

■ Endocrine neoplasia syndromes can involve the adrenal gland resulting in cortisol excess

(ectopic hormone-secreting tumours) or phaeochromocytoma and paraganglioma (see

Chapter 10)

The adrenal cortex

tomy. In contrast, either adrenal can be removed,

increasingly by laparoscopic approaches, without

disturbing the adjacent kidney. However, embryo-

Embryology and anatomy

logical variations can present challenges to the

Understanding the development of the adrenal

endocrine surgeon. Additional or unusual blood

gland can be necessary to appreciate adrenal pathol-

vessels can supply and/or drain the organ, or embry-

ogy (Box 6.1).

ological ‘rests’ of adrenocortical cells can lie outside

The adrenal cortex forms from epithelial cells

the gland.

that line the abdominal (‘coelomic’) cavity of the

developing embryo during the fifth week of devel-

Biochemistry by zones

opment (Figure 6.1). These cells generate concen-

tric functional layers called the outer definitive and

Although what determines and maintains the dis-

the inner fetal zones of the adrenal cortex. This

tinct adrenocortical zones remains unclear, knowl-

pattern is distinctive to higher primates and only

edge of the different regions is important because

begins its reorganization after birth into the more

they define, and are defined by, very different bio-

characteristic layers of the adult adrenal cortex

chemical activity (Box 6.2). This compartmental-

(Figure 6.2 and Box 6.2). The development of the

ized function is all the more remarkable in light of

adrenal medulla is described later.

the prevailing theory of adrenocortical ageing,

The adrenal gland lies immediately superior to

whereby steroid secretion changes as cells migrate

the kidney (hence the anatomical name, ‘suprarenal’

from the outer glomerulosa to the innermost reticu-

gland). This anatomy can be important clinically in

laris where they undergo apoptosis.

hypersecretion or tumours. For instance, when sam-

The principles of steroidogenesis were intro-

pling the veins that drain centripetally through the

duced in Chapter 2. To recap, the steroid product

adrenal gland to measure hormone secretion, access

depends on the complement of enzymes that cata-

on the left is via the renal vein and technically more

lyze the sequential modification of cholesterol

challenging. The adrenal and kidney capsules are

(Figure 6.3 and Box 6.3). Many of these enzymes

closely assimilated. Removal of the kidney (‘nephrec-

are members of the cytochrome P450 superfamily.

tomy’) almost always includes ipsilateral adrenalec-

Although the nomenclature for the corresponding

Chapter 6: The adrenal gland / 101

Neural crest cells

Spinal cord

Posterior root

ganglia

Sympathetic

ganglia

Aorta

Sympathetic

ganglia

Developing

adrenal

Coelomic

Mesonephros

epithelium

Mesentery

Abdominal

cavity

Gut

Figure 6.1 Development of the adrenal gland. The cortex is derived in part from the epithelium lining the

abdominal cavity. Neural crest cells migrate from the back of the embryo; some give rise to dorsal root and

sympathetic ganglia, while others invade the adrenal cortex to form the medulla. The rim of coelomic epithelium

shown in black also gives rise to steroidogenic cells of the gonad.

Function and regulation of the hormones

Box 6.1 Clinical consequences of

embryology

Aldosterone and cortisol serve as ligands for nuclear

hormone receptors, which then function as tran-

• The adrenal cortex and medulla develop

scription factors that influence target gene expres-

separately - clinical disorders almost

sion

(review Chapter

3). It seems that both

always affect either the cortex or medulla,

hormones also have more rapid non-genomic

but not both

actions, although these are less well understood.

• Forming the organ requires cell migration

The mechanism of action for dehydroepiandroster-

- adrenal disorders can occasionally cause

one (DHEA) remains unclear, other than serving

trouble in unexpected places from

as an extra-gonadal precursor for sex hormone

embryological ‘rests’ of cells

biosynthesis.

• The cells forming the adrenal cortex also

form the steroidogenic cell lineages in the

gonad - disorders of steroid production

Cortisol

can affect both organs simultaneously

Cortisol is the major glucocorticoid in humans.

Like all steroid hormones, it is not stored but syn-

thesized according to acute changes in demand. Its

genes has been unified, several names remain in

release into the circulation influences cells in virtu-

common usage (Table 6.1). Awareness of these

ally every organ of the body. In the blood, cortisol

names is important as several of the genes are subject

is largely bound (>90%) to cortisol-binding globu-

to mutation in congenital adrenal hyperplasia

lin (CBG) and is assayed as total serum cortisol.

(CAH), one of the more common paediatric endo-

Anything that alters the amount of CBG (e.g. oral

crine emergencies.

contraceptive use or critical illness) alters total

102 / Chapter 6: The adrenal gland

Figure 6.2 Section through

(a)

(b)

the adrenal cortex. (a) The

Capsule

Smooth endoplasmic reticulum

blood vessels run from outer

capsule to medullary venule.

Zona

(b) A zona fasciculata cell with

glomerulosa

Capillary

large lipid droplets, extensive

smooth endoplasmic

Zona

reticulum and mitochondria.

fasciculata

Lipid droplets Mitochondria

Zona

reticularis

Medulla

Venule

used as a test of glucocorticoid excess (UFC is ∼1%

Box 6.2 Zones of the adult adrenal

of cortisol production by the adrenal glands).

cortex and their steroid hormone

Measuring salivary cortisol similarly avoids issues

secretion

with fluctuating serum CBG.

• Zona glomerulosa, nests of closely packed

small cells creating the thinnest, outermost

Regulation of cortisol biosynthesis and

layer; secretes aldosterone

secretion - the hypothalamic-pituitary-

• Zona fasciculata, larger cells in columns

adrenal axis

making up ∼three-quarters of the cortex;

The major regulation of the adrenal cortex

secretes cortisol and some sex steroid

comes from the anterior pituitary, via the produc-

precursors

tion and circulation of adrenocorticotrophic hor

• Zona reticularis, ‘net-like’ arrangements of

mone (ACTH), a cleavage product of the pro-

innermost cells, formed at 6-8 years to

opiomelanocortin (POMC) gene (review Chapter 5).

herald a poorly understood change called

In turn, ACTH is regulated by corticotrophin-

‘adrenarche’; secretes sex steroid

releasing hormone (CRH) from the hypothalamus

precursors and some cortisol

(Figure 6.4). By binding to cell-surface receptors

and activating cAMP second messenger pathways,

ACTH increases flux through the pathway from

cortisol measurement; an important clinical issue.

cholesterol to cortisol, particularly at the rate-

Like thyroid hormones, it is only the free compo-

limiting step catalyzed by CYP11A1. This happens

nent that enters target cells. The free component

acutely such that a rise in ACTH increases cortisol

also passes into urine - ‘urinary free cortisol’ (UFC)

levels within

5 min. Cortisol provides feedback

– where its collection and assay over 24 h has been

to the anterior pituitary and hypothalamus to

Chapter 6: The adrenal gland / 105

600

500

400

300

200

100

09.00

11.00

13.00

15.00

17.00

19.00

21.00

23.00

01.00

03.00

05.00

07.00

09.00

Clock time

Figure 6.5 Typical diurnal variations in serum cortisol. Levels peak in the early morning and trough in the

evening. In Cushing syndrome, diurnal variations are lost.

reticularis zones. In contrast, overactivity of the

Box 6.4 Important cortisol

anterior pituitary induces a bilateral bulky increase

metabolism takes place in

in adrenocortical size. Unilateral growth also occurs

following adrenalectomy of the contralateral gland.

peripheral tissues and target cells

Cortisol is metabolized in peripheral tissues to

• Cortisol and cortisone are interconverted

inactive cortisone, which can, in turn, be converted

by isoforms of 11β-hydroxysteroid

back to active hormone; the two enzymatic reac-

dehydrogenase (HSD11B):

tions being catalyzed by type 2 and type 1 11β-

° Type 2 (HSD11B2) inactivates cortisol to

hydroxysteroid dehydrogenase

(HSD11B2 and

cortisone (the bulk of which occurs in

HSD11B1) respectively (Figure 6.4 and Box 6.4).

the liver)

° Type 1 (HSD11B1) reactivates cortisone

to cortisol

Functions

• HSD11B1 is prevalent over HSD11B2 in

Intermediary metabolism

visceral adipose tissue, making fat a

The net metabolic action of cortisol is to raise cir-

significant source of cortisol:

culating free fatty acids and glucose, the latter stim-

ulating glycogen synthesis

(Box 6.5; see Figure

° Centripetal obesity is associated with

excess glucocorticoid

11.11). Excess cortisol also fosters an unfavourable

serum lipid profile: raised total cholesterol and trig-

lyceride with decreased high-density lipoprotein

stimulates adipocyte differentiation, particularly in

(HDL)-cholesterol. Cortisol has a permissive effect

the viscera, predisposing to centripetal obesity.

on epinephrine and glucagon, all of which creates a

phenotype of ‘insulin resistance’

- the need for

greater insulin secretion to maintain a normal blood

Skin, muscle and bone

glucose concentration (euglycaemia) (see Chapter

In skin, glucocorticoids inhibit keratinocyte prolif-

13 on type 2 diabetes). In the long-term, cortisol

eration and collagen synthesis. In muscle, the

106 / Chapter 6: The adrenal gland

for post-natal life. Too much glucocorticoid inhibits

Box 6.5 Cortisol, like glucagon,

growth, in keeping with its largely catabolic effects

epinephrine and growth hormone,

on the musculoskeletal system. Cushing syndrome

can be thought of as antagonistic

presents to the paediatric endocrinologist as cessa-

to insulin (also see Figure 11.11)

tion of linear growth.

Cortisol tends to increase blood glucose

levels by:

Lactation

• Promoting gluconeogenesis

Post-partum, cortisol is required for the initiation

• Raising hepatic glucose output

of lactation by PRL. Its loss leads to a gradual reduc-

• Inhibiting glucose uptake by muscle and

tion in milk secretion.

fat

Other effects

Central nervous system and psyche

• Lipolysis from adipose tissue

The role of glucocorticoids in the brain is highly

• Protein catabolism to release amino acids

complex, matched by their potential to cause a

range of emotional symptoms from euphoria to

depression.

catabolic effects reduce protein synthesis, resulting

in atrophy. Similar catabolic effects in bone shift the

Anti-inflammatory effects

balance of activity from osteoblast

(the bone-

Glucocorticoid actions on inflammation and

forming cell type) to osteoclast (the bone-resorbing

autoimmunity are among its most important,

cell type), predisposing to osteoporosis (see Chapter

reflected by the use of potent synthetic steroids to

9). Taken together, there is a net flow of amino acids

treat a range of disorders. With glucocorticoid treat-

towards the liver.

ment, circulating T lymphocytes and eosinophils

fall; however, neutrophils rise. This is a catch to

remember for the patient with an acute exacerba-

Salt and water homeostasis and

tion of asthma. Raised circulating neutrophil count

blood pressure

does not necessarily mean infection; it may simply

Glucocorticoids can potentially increase sodium

reflect glucocorticoid treatment. In tissues, for

resorption and potassium loss at the distal tubule

instance, the acutely inflamed joints of a patient

through effects, not on the glucocorticoid receptor

with rheumatoid arthritis, glucocorticoids rapidly

(GR), but thought to be via the mineralocorticoid

suppress inflammation by inhibiting cytokine pro-

receptor (MR). More proximally, cortisol increases

duction and antagonizing macrophage action.

glomerular filtration rate (GFR) and inhibits vaso-

pressin to increase free water clearance. Cortisol

raises blood pressure by several mechanisms, includ-

Aldosterone

ing increased sensitivity of the vasculature to

The synthesis of aldosterone in the zona glomeru-

catecholamines.

losa is demarcated by the absence of CYP17A1 and

the presence of CYP11B2. The hormone circulates

Growth and development

∼1000-fold lower concentration and with a

Cortisol is an important hormone during growth

shorter half-life (∼20-30 min) than cortisol. In part,

and development of the fetus. It stimulates the dif-

this results from a diminished affinity for serum

ferentiation of cell types to their mature phenotype.

carrier proteins. It acts via binding the MR to influ-

This is particularly evident in the lung, where it

ence gene expression in the nucleus of target cells

stimulates the production of surfactant, which

(review Chapter 3). The MR is not specific for

reduces alveolar surface tension. This is one of the

aldosterone, binding cortisol with equal affinity.

final steps in preparing the fluid-filled fetal airways

However, specificity is preserved by HSD11B2,

Chapter 6: The adrenal gland / 107

impact on circulating aldosterone levels. More

Box 6.6 Aldosterone is the body’s

importantly, the cellular mass of the zona glomeru-

major mineralocorticoid

losa influences longer term mineralocorticoid pro-

duction. Thus, ‘westernized’ high salt diets, which

• Promotes sodium resorption from the urine

expand the intravascular volume and raise blood

and potassium excretion

pressure, suppress the renin-angiotensin system,

• Increases blood pressure

leading to a shrivelled zona glomerulosa.

Aldosterone biosynthesis is regulated

primarily by:

Sex steroid precursors

• Renin-angiotensin system (forming a

negative feedback loop)

DHEA and its downstream derivative, androstene-

• Serum potassium concentration

dione, possess only weak androgenic activity;

however, their conversion in other tissues can give

rise in adults to both potent androgen (e.g. testo-

sterone) and oestrogen

(e.g. oestradiol)

(review

which inactivates cortisol to cortisone, at the major

Figure 2.6). Therefore, these 19-carbon steroids are

sites of mineralocorticoid action, the distal tubule

best termed ‘sex steroid precursors’

(rather than

and collecting ducts of the kidney (Table 3.2). Here,

‘adrenal androgens’). Like cortisol, biosynthesis is

aldosterone acts on the Na⁺/K⁺-ATPase transporter

primarily regulated by ACTH but emanates pre-

to increase sodium resorption in exchange for potas-

dominantly from the reticularis zone. The relative

sium excretion

(Box 6.6). The net effect is to

activity of CYP17A1 and HSD3B2 on

17α-

increase osmotic potential within the circulation,

hydroxypregnenolone determines the production of

causing expansion of circulating volume. The direct

DHEA (and androstenedione) versus cortisol.

effect of aldosterone to increase blood pressure

The function of the sex steroid precursors is

comes from vasoconstriction.

debated. During the first trimester of pregnancy, the

fetal adrenal gland actually secretes some potent

Regulation of aldosterone secretion

androgen (including testosterone) even in females.

The enzyme, renin, is synthesized predominantly in

During the second and third trimesters, huge

the kidney, in specialized cells of the juxtaglomerular

amounts of DHEA and its sulphated derivative,

apparatus. These cells surround the afferent arteriole

DHEAS, are generated. However, these steroids

before it enters the glomerulus (Figures 6.6 and 6.7)

are not essential and their roles remain poorly

and form a sensing mechanism for intravascular

understood. Post-natally, little sex steroid precursor

volume whereby decreased volume stimulates renin

is produced until adrenarche at 7-8 years when

biosynthesis. Renin acts upon its substrate, circulat-

the zona reticularis becomes functionally mature.

ing angiotensinogen, to generate the decapeptide,

Further metabolism of the precursors to active sex

angiotensin I, which is subsequently converted into

steroids stimulates linear growth in middle child-

angiotensin II (AII). This latter octapeptide binds

hood, sometimes accompanied by some pubic and

to the type 2 angiotensin II receptor in the zona

axillary hair growth. This physiology is important

glomerulosa cells to stimulate aldosterone pro

as it needs to be distinguished from precocious

duction. In addition, AII is a very potent ‘pressor’

puberty, the hallmarks of which include breast

agent, causing arteriolar vasoconstriction. Renin-

development in females and testicular enlargement

angiotensin axes exist to some extent within indi-

in males (see Table 7.5).

vidual organs, providing an element of paracrine

adrenocortical regulation of aldosterone biosynthe-

Clinical disorders

sis and secretion. High potassium also stimulates

aldosterone biosynthesis (Figure 6.6). ACTH plays

The major clinical disorders affecting the adrenal

a minor role in regulating aldosterone synthesis,

cortex arise from either too much or too little cor-

although too much or too little ACTH does not

tisol and aldosterone.

108 / Chapter 6: The adrenal gland

Extracellular fluid

volume

Juxtaglomerular

cells

Renin

Angiotensinogen

Angiotensin I

Extracellular

fluid volume

Angiotensin II

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe

Sodium

Adrenal cortex

Aldosterone

(and water)

resorption

Potassium

ACTH

Figure 6.6 The renin-angiotensin-aldosterone axis. A

II-stimulated aldosterone secretion. This leads to

fall in extracellular fluid (ECF) volume produces

increased sodium resorption with expanding ECF

increased activity in renal nerves, reduced sodium flux

volume providing negative feedback on further renin

in the macula densa and a fall in transmural pressure.

production. High potassium, and to a lesser extent

These activate the juxtaglomerular apparatus to

adrenocorticotrophic hormone (ACTH), also

increase renin production, which catalyzes the

increase aldosterone production.

beginning of the cascade that ends with angiotensin

of underactivity are more unusual, although devel-

Hypoadrenalism

opmental abnormalities should not be discounted

Primary hypoadrenalism arises from direct destruc-

in the paediatric setting (Case history 6.1).

tion of the adrenal cortex, whereas secondary disease

arises from loss of the anterior pituitary cortico-

troph. In all circumstances there is shortage of cor-

Symptoms and signs

tisol and in primary disease additional deficiency of

Symptoms and signs relate to:

aldosterone.

• Diminished vascular volume and tone

• Renal sodium loss

Primary hypoadrenalism - Addison disease

• Bowel water and electrolyte loss

Worldwide, the commonest cause of adrenocortical

• Removal of negative feedback (causing pigmenta-

deficiency results from infection (either AIDS or

tion, see Chapter 5)

tuberculosis). In the western world, autoimmune

• Loss of cortisol action on hepatic and peripheral

destruction of the cortex, first described by Thomas

metabolism (Box 6.7).

Addison in 1855, is prevalent. The disorder carries

his eponymous title with the adjective ‘Addisonian’

The consequent classical laboratory findings are

referring to the clinical crisis from acute, severe

hyponatraemia (the vast majority) and hyperkalae-

cortisol (and aldosterone) deficiency. Other causes

mia (in most cases). Raised urea (a sign of con-

110 / Chapter 6: The adrenal gland

Box 6.7 Symptoms and signs of

Box 6.8 A testing regimen for

hypoadrenalism

inadequate cortisol secretion

• Weight loss and anorexia

ACTH stimulation test [‘short Synacthen test

• Fatigue and weakness

(SST)’ in the UK; ‘Cortrosyn stimulation test’ in

• Nausea, vomiting, abdominal pain and

USA]

diarrhoea

• Standard test: 250 µg IV or IM

• Generalized wasting and muscle cramps

• Measurements: pre-injection serum cortisol

• Hypoglycaemia (especially in children)

(and ACTH); serum cortisol 30 min

• Dizziness and postural hypotension

post-injection

• Loss of body hair

• Response: post-injection serum cortisol is

• Pigmentation of light-exposed areas,

>525 nmol/L (∼19 µg/dL) in 95% of normal

pressure points, scars and buccal mucosa

people

(in primary disease)

• Vitiligo (associated with autoimmune

adrenalitis)

mineralocorticoid, fludrocortisone, according to

• Circulatory shock (in acute circumstances)

the mantra ‘if it is missing, replace it’. Historically,

endocrinologists have tended to over-replace corti-

sol with detrimental side-effects similar to those of

Cushing syndrome (see next section). The standard

primary hypoadrenalism. If under-activity is sus-

adult replacement dose is 15-20 mg hydrocortisone/

pected, try to stimulate it; the hallmark of diagnosis

day - 10 mg on awakening, followed by either 5 or

is dynamic testing. Serum cortisol is measured

10 mg mid-afternoon, or 5 mg at midday and a

30 min after intramuscular or intravenous injection

further 5 mg mid-to-late afternoon. This regimen is

of synthetic ACTH (Box 6.8), which contains the

relatively effective at replicating the normal circa-

biologically active first 24 amino acids of ACTH.

dian rhythm: high levels in the morning, low levels

Tetracosactide is the generic name; however, it is

by bedtime. Disturbance to this profile can present

better known by the trade names, ‘Synacthen’ in the

as either difficulty or tiredness executing daily tasks

UK and ‘Cortrosyn’ in the USA, leading to the

(inadequate cortisol) and inability to sleep at night

‘short Synacthen test (SST)’ and ‘Cortrosyn stimu-

(too much cortisol). Fludrocortisone is much longer

lation test’. Although lower dose tests have been

acting and therefore is taken orally once daily (com-

developed, the mainstay of adult endocrinology is

monly 100 µg in adults).

to administer the full ampoule of 250 µg. Bearing

To monitor hydrocortisone treatment, some

in mind assay-to-assay variability and potential fluc-

endocrinologists advocate an intermittent series of

tuations in CBG, a serum cortisol level, 30 min

serum measurements during the day (a ‘cortisol day

later, greater than 525 nmol/L (∼19 µg/dL) identi-

curve’), although no robust evidence supports its

fies the fifth percentile response (i.e. 95% of the

value. In contrast, mineralocorticoid replacement is

population achieve higher values). In primary

frequently overlooked. Normalized renin

(either

adrenocortical disease, plasma aldosterone may be

serum concentration or plasma activity) from high

low or normal; however, more tellingly, elevated

values at diagnosis and normotension are valuable

renin (measured either as plasma activity and con-

guides. Over-replacement tends to generate hypoka-

centration) is indicative of adrenocortical failure.

laemia and hypertension.

The major message for glucocorticoid replace-

Treatment

ment is that the patient is entirely dependent on

The mainstay of oral replacement therapy is hydro-

tablets as the normal ability of the adrenal cortex to

cortisone (the pharmacological name for cortisol -

increase cortisol output during illness or stress is lost.

they are the same substance) and the synthetic

Failure to advise the patient to double replace

Chapter 6: The adrenal gland / 111

Secondary hypoadrenalism

Box 6.9 Glucocorticoid

If the anterior pituitary corticotrophs are underac-

replacement

tive, ACTH-dependent processes in the adrenal

• Double the dose during illness

gland also suffer. This translates as cortisol defi-

• Carry a steroid alert card or bracelet

ciency and loss of adrenal sex steroid precursors

with retained aldosterone biosynthesis. The causes

of corticotroph loss are covered in Chapter

ment doses when unwell (i.e. illness sufficient to

However, the principles of glucocorticoid replace-

require bedrest) risks an Addisonian crisis, a critical

ment therapy, and the consequences of its failure,

lack of glucocorticoid presenting as circulatory col-

are the same. Fludrocortisone is not required.

lapse, hyponatraemia, hyperkalaemia and hypogly-

caemia. This medical emergency demands immediate

treatment with intravenous hydrocortisone as well as

Hyperadrenalism

significant intravenous fluids to expand the con-

tracted circulating volume. For these reasons,

Adrenocortical overactivity most commonly pro-

patients with adrenal insufficiency (either primary

duces either excess mineralocorticoid or excess glu-

or secondary) should carry notification (Box 6.9).

cocorticoid (± sex steroid precursors).

Case history 6.1

Glucocorticoid excess - ‘Cushing

syndrome’

A 35-year-old woman presented with

An excess of glucocorticoid is called Cushing syn-

tiredness and abdominal pain. She had

drome, named after Harvey Cushing, who in 1912

fainted twice recently when unwell with

described the first case in a woman characterized by

vomiting and diarrhoea. Her sister takes

obesity and hirsuitism. Twenty years later, its hor-

thyroxine. On examination, she looked

monal basis was proposed. The commonest cause is

tanned with patches of skin

exogenous glucocorticoid medication, e.g. as used

depigmentation. Blood pressure was

in asthma. Discounting this, there are several

90/60. Serum urea was slightly raised;

endogenous causes of Cushing syndrome. However,

however, creatinine was normal. Serum

despite greatly advanced knowledge, delays in

potassium was 5.5 mmol/L (5.5 mEq/L);

detection remain problematic, the main hindrance

serum sodium was low. Thyroid function

being a failure of perception when presented with

tests were normal. The doctor also

common, insidious symptoms. It most frequently

measured a full blood count. Haemoglobin

occurs in women (Case history 6.2).

was only 100 g/L with a mean cell volume

(MCV) of 110 fl.

Symptoms and signs

What is the likely diagnosis and what tests

The symptoms and signs of exaggerated cortisol

should be performed to confirm it?

action are shown in Box 6.10, and Figures 6.8 and

What treatment should the patient be

6.9. ‘Buffalo hump’ refers to the growth of a fat pad

given?

at the back of the neck.

What additional information should be

provided?

What associated disorder should be

Diagnosis

considered to explain the

The first and most important step is to prove glu-

haematological findings?

cocorticoid excess; this diagnoses Cushing syn-

drome. Random plasma cortisol estimations are not

Answers, see p. 124

useful as cortisol is a stress hormone and circulating

levels vary during the day (see Figure 6.5).

Chapter 6: The adrenal gland / 113

midnight or bedtime failing to drop from daytime

test (Table 6.2). Occasionally, patients fail the 1-mg

values (see Figure 6.5). Bedtime salivary collection

overnight test because they rapidly metabolize

avoids problems with CBG and can be done at

the dexamethasone; this should not occur using

home, avoiding the cortisol-raising stress and

the formal 48-h test, which is otherwise more intru-

expense of hospitals (in-patient testing should be

sive. Using either approach, Cushing syndrome

preceded by an acclimatization period of 1 or 2

is excluded if cortisol is less than

50 nmol/L

days). In moderate-to-severe Cushing syndrome,

(∼1.8 µg/dL) the morning following the tablet(s).

cortisol is also raised several-fold in the urine.

Additional factors can increase serum cortisol and

Patients are advised to collect all urine following the

complicate the differential diagnosis of Cushing

first micturition of the day and include the first

syndrome. This is called ‘pseudo-Cushing syndrome’

sample from the following morning (i.e. capturing

(Box 6.11).

an entire

24-h period). Collection is relatively

Alongside cortisol, DHEA and androstenedi-

inconvenient to perform and is frequently incom-

one, which can be converted into potent androgens

plete. Subtle increases in cortisol excretion are

causing hirsuitism and menstrual irregularities in

seen in obesity and polycystic ovarian syndrome

women, may be elevated.

(PCOS). The third test is the low-dose dexametha-

If cortisol remains high after low-dose dexam-

sone suppression test (Table 6.2); a dynamic test

ethasone testing, is raised in the urine and shows

based on the endocrine principle ‘if overactivity is

loss of diurnal variation (clinical endocrinologists

suspected, try to suppress it’. Dexamethasone is a

commonly use a combination of screening tests),

potent synthetic glucocorticoid, available orally,

Cushing syndrome has been diagnosed. The next

that inhibits physiological ACTH production

phase of investigation seeks to locate the causative

from the anterior pituitary by negative feedback,

site of the disease.

decreasing cortisol production by the adrenal. There

are two forms of the low-dose dexamethasone

Diagnosing the cause and site of

glucocorticoid excess

Primary adrenal Cushing syndrome is most com-

monly due to a benign adenoma of the zona fascicu-

lata. The excess cortisol suppresses pituitary ACTH

Table 6.2 Dexamethasone suppression tests

by negative feedback usually to undetectable levels

Low-dose dexamethasone suppression test

(Box 6.12). In contrast, ACTH-secreting tumours

may not increase serum ACTH above the normal

Diagnoses glucocorticoid excess

0.5 mg × 8 doses 6-hourly ending at 3 am or

single 1 mg dose at midnight

Box 6.11 Pseudo-Cushing

Positive diagnosis of Cushing syndrome: failure

to suppress 9 am serum cortisol the following

syndrome

morning to below 50 nmol/L (∼1.8 µg/dL)

Causes

High-dose dexamethasone suppression test

• Obesity

• Alcoholism

Localizes glucocorticoid excess

• Depression

2 mg × 8 doses 6-hourly ending at 3 am

Anterior pituitary source: >50% suppression of

Distinction from Cushing syndrome

9 am

serum cortisol from pre- to post-test

• Diurnal variation is usually retained

• Cortisol falls on removal of alcohol abuse

Extra-pituitary ectopic source of ACTH (or

adrenal tumour): <50% suppression of 9 am

• Cortisol tends to rise with insulin-induced

serum cortisol from pre- to post-test

hypoglycaemia

114 / Chapter 6: The adrenal gland

dient (3:1 or more) of ACTH from petrosal sinus

Box 6.12 Causes of Cushing

to peripheral blood points to the anterior pituitary

syndrome

rather than an ectopic source and can also help to

lateralize the tumour within the pituitary fossa.

• Anterior pituitary tumour (Cushing

Because the normal pituitary gland would also show

disease): ACTH inappropriately normal or

such a central:peripheral gradient, it is imperative

raised but can be suppressed by high

that glucocorticoid excess is still present when IPSS

dose dexamethasone

is undertaken.

• Ectopic ACTH: extra-pituitary ACTH-

Having defined the excess and gained clues to

secreting tumour: ACTH inappropriately

location, it is now appropriate to image the anterior

normal or raised, less easily suppressed

pituitary by MRI; the adrenal glands by MRI or

by high dose dexamethasone

CT; or continue the search for the ectopic source of

• Adrenocortical tumour: baseline ACTH

ACTH (potentially by ‘fine-cut’ CT of the chest,

suppressed

PET scans where available or uptake scans that

• Exogenous glucocorticoids: baseline

might identify a carcinoid tumour; review imaging

ACTH suppressed

in Chapter 4).

reference range, but the hormone is inappropriately

present for the level of circulating cortisol. The

Treatment

ACTH comes either from a corticotroph tumour of

Cushing syndrome causes premature mortality,

the anterior pituitary or from an ectopic source, e.g.

predominantly from cardiovascular disease. The

small cell carcinoma of the lung (see Table 10.6).

goal of treatment is to normalize glucocorticoid

The high-dose dexamethasone suppression test has

production and restore diurnal rhythm. For

been used to distinguish between these options

adrenal adenomas, unilateral adrenalectomy is

(Table 6.2). Baseline serum cortisol is assessed, fol-

undertaken. For pituitary adenomas, trans-

lowed by a total of 16 mg of dexamethasone over

sphenoidal surgery is commonplace in major centres

48 h (2 mg 6 hourly). ACTH-secreting pituitary

but should be restricted to nominated surgeons

adenomas usually retain negative feedback in

(either ENT or neurosurgeons). The results of treat-

response to this high-dose dexamethasone sufficient

ing Cushing syndrome can be striking (see Figures

to suppress serum cortisol by more than 50% from

6.8 and 6.9).

the baseline value. Cushing syndrome due to a cor-

In the immediate postoperative period, if the

ticotroph adenoma is referred to as ‘Cushing disease’.

cause of excess glucocorticoid has been removed,

Less effective suppression of serum cortisol (by less

the hypothalamic-anterior pituitary-adrenal axis

than 50%) suggests an ectopic source of ACTH.

should be so suppressed that endogenous cortisol

Although unreliable, serum ACTH levels tend to be

cannot be detected. The body is so accustomed

higher from ectopic tumours than pituitary

to high cortisol levels that the patient is commonly

tumours. The high-dose dexamethasone suppres-

symptomatic of relative adrenal insufficiency

sion test lacks complete sensitivity and specificity;

on normal hydrocortisone replacement doses.

in experienced centres, venous sampling from the

Hydrocortisone therapy is needed for a sufficient

inferior petrosal sinus can be more effective for

period until the hypothalamic-anterior pituitary-

determining the origin of ACTH secretion, albeit

adrenal axis returns to normal function. In those

with greater discomfort and risk from an invasive

not fit for surgery, medical therapy, e.g. with

procedure, e.g. a very small percentage risk of

metyrapone, can directly inhibit glucocorticoid

stroke. Inferior petrosal sinus sampling (IPSS) is

secretion. For inoperable pituitary adenomas or fol-

undertaken by interventional radiologists. The

lowing failed surgery, either because of location

hormone is measured in left and right inferior pet-

or size, pituitary radiotherapy remains a valuable

rosal sinus following CRH stimulation. A clear gra-

option (review Chapter 5).

Chapter 6: The adrenal gland / 115

Case history 6.2

Box 6.13 Think of unusual causes

of hypertension, especially in

A 44-year-old woman had suffered

younger patients

symptoms that she attributed to PCOS by

• Conn syndrome

virtue of reading articles on the internet.

• Phaeochromocytoma

She went to see the doctor because of

• Renal artery stenosis

feeling generally unwell, having put on

• Coarctation of the aorta

10 kg in weight and developing nocturia.

She took no medication. The doctor

suspected diabetes and, indeed, the

patient’s fasting blood glucose was

8.5 mmol/L (∼153 mg/dL). However, the

hypertension (e.g. thiazides). However, aldosterone

doctor was more struck by the patient’s

excess also underlies a subset of normokalaemic

appearance of a flushed round face, poor

hypertension. The symptoms tend to be vague.

facial skin quality and purple stretch

Hypertension may present with headaches and

marks on the abdomen. Blood pressure

visual disturbances; hypokalaemia may cause muscle

was 160/95 mmHg. The doctor arranged

fatigue or tiredness (Case history 6.3). Initial bio-

several tests that confirmed the diagnosis.

chemical screening becomes increasingly relevant in

Serum ACTH was then measured and was

younger patients with marked hypertension, espe-

undetectable.

cially if it is resistant to multiple antihypertensive

drugs and accompanied by hypokalaemia (either

What is the initial diagnosis and what

spontaneous or induced by diuretics). The inci-

tests were used to make it?

dence of Conn syndrome is seemingly higher in

Where is the causative lesion and what

women in their third decade. If blood pressure is

imaging investigations might be

normal for age, other causes of hypokalaemia merit

considered?

consideration (Box 6.14).

Answers, see p. 124

Diagnosis

The diagnosis of primary aldosterone excess requires

assessment of the renin-angiotensin-aldosterone

axis by screening and then diagnostic tests.

Concomitant use of antihypertensive medications

Primary mineralocorticoid excess - Conn

that affect the hormone axis is potentially con-

syndrome

founding. MR antagonists need to be withdrawn

Tumours or bilateral idiopathic hyperplasia of the

for 4 weeks. It is debatable whether other agents,

zona glomerulosa result in excess aldosterone with

such as diuretics, β-blockers and ACE inhibitors,

normal cortisol levels.

need to be stopped for initial screening because the

hypertension can be dangerous and difficult to

Symptoms and signs

control without treatment. If initial testing is equiv-

Hyperaldosteronism most characteristically presents

ocal, medications may need to be withdrawn or

with hypokalaemic hypertension. In common

substituted with drugs such as doxazasin, an α-

with diagnosing any of the more unusual causes

adrenergic blocker. Serum potassium should be

of hypertension, a high index of suspicion is

restored to the normal range with oral supplementa-

required (Box 6.13). The electrolyte disturbance

tion in the days prior to testing. Salt intake should

may be unmasked or exacerbated by concomitant

be unrestricted to ensure the patient is sodium

potassium-losing diuretic therapy prescribed for the

replete. For screening, plasma aldosterone and renin

116 / Chapter 6: The adrenal gland

Aside from rare genetic causes, hyperaldosteronism

Box 6.14 Causes of hypokalaemia

usually arises from two pathologies: a discrete

• Primary hyperaldosteronism

adenoma (Conn tumour) or bilateral hyperplasia

• Vomiting with metabolic alkalosis

that can often be discriminated by MRI or CT.

• Diarrhoea or other fluid loss from the lower

If the patient is over 40 years old, when there is

bowel:

increased risk of an incidental non-functional

adenoma, or if imaging is equivocal, adrenal vein

° Ileostomy

sampling helps to localize the source of mineralo-

° Villous adenoma of the rectum

• Diuretic use

corticoid excess (but this is challenging; see earlier

• Hypomagnesaemia

details on adrenal anatomy).

• Insulin infusion

• Rare causes include renal tubular acidosis

Treatment

and various monogenic defects of renal

A Conn tumour is ideally treated by unilateral

tubule function:

adrenalectomy when hypertension can be cured or

° Gitelman syndrome (usually

improved such that the number and dose of anti-

normotensive)

hypertensives can be markedly reduced. Bilateral

° Liddle syndrome (hypertensive)

hyperplasia or adenomas in patients unfit for

° Bartter syndrome (usually hypo- or

surgery are managed by drugs. Spironolactone has

normo-tensive)

been used for many years as an MR antagonist.

° Hypokalaemic periodic paralysis

Indeed, a clue to diagnosis can come from its use

followed by a rapid fall in previously refractory high

blood pressure. Unfortunately, the drug also antago-

nizes the androgen receptor (AR), causing breast

development (gynaecomastia) in men and necessi-

(either plasma activity or serum concentration) are

tating contraceptive advice in fertile women to

measured mid-morning

(aldosterone levels fall

guard against feminizing a male fetus. The more

during the day) with the patient having been seated

specific but less potent antagonist, eplerenone, is

for

∼15 min, but having been out of bed for a

available as an oral twice-daily preparation.

couple of hours. Positive screening detects a high

ratio of aldosterone to renin concentration or activ-

ity in the serum. Applied cut-offs vary and depend

Tumours involving the zona reticularis

on assay units. For instance, measuring aldosterone

In addition to cortisol, tumours from the fasciculata

in pmol/L and renin activity in nmol/L/h, a ratio

and reticularis zones can secrete sex steroid precur-

of more than 2000 gives a very high likelihood of

sors. These steroids are converted in the periphery

primary hyperaldosteronism. Some endocrinolo-

to androgens and, potentially, oestrogens, causing

gists argue that the ratio is best interpreted only

virilization in women (deepened voice and clitor-

when serum aldosterone is above a certain threshold

omegaly) or feminization in men (e.g. gynaecomas-

[e.g.

∼200 pmol/L (∼7 ng/dL)]. This avoids mis-

tia). The tumours may be diagnosed by increased

leading high ratios simply due to a very low renin

serum DHEA (some laboratories only measure

concentration. A normal or low ratio excludes

DHEAS), androstenedione, testosterone and oestra-

primary aldosterone excess (see Box 6.13 for poten-

diol according to sex, and assessment of glucocorti-

tial causes other than ‘essential’ hypertension).

coid status. Where cortisol is normal, and only sex

If the aldosterone:renin ratio is raised, a variety

steroids and their precursors are raised, discrimina-

of tests in the specialist setting confirm the diagno-

tion between an adrenal or gonadal source requires

sis by observing a failure of aldosterone suppression

imaging by CT or MRI and potential catheteriza-

in response to intravenous saline or fludrocortisone.

tion and sampling of the adrenal and ovarian veins.

Once a biochemical diagnosis has been made, the

The tumours are treated surgically with removal of

cause of excess aldosterone needs to be determined.

the offending adrenal gland.

Chapter 6: The adrenal gland / 117

Case history 6.3

Box 6.15 A pragmatic approach to

adrenal incidentalomas?

A physically active 23-year-old student is

• Exclude over-secretion of aldosterone,

referred with a blood pressure of

glucocorticoid, sex steroid precursors and

158/94 mmHg. On examination, body

catecholamines (see other sections)

mass index (BMI) is 20.5 kg/m². Serum

• Assess likelihood that it is a metastasis:

sodium was 144 mmol/L (144 mEq/L) and

serum potassium was 2.8 mmol/L

° Full history and examination

(2.8 mEq/L).

° Is it poorly demarcated on CT or MRI?

° Consider chest X-ray in smokers

• If >4 cm, risk of malignancy is increased,

What endocrine diagnosis should be

unilateral adrenalectomy advised

suspected?

• If <4 cm, hormone-negative and not

What biochemical screening test is

suspicious on imaging: follow-up with

required with what electrolyte

repeat investigation at 6 months and

preparation?

potentially annually thereafter if no change

Outline the subsequent investigation

or discharge

plans if the screening test is positive.

Answers, see p. 125

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is an auto-

somal recessive disorder (i.e. inactivating mutations

Other tumours of the adrenal cortex

in both copies of the gene are required for the phe-

Adrenocortical carcinoma

notype). The causative genes encode enzymes in the

The commonest malignant tumour of the adrenal

pathway to cortisol (see Figure 6.3, plus others not

cortex is metastatic. Primary adrenal carcinoma is

shown for simplicity, such as cytochrome P450

rare. The vast majority is functional (80%), and

oxidoreductase). This leads to cortisol deficiency,

most secrete a mixture of steroids characteristic of

diminished negative feedback at the anterior pitui-

different zones and best detected by mass spectrom-

tary and raised ACTH

(see Figure

6.4). High

etry. The clinical picture tends to be one of rapidly

ACTH and raised intermediaries ‘upstream’ of the

progressive Cushing syndrome and virilization

inactive enzyme increase flux through the remain-

accompanied by the more general effects of an

ing intact steroidogenic pathways. For instance,

aggressive tumour (e.g. weight loss, abdominal pain,

inactivating mutations in CYP21A2 account for

anorexia and fever). Most tumours have metasta-

90% of CAH and cause decreased cortisol and

sized by presentation so adrenalectomy is no longer

raised 17α-hydroxyprogesterone; in the presence of

curative. Mitotane, an adrenolytic drug, palliates

high ACTH, pathways are stimulated to convert

symptoms and can reduce tumour growth, but sur-

this build-up of CYP21A2 substrate to sex steroid

vival is poor; historically, 20% or less of patients

precursors and potent androgens. In addition to the

have survived 5 years. Newer trials with additional

cortisol deficiency, this causes:

agents are underway.

• Ambiguous genitalia in females at birth (Figure

6.10)

Incidentalomas

• Precocious puberty in males; and

An increasing problem is the management of

• Hirsuitism, menstrual irregularities and sub-

tumours identified on CT or MRI performed for

fertility in women.

other reasons (Box 6.15). These ‘incidentalomas’ are

common in individuals over 40 years, potentially

Many patients also have inadequate aldosterone

affecting 5% of individuals (Case history 6.4).

production

(‘salt wasting’ CAH); some do not

118 / Chapter 6: The adrenal gland

Case history 6.4

A 74-year-old man is referred to the gastroenterology clinic with a 6-month history of right

upper quadrant discomfort. His weight is steady, appetite maintained and there has been no

change in bowel habit. He is a non-smoker. His past medical history includes diet-controlled

type 2 diabetes diagnosed 4 years previously and mild hypertension for which he takes a

thiazide diuretic. On examination, his BMI is 27.3 kg/m² and blood pressure 154/82 mmHg.

Otherwise there is nothing to find. Serum sodium is 142 mmol/L (142 mEq/L), serum potassium

is 3.2 mmol/L (3.2 mEq/L), liver function tests are normal and HbA_1c is 7.2% (55 mmol/mol).

Upper abdominal ultrasound scan is unremarkable. The doctor orders CT of the upper

abdominal region, which is reported as showing no abnormality other than a 3.2-cm well-

defined mass with uniform appearance in the right adrenal gland. The left adrenal gland

appears normal. The gastroenterologist refers the patient to you as the endocrinologist.

What potential pathologies need to be considered to explain the findings in the adrenal

gland?

What investigations for hormone secretion are warranted?

If hormone secretion appears normal from the adrenal gland, what follow-up would you

suggest?

Answers, see p. 125

(‘simple virilizing’ CAH). Partial inactivation of

Case history 6.5

CYP21A2 can cause a late-onset form of CAH with

milder post-pubertal features in women.

A 3-day old 46,XX neonate with virilized

Neonates with hypotension and hyperkalaemia

external genitalia develops profound

need investigation, especially when females are viri-

hypotension and circulatory shock.

lized

(Case history 6.5). In CYP21A2 deficiency

basal ACTH is high, serum cortisol is low and 17α-

What is the most likely diagnosis?

hydroxyprogesterone is commonly greater than

What immediate therapy is required to

100 nmol/L (∼3300 ng/dL). On ACTH stimulation

replace a missing hormone?

testing (similar to testing for Addison disease; see

What other hormone may be missing?

Box 6.8), cortisol fails to rise significantly

[i.e.

<525 nmol/L (∼19 µg/dL)], but in CYP21A2 defi-

Answers, see p. 126

ciency serum, 17α-hydroxyprogesterone increases

substantially [commonly >300 nmol/L (10,000 ng/

dL)]. In rarer forms, mass spectrometry is useful to

detect which intermediates are increased, hence

Therapeutic use of glucocorticoids

which enzyme is inactive.

Treatment is with glucocorticoid (± mineralocor-

Glucocorticoids are used therapeutically through-

ticoid) to replace missing steroid hormones, restore

out life. Dexamethasone is used in premature labour

negative feedback on ACTH production and mini-

to stimulate fetal surfactant production. Post-natally,

mize androgen over-production. This can be complex:

potent synthetic glucocorticoids are used in a range

one extreme of treatment is bilateral adrenalectomy

of autoimmune and inflammatory disorders for

and life-long hydrocortisone and fludrocortisone

their immunosuppressive and anti-inflammatory

replacement.

properties. However, the morbidity and mortality

Chapter 6: The adrenal gland / 119

of stored hormones into the circulation (sometimes

called ‘neuroendocrine tumours’), such as phaeo-

chromocytoma, paragangliomas, carcinoids and gut

endocrine tumours (see later in this chapter and

Chapter 10).

Embryology and anatomy

In contrast to the outer cortex, the adrenal medulla

is derived from the neuroectoderm (‘neural crest’)

cells that migrate in a forward direction from the

peri-vertebral to the peri-aortic region (see Figure

6.1). Here, these cells predominantly give rise to the

autonomic chain of ganglia that innervate much of

the gut and blood vessels. However, some specialize

by invading the adrenal to form the chromaffin cells

of the adrenal medulla; both structures are inner-

vated by pre-ganglionic sympathetic neurones that

emanate from nerve roots T7-L3. Realizing this

common neural crest origin, it becomes easy to

understand why the clinical presentation of phaeo-

chromocytoma (tumour of the adrenal medulla) and

Figure 6.10 Ambiguous genitalia of a 46,XX infant

paraganglioma (tumour of the autonomic chain of

with congenital adrenal hyperplasia. Virilization in

ganglia) can be very similar (see later clinical section).

utero presented at birth with clitoral hypertrophy,

fusion of the labia and a urogenital opening at the

base of the phallus.

Catecholamine biosynthesis and

metabolism

The biosynthesis of catecholamines occurs in four

from Cushing syndrome illustrates that these agents

steps (Figure 6.12, upper half ). The hydroxylation

should only be used short-term and at the lowest

of tyrosine is rate-limiting and subject to negative

possible dose.

feedback by the downstream hormone products,

norepinephrine and dopamine. The two steps to

dopamine also occur in the substantia nigra of the

The adrenal medulla

brain stem - the cells that are lost in Parkinson

The adrenal medulla comprises chromaffin cells,

disease. The last step converting norepinephrine to

which are like post-ganglionic neurones. However,

epinephrine reflects the unusual embryology of the

rather than possessing distant nerve terminals, they

adrenal medulla. Expression of phenylethanolamine

respond to synaptic activation by releasing pre-

N-methyl transferase

(PNMT) is induced and

formed catecholamine hormones into the circula-

depends upon high concentrations of glucocorti-

tion (Figure 6.11). Norepinephrine (noradrenaline)

coid that are only present in the adrenal medulla

comprises 20% of circulating catecholamine, with

because of the centripetal drainage of venous blood

an additional biochemical step generating the

from the outer adrenal cortex. Stimulation of the

remaining 80% as epinephrine (adrenaline). The

chromaffin cell by pre-ganglionic neurones is medi-

hormones are stored intracellularly in secretory

ated by acetylcholine, and to a lesser extent serot-

granules complexed with proteins called chrom-

onin and histamine. Catecholamines are released

ogranins. The latter serve as clinical biomarkers of

and diffuse the short distance into the adjacent

endocrine tumours characterized by periodic release

blood vessels (Figure 6.11).

120 / Chapter 6: The adrenal gland

Fenestrated endothelial

Capillary

cell

Norepinephrine Tyrosine Epinephrine

Dopa

Dopamine

Golgi complex

Epinephrine

Mitochondrion

Norepinephrine

Rough endoplasmic

reticulum

Nucleus

Cholinergic synapse

Figure 6.11 The synthesis, storage and release of

norepinephrine can be further converted to

catecholamines from the chromaffin cell of the adrenal

epinephrine (G3) and released by exocytosis (G4).

medulla. The components of the storage granules (G),

Each cell has a cholinergic synapse where

including the chromogranins, are synthesized on the

acetylcholine initiates the train of events leading to

rough endoplasmic reticulum and packaged in the

exocytosis. Individual chromaffin cells usually only

Golgi complex. Dopamine enters a granule (G1) and

secrete either norepinephrine or epinephrine, but

is converted to norepinephrine, which can then be

phaeochromocytomas usually over-secrete both

released exocytotically (G2). Alternatively,

hormones.

Ending the effect of catecholamines relies on

6.3). Subtle differences in their action reflect

several different mechanisms (Figure 6.12, lower

relative affinities for the different adrenoreceptors,

half ). The most efficient method sees norepine-

predominantly α and β sub-types

1 and

phrine taken up by post-ganglionic sympathetic

Norepinephrine stimulates α and β1 receptors, and

nerve terminals, where it can be metabolized by

thus does not cause bronchodilation, a β2 response.

monoamine oxidase (MAO). Similar mechanisms

In contrast, the distribution of α and β2 receptors

in platelets take up mainly epinephrine. Circulating

in skeletal muscle beds can actually cause vasodila-

catecholamines are also metabolized in neuronal

tion (i.e. increased muscle blood flow) compared to

and other sites

(e.g. the liver) and metabolites

vasoconstriction in the gut. Thus, the combined

excreted in urine (Figure 6.12).

effects of both catecholamines raise blood pressure,

divert nutrients away from non-essential organs and

promote their delivery to muscles that are active in

Physiology

the ‘fight or flight’ response to danger.

Epinephrine and norepinephrine are major stress

Both hormones also raise blood glucose by

hormones responsible for the body’s ‘fright, fight

stimulating glycogenolysis in liver and muscle,

and flight’ responses following provocation (Table

and hepatic gluconeogenesis. Fatty acid release is

Chapter 6: The adrenal gland / 121

Table 6.3 The effects of catecholamines

Tyrosine

Tyrosine hydroxylase

Epinephrine

Norepinephrine

SYNTHESIS

DOPA

Systolic blood pressure Systolic and

Dopa decarboxylase

and heart rate rise

diastolic blood

pressure rise

Dopamine

(increasing mean

Dopamine β-hydroxylase

arterial pressure)

PNMT

Norepinephrine

Epinephrine

Gut motility decreases

Heart rate decreases

MAO

Circulation diverted to

COMT

DOMA

COMT

limb muscle beds and

away from the gut

COMT

Bronchodilation;

Normetanephrine

Metanephrine

reduction in mucus

MAO

secretion

VMA

Piloerection

DEGRADATION

Mydriasis (pupil

Urine

dilation)

Figure 6.12 The synthesis (upper half) and

degradation (lower half) of catecholamines. DOPA,

3,4-dihydroxyphenylalanine; dopamine, 3,4-dihydroxy

the chromaffin cells called

‘phaeochromocytoma’

phenylethylamine; PNMT, phenylethanolamine

(Case history

6.6). Similar excessive episodic

N-methyl transferase; MAO, monoamine oxidase;

COMT, catechol-O-methyl-transferase; DOMA,

release of catecholamines results from some para-

3,4-dihydroxymandelic acid; VMA, vanillylmandelic

gangliomas (previously sometimes called ‘ectopic

acid (3-methoxy-4-hydroxymandelic acid).

phaeochromocytomas’).

Components measured clinically in the urine are

shown in yellow.

Symptoms and signs

Catecholamine-secreting tumours are rare and can

occur sporadically or as part of familial syndromes

increased. These metabolic actions increase energy

(see multiple endocrine neoplasia in Chapter 10).

substrate availability, making catecholamines counter-

As a teaching aid, a ‘10% rule’ has been described:

regulatory hormones to insulin (see Chapter 12).

10% are malignant, 10% are ectopic to the adrenal

gland and 10% are bilateral. These points serve as

useful reminders that the vast majority of these

Clinical disorders

tumours are benign and paragangliomas may occur

Catecholamines from the adrenal medulla are dis-

outside the adrenal gland along the sympathetic

pensable. In bilateral adrenalectomy, glucocorticoid

chain. It used to be said that 10% were inherited,

replacement is mandatory, but catecholamine

although, with the wider availability of molecular

replacement is not required.

genetic testing and greater knowledge of causative

mutations, this is an underestimation of the 25-

30% of tumours with accompanying germline

Phaeochromocytoma

mutations (see below and Chapter 10). Excessive

The only important clinical disorder of the adrenal

unregulated catecholamine release occurs at inap-

medulla is overactivity caused by a tumour of

propriate times, resulting in unusual and distinctive

122 / Chapter 6: The adrenal gland

Treatment

Box 6.16 The triad of classical

Treating phaeochromocytoma has two steps: block-

symptoms in phaeochromocytoma

ing the effects of catecholamine excess using α- and

β-adrenoreceptor blockers, and then surgical

• Sweating

removal of the offending tumour. α-Blockade is the

• Throbbing bilateral headaches

first step to avoid a potential hypertensive crisis

• Palpitations

from unopposed α-adrenoreceptor stimulation (i.e.

if β-blockers had already prevented muscle vasodila-

tation). One example regimen is the introduction

of increasing doses of phenoxybenzamine followed

symptoms (Box 6.16). Hypertension is the most

by metoprolol, if needed, in the run-up to surgery.

common finding (90-100% of cases), which may

This preparation is mandatory as manipulation of

be constant

(in

∼50%, especially children) or

the tumour at operation can result in catastrophic

episodic.

release of stored catecholamines.

The frequency of symptomatic events can vary

from daily to monthly, which can make diagnosis

difficult. If suspicion is high, investigation should

Follow-up including the identification of

be repeated at intervals. Sweating, tremor, angina,

germline mutations

nausea and anxiety can also occur. Diabetes may

All tumours arise from genetic abnormalities in

have been recently diagnosed.

the affected cell type. However, in ∼25-30% of

catecholamine-secreting tumours, these mutations

Diagnosis

are present in the germline, meaning every cell in

Secretion is episodic. The commonest screening test

the body is affected and risk of recurrence or

to detect excess catecholamines is assay of urine

tumours in family members is hugely increased

collected over

24 h. Collections can be done on

(Table 6.4). Suspicious features demanding a rigor-

random days, starting after the first micturition of

ous family history, additional examination, and,

the day until the equivalent time the following day;

after counselling and consent, genetic testing are as

or, with infrequent symptoms, starting immediately

follows:

after an attack and continued for 24 h. Most labo-

ratories will assay a range of substances: metane-

• Bilateral tumours

phrine and normetanephrine, their parent hormones

• Paragangliomas

epinephrine and norepinephrine, and possibly the

• Previous catecholamine-secreting tumours

precursor, dopamine (Figure 6.12). This combined

• Young age at presentation

approach is helpful as it is unusual for catecholamine-

• Presence of other tumours.

secreting tumours to over-secrete one of the parent

hormones in isolation without the corresponding

Two syndromes of ‘multiple endocrine neo

metabolite. Occasionally, very large phaeochromo-

plasia

(MEN)’ have been described in particular

cytomas or paragangliomas (because they are extra-

detail

(see Chapter

10). Phaeochromocytoma

adrenal) escape the normal influence of cortisol on

most commonly associates with type

2 MEN.

PNMT and secrete an increased proportion of nore-

Catecholamine-secreting tumours are also part of

pinephrine. Once a biochemical diagnosis has been

Von Hippel-Lindau syndrome and neurofibroma-

made, imaging, ideally by MRI, aids localization.

tosis type 1.

In specialized centres, uptake scans with meta-

If genetic defects are found (Table 6.4), appro-

iodobenzylguanidine (mIBG) is possible (see Figure

priate life-long clinical follow-up is required with

4.9). PET scanning is becoming available in research

assessment of first-degree relatives. Historically, this

centres. Patients should be screened for diabetes or

has relied on annual 24-h urine screening (as above

glucose intolerance (see Chapter 11).

for diagnosis). However, current guidelines argue for

Chapter 6: The adrenal gland / 123

Table 6.4 Genetic defects predisposing to catecholamine-secreting tumours

Gene Associated syndrome Other associations

Inheritance of

germline mutations

RET

MEN2 (see Chapter

Medullary thyroid cancer, primary

10)

hyperparathyroidism; Marfanoid appearance

and mucosal neuromata (type B)

SDHB Familial paraganglioma Paragangliomas, commonly malignant,

anywhere along sympathetic chain; renal

cell carcinoma

SDHD Familial paraganglioma Paragangliomas, commonly benign,

anywhere along sympathetic chain

VHL

Von Hippel-Lindau

Haemangioblastomas of central nervous

system, kidney and retina; renal cell

carcinoma, café-au-lait spots, pancreatic

cysts

NF1

Neurofibromatosis type

Neurofibromata, optic nerve gliomas, axillary

1 (Von Recklinghausen

freckling, café-au-lait spots and skeletal

syndrome)

abnormalities

RET, RET proto-oncogene; SDHB, succinate dehydrogenase, subunit B; SDHD, succinate dehydrogenase, subunit D; VHL,

Von Hippel-Lindau tumour suppressor, NF1, neurofibromatosis type 1; MEN2, multiple endocrine neoplasia type 2; AD,

autosomal dominant.

more frequent analysis. In addition, plasma assays of

Case history 6.6

catecholamine metabolites, especially normetane-

phrine, are proving a more sensitive means of detect-

A 44-year-old man attended his doctor

ing excess hormone and are especially useful in

because of headaches. His partner

screening where excluding a tumour is the primary

attended the consultation and also

goal (i.e. a very low false-negative rate).

commented on several occasions during

Even in seemingly sporadic phaeochromocyto-

the last few months when he had gone

mas without known germline mutations, many

extremely pale and appeared ill at ease.

centres regard it as important and prudent to

Closer questioning elicited the presence of

perform annual follow-up with 24-h urine collec-

palpitations during these events, which

tion for catecholamine measurement.

lasted ∼15 min. Examination was

unremarkable except for a blood pressure

of 180/110 mmHg. The man was not

Therapeutic uses of catecholamines

overweight, took plenty of exercise and

Based on their physiology, catecholamines, particu-

had no significant past medical history.

larly epinephrine, are useful in clinical scenarios

that range from the trivial to the profoundly serious.

What diagnosis should be considered?

In intensive care medicine, catecholamine infusions

What investigations are appropriate?

can maintain blood pressure in septic shock. In

everyday life, their vasoconstrictive action makes

Answers, see p. 126

catecholamines useful nasal decongestants.

124 / Chapter 6: The adrenal gland

Key points

• The adrenal cortex and adrenal medulla

• The major hormones from the adrenal

develop as separate organs

medulla are the catecholamines,

• The adrenocortical hormones are

epinephrine and norepinephrine

aldosterone, cortisol and the sex steroid

• Phaeochromocytoma and paraganglioma

precursors

are tumours that over-secrete

• Excess and deficiency of adrenocortical

adrenomedullary hormones

hormones cause important disorders,

Cushing syndrome, Conn syndrome and

Addison disease

Answers to case histories

about steroid alert bracelets. Advice should

Case history 6.1

be given to double hydrocortisone doses

The patient has Addison disease as a result

during illness. If unable to take tablets (e.g. if

of autoimmune destruction of the adrenal

vomiting during an episode of

cortex. Decreased circulating volume has

gastroenteritis), the patient needs

caused hypotension associated with

intravenous treatment. Hydrocortisone is

dehydration and raised serum urea. The

absorbed ∼30 min after consumption.

pigmentation is caused by inadequate

This patient has an increased risk of

negative feedback from cortisol, leading to

autoimmune disease affecting other

corticotroph overactivity and increased ACTH

endocrine organs and cell types. This is

stimulating the MC1R. The pale areas are

exemplified by the vitiligo and family history

vitiligo, another autoimmune condition.

of thyroid disease. The haematology results

Addison disease is diagnosed by an ACTH

are suspicious of pernicious anaemia.

stimulation test with serum cortisol measured

Autoimmune destruction of the parietal cells

at 30 min. Putting aside slight variation

in the stomach that make intrinsic factor

between assay platforms and fluctuations in

prevents vitamin B₁₂ absorption. This causes

serum CBG, a response of greater than

defective red blood cell biosynthesis with the

525 nmol/L (∼19 µg/dL) occurs in 95% of the

presence of large red cells in the circulation

normal population; lower values increasingly

(‘macrocytosis’). Hypothyroidism is another

raise suspicion of Addison disease. Serum

cause of macrocytosis; however, this was

ACTH at baseline would be expected to be

excluded. Serum vitamin B₁₂ levels should

elevated. Plasma renin concentration or

be measured.

activity may also be increased secondary to

aldosterone deficiency.

Case history 6.2

Once diagnosed, the patient should be

commenced on hydrocortisone and,

The patient has signs and symptoms of

potentially, fludrocortisone. If there is concern

Cushing syndrome, which has precipitated

over Addisonian crisis, treatment should be

diabetes mellitus, centripetal weight gain and

started before diagnosis. The patient should

the cardinal feature of purple abdominal

be given a steroid alert card and informed

‘striae’. On closer examination, thin bruised

Chapter 6: The adrenal gland / 125

skin and proximal myopathy might be

guided by the likelihood of surgical

evident.

intervention if a unilateral source of the

Initial investigations aim to demonstrate

aldosterone excess is found. In this case,

glucocorticoid excess; midnight serum or

surgery is highly likely to be curative for the

bedtime salivary cortisol estimation, low-dose

hypertension and hypokalaemia in a young

dexamethasone suppression tests and 24-h

fit patient. This might not be the case in an

urine collections on three occasions can all

80-year-old with co-morbidities and in whom

be used to confirm glucocorticoid excess.

blood pressure is satisfactorily controlled on

In the absence of steroid medications, the

an MR antagonist. Adrenal venous sampling

undetectable ACTH means the Cushing

is undertaken by an interventional radiologist

syndrome is of adrenal origin. CT (or MRI) is

with cortisol and aldosterone measured on

appropriate (review Figure 4.7). CT scans

samples drawn from both adrenal veins and

can even suggest whether the lesion is lipid

the inferior vena cava. Cortisol levels at least

rich, consistent with a functional

twice those of the peripheral circulation are

adrenocortical adenoma.

proof that the catheter is/was correctly

positioned in the adrenal vein (some centres

Case history 6.3

have access to rapid assays allowing

intraprocedural assessment).

The patient has marked hypertension with

spontaneous hypokalaemia. This points

Case history 6.4

strongly to aldosterone excess, especially if

there are no other causes of potassium loss

The incidental abnormality in the right

such as diarrhoea or vomiting.

adrenal gland has the appearances of a solid

A serum aldosterone-to-renin ratio is

mass rather than an abscess or cyst. The

required to investigate whether this is

first question is whether the mass arises

primary aldosterone excess, i.e. Conn

directly from the adrenal gland or whether it

syndrome. Prior to this, potassium should be

is metastastic. There is little to suggest the

replaced to restore serum values to the

latter both in the history (e.g. no loss of

normal range and unrestricted salt intake

weight or appetite; normal bowel habit) and

should be recommended for the few days

the examination. If the mass arises from the

before testing. On the day of testing, the

adrenal gland then it could be cortical or

patient should be ambulant for ∼2 h after

medullary.

wakening, with blood drawn mid-morning

Before it is classified as a non-functional

after sitting down for ∼15 min.

‘incidentaloma’, several types of hormone

If the screening test is positive, a

excess need to be considered. It could be a

confirmatory biochemical test, such as

phaeochromocytoma secreting

intravenous saline challenge or

catecholamines, which could underlie both

fludrocortisone suppression test, should be

the hypertension and the diabetes. 24-h

performed. If a biochemical diagnosis is

urine collection for catecholamines would be

made, CT (or MRI) of the adrenals should be

a sensible screening test. If suspicion is high,

performed. If there is a clear Conn adenoma,

demonstrating normal serum

usually smaller than 2 cm in diameter,

normetanephrine would be the most

accompanied by clear biochemistry results,

sensitive way to exclude

then adrenal venous sampling is probably

phaeochromocytoma. The mass would be

not needed in a young patient. Non-

larger than average for a Conn tumour

functioning incidentalomas are unlikely at

secreting aldosterone, but the patient is

this age. If imaging is equivocal, then the

hypertensive and mildly hypokalaemic (the

decision to proceed to venous sampling is

most likely cause of these findings is

126 / Chapter 6: The adrenal gland

essential hypertension treated by thiazide

hospital setting. If similar levels persisted,

diuretic). Measuring the aldosterone-to-renin

antihypertensive therapy should be optimized

ratio would screen for primary

to lower blood pressure to less than

hyperaldosteronism. The hypertension,

140/80 mmHg.

diabetes and slightly raised BMI could also

be explained by cortisol excess. Cushing

Case history 6.5

syndrome should be excluded by any of the

The most likely diagnosis is CAH caused by

screening tests described in the chapter.

mutations in both copies of CYP21A2.

Finally, measurement of sex steroid

Intravenous hydrocortisone and

precursors, androstenedione and DHEA (or

intravenous fluids are required. Ideally, a

DHEAS), should be undertaken.

blood sample should be taken beforehand

This tumour diameter is less than 4 cm and

for cortisol and ACTH, but immediate therapy

therefore there is a low risk of malignancy.

is mandatory.

Follow-up strategies for incidental tumours

Aldosterone may also be lacking if this is

with no detectable hormone secretion vary.

salt wasting rather than a simple virilizing

One approach would be to repeat

CAH. CYP21A2 catalyzes steps in the

investigations after 6 months, which, if

pathway to both cortisol and aldosterone.

normal, could then be monitored annually. If

excessive hormone secretion was not

Case history 6.6

detected on two occasions, it is unlikely to

develop subsequently. Some

The history and the finding of hypertension

endocrinologists discharge such patients.

are suggestive of a catecholamine-secreting

Repeat imaging at 6 months looks for

tumour.

growth, which would press the case for

24-h urine collection for excreted

surgical removal, most likely via the

catecholamines and their metabolites should

laparoscopic approach.

be undertaken on several occasions, ideally

The patient can be reassured for now on

incorporating an episode. Given the

the original symptom of discomfort.

convincing history, it would be reasonable to

Reinforcement of good diabetes care is

measure serum normetanephrine as a

important. If future medical intervention

normal result practically excludes a

became warranted, metformin would be the

catecholamine-secreting tumour. In addition,

appropriate first-line agent. Assessment of

electrocardiography and echocardiography

fasting lipids would be prudent given

might be considered. The latter may show

diabetes and hypertension, with statin

left ventricular hypertrophy. Only if

therapy warranted according to published

catecholamine excretion is increased, should

risk tables (e.g. in the British National

the adrenal glands be imaged by CT or MRI.

Formulary). A series of further blood pressure

Although more restricted in availability, mIBG

measurements would be sensible outside the

scans delineate phaeochromocytoma tissue.

128 / Chapter 7: Reproductive endocrinology

To recap

■ Gonadal regulation depends on both negative and positive feedback loops, the principles of

which are introduced in Chapter 1

■ Understanding gametogenesis requires knowledge of meiosis, covered in Chapter 2

■ The most important gonadal hormones are steroids; review the general principles of steroid

hormone biosynthesis described in Chapter 2

■ The effects of gonadal steroid hormones are diverse; however, they are all based upon the

same principles of steroid hormone action introduced in Chapter 3

Cross-reference

■ Ovarian and testicular function is dependent upon the function of the hypothalamus and

anterior pituitary gonadotroph, which is covered in Chapter 5

■ Development of the gonad is intimately linked to that of the adrenal cortex (see Chapter 6),

resulting in overlapping steroidogenic pathways that affect normal physiology and several

clinical disorders (e.g. congenital adrenal hyperplasia or sex-steroid secreting tumours)

Embryology of the reproductive

Box 7.1 The early development of

organs

sexual phenotype

Reproductive development in utero can be broken

At fertilization

down into two processes: sex determination,

• Spermatozoan with either an X or a Y

whereby the bipotential gonad becomes either the

chromosome determines sex by fusing

testis or ovary; and sex differentiation, the male

with an X-bearing ovum

or female phenotype that unfolds according to the

presence or absence of male hormones from the

At ∼4 weeks of development

testis. Both are remarkable for normally showing

• Proliferation of cells in the urogenital ridge

complete dimorphism, i.e. one or the other but not

creates the bipotential gonad

both, without which our species would be a repro-

ductive failure.

At ∼7 weeks of gestation (sex determination)

• 46,XY gonad becomes a testis

Sex determination

• 46,XX gonad remains as an ovary

Chromosomal sex depends on whether the fertiliz-

ing spermatozoon bears an X or a Y chromosome.

However, the translation of chromosomal sex into

(review Chapter 2), foremost amongst which are

gonadal sex depends on events during the second

Sex-determining region of the Y chromosome (SRY)

month of gestation (Box 7.1). Initially, there is no

and SRY high mobility group box family member

morphological difference between

46,XX and

9 (SOX9). These regulators orchestrate a range

46,XY gonads (Figure 7.1a). However, at ∼7 weeks

of gene expression that creates a testis. During

of development, the cells of the male gonad start to

this period, called ‘sex determination’, the cells of

express critical genes encoding transcription factors

the 46,XX gonad undergo far less morphological

130 / Chapter 7: Reproductive endocrinology

change. Although genes have been discovered that

Box 7.2 Differentiation of the

influence ovarian development, the process is still

internal genitalia

defined by relative lack of activity.

Future gonadal function also relies on germ cells

Female

generating either spermatozoa or ova. Prior to and

• Müllerian duct derivatives:

during sex determination, primordial germ cells

° Fallopian tubes (oviducts)

migrate from the wall of the yolk sac through the

° Uterus

gut mesentery into the gonad. In males, the forma-

° Upper third of the vagina

tion of Sertoli cells within testicular cords induces

mitotic arrest in germ cells. In females, prolifera-

Male

tion, some atresia and, ultimately, entrance into the

• Wolffian duct derivatives:

first stage of meiosis over the next few weeks deter-

° Rete testis

mines the total number of ova for reproductive life.

° Epididymis

° Vas deferens

Sexual differentiation

The differentiation of the sexual organs occurs from

two pairs of ducts and the urogenital sinus. Male

thral folds to fuse in the midline, enclosing the

events progress rapidly so that major development

terminal urethra, and the primitive genital tubercle

is complete by the end of the first trimester. Without

to expand and elongate into the penis. The labio-

high levels of male hormones during this period,

scrotal swellings migrate posteriorly and fuse

default female differentiation occurs.

together as the scrotum into which the testes finally

The internal genitalia originate from the bilat-

descend (Figure 7.3). DHT also stimulates prostate

eral Müllerian (also called mesonephric) ducts that

formation.

drain the primitive kidney (the mesonephros) and

In the female, relative lack of androgen lessens

the Wolffian ducts that form along the length of

growth of the genital tubercle as the clitoris and

each urogenital ridge (Figure 7.1b). In each sex, the

retains patency between the urethral and labioscro-

pair of ducts that is not required regresses, while the

tal folds as a vaginal opening flanked by the labia

other matures into recognizable parts of the adult

minora and majora (Figure 7.3).

anatomy (Box 7.2). In the male, anti-Müllerian

After 12 weeks the testes descend under the dual

hormone (AMH), also known as Müllerian inhibit-

hormonal influence of insulin-like 3 (INSL3) and

ing substance

(MIS), from Sertoli cells causes

androgen, while the latter also causes continued

regression of the Müllerian ducts (Figure 7.1c). In

growth of the penis.

its place, androgen, thought to be testosterone,

from the interstitial Leydig cells, virilizes the

Disorders of sex development

Wolffian ducts into the structures that transport

and mature spermatozoa from the testicular cords

The more severe the disruption or complete the sex

to the seminal vesicles and prostate (Figure 7.2 and

reversal at birth, the earlier in utero the problem

Box 7.2). In the female, the absence of AMH and

occurred. Clinical nomenclature used to be based

the much lower androgen levels allow growth of the

on the very rare disorder of hermaphroditism—the

Müllerian ducts, while the Wolffian system regresses

presence of both testicular and ovarian tissue causing

(Figures 7.1c and 7.2).

aspects of both male and female sexual develop-

5α-dihydrotestosterone (DHT) is required for

ment. These conditions are now classified as 46,XY

the urogenital sinus to deviate from female differ-

46,XX disorders of sex development (DSD).

entiation. DHT forms in target tissues by the action

Hermaphroditism is now termed 46,XX ovotesticu-

of type 2 5α-reductase (SRD5A2) on high levels of

lar DSD. Completely disrupted gonad formation

testosterone (review Table 3.2; see Figure 7.7). It

(streak gonads) in chromosomal males is 46,XY

virilizes the external genitalia by causing the ure-

complete gonadal dysgenesis (CGD) (Box 7.3).

Chapter 7: Reproductive endocrinology / 133

Box 7.5 Contentious issues in the

management of disorders of sex

development

• To what extent has the developing brain

been virilized by inappropriate androgen in

46,XX DSD and with what future

consequences on sexuality and behaviour?

Knowledge is limited of ‘normal’ central

nervous system virilization during 46,XY

development

• To what extent should surgery reconstruct

the external genitalia in 46,XX DSD, at

what age and under whose consent?

° Neonatal reduction of clitoral size could

Figure 7.4 Genitalia of a 2-year-old with 46,XY

create a visually more ‘normal’ female

disorder of sex development due to mutation of the

appearance, but nullify future sexual

SRD5A2 gene encoding type 2 5α-reductase. Note

sensation. Surgery is now undertaken at

the genital ambiguity and swelling in the left ‘labium’

an older age when reconstruction is

due to a testis.

more sympathetic to future sexual needs

and some form of direct patient consent

can be gained

Box 7.4 Defining the diagnosis in

46,XX Disorder of sex development

disorders of sex development

Translocation of the SRY gene onto the X chromo-

some can cause testicular development in 46,XX

• What is the extent of under-development

individuals. Exposure of female fetuses with normal

or sex reversal?

gonads to androgens before week 12 of pregnancy

° Complete - early fetal influence

risks virilization with fusion of the urethral folds,

° Incomplete - later fetal influence, e.g.

posterior migration of the labioscrotal folds and

clitoromegaly or hypospadias

growth of the phallus. Later exposure is less damag-

• Are there associated clinical emergencies

ing, more limited to phallic growth as clitor

(salt-wasting hypoadrenalism in CAH, see

omegaly. The most common

46,XX DSD is

Chapter 6)?

congenital adrenal hyperplasia (CAH) caused by

• Are there other congenital abnormalities?

21-hydroxlase (CYP21) deficiency, which may pre

• Is there a family history of similar events?

sent with Addisonian crisis (see Case History 7.1

and Chapter 6). As there is no abnormality in the

Answering two questions is particularly

ovary or internal genitalia, reproductive function

important

may be possible after appropriate treatment.

• What is the karyotype?

Chromosomal disturbances without obvious

° Is it 46,XY or 46,XX DSD? (or possibly

phenotypes beyond the gonad may not present

45,XO may be suspected)

as DSD at birth but as later failure of puberty

• In 46,XY DSD, is there a uterus?

(e.g. Klinefelter syndrome/47,XXY), hypogon

° Yes - deficient action of both androgen

adism or premature ovarian failure

(e.g. Turner

and AMH

syndrome/46,XO). Turner syndrome usually has

° No - deficient androgen action but

other features

(see later section on amenorrhoea

appropriate AMH

with absent oestrogen).

134 / Chapter 7: Reproductive endocrinology

Case history 7.1

Box 7.6 The testis has two

important functions

The paediatric endocrinologist receives a

• Synthesis of androgens - the male sex

request from the neonatal unit for ‘routine

hormones

review of a baby boy born the previous

• Production of gametes - spermatogenesis

day with ambiguous external genitalia’.

The parents are cousins and this is their

first child. The call is followed later in the

day by an urgent referral because the

spermatids and spermatozoa. The tubules of each

baby has become very unwell and is

testis lead via the rete testis to the epididymis, where

hypotensive. On arrival, a junior doctor is

maturation of the spermatozoa occurs, and on to

in the process of taking a blood sample

the vas deferens.

from the baby.

Spermatogenesis

What diagnosis was the endocrinologist

The primordial germ cells that invade the embry-

considering and why were serum urea

onic gonad enter mitotic arrest as spermatogonia

and electrolytes, ACTH, cortisol,

until puberty, after which they become reactivated

17α-hydroxyprogesterone, renin and

by hormones (see following section on puberty).

aldosterone requested on the blood

During mitosis (see Figure 2.1), the basal sperma-

sample?

togonial stem cell renews itself and gives rise to a

What emergency treatment is needed?

diploid daughter cell (the primary spermatocyte)

The blood results confirm the

that moves into the adluminal compartment (Figure

endocrinologist’s suspicion. What is

7.6). Primary spermatocytes then undergo the first

the baby’s karyotype?

meiotic division to form haploid secondary sperma-

What mistake was made in ascribing a

tocytes

(review Figure

2.1). The second meiotic

sex identity to the baby at birth?

division produces spermatids, which gradually

mature into spermatozoa. An intimate association

Answers, see p. 162

with the Sertoli (‘nurse’) cells is essential for this

process. The spermatozoa are extruded into the

lumen of the tubule and pass to the epididymis,

The male reproductive system

following which they become mixed with the secre-

tions of the seminal vesicles, prostate and bulbo

urethral glands at the time of ejaculation. Volumetric

Morphology and function of the testis

and microscopic analysis of the semen is an impor-

The testis can be thought of as two compartments:

tant part of assessing clinical testicular function

sperm-producing seminiferous tubules that develop

because normal measurements strongly imply phys-

from the testicular cords, largely determining tes-

iological follicle-stimulating hormone (FSH) and

ticular volume and requiring an operating tempera-

androgen secretion, and anatomical integrity (see

ture in the scrotum a few degrees below that of the

next sections). Semen analysis can be part of inves-

body’s core; and an interspersed interstitium con-

tigating hypogonadism or subfertility (Box 7.7; see

taining lipid-laden, steroidogenic Leydig cells

later clinical sections).

(Figure 7.5 and Box 7.6). The seminiferous tubules

contain the germ cells and the Sertoli cells (Figure

Androgen biosynthesis, secretion and

7.6). Tight junctions between adjacent Sertoli cells

metabolism

produce two compartments: a basal compartment

with spermatogonia (self-renewing stem cells), and

Androgen biosynthesis in the Leydig cell follows the

an adluminal compartment for the spermatocytes,

same path by which cholesterol is converted to the

136 / Chapter 7: Reproductive endocrinology

Box 7.7 Semen analysis (WHO

Dehydroepiandrosterone

standards)

• Critical to investigation of infertility (see last

section of chapter)

• Very useful bioassay for normal testicular

function

• Standards within 60 min of ejaculation:

Androstenedione

° Volume > 2.0 mL (usually 2-6 mL)

Type 3

° pH 7.2-8.0

17β-hydroxysteroid

dehydrogenase

° Concentration > 20 million/mL

(HSD17B3)

° Total sperm count > 40 million

° Morphology > 30% normal forms

° Motility > 50% with forward progression

(or >25% with rapid progression)

° Vitality > 75%

TESTIS

° White blood cells < 1 million/mL

• Useful clinical terms:

Testosterone

° Normozoospermia: normal as defined

above

Type 2 5α-reductase (SRD5A2)

° Oligozoospermia: spermatozoa present

but <20 million/mL

Target tissue

° Azoospermia: no spermatozoa in

(e.g. external

ejaculate

genitalia and

prostate)

° Aspermia: no ejaculate

potent DHT (Table 3.2 and Figure 7.7). There are

5α-dihydrotestosterone

two isoforms of SRD5A, type 1 (SRD5A1) and type

2 (SRD5A2) encoded by different genes. SRD5A2

Figure 7.7 The biosynthesis of androgens in Leydig

functions in the external genitalia and prostate.

cells. Earlier steps can be reviewed in Figure 2.6.

DHT binds with greater affinity than testosterone

to the AR. The DHT-AR complex then mediates

androgen action by regulating the transcription of

rium dynamics of androgen binding to protein

downstream target genes (review Figures 3.18 and

mean that ∼50% of circulating testosterone has

3.20). As well as forming DHT, testosterone may

the potential to enter target cells (‘bioavailable’).

also be aromatized by the cytochrome P450 enzyme,

Testosterone secretion also has some diurnal varia-

CYP19, to oestradiol in target cells (see Figure 2.6

tion, falling later in the day. Therefore, borderline

and Table 3.2); or, alternatively, metabolized to deg-

low serum measurements from afternoon clinics

radation products that are excreted in the urine. The

should be repeated at 9 am.

conversion of testosterone to oestradiol is important

for normal bone health in men.

Regulation of testicular function -

Clinical laboratories measure total serum testo-

the hypothalamic-anterior

sterone; DHT is less commonly assayed. In the

pituitary - testicular axis

circulation, testosterone is largely protein bound

to albumin and sex hormone-binding globulin

The testis is regulated by the two pituitary gonado-

(SHBG) with only ∼2% circulating free (i.e. directly

trophins, FSH and luteinizing hormone (LH), both

capable of entering cells). In practice, the equilib-

of which act via cell surface G-protein-coupled

Chapter 7: Reproductive endocrinology / 137

receptors predominantly linked to adenylate cyclase

down’ the reproductive endocrine axis in both

second messenger systems

(review Chapter

3).

men (e.g. to provide chemical castration in prostate

Testosterone biosynthesis is stimulated by pulsatile

cancer) and women (to treat oestrogen-responsive

LH, particularly at the rate-limiting step of catalysis

breast cancer; see Chapter 10).

by the cholesterol side-chain cleavage enzyme

Testosterone inhibits the release of LH (more

(CYP11A1). LH-induced testosterone diffusing

than FSH), with a minor contribution from periph-

from the Leydig cells acts along with FSH on the

erally converted oestradiol and DHT (Figure 7.8;

Sertoli cells to stimulate spermatogenesis (Box 7.8).

review Figure

1.4). The secretion of FSH from

The secretion of LH and FSH is regulated by

gonadotrophs is selectively inhibited by the Sertoli

gonadotrophin-releasing hormone

(GnRH, also

cell hormone, inhibin. Inhibin comprises α- and

known as LHRH); a decapeptide released by the

β-peptide chains, linked by disulphide bonds.

hypothalamus in pulses every 90 min (Figure 7.8).

Different types of β-chain generate two forms of the

The pulsatility is important to the extent that con-

whole protein, called inhibin A and inhibin B.

tinuous GnRH inhibits LH and FSH release and

Inhibin B is of major physiological relevance; it is

can be used clinically as a constant infusion to ‘shut

produced by the testis under stimulation by FSH

and creates a complete negative feedback loop.

Phases of testicular function and

Box 7.8 Major functions of the

reproductive development after birth

gonadotrophins

Only by understanding normal development can

• FSH - spermatogenesis

abnormality be correctly diagnosed during the dif-

• LH - androgen biosynthesis

ferent phases of life.

Figure 7.8 The

hypothalamic-anterior

Circadian

PRL

Stress

rhythm

pituitary-testicular axis.

Negative feedback at the

gonadotroph and

hypothalamus is complex

Hypothalamus

and involves: 5α-

dihydrotestosterone (DHT)

and testosterone on

luteinizing hormone (LH);

and inhibin, testosterone

GnRH (pulsatile)

PRL

Peripheral

and oestrogen on follicle-

tissues

stimulating hormone (FSH).

Prolactin (PRL) exerts a

5α-reductase

negative influence on

pituitary

DHT

gonadotrophin release,

(gonadotroph)

Testosterone

Inhibin

Oestradiol

probably via altering

aromatase

gonadotrophin-releasing

FSH / LH

hormone (GnRH) pulsatility

and action. Stress inhibits

GnRH release and action at

least in part by stimulating

PRL.

Testes

Spermatogenesis

138 / Chapter 7: Reproductive endocrinology

Neonatal life and childhood

patient becomes hypogonadal. Other aspects, such

During the first year of life, gonadotrophin levels

as maintenance of muscle mass and sex drive,

rise, providing a surge in testosterone and inhibin

require an ongoing supply of androgen. Beard

secretion of uncertain significance. During child-

growth is only likely to slow rather than stop if

hood, gonadotrophin secretion is low because of the

androgen is lost later in life. In old age testosterone

very sensitive negative feedback from the testis.

usually remains in the normal range. However,

However, occasional nocturnal pulses of LH and

levels do fall slightly and circadian rhythm is dimin-

FSH occur in young children, the frequency and

ished, which, when pronounced, has recently been

amplitude of which gradually increase with advanc-

described as a new syndrome of ‘late-onset male

ing years. By 9-11 years, children normally experi-

hypogonadism’.

ence regular nocturnal pulses of gonadotrophins

as a result of increased GnRH secretion and gona-

Clinical disorders

dotroph sensitivity. Ultimately, this stimulates

sufficient sex steroid to initiate secondary sexual

Hypogonadism

development and entrance into puberty. Note that

The major clinical disorder of the testis is underac-

minor signs of androgen action, such as some emer-

tivity - ‘hypogonadism’. Its presentation in adults

gent axillary and pubic hair, are a normal reflection

may occur as a result of primary (i.e. testicular),

of adrenarche (review Chapter 6).

Box 7.9 The effects of rising

Puberty

androgens at puberty

Male pubertal development is categorized into five

Tanner stages (Figure 7.9). Most of the changes

• Skeletal muscle growth

reflect rising concentrations of testicular androgens

• Lengthening and development of the

from an increased number and size of Leydig cells

larynx/deepening of the voice

(Box 7.9). However, in addition to penile growth,

• Pubic hair and beard growth

the onset of puberty can also be detected by an

• Sebaceous gland activity and odorous

increase in testicular volume following maturation

sweat

of the seminiferous tubules and the onset of sper-

• Thickened and pigmented skin over

matogenesis (Figure 7.9).

external genitalia

• Increased size of the prostate, seminal

vesicles and epididymis

Adulthood and old age

• Epiphyseal fusion and termination of linear

The effects of puberty are largely permanent; a

growth

deepened (‘broken’) voice does not regress if a

Figure 7.9 The stages of

Stage 1: Preadolescent genitalia, no pubic hair or

pubertal development in

breast development

males and females as

Stage 2: Scrotal reddening; testicular enlargement (

)

defined by Tanner.

Breast bud, increased areola diameter (

)

Straight, pigmented pubic hair

Stage 3: Penile and testicular growth; scrotal darkening (

)

Increase in breast and areola size, same contour (

)

Darker, coarser, curlier hair

Stage 4: Penile (and glans) growth in length and breadth (

)

Projection of areola and nipple (secondary mound) (

)

Adult hair but restricted coverage

Stage 5: Adult genitalia and hair distribution

Projection of papilla, areola and breast of same contour (

)

Chapter 7: Reproductive endocrinology / 139

secondary (i.e. pituitary) or tertiary (i.e. hypotha-

Other questions should address potential trauma

lamic) causes. In practice, the latter two can be

or infection, orchidectomy, previous chemotherapy

largely categorized together (Case history 7.2).

or radiotherapy, alcohol intake and anabolic steroid

abuse (present or past) (Box 7.11). Performance

enhancing drug use is under-recognized and, while

Symptoms and signs

current use would not cause loss of muscle bulk (the

Understanding normal physiology and hormone

opposite is the case), it would cause infertility and

action predicts the symptoms of hypogonadism

the testes to shrink through secondary hypogonad-

(Box 7.10). The history should take special care to

ism. Wider questioning should consider other

document two aspects of earlier development:

causes of secondary or tertiary hypogonadism and

whether other pituitary hormones might be present

• Was virilization complete at birth

(see earlier

in excess (e.g. prolactin) or absent (e.g. in panhypo-

section on 46,XY DSD)?

pituitarism) (review Chapter 5). Kallman syndrome

° For instance, hypospadias might indicate

results from inactivating mutation in a range of

androgen deficiency in utero:

genes. There is aberrant migration of the GnRH-

☐ Did the patient have to sit to urinate as a

producing neurones and a failure of smell (anosmia).

child?

Other specific causes of secondary hypogonadism

° Was testicular descent complete or was surgical

include haemochromatosis (does the patient also

intervention necessary?

have diabetes?) or Prader-Willi syndrome (is there

• The second important time point is puberty:

morbid obesity? See Chapter 15). Opiate use can

° Did puberty begin and progress at the same

also cause secondary hypogonadism.

time and rate as for his peers?

Examination should assess the degree of viriliza-

tion (Box 7.10), the existence and size of both testes

correctly positioned in the scrotum, and signs from

Box 7.10 Clinical features of male

other hormone axes and organ systems that might

hypogonadism

potentially point to the diagnosis (e.g. Does the

patient have acromegaly? Can the patient smell?).

Post-puberty

• Loss of libido

Investigation and diagnosis

• Subfertility/abnormal semen analysis (see

Primary hypogonadism is defined by low serum

Box 7.7)

testosterone, most commonly assayed as total testo-

• Decreased muscle mass and exercise

sterone, and raised gonadotrophins. Sub-clinical

tolerance; tiredness

(i.e. no symptoms), subtle or incipient primary

• Decreased shaving frequency

hypogonadism might be reflected by serum testo-

• Smooth skin, loss of pubic hair

sterone in the lower half of the normal range

• Small, soft testes, possibly not fully

with raised gonadotrophins. Equivocal testosterone

descended into scrotum

values from afternoon clinics should be repeated at

• Gynaecomastia

9 am to allow for diurnal variation. Serum total

• Decreased bone mineralization, e.g.

testosterone is also influenced by SHBG and

osteoporosis or osteopaenia

albumin, measurement of which allows estimated

calculation of free testosterone levels (several online

At (or dating back to) puberty

calculators are freely available). These calculations

• Failure of voice to deepen

can be important as low SHBG (e.g. in obesity or

• Failure of testicular enlargement and penile

hypothyroidism) lowers total testosterone and can

growth

cause diagnostic confusion. In primary hypogonad-

• Lack of scrotal pigmentation

ism, raised LH more sensitively reflects loss of

• Eunuchoidism (arm span > height)

testosterone negative feedback; FSH is primarily

• Delayed bone age

regulated by inhibin B, but this Sertoli cell hormone

140 / Chapter 7: Reproductive endocrinology

is not frequently available as a clinical assay. After

Box 7.11 Causes of male primary

confirming primary hypogonadism, the cause needs

hypogonadism/testicular failure

to be determined (Box 7.11). Obtaining the karyo-

type may define chromosomal disorders.

• Maldescended or undescended testes:

In secondary or tertiary hypogonadism, normal

° Common cause

gonadotrophin levels are inappropriate and patho-

° 10% risk of malignancy

logical when accompanied by unequivocally low

• Inflammation:

serum testosterone (i.e. the physiological response

° Mumps orchitis

should be raised LH and FSH) (Box 7.12). All the

° Trauma

other anterior pituitary hormone axes should be

• Post-chemotherapy or post-radiotherapy

investigated and the pituitary delineated by mag-

- semen storage advisable pre-treatment

netic resonance imaging (MRI; review Chapter 5

for future fertility

and see Figure 4.8). In younger patients, congenital

• Drugs - rare side-effect of commonly used

deficiency needs to be excluded, as does craniophar-

drugs such as HMGCoA reductase

yngioma, a histologically benign but erosive tumour

inhibitors (‘statins’)

derived from cells thought to have lined Rathke’s

• Anabolic steroid abuse

pouch. Although rarely performed, a GnRH test,

• Alcohol

where GnRH is injected and LH and FSH are

• Chronic illness

measured at baseline and after 30 min, distinguishes

• Autoimmune disorder

hypothalamic or tertiary

(greater than two-fold

• Chromosomal disorders:

increase in serum LH and FSH) from pituitary or

° Klinefelter syndrome (47,XXY; 1:500

secondary (little or no LH or FSH response) causes

males), possible intellectual impairment

of hypogonadism.

° Others rare (47,XYY; 46,XX with SRY

Hypogonadism from pathology at any level of

translocation)

the hormone axis would be expected to cause an

• Idiopathic/unknown

abnormal semen analysis (e.g. oligozoospermia or

azoospermia; see Box 7.7). Conversely, a normal

semen analysis should give reassurance in the face

of dubious symptoms and signs and equivocal

Box 7.12 Distinguishing primary

blood results. Gaining a prescription for testoster-

and secondary or tertiary male

one replacement (see below) can be a motivation for

hypogonadism

individuals interested in performance enhancing

• Low testosterone/high LH and FSH =

drugs. Once hypogonadism is diagnosed, bone den-

testicular cause (primary)

sitometry (a dual energy X-ray absorptiometry or

• Low testosterone/normal or low LH and

‘DEXA’ scan) assesses the consequence of androgen

FSH = pituitary or hypothalamic cause

deficiency on bone mineralization (see Chapter 9).

(secondary or tertiary)

Treatment

‘If it is missing, replace it’: give testosterone. As

hand-washing. Transbuccal absorption is ineffective

androgens are removed by first-pass metabolism

for most patients. Monitoring replacement therapy

through the liver, oral preparations are relatively

should aim for a serum testosterone in the normal

ineffective at delivering testosterone to the systemic

range. Serum LH can become normalized. For

circulation. The mainstay has been depot intramus-

monthly depot testosterone injection, total serum

cular injection, which lasts between 3 and 4 weeks.

testosterone is commonly measured immediately

Newer preparations last approximately 3 months,

prior to an injection. This ‘trough’’ value should be

superseding much of the use of testosterone

at the low end of the normal range.

implants. Transdermal gel preparations are applied

Supra-physiological androgen replacement

daily after washing and before dressing, followed by

carries risk. Polycythaemia (a raised red blood cell

Chapter 7: Reproductive endocrinology / 141

count) increases the risk of thrombosis, and stimu-

Testicular tumours

lation of the prostate may promote prostatic hyper-

Testicular tumours occur at all ages. The type of

trophy or accelerate androgen-dependent prostatic

tumour is age-dependent (Box 7.13). Incidence is

cancer. Full blood count (FBC), haematocrit and

raised in undescended or dysgenetic testes (∼five-

serum prostate-specific antigen (PSA; an imperfect

fold; see Chapter 10). Testicular germ cell tumours

biomarker of prostate cancer) are measured at least

are associated with extra copies of the short (p) arm

annually at follow-up appointments.

of chromosome 12, where several genes important

When fertility is desired in secondary or tertiary

for germ-cell proliferation are located

(review

hypogonadism, testosterone is exchanged for twice-

Chapter 2). Tumours of Sertoli or Leydig cells are

weekly injections of human chorionic gonado-

less common.

trophin (hCG) as a mimic for LH and, if needed

Tumours usually present as painless testicular

to achieve spermatogenesis, human menopausal

enlargement; however, they metastasize early.

gonadotrophins (hMG; a mimic for FSH) (see last

Reticence regarding the need to consult a physician

section of this chapter). Over the course of a few

is common; the cyclist Lance Armstrong thought a

months, these hormones stimulate the quiescent

grapefruit-sized swelling was a consequence of

testes into active steroidogenesis and spermatogen-

trauma from his saddle. Thus, education to self-

esis. This therapy is not the first-line method for

examine is as important for men as breast-care is for

replacing testosterone as it requires regular injection

women. For functional Leydig cell tumours, abnor-

and is more expensive.

mal sex steroid production is usually obvious as

virilization

(e.g. precocious puberty) or feminiza-

tion

(e.g. gynaecomastia, see below). For non-

Case history 7.2

seminomatous germ cell tumours, serum hCG and

α-fetoprotein (AFP) are very useful as they fall with

A 35-year-old man was referred to the

successful treatment and can be used as serum

endocrinologist after his partner had

biomarkers.

persuaded him to see his doctor. His

Orchidectomy is important, if only for debulk-

partner had commented that the patient

ing tumour mass, and may need to be bilateral.

had no interest in sex, had lost interest in

Chemotherapy is very successful and combina

social life and was commonly asleep in

tions of vinblastine, bleomycin, etopiside and cis-

the evenings. Total serum testosterone

platin cure most tumours. Prior cryopreservation of

was 3 nmol/L (∼86 ng/dL) with an SHBG in

sperm allows future in vitro fertilization (IVF) if

the upper part of the normal range. Levels

surgery and chemotherapy render the patient infer-

of both gonadotrophins were three times

tile (see final section). Androgen replacement may

the upper limit of normal. On further

be needed for primary hypogonadism (see previous

questioning, the man, who was tall, had

section).

never really felt much sex drive. He only

needed to shave once a week to avoid

facial hair growth. On examination,

bilateral gynaecomastia was noted and

both testes were small and soft.

Box 7.13 Testicular tumours of

germ cell origin

Where is the site of pathology?

What chromosomal disorder might this

Embryonal carcinoma or teratocarcinoma

be and how might this be investigated?

• Tends to affect children

What treatment and advice are needed?

• hCG and AFP are useful serum markers

What abnormality might a DEXA scan

indicate?

Seminoma

• Tends to occur in early adulthood or old

Answers, see p. 163

age

142 / Chapter 7: Reproductive endocrinology

Gynaecomastia

short-lived. A similar increase commonly follows

puberty. It can be unilateral and painful, although it

Gynaecomastia is defined as the development of

usually involutes by the end of the teenage years.

breast tissue of greater than 2 cm diameter in males.

Gynaecomastia can also occur in old age because of a

It can be physiological or represent abnormal sex

variety of factors, including a rise in SHBG, reduced

hormone production or metabolism (Table 7.1).

androgen availability or increased aromatization to

Enlargement of breast tissue at birth because of oes-

oestrogen (review Figure 2.6). Normal physiological

trogens of either placental or maternal origin is

variation should only be diagnosed by exclusion,

especially if onset is rapid and persistent. History

Table 7.1 Gynaecomastia

(especially drug history), examination and investiga-

tion are important. Treatment is most commonly

Causes of

Investigations to

one of reassurance, withdrawal of offending medica-

gynaecomastia

consider

tions (e.g. spironolactone) or cosmetic surgery.

Physiological

General investigations

Neonatal

Serum

The female reproductive system

testosterone, LH,

Pubertal

Puberty in females heralds the beginning of the

FSH, prolactin,

female menstrual cycle when usually one germ cell

Old age

thyroid function

reaches full maturity at intervals of ∼28 days. This

test, urea and

cycle has limited lifespan as only ∼400 germ cells

creatinine

reach full maturity and ovulation. The cycle is asso-

Any cause of

Karyotype analysis

ciated with coordinated changes in ovarian ster-

hypogonadism, e.g.

oidogenesis that prime the reproductive tract for

Klinefelter syndrome

potential pregnancy.

(47,XXY)

Adrenal or testicular

Serum hCG,

Ovarian morphology and function

tumours, oestrogen

DHEA(S),

or androgen (+

androstenedione,

Oogenesis begins in the fetal ovary when, towards

peripheral aromatase

oestrogen, imaging

the end of the first trimester, germ cells start

activity) secretion

entering the first stage of meiosis and arrest in

Liver disease

Liver function tests

prophase

(review Figure

2.1). Termed primary

oocytes, they are surrounded by a layer of steroid-

Inadequate

producing granulosa cells as primordial follicles

clearance and

altered metabolism

(Figure 7.10). There are ∼6-7 million primordial

of steroid

follicles at 20 weeks of gestation, after which their

hormones

number declines inexorably. At birth, there are ∼2

million and by puberty only 300,000. Menopause

Alcohol

marks the depletion of all germ cells within the

Drugs

ovaries.

Oestrogens,

antiandrogens

Follicle development, ovulation and early

(spironolactone),

embryogenesis

cimetidine, ACE

inhibitors

At the beginning of a menstrual cycle, the granulosa

LH, luteinizing hormone; FSH, follicle-stimulating

cells in

10-20 primordial follicles proliferate to

hormone; hCG, human chorionic gonadotrophin; DHEA,

form primary and then secondary follicles (Figure

dehydroepiandrosteone; DHEAS, DHEA sulphate; ACE,

7.10). In any one menstrual cycle, only one follicle

angiotensin-converting enzyme.

usually reaches full maturity as the dominant

Chapter 7: Reproductive endocrinology / 143

Graafian follicle, when stromal cells become

Formation of the corpus luteum

arranged around the outside to form the vascular-

ized ‘theca’. At mid-cycle, the follicle ruptures (ovu-

Thecal cells plus some granulosa cells of the rup-

lation) and the oocyte is captured by the fimbriated

tured follicle play a critical role in the second half

opening of the Fallopian tube, down which it is

of the menstrual cycle. They proliferate, enlarge

wafted by ciliated epithelial cells and peristaltic con-

and fill the collapsed antrum of the follicle as a

tractions towards the uterine cavity

(see Figure

solid, round mass of steroidogenic cells called the

7.2b). During this course, if the ovum meets sper-

corpus luteum; so named because it is initially red,

matozoa and is fertilized, embryogenesis starts such

but matures to a yellowish colour (Figure 7.10). If

that, upon arrival in the uterine cavity, it has devel-

fertilization and blastocyst implantation do not

oped into a blastocyst ready for implantation

occur, the corpus luteum is only active for ∼2 weeks,

into the endometrium. If the ovum is not fertilized,

after which it stops synthesizing steroids and dies

it dies. Hormonal regulation of this process is

(luteolysis), leaving white atrophied tissue

(the

described below.

corpus albicans). However, if implantation occurs,

Primordial follicle

Primary follicle

Secondary follicle

Antrum

Oocyte

Secondary follicle

Membrana

granulosa

Antrum

Corona radiata

Ovum

Theca

Membrana

granulosa

Cumulus

oophorus

Graafian follicle

Ovulation

Corpus luteum

Figure 7.10 Follicle growth, maturation and ovulation.

attaches the oocyte to the membrana granulosa.

The entire process takes place close to the ovarian

Stromal cells form the outer steroidogenic theca

surface. The outer steroid-producing granulosa

cell layer. The entire structure is now termed a

cells divide and grow to form a multi-layered

Graafian follicle, which ruptures at ovulation,

membrana granulosa. The appearance of a liquid-

expelling the ovum surrounded by a layer of cells,

filled antrum defines the transition from a primary

the corona radiata. The collapsed follicle becomes

to a secondary follicle. The antrum enlarges,

the corpus luteum.

creating a stalk of cells (the ‘cumulus oophorus’) that

144 / Chapter 7: Reproductive endocrinology

the corpus luteum grows and its hormone secretion

The follicular phase: the control of follicle

maintains the uterine endometrium during the

development

early weeks of pregnancy until, in humans, the pla-

At the beginning of each cycle, pulsatile GnRH

centa assumes steroidogenic function. The hor-

stimulates FSH secretion (see Chapter 5). Under

mones involved in this process are described below.

FSH regulation, a cohort of ∼20 primary follicles

develops into secondary follicles, which produce

oestradiol (Figures 7.10 and 7.12). In turn, oestra-

Ovarian steroidogenesis and the

diol increases FSH receptors on the surface of the

hypothalamic-anterior pituitary-ovarian

proliferating granulosa cells. Because of this regular,

axis: the menstrual cycle

predictable start to the menstrual cycle, this is also

the best time for clinical investigation of serum

During the reproductive years, ovarian hormone

LH, FSH and oestradiol (Box 7.14). Oestradiol

production accompanies egg development in ∼4-

and inhibin secretion suppress FSH production

week cycles (Box 7.14 and Figure 7.11). In the

from the anterior pituitary by negative feedback

absence of fertilization, the cycle is terminated by

(Figure 7.13). As the concentration of FSH falls,

the restricted 2-week lifespan of the corpus luteum.

only the ripening follicles with the highest concen-

The most potent oestrogen in humans is oestra-

tration of FSH receptors are able to sustain develop-

diol. Its biosynthesis relies on two somatic cell types

ment, while the rest atrophy. Thus, progressively,

within the developing follicle, the inner theca cells

one dominant follicle is selected, around which

(theca interna) that synthesize testosterone, which

theca cells develop under the influence of LH

is then aromatized by CYP19 (also called aromatase)

(Figure 7.10).

to oestradiol in the granulosa cell (Figure 7.12 and

review Figure 2.6). Oestrogen can also be generated

by CYP19 acting on androstenedione to form

Ovulation

oestrone that can be converted to oestradiol by

Mid-cycle is associated with a surge of LH and, to

HSD17B1. Progesterone biosynthesis is relatively

a lesser extent, FSH from the pituitary

(Figure

straightforward. Removal of the cholesterol side

7.11). The LH surge lasts ∼36 h, stimulating factors

chain generates pregnenolone in theca cells, which

that aid follicle rupture and final maturation of the

is converted to progesterone by HSD3B activity

oocyte. The principal cause for this gonadotrophin

(review Figure 2.6).

surge from the pituitary is a temporary switch in

The menstrual cycle is regulated by the

oestradiol feedback. At mid-cycle, as the dominant

hypothalamic-anterior pituitary-ovarian axis and

follicle ripens, oestrogen output increases and at

intra-ovarian mechanisms (Figure 7.13).

∼day 12, a threshold is exceeded, which, if main-

Box 7.14 Ovarian hormone action and measurement during the menstrual

cycle

A cycle of two halves

• Luteal phase is relatively fixed at 14 days

• Oestrogen: prepares the egg for release

during the follicular phase (Figure 7.12)

This physiology determines the timing of

• Progesterone: maintains early pregnancy

clinical hormone measurement

(i.e. ‘pro-gestation’) in the luteal phase

• Day 1: first day of vaginal bleeding from

preceding cycle

Ovulatory cycles are usually 28 days but may

• Days 2-5: time to measure FSH, LH and

vary slightly

oestradiol

• Variation in length reflects speed of egg

• Day 21 (or mid-luteal phase if cycle ≠ 28

preparation, i.e. follicular phase

days): time to measure progesterone

Chapter 7: Reproductive endocrinology / 145

Ovulation

Figure 7.11 The 28-day

Progesterone

menstrual cycle. The start of

Oestradiol

menstruation is day 1 of a new

FSH

cycle. LH, luteinizing hormone;

FSH, follicle-stimulating

Hormone

hormone.

concentrations

Ovarian

Corpus luteum

Luteolysis

changes

Follicle growth and

maturation

and function

Uterine

changes

Menstruation Proliferative phase

Secretory phase Pre-decidual

phase

Vaginal

changes

High pH watery mucus

Low pH viscous

conducive to sperm survival

mucus antagonistic to

sperm survival

Effects of oestradiol

Effects of progesterone

tained for 36 h, turns feedback at the gonadotroph

like LH at the LH receptor. hCG maintains the

from negative to positive. Now, high levels of

corpus luteum and, in the face of continuing

oestradiol drive further gonadotrophin secretion,

oestradiol and progesterone, menstruation is

creating the feed-forward surge that culminates in

postponed (covered in more detail later and in

and is ended by ovulation.

Figure 7.15).

The luteal phase: maintaining an early

Cyclical effects on the uterus and vagina

pregnancy

The changing ovarian steroid output causes cyclical

After ovulation, negative feedback at the gonado-

alterations in the uterine endometrium and the rest

troph is restored and lower levels of LH stimulate

of the female genital tract (Figures 7.11 and 7.14).

progesterone from the corpus luteum. This allows

Increased secretion of oestradiol at the start of a

clinical measurement of progesterone at day 21,

cycle stimulates repair and proliferation of the

which, if > 30 nmol/L

(∼9.4 ng/mL), strongly

endometrium and expression of receptors for pro-

implies ovulation has occurred

(Box 7.14). The

gesterone and oestradiol. After ovulation, raised

corpus luteum also secretes oestradiol, now provid-

progesterone prepares the endometrium for poten-

ing negative feedback on LH and FSH (Figure

tial implantation. It doubles in thickness, and the

7.12). By ∼day 25, the falling LH is no longer able

simple tubular glands become tortuous and saccu-

to maintain adequate steroidogenesis. The fall in

lar. However, with luteolysis the endometrium

progesterone leads to endometrial degeneration

breaks down and sloughs off as menstrual bleeding.

and menstruation follows (see next section). This

The cyclical hormones also alter the consistency and

drop in oestradiol and progesterone also removes

pH of cervical mucus (Figure 7.11).

negative feedback from the pituitary, which,

under the ongoing stimulus of GnRH pulses,

Phases of ovarian function and

resumes secretion of FSH and LH. So begins the

reproductive development after birth

next cycle.

If fertilization has occurred and a blastocyst

Neonatal life and childhood

has implanted (∼day 20 of the menstrual cycle),

Ovarian function should be quiescent after birth

the resulting embryonic trophoblast begins to

and during childhood such that precocious puberty

secrete hCG, a glycoprotein hormone that acts

always needs investigation.

146 / Chapter 7: Reproductive endocrinology

Figure 7.12 The two-cell

Theca externa cells

biosynthesis of oestrogens.

Luteinizing hormone (LH)

stimulates its receptor on the

theca interna cells and, via cAMP,

ATP

leads to androstenedione and

testosterone synthesis (review

Cholesterol

Figure 2.6). These either pass

cAMP

into the local capillaries or cross

Testosterone

the basement membrane into the

Theca interna

Androstenedione

adjacent granulosa cells. The

cell

granulosa cells are stimulated by

follicle-stimulating hormone

Capillary

(FSH) to aromatize testosterone

and androstenedione to

FSH

oestradiol and oestrone,

respectively, via the action of

CYP19. These female hormones

Granulosa cell

Testosterone

enter the circulation or pass into

Androstenedione

the antrum of the follicle and act

cAMP

Aromatase

on the oocyte. LH, luteinizing

Oestradiol

hormone; FSH, follicle-stimulating

Oestrone

ATP

hormone.

Puberty

first few cycles after menarche are potentially ano-

Puberty sees the transition from a quiescent, imma-

vulatory and slightly irregular, but a regular pattern

ture state to a fully developed, fertile female (Table

should emerge relatively quickly. Failure to establish

7.2). Although the growth spurt starts first, the

a regular cycle is suggestive of polycystic ovarian

most obvious early pubertal sign is breast develop-

syndrome (see later).

ment (see Figure 7.9). Tanner stages 1-4 are depend-

ent on oestrogen; stage 5 also requires progesterone.

Menopause

Coincident with breast development, pubic hair

Fertility tends to decline progressively once a

starts to grow. Pubic hair growth is largely under

woman has entered her 30s. Thus, the menopause

the influence of androgen from both adrenal

may be preceded by some years of less regular

sex steroid precursors and the ovary, and may

ovarian function. Cycles may release multiple ova

have commenced at adrenarche (see Chapter 6).

interspersed with spells of anovulation. Low follicle

However, it usually progresses in parallel with

counts during this pre-menopausal stage increase

oestrogen-stimulated breast development. There are

follicular phase gonadotrophin levels. Clinically, a

also oestrogen-dependent changes in vaginal size,

raised serum FSH on day 3-5 or low serum levels

mucosal appearance and pH. The labia thicken

of ovarian AMH indicates relatively poor ‘ovarian

and rugate, a process similar to that which occurs

reserve’ and lower likelihood of successful IVF

in male scrotal skin. Periods usually commence

therapy. This normal sequence culminates in the

(menarche) during Tanner stage 4.

menopause, defined as the last menstrual period,

Puberty in females also marks a transition from

usually aged 50 or slightly later, after which the

nocturnal pulsatile secretion of gonadotrophins to

ovaries are depleted of follicles, serum oestrogen and

the 24-h pulsatility that is necessary for fertility. The

inhibin fall, and circulating LH and FSH rise

Chapter 7: Reproductive endocrinology / 149

Table 7.2 Different phases of ovarian function and its effects

Phase

Oestrogen

Progesterone

Puberty

Stimulates growth of the uterus and

Aids transition from Tanner Stage 4 to 5

breast

Shapes female figure via fat deposition

Contributes to closure of epiphyses

Exerts important effects on

psychological development and

sexual responsiveness

Menstrual cycle

Follicular phase:

Luteal phase:

Causes endometrial proliferation; and

Causes a rise in body temperature;

secretion of clear, high pH cervical

development of secretory endometrium;

mucus - conducive to sperm survival

and secretion of thick, low pH cervical

mucus - not conducive to sperm survival

Matures the vaginal epithelium

Causes negative and temporary

Negative feedback at the hypothalamus

positive feedback at the hypothalamus

and pituitary

and anterior pituitary

Pregnancy

Causes growth of the breast duct

Causes reduction of uterine contractions

system and myometrial hypertrophy

and reduced smooth muscle tone

together with fluid retention and

Causes a rise in body temperature and

increased uterine blood flow

growth of the alveoli of the breasts

General cellular

Enhances receptors for progesterone

Stimulates HSD17B isoforms which

effects

(i.e. oestrogen is needed for

inactivate oestradiol to weak oestrone

progesterone to exert its intracellular

actions)

HSD17B, type 3 17β-hydroxysteroid dehydrogenase.

Endocrine changes during pregnancy,

Box 7.15 Local environmental

parturition and lactation

factors for early embryo growth

and implantation

Successful implantation leads to development of the

trophoblast, which begins to secrete hCG into the

• Healthy Fallopian and intrauterine

maternal bloodstream. hCG is similar enough to

nutritional/metabolic milieu (e.g.

LH to act via the LH receptor, and it maintains the

euglycaemia)

corpus luteum and early pregnancy, and postpones

• Poorly controlled diabetes is associated

the next cycle of ovulation (Figure 7.15). Its high

with early miscarriage (see Chapter 14)

levels during the first trimester also stimulate

• Receptive endometrium for implantation

the thyroid (see Chapter 8) as hCG also mimics

thyroid stimulating hormone (TSH; the α-chain is

Failure of these attributes is likely to

identical between hCG, LH, FSH and TSH). This

contribute to subfertility

offsetting of TSH action leads to lower serum TSH

150 / Chapter 7: Reproductive endocrinology

hCG

Box 7.16 Endocrine alterations

(mimics LH)

during pregnancy, parturition and

lactation

Pregnancy

Maintains oestradiol

and progesterone

• Maternal:

from corpus luteum

° Hypertrophy/hyperplasia of lactotrophs

synthesizing prolactin

° hCG (partially mimics TSH) stimulation

Suppresses pituitary

of thyroid hormone synthesis

gonadotrophins

° Increased β-cell function and potential

growth of pancreatic islets

° Increased adrenal cortisol output

Postpones next cycle

° Increased heart rate; cardiac output rises

of follicle maturation

by 30-50% because of alterations in the

hormonal milieu and placental circulation

• Fetal growth and development:

Maintains

° Requires thyroid hormone (CNS

early pregnancy

development), insulin and GH-IGF axes

° Maturation of the fetal lung (surfactant

Figure 7.15 The role of human chorionic

production) by cortisol near term

gonadotrophin (hCG) in postponing menstruation.

Parturition

• Local prostaglandins stimulate the early

levels (Box 7.16), which is physiological but needs

uterine contractions

to be remembered when interpreting thyroid func-

• Oxytocin increases as the fetus descends

tion tests in the first trimester (see Table 8.1). In a

the birth canal and distends the vagina

small minority of women, higher hCG levels, as can

(see Chapter 5)

arise in molar pregnancy (when there is only tro-

phoblast and no embryo proper) or a twin preg-

Lactation

nancy, causes a transient thyrotoxicosis. It also

• High oestrogen and progesterone during

associates with excessive early morning vomiting

pregnancy inhibit lactation

(hyperemesis gravidarum). hCG excreted into the

• Post-partum, lactation relies on continued

maternal urine forms the basis of most pregnancy

prolactin and cortisol

tests. Levels can be detected by urine strip assays

• Oxytocin, released via the suckling reflex,

soon after menstruation / a period is delayed (∼3

stimulates milk ejection

weeks of embryo development).

Towards the end of the first trimester, fetal ster-

oidogenesis occurs across several organs, leading to

detected from the end of the first trimester onwards

the term, the ‘feto-placental unit’. Placental secre-

in maternal urine. Growth hormone (GH) and

tion of progesterone takes over from the corpus

especially insulin-like growth factor

(IGF) hor-

luteum, which regresses. In the fetal adrenal cortex

mones are important for fetal growth. Similarly,

there is early cortisol biosynthesis, followed by the

fetal insulin secretion acts more to stimulate growth

production of large amounts of dehydroepiandros-

than control glucose levels, which are ordinarily

terone

(DHEA) and its sulphated derivative,

regulated by the mother. However, if the mother

DHEAS (review Figures 2.6 and 7.16). A series of

has diabetes, the increased transfer of glucose to the

enzymatic reactions gives rise to different oestro-

fetus stimulates excessive insulin secretion, leading

gens: oestradiol, oestrone and oestriol, the latter

to overgrowth (macrosomia), difficult delivery (e.g.

Chapter 7: Reproductive endocrinology / 151

Maternal

Box 7.17 Amenorrhoea

Fetus

Placenta

circulation

In the UK

Cholesterol

• ∼95% of girls have undergone menarche

Week 9

by 15 years

Pregnenolone

• ∼50% have done so by 12½ years

Progesterone

Absence of periods is ‘amenorrhoea’

Dehydro-

• Primary amenorrhoea: menstruation not

epiandrosterone

DHEA

(DHEA)

started by 16 years

Androstenedione

• Secondary amenorrhoea: menstruation

started but now absent for > 6 months

Oestrone

Defining the cause: first determine if

DHEA sulphate

Oestradiol

oestrogen is present or absent

(DHEAS)

16-Hydroxy-

16-hydroxy-

glucocorticoids and prolactin with contributions

DHEAS

from insulin and thyroid hormones [in boys, the

Week 12

process is inhibited by testosterone; however, some

Oestriol

breast development (gynaecomastia) may occur (see

Table 7.1)].

Figure 7.16 Steroid production in the feto-placental

In early pregnancy, oestrogens cause further

unit.

growth of the ducts and the breasts enlarge. Later

on, glucocorticoids from the adrenal cortex, prolac-

shoulder dystocia) and risk of neonatal hypoglycae-

tin from the anterior pituitary and placental lac-

mia (see Chapter 14).

togen (a prolactin-like hormone from the placenta)

Approaching term, cortisol stimulates synthesis

induce enzymes needed for milk production (Box

of surfactant proteins, which decrease surface

7.16). So long as breast-feeding is continued, prol-

tension in the lungs (Box 7.16). This allows the

actin levels stay high and inhibit pituitary gonado-

fluid-filled alveoli to expand with air at birth and

trophin release, tending to postpone cyclical

begin gas exchange. The mechanism is so important

ovulation. Even though this is unreliable for an

that dexamethasone, a synthetic glucocorticoid that

individual unless the infant is exclusively breast-fed

crosses the placenta, is given to women in prema-

every few hours, globally this mechanism is an

ture labour to decrease the incidence of neonatal

important contraceptive.

respiratory distress syndrome.

The signal for birth

(parturition) after

∼9

Clinical disorders

months remains unclear. However, as progesterone

Amenorrhoea

levels fall, two factors, oxytocin and prostaglandins,

are important [Box 7.16; the role of oxytocin in

Ovarian hormone disruption causes loss of ovula-

parturition and milk production

(lactation) is

tory cycles and, consequently, absence of periods

described in Chapter 5]. Preparation for lactation

(amenorrhoea; Box

7.17). Amenorrhoea can be

begins with breast development (thelarche) ∼2 years

classified as either primary (periods never started)

before menarche, under the influence of ovarian

or secondary (periods started but now absent for

oestrogens, which initiate duct proliferation and

>6 months); this distinction becomes arbitrary

accumulation of fat in the breast. During female

when the same pathology underlies both. Clinically,

adolescence, oestrogen, GH and adrenal steroids

in determining the cause, the first task is to assess

stimulate further growth of the duct system. Alveolar

whether oestrogen is present or absent (Tables 7.3

growth is promoted by oestrogen, progesterone,

and 7.4).

Chapter 7: Reproductive endocrinology / 153

Assessment is needed of whether the ovaries ever

mones. Unopposed oestrogen increases the risk of

functioned:

endometrial carcinoma: if the uterus is present,

treatment must include a progestogen. In perma-

• Is there any breast development?

nent loss of ovarian function, HRT is advised until

• Are there features of Turner syndrome?

the normal age of the menopause at ∼50 years, at

° Shield chest

which point DEXA can assess bone mineral density,

° Widely spaced nipples

allowing informed choices to be made on future

° Webbed neck

fracture risk (see Chapter 9). Treatment relating to

° Increased carrying angle

other pituitary hormone axes, if appropriate, is

• Have there been recent clear menopausal symp-

covered in Chapter 5.

toms such as hot flushes (flashes) due to the acute

Other treatment is more tailored, such as fertil-

withdrawal of oestrogen?

ity management (see last section). In permanent

secondary or tertiary hypogonadism (i.e. amenor-

Investigation and diagnosis

rhoea due to pathology in the pituitary or the

Serum oestradiol is very low or undetectable.

hypothalamus) the ovaries and uterus can poten-

If the aetiology is ovarian, loss of negative feed-

tially support pregnancy. Fertility can be restored by

back causes a pronounced rise of serum gonado-

hCG and hMG injections to mimic the gonado-

trophins into the post-menopausal range (several-fold

trophins. If GH-deficient, prior GH treatment may

the upper limit of normal for the reproductive years;

be needed to stimulate uterine growth prior to

Table 7.3). Ultrasound can determine the presence

stimulating ovulation. Egg donation is required to

and structure of the ovaries. A karyogram excludes

achieve pregnancy in ovarian failure. These scenar-

gross chromosomal abnormality

(e.g. Turner

ios are emotionally charged, requiring specialist

syndrome/45,XO) and screening is increasingly

services, fertility experts and psychological support.

available for other genetic causes of premature

For Turner syndrome, there are additional con-

ovarian failure (POF; menopause before 40 years of

siderations because of the X chromosome genes that

age), such as fragile X syndrome.

play roles beyond the ovary. To collate these issues,

As for male hypogonadism (see earlier), low or

dedicated clinics and care are indicated (Box 7.18).

inappropriately normal serum gonadotrophins indi-

cate that the pathology is in the hypothalamus or

Case history 7.3

anterior pituitary (Table 7.3; review Chapter 5).

Although rarely performed, hypothalamic and ante-

A 25-year-old woman is referred because

rior pituitary pathology can be distinguished by

of spontaneous galactorrhoea. Her

measuring LH and FSH 30 min after GnRH admin-

periods have stopped and she is sexually

istration; if they rise adequately (more than two-

inactive. Serum prolactin is found to be

fold), this is indicative of hypothalamic pathology,

4500-6000 U/L (∼212-283 ng/mL) on

while a poor response suggests a lesion in the anterior

repeated investigation.

pituitary. In younger patients, craniopharyngioma

or congenital deficiency needs to be excluded. The

What other questions need to be asked?

pituitary should be delineated by MRI (Figure 4.8).

What is the most likely diagnosis and

would serum oestradiol be high or

low?

Treatment

What other investigations need to be

The primary issue is: ‘if it is missing, replace it’. Lack

considered?

of oestrogen for prolonged spells leads to bone

What drug treatment will lower the

demineralization and risk of future osteoporosis. If

prolactin and most likely stop the

persistent for longer than

6 months, oestrogen

galactorrhoea?

should be replaced, either by the combined oral

contraceptive pill (COCP) or hormone replacement

Answers, see p. 163

therapy

(HRT) preparations of female sex hor-

154 / Chapter 7: Reproductive endocrinology

Box 7.18 Caring for patients with Turner syndrome

During childhood and adolescence

• Cardiology monitoring to detect

• GH is used to maximize growth,

abnormalities of the left outflow tract

compromised because of a missing copy of

(ventricle, aortic value and aorta):

the SHOX gene

° Increased risk of aortic dissection:

• Checks to ensure that hearing is satisfactory

rigorously treat hypertension and periodic

and thyroid function is normal

imaging of aortic root (e.g. MRI)

• Pubertal development is likely to need

° Aortic valve may be bicuspid requiring

increasing doses of oestrogens, finally

prophylactic antibiotics during procedures

adding progestogens

to guard against endocarditis

° Increased incidence of coarctation of aorta

During adulthood

• Remain mindful of increased risk of type 1

• Oestrogen replacement (HRT or COCP) for

diabetes

bone mineral density

• Assessment of bone mineral density by

• Annual screening with thyroid function tests

DEXA

(increased incidence of primary

• Psychological support may be necessary;

hypothyroidism)

interaction with patient support groups

Amenorrhoea with oestrogen present:

weight gain per se increases resistance to insulin

polycystic ovarian syndrome and

action and obesity associates with decreased

other causes

menstrual frequency and subfertility. A key ques-

The commonest cause of decreased or irregular

tion to address this is whether, prior to weight

menstrual frequency with detectable oestrogen is

gain, periods were regular. A persistent tendency to

PCOS. The pathological mechanism underlying

irregular periods soon after menarche is supportive

PCOS is incompletely understood; however, it

of a true genetic predisposition to PCOS (Case

includes a polygenic predisposition to insulin resist-

history 7.4).

ance and altered insulin action in the ovary and in

other sites (see Chapter 13).

Investigation and diagnosis

PCOS is a diagnosis of exclusion. Other endo-

PCOS is a diagnosis of exclusion, such that no test

crine disorders can present similarly and must be

confirms PCOS and investigations must exclude

ruled out before diagnosing PCOS.

other curable endocrinopathy. In PCOS, the ratio

of LH to FSH tends to be increased and SHBG

Symptoms and signs

tends to be low. Low SHBG associates with hyper-

PCOS is encapsulated by amenorrhoea with relative

insulinism

(circulating insulin and C-peptide

clinical or biochemical androgen excess in the

levels are increased), but this is also prevalent in

absence of other causes. Whether or not cysts con-

simple obesity. The androgen excess of PCOS is

tribute to making the diagnosis is contentious (see

both ovarian and adrenal in origin. A particularly

below). Symptoms and signs, and features of the

high DHEA or DHEAS may suggest an adrenal

history and examination are covered in Table 7.4.

tumour. The higher serum testosterone is greater

PCOS associates with an increased incidence of

than 4 nmol/L (∼115 ng/mL), the more likely an

impaired glucose tolerance

(IGT), gestational

ovarian or adrenocortical androgen-secreting

(GDM) and type 2 diabetes (T2DM), although the

tumour becomes, especially if supported by true

same is true of Cushing syndrome and other endo-

virilization, which practically excludes PCOS (Table

crinopathy. Maintaining a normal body mass index

7.4). Ultrasound can help to exclude ovarian

(BMI) is commonly difficult in PCOS. However,

tumours (the best views of the pelvic anatomy are

Chapter 7: Reproductive endocrinology / 157

Without menstruation, chronic low-level oes-

Other female reproductive endocrinology

trogen stimulates endometrial growth that is not

referrals

shed, increasing the risk of endometrial carcinoma

∼six-fold. Withdrawal bleeds need to be induced by

Hirsuitism and male-pattern balding

progesterone therapy (e.g. 5 mg norethisterone once

Excess hair growth in women

(hirsuitism) is a

daily for 7 days) every 3-4 months. The fall in

common endocrine referral. The first distinction to

progesterone after the last dose simulates the end

make is between androgen-dependent and inde-

of a menstrual cycle and provokes endometrial

pendent growth. For the latter, hypothyroidism and

shedding.

causative drugs (e.g. phenytoin) should be excluded,

Weight gain leading to obesity in patients with a

after which effective treatment is difficult beyond

polygenic tendency to insulin resistance massively

standard cosmetic measures.

increases risk of diabetes, either as GDM or T2DM.

Androgen-dependent hair growth takes place in

Encouragement, counselling and advice are impor-

the region of the beard, chest and in the midline to

tant to maintain cardiovascular fitness and avoid

the umbilicus (the male escutcheon). It may be

obesity. These measures are also first-line fertility

accompanied by male-pattern scalp hair loss.

measures, followed by metformin (see Chapter 13),

Symptoms or signs of virilization imply major

and, if this is insufficient, specialist referral (see later

androgen excess. Consumption of performance

section). It is always useful to advise that female fer-

enhancing drugs or supplements should be ques-

tility declines progressively after the age of 30 years

tioned. Some forms of the COCP possess andro-

and if there are known potential problems, preg-

genic activity.

nancy should ideally be planned earlier rather

Serum testosterone

(ideally at

9 am) greater

than later. For women with a history of irregular

than 4 nmol/L (∼115 ng/mL) brings risk of androgen-

periods presenting beyond 35 years, prompt referral

secreting tumours when visualization by ultrasound,

is critical.

CT or MRI is indicated (Case history 7.5). If

imaging is inconclusive

(remembering the fre-

quency of adrenal incidentalomas; see Chapter 6),

Case history 7.4

venous sampling of adrenal and ovarian veins under

radiological guidance may be helpful. Concomitant

A 25-year-old woman is referred to the

cortisol measurement can confirm cannulation of

endocrinology clinic with irregular periods

the adrenal veins. A clear androgen gradient between

and hair growth affecting the chin and

left or right adrenal or ovary and peripheral samples

chest. On closer questioning, the menstrual

indicates the likely source of pathology. For a pre-

cycle has never been shorter than 35 days

sumed ovarian source in post-menopausal women,

in length since menarche. LMP was 7

both ovaries are usually removed (bilateral oophorec-

months ago. Her mother has type 2

tomy) laparoscopically. Removing both ovaries

diabetes. Her BMI is 26.4 kg/m² and serum

lowers risk of future ovarian cancer. Androgen-

oestradiol is 340 pmol/L (~90 pg/mL).

secreting tumours are most commonly benign and

Pregnancy test is negative. She thinks she

removal is curative, although frontal hair loss may

has PCOS.

not fully recover.

Clinical hyperandrogenism with normal serum

Are any other tests necessary to make a

testosterone is common. Individuals vary in their

diagnosis of PCOS?

sensitivity to androgens. Serum total testosterone is

In addition to the patient’s issues, what

a blunt measure of androgen action in target cells:

two aspects of long-term healthcare

free testosterone varies according to serum proteins;

should the clinician address?

SRD5A2 is required to generate DHT (Figure 7.7);

What uterine treatment is indicated now?

and AR activity differs between individuals through

Answers, see p. 163

variability (polymorphism) in its first exon. Blocking

DHT production (e.g. by SRD5A2 inhibitors such

158 / Chapter 7: Reproductive endocrinology

as finasteride) or androgen binding to AR (e.g. by

Fibroids are benign tumours of the muscle

antagonists such as spironolactone) can be effective.

layer of the uterus (myometrium) and respond to

Waxing, plucking, laser therapy and the application

oestrogen and, potentially, progesterone. Hormone

of eflornithine cream that inhibits hair follicle cell

modulation is most likely of short-term benefit,

division are also valid strategies that are free from

whereas surgery offers more definitive treatment.

systemic side-effects.

Total hysterectomy ends fertility. However, local

laparoscopic resection can preserve the uterus, albeit

with increased risk of rupture in future pregnancy.

Galactorrhoea

Inappropriate milk production outside of breast-

feeding is common in young women and results

Menopause and hormone replacement

from excess prolactin

(hyperprolactinaemia; see

therapy

Chapter 5) or increased sensitivity to its action.

HRT in the menopausal period can overcome

Galactorrhoea with normal serum prolactin occurs

the acute symptoms of oestrogen withdrawal, typi-

with increased breast sensitivity

(e.g. after cessa

fied by hot flushes

(flashes). The duration and

tion of breast-feeding), but still responds well to

relative benefit of HRT therapy is contentious.

dopamine agonists, such as cabergoline.

Historically, it has been given to maintain bone

mineral density, but this effect is rapidly lost upon

Hormone-dependent gynaecological

cessation (see Chapter 9). It has also been used to

disorders

protect against cardiovascular disease until trials

Endometriosis and uterine fibroids (leiomyomata)

showed the opposite effect. One approach is to

are hormone-dependent and prevalent in women

prioritize HRT for symptoms of oestrogen with-

during the reproductive lifespan. Both conditions

drawal during the 5 years around and following

are covered in greater depth in Essential Reproduction.

the menopause. This largely avoids any increased

Endometriosis is the presence of endometrial

risk, potential or otherwise, of cardiovascular

tissue outside of the uterine cavity and may

disease and breast cancer from longer term use. In

affect the ovaries, broad ligament, or other perito-

the presence of a uterus, oestrogen needs to be

neal surfaces. The cells contain oestrogen receptor

combined with progesterone, which reduces oestro-

that when bound by oestradiol mediates prolifera-

gen receptor number in target cells and increases

tion and hypertrophy. This can cause chronic

inactivation of oestradiol to oestrone. Given inter-

pelvic pain or, if affecting the Fallopian tube, sub-

mittently, withdrawal bleeding can continue with

fertility. In addition to surgery, decreasing the

this combined therapy. Progesterone can also be

supply of oestrogen

(e.g. by continuous GnRH

administered by an intrauterine coil, in which

agonist or the progesterone-only contraceptive pill)

case vaginal bleeding may be erratic or cease

can help.

completely.

Case history 7.5

A 72-year-old woman presents with frontal hair loss over the last 5 years. Serum total

testosterone was 7.4 nmol/L (∼213 ng/mL). She is otherwise very fit.

Name two clinical features that might characterize this androgen level in a woman?

What is the diagnosis until proven otherwise and in which two organs might it be located?

What investigations need to be considered and what is the most likely eventual treatment

they may lead to?

Answers, see p. 163

Chapter 7: Reproductive endocrinology / 159

Pubertal disorders

In females, progesterone is added once uterine bleed-

ing starts (Case history 7.6).

Children with endocrine abnormalities causing

pubertal precocity or delay must be distinguished

from those who simply represent the extremes of

Case history 7.6

the normal range (Case history 7.6). Even where

observation may be feasible in the latter group,

A 15-year-old girl was referred because of

there are major psychosocial consequences of

a failure to commence periods. Her

puberty occurring out of synchrony with the indi-

mother frequently interrupted the

vidual’s peer group. Early puberty, subject to ethnic

consultation and strongly wished for

differences, also induces the growth spurt, which

‘something to be done’. The patient

ultimately causes earlier epiphyseal fusion and

declined examination but was noted to

shorter adult height.

look healthy if rather short for predicted

family height. She agreed to some blood

tests, which revealed LH and FSH below

Precocious puberty

the normal range and undetectable

Precocity may result from either the normal process,

oestradiol. Thyroid function, karyotype and

driven by GnRH pulses, occurring abnormally

serum prolactin were normal.

early (central or true), or aetiology extrinsic to the

hypothalamic-anterior pituitary-gonadal axis that

Does anything need to be done urgently?

results in premature sex steroid biosynthesis

What other questioning might be

(Table 7.5). Precocity may be caused by oestrogen in

insightful?

boys and androgen in girls, leading to inappropriate

feminization or virilization respectively (contra-sexual

Answers, see p. 164

precocity). The goal is to treat the underlying cause and

avoid significant disruption of psychosocial develop-

ment or the attainment of predicted final height. It

needs to focus on the individual cause. For true precoc-

Box 7.19 Delayed puberty: defined

ity, continuous GnRH can be used to suppress the

as >2 standard deviations above

pituitary gonadotrophins. For isolated premature breast

mean age

development (‘thelarche’), reassurance is appropriate.

• Boys ≥ 16 years of age

• Girls ≥ 14 years

Delayed puberty

As well as slow entry into puberty, delay may also

Subfertility

occur within pubertal stages (Box 7.19). The com-

monest cause is constitutional or chronic illness when

Subfertility is defined as the failure of a woman

bone age is also appropriately delayed. Delayed

to become pregnant despite a year of unprotected

puberty may also reflect gonadal failure when serum

regular intercourse with her male partner

(Case

gonadotrophins are raised and sex steroids are low. In

history 7.7). Both partners must be assessed (Table

females, ultrasound may show streak gonads and a

7.6).

karyotype might indicate Turner syndrome (45,XO).

Secretion of pituitary gonadotrophins can be assessed

Male factor treatment

in response to GnRH (see earlier section on amenor-

rhoea with absent oestrogen). In boys, a rise in testo-

Review earlier sections on semen analysis (Box 7.7)

sterone after hCG injection indicates normal testicular

and hypogonadism. Treatment depends on cause.

potential. If necessary, treatment is with increasing

In secondary hypogonadism, testicular function can

doses of sex steroids to induce pubertal changes with

be restored with injections of hCG and, if needed,

close monitoring of pubertal progression and growth.

hMG to mimic endogenous LH and FSH. In the

Chapter 7: Reproductive endocrinology / 161

Table 7.6 An approach to subfertility

Female factor subfertility

Male factor subfertility

Was there normal development at birth?

Was childhood normal?

Did the individual enter puberty at the appropriate time?

Consider PCOS, pituitary, thyroid or adrenal disease

All the potential causes of primary or

secondary hypogonadism need consideration

Pelvic inflammatory disease (PID) can block the

Fallopian tubes - symptoms include discharge and

pain

Examination

Is testicular size normal (20-25 mL)?

What is the cycle length and regularity?

Is there a varicocoele?

A regular 28-day cycle is likely to be ovulatory

Are the external genitalia structurally normal?

Biochemical profile and investigation

Day 2-5: serum LH, FSH, oestradiol, prolactin and

Serum LH, FSH, testosterone, SHBG, prolactin

thyroid function tests

and thyroid function tests

Consider investigations related to PCOS (Table 7.4)

Consider testing for other anterior pituitary

disorders

Day 21: serum progesterone to assess ovulation

Consider analyzing karyotype (Klinefelter

syndrome/46,XXY)

BMI - fertility declines with obesity

Semen analysis - volume, concentration,

motility and morphology

Swab for PID, e.g. chlamydia

Consider laparoscopy (or hysterosalpingogram) to

assess tubal patency

PCOS, polycystic ovarian syndrome; LH, luteinizing hormone; FSH, follicule-stimulating hormone; SHBG, sex hormone-

binding globulin; BMI, body mass index.

event of spermatozoa being deemed inadequate for

Cycles of longer than

30 days are increasingly

spontaneous fertilization in vivo or in vitro, they can

likely to be anovulatory. In overweight individuals

be assessed for suitability for intra-cytoplasmic

or those with PCOS, increased cardiovascular

sperm injection (ICSI).

fitness and weight reduction may be sufficient to

generate this regular pattern. Metformin, an

insulin sensitizer, can be useful, prescribed as

Female factor treatment

for type 2 diabetes (see Chapter 13). The impor-

The initial goal is to regularize the ovulatory

tance of fitness and weight control prior to

cycle to no longer than ∼28 days in length to maxi-

pregnancy cannot be over-emphasized: patients

mize the frequency of egg release by the ovary

with PCOS are already at higher risk of first

(i.e. the number of opportunities for pregnancy).

trimester miscarriage; PCOS (with its resistance to

162 / Chapter 7: Reproductive endocrinology

insulin action) and obesity link to GDM; and

cycle of hCG and hMG injections is used for

obesity and GDM can cause difficulties at term and

women with secondary or tertiary hypogonadism

in labour.

whose ovaries are healthy and/or to recover ova

Other methods of ovulation induction increase

for in vitro fertilization (IVF) or ICSI (e.g. if there

risk of multiple pregnancies, which, in turn,

was co-existing tubal damage or male factor con-

increases risk of maternal and fetal morbidity.

cerns). For women with primary ovarian failure, egg

Blocking oestrogen feedback at the gonadotroph

donation can be considered. Other aspects of

(most commonly with clomiphene) is the

fertility management are described in Essential

simplest approach. Ovulation induction using a

Reproduction.

Case history 7.7

A couple attends the subfertility clinic. Semen analysis was satisfactory. The female partner had

a regular 28-day cycle and normal BMI. However, 5 years previously, she had had a 6-month

history of pelvic pain and some green coloured vaginal discharge that resolved on treatment

with antibiotics.

What investigations are warranted?

What treatments can be offered?

Answers, see p. 164

Key points

• In the relative absence of androgens and

• Disorders of male and female reproductive

AMH, the default in utero is female

endocrinology are investigated by

development

interrogating negative feedback within the

• Disorders of sexual development present to

hypothalamic-anterior pituitary-gonadal

the paediatric endocrinologist and are

axis

highly emotive

• The reproductive axis in both sexes is

• The critical aspects of male and female

vulnerable to disruption from other

reproductive endocrinology are sex

endocrine disorders

hormone biosynthesis and gamete

• Subfertility requires assessment of both

production

partners

Answers to case histories

Case history 7.1

hyponatraemia and hyperkalaemia may be

present; ACTH would be raised, with cortisol

The ambiguous genitalia and potential

very low [e.g. <100 nmol/L (∼3.6 µg/dL)];

signs of hypoadrenalism made the

17α-hydroxyprogesterone would be

endocrinologist consider CAH, most likely

expected to be raised. Renin might be raised

caused by deficiency of CYP21. Raised urea

and aldosterone low if this is salt-wasting

would be consistent with dehydration;

CAH.

Chapter 7: Reproductive endocrinology / 163

Intravenous hydrocortisone is indicated in

the prolactin level is atypically high for

potential hypoadrenal crisis. This could be

primary hypothyroidism.

given after the first blood sample was taken.

At this level, a microprolactinoma is the

Although ACTH stimulation test with

most likely diagnosis. Oestradiol would be

measurement of cortisol and 17α-hydroxy

low and may well be undetectable.

progesterone would be desirable, emergency

MRI of the pituitary gland is indicated,

treatment with cortisol outweighs this wish.

which may appear normal as some

The baby actually has 46,XX DSD caused

lactotroph tumours are tiny and below

by CAH, i.e. a virilized female, who in all

resolution of the imaging.

likelihood will be raised as a girl. This is

Once a microprolactinoma has been

incredibly emotive to parents. Sexual identity

diagnosed, the patient should be reassured

in the presence of ambiguous genitalia

that these tumours are benign and offered

should not have been ascribed without

treatment with a dopamine agonist, such as

investigation.

cabergoline. She should be warned that

periods and fertility are likely to return with

Case history 7.2

treatment. The galactorrhoea should stop

within a matter of weeks. After 5 years, ∼60%

The pathology lies in the testes. Serum

of patients with microprolactinomas can stop

testosterone is very low. LH and FSH are

treatment and serum prolactin remains

high. The diagnosis is primary

normal. Further details relevant to this case

hypogonadism.

are provided in Chapter 5.

Karyotype analysis is important given

suspicion of Klinefelter syndrome (47,XXY).

The patient should be commenced on

Case history 7.4

testosterone, initially at low dose (gel

PCOS is a diagnosis of exclusion; therefore,

administration would be a good option) given

other investigations are very important (see

the likely long-standing deficiency. Sudden

Table 7.4).

full replacement in Klinefelter syndrome can

Advice should be given on (1) future

impact adversely on mood and other

cardiovascular and diabetes risk with

psychosocial issues. If confirmed, information

encouragement to stay fit, active and of ideal

should be offered about the Klinefelter

body weight; and (2) endometrial shedding

support group. The patient can anticipate

during reproductive years at least every ∼4

increased beard growth, improved energy

months to normalize the risk of endometrial

levels and sexual drive. The gynaecomastia

carcinoma.

might persist, at least in part, at which point

It is 7 months since LMP. A week-long

cosmetic correction should be offered.

course of progesterone is indicated (e.g.

A DEXA scan would probably demonstrate

norethisterone 5 mg daily for 7 days) to

bone demineralization and quite possibly

stimulate endometrial shedding on

osteoporosis due to the hypogonadism (see

withdrawal.

Chapter 9). Performing this investigation at

diagnosis offers a ‘benchmark’ against which

replacement therapy can be judged.

Case history 7.5

The woman might be virilized with

Case history 7.3

clitoromegaly and deepened voice.

A drug history should be obtained. Chronic

This level of serum testosterone in a

medical illnesses should be excluded.

woman is indicative of an androgen-secreting

Pregnancy should not be an issue. Thyroid

tumour until proven otherwise, most likely

function tests should be performed, although

located in the ovary or adrenal gland.

166 / Chapter 8: The thyroid gland

To recap

■ Regulation of the thyroid gland occurs as part of a negative feedback loop, the principle of

which is introduced in Chapter 1

■ Thyroid hormones are synthesized from tyrosine; review the biosynthesis of hormones

derived from amino acids (Chapter 2)

■ Like steroid hormones, thyroid hormones act in the nucleus; review the principles of nuclear

hormone action covered in Chapter 3

Cross-reference

■ The thyroid is regulated by the hypothalamus and anterior pituitary thyrotroph, which are

covered in Chapter 5

■ Medullary carcinoma of the thyroid is part of multiple endocrine neoplasia type 2, covered in

Chapter 10

■ Other autoimmune endocrinopathies can co-exist with autoimmune thyroid disease,

especially Addison disease (see Chapter 6) and type 1 diabetes (see Chapter 12)

Te thyroid gland is responsible for making thyroid

hormones by concentrating iodine and utilizing the

amino acid tyrosine (review Chapter 2). Te hor-

mones play major metabolic roles, affecting many

Foramen

different cell types in the body. Clinical conditions

Tongue

caecum

affecting the thyroid gland are common. Terefore,

a thorough understanding is important.

Thyroid

Tooth

gland

Embryology

Understanding development of the thyroid and its

Larynx

anatomical associations underpins the gland’s exam-

ination and surgical removal to treat overactivity or

Upper

parathyroid

enlargement. In the fourth week of human embryo-

gland

genesis, the thyroid begins as a midline thickening

Thyroid

gland

Lower

at the back of the tongue that subsequently invagi-

parathyroid

nates and stretches downward (Figure 8.1). Tis

gland

creates a mass of progenitor cells that migrates in

front of the larynx and comes into close proximity

with the developing parathyroid glands (see Chapter

9). In adulthood, the pea-sized parathyroids located

Figure 8.1 The thyroid gland and its downward

on the back of the thyroid as pairs of upper and

migration. The point of origin in the tongue persists

lower glands regulate calcium by secreting parathy-

as the foramen caecum. Common sites of

thyroglossal cysts (

) are shown. The final position

roid hormone (PTH). Te lower parathyroids origi-

of the paired parathyroid glands (

) is also

nate higher in the neck than the upper glands and

indicated. Modified from Moore KL. The Developing

only achieve their final position by migrating down-

Human. W.B. Saunders, Philadelphia.

wards. Te migrating thyroid also comes into

Chapter 8: The thyroid gland / 167

contact with cells from the lower part of the

Abnormal embryology can be clinically impor-

pharynx. Tese latter cells eventually comprise

tant

(Box

8.1). Tyroid agenesis or hypoplasia

∼10% of the gland as future C-cells, which will

caused by loss-of-function mutation in genes, such

secrete calcitonin (see Chapter 9).

as PAX8, requires immediate detection and treat-

Towards the end of the second month, the

ment with thyroid hormone in order to minimize

thyroid comprises two lobes joined at an isthmus in

severe and largely irreversible neurological damage

front of the trachea. It lies just below the larynx,

which forms a convenient landmark for locating the

bowtie-shaped gland during clinical examination

(see Box 8.12). Te thyroglossal duct atrophies and

Box 8.1 Embryological

loses contact with the thyroid in all but ∼15% of

abnormalities with clinical

the population, in whom a finger-like pyramidal

consequences

lobe of thyroid projects upward. By ∼11 weeks,

• Failure of the gland to develop causes

primitive follicles are visible as simple epithelium

congenital hypothyroidism

surrounding a central lumen

(Figure

8.2). Tis

• Under- or over-migration of the thyroid can

signals the gland’s first ability to trap iodide and

cause a lingual or retrosternal thyroid

synthesize thyroid hormone, although it only

respectively

responds to thyroid-stimulating hormone (TSH)

• Failure of thyroglossal duct to atrophy can

from the anterior pituitary towards the end of the

lead to a thyroglossal cyst

second trimester.

Figure 8.2 Histology of

(a)

the human thyroid gland.

Lymphatic vessel

(a) Euthyroid follicles are

shown lined with cuboidal

Follicular epithelial

epithelium and lumens filled

cell

with gelatinous colloid that

contains stored thyroid

Colloid

C-cell

hormone. Surrounding

C-cell

each follicle is a basement

Basement

membrane enclosing

membrane

Sympathetic

parafollicular C-cells within

nerve

stroma containing

Capillary

ending

fenestrated capillaries,

lymphatic vessels and

sympathetic nerve endings.

(b) Underactive follicles

(b)

(c)

with flattened epithelial cells

and increased colloid. (c)

Overactive follicles with tall,

columnar epithelial cells

and reduced colloid.

168 / Chapter 8: The thyroid gland

in the infant. Less critically, thyroglossal cysts can

are distended with colloid and the epithelial cells

occur in the midline and move upwards on tongue

are flattened with little cytoplasm. Conversely, in an

protrusion (a clinical test).

overactive gland, follicular cells are columnar and

there is less stored colloid (Figure 8.2).

Anatomy and vasculature

Thyroid hormone biosynthesis

Te adult thyroid weighs 10-20 g, is bigger in

women than men and is also larger in areas of the

Tere are two active thyroid hormones: thyroxine

world with iodine deficiency. It enlarges during

(3,3′,5,5′-tetra-iodothyronine; abbreviated to T₄)

puberty, pregnancy and lactation. Te right lobe is

and 3,5,3′-tri-iodothyronine (T₃); the subscripts 4

usually slightly larger than the left. Its outer capsule

and 3 represent the number of iodine atoms incor-

is not well-defined, but attaches the thyroid poste-

porated on each thyronine residue (Figure 8.3).

riorly to the trachea. Te parathyroid glands are

Tese hormones are generated from the sequential

situated between this and the inner capsule, from

iodination and coupling of the amino acid tyrosine

which trabeculae of collagen pervade the gland car-

and inactivated by de-iodination and modification

rying nerves and a rich vascular supply (Figure 8.2).

to 3,3′,5′-tri-iodothyronine [reverse T₃ (rT₃)] and di-

Te thyroid receives ∼1% of cardiac output from

iodothyronine (T₂). Te equilibrium between these

superior and inferior thyroid arteries, which are

different molecules determines overall thyroid hor

branches of the external carotid and subclavian

mone activity. Synthesis of thyroid hormone can be

arteries respectively. Per gram of tissue, this blood

broken down into several key steps (Figure 8.4).

supply is almost twice that of the kidney and is

increased during autoimmune overactivity when it

Uptake of iodide from the blood

may cause a bruit on auscultation (Box 8.2; and see

Synthesis of thyroid hormone relies on a constant

Box 8.12). Blood flow through fenestrated capillar-

supply of dietary iodine as the monovalent anion

ies is controlled by post-ganglionic sympathetic

iodide (I⁻). When the element is scarce the thyroid

nerves from the middle and superior cervical ganglia.

enlarges to form a goitre (Figure 8.5 and Box 8.3).

Te functional unit of the thyroid is the follicle,

Circulating iodide enters the follicular cell by active

comprised of cuboidal epithelial (‘follicular’) cells

transport through the basal cell membrane. Te

around a central lumen of colloid. Colloid is com-

sodium (Na⁺)/I⁻ pump is linked to an adenosine

posed almost entirely of the iodinated glycoprotein,

triphosphate

(ATP)-driven Na⁺/potassium

(K⁺)

thyroglobulin (pink on periodic acid-Schiff (PAS)

pump. Tis process concentrates I⁻ within the

staining). Tere are many thousands of follicles

thyroid gland to 20-100-fold that of the remainder

20-900 µm in diameter, interspersed with blood

of the body. Tis selectivity allows use of radioiod-

vessels, an extensive network of lymphatic vessels,

ine both diagnostically and therapeutically

(see

connective tissue and the parafollicular calcitonin-

later). Several structurally related anions can com-

secreting C-cells. When the gland is quiescent (e.g.

petitively inhibit the I⁻ pump. For instance, large

in hypothyroidism from iodine deficiency), follicles

doses of perchlorate (ClO₄₋) can block I⁻ uptake in

the short term (e.g. to treat accidental ingestion of

Box 8.2 The thyroid gland

radioiodine). Te pertechnetate ion incorporating a

γ-emitting radioisotope of technetium is also taken

• Thyroid enlargement is called goitre

up by the I⁻ pump, allowing the thyroid to be

• The gland is encapsulated:

imaged diagnostically.

° Breaching the capsule is a measure of

invasion in thyroid cancer

The synthesis of thyroglobulin

• The thyroid receives a large arterial blood

supply:

Tyroglobulin (Tg) is the tyrosine-rich protein that

° May cause a bruit in Graves disease

is iodinated within the colloid to yield stored

Chapter 8: The thyroid gland / 169

Figure 8.3 The structures

COOH

of active and inactive

CH₂

thyroid hormones and their

precursors. Mono-

NH₂

iodotyrosine and

Mono-iodotyrosine

Di-iodotyrosine

di-iodotyrosine are

precursors. Thyroxine (T₄)

and tri-iodothyronine (T₃)

COOH

are the two thyroid

CH₂

hormones, of which T₃ is

the biologically more active.

NH₂

Reverse T₃ and T₂ are

Thyroxine (T₄)

3, 5, 3' - Tri-iodothyronine (T₃)

inactive metabolites formed

by de-iodination of T₄ and

T₃ respectively. The

COOH

numbering of critical

CH₂

positions for iodination is

shown on the structure

NH₂

of T₃.

3, 3', 5' - Tri-iodothyronine (reverse-T₃)

3, 3' - Di-iodothyronine (T₂)

Capillary

Basal

Apical membrane

Colloid

membrane

(microvilli on the surface)

Thyroglobulin and

Thyroglobulin +

Na+

TPO biosynthesis

Active

and packaging

I-

process

I-

TPO

Active

‘Organification’

TPO

TSH

Receptor

cAMP

Intracellular

Thyroglobulin-

effects (see Box 8.5)

containing

thyroid hormone

Pendrin

I-

Thyroglobulin

4, T3

degradation

Figure 8.4 Thyroid hormone biosynthesis within the

and microtubules organize the return of iodinated

follicular cell. Active iodide (I⁻) import is linked to the

thyroglobulin into the cell as endocytotic vesicles of

Na⁺/K⁺-ATPase pump. Thyroglobulin is synthesized

colloid, which is broken down to release thyroid

on the rough endoplasmic reticulum, packaged in the

hormone. TSH, thyroid-stimulating hormone; TPO,

Golgi complex and released from small, Golgi-derived

thyroid peroxidase; T₄, thyroxine; T₃, tri-iodothyronine.

vesicles into the follicular lumen. Its iodination is also

Modified from Williams’ Textbook of Endocrinology,

known as ‘organification’. Cytoplasmic microfilaments

10th edn. Saunders, 2003, p. 332.

170 / Chapter 8: The thyroid gland

Box 8.3 Iodine deficiency

Some areas of the developing world remain

iodine-deficient, which can cause particularly

large goitres (Figure 8.5) and

hypothyroidism. Thyroglobulin in the normal

thyroid stores enough thyroid hormone to

supply the body for ∼2 months. When

dietary I⁻ is limited (<50 µg/day), less is

incorporated into thyroglobulin, providing a

higher proportion of the more active T3

compared to T4. However, eventually thyroid

hormone synthesis fails. Diminished negative

feedback increases TSH secretion, which

Figure 8.5 A large goitre caused by iodine

induces thyroid enlargement (a

deficiency in rural Africa. Note the engorged veins

compensatory mechanism to increase

overlying the gland, implying venous obstruction.

Image kindly provided by Professor David Phillips,

capacity for I⁻ uptake). This may restore

University of Southampton.

sufficient thyroid hormone biosynthesis for

normal circumstances; however, during

pregnancy, the supply of iodine and thyroid

hormones is insufficient for the fetus, which

thyroid hormone. It is synthesized exclusively by the

becomes at risk of severe neurological

follicular cell, such that the small amount in the

damage and may also develop a goitre.

circulation can serve as a tumour marker for thyroid

Post-natally, the syndrome of intellectual

cancer. Tg contains ∼10% carbohydrate, including

impairment, deafness and diplegia (bilateral

sialic acid responsible for the pink PAS staining of

paralysis) has been termed cretinism and

colloid. Tg is transcribed, translated, modified in

affects many millions of infants worldwide.

the Golgi apparatus and then packaged into vesicles

Decreased iodine intake with a marginal but

that undergo exocytosis at the apical membrane to

chronic elevation of TSH may also increase

release Tg into the follicular lumen (Figure 8.4; and

the incidence of thyroid cancer, especially if

review Figures 2.3 and 2.4).

irradiation is involved, as with the Chernobyl

disaster. Prophylaxis with iodine supplements

has reduced the incidence of cretinism,

Iodination of thyroglobulin

although tends not to shrink adult goitres

Tyroid peroxidase (TPO) catalyzes the iodination

effectively. Many countries supplement

of Tg (mature Tg is ∼1% iodine by weight). Te

common dietary constituents such as salt or

enzyme is synthesized and packaged alongside Tg

bread. In extremely isolated communities,

into vesicles at the Golgi apparatus (Figure 8.4).

depot injections of iodized oils can supply

TPO becomes activated at the apical membrane

the thyroid for years.

where it binds I⁻ and Tg (at different sites), oxidizes

I⁻, and transfers it to an exposed Tg tyrosine residue.

Te enzyme is particularly efficient at iodinating

brassicae vegetables (cabbages, sprouts)] may also

fresh Tg; as the reaction proceeds, the efficiency of

inhibit Tg iodination. Tis leads to diminished

adding further I⁻ decreases. Drugs inhibiting TPO

negative feedback at the anterior pituitary causing

and iodination are used to treat hyperthyroidism

TSH secretion to rise (Figure 8.6), which chroni-

(Box 8.4). Some naturally-occurring chemicals [e.g.

cally can stimulate a goitre; hence the chemicals are

milk from cows fed on certain green fodder or from

known as ‘goitrogens’.

Chapter 8: The thyroid gland / 171

The production of thyroid hormone

Box 8.4 Antithyroid drugs -

effective at suppressing the

Iodination of Tg initiates thyroid hormone forma-

tion (Figures 8.3 and 8.4). Within the Tg structure,

synthesis and secretion of thyroid

di-iodotyrosine couples to either mono-iodotyrosine

hormones

or another di-iodotyrosine to generate T₃ or T₄

• Carbimazole

respectively. Tis coupling occurs during the TPO-

• Methimazole (active metabolite of

mediated iodination, yielding thyroid hormone

carbimazole; used in the USA)

stored as colloid in the lumen of the thyroid

• Propylthiouracil (PTU)

follicle.

The secretion of thyroid hormone

To secrete thyroid hormone, colloid is first envel-

oped by microvilli on the cell surface (endocytosis)

Hypothalamus

to form colloid vesicles within the cells that fuse

with lysosomes (Figure 8.4). Te enzymes from the

lysosomes break down the iodinated Tg, releasing

thyroid hormones. Other degradation products are

recycled; for instance, the transporter, Pendrin,

TRH

moves I⁻ back into the follicular lumen. Loss-

of-function mutations in the PENDRIN gene cause

a congenital form of hypothyroidism

(Pendred

syndrome).

Te thyroid hormones move across the basal cell

pituitary

membrane and enter the circulation, ∼80% as T₄

(thyrotroph)

and 20% as T₃.

TSH

Regulation

Te thyroid is controlled by TSH from the anterior

pituitary, which in turn is regulated by thyrotrophin-

releasing hormone (TRH) from the hypothalamus

(review Chapter 5). Tyroid hormone, predomi-

nantly T₃ (the more active), completes the negative

Thyroid

feedback loop by suppressing the production of

TRH and TSH (Figure 8.6). TSH binds to its spe-

cific G-protein-coupled receptor on the surface of

Figure 8.6 The hypothalamic-anterior pituitary-

the thyroid follicular cell and activates both ade-

thyroid axis. The more active hormone, T₃, provides

nylate cyclase and phospholipase C (review Chapter

the majority of negative feedback. TRH, thyrotrophin-

3). Te former predominates and cAMP mediates

releasing hormone; TSH, thyroid-stimulating

most of the actions of TSH (Box 8.5). Tis increases

hormone.

fresh thyroid hormone stores and, within

∼1 h,

increases hormone release. Te most recently syn-

thesized Tg is the first to be resorbed as it is nearest

to the microvilli. Tis Tg has also had less time to be

iodinated than the mature, central colloid, such that

172 / Chapter 8: The thyroid gland

Box 8.5 Thyroid-stimulating

Box 8.6 Circulating thyroid

hormone action on the follicular

hormones

cell

• Thyroid hormones are almost entirely

Increases

bound to serum proteins (in order of

• Intracellular cAMP concentration

decreasing affinity):

• Tg iodination

° Thyroxine-binding globulin (TBG)

• Apical microvilli number and length

° Thyroxine-binding pre-albumin (TBPA)

• Endocytosis of colloid droplets

° Albumin

• Thyroid hormone release

• The unbound fraction is tiny, yet

• I⁻ influx into the cell (relatively late effect

critical - only free thyroid hormone enters

as activation of the I⁻ pump requires

cells and is biologically active:

protein synthesis)

° Free T4 (fT4) ∼0.015% of total T4

• Cellular metabolism

° Free T3 (fT3) ∼0.33% of total T3

• Protein synthesis (including Tg)

° Circulating half-life of T3, ∼1-3

• DNA synthesis

days - needs to be prescribed several

times a day if used to achieve steady

levels

° Circulating half-life of T4, ∼5-7

days - can be prescribed as single daily

it releases thyroid hormone with a relatively higher

dose

T₃:T₄ ratio and, consequently, greater activity.

° Both fT4 and fT3 are measured by

immunoassay

Circulating thyroid hormones

• T₃ is more potent than T₄ (∼2-10-fold

depending on response monitored)

From ∼3 days after birth serum levels of free thyroid

hormones remain relatively constant in normal

individuals throughout life. Tyroid hormones are

T₄ (de-iodination) (Figures 8.3 and 8.7). Tis step

strongly bound to serum proteins, with only a tiny

is catalyzed by selenodeiodinase enzymes, which

amount free to enter and function in cells (Box 8.6).

contain selenium that accepts the iodine from the

Te free (f )T₃ concentration is ∼30% that of fT₄

thyroid hormone. Selenium deficiency in parts of

to each of

T₃ is bound slightly less strongly than T₄

western China or Zaire can be a rare contributory

the three principal serum-binding proteins. Te

factor to hypothyroidism. Type 1 selenodeiodinase

interaction with albumin is relatively non-specific.

(D1) predominates in the liver, kidney and muscle,

Total thyroid hormone levels can alter. For

and is responsible for producing most of the circu-

instance, some drugs, such as salicylates, phenytoin

lating T₃. It is inhibited by PTU (Box 8.4 and

or diclofenac, which structurally resemble iodothy-

Figure 8.7). Te type 2 enzyme (D2) is predomi-

ronine isoforms, can compete for protein binding;

nantly localized in the brain and pituitary, key sites

starvation or liver disease lowers the concentration

for regulating T₃ production for negative feedback

of binding proteins. However, free thyroid hormone

at the hypothalamus and thyrotroph. Te third

concentrations remain essentially unaltered.

selenodeiodinase, D3, de-iodinates the inner ring

and converts T₄ to rT₃ (Figures 8.3 and 8.7). rT₃ is

biologically inactive and cleared very rapidly from

Metabolism of thyroid hormones:

the circulation (half-life ∼5 h). D3 action on T₃ is

conversion of T₄ to T₃ and rT

one method by which inactive T₂ is generated.

T₃ is the more active hormone, yet only 20% of

Tese combined steps are important: at least in part,

thyroid hormone output. Most T₃ is generated by

T₄ can be thought of as a ‘prohormone’; when a

removing one iodine atom from the outer ring of

given cell has sufficient T₃, it can limit its exposure

Chapter 8: The thyroid gland / 173

Circulation and peripheral tissues

Minor

15%

T₄

degradative

Thyroid

80%

45%

pathways

PTU

40%

Inactive

reverse

T₃

20%

Rapidly

Biological

excreted

activity

Inactive

Brain and pituitary thyrotroph

Negative feedback

T₄

T₃

on TRH and TSH

Figure 8.7 Metabolism of thyroid hormones in the

T₃ to T₂ by D3 is shown, although other pathways

circulation. Four times more T₄ is produced by the

also exist for this reaction. The type 2

thyroid gland than T₃. Under normal ‘euthyroid’

selenodeiodinase (D2) is predominantly located in

physiology, ∼40% of circulating T₄ is converted to

the brain and pituitary gland where it catalyzes the

active T₃ by type 1 selenodeiodinase (D1; inhibited

production of T₃ for negative feedback at the

by propylthiouracil - see Box 8.4) and ∼45% of T₄ is

hypothalamus and anterior pituitary. TRH,

converted to rT₃ by the type 3 selenodeiodinase

thyrotrophin-releasing hormone; TSH, thyroid-

(D3). The remaining 15% of T₄ is degraded by minor

stimulating hormone.

pathways, such as deamination. The conversion of

to further thyroid hormone action by switching to

T₃ acts in the target cell nucleus as a ligand for

rT₃

generation (review Table 3.2).

the thyroid hormone receptor (TR), which itself

functions as a transcription factor altering gene

expression (review Chapter 3 and Figure 3.20). It

Function of thyroid hormones

binds TR with a 15-fold greater affinity than T₄,

Tyroid hormones affects a vast array of tissue and

which is the main reason why T₃ is the more potent

cellular processes, most obviously increasing meta-

hormone. Te predominantly genomic action

bolic rate, but also influencing the actions of other

explains why most effects of thyroid hormones

hormones. For instance, they synergize with cate-

occur slowly, in days rather than minutes or hours.

cholamines to increase heart rate, causing palpita-

TR is not identical in all tissues. Tere are

tions in thyrotoxicosis. In amphibians, thyroid

two predominant isoforms, TRα and TRβ, each

hormones cause metamorphosis, a highly complex

encoded by different genes and each subject to alter-

reprogramming of several internal organs and the

native promoter use and/or mRNA splicing (review

growth of limbs.

Figure

2.2). Tis creates a number of receptor

174 / Chapter 8: The thyroid gland

sub-types, all of which perform the basic activities

to its own thyroid hormone levels. Low TSH indi-

of binding thyroid hormone, binding DNA and

cates hyperthyroidism; raised TSH indicates

influencing target genes, but with subtly different

hypothyroidism. Te normal range for serum TSH

efficacy. Clinically, this can be evidenced in the rare

is wide (~0.3-5.0 mU/L) but for the large majority

condition of thyroid hormone resistance caused by

of the population, TSH is less than 2.0 mU/L.

mutations mostly located in the TRβ gene. Some

Pituitary underactivity can reduce TSH levels

tissues show thyroid hormone overactivity

(e.g.

and cause secondary hypothyroidism, in which case

tachycardia), while the pituitary thyrotroph

it is very important to consider the other pituitary

responds as if thyroid hormone is inadequate (i.e.

hormone axes, which might also be underactive.

TSH secretion is maintained or slightly raised).

Similar TFT results may be seen in patients suffer-

ing from physical (or in some instances psychiatric)

illnesses that do not directly involve the thyroid

Thyroid function tests

gland. Severe illness in a patient is usually obvious,

Clinical investigation of thyroid activity hinges upon

when fT₄, and especially fT₃, may fall below normal

immunoassay of circulating free thyroid hormones

without a compensatory increase in TSH. Te

and TSH, in combination termed thyroid function

body’s type 1 selenodeiodinase activity is low. Tis

tests

(TFTs). Tey indicate whether the thyroid

condition is referred to as the ‘sick euthyroid’ syn-

gland is overactive

(‘hyperthyroid’), underactive

drome. Although contentious, treatment is not nor-

(‘hypothyroid’) or normal (‘euthyroid’) (Table 8.1).

mally undertaken. If recovery occurs, T₃ and T₄

Interpretation is based on understanding negative

spontaneously return to normal. In pregnancy, TSH

feedback (Figure 8.6 and review Chapter 1). Serum

is low in the first trimester, as human chorionic

TSH is the critical measurement as, in the absence

gonadotrophin (hCG) from the placenta mimics

of pituitary disease, it illustrates the body’s response

TSH action (see Chapter 7).

Table 8.1 Interpretation of thyroid function tests

Test results

Interpretation

TSH

fT₄

fT₃

Normal

Euthyroidism

Low

High

Primary hyperthyroidism

Low

(High) normal

Sub-clinical primary hyperthyroidism or early

pregnancy

Low

Normal

High

T₃-toxicosis

High/normal

High

Pituitary (secondary) hyperthyroidism or thyroid

hormone receptor mutation; both are very rare

High

Low

Primary hypothyroidism

High

(Low) normal

Sub-clinical primary hypothyroidism

Low

Consider secondary hypothyroidism (assess other

pituitary hormone axes)

Normal/low

Low

‘Sick euthyroid’ syndrome

For simplicity, higher axis disorders have been listed as secondary, i.e. pituitary, although tertiary hypothalamic disease is

possible.

Chapter 8: The thyroid gland / 175

Clinical disorders

later). Tis common genetic predisposition leaves the

patient at increased risk of other autoimmune endo-

Te major clinical disorders affecting the thyroid

crinopathies as part of type 2 autoimmune polyglan-

gland arise from over- or under-activity, goitre or

dular syndrome (APS-2, see Chapter 9 for APS-1)

cancer.

(Box 8.8). In autoimmune hypothyroidism, an exten-

sive lymphocytic infiltration is accompanied by auto-

Hypothyroidism

antibodies blocking the TSH receptor and also

directed against Tg and TPO. Progressive destruction

Tyroid hormone deficiency is most commonly a

of thyroid follicular tissue results in hypothyroidism.

primary disease of the thyroid (primary hypothy-

Riedel thyroiditis is rare and results from pro-

roidism) and less frequently caused by deficiency

gressive fibrosis that causes a hard goitre. Congenital

of TSH (secondary hypothyroidism)

(Box 8.7).

failure of thyroid gland formation, migration or

Tertiary hypothyroidism, which results from loss of

hormone biosynthesis

(∼1/4000 births) usually

hypothalamic TRH, is rare.

presents early to the paediatric endocrinologist; the

biosynthetic defects, collectively called ‘thyroid dys-

Primary hypothyroidism

hormonogenesis’, usually present with goitre. Along

In the western world, thyroid underactivity from

with testing for phenylketonuria (the eponymously

autoimmune attack on the gland is very common. It

named Guthrie test) and other conditions, using a

is six-fold more frequent in women than men and

dried blood spot to measure TSH in the neonatal

incidence increases with age

(up to 2% of adult

period is aimed at early postnatal detection of con-

women). Tis autoimmune thyroiditis can be classi-

genital hypothyroidism (see Table 8.1).

fied by the presence

(Hashimoto thyroiditis) or

Some exogenous factors can lead to thyroid

absence (atrophic thyroiditis or primary myxoedema)

underactivity. Excessive iodine intake, such as from

of goitre. However, the disease process is essentially

radiocontrast dyes, can transiently block synthesis

the same for both and even overlaps with that of

and hormone release. Lithium, used in the treat-

hyperthyroidism secondary to Graves disease

(see

ment of bipolar disorder, can do the same. Indeed,

lithium and iodine (either as potassium iodide or

Lugol’s iodine) can be used to control hyperthy-

Box 8.7 Causes of hypothyroidism

roidism temporarily (see next section).

Primary

• Goitre

Box 8.8 Organ-specific

° Autoimmune Hashimoto thyroiditis

autoimmune diseases with shared

° Iodine deficiency (Box 8.3 and Figure 8.5)

genetic predisposition (type 2

° Drugs (e.g. lithium)

° Riedel thyroiditis

autoimmune polyglandular

° Congenital hypothyroidism

syndrome)

- dyshormonogenesis

• Autoimmune hyperthyroidism (Graves

• No goitre:

disease)

° Autoimmune atrophic thyroiditis

• Autoimmune hypothyroidism

° Post-radioiodine ablation or surgery (see

• Addison disease (see Chapter 6)

treatment of hyperthyroidism)

• Type 1 diabetes mellitus (see Chapter 12)

° Post-thyroiditis (hypothyroidism is

• Premature ovarian failure (see Chapter 7)

transient)

• Pernicious anaemia:

° Congenital hypothyroidism - hypoplasia

° Destruction of the parietal cells with loss

or aplasia

of intrinsic factor secretion causing

Secondary/tertiary

vitamin B₁₂ deficiency

• Pituitary or hypothalamic disease (assess

• Autoimmune atrophic gastritis

other hormone axes)

• Coeliac disease

176 / Chapter 8: The thyroid gland

Viral infection, e.g. Echo or Coxsackie

Box 8.9 Symptoms, signs and

virus, can cause painful inflammation of the

features of hypothyroidism

thyroid and release of stored hormone. A brief

thyrotoxicosis is followed by transient hypothy-

• Weight gain

roidism and is known as ‘De Quervain’s subacute

• Cold intolerance, particularly at extremities

thyroiditis’.

• Fatigue, lethargy

• Depression

• Coarse skin and puffy appearance

• Dry hair

Symptoms and signs

• Hoarse voice

Hypothyroidism in adults lowers metabolic rate.

• Constipation

Common symptoms and signs are listed in Box 8.9

• Menstrual irregularities (altered luteinizing

(Case history 8.1). Te facial appearance and the

hormone/follicle-stimulating hormone

potential for carpal tunnel syndrome are caused by

secretion)

the deposition of glycosaminoglycans in the skin.

• Possible goitre

Children tend to present with obesity and short

• ‘Slow’ reflexes, muscles contract normally,

stature. Distinguishing between hypothyroidism

but relax slowly

that is permanent (treatment mandatory) and tran-

• Generalized muscle weakness and

sient (treatment usually not needed) is important.

paraesthesia

Short-lived symptoms (less than a few months)

• Bradycardia (with reduced cardiac

preceded by sore throat or upper respiratory tract

output)

infection may indicate the latter. Permanent

• Cardiomegaly (with possible pericardial

hypothyroidism is more likely if other family

effusion)

members have thyroid disease. A drug history

• Possible carpal tunnel syndrome

should be taken and questions should address

• Loss of outer third of eyebrows (reason

the chance of other coincident endocrinopathies

unclear)

(Box 8.8).

Case history 8.1

A 45-year-old woman attended her doctor having felt ‘not quite right’ for the last 6 months. She

was tired and her hair had been falling out. She had noticed her periods being heavy and

rather erratic and wondered whether she was entering the menopause. She had put on 5 kg

during the last 6 months. The doctor did some blood tests: Na⁺ 134 mmol/L (134 mEq/L), K⁺

3.8 mmol/L (3.8 mEq/L), urea 4.2 mmol/L (∼11.8 mg/dL), creatinine 95 µmol/L (∼1.1 mg/dL), TSH

23.4 mU/L, fT₄ 6.7 pmol/L (∼0.5 ng/dL), Hb 112 g/L, gonadotrophins were normal.

What is the endocrine diagnosis and why?

What is the treatment?

What is the potential significance of the haemoglobin level?

Answers, see p. 187

Chapter 8: The thyroid gland / 177

Investigation and diagnosis

assessed by repeat TFTs 6 weeks later (the pituitary

TFTs are mandatory as thyroid disease can be insid-

thyrotroph responds sluggishly to acute changes in

ious, especially primary hypothyroidism in the

thyroid hormones). Tyroxine may need slight

elderly

(see Table

8.1). Four scenarios are com-

increases or decreases until the correct replacement

monly encountered.

dose is reached. In patients with long-standing

hypothyroidism and co-existing ischaemic heart

• Raised TSH at least twice the normal upper limit

disease, graded introduction of replacement therapy

(can be >10-fold increased) plus thyroid hormone

over several weeks is frequently used (e.g. escalate

levels clearly below the normal range. Tis diagnosis

from a starting dose of 25 µg/day). A final caveat to

of primary hypothyroidism is clear-cut. When

initiating treatment is to be confident of excluding

accompanied by long-standing symptoms, underac-

Addison disease (see Chapter 6), a clue to which

tivity will be permanent.

might be hyperkalaemia or postural hypotension.

• Raised TSH at least twice the normal upper limit

Increasing basal metabolic rate with thyroxine

with normal thyroid hormone levels. Te biochemis-

increases the body’s demand for an already vulnerable

try implies compensation to try and retain normal

cortisol supply and can send a patient into Addisonian

thyroid hormone levels. With significant symptoms,

crisis. Te rare, yet high, mortality clinical scenario

treatment is worthwhile. Even as sub-clinical

of myxoedema coma is summarized in Box 8.10.

hypothyroidism, treatment can be justified, as ulti-

mately the gland is likely to fail and produce frank

hypothyroidism, especially if auto-antibodies are

Box 8.10 Myxoedema coma: very

detected or if there is a family history of thyroid

severe hypothyroidism

disease.

• TSH is only moderately raised and thyroid

Features

hormone levels are normal. Tese patients have an

• Diminished mental function → confusion

increased progression to frank hypothyroidism and,

→ coma

in the presence of significant symptoms, a therapeu-

• Usually in the elderly

tic trial of thyroxine is one option. If the results are

• Hypothermia

an incidental finding, repeat testing over the follow-

• Low cardiac output/cardiac failure

ing months is an alternative, especially if there is

• Pericardial effusion

concern over a transient viral hypothyroidism.

• Hyponatraemia and hypoglycaemia

• All aspects of the TFTs are unequivocally normal.

• Hypoventilation

Do not treat with thyroxine, regardless of symp-

toms, as the patient is not hypothyroid.

Management

• Identify any precipitating cause (e.g.

Other investigations are commonly not needed;

infection)

however, if measured, a raised titre of thyroid auto-

• Gradual re-warming

antibodies may be detected. Creatinine kinase may

• Supportive ITU management (protect

be elevated. Dyslipidaemia is common with raised

airway in coma, oxygen, broad-spectrum

low-density lipoprotein (LDL)-cholesterol. Serum

antibiotics, cardiovascular monitoring,

prolactin may be elevated (stimulated by increased

glucose, monitor urine output)

TRH secretion; see Chapter 5).

• Take blood for TFTs

• Treat with hydrocortisone until

hypoadrenalism excluded

Treatment

• Thyroid hormone replacement - both oral

Clear-cut hypothyroidism requires life-long replace-

and intravenous T₄ and T₃ have been

ment with oral thyroxine (T₄, 100 µg/day is the

advocated with no clear consensus

starting point for standard adult replacement; ∼100

• Recognize and counsel that even with

µg/m²/day in children). Te goal of replacement is

treatment, mortality is high

to normalizeTSH, ideally in the range 0.5-2.0 mU/L,

178 / Chapter 8: The thyroid gland

Monitoring

a viral infection or overdose of oral thyroxine will

Once stable, TFTs can be measured annually,

cause transient thyrotoxicosis, but this is not hyper-

although replacement rarely changes. Compliance

thyroidism. Most commonly, hyperthyroidism has

issues can be encountered where fT₄ is normal (the

an autoimmune origin, is 10-fold more common in

patient took a tablet prior to clinic) but TSH is raised

women than men, and is named after its discoverer,

(chronically, the patient is missing tablets). Despite

Tomas Graves. Other causes are associated with

large trials, there is no convincing evidence that treat-

the antiarrhythmic drug amiodarone and over-

ment with T₃ is better than with thyroxine. T₃ needs

production of hormone from an autonomous

to be taken three times daily and usually only worsens

thyroid nodule, either single or part of a multinodu-

adherence. All other forms of thyroid hormone

lar goitre. Occasionally, thyroid overactivity can be

replacement (e.g. ‘natural’ gland extracts sold over

a feature of the first few months of pregnancy asso-

the internet) are unregulated and are to be avoided.

ciated with hyperemesis. Te pathology involves

high human chorionic gonadotrophin (hCG) levels

capable of signalling via the TSH receptor (see preg-

Secondary hypothyroidism

nancy in Chapter 7). Overactivity from excess TSH

If the anterior pituitary thyrotrophs are underactive,

is incredibly rare.

TSH-dependent thyroid hormone production fails

(see Chapter 5). Te principle of thyroxine treat-

Graves disease

ment is similar to that in primary hypothyroidism,

Autoimmune hyperthyroidism affects

∼2% of

although TSH is no longer a reliable marker of

women in the UK. Its immune pathogenesis

adequate replacement. Te easiest approach is to

includes thyroid-stimulating IgG antibodies that

treat with sufficient thyroxine for fT₄ to lie in the

activate the TSH receptor on the follicular cell

upper half of the normal range and for fT₃ also to

surface (Box 8.5), leading to hyperthyroidism and,

lie within the normal range.

in many cases, goitre (Figure 8.8).

Hyperthyroidism

Symptoms and signs

Hyperthyroidism is thyroid overactivity causing

Te natural history of Graves disease is waxing and

increased circulating thyroid hormones (thyrotoxi-

waning. However, the diagnosis is important as

cosis). Note that release of stored hormone during

symptoms are unpleasant, potentially serious, yet

At rest

On swallowing

Figure 8.8 Hyperthyroidism caused by Graves disease in a young woman. The dotted outline in the line drawing

illustrates the position of the goitre visible at rest in the central image. The broken line and arrowhead illustrate

the goitre’s lower margin. Upon swallowing (right image), the goitre rises in the neck; its lower margin is

demarcated by the stepped arrow.

Chapter 8: The thyroid gland / 179

Box 8.11 Symptoms and signs of

Box 8.12 3-min clinical

thyrotoxicosis plus features

assessment of the thyroid and

associated with Graves disease

thyroid hormone status

• Weight loss despite full, possibly

• General inspection:

increased, appetite

° Is there obvious goitre (Figure 8.8) or

• Tremor

thyroid eye disease (Figure 8.9)?

• Heat intolerance and sweating

° Is the patient appropriately dressed for

• Agitation and nervousness

the temperature?

• Palpitations, shortness of breath/

° Is the patient underweight, normal

tachycardia ± atrial fibrillation

weight or overweight?

• Amenorrhoea/oligomenorrhoea and

° Note nearby pill containers or medicines

consequent subfertility

(e.g. lithium or throat lozenges)

• Diarrhoea

• Start with the hands:

• Hair loss

° Are they warm and sweaty? Is there

• Easy fatigability, muscle weakness and

onycholysis (detachment of the nail from

loss of muscle mass

the nail bed) or palmar erythema?

• Rapid growth rate and accelerated bone

° Is there thyroid acropachy (similar to

maturation (children)

clubbing)?

• Goitre, diffuse and reasonably firm ± bruit

° Place sheet of paper on outstretched

in Graves disease (Figure 8.8)

hands to assess tremor

° Assess rate and rhythm of the radial

Extra-thyroidal features associated with

pulse

Graves disease

° Briefly assess character of pulse at the

• Thyroid eye disease, also called Graves

brachial artery

orbitopathy (Figure 8.9)

• Inspect front of neck, ask patient to

• Pretibial myxoedema - rare, thickened skin

swallow with the aid of a sip of water; is

over the lower tibia (Figure 8.9d)

the neck tender?

• Thyroid acropachy (clubbing of the

• Move behind patient to palpate neck - is

fingers)

there a goitre? If so:

• Other autoimmune features, e.g. vitiligo

° Assess size and movement on

swallowing (Figure 8.8)

° Can the lower edge be felt (if not, it may

amenable to treatment. Te commonest symptoms

extend retrosternally)?

are attributable to an increased basal metabolic rate

° Assess quality (e.g. firm, soft or hard)

and enhanced β-adrenergic activity (Box 8.11and

° Is it symmetrical?

Case history 8.2). Additional features specific to

° Palpate for lymphadenopathy, especially

Graves disease are caused by the autoimmune

if there is a goitre in a euthyroid patient

disease process affecting other sites in the body.

• Percuss for retrosternal extension

Tyroid acropachy and pre-tibial myxoedema are

• Auscultate for a bruit

caused by cytokines that stimulate the deposition of

• Examine for other features of Graves

glycosaminoglycans. (Figure 8.9d)

disease (thyroid eye disease, pre-tibial

Efficient clinical assessment of thyroid status is

myxoedema)

required (Box 8.12).

Investigation and diagnosis

Tyrotoxicosis requires biochemical proof of sup-

pressed TSH and raised free thyroid hormone levels

180 / Chapter 8: The thyroid gland

(Table 8.1). In the absence of extra-thyroidal fea-

drug and requires further treatment. Te risk of

tures (e.g. Graves orbitopathy or pre-tibial myxo-

falling into the last group is increased for men, or

edema), additional tests may help to distinguish

those presenting with a particularly high fT₄

between Graves disease and other forms of hyper-

[e.g. >60 pmol/L

(4.7 ng/dL)] or large goitre,

thyroidism. Tere may be elevation of the titre of

and for those in whom TSH remains suppressed

anti-Tg and anti-TPO antibodies, which are more

despite antithyroid drug treatment that normalizes

commonly assayed than anti-TSH receptor anti-

serum fT₄.

bodies (the disease-relevant auto-antibody); thyroid

ultrasound should show generalized increased vas-

Surgery

cularity in Graves disease (features that correlate to

If drugs fail or if a prompt definitive outcome is

a bruit on auscultation); and radionuclide scans

required (e.g. in pregnancy), sub-total or increas-

[commonly using iodine-123 (I¹²³) which has a

ingly commonly total thyroidectomy can be used so

short half-life] may show diffuse (Graves disease),

long as the patient is adequately blocked pre-

patchy

(toxic multinodular goitre) or localized

operatively. Operating on an acutely overactive

uptake (a single toxic nodule). Transient hyperthy-

gland risks ‘thyroid storm’ when physical handling

roidism will appear normal on ultrasound and have

releases huge stores of hormone, causing raging,

normal isotope uptake.

life-threatening thyrotoxicosis. Over weeks pre-

operatively, carbimazole can be used to achieve bio-

chemical euthyroidism; more acutely, Lugol’s iodine

Treatment

or potassium iodide temporarily blocks thyroid

Tere are three options for treatment.

hormone release. Sub-total thyroidectomy leaves

a small amount of tissue to try and minimize the

risk of post-operative hypothyroidism (Box 8.7).

Antithyroid drugs

Complications include: bleeding; damage to the

Since Graves disease waxes and wanes, a valid

recurrent laryngeal nerve controlling the laryngeal

approach is to block hyperthyroidism until remis-

muscles and voice; and transient or permanent

sion. It is common to maintain patients on antithy-

hypoparathyroidism from damage or removal of the

roid drugs (Box 8.4) for 12-18 months and then to

parathyroids (see Chapter 9). Te scar, parallel to

withdraw treatment to test for spontaneous remis-

natural skin creases, usually becomes barely notice-

sion. During this period, TFTs are needed to ensure

able over time.

biochemical euthyroidism (i.e. thyroid hormones in

the normal range). A high dose of drug can be

started

(e.g. carbimazole 40 mg/day) and titrated

Radioiodine

down according to falling fT₄ levels on TFTs.

Iodine-131 (I¹³¹) can be used to treat thyroid over-

Alternatively, antithyroid drugs can be maintained

activity. It requires the same preparation as surgery

at high dose in combination with thyroxine (100 µg

to avoid thyroid storm. In the UK, I¹³¹ has tended

/day) as a ‘block and replace’ regimen. Very rarely,

to be reserved for women who have completed their

antithyroid drugs can cause agranulocytosis and the

family, although there is little evidence to suggest

patient must be warned to attend for a blood neu-

that the radiation increases tumour risk or dimin-

trophil count in the event of sore throat or fever.

ishes fertility. It is used more liberally in Europe. It

Rash is a common side-effect and may settle with

is taken orally and absorbed by the stomach.

hydrocortisone cream.

Compared to surgery it carries no risk to surround-

Te success of antithyroid drug treatment can

ing structures but it is more likely to induce perma-

be broken down into three categories: approxi-

nent hypothyroidism than sub-total thyroidectomy;

mately one-third of patients remits and remains

the patient needs pre-operative counselling, postop-

well; one-third remits but relapses at some future

erative monitoring and, in all likelihood, life-long

time; and one-third relapses soon after stopping the

thyroxine replacement. I¹³¹ is contraindicated in

Chapter 8: The thyroid gland / 181

pregnancy, children, thyroid eye disease

(it can

Case history 8.2

make this worse) and incontinence. It is also inap-

propriate where small children or babies need close

A 32-year-old man attended his doctor

contact with the patient in the immediate post-

having lost 10 kg in weight and with poor

administration period.

sleep. He felt on edge and had had

For all three treatment approaches, β-blockers,

difficulty concentrating at work. He

most commonly propranolol, can be used to control

smokes five cigarettes/day. Colleagues

the symptoms of adrenergic excess, especially as

had commented on his staring

antithyroid drugs take two weeks to have much

appearance. The doctor completes the

effect. As a minor effect, propranolol also inhibits

history and examination and takes a blood

selenodeiodinase, thus tending to prevent the con-

test. He knew the likely diagnosis

version of T4 to T3.

beforehand, however, the results provided

proof: TSH less than 0.01 mU/L, fT₄

Graves disease in pregnancy

82.7 pmol/L (∼6.5 ng/dL), fT₃ 14.2 pmol/L

Autoimmune disorders, including Graves disease,

(∼0.9 ng/dL).

tend to ameliorate during pregnancy. A common

What is the biochemical diagnosis and

scenario is one of relative subfertility while hyper-

why?

thyroidism is undiagnosed, followed by pregnancy

What features of the examination could

once treatment becomes effective. If surgery to the

have implied the diagnosis without the

mother’s thyroid is required during pregnancy, it is

blood test?

best planned for the second trimester. Post-partum,

Describe a suitable management plan?

the relative immunosuppression of pregnancy abates

Once the thyrotoxicosis has settled, what

and Graves disease may relapse. Monitoring TFTs

definitive treatment of hyperthyroidism

is warranted.

might be ill-advised at present?

Two scenarios can arise in the fetus during

pregnancy:

Answers, see p. 188

• If blocking the mother’s thyroid, the minimum

dose should be used and ‘block and replace’ avoided

as antithyroid drugs cross the placenta more effi-

Thyroid eye disease (Graves orbitopathy)

ciently than thyroxine, risking fetal hypothyroidism.

As carbimazole increases the risk of aplasia cutis (a

Te same autoimmune inflammation that affects

rare scalp defect), propylthiouracil (PTU) has been

the thyroid can also affect the extra-ocular muscles

preferred in the past. However, PTU has recently

of the orbit, causing Graves orbitopathy, also known

acquired a US Food & Drug Administration alert

as ophthalmopathy (Table 8.2 and Figure 8.9). It is

for idiosyncratic liver toxicity. Monitoring LFTs in

most commonly synchronous with hyperthyroidism

each trimester should be considered.

when it confirms Graves disease as the cause of

• In ∼1% of mothers with Graves disease, past or

thyrotoxicosis. However, it is possible for thyroid

present, high levels of thyroid-stimulating antibod-

eye disease to occur separately. For reasons that are

ies cross the placenta. Fetal hyperthyroidism is

unclear, it is much worse in smokers.

easy to miss if the mother has had previous defini-

Symptoms of grittiness are common, for which

tive treatment (surgery or I¹³¹) and is euthyroid.

liquid teardrops are effective. All but minor thyroid

Fetal heart rate is a useful guide to fetal thyroid

eye disease warrants referral to ophthalmology (Case

status and goitre may be visible on fetal ultrasound.

history 8.3). Patients who can no longer close their

If needed, antithyroid drugs can be used. After

eyes because of proptosis (forward displacement of

delivery, symptoms recede as maternal antibodies

the orbit; Figure 8.9) are at risk of ulcerated cornea;

are cleared.

taping the eyelids closed may be necessary at night.

182 / Chapter 8: The thyroid gland

Table 8.2 Symptoms, signs and examination of thyroid eye disease

Symptoms and signs

Gritty, weepy, painful eyes

Retro-orbital pain

Difficulty reading

Diplopia

Loss of vision

‘Staring’ appearance (Figure 8.9a)

Proptosis (Figure 8.9b)

Periorbital oedema and chemosis (redness; Figure 8.9c) of the conjunctiva

Injection (redness) over the insertion point of lateral rectus (Figure 8.9c)

Lid retraction

Examination

Inspect from the front for signs of inflammation and lid retraction

Is the sclera visible around the entire eye (this is not normal) (Figure 8.9a)?

Inspect from the side for proptosis

Assess eye movements from the front asking the patient to report double

vision

Assess visual fields

Ask the patient to look away while retracting the lateral portion of each eyelid

in turn. The insertion point of lateral rectus is visible

Is it inflamed?

Assess whether the patient can close the eyelids completely

Although cosmetically undesirable, proptosis acts as

radiotherapy is contentious. Surgery can relieve

a safeguard, relieving the retro-orbital pressure from

sight-threatening compression. Te natural disease

swollen muscles. A relatively normal external

history is for regression, leaving fibrosed muscles

appearance associated with retro-orbital pain or

such that diplopia may remain; however, at this late

visual disturbance is worrying as pressure on the

stage, corrective surgery is highly effective.

optic nerve risks loss of vision.

Te degree of retro-orbital inflammation and

compression can be assessed by magnetic resonance

Amiodarone-associated thyroid disease

imaging (MRI). Treatment begins with advice to

stop smoking. Carbimazole possibly possesses some

Amiodarone is frequently used in cardiology to treat

immunosuppressive qualities, so ‘block and replace’

arrhythmias. It contains a lot of iodine and has a

(see earlier) may be useful if there is co-existing

half-life longer than 1 month. In addition to poten-

thyroid disease. Radioiodine is contraindicated

tial pulmonary fibrosis, it causes disordered TFTs

during active orbitopathy. Anti-inflammatory or

in as many as 50% of patients as well as frank

immunosuppressive agents such as glucocorticoid

hyperthyroidism or hypothyroidism in up to 20%

or azathioprine can be used. Te efficacy of orbital

(Box 8.13 and Case history 8.4).

184 / Chapter 8: The thyroid gland

Case history 8.4

An 81-year-old man was referred by the cardiologist with TSH less than 0.14 mU/L, fT₄

32.4 pmol/L (∼2.5 ng/dL), and fT₃ 6.2 pmol/L (0.4 ng/dL). He has been taking amiodarone for the

last 6 months for supraventricular arrhythmia. On questioning he has shortness of breath.

Give three possible causes of the mild thyrotoxicosis.

If considered to be hyperthyroidism, what treatment would restore euthyroidism?

Give one drug-related reason why the patient might be short of breath.

Answers, see p. 189

Box 8.13 Amiodarone affects the thyroid gland and thyroid function tests

Effects on peripheral hormone metabolism and

• Potential thyroid toxicity by causing

TFTs

thyroiditis (type 2 amiodarone-induced

• fT₃ slightly decreased

inhibition of D1

thyrotoxicosis), possibly followed by

• fT₄ slightly increased

nd D2 activity

hypothyroidism

• rT₃ formation increased

(Figure 8.7)

• Transient TSH increase

Treatment

• Hypothyroidism: thyroxine

Amiodarone-associated hypothyroidism

• Hyperthyroidism:

• Iodine content may inhibit hormone

° Consider withdrawal of amiodarone (but

synthesis and release

treatment may be needed during long

washout period)

Amiodarone-associated hyperthyroidism

° Try carbimazole

• Iodine content may stimulate overactivity in

° I¹³¹ uptake may be limited as thyroid

susceptible individuals (type 1 amiodarone-

already loaded with iodine

induced thyrotoxicosis)

° If drugs fail, surgery can be considered

Toxic adenoma

uptake scans will demonstrate the lesion. Unlike

Graves disease, spontaneous remission does not

Hyperthyroidism other than Graves disease is

occur and definitive treatment with surgery or I¹³¹

usually secondary to autonomous function of a

radioiodine is indicated. With thyroid lobectomy or

benign adenoma (a single ‘toxic nodule’) or domi-

with radioiodine (when the remainder of the gland

nant nodule(s) within a multinodular goitre (see

is quiescent and will not take up the I¹³¹), the risk

below). Occasionally, nodules secrete an excess of

of post-treatment hypothyroidism is low.

T₃ to cause ‘T₃-toxicosis’ with normal fT₄ levels (a

specific request to the laboratory may be needed to

Single thyroid nodules and multinodular

measure serum fT₃).

goitre

Such patients will not have the diffuse and sym-

metrical goitre of Graves disease, nor will they have

For nodules that are not functional

(i.e.

‘cold’

signs of Graves eye disease. Ultrasound and I¹²³

nodules that lack I¹²³ uptake in a euthyroid patient),

Chapter 8: The thyroid gland / 185

the critical diagnosis to exclude is thyroid malig-

Case history 8.5

nancy (see Box 8.14):

A 55-year-old woman who had lived in the

• Single cold nodules must always be regarded with

UK all her life attended her family doctor

suspicion

because of a sense of fullness in her neck.

• Multinodular goitres contain many colloid-filled

It had been present for at least 5 years and

follicular nodules. Frequency is increased in women,

had not changed in nature but was perhaps

with age and with iodine deficiency. Te pathogen-

minimally larger. The patient was worried.

esis is unclear, although clinically, they almost

The doctor examined her and discovered a

always behave benignly.

non-symmetrical firm mass either side of

and close to the midline at the base of her

Absence of lymphadenopathy, no family history

neck that moved on swallowing. There was

of thyroid cancer, no rapid growth, no alteration of

no palpable lymphadenopathy. There was

voice, and a goitre that moves freely on swallowing

no family history of cancer. TSH 1.34 mU/L,

(as shown in Figure 8.8) are all reassuring features.

fT₄ 21.4 pmol/L (∼1.7 ng/dL), fT₃ 4.7 pmol/L

Fine needle aspiration cytology (FNAC) under

(∼0.3 ng/dL).

ultrasound guidance is an excellent modality to

investigate nodules greater than 0.5 cm diameter.

What is the likely diagnosis?

Whether and when nodules require FNAC is

What further investigation would help

debatable. Te American Tyroid Association has

provide complete reassurance?

comprehensive recommendations governed by

What follow-up might be suggested?

ultrasound characteristics and clinical suspicion.

Answers, see p. 189

FNAC tends to produce four results: normal, suspi-

cious, malignant and ‘non-diagnostic’. Pragmatically,

if history (Box 8.14) and ultrasound are encourag-

ing, and histology is normal, FNAC should be

Thyroid cancer

repeated once after a few months for reassurance.

In part, this caution has been precipitated by histol-

Te various types of thyroid cancer have quite dif-

ogy showing atypical cells even in clinically benign

ferent prognoses (Table 8.3). Tere is a female pre-

goitres. For suspicious, malignant and non-

dominance, but as all thyroid disease has much

diagnostic FNAC, see the next section.

higher incidence in women, goitre in a man increases

Having addressed malignancy risk, most com-

the relative risk of malignancy (Box 8.14 and Case

monly no treatment is needed for multinodular

history 8.6). In any patient with goitre, hyperthy-

goitres

(Case history

8.5). If local compressive

roidism greatly reduces the likelihood of thyroid

symptoms occur (e.g. on the trachea, assessed by

malignancy. Overall, ∼12% of ‘cold’ nodules prove

spirometry) or if there is cosmetic dissatisfaction

to be malignant.

from a large goitre, surgery is the best treatment.

Clear malignancy on FNAC requires total thy-

Autonomous function can develop in the largest

roidectomy. Suspicious FNAC in high-risk indi-

(‘dominant’) nodule(s) and cause thyrotoxicosis.

viduals is probably best managed by local resection

Long-term, even sub-clinical thyrotoxicosis (sup-

to provide a clear tissue diagnosis followed by total

pressed serum TSH and normal fT₄ and fT₃; see

thyroidectomy if malignancy is confirmed. Repeated

Table 8.1) increases mortality from cardiovascular

non-diagnostic aspirations and biopsies are rela-

disease. I¹³¹ is effective with a relatively low risk of

tively common and, if clinical suspicion is high,

post-treatment hypothyroidism compared to Graves

local surgery is probably the best option (as for

disease. If no treatment is needed or if treatment is

suspicious biopsies).

decided against, annual TFTs are useful as progres-

Papillary cell cancer carries a good prognosis.

sion to frank thyrotoxicosis occurs in ∼1%, particu-

Spread is characteristically via the lymphatic system.

larly with nodule(s) greater than 2 cm in diameter.

Following thyroidectomy, slightly high doses of

Chapter 8: The thyroid gland / 187

Case history 8.6

A 48-year-old man presented to his family doctor with a swelling at the base of the neck that

had come on over the last 3 months. He had had a hoarse voice for the last 2 weeks. TFTs

were normal.

Is this presentation concerning?

What additional features might be present on examination of the neck?

Answers, see p. 189

Key points

• T₃ and T₄ are produced by the thyroid

• Overactive and underactive thyroid disease

gland in response to TSH stimulation

are common, especially in women

• The thyroid stores significant amounts of

• TSH levels are the main diagnostic

hormone compared to other endocrine

biochemical measure of hypothyroidism

organs

and hyperthyroidism

• T₃ is the major, active thyroid hormone

• Most goitres are benign

• The effects of thyroid hormone happen

• The majority of thyroid malignancy has a

rather slowly by virtue of its action on gene

good outcome

expression

Answers to case histories

Case history 8.1

She has mild anaemia, possibly secondary

to iron deficiency from menorrhagia, which

The woman has primary hypothyroidism,

might also contribute to the hair loss.

which probably accounts for the tiredness

Alternatively, hypothyroidism can cause

and the hair loss. TSH is markedly elevated

anaemia, usually normochromic normocytic,

and fT₄ levels are below the normal range. fT₃

but possibly associated with mild

measurement is not needed. The slightly low

macrocytosis. Macrocytosis would also raise

serum sodium is probably associated with the

concern over pernicious anaemia, of which

hypothyroidism. Treatment is life-long oral

this patient is at increased risk. The mean

thyroxine to normalize serum TSH on repeat

cell volume should be measured and the

TFTs, which should be performed 6 weeks to

anaemia should be investigated further by

2 months after starting treatment. Commonly,

examining iron stores. If low, then a course

replacement is a single daily tablet of 100 µg,

of ferrous sulphate would be appropriate, but

which in the UK does not currently attract a

this can affect absorption of thyroxine so

prescription charge. She could start on this

should be taken separately from the

dose straight away.

thyroxine.

188 / Chapter 8: The thyroid gland

Finally, the patient should be advised that

during the 2 weeks or so while the

euthyroidism by itself will not necessarily

carbimazole begins to take effect.

promote weight loss. However, alongside

Endocrinologists vary in their follow-up

careful diet and exercise, this may be

strategy; either titrating the dose of

attainable.

carbimazole or using ‘block-and-replace’. By

either approach, TSH would most likely

remain undetectable at first; however, in time,

Case history 8.2

it should rise back towards the normal range.

The TFTs reveal thyrotoxicosis. TSH is

Biochemical hypothyroidism should be

undetectable and both free thyroid hormones

avoided. As a man with high levels of free

are ∼three-fold the normal upper limit.

thyroid hormones at diagnosis, the patient

The scale of these blood results is very

should be advised of the increased risk of

unlikely to be caused by transient

future relapse and the need for definitive

thyrotoxicosis and the history contains no

treatment. Persistently undetectable TSH

clues of recent viral infection. The diagnosis

during treatment and a large goitre would

is clinched by the thyroid eye disease. The

increase this risk further. Further assessment

staring appearance is explained by the entire

of thyroid eye disease is needed. The patient

sclera being visible because of lid retraction

should be advised to stop smoking. If

and possible proptosis. In combination with

symptoms are limited to minor ‘grittiness’,

the thyrotoxicosis, this diagnoses primary

the patient can close his eyes completely,

hyperthyroidism caused by Graves disease.

and the remainder of the eye examination is

The other relevant feature of the examination

largely unremarkable (e.g. vision normal, no

could have been the detection of a thyroid

retro-orbital pain), then observation would

bruit on auscultation over each lobe of the

suffice. However, if the disease is any more

gland. A characteristic goitre is strongly

significant, he should be referred to an

suggestive of Graves disease; however, the

ophthalmologist.

bruit, indicative of diffusely increased

Radioiodine would be ill-advised as

vascularity, confirms the diagnosis. Although

definitive treatment, especially in an active

rare, pre-tibial myxoedema would also

smoker, as it would risk exacerbating the eye

indicate thyrotoxicosis from Graves disease.

disease.

A family history of autoimmune thyroid

disease would also be supportive.

Case history 8.3

The patient should be referred to an

endocrinologist. However, treatment could be

The scar is a clue to diagnosing thyroid eye

initiated with antithyroid drugs to attain

disease because it suggests previous

biochemical euthyroidism. The most likely

thyroidectomy for Graves disease, which

treatment plan is their use for 12-18 months,

should be the topic of specific questions.

followed by withdrawal. In the UK, the most

The left retro-orbital pain is very significant

common agent is carbimazole at a starting

for a number of reasons. It makes a unilateral

dose of ∼40 mg daily for this level of thyroid

retro-orbital mass (e.g. lymphoma) less likely

hormone excess. The prescription should be

to explain the more obvious right-sided

issued with a warning over the rare side-

symptoms and signs. Bilateral symptoms

effect, agranulocytosis, and the need for

make the diagnosis of thyroid eye disease

urgent consultation in the event of sore

far more probable. It is easy to be distracted

throat or fever. Rash is a more common

by the more obvious signs on the right;

side-effect and may settle after a few days.

however, the normal appearance of the left

Propranolol 40 mg three times daily could be

eye plus retro-orbital pain may indicate

prescribed to control symptoms, certainly

significant retro-orbital pressure and potential

Chapter 8: The thyroid gland / 189

damage to the optic nerve and vision. Urgent

failure); however, amiodarone can cause

referral to ophthalmology is warranted.

pulmonary fibrosis. It has been advocated

Vision should be assessed and imaging

that baseline pulmonary function tests should

(e.g. MRI) of the orbits undertaken. It should

be done before treatment to allow monitoring

be ensured that the right eye can close

for this.

properly. Liquid tears may be useful. TFTs

Case history 8.5

should be done and treatment for

hypothyroidism or hyperthyroidism started, if

The patient most likely has a multinodular

necessary. The patient should be advised

goitre. She is euthyroid.

and helped to stop smoking. If specific

This is highly unlikely to be malignancy as

treatment of thyroid eye disease is needed,

the mass has not changed, particularly over

this requires specialist input and may involve

5 years, and there is no lymphadenopathy,

anti-inflammatory glucocorticoids,

tethering, symptoms such as hoarseness

immunosuppression and/or decompression

(implies local invasion), or family history.

surgery.

Ultrasound of the neck would confirm a

multi-nodular goitre with FNAC possible for

any of the larger nodules.

Case history 8.4

For any nodules that were aspirated and

The patient may have a transient thyroiditis

unremarkable, repeat FNAC a few months

(e.g. has he had a recent sore throat or

later accords with the British Thyroid

fever?). Graves disease is relatively unlikely

Association guidelines. There is a risk of

de novo at 81 years, but possible. An

future hyperthyroidism in multi-nodular goitre

alternative is a toxic adenoma, either as a

such that annual TFTs could be suggested

solitary nodule or as part of a multinodular

even though there is no current suspicion of

goitre. However, in this history, the most

TSH suppression.

likely cause is hyperthyroidism secondary to

Case history 8.6

amiodarone therapy.

Low-dose carbimazole (or equivalent

Yes. The presentation is suspicious of thyroid

antithyroid medication) would most likely be

malignancy. There is a rapidly growing mass

effective at restoring euthyroidism, which is

in the region of the thyroid in a euthyroid

important as thyrotoxicosis risks destabilizing

patient. There is alteration of the voice. This

the patient’s well being, especially given the

warrants urgent specialist referral as

supraventricular arrhythmia and risk of

suspected cancer.

cardiac failure, which would exacerbate the

The goitre may be hard, tethered to the

shortness of breath.

skin and underlying structures and not move

There are several reasons why the man

with swallowing. There may be associated

might be short of breath (e.g. cardiac

lymphadenopathy.

Chapter 9: Calcium and metabolic bone disorders / 191

Cross-reference

■ The development of the parathyroid and parafollicular C-cells is described alongside the

thyroid in Chapter 8

■ Tumours of the parathyroid glands are an important component of multiple endocrine

neoplasia, covered in Chapter 10

■ Other hormones such as cortisol (see Chapter 6) and sex hormones (see Chapter 7) affect

mineralization of the bones

Calcium

Calcium (Ca²⁺) performs vital functions (Box 9.1)

and its concentration at all locations requires tight

Oral daily intake

Bone

25 mmol

control [serum, 2.20-2.60 mmol/L (8.8-10.4 mg/

dL); interstitium,

∼1.5 mmol/L (6.0 mg/dL); and

inside the cell, 0.1-1.0 mmol/L (0.4-4.0 mg/dL)].

Intestine

10 mmol

In the circulation, Ca²⁺ is bound to plasma proteins,

10 mmol

mainly albumin, with

∼10% complexed with

Secretion

citrate. The important fraction is the ∼50% that is

7 mmol

unbound (free) and biologically active. Thus, serum

Blood

Ca²⁺ always requires correction for albumin concen-

Absorption

tration. An approximation is to increase or decrease

10-14 mmol

Ca²⁺ by 0.02 mmol/L for every gram that albumin

240 mmol/

233 mmol/

is below or above 40 g/L (or by 0.08 mg/dL for 0.1 g

day

that albumin is below or above 4.0 g/dL) (Case

history 9.3). Otherwise, hypocalcaemia or hypercal-

caemia may be erroneously diagnosed if albumin

Kidney

concentrations are respectively low or high.

Under normal circumstances Ca²⁺ is in equilib-

Faecal excretion

rium across different ‘pools’ in the body (i.e. bones,

18-22 mmol

circulation, tissues and organs) (Figure 9.1). During

Excretion

3-7 mmol

Figure 9.1 Calcium homeostasis. In an adult, daily

net absorption from the gut equals urinary loss. For a

Box 9.1 Key facts about calcium

child in positive Ca²⁺ balance, net absorption

Ca²⁺ is critical for:

exceeds renal excretion with retention of Ca²⁺ in the

growing skeleton.

• Bone mineralization

• Blood clotting

• Muscle contraction

childhood, overall Ca²⁺ balance is positive as new

• Enzyme action

bone is laid down. During young adulthood, the

• Exocytosis of hormones and

daily uptake of Ca²⁺ from the gut matches losses,

neurotransmitters

mainly from urine (but some from sweat and the

• Nerve function

bowels). In older age, particularly in post-

• Intracellular signaling (review Figure 3.16)

menopausal women, output (from bone) is greater

192 / Chapter 9: Calcium and metabolic bone disorders

than input, putting Ca²⁺ into negative balance. Ca²⁺

Box 9.2 Major hormones that

is in part regulated alongside phosphate

[PO_43-;

regulate serum calcium

normal range in serum, 0.8-1.45 mmol/L (2.5-

4.5 mg/dL), higher in children]. However, a higher

Serum Ca²⁺ concentration is increased by

proportion of PO_43- than Ca²⁺ is absorbed from the

two hormones:

diet and so correspondingly more PO_43- is excreted

• PTH

in the urine. PO_43- absorption and excretion is also

• Vitamin D

increased with high meat intake. A gene on the

short arm of the X chromosome, PHEX, is impor-

tant in regulating renal PO_43- excretion. Mutations

Box 9.3 Why vitamin D is a

in this gene cause X-linked hypophosphataemic

hormone

rickets (see last section of the chapter).

Ca²⁺ is a major constituent of all cell types and

• By definition, a vitamin must be provided

acts as an intracellular signalling mechanism (review

in the diet; 90% of vitamin D is synthesized

Figure 3.16) linking external stimulation of a cell

in the skin

to function. For instance, in myocytes, Ca²⁺ medi-

• Active vitamin D mainly circulates via the

ates contraction.

bloodstream to act on a distant tissue (a

feature of a hormone)

• The receptor for vitamin D is a member of

Dietary intake of calcium

the nuclear hormone receptor superfamily

The recommended daily allowance for Ca²⁺ is ∼1 g.

Ca²⁺ is abundant in many foods, especially dairy

products such as cheese, yoghurt and milk.

Vitamin D

Absorption from the gut is inefficient; only ∼30%

Vitamin D functions more like a hormone than a

of ingested Ca²⁺ is absorbed. However, gut absorp-

vitamin (Box 9.3). It is derived from cholesterol and

tion is highly regulated as one method of control-

has a similar structure to steroid hormones (review

ling serum Ca²⁺. Absorption increases in childhood

Chapter 2). There are a number of different forms

and during pregnancy and lactation, but decreases

of vitamin D. At least 10% is acquired from dietary

with age and if Ca²⁺ intake is high.

sources like fish and eggs as vitamin D₂ (ergocalcif-

A number of dietary factors also affect Ca²⁺

erol; Figure 9.2), which places vegans at increased

absorption. Basic amino acids and lactose enhance

risk of vitamin D deficiency (see Box 9.18). Several

absorption, making milk supplementation particu-

foodstuffs, including margarine and milk, are forti-

larly effective at increasing Ca²⁺ in children. In con-

fied with vitamin D₂. Vitamin D₃ (cholecalciferol)

trast, phytic acid, present in unleavened or brown

accounts for 90% of total vitamin D and is synthe-

bread, inhibits Ca²⁺ absorption by chelating it in the

sized in the skin by photoisomerization induced by

gut. During the Second World War, bread was forti-

ultraviolet (UV) light (see below and Figure 9.2).

fied with Ca²⁺ in the UK and this practice continues

The last section of the chapter provides details on

to this day.

vitamin D deficiency.

Hormones that regulate calcium

Synthesis of active vitamin D

Vitamin D and parathyroid hormone (PTH) are

Vitamin D₂ and vitamin D₃ serve as precursors for

the two major hormones that regulate Ca²⁺ through

active hormone synthesis and are structurally iden-

a complex interaction (Box 9.2). Both hormones

tical except for the double bond in vitamin D₂

increase serum Ca²⁺ levels. Calcitonin and parathy-

between carbon (C) 22 and C23 of the side chain.

roid hormone-related peptide (PTHrP) can affect

In the inner layers of the sun-exposed epidermis,

Ca²⁺, but they play limited roles in human

vitamin D₃ is synthesized from 7-dehydrocholesterol.

physiology.

The B ring opens to form pre-vitamin D followed

Chapter 9: Calcium and metabolic bone disorders / 193

Figure 9.2 The sources and

UV light /

metabolism of vitamin D.

sunshine

Diet

Skin

Vitamins D₂ and D₃

Vitamin D₃

Liver

25-hydroxyvitamin D₂

or 25-hydroxyvitamin D₃

Kidney

1,25-dihydroxyvitamin D₂

24,25-dihydroxyvitamin D₂

or 1,25-dihydroxyvitamin D₃

or 24,25-dihydroxyvitamin D₃

(calcitriol)

Active vitamin D

No clear physiological

role in adult humans

by rotation of the A ring (Figure 9.3). Activation

Regulation of vitamin D synthesis

occurs by two hydroxylation steps. The first occurs

Prevailing Ca²⁺ levels control production of active

predominantly in the liver at C25 to form

or inactive vitamin D by negative feedback (review

25-hydroxyvitamin D, which circulates at quite

Chapter

1). Inactivation of vitamin D occurs

high concentrations [20-40 nmol/L (8-16 ng/mL)]

in the kidney by

24-hydroxylation to

1,24,25-

and is then converted in the kidney to fully active

trihydroxyvitamin D.

24-hydroxlyase also acts

1,25-dihydroxyvitamin D (calcitriol; Figure 9.3),

25-hydroxyvitamin D to form

24,25-

the serum concentration of which is very low [48-

dihydroxyvitamin D. This metabolite may play a

110 pmol/L (20-46 pg/mL)]. As for steroid hor-

role in bone development; however, no clear func-

mones (review Chapter 2), there is a circulating

tion is apparent in adulthood, other than to limit

vitamin D-binding protein with high affinity for

formation of calcitriol. For instance, high Ca²⁺

25-hydroxyvitamin D but low affinity for calcitriol.

increases activity of 24-hydroxylase, thereby restrict-

This means calcitriol circulates largely free and

ing levels of active vitamin D in circumstances

has a short half-life of ∼15 h, compared to 15 days

where it would be detrimental to increase serum

for 25-hydroxyvitamin D. The longer half-life of

Ca²⁺ (Figure 9.4). Conversely, low Ca²⁺ or PO_43-

25-hydroxyvitamin D makes it a more reliable

levels stimulate

1α-hydroxylase

(a cytochrome

measure of overall vitamin D status in patients.

P450 enzyme officially known as CYP27B1) to

Chapter 9: Calcium and metabolic bone disorders / 195

Figure 9.4 Effects of

changing Ca²⁺ and PO_43- on

1α-hydroxylase

renal hydroxylation of

25-hydroxycholecalciferol.

Low Ca²⁺ and low PO_43-

stimulate 1α-hydroxylation to

24-hydroxylase

yield calcitriol, while high

Ca²⁺ and high PO_43- increase

24-hydroxylation to give

24-hydroxylase

24,25-dihydroxy-

1.5

2.5

1.5

2.5

3.5

cholecalciferol.

Ca²⁺ (mmol/L)

PO43- (mmol/L)

Table 9.1 Comparative actions of vitamin D, parathyroid hormone (PTH) and calcitonin

Vitamin D

PTH

Calcitonin

Bone

↑ Osteoclast activity

↓ Osteoblast activity (if constant)

↓ Osteoclast activity

↑ Bone resorption

↑ Bone resorption (if constant)

↓ Bone resorption

(but note that vitamin D

↑ Osteoblast activity (if

deficiency causes

intermittent)

demineralization)

↓ Bone resorption (if intermittent)

Kidney

↑ Calcium re-absorption

↑ 1α-hydroxylase synthesis

↓ Calcium re-absorption

↑ Phosphate re-absorption

↑ Calcium re-absorption

↓ Phosphate re-absorption

Gut

↑ Calcium absorption

(Indirect action only)

↑ Phosphate absorption

↑ Calcium absorption

↑ Phosphate absorption

Blood

↑ Calcium

↓ Calcium

↑ Phosphate

↓ Phosphate

encourage active vitamin D synthesis. The expres-

with the retinoid X receptor

(RXR) [RXR also

sion of 1α-hydroxylase requires and is increased by

interacts with thyroid hormone receptor (review

PTH. As a consequence, calcitriol rather than

Figure 3.20) and PPARγ (see Chapter 13)]. The

cholecalciferol or ergocalciferol needs to be given to

VDR-RXR heterodimer orchestrates the expression

treat hypocalcaemia secondary to hypoparathy-

of genes involved in Ca²⁺ absorption and homeos-

roidism (see later). 1α-hydroxylase expression is also

tasis, mainly in the intestine, bone and kidney

increased by growth hormone (GH), cortisol, oes-

(Table 9.1). In the gut, vitamin D increases the

trogen and prolactin.

absorption of dietary Ca²⁺ and PO_43-. Vitamin D’s

effects on bone are complex and in part mediated

via complex interactions with PTH. On the whole,

Function of vitamin D

if vitamin D is deficient, bones can become demi

Like steroid and thyroid hormones, calcitriol binds

neralized, leading to osteomalacia. However, direct

a specific nuclear receptor, the vitamin D receptor

vitamin D action in bone tends to increase the

(VDR), which functions as a ligand-activated tran-

release of Ca²⁺ and PO_43- by some activation of

scription factor in the nucleus by heterodimerizing

osteoclast activity (see section on metabolic bone

196 / Chapter 9: Calcium and metabolic bone disorders

disease for detailed roles of the osteoblast and osteo-

Tongue buds

clast in bone turnover). In the kidney, vitamin D

increases Ca²⁺ and PO_43- re-absorption.

Vitamin D is implicated outside of Ca²⁺ metab-

olism in direct effects on the vasculature, insulin

secretion and immune function.

Foramen

caecum

Parathyroid glands and parathyroid

Palatine

Thyroglossal

hormone

tonsil

duct

Parathyroid

PTH is secreted by four parathyroids, located as

glands

Thymus

upper and lower glands behind each lobe of the

Parafollicular/

thyroid. They are small, lentil-sized glands, each

C-cells

Ultimobranchial

weighing 40-60 mg. They develop from the third

body

and fourth pharyngeal pouches, which emerge at

Parathyroid

Thyroid

the upper end of the foregut during the third week

gland

glands

of development

(Figures

9.5 and

8.1). During

embryogenesis, the two uppermost glands on each

Figure 9.5 Section through the fetal pharynx

side descend to become the lower parathyroids; this

illustrating development of the thyroid and

parathyroid. The thyroid migrates down the midline

complex migration can go wrong leaving ectopic

from the foramen caecum beneath the tongue

tissue in the neck or mediastinum. If overactive, this

muscle buds. The parathyroid glands develop as

can present a challenge to the endocrine surgeon.

paired cell masses at the third (P3, lower parathyroid

There are two parathyroid cell types: chief cells

gland) and fourth (P4, upper parathyroid gland)

secreting PTH and oxyphil cells, the function of

pharyngeal pouches and migrate to the posterior

which is unknown. There is a rich vascular supply

surface of the thyroid. The origins of the thymus and

mainly from the inferior thyroid arteries. Blood

palatine tonsils are also shown.

drains into the thyroid veins.

Synthesis of parathyroid hormone

increases PTH production; at levels above the set

PTH is produced from a single gene as a precursor

point, PTH secretion is shut off. Alterations to this

peptide that is cleaved to a mature single-chain 84-

mechanism explain biochemical findings in primary

amino acid hormone stored in vesicles in the chief

hyperparathyroidism and rare individuals with inac-

cells (review Figures 2.2 and 2.4). The potential for

tivating mutations in the CaSR (see later).

rapid changes in PTH secretion indicates that it is

not dependent on de novo synthesis. Full biological

Function of parathyroid hormone

activity resides within the first

34 amino acids,

In general, PTH acts to increase serum Ca²⁺. The

which are now synthetically available as a treatment

hormone acts via a specific G-protein-coupled

for osteoporosis (teriparatide, see later).

receptor on the surface of renal tubule, osteoblast

and gut epithelial cells (review Chapter 3). In the

Regulation of parathyroid hormone

kidney, PTH increases 1α-hydroxylase expression,

production

thereby activating vitamin D. PTH also increases

PTH release is controlled by negative feedback

Ca²⁺ and hydrogen absorption at the distal tubule.

according to serum Ca²⁺ concentration via the

Unlike vitamin D, PTH decreases PO_43- and bicar-

G-protein-coupled Ca²⁺-sensing receptor (CaSR)

bonate re-absorption. Collectively, this promotes a

(Figure 9.6). This ‘calciostat’ regulates serum Ca²⁺

metabolic acidosis. In the bone, constant PTH

around a set point. If serum Ca²⁺ falls below this

inhibits bone-forming osteoblast activity but signals

threshold, signalling downstream of the CaSR

via this cell type to stimulate osteoclasts, leading to

Chapter 9: Calcium and metabolic bone disorders / 197

(a)

(b)

Figure 9.6 Parathyroid

Intravenous CaCl₂

Intravenous EDTA

hormone (PTH) secretion in

response to serum Ca²⁺.

(a) Rise in serum Ca²⁺ [from

intravenous calcium chloride

(CaCl₂) infusion] inhibits PTH

secretion. (b) Fall in serum Ca²⁺

[from infusion of

ethylenediamine tetra-acetic

acid (EDTA) to complex Ca²⁺]

stimulates PTH secretion.

3.5

2.6

2.5

Normal

range

2.2

Time (h)

net release of Ca²⁺ and PO_43- into the circulation

lactating breast, when it can contribute to

1α-

(see Box 9.15). Of these opposing effects on PO_43-,

hydroxylase activation. PTHrP is very important in

the renal action is larger such that the net effect of

the fetus for bone development.

PTH is to lower serum PO_43-. Intermittent PTH

can stimulate osteoblasts (injection regimens now

Calcitonin

exploit this clinically; see later section on osteoporo-

sis). PTH also acts via osteoblasts to increase the

Calcitonin is secreted from the parafollicular or

number of haematopoietic stem cells in adjacent

C-cells of the thyroid gland

(see Figure

8.2) in

bone marrow. There appears to be no direct effect

response to a rise in extracellular Ca²⁺. It acts to

of PTH in the gut but there is an indirect increase

reduce Ca²⁺ levels via binding to its specific

in Ca²⁺ uptake by enhanced formation of active

G-protein-coupled receptor on the surface of renal

vitamin D.

tubule cells, where it inhibits Ca²⁺ and PO_43- re-

absorption, and osteoclasts, where it suppresses the

release of Ca²⁺ and PO_43-.

Parathyroid hormone-related peptide

The physiological relevance of calcitonin is

During evolution, duplication has given rise to a

unknown because no clinical syndrome arises from

second gene very closely related to PTH that

its deficiency, e.g. after total thyroidectomy, or

encodes PTH-related peptide (PTHrP). PTHrP is

excess, as in medullary thyroid cancer (see Chapters

larger but acts via the same cell surface receptor to

8 and 10). It may be important in growing children

raise cAMP levels. PTHrP was discovered as the

and pregnant women, contributing to growth or

hormonal cause of hypercalaemia of malignancy

preservation of the skeleton, and it may have a role

(see later). Ordinarily, it does not regulate serum

in the treatment of several metabolic bone diseases.

Ca²⁺ levels but is synthesized by the placenta and

In birds, it regulates eggshell formation.

198 / Chapter 9: Calcium and metabolic bone disorders

Clinical disorders of calcium

Approximately

1-2% of patients undergoing

thyroid surgery experience damage to the parathy-

homeostasis

roids (Case history 9.1). Autoimmune damage to

Most clinical problems reflect either too much

the parathyroids can be isolated or occur as part of

(hypercalcaemia) or too little (hypocalcaemia) cir-

type 1 autoimmune polyglandular syndrome (APS-

culating Ca²⁺.

1), an autosomal recessive disorder caused by muta-

tions in the AIRE gene (Case history 9.2). Along

Hypocalcaemia

with a tendency to mucosal candidiasis, adrenocor-

tical, thyroid and gonadal failure can occur (see

The commonest cause of hypocalcaemia (Box 9.4)

Chapters 6-8; see Box 8.8 for APS-2). Parathyroid

is lack of PTH due to hypoparathyroidism (Box 9.5).

under-development (hypoplasia) or absence (agen-

esis) occurs in DiGeorge syndrome when the third

Box 9.4 Causes of hypocalcaemia

and fourth pharyngeal pouches fail to develop prop-

• Hypoparathyroidism

erly. The thymus may also be missing and there may

• Hypomagnesaemia

be variable congenital heart disease (see Figure 4.4).

• Renal failure

When hypocalcaemia is not caused by hypopar-

• Neonatal hypocalcaemia (temporary

athyroidism, it is most commonly a result of inef-

suppression of PTH following maternal

fective PTH action, e.g. due to lack of magnesium

hypercalcaemia during gestation; see

(Mg²⁺)

(hypomagnesaemia; Box

9.4). Mg²⁺ is

hyperparathyroidism)

required as a co-factor for PTH action. In renal

• Pancreatitis

failure, PTH can no longer increase 1α-hydroxylase

• Pseudohypoparathyroidism

activity, leading to a lack of active vitamin D and

potential hypocalcaemia.

Neonatal hypocalcaemia can occur per se in pre-

Box 9.5 Causes of

mature babies. It can also reflect maternal hypercal-

hypoparathyroidism

caemia (see later) that suppressed fetal PTH in utero

and continued to cause transient low Ca²⁺ in the

In approximate order of descending

neonate.

frequency:

Inactivating mutations in the PTH signalling

• Surgical - damage or unintended removal

pathway cause hypocalcaemia due to PTH resist-

during thyroid surgery

ance. Collectively, these conditions are termed

• Autoimmune - isolated or part of type 1

pseudohypoparathyroidism. In addition to the

autoimmune polyglandular syndrome (APS-1)

hypocalcaemia and hyperphosphataemia, patients

• Congenital - may be part of DiGeorge

are short with a round face and characteristically

syndrome

short fourth metacarpals (Figure 9.7). There may be

Figure 9.7 Short fourth

metacarpals in

pseudohypoparathyroidism.

Chapter 9: Calcium and metabolic bone disorders / 199

Ca²⁺, in the absence of PTH, leads to excessive Ca²⁺

Box 9.6 Symptoms and signs of

flux through the urine, risking renal calcification

hypocalcaemia

and stone formation, especially if the renal anatomy

is abnormal.

• Muscle cramps and carpopedal

spasm - when induced by applying a

blood pressure cuff to the arm, it is called

Case history 9.1

Trousseau’s sign

• Numbness and paraesthesiae

A 30-year-old woman underwent a difficult

• Mood swings and depression

thyroidectomy for the treatment of Graves

• Tetany and neuromuscular excitability -

disease. She is anxious about the

tapping over the facial nerve causes the

outcome of her operation and 2 days

facial muscles to twitch (Chvostek’s sign)

postoperatively, she complains of tingling

• Convulsions

in her fingers and mouth.

• Cardiac arrythmias (long QT interval on

ECG)

What are the possible explanations for

• Cataract

her symptoms?

What would be your management?

paradoxical ectopic calcification in muscle and

Answers, see p. 211

brain and some degree of intellectual impairment.

Mutations in the G_sα subunit downstream of the

PTH receptor cause autosomal dominant Albright

hereditary osteodystrophy (review Box 3.8).

Case history 9.2

A 26-year-old woman was referred by her

Symptoms and signs

family doctor because of hypocalcaemia

Other than when caused by surgical hypoparathy-

[corrected serum Ca²⁺ 1.94 mmol/L

roidism, hypocalcaemia is usually insidious in onset

(7.76 mg/dL)]. The doctor had measured

(Box 9.6). However, once corrected serum Ca²⁺

serum PTH, which was also low. On close

falls below 1.5 mmol/L (6.0 mg/dL), the condition

questioning, her parents were cousins,

becomes increasingly dangerous.

and a cousin and a grandparent of the

patient took long-term Ca²⁺ replacement.

Investigation and diagnosis

The cousin also took thyroxine. The

Low serum Ca²⁺ makes the diagnosis. Concomitant

patient had always suffered from recurrent

assessment of serum PO_43-, renal function and PTH

sore throats; on examination, white

levels are helpful. Serum Mg²⁺ rarely needs checking.

plaques were visible.

Treatment

What diagnosis is consistent with all

The broad aim is Ca²⁺ restoration to prevent symp-

aspects of the history and

toms and signs. In hypoparathyroidism, treatment

examination? What is the differential

with PTH, although possible (see later section on

diagnosis?

osteoporosis), is expensive and would need to be

Assuming the unifying diagnosis is

given by injection. Therefore, treatment is com-

correct, what endocrine management

monly with oral Ca²⁺ and calcitriol tablets (because

would you consider beyond the

in the absence of PTH, renal 1α-hydroxylation of

hypocalcaemia and sore throat?

ergocalciferol or cholecalciferol would be lacking).

The goal is to restore serum Ca²⁺ to the lower end

Answers, see p. 211

of the normal range. Complete normalization of

200 / Chapter 9: Calcium and metabolic bone disorders

Box 9.7 Causes of hypercalcaemia

Box 9.8 Primary tumours that

commonly metastasize to bone

Common

• Primary hyperparathyroidism

• Lung

• Malignancy

• Breast

• Drugs and dietary causes

• Prostate

• Kidney

Rare

• Thyroid

• Familial benign hypercalcaemia

• Thyrotoxicosis

• Hypoadrenalism

• Acromegaly

and over-secrete PTH even after Ca²⁺ concentra-

• Sarcoidosis

tions are normalized. This leads to hypercalcaemia

• Tertiary hyperparathyroidism

and tertiary hyperparathyroidism.

Malignancy

Hypercalcaemia

Hypercalcaemia is frequently seen in later stage

Primary hyperparathyroidism and malignancy are

malignancy either because of eroding local bony

the commonest causes of raised serum Ca²⁺ levels.

metastases, secretion of paracrine factors, such as

However, several other conditions need considera-

prostaglandins, that activate osteoclasts (Box 9.8) or

tion (Box 9.7) (Case history 9.3). Hypercalcaemia

because of humoral hypercalcaemia of malignancy

can be severe [serum Ca²⁺ > 3.0 mmol/L (12.0 mg/

from PTHrP secretion (see earlier).

dL)] and can be exacerbated by dehydration.

Drugs and dietary causes

It is important to take a drug history as thiazide

Primary hyperparathyroidism

diuretics cause hypercalcaemia by increasing Ca²⁺

Primary hyperparathyroidism is common after

resorption at the distal tubule. Overdose of vitamin

middle age with a female predominance of ∼2:1 and

D may also cause hypercalcaemia, sometimes from

an incidence of 1 in 1000. It reflects elevation of

non-prescription multivitamins. Rarely, ingestion

the set-point at which serum Ca²⁺ signals via the

of large amounts of milk or Ca²⁺-containing antac-

CaSR to shut off PTH production (review Figure

ids can cause hypercalcaemia, although this is much

9.6). Around 80% of cases are caused by a single

less common now that H₂ antagonists and proton

parathyroid adenoma with the remainder resulting

pump inhibitors exist to treat peptic ulceration.

from hyperplasia of all glands. Parathyroid cancer is

extremely rare; however, primary hyperparathy-

roidism in someone younger than 45 years should

Familial benign hypercalcaemia

raise suspicion of multiple endocrine neoplasia

Also known as familial hypocalciuric hypercalcaemia,

(MEN) type 1 (see Chapter 10).

this autosomal dominant condition of inactivating

Secondary and tertiary hyperparathyroidism

mutations in CaSR can masquerade as primary

usually occur in renal failure, although they can

hyperparathyroidism (Case history 9.4). The main

occasionally result from Ca²⁺ malabsorption. Failure

difference is that 24-h urine Ca²⁺ excretion tends to

of 1α-hydroxylation of vitamin D in renal impair-

be diminished, not raised. The distinction is impor-

ment causes a compensatory increase in PTH to

tant as falsely diagnosing primary hyperparathy-

maintain normal serum Ca²⁺ (secondary hyperpar-

roidism in the paediatric clinic would raise concern

athyroidism). This is at the expense of normal bone

of MEN1. CaSR inactivation reduces negative feed-

health and a typical osteodystrophy occurs. With

back from Ca²⁺ and consequently leads to increased

prolonged high secretion of PTH, there is a risk that

PTH and mild hypercalcaemia; however, familial

the parathyroid glands then become autonomous

benign hypercalcaemia requires no treatment.

Chapter 9: Calcium and metabolic bone disorders / 201

Other causes

Investigations for primary hyperparathyroidism

Hypercalcaemia may occur in thyrotoxicosis because

are shown in Box 9.10. Serum PTH is either inap-

of increased osteoclast activity. In 1-2% of patients

propriately ‘normal’ (in the presence of raised serum

with sarcoidosis, serum Ca²⁺ rises because of 1α-

Ca²⁺, PTH should be suppressed) or raised. Serum

hydroxylase activity in the non-caseating granulo-

PO_43- is likely to be low. Note that PTH is increased

mata. Somewhat similarly, excessive GH in

in vitamin D deficiency (very common in the UK),

acromegaly can stimulate renal 1α-hydroxylase.

making it important to be clear that serum Ca²⁺ is

truly raised. 24 hour urinary Ca²⁺ is always expected

Symptoms and signs

to be increased in primary hyperparathyroidism

Automated biochemistry laboratories have meant

(note this assay requires an acidified container, see

that most patients are identified with asymptomatic

Box 4.1).

mild hypercalcaemia [e.g. 2.5-2.8 mmol/L (10.0-

11.2 mg/dL)] (Box 9.9). Common symptoms are

non-specific. Others associated with more severely

Box 9.10 Investigating

elevated serum Ca²⁺ [>3.0 mmol/L (>12.0 mg/dL)]

hypercalcaemia

led to the clinical adage ‘bones, stones, abdominal

• Serum Ca

groans and psychic moans’. Persistent hypercalcae-

• Investigating primary hyperparathyroidism:

mia can lead to ectopic calcification visible on plain

^ Serum PO_43- (decreased)

radiographs of the heart, joints and kidney, and



24-h urinary Ca²⁺ (increased)

more rarely seen in the liver and pancreas.

^ Serum PTH (normal or raised)

Hypercalcaemia resulting from PTHrP tends to be

^ DEXA (to assess bone mineralization)

a late feature of malignancy.

Plain X-ray of kidneys (potential



calcification)

Investigation and diagnosis

^ Neck ultrasound (if surgery is considered)

Commonly, raised serum Ca²⁺ is a serendipitous

^ Isotope scan using technicium

finding. If there is any doubt, a fasting sample taken

99m-sestamibi

without use of a tourniquet in a well-hydrated

^ CT or MRI

patient minimizes spurious minor rises in Ca²⁺.

^ Venous sampling (if surgery if necessary

and adenoma unlocalized)

Box 9.9 Symptoms and signs of

• Serum angiotensin-converting enzyme

hypercalcaemia

(ACE) and chest X-ray (can be helpful if

• Asymptomatic serendipitous finding

considering sarcoidosis)

• Tiredness and fatigue

• Serum cholecalciferol

• Anorexia and nausea

(25-hydroxycalciferol) (if vitamin D toxicity

• Thirst and polyuria

is possible)

• Muscle weakness

• Investigating malignancy (see Box 9.8):

• Headache

^ Chest X-ray (carcinoma of the bronchus)

• Hypertension

^ Prostate examination and serum

• Bony pain

prostate-specific antigen (PSA)

• Renal stones

^ Mammogram

• Abdominal pain from constipation, peptic

^ Thyroid ultrasound (see Chapter 8)

ulceration or, rarely, acute pancreatitis

^ Bone scintigraphy using technicium

• Confusion and mood disturbance

99m-methylene diphosphate (bone scan)

• Palpitations through cardiac arrhythmias

^ Serum electrophoresis and urinary Bence-

• Bone fractures

Jones proteins (for multiple myeloma)

• Convulsions and coma if severe

^ PTHrP (rarely assayed but

• Corneal calcification

distinguishable from PTH which is low)

202 / Chapter 9: Calcium and metabolic bone disorders

Prior to automated biochemical analyses, hyper-

Treatment

calcaemia as a result of primary hyperparathyroidism

Severe hypercalcaemia [> 3.0 mmol/L (12.0 mg/dL)]

tended to present more severely (Box 9.9), when

may present as a medical emergency (e.g. with

hand X-rays would show characteristic features of

arrhythmias) (Box 9.11). Most patients are dehy-

bone resorption. This is uncommon now but dual

drated and simple rehydration can significantly

X-ray absorptiometry (DEXA) should still be done

reduce serum Ca²⁺. Intravenous bisphosphonates

to assess bone mineralization and fracture risk.

(see section later on osteoporosis), such as pamidro-

Having made the diagnosis of primary hyper-

nate, inhibit bone resorption and rapidly reduce

parathyroidism and if surgery is desired, locating

Ca²⁺ in the emergency setting. Glucocorticoids are

the causative gland(s) may be difficult because of

effective in cases of haematological malignancy or

variation in embryological migration. Ultrasound

sarcoidosis (see Chapter 6). Calcitonin also lowers

scanning may indicate a single adenoma. Selective

serum Ca²⁺. Dietary Ca²⁺ intake should be restricted.

venous sampling can occasionally be undertaken

Primary hyperparathyroidism with mildly

(Figure 9.8). Isotope uptake scans and computed

increased serum Ca²⁺ in asymptomatic individuals

tomography (CT) or magnetic resonance imaging

can commonly be monitored as it rarely worsens.

(MRI) may be useful (Box 9.10).

However, some argue that even mild hypercalcae-

mia is associated with excess morbidity, including

depression, malaise and hypertension. Features

other than very high Ca²⁺ levels that warrant defini-

tive surgical treatment are clearly associated symp-

toms, renal impairment, stones or structural

abnormality (increasing the risk of calcification or

Thyroid

stone formation), and bone demineralization (see

later section on osteoporosis) (Box 9.12). Although

guidelines for when to intervene are relatively flex-

ible, primary hyperparathyroidism associated with

raised Ca²⁺ excretion and evidence of bone deminer-

alization in a younger and otherwise fit patient

should prompt serious thought of surgery, even

when there are no symptoms, as long-term fracture

risk is a concern. Even asymptomatic individuals

may feel better once their Ca²⁺ has fallen to normal.

For a discrete adenoma, single parathyroidec-

tomy with visualization of the normal glands is

usually curative. Intraoperative dyes taken up by

parathyroid tissue and histology of snap-frozen

samples can improve the likelihood of curative

removal.

Box 9.11 Emergency management

Figure 9.8 Venous sampling for parathyroid

of hypercalcaemia

hormone (PTH) prior to surgery to localize a tumour

• Intravenous rehydration

in the upper right parathyroid gland (blue circle). The

• Bisphosphonates

numbers indicate relative PTH levels (arbitrary scale).

Values are higher in the right superior thyroid and

• Steroids if vitamin D toxicity or

right internal jugular veins than in other places such

haematological malignancy

as the inferior thyroid veins and superior vena cava.

• Loop diuretics may be of limited value

Chapter 9: Calcium and metabolic bone disorders / 203

Box 9.12 Indications for

Case history 9.4

parathyroidectomy in primary

At a routine occupational health check a

hyperparathyroidism

30-year-old man was found to have mild

• Renal stones, structural abnormality or

hypercalcaemia. He is anxious because

impairment

the problem failed to resolve in his father,

• Bone disease (history of fractures,

despite neck surgery. His uncle also has

osteopaenia or osteoporosis)

high Ca²⁺ levels. Both men are well into

• Clearly associated symptoms

their late 50s.

• Age < 50 years irrespective of symptoms if

otherwise fit

What are the possible familial causes of

• More severe hypercalcaemia [>3.0 mmol/L

hypercalcaemia?

(12.0 mg/dL)]

Other possible indications should be

Answers, see p. 212

considered carefully and may include:

• Hypertension

• Psychiatric morbidity

alcaemia in the immediate postoperative period is

mandatory, although most patients can be dis-

Case history 9.3

charged with outpatient follow-up the following

day if serum Ca²⁺ is normal.

An overweight, 50-year-old woman with a

Cinacalcet is a new drug that activates the

history of hypertension was found to have

CaSR. It can be used in secondary hyperparathy-

a serum Ca²⁺ of 2.58 mmol/L (10.32 mg/

roidism and is licensed to treat hypercalcaemia in

dL) and albumin of 36 g/L (3.6 g/dL). She

the very rare setting of parathyroid carcinoma.

consumed multiple supplements from

For most other causes of hypercalcaemia (e.g.

health food shops. Her mother died aged

thyrotoxicosis; see Box 9.7), normalization occurs

35 years from breast cancer and our

with treatment of the underlying condition.

patient is concerned that she may have

breast cancer too.

Bone health and metabolic bone

disease

What is her corrected calcium?

What are the possible explanations for

the hypercalcaemia?

Bone and its composition

The skeleton comprises two types of bone (Box

Answers, see p. 211

9.13). Even in adulthood, bone remodelling is per-

petual and involves two matrices: ∼35% of bone

Removing all four glands would be necessary to

mass is organic matrix (osteoid), of which 90-95%

treat parathyroid hyperplasia and is less readily

is collagen (mainly type 1) (Box 9.14), with the

undertaken; in the past, fragments of one gland

remainder being proteoglycans, glycoproteins, sia-

have been re-implanted in the forearm to avoid

loproteins and a small amount of lipid. Osteoid is

hypoparathyroidism. Repeat neck surgery is techni-

subsequently mineralized into a hard, calcified

cally difficult and it was considered easier to re-

extracellular matrix of hydroxyapatite [3Ca₃(PO₄)₂.

operate on the forearm if the patient redeveloped

Ca(OH)₂]. This inorganic component accounts for

hypercalcaemia post-operatively.

∼65% of bone mass and contains the vast majority

For decision making in MEN1, see Chapter 10.

of the adult body’s ∼1.2 kg of Ca²⁺, 90% of its

For any parathyroid surgery, monitoring for hypoc-

PO_43-, 50% of its Mg²⁺ and 33% of its Na⁺.

204 / Chapter 9: Calcium and metabolic bone disorders

Box 9.13 The two types of bone

Box 9.15 Osteoblasts and

osteoclasts

Lamellar or compact bone

• In the shaft of adult long bones

Osteoblasts

• Consists of concentric lamellae around a

• Synthesize new bone

central blood vessel

• Stimulated by intermittent PTH, GH/IGF-I,

• Relatively inert metabolically

androgens

• Differentiate from osteoprogenitors

Cancellous or spongy bone

• Differentiate into osteocytes

• In young subjects, at fracture sites and at

the end of long bones

Osteoclasts

• Collagen fibres in loosely woven bundles

• Differentiate from haematopoietic stem

• Proportion increased in

cells

hyperparathyroidism

• Break down bone

• High rate of turnover

• Stimulated by constant PTH,

• Large numbers of osteocytes present

glucocorticoids and oestrogen withdrawal

• Inhibited by anti-resorptive agents (see

Table 9.2)

Box 9.14 What is collagen?

genitors. Osteoblasts stimulate new bone formation

• Many different types, bone contains mainly

by synthesizing osteoid and then help its minerali-

type 1 collagen

zation. Although osteoid formation is relatively

• Each type composed of different sub-units

rapid (<1 day), its secondary mineralization takes

• Large protein (MW ∼300,000 kDa) rich in

much longer (1-2 months). Once bone formation

amino acids glycine, proline and

is complete, the osteoblasts, embedded in new inor-

hydroxyproline

ganic matrix, differentiate into relatively inactive

• General formula is (glycine-proline.X)₃₃₃

cells called osteocytes.

(i.e. 333 repeating units) where X is

Osteoclasts are responsible for resorption of

another amino acid

bone at its surfaces through the action of lysosomal

• Semi-rigid, rod-like molecule of

enzymes. They are large, multinucleated cells that

∼300 × 1.5 nm

differentiate as part of the myeloid lineage from

• Molecules readily polymerize to form

haematopoietic stem cells in response to a range of

microfibrils and fibrils

growth factors and cytokines, some of which are

• Secreted in immature form and cleaved

secreted by osteoblasts, such as the ligand for the

into mature collagen in extracellular space

receptor activator of nuclear factor-kappa B (RANK

• Major component of osteoid

ligand) (Figure 9.9).

• Framework for initiating hydroxyapatite

crystallization

Bone growth and remodelling during life

During childhood new bone formation matches

Cell types in bone

requirements for linear growth, with both length

Although several cell types lie in the bony matrix,

and diameter of long bones increasing. Bone mass

it is the balance of action between two that deter-

peaks in early adulthood (Figure 9.10). Thereafter,

mines bone formation versus resorption (Box 9.15

turnover of bone probably reflects the need to repair

and Figure 9.9).

microtrauma and contribute to Ca²⁺ and PO_43-

The bone-forming osteoblasts arise from imma-

metabolism. It is tightly regulated by paracrine and

ture fibroblast-like precursor cells called osteopro-

endocrine factors. Although the mechanisms are

206 / Chapter 9: Calcium and metabolic bone disorders

Box 9.16 Diagnostic criteria for

Box 9.17 Risk factors for

osteoporosis on DEXA

osteoporosis

Non-modifiable

Mean reference

T score of 0

• Age

value:

• Female sex

Normal:

T score above −1.0

• Polygenic inheritance; Caucasian or Asian

Osteopaenia:

T score −1.0 to −2.5

race and family history

Osteoporosis:

T score below −2.5

• Low body mass index

Severe osteoporosis:

T score below −2.5

plus one or more

Modifiable

fractures

• Hypogonadism (see Chapter 7)

• Cushing syndrome or glucocorticoid

mean reference value for healthy young individuals

therapy (e.g. for asthma) (see Chapter 6)

with peak bone mass. Osteoporosis is defined when

• Thyrotoxicosis (see Chapter 8)

the T-score is −2.5 or lower (Box 9.16).

• Hyperparathyroidism

Osteoporosis increases the risk of fracture,

• Type 1 diabetes (see Chapter 12)

mainly at the hip, spine and wrist. The scale of the

• Drugs (alcohol, heparin, tobacco smoking,

problem is massive. The lifetime risk of a fracture

some antipsychotics)

related to osteoporosis is 1 in 2 for US women

• Chronic disease:

compared to 1 in 8 for US men. In the UK, it is

^ Liver

estimated that 1.2 million women have osteoporo-

^ Renal

sis; ∼60,000 hip fractures, 50,000 distal radial frac-

^ Malabsorption/bowel

tures and 40,000 vertebral fractures occur annually.

^ Post-transplantation

This may be an underestimate as many vertebral

^ Rheumatoid arthritis

fractures may not come to clinical attention. Hip

^ Malignancy

fractures occupy 20% of all orthopaedic hospital

^ Connective tissue disorders

beds. Up to 20% of patients with osteoporotic hip

fracture die within 1 year and up to 50% lose their

independence. The estimated total NHS cost of

Table 9.2 Drugs used to prevent bone

acute management of osteoporotic fractures is ∼£2

demineralization and to treat osteoporosis

billion in 2011.

Inhibitors of resorption

Stimulators of

Age is the major risk factor for osteoporosis as

bone formation

bone mass gradually declines after the mid-20s (Box

9.17). Elderly women are at the greatest risk because

Calcium and vitamin D

Parathyroid

bone loss is accelerated to varying degrees after the

hormone

(intermittent)

menopause secondary to the loss of oestrogen. This

makes women with premature ovarian failure and

Bisphosphonates

Strontium ranelate

no oestrogen replacement at particular risk (review

Sex hormone replacement Sodium fluoride

hormone replacement therapy in Chapter

7).

therapy*

Polygenic factors and race are other non-modifiable

Selective oestrogen

risk factors. Lighter, slight individuals are also at

receptor modulators

greater risk as BMD is lower throughout life.

(SERMS)

Osteoporosis may also be secondary to a number of

other more modifiable causes (Box 9.17). This can

Calcitonin (rarely used)

be so predictable that anti-resorptive agents should

Denosumab

be started routinely when patients commence long-

*In men and pre-menopausal women.

term glucocorticoids (Table 9.2).

Chapter 9: Calcium and metabolic bone disorders / 207

Symptoms and signs

Anti-resorptive drugs

The most common presentation of osteoporosis is

The two first-line therapies for osteoporosis are both

fracture (or bone pain); particularly suspicious is

primarily anti-resorptive. Combined dietary Ca²⁺

fracture following trivial impact (Case history 9.5).

and vitamin D supplementation reduces fracture

Many patients will also be diagnosed by DEXA

rates in the elderly. Bisphosphonates, such as alen-

performed routinely in high-risk individuals, such

dronate, zoledronic acid and risedronate, robustly

as those with hypogonadism.

reduce fracture risk; 40-50% reduction for verte-

brae, 40-60% for hip and 30-40% at other non-

vertebral sites. Bisphosphonates are synthetic

Investigation and diagnosis

analogues of pyrophosphate that become incorpo-

Osteoporosis is diagnosed on the basis of T-score

rated into bone where they have a very long half-life.

measured by DEXA (see Box 9.16). DEXA values

They inhibit osteoclast activation and function and

are obtained bilaterally at the hip, spine and some-

promote their apoptosis. Many are now available as

times the wrist. T-scores that are abnormally low

long-acting preparations (e.g. once yearly zoledro-

(below −1.0) but not osteoporotic are termed osteo-

nate infusion). All bisphosphonates raise concern

paenic (T-score of −1.0 to −2.5).

that while profound suppression of bone turnover

Where osteoporosis has been detected unexpect-

enhances BMD on DEXA, it may also compromise

edly, history, examination and investigations should

the bone’s capacity to repair minor trauma.

seek to exclude modifiable factors (Box 9.17).

Alendronate can cause significant upper gastrointes-

tinal symptoms and lower oesophageal erosions.

Treatment

In women with premature ovarian failure, sex

Management can be divided into treating oste-

steroid hormone replacement therapy

(HRT)

oporosis with drugs and supplements, and address-

should be given to maintain bone mineralization

ing wider issues. As immobilization causes bone

until the normal time of the menopause (∼50 years;

loss, weight-bearing activity is important. This

review Chapter 7). Similarly, the need for sex steroid

should not be so excessive as to cause oestrogen

action on bone is why it is important to treat hyper-

deficiency through hypothalamic amenorrhoea, as

prolactinaemia that results in secondary hypogo-

occurs in elite female runners and ballet dancers (see

nadism. HRT was used previously to treat post

Chapter 7). Patients should moderate alcohol con-

-menopausal osteoporosis. It is effective at reducing

sumption and be encouraged to stop smoking.

fracture rates while it is taken. However, bone mass

Other modifiable risk factors should be minimized

rapidly declines after cessation of treatment such

(Box 9.17). As the major outcome measure is mor-

that

5 years of peri-menopausal therapy fails to

bidity and mortality, not T-score, risk of falls should

protect against fracture two to three decades later

be addressed, especially in the elderly and infirm.

(when it matters). Long-term HRT is reported to

Sometimes, very simple interventions are possible

increase the risk of cardiovascular disease and stroke,

such as avoiding ill-fitting slippers and removing

and some forms of cancer. Selective oestrogen recep-

rugs. Additional risk factors for falls include dehy-

tor modulators (SERMs, e.g. raloxifene) act as weak

dration, postural hypotension and untreated

oestrogen receptor (ER) agonists in some tissues,

Parkinson disease.

including bone, and as ER antagonists in others. As

In the UK 10-20% of women receive drug

such, they significantly reduce vertebral fracture risk

treatment for bone mineralization. The choice of

while minimizing side-effects of HRT. In male

anti-resorptive or anabolic agent is influenced by

hypogonadism, androgen should be replaced long

age, BMD, stage of disease, whether there has been

term when it has beneficial effects on bone mass

a fracture (and if so, where and what type), co-

(review Chapter 7).

morbidities and side-effects

(Table

9.2). Anti-

Calcitonin nasal spray is associated with reduced

resorptive drugs preserve existing bone mass, while

fracture risk but is not routinely used.

anabolic agents increase de novo cancellous bone

Denosumab is a human monoclonal antibody

mass.

that binds RANK ligand and prevents its activation

208 / Chapter 9: Calcium and metabolic bone disorders

of osteoclasts (review Figure 9.9). Its use is approved

Vitamin D deficiency, osteomalacia and

in women with post-menopausal osteoporosis and

rickets

high fracture risk.

Although vitamin D intimately regulates Ca²⁺

metabolism, its deficiency tends not to cause hypo

calcaemia, but does cause failure of osteoid miner-

Anabolic drugs

alization

(Figure 9.11). In growing children this

Intermittent PTH stimulates new bone formation.

presents more severely as rickets with bowing

Synthetic PTH(1-34)

(teriparatide; the first

deformity of long bones, which are described as

amino acids of PTH, see earlier) can be given

rachitic. The normal columnar arrangement of

by daily injection in osteoporosis with high

chondrocytes in the hypertrophic zone of cartilagi-

fracture risk refractory to first-line approaches.

nous growth is elongated and distorted, and calci-

There is some concern that it increases risk of

fication is delayed or absent (Figure 9.11). There are

osteosarcoma.

vascular abnormalities. In adulthood, once bones

Strontium ranelate (registered in the UK and

have stopped growing, presentation is that of milder

much of Europe but not in the USA) is the only

osteomalacia with bone pain and fragility.

agent that both activates osteoblasts and inhibits

Vitamin D deficiency in children was a major

osteoclasts. It has been shown to reduce vertebral

public health problem in industrialized nations in

and non-vertebral fracture risk.

the northern hemisphere (i.e. poor sunlight expo-

sure) until the 1920s when it was discovered that

Monitoring

cod liver oil could cure rickets. This led to wide-

Treatment can be monitored by serial DEXA every

spread vitamin D fortification of milk, which was

2 years or so. More frequent investigation is unhelp-

effective in virtually eliminating rickets. More

ful. Although some serum biomarkers of bone

recently, ceasing free milk programmes in UK

turnover have been identified, large inter- and intra-

schools, coupled to very effective total sun block

individual variability restricts their value in clinical

marketing, has led to a resurgence of vitamin D

practice; serial measurements may be useful in mon-

deficiency. A number of groups are at particularly

itoring short-term responses to therapy.

high risk (Box 9.18) (Case history 9.6).

Symptoms and signs

Bone pain is now the predominant clinical feature,

which may occur because of mineralization defects

leading to the X-ray appearance of pseudofractures

Case history 9.5

(also called Looser zones). In addition, there may

be a proximal myopathy causing profound weak-

A 57-year-old woman with long-standing,

ness of the hip and shoulder girdle. Hypocalcaemia

severe asthma tripped on the carpet. She

may occur (see Box 9.6).

now complains of a pain in her back and

Specifically in rickets, physical and radiological

a radiograph suggests demineralized

signs tend to be found where bone growth is most

bone and a wedge fracture of her L3

active; usually the metaphyseal region of long bones.

vertebra.

At birth, the skull is growing most rapidly and

therefore neonatal rickets may show craniotabes,

Why has this woman had a fracture?

where the cranial vaults have the consistency of a

What are the possible treatments?

ping-pong ball. From the age of 1 year, rickets

manifests as swollen epiphyses of the wrist and

Answers, see p. 212

swelling of the costochondral junction, so-called

‘rickety rosary’.

210 / Chapter 9: Calcium and metabolic bone disorders

Treatment

Box 9.18 Groups at risk of vitamin

The normal treatment of vitamin D deficiency is

D deficiency

oral cholecalciferol, either as a daily dose, e.g. 25 µg

• The elderly, particularly those in residential

(1000 IU) in adults or as a single large dose, e.g.

care

5 mg (225,000 IU). Improvement occurs within

• Babies of vitamin D-deficient mothers

weeks, but it may take as long as a year before

• Those with skin conditions where

the skeleton returns to normal. Although vitamin

avoidance of sunlight is advised

D replacement leads to rapid normalization of

• Dark skinned people, particularly if fully

25-hydroxycholecalciferol concentrations, calcitriol

veiled for cultural or religious beliefs

levels become and remain elevated for many months

• Vegans

because of increased 1α-hydroxylase activity; a con-

• Patients with malabsorption

sequence of secondary hyperparathyroidism.

Other causes of rickets and osteomalacia will

respond to vitamin D replacement, although much

higher doses may be required in hypophosphatae-

mic rickets. As in primary hypoparathyroidism

Box 9.19 Secondary causes of

leading to lack of

1α-hydroxylase activity active

rickets and osteomalacia

vitamin D (calcitriol) should be given.

Long-term, it is important not to over-treat to

• Chronic renal failure - lack of 1α-

avoid hypercalcaemia (see Box 9.9).

hydroxylase activity

• Drugs - barbiturate and phenytoin interfere

with vitamin D metabolism

• Congenital deficiency of 1α-hydroxylase

activity

Case history 9.6

• PO_43- depletion

• Renal tubular disorders - these may be

A 73-year-old South Asian woman taking

congenital, e.g. inactivating PHEX

bendrofluazide for hypertension attended

mutations in X-linked dominant

her local practitioner because of tiredness.

hypophosphataemic rickets

She was vegan and wore a veil. The doctor

identified a corrected serum Ca²⁺ of

2.60 mmol/L (10.4 mg/dL) and went on to

measure PTH, which was increased several

Investigation and diagnosis

fold above the upper limit of normal.

Vitamin D measurement is usually done as chole-

Primary hyperparathyroidism was

calciferol (25-hydroxyvitamin D) rather than calci-

diagnosed.

triol

(1,25-hydroxyvitamin D) because of the

former’s longer half-life. Serum alkaline phosphatase

Is the diagnosis necessarily correct?

is raised and Ca²⁺ and PO43- may be low. Plain

What other hormone measurement might

X-rays of painful sites may show pseudofractures.

demonstrate an alternative diagnosis?

Conditions causing osteomalacia and rickets other

than dietary vitamin D deficiency should be con-

Answers, see p. 212

sidered (Box 9.19).

Chapter 9: Calcium and metabolic bone disorders / 211

Key points

• Hormonal Ca²⁺ homeostasis is via PTH and vitamin D

• Hypocalcaemia in the western world is commonly from surgical trauma/removal or

autoimmune destruction of the parathyroids

• Hypocalcaemia may be asymptomatic, but can present with muscle cramps, numbness and

paraesthesia

• Hypocalcaemia is treated with Ca²⁺ and vitamin D

• Common causes of hypercalcaemia include primary hyperparathyroidism and malignancy

• Hypercalcaemia may be asymptomatic, but remember ‘bones, stones, moans and groans’

• Osteoporosis, defined by DEXA T-score, is low bone mass and micro-architectural deterioration

leading to increased fracture risk

• Osteomalacia (adults) and rickets (children) result from vitamin D deficiency causing a failure

to calcify osteoid

Answers to case histories

Case history 9.1

paraesthesia. The two causes can be easily

distinguished because total serum Ca²⁺

The most likely explanation of the

would not change in hyperventilation, while it

paraesthesia is hypocalcaemia because of

would fall if there were parathyroid

inadvertent removal of or damage to the

dysfunction.

parathyroid glands (i.e. hypoparathyroidism).

Hypoparathyroidism is treated by

Alternatively, she may be hyperventilating

supplementation with Ca²⁺ and vitamin D,

because of her anxiety. The symptoms are

usually α-calcidol (because 1α-hydroxylase

the same because over-breathing may induce

activity is lacking), to maintain serum

a fall in serum ionized Ca²⁺ concentration.

Ca²⁺ values at the lower end of normal

This results from the disturbance of the

(to avoid excessive Ca²⁺ flux through the

following equilibria:

kidney). The hypoparathyroidism may

be temporary from reversible operative

−

CO +H O ⇌H CO

trauma. Withdrawal of treatment could be

−

H CO −⇌H++HCO

trialled at out-patient follow-up.

Hyperventilation can be treated by re-

Albumin-H ⇌ Albumin−+ H⁺

breathing into a paper bag.

Albumin−+Ca

⇌

Albumin-Ca

Case history 9.2

As the woman over-breathes, the

partial pressure of carbon dioxide falls,

Type 1 autoimmune polyglandular syndrome

leading to respiratory alkalosis from

(APS-1) is consistent with all aspects of the

decreased production of hydrogen

history and examination. The patient has

ions (H⁺) from H₂CO₃₋. To compensate H⁺

primary hypoparathyroidism with a family

ions dissociate from albumin allowing

history suggesting an inherited cause. The

increased binding of Ca²⁺ to the protein.

white plaques are suggestive of candidiasis

Thus, ionized Ca²⁺ concentration falls and

(‘thrush’), more commonly found in the

can be sufficient to induce tetany or

genital tract, but in APS-1 this manifests in

212 / Chapter 9: Calcium and metabolic bone disorders

the throat. The syndrome is very rare;

Case history 9.4

therefore, it is important to consider more

There are several causes of familial

common diagnoses, e.g. by taking a history

hypercalcaemia. The most serious one is

and examining for previous neck surgery.

MEN1 (primary hyperparathyroidism is

The sore throat and family history could also

commonly the first manifestation; see

be chance findings in a patient with isolated

Chapter 10). However, the fact that both men

autoimmune hypoparathyroidism.

are well and neck surgery was unsuccessful

If the family has APS-1, gaining a molecular

suggests familial benign hypercalcaemia. It is

genetic diagnosis is important as a mutation

benign in most situations but is important to

would allow straightforward identification or

recognize so that parathyroidectomy for

exclusion of the syndrome in other family

mis-diagnosed primary hyperparathyroidism

members. The AIRE gene should be amplified

is avoided.

and sequenced from genomic DNA (review

Chapter 4). To facilitate this investigation and

Case history 9.5

family assessment, referral to clinical genetics

should be considered. The patient and

Although we do not know the force with which

affected family members are at risk of other

she fell, the impact seems rather trivial,

autoimmune endocrinopathies; e.g.

suggesting a pathological fracture. Given the

hypoadrenalism, which can be life-

X-ray, the most likely cause is osteoporosis,

threatening. Therefore, potential underactivity

although other pathology like tumour

of the thyroid, adrenal cortex and reproductive

metastasis needs consideration. Likely

axis should be assessed by history,

contributing factors to osteoporosis here are

examination and investigation (see Chapters

post-menopausal age and severe asthma,

6-8). Follow-up should ideally be in a

most likely treated with glucocorticoids

specialist endocrinology clinic. Finally, a

(possibly systemic). Other factors need

young woman at risk of premature ovarian

interrogation (e.g. smoking and alcohol intake).

failure should be counselled on future fertility

Having made a diagnosis of osteoporosis

and family planning to allow her to make

by DEXA, calcium and vitamin D

informed choices.

supplementation, and bisphosphonate

therapy (especially if on long-term oral

Case history 9.3

glucocorticoid therapy) would be first-line

treatments.

Albumin is 4 units below 40 g/L; therefore

4 × 0.02 (i.e. 0.08) needs to be added to the

Case history 9.6

uncorrected serum Ca²⁺ of 2.58 mmol/L,

making the corrected serum Ca²⁺

The diagnosis is not necessarily correct.

2.66 mmol/L (10.64 mg/dL).

Bendrofluazide could cause mildly increased

There are several potential reasons for her

serum Ca²⁺. Raised serum PTH could reflect

hypercalcaemia: vitamin D excess from her

vitamin D deficiency. She most likely has poor

non-prescribed supplements; venesection

UV light exposure and a diet quite possibly

may have been difficult with prolonged

deficient in vitamin D. Serum vitamin D should

tourniquet application; she may be taking a

be measured, most likely as cholecalciferol. If

thiazide diuretic for hypertension; she may

low, vitamin D should be replaced. Once

have a familial form of breast cancer with

replete, PTH is likely to have fallen to normal.

hypercalcaemia of malignancy. These

It would also be worth re-checking the serum

possibilities need addressing alongside

Ca²⁺ as the first very subtly raised value might

potential primary hyperparathyroidism.

have been spurious.

214 / Chapter 10: Pancreatic and gastrointestinal endocrinology and endocrine neoplasia

To recap

■ Gastrointestinal and pancreatic hormones are peptides, the biosynthesis of which is covered

in Chapter 2

■ Some solid tumours in the breast and prostate are sensitive to steroid hormones, providing

therapeutic strategies and making it timely to review nuclear hormone action (see Chapter 3)

Cross-reference

■ Function of the pancreatic islet β-cell and α-cell is also covered in Chapter 11 on diabetes

mellitus

■ Tumours secreting adrenomedullary hormones are an important component of familial

neoplasia syndromes and are also covered in Chapter 6

■ Tumours of the thyroid present with goitre, the examination and investigation of which is

described in Chapter 8

■ Tumours and hyperplasia of the parathyroid glands, part of multiple endocrine neoplasia

syndromes, cause primary hyperparathyroidism (see Chapter 9)

■ Incretin hormones, an important area of gastrointestinal endocrinology, are now exploited

therapeutically in diabetes (see Chapter 13)

This chapter is arranged into three sections: pancre-

dromes with distinctive symptoms and signs. Some

atic and gastrointestinal endocrinology as a forerun-

of the tumours arise as part of multiple endocrine

ner to understanding hormone-secreting tumours

neoplasia (MEN) type 1 (see later section).

from these sites; familial endocrine neoplasia syn-

dromes; and other tumours and hormone-sensitive

Pancreatic islet endocrinology

cancers. While the latter are the mainstay of other

specialties, antagonizing hormone action can be an

In the pancreas, endocrine cell types aggregate as

important component of therapy.

islets of Langerhans and comprise ∼1% of the organ

embedded within the surrounding exocrine tissue

that secretes digestive enzymes

(Table

10.1 and

Pancreatic and gastrointestinal

Chapter 11).

endocrinology

Endocrine cells secreting a multitude of hormones

Insulin

are present throughout the gastrointestinal tract and

in the pancreas (Table 10.1). Their development is

The predominant islet cell type is the insulin-

similar and regulated by critical transcription factors,

secreting β-cell

(Table

10.1 and Figure

10.1).

foremost amongst which is neurogenin-3 (Neurog3

Insulin acts to lower blood glucose. Its release is

or Ngn3). If Neurog3 fails to act, no endocrine cell

proportional to the ambient glucose concentration.

types are formed either in the pancreas or in the

Its inadequacy leads to diabetes (Chapters 11-14).

gastrointestinal tract.

The hormone is synthesized initially as pre-

Pancreatic and gastrointestinal hormones regu-

proinsulin and stored in intracellular granules com-

late digestion and broad aspects of metabolism.

plexed with zinc. Enzymatic cleavage by prohormone

Therefore, tumours secreting inappropriate or

convertase 1/3 (PC1/3) during hormone secretion

excessive amounts of these hormones can cause syn-

yields mature insulin and equimolar amounts of

Chapter 10: Pancreatic and gastrointestinal endocrinology and endocrine neoplasia / 217

loads, particularly those containing refined sugars, in

the intestine are thought to over-stimulate insulin

secretion, causing a ‘reactive hypoglycaemia’ (Case

history

10.1). This can occur in patients with

dumping syndrome which may also be a complica-

tion of bariatric surgery (Chapter 15) and in patients

with co-existing cortisol deficiency (Addison disease;

see Chapter 6 and Case history 10.2).

In patients who are usually clearly unwell (e.g.

cachectic) with large solid mesenchymal tumours,

an alternative IGF-II protein (called big IGF-II) can

cause non-islet cell tumour hypoglycaemia (NICTH)

by failing to bind IGF binding proteins with con-

sequent excessive hormone action. In contrast to

insulinoma, serum insulin is undetectable. Surgical

removal of the tumour is the treatment of choice

but if this is impossible, glucocorticoids or growth

hormone (GH) can prevent the hypoglycaemia.

Figure 10.1 A pancreatic islet surrounded by

In children, GH deficiency can present with

exocrine tissue. β-cells are demonstrated by

hypoglycaemia.

immunohistochemistry for stored insulin (brown

staining). Image courtesy of Rachel Salisbury,

Investigation and diagnosis

University of Manchester.

The diagnosis of hypoglycaemia is made by dem-

onstrating serum glucose <2.2 mmol/L (40 mg/dL)

C-peptide [PC1/3 also cleaves adrenocorticotrophic

by laboratory assay (i.e. not by capillary glucose

hormone

(ACTH) from pro-opiomelanocortin

monitor as used in diabetes; see Chapter 12). This

(POMC); review Figure 2.4 and Chapter 5].

can be precipitated by admission to hospital for a

72-h fast when plasma glucose is measured regularly

Insulinoma (and the differential diagnosis of

and, if hypoglycaemia occurs, a simultaneous

hypoglycaemia)

sample can be assayed for insulin and C-peptide.

Insulinomas are rare β-cell tumours that secrete

Detecting the latter alongside insulin indicates

insulin excessively and inappropriately (i.e. when

endogenous β-cell overactivity rather than injection

blood glucose is already low; Table 10.1). They are

of synthetic insulin. Sulphonylureas, which stimu-

usually benign with a median age of presentation of

late the β-cell, are used to treat type 2 diabetes (see

∼50 years. However, they may present earlier and

Chapter 13) and can also cause hypoglycaemia; they

be malignant, especially when part of MEN-1.

can be detected in toxicological screens of urine and

blood. It is exceptional for reactive hypoglycaemia

Symptoms and signs

in otherwise well individuals to lower blood glucose

The major clinical feature is a tendency to hypogly-

below 2.2 mmol/L (40 mg/dL) (Box 10.1).

caemia. Symptoms include light-headedness and

Once a biochemical diagnosis of hypoglycaemia

hunger, precipitated by fasting or exercise and

secondary to endogenous insulin has been made,

relieved temporarily by eating. More profound

the search for an insulinoma is performed by mag-

hypoglycaemia is an ever-present risk in diabetes

netic resonance imaging (MRI) or computed tom-

treated with insulin injections (see Chapter 12).

ography (CT). Imaging facilitates surgery yet can

Insulinomas are very rare, making the differential

be challenging because tumours may be small and

diagnosis important (see Boxes 10.1 and 10.2). Some

multiple. Arteriography and endoscopic ultrasound

individuals develop hypoglycaemic symptoms a few

can be used. Insulinomas occur more frequently in

hours after a large meal when large carbohydrate

the pancreatic tail where most β-cells reside.

218 / Chapter 10: Pancreatic and gastrointestinal endocrinology and endocrine neoplasia

Box 10.1 Differential diagnosis of

hypoglycaemia

Inappropriate levels of insulin and C-peptide

• Insulinoma

• Sulphonylurea overdose

• Congenital hyperinsulinism

• Neonatal consequence of maternal

diabetes in pregnancy

• Reactive hypoglycaemia [highly unlikely to

lower serum glucose <2.2 mmol/L (40 mg/

dL) if patient otherwise well]

Inappropriate level of insulin, low C-peptide

• Exogenous insulin overdose - accidental

(common in diabetes, Chapter 12) or

deliberate/malicious

Figure 10.2 Congenital hyperinsulinism (diffuse

Low insulin

form). Immunohistochemistry for insulin (brown

• Non-islet cell tumour hypoglycaemia

staining) shows widespread clusters of β-cells in the

• Hypoadrenalism (can exacerbate reactive

pancreas resected from an infant who presented

hypoglycaemia)

with hypoglycaemia. Image courtesy of Rachel

• GH deficiency (in children)

Salisbury, University of Manchester.

Treatment

caemia increases fetal insulin secretion in late gesta-

Treatment is by surgery, but where this is impossi-

tion that persists transiently at inappropriately high

ble, diazoxide may ameliorate hypoglycaemia.

levels after birth (see Chapter 14).

Somatostatin analogues, such as octreotide, may

also be useful in preventing hypoglycaemia by

inhibiting insulin secretion.

Case history 10.1

Congenital hyperinsulinism and neonatal

An overweight 37-year-old woman

hypoglycaemia

consulted her doctor because 2-3 h after a

Excessive and inappropriate insulin secretion can also

meal she became light-headed, sweaty

arise from genetic defects in components of the

and felt faint. Her symptoms improved with

glucose-sensing/insulin secretion pathway, such as

food. She has a family history of type 2

constitutive activity of the ATP-sensitive K⁺ channel

diabetes. She mentioned that once when

(see Figure

11.9). This congenital hyperinsulinism

she felt unwell, she borrowed her mother’s

presents in infancy as either focal or diffuse pancreatic

blood glucose meter and found that the

disease and is treated by diazoxide and surgical resec-

reading was 3.2 mmol/L (∼60 mg/dL).

tion (Figure 10.2). The latter is inherited as an auto-

somal recessive disorder. Conversely neonatal diabetes,

What is the most likely diagnosis?

which affects 1 in 100,000-200,000 live births, may

How might you investigate the cause of

result from inactivating mutations of the ATP-sensitive

her symptoms?

K+ channel (type 1 diabetes is rare before 1 year).

Transient hypoglycaemia can also occur in

Answers, see p. 231

neonates of mothers with diabetes; fetal hypergly-

Chapter 10: Pancreatic and gastrointestinal endocrinology and endocrine neoplasia / 219

Case history 10.2

Box 10.2 Gastrointestinal

hormone-secreting tumours

A 34-year-old man presented as an

Gastrinoma

emergency to hospital having fainted upon

• Profound reduction in gastric pH causing

standing up. A passerby who had

severe ulceration of stomach and

diabetes used her glucose monitor and

duodenum

obtained a reading of 1.9 mmol/L (∼34 mg/

• Treated by proton pump inhibitors or

dL). She called an ambulance. The man

surgery

recovered quickly and on questioning

reported that he had a mother who took

Insulinoma

thyroxine. He was tanned. A blood result

• Causes hypoglycaemia (Box 10.1)

from hospital revealed serum K⁺ of

• Treated by surgery but may be improved

5.6 mmol/L (5.6 mEq/L).

with diazoxide or somatostatin analogues

What is the diagnosis until proven

Glucagonoma

otherwise?

• Causes secondary diabetes (+ typical skin

What other examination and

rash)

investigations would you perform?

• Villous hypertrophy on gastroscopy

What emergency treatment is needed?

• Treated by surgery

Answers, see p. 231

Somatostatinoma

• Causes secondary diabetes, reduced

gastric acid secretion, gallstones,

Glucagon

steatorrhoea and weight loss

α-cells are arranged around the β-cells in pancreatic

• Treated by surgery

islets and secrete glucagon

(see Table

10.1 and

Figure 11.7). Glucagon is antagonistic to insulin,

VIPoma/Verner-Morrison syndrome

acting to mobilize the liver’s stored carbohydrate

• Presents with severe watery diarrhoea,

and raise serum glucose (see Chapter 11). It acts via

hypokalaemia and skin flushing

its cell surface G-protein-coupled receptor and is

• Treated by surgery or somatostatin

used by injection in an emergency to treat hypogly-

analogues

caemia in diabetes (see Chapter 12).

Glucagonomas are tumours of the pancreatic

Carcinoid tumour

α-cells secreting excess glucagon, the hallmark of

• See Box 10.3

which is secondary diabetes (Box 10.2). In addition,

there can be an unusual migratory skin rash associ-

and glucagon (Table 10.1). It is also synthesized by

ated with amino acid and zinc deficiency (necrolytic

hypothalamic neurones to regulate growth hormone

migratory erythema). Glucagonomas may also lead

(GH) (see Figure 5.5) and in other endocrine cell

to hypertrophy of the intestinal villi and mucosal

types throughout the gastrointestinal tract, where it

thickening, which may be noted during gastroscopy

has multiple inhibitory effects on gut motility and

or CT scanning of the abdomen. Treatment is by

exocrine secretion.

surgery wherever possible.

Rare tumours of the pancreatic δ-cells are called

somatostatinomas and present variably, but tend to

Somatostatin

cause diabetes, reduced gastric acid secretion, gall-

Somatostatin is secreted by δ-cells scattered in the

stones, steatorrhoea and weight loss (Box 10.2).

pancreatic islets where it inhibits secretion of insulin

Treatment is by surgery wherever possible.

220 / Chapter 10: Pancreatic and gastrointestinal endocrinology and endocrine neoplasia

duodenum or the pancreas (Box 10.2). Profound

Pancreatic polypeptide

gastric acidity causes severe ulceration of the

The pancreatic polypeptide cells of the islet secrete

stomach and duodenum (Case history 10.3). From

pancreatic polypeptide (see Table 10.1). The func-

its original description, Zollinger-Ellison syndrome

tion of this hormone remains somewhat unclear

refers to the triad of peptic ulceration, excess gastric

and tumours secreting it are exceptionally rare.

acid and a pancreatic islet tumour secreting gastrin.

Diagnosis is made by assaying fasting levels of

Ghrelin

serum gastrin. Visualizing the tumour can be dif-

ficult, but MRI, CT and endoscopic ultrasound

Ghrelin is secreted by ε-cells of the pancreatic islet

may be useful. Proton pump inhibitors (drug names

and by cells in the body of the stomach. It inhibits

ending with ‘-prazole’) are effective in controlling

GH secretion and is involved in appetite control

the acid secretion. The ideal surgical treatment is

(see Chapters 5 and 15; Figure 5.5). No syndrome

discrete removal of the tumour or, if this is not pos-

has been described from its excess or inappropriate

sible, partial gastrectomy.

action.

Gastrointestinal endocrinology

Case history 10.3

Intestinal hormone-secreting cells scattered through-

A 64-year-old man presented to the

out the stomach wall and at the bottom of intestinal

emergency surgery team with sudden

crypts are termed ‘enteroendocrine’. They secrete a

onset of severe upper abdominal pain. On

multitude of hormones that regulate gastrointesti-

examination, his abdomen was rigid.

nal function and metabolism (see Table 10.1). Some

Serum amylase was normal. Erect

of the hormones, such as vasoactive intestinal

abdominal X-ray revealed air under the

polypeptide (VIP), are actually released from the

diaphragm. He took no medications. At

enteric nervous system and function as neurotrans-

operation there was a perforated duodenal

mitters (review Figure 1.1). Not all of the cells and

ulcer. Five years previously he had had

hormones are associated with tumour syndromes.

emergency endoscopy to control a

bleeding duodenal ulcer. A doctor

Gastrin

measured a fasting level of a

Gastrin is secreted as peptides of three sizes from

gastrointestinal hormone that could

G-cells in the duodenum, pancreas and antral part

account for the repeated ulceration. The

of the gastric mucosa following distension of the

hormone was elevated.

stomach by food or by the presence of small pep-

tides or amino acids within the stomach (see Table

What was the hormone?

10.1). Anticipation of eating also increases gastrin

What further investigations are warranted

secretion via the vagus nerve. Gastrin increases

to investigate this elevated hormone

stomach acid secretion and blood flow to the gastric

level?

mucosa. Gastrin is thought to play a role in gastric

motility and peristalsis. Once the pH of the stomach

Answers, see p. 231

falls below 2.5, negative feedback inhibits further

gastrin release. Its secretion is also inhibited by

somatostatin, glucagon and VIP.

Vasoactive intestinal polypeptide

Zollinger-Ellison syndrome

VIP is a 28-amino acid peptide neurotransmitter in

Gastrinomas, first described by Zollinger and

the gut and central nervous system. At pharmaco-

Ellison, over-secrete gastrin and tend to arise in the

logical doses, VIP increases hepatic glucose release,

Chapter 10: Pancreatic and gastrointestinal endocrinology and endocrine neoplasia / 221

insulin secretion and pancreatic bicarbonate pro-

GIP is also an incretin (see Table 10.1). It is

duction, while inhibiting stomach acid production,

secreted higher up in the gut than GLP-1 by K-cells

partly through relaxation of gastric blood vessels

in the duodenum and jejunum, but acts similarly

and smooth muscle. These actions are similar to

to enhance glucose-stimulated insulin secretion by

those of glucagon, secretin and glucose-dependent

pancreatic β-cells.

insulinotrophic peptide (GIP; also known as gastric

inhibitory peptide). GIP and VIP may have evolved

Cholecystokinin, secretin and motilin

from a single gene.

Cholecystokinin (CCK), secretin and motilin are all

peptide hormones secreted by the small intestine in

VIPomas and Verner-Morrison syndrome

response to a variety of stimulants and act via cell

VIPomas, first described by Verner and Morrison, are

surface G-protein-coupled receptors (Table 10.1).

enteric neural gangliomas over-secreting VIP and

CCK increases gallbladder contraction and stimu-

causing severe watery diarrhoea and flushing of the

lates pancreatic exocrine secretion. Secretin is

skin (Box 10.2). The diarrhoea may provoke dehy-

released in response to stomach acid entering the

dration and severe hypokalaemia (see Box 6.14).

duodenum and stimulates the pancreas to secrete

Diagnosis is by detecting raised fasting serum VIP

bicarbonate-rich fluid that neutralizes the acidity.

levels and visualization by MRI or CT. The somato-

Motilin, synthesized in duodenal and jejunal M-cells,

statin analogue, octreotide, can help identify the

enhances gut peristalsis and pepsin secretion.

tumour when labelled (review Chapter 4) or treat its

symptoms if tumour resection is not possible.

Carcinoid syndrome

Pancreatic islet tumours or those secreting gastrin

Glucagon-like peptide-1 and

or VIP all appear ‘neuroendocrine’ on histology (i.e.

glucose-dependent insulinotropic

they contain secretory granules). However, in addi-

peptide

tion to these tumour types defined by hormone

Alternative cleavage of proglucagon gives rise to

product, there is another broad category of tumour

hormones other than glucagon; PC1/3 (the enzyme

called ‘carcinoid’. Most are non-functioning without

that cleaves insulin from proinsulin and ACTH

detectable hormone secretion. Functional tumours

from POMC) generates glucagon-like peptide 1

can cause ‘carcinoid syndrome’, the hallmark of

(GLP-1) (see Table 10.1). GLP-1 is released in

which is symptoms and signs from the release of

response to nutrients by L-cells, which are predomi-

serotonin (5-hydroxytryptamine) and its metabo-

nantly located in the terminal ileum and large bowel

lites (plus other factors) into the systemic circula-

but are also found elsewhere. It also seems increas-

tion

(Figure

10.3). Systemic detection is more

ingly likely that some GLP-1 is produced by α-cells

prevalent with tumours that lie outside the portal

in the pancreatic islet.

circulation, such as lung carcinoids or intestinal

GLP-1 acts as an incretin, magnifying insulin

tumours that have metastasized to the liver.

secretion from stimulated β-cells. Its secretion from

Carcinoid tumours can be classified according

the gut is the main reason why insulin secretion

to embryological origin of tumour location (Table

after oral glucose is greater than from an equivalent

10.2). Foregut carcinoids lie proximal to the second

dose of intravenous glucose. L-cell tumours have

part of the duodenum and include those in lung,

not been described, but it has been questioned

thymus, pancreas and thyroid. Midgut ones arise

whether reactive hypoglycaemia in dumping syn-

between the distal duodenum and transverse colon

drome (Box 10.1) is mediated by GLP-1 (and GIP)

with hindgut tumours situated more distally.

overactivity. GLP-1 analogues and inhibitors of

Colonic and ileal carcinoids are more prone to

the enzyme dipeptidyl peptidase 4 (DPP-4) that

metastasize. Distant deposits in either the liver or

degrades GLP-1 are now in widespread use as treat-

lymph nodes are observed in ∼70% of colonic car-

ments for diabetes (see Chapter 13).

cinoids compared with only 2-5% of those in the

222 / Chapter 10: Pancreatic and gastrointestinal endocrinology and endocrine neoplasia

SYNTHESIS

L-Tryptophan

Tryptophan hydroxylase*

5-hydroxytryptophan (5-HTP)

Aromatic L-amino acid decarboxylase

Serotonin (5-HT)

Monoamine oxidase

5-hydroxyindoleacetic acid**

DEGRADATION

Figure 10.3 Synthesis and degradation of serotonin. *Rate-limiting step: two isoforms exist. **Measured in

urine in carcinoid syndrome.

Carcinoids constitute around a third of all

Table 10.2 Distribution of carcinoid tumours

tumours in the small intestine but only 1% of those

Site

Frequency (%)

in the stomach, colon or rectum. In total, carcinoid

tumours constitute around

2% of all malignant

Foregut

tumours. The incidence is approximately 1 in 100,000

Thymus

and may occur at all ages, including in children.

Lung

Stomach

Symptoms and signs

The majority of carcinoids are asymptomatic and

Duodenum

only detected at post-mortem examination. Carcinoid

Midgut

syndrome has distinctive symptoms and signs (Box

10.3 and Case history 10.4). Pellagra-like skin lesions

Ileum

reflect tryptophan deficiency from consumption of

Jejunum

the amino acid in serotonin synthesis (Figure 10.3).

Appendix

Investigation and diagnosis

Caecum

Carcinoid syndrome is diagnosed by detection of

Hindgut

excessive 5-hydroxyindoleacetic acid (5-HIAA) in a

Colon

24-h urine sample (Figure 10.3). An acidified con-

tainer is necessary

(see Box

4.1) and avocadoes,

Rectum

bananas, tomatoes, plums, walnuts, pineapples,

aubergines and chocolate need to be avoided for the

preceding 24 h and during the collection period. The

collection starts after the first micturition of the day is

appendix, the

commonest

tumour location in

discarded and continues for the next 24 h up to and

young patients when it is an incidental finding at

including the first urination of the following day. The

appendicectomy. The risk of metastasis increases

assay has a sensitivity of ∼70% and specificity of

with the size of the tumour. In older patients, car-

100% in carcinoid syndrome. Serum chromogranin

cinoids are more frequently found in the ileum and

A can also be raised but is relatively non-specific as it

jejunum.

is a component of all secretory granules. After making

Chapter 10: Pancreatic and gastrointestinal endocrinology and endocrine neoplasia / 223

Case history 10.4

Box 10.3 Clinical features of

carcinoid syndrome

A 65-year-old man presents with

• Flushing

breathlessness, rash, flushing, abdominal

• Diarrhoea

pain and diarrhoea. Examination revealed a

• Abdominal pain

wheeze and his peak flow rate was reduced.

• Bronchoconstriction and asthma-like

A chest X-ray was unremarkable but

episodes

abdominal ultrasound showed a single mass

• Tricuspid or pulmonary valve

in his liver. A barium meal and follow through

abnormalities:

demonstrated an ileal mass. Urinary 5-HIAA

^ Occur in 60-70%

was markedly raised upon 24-h collection.

^ May be complicated by right heart failure

^ Fibrotic change in mural and valvular

What is the likely diagnosis?

endocardium

What are the treatment options?

^ Seem unrelated to tumour mass or

What factors are likely to affect his

duration; possibly related to secretion of

prognosis?

serotonin and tachykinins

Answers, see p. 232

• Pellagra-like skin lesions

• Treated by somatostatin analogues,

surgery, chemotherapy, or, potentially,

interferon-α

Box 10.4 Warning signs for

neoplasia syndromes

a biochemical diagnosis, the tumour is potentially

• Family history of tumours

localized by a range of techniques, including endos-

• Unusually early age of onset

copy, barium enema, chest radiograph, ultrasound,

• History of multiple tumours

CT, MRI, angiography, selective venous sampling

and labelled somatostatin scanning.

Familial endocrine neoplasia

Treatment

Surgical resection of carcinoid tumours may be

Inheritance of endocrine tumour predisposition

curative for local disease. Even with more extensive

syndromes is usually dominant (i.e. mutation in

metastatic disease, aggressive surgery to debulk

only one of the two alleles is sufficient to predispose

tumour mass can improve symptoms markedly.

to tumour formation). Four different categories are

Carcinoid tumours express somatostatin receptors

discernible (Table 10.3). By inheriting a tumour-

and medical treatment with somatostatin analogues

promoting mutation in every cell in the body,

can be highly effective. Other treatment includes

tumours tend to be familial, multiple and occur at

chemotherapy and, potentially, interferon-α.

an earlier age than usual; all warning signs for famil-

Outcome from carcinoid tumours can be good

ial tumour predisposition syndromes (Box 10.4).

with some patients living for

10-15 years with

In general, neoplasms arise through sequential

metastatic disease. However, overall 5-year survival

acquisition of mutations in four types of gene,

rates, when liver metastases are present, are 18-38%

giving a cell a proliferative or survival advantage

with a median survival time of

∼23 months.

over its neighbours to produce clonal growth (Box

Approximately one-third of patients die from carci-

10.5). Two of these, proto-oncogenes and tumour

noid heart disease and heart valve replacement can

suppressor genes, are associated with familial endo-

be important to prevent this.

24-hour urinary

crine neoplasia syndromes. Inheritance of a mutated

5-HIAA and serum chromogranin assay allow mon-

proto-oncogene usually leads to hyperplasia of all

itoring of disease activity.

cells in which the gene is expressed (e.g. mutations

224 / Chapter 10: Pancreatic and gastrointestinal endocrinology and endocrine neoplasia

Table 10.3 Categories of endocrine tumour pre-disposition syndromes

Category

Primarily

Description

Example

endocrine

Multiple endocrine

Yes

Multiple tumours in multiple

MEN-1

neoplasia (MEN)

endocrine glands

Single organ

Yes

Multiple tumours in one endocrine

Familial parathyroid

gland

tumours

Non-endocrine

Only a minority develop endocrine

Neurofibromatosis

tumour with minor

tumours

endocrine component

Other syndrome

Diverse dysfunction with some

McCune-Albright

endocrine abnormality

(review Figure 3.14)

ics alongside endocrinology professionals are impor-

Box 10.5 Four types of tumour-

tant for tracing relatives, counselling, screening,

promoting mutation

diagnosis, treatment and management.

• Proto-oncogenes - mutation confers a

positive growth advantage and hyperplasia

MEN-1

of the affected cell type

Tumours characterizing MEN-1 are listed in Table

• Tumour suppressor genes - mutation

10.4; carcinoids, lipomas, VIPomas and adrenocor-

de-restricts clonal cell growth

tical tumours are more unusual. It is caused by

• DNA repair genes - mutation increases

inactivating mutations in MEN1, the gene encod-

likelihood of further mutations

ing the MENIN tumour suppressor protein.

• Cell adhesion and invasion genes -

Clinical features and treatment of MEN-1 are

mutation increases chance of metastasis

related to tumour site

(Table

10.4). Having

ascertained a diagnosis genetically or, failing that, by

in the RET oncogene, which causes MEN-2; Figure

a history of tumours in at least two organs, regular

10.4). On this background, tumour development

screening is vital for the index case and asympto-

then depends on the chance acquisition of tumour-

matic family members, as early diagnosis and treat-

promoting mutations in other genes. In contrast,

ment of new tumours reduces mortality and

inheriting a mutation in one copy of a tumour sup-

morbidity. A genetic diagnosis can be established in

pressor gene (e.g. NF1 in neurofibromatosis) tends

∼80% of cases and allows easy identification of

not to cause hyperplasia. However, losing function

affected or discharge of unaffected family members.

of the other normal allele

(i.e. by mutation or

Frequency of screening is debated and influ-

silencing) can lead to a tumour; the ‘second hit’ in

enced by detection of ever-smaller lesions of unclear

Knudsen’s two-hit hypothesis.

significance by high-resolution imaging. Arguably

it should commence in early childhood and con-

tinue for life as some individuals have developed

Multiple endocrine neoplasia

first manifestations as early as 5 years or as late as

There are two types of MEN (Table 10.4). Although

the eighth decade. However, virtually all affected

both are rare outside of tertiary referral centres,

individuals have primary hyperparathyroidism by

management is time-intensive and morbidity and

age 50 years. Somewhat unusually as MENIN is a

mortality are significantly increased. Both may be

tumour suppressor, this can be from hyperplasia of

familial or sporadic [i.e. the occurrence of a new (‘de

all glands as well as individual tumours.

novo’) mutation; note most endocrine tumours are

In addition to history and examination, serum

sporadic]. Multidisciplinary teams of clinical genet-

calcium (Ca²⁺), fasting gastrointestinal hormones

226 / Chapter 10: Pancreatic and gastrointestinal endocrinology and endocrine neoplasia

and pituitary assessment [e.g. prolactin, insulin-like

MEN-2

growth factor I

(IGF-I), exclusion of Cushing

disease and thyroid function tests] should be per-

The tumours characterizing MEN-2 are listed in

formed annually. MRI of the anterior pituitary (e.g.

Table 10.4, with reference to relevant chapters else-

every few years) and pancreas (arguably annually)

where. Phaeochromocytomas

(adrenal medulla)

complements biochemical screening and allows

and medullary thyroid cancer (MTC; thyroid C

detection of non-functioning tumours. Most

cells) are both derived embryologically from the

tumours are benign but can be malignant, especially

same source, neural crest cells. Clinically, MEN-2

in the pancreas. Some published guidelines suggest

can be further sub-divided into 2A (including par-

more frequent imaging surveillance; however, as

athyroid disease; Case history 10.5) or 2B (includ-

with all screening, outcome benefits (e.g. mortality)

ing neurofibromata and Marfanoid habitus where

need to justify intrusiveness and cost. This remains

arm span is greater than height). Both are auto-

contentious, especially for asymptomatic pancreatic

somal dominant, highly penetrant and caused by

tumours that can require very intensive surgery,

inactivating mutations in the RET proto-oncogene,

leaving the patient with life-long insulin-requiring

which encodes a cell-surface receptor with tyrosine

diabetes. CT scanning should not be used for sur-

kinase activity (review Chapter 3). Mutations lead

veillance as the cumulative lifetime dose of radiation

to potent growth stimulation and hyperplasia, pre-

itself becomes a tumour risk factor.

disposing to ‘second hit’ tumour formation.

Genetic screening for MEN-2 is more effective

Familial isolated hyperparathyroidism

than for MEN-1 because, in most cases, the causa-

Primary hyperparathyroidism can run in families.

tive mutation can be identified within the RET

In 20% of kindreds, mutations can be identified in

coding region (review Figure 2.2 on gene structure

MEN1.

and Figure

4.5 on polymerase chain reaction).

Those without the mutation can be reassured, while

Case history 10.5

a definitive diagnosis can be made in affected indi-

viduals during early childhood and biochemical

A 35-year-old active fit man was referred

monitoring commenced.

with hypercalcaemia and hypertension. He

For MTC or its preceding C-cell hyperplasia

had also been suffering with palpitations

(see Chapter

8), surveillance is done by annual

and headaches. He had been well

measurement of calcitonin either without stimula-

previously. There was no family history of

tion or less commonly during a pentagastrin stimu-

endocrine disease. Investigations

lation test. Once over the age of

5-6 years,

confirmed raised serum Ca²⁺ and the

prophylactic thyroidectomy should be considered as

doctor went on to detect elevated serum

the tumour almost inevitably develops in affected

parathyroid hormone (PTH) and normal

individuals (>90% by 30 years). Absolute risk and

vitamin D levels. In addition, the doctor

timing of surgery depend on which codon is

prescribed a β-blocker for the

mutated. If surveillance and prophylaxis fails (which

hypertension and palpitations. Five days

should not happen in familial cases), presentation

later, the man was admitted collapsed with

is with goitre (see Chapter 8).

a blood pressure of 230/110.

Screening for phaeochromocytoma is increas-

ingly done by annual measurement of serum metane-

What diagnosis did the doctor detect?

phrine and, especially, normetanephrine as a normal

What diagnosis was missed?

result practically excludes the tumour (see Chapter

Why was he admitted?

6). Periodic measurement of serum Ca²⁺ screens for

What other condition needs urgent

primary hyperparathyroidism due to parathyroid

consideration for him and his family?

adenomas (note that calcitonin secreted from MTC

does not alter serum Ca²⁺). Interestingly, some RET

Answers, see p. 232

mutations have never been associated with phaeo-

Chapter 10: Pancreatic and gastrointestinal endocrinology and endocrine neoplasia / 227

chromocytoma, emphasizing the value of careful

norepinephrine secretion can predominate over

genotype-phenotype correlations and research.

epinephrine (see Chapter 6).

Familial medullary thyroid cancer

McCune-Albright syndrome

Familial MTC, still caused by mutations in the RET

McCune-Albright syndrome is caused by gain-of-

proto-oncogene, can occur without the other mani-

function mutations in Gsα (review Box 3.8 and

festations of MEN-2. However, its management is

Figure 3.14) in somatic cells partway through devel-

the same as if it were part of MEN-2.

opment. This gives rise to a sporadic syndrome of

endocrine overactivity and other features, including

Other familial endocrine tumour

café-au-lait spots and fibrous dysplasia of the bones.

predisposition syndromes

It is a cause of isosexual gonadotrophin-independent

precocious puberty (see Table 7.5). Although dis-

Familial phaeochromocytoma syndromes

tinct from true neoplasia, it can give rise to hyper-

Approximately one-quarter of phaeochromocyto-

functioning nodules in the adrenal cortex, thyroid

mas occur because of germline (i.e. potentially her-

and pituitary, respectively giving rise to Cushing

itable) mutations in one of several tumour suppressor

syndrome

(see Chapter

6), thyrotoxicosis

(see

genes, all inherited as autosomal dominant disor-

Chapter 8) and acromegaly (see Chapter 5).

ders (Table 10.5). Management and screening are

detailed in Chapter 6 with additional imaging sur-

Carney complex

veillance required for relevant extra-adrenal mani-

festations

(e.g. annual MRI for head and neck

Carney complex is an autosomal dominant condi-

paragangliomas).

tion caused by mutations in the PRKAR1α gene,

Phaeochromocytomas are unusual in Von

giving rise to adrenocortical overactivity (Cushing

Hippel Lindau (VHL) and neurofibromatosis type

syndrome; see Chapter 6), hyperpigmentation and

1 (NF1) syndromes. SDHB and SDHD genes

rare atrial myxoma tumours.

encode subunits of the succinate dehydrogenase

enzyme complex. Phaeochromocytomas or para-

Ectopic hormone syndromes

gangliomas associated with SDHB mutations are

commonly malignant whereas those due to SDHD

Some solid tumours unexpectedly secrete peptide

mutations tend to be benign. Some mutations have

hormones (ectopic hormone secretion) (Table 10.6

also been identified in the SDHC subunit. VHL

and Case history 10.6). Various mechanisms have

and SDH mutations (especially SDHB) are associ-

been proposed: the tumour might derive from

ated with extra-adrenal phaeochromocytomas when

neural crest cells with some endocrine capacity;

Table 10.5 Familial phaeochromocytoma syndromes

Mutated gene

Wider syndrome

Other features

SDHB*

Hereditary paragangliomas

Paragangliomas

SDHD*

Hereditary paragangliomas

Paragangliomas

VHL

Von Hippel Lindau syndrome

Haemangiomas, renal cell carcinoma, café-au-lait

spots

NF1

Neurofibromatosis (type 1)

Neurofibromas, café-au-lait spots, axillary

freckling, optic glioma

*SDHB/D encode the B and D subunits of succinate dehydrogenase.

228 / Chapter 10: Pancreatic and gastrointestinal endocrinology and endocrine neoplasia

Table 10.6 Examples of ectopic hormone secretion

Tumour

Hormone

Endocrine abnormality

Small cell carcinoma of the lung,

ACTH or ACTH-like peptides

Cushing syndrome; sometimes

medullary thyroid cancer, thymic

(see Chapter 5)

isolated hypokalaemia (see

carcinoma, islet cell tumours

Chapter 6)

Small cell carcinoma of the lung,

Vasopressin (see Chapter 5)

SIADH/ hyponatraemia (see Box

gastrointestinal tumour

5.12)

Carcinoma of the bronchus, liver

Human placental lactogen,

Gynaecomastia (ultimately due to

or kidney

oestrogen, testosterone

oestrogen activity; see Chapter 7)

Hepatomas, large mesenchymal

Insulin-like activity, big IGF-II

Hypoglycaemia (see Box 10.1)

tumours

Carcinoma of the bronchus or

Prolactin

Galactorrhoea (see Chapter 5)

kidney

Squamous cell carcinoma of the

Parathyroid hormone-related

Hypercalcaemia (see Chapter 9)

bronchus, breast carcinoma

peptide (PTHrP)

Carcinoma of the kidney and

Erythropoietin

Polycythaemia

uterus

ACTH, adrenocorticotrophic hormone; IGF, insulin-like growth factor; SIADH, syndrome of inappropriate antidiuretic hormone.

malignant cells have lost their differentiated pheno-

Case history 10.6

type allowing expression of normally repressed

genes, some of which encode hormones; or specific

A 76-year-old lifelong smoker was referred

oncogenes might activate hormone expression.

during winter to the respiratory clinic

because of failure to resolve bronchitis,

haemoptysis, and opacities on chest X-ray

Hormone-sensitive solid tumours

in the upper zone of the left lung and left

Hormone and growth factor stimulation of both

hilum. His serum sodium was 152 mmol/L

normal and tumour cells is a major mechanism

(152 mEq/L) and serum potassium was

regulating cell growth. Antagonizing these stimuli

2.4 mmol/L (2.4 mEq/L). An overnight

can provide valuable therapeutic options.

dexamethasone suppression test

produced serum cortisol of 134 nmol/L

Prostate cancer

(∼4.8 µg/dL). The man looked tanned and

had lost 10 kg (22 lb) during the last 6

Prostate cancer accounts for ∼8% of all cancers in

months without dieting.

men and is the fourth commonest malignant

cause of male death in England and Wales.

What diagnosis is of concern from the

Carcinoma of the prostate becomes increasingly

history and chest investigations?

common with age such that by 80 years, 80% of

What endocrine complication seems

men have malignant foci within the gland, although

likely?

most seem clinically insignificant. Androgenic hor-

What is the prognosis?

mones play an important role in the aetiology and

progression of the tumour and consequently endo-

Answers, see p. 232

crine manipulation is an important treatment

(Box 10.6).

Chapter 10: Pancreatic and gastrointestinal endocrinology and endocrine neoplasia / 229

Box 10.6 Endocrine treatments of

Box 10.7 Endocrine treatments of

prostate cancer

breast cancer

• Continuous GnRH analogues

Oestrogen antagonist

(see Chapter 7) - leuprorelin or goserelin

• Tamoxifen

• Androgen receptor antagonists -

• Effective in both pre- and post-menopausal

cyproterone acetate

women

• Bilateral orchidectomy

Blockade of oestrogen production

• Continuous GnRH analogues or bilateral

Surgical prostatectomy is the first line of therapy;

oophorectomy - both induce premature

other options include radiotherapy, chemotherapy

menopause

and cryotherapy. However, endocrine manipulation

• Aromatase (CYP19) inhibitors - anastrozole

can be used to reduce or inhibit androgen action.

or letrozole; used in post-menopausal

Continuous gonadotrophin-releasing hormone

women

(GnRH) analogues, such as leuprorelin or goserelin,

cause a secondary hypogonadism (review Chapter 7).

Progestins

Around 30% of prostate tumours respond to this

• E.g. medroxyprogesterone acetate or

therapy, which can be combined with the androgen

megestrol acetate

receptor antagonist, cyproterone acetate. 5α-reductase

• Effective in both pre- and post-menopausal

inhibitors can also be used to block formation of dihy-

women

drotestosterone (see Figure 7.7); finasteride is already

• Second-line therapy

used clinically to control prostatic hypertrophy and

HER2 antagonists (human epidermal growth

related urinary symptoms. Surgical removal of the

factor 2)

testes

(bilateral orchidectomy) is also possible to

remove androgen supply to the tumour.

action in breast cancers and are effective in both

Breast cancer

pre- and post-menopausal women. They are consid-

Breast cancer is the commonest tumour in women.

ered second-line agents and are helpful in ∼50% of

Its incidence has increased in recent years to 54 per

women who have previously responded to endo-

100,000 women per year. Hormone and growth

crine therapy.

factor-related treatment of breast cancer is impor-

In pre-menopausal women, drugs that block

tant (Box 10.7). A major factor is whether the oes-

ovarian oestrogen production, such as continuous

trogen receptor (ER) is present in the tumour cells:

GnRH analogues, lead to a significant fall in oes-

if it is,

60% of these tumours respond to antioes-

trogen concentrations (see Chapter 7). The una-

trogen therapy; if ER-negative, this falls to only

voidable ‘side-effect’ (= desired effect) of these drugs

10%. Around 60% of breast cancers are ER-positive.

is that they induce a premature menopause. An

Endocrine treatment aims to decrease oestrogen

alternative is bilateral oophorectomy

(surgical

supply or antagonize ER action.

removal of the ovaries).

Tamoxifen is the most commonly prescribed

In post-menopausal women, oestrogens are

hormone-related therapy. It acts as an ER antago-

mainly formed through the peripheral conversion

nist in breast cancer cells while acting as a weak

of androgens by the action of aromatase (CYP19;

agonist in other tissues. It has a low incidence of

see Figure 7.12). Inhibition of this enzyme with

side-effects, is effective in both pre- and post-

drugs such as anastrozole or letrozole leads to a

menopausal women and can be used for metastatic

significant fall in oestrogen levels.

disease as well as adjuvant therapy.

More recently, there has been much interest in

Progestins, such as medroxyprogesterone acetate

monoclonal antibodies that block the epidermal

or megestrol acetate, help to diminish oestrogen

growth factor receptor

(HER2 antagonists, e.g.

230 / Chapter 10: Pancreatic and gastrointestinal endocrinology and endocrine neoplasia

trastuzumab) and limit signalling through tyrosine

setting. Progesterone is certainly important in pre-

kinase pathways.

venting endometrial carcinoma; chronic unopposed

oestrogen increases risk

∼six-fold, explaining the

need for a withdrawal bleed every 4 months or so

Other tumours of relevance to

in polycystic ovarian syndrome (see Chapter 7).

endocrinology

Testicular cancer

Ovarian cancer

Testicular cancer is uncommon but increasing with

Excluding the breast, ovarian cancer is the com-

incidence rates of 3-9/100,000 per year in white

monest malignancy of an endocrine organ, account-

men and much lower rates in Africans and Asians.

ing for 4-6% of all cancers in women. There are

The majority of testicular cancer is of germ cell

three types of ovarian neoplasm: epithelial, germ

origin and can be divided into seminoma and non-

cell and sex cord stromal tumours. The vast major-

seminomatous tumours. Most testicular cancer

ity of malignant tumours are epithelial. Ovarian

presents before the age of 40 years. Incidence increases

cancer is generally more common in developed

modestly after the age of 65 years (see Box 7.13).

countries with incidence rates in northern Europe

A major, established risk factor is maldescent of

and North America of 8-12/100,000 per year.

the testis. The mechanism is unknown but it appears

The cause of ovarian cancer remains unclear,

that risk is only raised for the maldescended testis

but hormonal factors appear to be important as risk

and not the opposite side. Increased exposure to

relates to the lifetime number of ovulations.

environmental oestrogens has also been proposed as

Nulliparity, low parity and older age at menopause

a cause, but as yet there is no definite evidence to

all increase risk, while use of the oral contraceptive

support this hypothesis. At present, hormonal treat-

pill is protective. Thus, it appears that total oestro-

ments are not available for testicular cancer, but

gen exposure is important to some degree. Despite

measurement of the hormonal marker, human cho-

this, no hormonal therapy has been approved for

rionic gonadotrophin, is important in monitoring

ovarian cancer.

the treatment of non-seminomatous germ cell

tumours.

Endometrial cancer

Endometrial cancer affects

∼142,000 women

Key points

worldwide each year, with an estimated 42,000

women dying from this cancer. Most cases are diag-

• The pancreas and gastrointestinal tract

nosed after the menopause, with the highest inci-

contain cell types that release many

dence around the seventh decade of life. Readily

important hormones and are vulnerable

detected symptoms, such as post-menopausal bleed-

to tumour formation

ing, explain why most women with endometrial

• Endocrine neoplasms can occur

cancer are diagnosed with early-stage disease.

sporadically or as inherited syndromes

Overall, the 5-year survival is ∼80%.

• For most inherited endocrine tumours,

The most common lesions are hormone sensi-

the genetic cause is known, allowing

tive and low grade, and have an excellent prognosis.

precise diagnoses that influence

First-line treatment is hysterectomy, which is

subsequent management of the patient

important for staging and enables appropriate tai-

and relatives

loring of adjuvant treatment in high-risk patients.

• Familial syndromes should be considered

Currently, there is no proof that adjuvant hormone

in those with multiple endocrine tumours,

therapy improves outcome in early cancers but pro-

those diagnosed at an early age, or in

gestagens may have a place in the treatment of

those with a positive family history

metastatic endometrial cancer. The response rate is

• Prostate and breast cancer are hormone-

15-20%, related to expression of steroid-hormone

responsive tumours

receptors. Tamoxifen has a small benefit in this

Chapter 10: Pancreatic and gastrointestinal endocrinology and endocrine neoplasia / 231

Answers to case histories

Case history 10.1

therapy, an ACTH stimulation test should be

done with ACTH measured on the time 0

The symptoms are those of hypoglycaemia

sample. If hydrocortisone has been started,

and are relieved by food. Even without

the test can be done later if preceding

venesection, biochemical hypoglycaemia is

dose(s) of hydrocortisone are withheld (see

unlikely with this monitor reading. The

Chapter 6). Random cortisol could be

differential diagnosis of hypoglycaemia is

requested on the original blood sample; if

given in Box 10.1. Given her family history,

<100 nmol/L (∼3.6 µg/dL) during the morning,

the most likely diagnosis is reactive

it is supportive evidence for hypoadrenalism.

hypoglycaemia (or potential sulphonylurea

Serum renin could also be measured and

misuse of her mother’s tablets).

would likely be raised in Addison disease. If

A 72-h fast could be performed, which in all

primary hypoadrenalism is confirmed, other

likelihood would exclude true hypoglycaemia

potential autoimmune endocrinopathy should

and rule out insulinoma. A prolonged 75-g oral

be investigated (see Box 8.8).

glucose tolerance test could assess the

As hypoadrenalism is potentially life-

possibility of reactive hypoglycaemia. Low

threatening, treatment with hydrocortisone is

glucose after 3 h [but almost certainly

warranted, and should be started if

>2.2 mmol/L (>40 mg/dL)] with detectable

investigation to confirm the diagnosis is not

insulin and C-peptide concentrations would

immediate. As the man had recovered

support the diagnosis. Management would be

quickly, this could be given orally at the

dietary advice on low glycaemic index, high

hospital with a prescription for 10 mg twice

fibre foods and weight loss.

daily oral hydrocortisone thereafter. He

may also require oral fludrocortisone (e.g.

Case history 10.2

100 µg daily). The man should also eat and

The diagnosis until proven otherwise is

should not be discharged until the diagnosis

hypoadrenalism, most likely Addison disease

is clear and his blood glucose is consistently

(see Chapter 6). The reasoning is as

normal.

follows. The man has hypoglycaemia

(see Box 10.1); had fainted on standing

Case history 10.3

(postural hypotension); was tanned (excess

ACTH due to loss of negative feedback from

The hormone was gastrin.

cortisol; see Chapter 5); and has a family

Repeat ulceration and a raised serum

history consistent with autoimmune

gastrin raise concern over gastrinoma. He is

endocrinopathy (see Box 8.8). The final major

not on H₂ antagonists or proton pump

clue is raised serum K⁺. This is

inhibitors, both of which can raise gastrin

hypoadrenalism until proven otherwise

levels (stomach acid suppresses gastrin

because it is the most important, potentially

production; this effect is lost with medication

life-threatening consideration in the

that lowers acid production). MRI is

differential diagnosis.

warranted to look for a gastrinoma in the

Lying and standing blood pressure, and

pancreas (where there is a higher risk of

signs of Addison disease and other

malignancy) or duodenum. Scintigraphy with

autoimmune endocrinopathies should be

labelled somatostatin may also be useful. A

assessed. Laboratory serum glucose should

duodenal abnormality may also have been

be measured and if low, contemporaneous

observed at operation or by subsequent

insulin and C-peptide should be assayed.

endoscopy. Some consideration should be

Ideally, prior to starting hydrocortisone

given to the possibility of MEN-1.

232 / Chapter 10: Pancreatic and gastrointestinal endocrinology and endocrine neoplasia

Case history 10.4

phaeochromocytoma should suggest MEN-2.

He requires urgent investigation for medullary

The diagnosis is likely to be a carcinoid

thyroid cancer, which, if the patient has a

tumour with hepatic metastasis.

mutation in the RET proto-oncogene, is

The primary treatment is surgical. The

highly likely to be present by the age of 35

presence of hepatic spread is not a

years. Calcitonin should be measured. The

contraindication to surgery. Indeed surgical

patient should be referred to a clinical

removal of the hepatic tumour may even be

geneticist and the RET proto-oncogene

curative. If he is unfit for surgery, treatment

sequenced. The case may be sporadic;

with somatostatin analogues, interferon-α and

however, if a RET mutation is found, genetic

chemotherapy should be considered.

screening should be offered to family

His prognosis is reduced by the

members. Unaffected family members can be

metastasis, but nevertheless he may still live

reassured and discharged. Those with the

for a considerable time. Although

mutation or, if the mutation remains cryptic,

bronchoconstriction would appear to be

all first-degree relatives, should be

causing his breathlessness, it is important to

encouraged to undertake screening as

consider carcinoid heart disease, which has

described in the chapter text.

a poorer prognosis. High levels of tumour

markers, particularly post surgery, would

worsen his prognosis.

Case history 10.6

The features are all consistent with lung

Case history 10.5

cancer.

The doctor had diagnosed primary

The man failed a 1-mg dexamethasone

hyperparathyroidism.

suppression test [serum cortisol the following

A phaeochromocytoma was missed.

morning >50 nmol/L (∼1.8 µg/dL)] and so may

Although this is a rare diagnosis,

well have Cushing syndrome. The most likely

hypertension in a fit young man is unusual.

underlying cause is ectopic secretion of

He was admitted in hypertensive crisis

ACTH causing inappropriate skin

because of excessive unopposed

pigmentation from a small cell carcinoma of

catecholamine action on α-receptors after

the lung.

β-receptor blockade (see Chapter 6).

The prognosis is poor because of the hilar

The combination of a primary

mass, weight loss and ectopic hormone

hyperparathyroidism and

secretion.

Chapter 11: Overview of diabetes / 237

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.0

1940

1960

1980

1996

2004

2010

Figure 11.2 Prevalence of diabetes in the UK since 1940. Adapted from Diabetes UK: Diabetes in the UK in

2004. http://www.diabetes.org.uk/infocentre/reports/in_the_UK_2004.doc and York & Humber Public Health

Observatory (http://www/yhpho.org.uk/resource/view.aspx?RID=81090).

largely represents an increase in the prevalence of

Case history 11.1

type 2 diabetes, which accounts for ∼90% of all

cases of diabetes, but the prevalence of type 1 dia-

The local public health consultant would

betes is also increasing.

like to know the prevalence of diabetes in

The prevalence of diabetes in the USA in

your region and if it differs from the

2010 was almost 27 million (12.3%), while 3.6

national average.

million people are affected by diabetes in the

UK (7.4%). The prevalence of diabetes has doubled

What are the difficulties they may

in the UK every 20 years since the end of the

encounter?

Second World War (Figure 11.2). It is now recog-

How might these be overcome?

nized that low- and middle-income countries face

the greatest burden of diabetes, with around

Answers, see p. 255

two-thirds of those affected by diabetes living in

these areas of the world. Eight of the top 10 coun-

tries with the highest absolute numbers of people

with diabetes have developing or transitioning

economies

(Table

11.1). Similarly many of the

Diabetes is the fifth leading cause of death

countries with the highest percentage of the popula-

worldwide, accounting for 4 million deaths annu-

tion with diabetes are also from resource-poor

ally and outnumbering the global deaths from

nations (Table 11.2).

human immunodeficiency virus

(HIV)/acquired

Type 2 diabetes has a slow and gradual onset

immune deficiency syndrome (AIDS). The prema-

and the diagnosis is frequently delayed for many

ture mortality is predominantly driven by an

years; so many people with diabetes are undiag-

increase in atherosclerotic vascular disease, but dia-

nosed but still develop diabetic complications. This

betes also causes considerable morbidity through its

may lead to underestimates of the true global

microvascular complications, which affect the eye,

burden of disease (Case history 11.1).

nerve and kidney (Case history 11.2).

238 / Chapter 11: Overview of diabetes

Case history 11.2

An overweight 58-year-old man attended for a routine occupational health medical. Generally

he had been well but had noticed some tiredness in the previous year, which he attributed to

his long hours at work. His blood pressure was elevated (155/87 mmHg) and a routine blood

test showed that his fasting glucose was 9.7 mmol/L (174 mg/dL). Repeat testing confirmed the

diagnosis of diabetes. Retinal photography showed that he had bilateral background

retinopathy (described in Chapter 14).

Is it unusual for diabetes to be detected on routine testing?

Is it unusual that this man was found to have retinopathy at diagnosis?

Answers, see p. 255

A brief history of diabetes and its

Table 11.1 Prevalence of diabetes in people

aged 20-79 years in 2010 and projected

classification

prevalence in 2030.*

Diabetes was first described in ancient Egyptian

2010

2030

times (Box 11.1). Throughout history there has

been a focus on sugars or glucose, first from a

Country/

Millions Country/

Millions

recognition of excess sugar in the urine and then in

territory

the blood. This

‘glucocentric’ view of diabetes

India

50.8

India

87.0

has shaped our current means of diagnosis and

treatment.

China

43.2

China

62.6

Although there has been an awareness of differ-

USA

26.8

USA

36.0

ent degrees of severity of diabetes for many centu-

ries, the possibility of distinct types of diabetes only

Russian

9.6

Pakistan

13.8

emerged at the beginning of the 20th century.

Federation

The original World Health Organization

Brazil

7.6

Brazil

12.7

(WHO) classification of diabetes in 1980 and its

Germany

7.5

Indonesia

12.0

revision in 1985 were based on clinical characteris-

tics. The two commonest types of diabetes were

Pakistan

7.1

Mexico

11.9

termed insulin-dependent diabetes mellitus (IDDM)

Japan

7.1

Bangladesh

10.4

and non-insulin-dependent diabetes mellitus

Indonesia

7.0

Russian

10.3

(NIDDM), reflecting the body’s need for insulin to

Federation

survive. The WHO classification also recognized

malnutrition-related diabetes mellitus, other types

Mexico

6.8

Egypt

8.6

of diabetes mellitus associated with specific condi-

*The 10 countries with the highest numbers of people

tions (Case history 11.3) and gestational diabetes,

with diabetes are listed.

which is diabetes diagnosed for the first time during

Data from IDF Atlas 2009 (http://www.idf.org/

pregnancy.

diabetesatlas/downloads)

In 1997, the American Diabetes Association

The economic and social costs of diabetes are

(ADA) proposed a classification that distinguished

enormous, both for healthcare services and through

the types of diabetes according to aetiology and

loss of productivity. In developed countries, 10% or

clinical stages of the disease as it was hoped that this

more of the total health budget is spent on the

would be more clinically useful. The classification

management of diabetes and its complications.

was subsequently adopted by the WHO in 1999

240 / Chapter 11: Overview of diabetes

End 18th

John Rollo first used the term ‘diabetes mellitus’ (honey) to distinguish the condition

century

from ‘diabetes insipidus’ (insipid = tasteless), a deficiency of vasopressin, see

Chapter 5

19th

Claude Bernard, a French physiologist, discovered that:

century

• Sugar is stored as glycogen in the liver

• Transfixation of the medulla in conscious rabbits caused hyperglycaemia

1869

Paul Langerhans discovered the pancreatic islets

1889

Oskar Minkowski removed the pancreas from a dog and discovered that the animal

developed diabetes

1893

Edouard Laguesse showed islets were the endocrine tissue of the pancreas

1921

Frederick Banting, Charles Best, James Collip and JJR Macleod discovered insulin

in Toronto

1920s

First patients treated with insulin by physicians such as Elliot P Joslin, who

introduced systematic diabetes education in the USA, and Robin D Lawrence,

who had diabetes himself and founded the British Diabetic Association (now

Diabetes UK)

1955

Primary structure of insulin elucidated by Frederick Sanger

1966

First transplant of human pancreas to treat type 1 diabetes by Kelly, Lillehei, Goetz

and Merkel at the University of Minnesota

1969

Dorothy Hodgkin described the three-dimensional structure of insulin using X-ray

crystallography

1980

Introduction of recombinant human insulin

1994

First implantation of pancreatic islets to treat type 1 diabetes by Pipeleers and

colleagues in Belgium

1996

Introduction of insulin analogues

2000

James Shapiro and colleagues establish the ‘Edmonton protocol’ revitalizing efforts

to cure type 1 diabetes by transplantation

(see Box 11.2). The terms IDDM and NIDDM

in Chapters 12 and 13 respectively and gestational

were replaced with type 1 diabetes and type 2 dia-

diabetes in Chapter 14. A number of secondary

betes respectively. Malnutrition-related diabetes was

causes of diabetes are listed in Box 11.2 and include

omitted from the new classification because its aeti-

genetic mutations as well as other pathologies such

ology was uncertain and it was unclear whether it

as chronic pancreatitis.

is a separate type of diabetes. The classification was

Approximately 2-5% of cases of diabetes are

reassessed by the WHO in 2006 when no changes

caused by mutations in a single gene (monogenic

were made. It is currently under discussion again.

mutation). For instance, maturity-onset diabetes of

the young (MODY) is inherited as an autosomal

dominant condition and is caused in most cases by

Classification of diabetes

a mutation in one of six genes, most commonly the

The current classification of diabetes is shown in

one encoding hepatocyte nuclear family

1α

Box 11.2. Type 1 and type 2 diabetes are covered

(HNF1α) (Table 11.3 and review Chapter 2).

Chapter 11: Overview of diabetes / 241

Box 11.2 1999 World Health Organization classification of diabetes

Type 1 diabetes (β-cell destruction)

• Diabetes secondary to genetic abnormalities:

• Immune mediated

° Genetic defects of β-cell function:

• Idiopathic

☐ MODY (maturity-onset diabetes of the

• Formerly insulin-dependent diabetes

young):

Glucokinase mutations

Type 2 diabetes

Hepatic nuclear factor mutations

• Insulin resistance with inadequate insulin

Insulin promoter factor 1 mutations

secretion

☐ GATA6 mutations (neonatal diabetes)

• Formerly non-insulin-dependent diabetes

☐ Mitochondrial DNA 3243 mutation

Secondary diabetes

° Genetic defects of insulin action:

• Diabetes secondary to pancreatic disease:

☐ Leprechaunism

° Chronic pancreatitis

☐ Type A insulin resistance

° Haemochromatosis

☐ Rabson-Mendenhall syndrome

° Pancreatic surgery or trauma

☐ Lipoatrophic diabetes

° Cystic fibrosis

° Other genetic syndromes:

• Diabetes secondary to endocrine disease:

☐ Down syndrome

° Acromegaly

☐ Prader-Willi syndrome

° Cushing syndrome

☐ DIDMOAD (Wolfram) syndrome

° Phaeochromocytoma

• Infections:

• Diabetes secondary to drugs and chemicals:

° Congenital rubella

° Glucocorticoids

° Cytomegalovirus

° Diuretics

° Mumps

° Antipsychotics

° β-blockers

Gestational diabetes

Diagnosis of diabetes

Table 11.3 Genetic mutations in maturity-

onset diabetes of the young (MODY)

A diagnosis of diabetes is made if the fasting plasma

Gene

MODY

glucose is 7.0 mmol/L (126 mg/dL) or greater or if

type

the random or 2-h glucose tolerance test plasma

glucose is

11.1 mmol/L (200 mg/dL) or greater

Glucokinase

GCK

(Table 11.4). The WHO diagnostic criteria also

Hepatic nuclear factor 1α

HNF1α

recognize two further categories of abnormal glucose

Also known as

concentrations: impaired fasting glycaemia (IFG)

transcription factor 1

and impaired glucose tolerance (IGT), the latter of

Hepatic nuclear factor 4α HNF4α

which can only be diagnosed following a 75-g oral

glucose tolerance test (OGTT). The ADA defini-

Hepatic nuclear factor 1β

HNF1β

tion of impaired fasting glycaemia differs slightly

Also known as

transcription factor 2

from the WHO criteria in that the threshold for

IFG is 100 mg/dL (5.6 mmol/L).

Insulin promoter factor 1

IPF1

Only one abnormal glucose value is required in

Also known as

a patient with classical diabetic symptoms, such as

pancreatic duodenum

polydipsia (increased thirst) or polyuria (increased

homeobox gene 1

volume of micturition), but a supplementary test is

Neurogenic

NEUROD1

required in asymptomatic individuals (Case history

differentiation-1/β2

11.4). The gold standard test for diabetes, endorsed

242 / Chapter 11: Overview of diabetes

Case history 11.3

An 18-year-old woman with a strong family history of diabetes was diagnosed with insulin-

dependent diabetes in 1990 after she presented with classical hyperglycaemic symptoms.

Insulin therapy was commenced and her glycaemic control during the early stages of diabetes

was excellent with no significant hypoglycaemia or diabetic complications. Fifteen years later

she decided to start a family and requested genetic testing. She was found to have MODY

caused by an inactivating mutation in the gene encoding HNF1α.

Does this diagnosis matter?

Are there any therapeutic implications to the revised diagnosis?

Answers, see p. 256

Table 11.4 The 1999 WHO diagnostic criteria for diabetes

Fasting plasma glucose

(mmol/L or mg/dL)

<6.1

≥6.1-6.9

≥7.0

<110

≥110-125

≥126

2-h plasma

<7.8

Normal

Impaired fasting glycaemia*

Diabetes

glucose following

<140

a 75-g oral

≥7.8-11.0

Impaired glucose

Impaired fasting glycaemia and

Diabetes

glucose tolerance

≥140-200

tolerance

impaired glucose tolerance

test

(mmol/L or mg/dL)

≥11.1

Diabetes

≥200

*The American Diabetes Association defines impaired fasting glucose as between 110 and 125 mg/dL (5.6-6.9 mmol/L).

Diabetes may also be diagnosed if a random plasma glucose is ≥11.1 mmol/L (200 mg/dL).

by the WHO, is currently the OGTT, which

The criteria for the diagnosis of diabetes are

requires an overnight fast followed by a 75-g glucose

constantly being reviewed and it is instructive to

drink, with blood samples taken for plasma glucose

consider why there has been so much debate about

concentrations before the drink and 2 h afterwards

the diagnosis. Plasma glucose concentrations show

(Box 11.3).

a skewed normal distribution in the general popula-

tion and, as such, the delineation of abnormal from

Case history 11.4

normal becomes arbitrary (Figure 11.3). An analogy

to this would be height within the population.

An asymptomatic 80-year-old frail woman

Height is normally distributed and so any distinc-

is found to have a random plasma

tion between short, normal and tall is subjective.

glucose of 11.3 mmol/L (203 mg/dL).

For example, many would suggest a tall man is

someone over 6′ tall (∼180 cm), but in reality there

Does she have diabetes?

is little difference in height between this man and

another man who is 5′ 11″ (178 cm). The fact that

Answer, see p. 256

this analogy does not work for those using metric

measurements illustrates the point. The same is true

Chapter 11: Overview of diabetes / 243

for glucose and so it is important to consider why

‘pre-diabetes’ has been advocated to describe IGT

the WHO and ADA have chosen the cut-off values

and IFG. As many people with IFG or IGT do not

that they have. The reason is that the diagnostic

develop diabetes, however, ‘intermediate hypergly-

criteria reflect the concentration of plasma glucose

caemia’ is probably a better term. Other terminol-

at which there is an association with the develop-

ogy has also been used to describe this situation.

ment of microvascular complications, particularly

A diagnosis of diabetes has important social,

retinopathy. A clear threshold exists below which

legal and medical implications for the patient and

microvascular diabetic complications have not been

it is therefore essential that any diagnosis is secure

identified. By contrast, the relationship between

and handled sensitively. The diagnosis of diabetes

hyperglycaemia and macrovascular complications

should never be made on the basis of glycosuria,

extends across the normal range with no threshold

and the glucose concentration should be measured

for the development of cardiovascular disease

on a venous plasma sample in an accredited

(Figure 11.4). This implies that cardiovascular risk

laboratory.

also rises with increases in plasma glucose across the

normal population.

Glycated haemoglobin

Impaired fasting glycaemia (IFG) and impaired

glucose tolerance

(IGT) are not distinct clinical

Although glucose has been used for many years

entities, but rather risk factors for future diabetes

to diagnose diabetes, there are on-going discussions

and cardiovascular disease. Indeed, the new term

about the use of glycated haemoglobin (HbA_1c)

as an alternative method (Box 11.4). The major

advantage is that the person does not need to

Box 11.3 How a glucose tolerance

fast, but HbA_1c is also more reproducible than a

test is performed

non-fasting glucose value. The reliability of HbA_1c

may, however, be affected by a number of condi-

• The patient should ensure that they have

tions such as anaemia and haemoglobinopathy.

consumed >150 g of carbohydrate in the

Both the WHO and ADA have endorsed the use of

day prior to the test:

HbA_1c [≥6.5% (48 mmol/mol)] as a diagnostic test

° One slice of bread has 12 g of

for diabetes, while the ADA also recognizes that

carbohydrate

HbA_1c levels of 5.7-6.4% (39-47 mmol/mol) indi-

° 100 g of uncooked pasta contains 75 g of

cate increased risk for future diabetes.

carbohydrate

• The patient should fast overnight, although

water may be drunk

Insulin

• The patient should refrain from smoking

for 12 h prior to the test

Insulin is a 51-amino acid peptide hormone com-

• After collection of the fasting blood

prising two polypeptide chains, the A and B chains,

sample, the patient should drink 75 g of

anhydrous glucose in 250-300 mL of water

Box 11.4 What is glycated

over 5 min

haemoglobin?

• A second blood sample should be

collected exactly 2 h after the glucose

Glycated haemoglobin (HbA_1c) is a measure

challenge

of integrated glycaemic control over the

As glucose should stimulate insulin secretion,

preceding 2-3 months, reflecting the average

it also acts as a metabolic negative feedback

lifespan of erythrocytes (red blood cells).

stimulus to suppress growth hormone (GH)

Glucose becomes attached to adult

secretion. Thus, this test is also used with

haemoglobin in a non-enzymatic fashion that

more frequent blood sampling to diagnose

is dependent on the average concentration

acromegaly when GH fails to be suppressed

of blood glucose (Figure 11.5). This process

(see Chapter 5).

is known as the Amadori reaction.

244 / Chapter 11: Overview of diabetes

Impaired fasting glycaemia

Normal

Diabetes

Glucose (mmol/L)

Figure 11.3 Representative distribution of fasting plasma glucose within the general population. It can be seen

that people with impaired fasting glycaemia and diabetes are not discretely different from the rest of the

population. As such, the diagnostic cut-off limits are somewhat arbitrary, but are largely based on the risk of

developing microvascular complications.

which are linked by disulphide bridges

(Figure

in PC1/3 cause both secondary hypoadrenalism and

11.6). Insulin is synthesized in the β-cells of the

diabetes. In the pancreatic islet, both insulin

islets of Langerhans in the pancreas (Figure 11.7).

and C-peptide are released simultaneously in equi-

The other endocrine cell types of the islet are the

molar quantities by exocytosis in response to a

α-cells producing glucagon, the δ-cells producing

number of stimuli, including glucose and amino

somatostatin, the ε-cells producing ghrelin and the

acids (Table 11.5).

pancreatic polypeptide (PP) cells producing pancre-

atic polypeptide. The β-cells are the most numer-

Secretion

ous, tend to be located more centrally in islet

structures and are surrounded by the other cell

In response to nutrients following a meal, insulin is

types.

secreted in a coordinated pulsatile fashion from the

Insulin is synthesized on the ribosomes of the

β-cells into the portal vein in a characteristic bipha-

rough endoplasmic reticulum (RER) as a single

sic pattern (Figure 11.8); first there is an acute rapid

amino acid chain precursor molecule called pre-

‘first phase’ release of insulin, lasting for a few

proinsulin (review Chapter 2 and Figures 2.3 and

minutes, followed by a less intense more sustained

2.4). After removal of the signal peptide, proinsulin

‘second phase’. Pancreatic β-cells also secrete 0.25-

is transferred from the RER to the Golgi apparatus,

1.5 units of insulin/h during the fasting state.

where soluble zinc-containing proinsulin hexamers

Although at a low-level, this background secretion

are formed. The prohormone convertase enzyme,

accounts for over

50% of total daily insulin

PC1/3, finally acts outside the Golgi apparatus

production.

to produce the mature insulin and connecting

Glucose is the principal stimulus for insulin

peptide

(C-peptide). The same enzyme cleaves

secretion, though other macronutrients, and hor-

adrenocorticotrophic hormone (ACTH) from pro-

monal and neuronal factors may alter this response

opiomelanocortin (POMC) in the anterior pitui-

(Table 11.5). When glucose enters the β-cell via a

tary (see Chapter 5); hence, inactivating mutations

family of high-capacity glucose transporters (GLUT

246 / Chapter 11: Overview of diabetes

Haemoglobin

HbA_1C

NH₂

CHO

H C

H C OH

HO C

HO C H

H C OH

H C

H C OH

CH₂OH

Glucose

Schiff base

Amadori product

Figure 11.5 The Amadori reaction leading to the formation of glycated haemoglobin (HbA_1C). Haemoglobin

reacts in a non-enzymatic manner with glucose to form glycated derivatives. The extent of glycation depends on

the concentration of glucose and duration of exposure. Reproduced from Holt RIG et al., eds. Textbook of

Diabetes: A Clinical Approach, 4th edn. Oxford: Wiley-Blackwell, 2010, Chapter 25.

1-3, mainly GLUT-2), it undergoes phosphoryla-

and insulin secretion. Normal β-cell function is

tion by the enzyme glucokinase and metabolism by

dependent on the exquisite coupling of glucose

glycolysis to produce ATP (Figure 11.9). The rise in

sensing and insulin secretion. For instance, inacti-

ATP closes a type of potassium channel, the potas-

vating mutations in glucokinase causes a form of

sium inward rectifying channel type 6.2 (KIR6.2),

MODY and activating mutations in KIR6.2 or

on the cell surface, leading to depolarization of the

SUR1 can cause permanent neonatal diabetes. In

membrane. This is followed by an influx of calcium

contrast, inactivation of KIR6.2 or SUR1 can

ions which triggers insulin granule translocation to

uncouple secretion from glucose sensing and cause

the cell surface and the hormone’s release by exocy-

a rare syndrome of excessive insulin production and

tosis. The mechanism of action of sulphonylureas,

hypoglycaemia, called congenital hyperinsulinism.

a class of oral hypoglycaemic agents (see Chapter

13), is by binding to a receptor, the sulphonylurea

Action

receptor

1 (SUR1), in close apposition to the

KIR6.2 channels and resulting in their closure. This

Insulin exerts its biological actions by binding to

process can be divided in two: glucose sensing

the insulin receptor on the target cell surface. The

Chapter 11: Overview of diabetes / 247

Subcellular site

Sequence of reactions

Amino acids, transfer-RNA,

ATP, GTP, Mg²⁺, etc

Rough

endoplasmic

Pre-proinsulin synthesis

reticulum

Microvesicles

Proinsulin transfer

Packaging in vesicles containing

Golgi

membrane-bound proteases

Early granules

+Zn2+ and release of Arg, Lys

Conversion of pro-insulin

to insulin (see below)

Mature

granules

Crystalloid zinc-insulin core

surrounded by C-peptide

Plasma

and energy-dependent

Ca2+

membrane

secretion of insulin and

C-peptide

Insulin

S S

A-chain

Protease

B-chain

Proinsulin

C-peptide

Figure 11.6 Insulin synthesis and secretion from the

glucose, an energy-dependent and Ca2+-dependent

β-cells of pancreatic islets of Langerhans. Protein

fusion of the granules with the cell membrane

synthesis on the rough endoplasmic reticulum yields

releases the contents into the bloodstream. Insulin

pre-proinsulin, which is transferred into the lumen of

and C-peptide are released in approximately

the endoplasmic reticulum (see also Figures 2.3 and

equimolar amounts. The lower portion of the

2.4). Hydrolysis yields proinsulin, which is then

illustration shows a schematic diagram of the

transferred to the Golgi apparatus approximately

structures of proinsulin and insulin. Proinsulin, on

20 min after the initiation of protein synthesis.

the left, is cleaved at two points (arrows) by specific

Proinsulin is enclosed in vesicles that carry specific

proteases packaged into early β-cell granules. The

proteases bound to the membrane. Over a period of

C-peptide is cleaved from a single-chain peptide to

30 min to 2 h, the specific proteases act on proinsulin

leave insulin, which then has two chains, A and B,

to release C-peptide and insulin within the granule.

linked by two disulphide bridges, with the A chain

Progressive maturation and crystallization of the zinc

also carrying an intrachain disulphide bridge.

1-insulin complex yields a dense crystalloid region

Proinsulin contains 86 amino acids, while insulin

surrounded by a clear space containing C-peptide.

has 21 amino acids in the A chain and 30 in the

When the cells are stimulated, e.g. by a rise in blood

B chain.

248 / Chapter 11: Overview of diabetes

(a)

(b)

Oesophagus

Central core

of β-cell

Venule draining

the Islet

Stomach

Acinar tissue

α- and δ-

cells

Islets of

Pancreas

Small arteriole

Duodenum

Langerhans

supplying the Islet

embedded

in pancreas

(c)

(d)

Secretory granule

Venule draining

of α-cell

the Islet

Secretory granule

of δ-cell

Gap junction

Secretory granule

of β-cell

Arteriole supplying

Islet capillaries

Figure 11.7 The endocrine pancreas. (a) Small

of the islet is the first to be exposed to high glucose

clusters of cells, the islets of Langerhans, are

concentrations, and the peripheral α- and δ-cells

embedded in the exocrine acinar tissue. (b) Each

are exposed to high insulin concentrations from the

islet consists of a core mainly of β-cells surrounded

inner β-cells. (c) The different cell types of the islet

by α- and δ-cells. The islet is supplied with one or

have distinctive secretory granules, which enable

more small arterioles that penetrate the centre of the

them to be easily identified under the electron

islet and then break up into capillaries. These first

microscope. The islet cells are also coupled to each

supply the central β-cells and then flow to the more

other via gap junctions. (d) Part of a β-cell, showing a

peripherally located α- and δ-cells. The capillaries

secretory granule discharging its contents in the

leave the islet and form the draining venules. In this

process of exocytosis, leading to the release of

way, the circulation ensures that the β-cell rich core

insulin.

insulin receptor is a heterotetramer consisting of

of the β-subunit, conferring tyrosine kinase activity

two α- and two β-glycoprotein subunits linked by

(Figure 3.6). Tyrosine phosphorylation of intracel-

disulphide bonds. Insulin binds to the extracellular

lular substrate proteins, known as insulin responsive

α-sub-units, resulting in conformational change

substrates (IRSs), ensues, and these can then bind

enabling ATP to bind to the intracellular compo-

other signalling molecules that in turn mediate

nent of the β-subunit; this triggers phosphorylation

further cellular actions of insulin (Figure 11.10).

Chapter 11: Overview of diabetes / 249

Effects on intermediate metabolism

Table 11.5 Factors regulating insulin release

from the β-cells of the pancreatic islets

Insulin may be considered as a hormone that signals

the ‘post-meal’ fed state. During this period, insulin

Insulin secertion

Insulin secretion

is pivotal in regulating cellular energy supply and

increased by

decreased by

macronutrient balance, and directing anabolic

processes (Figure 11.11).

Nutrients

Raised glucose

Low glucose

Amino acids

Hormones

Somatostatin

Glucagon

NPY

Gastrin, secretin

Ghrelin

Cholecystokinin

Pancreatic innervation

GIP

Signalling via

GLP-1

sympathetic β

Pancreatic innervation

receptors

Signalling via

Adipokines

Early phase

sympathetic

Leptin

α-receptors

Resistin

Parasympathetic

Stress

Late phase

Basal

stimulation

Exercise

Adipokines

Hypoxia

Adiponectin

Hypothermia

100

Surgery

Time (min)

Severe burns

GIP, glucose-dependent insulinotrophic peptide

Figure 11.8 Characteristic biphasic release of

(previously known as ‘gastric inhibitory peptide’); GLP-1,

insulin.

glucagon-like peptide 1; NPY, neuropeptide Y.

ATP sensitive

Sulphonylurea

K⁺ (KIR 6.2)

channel closes

Ca⁺⁺

SUR1

Ca⁺ channel

Glucose

opens

K⁺

Glucose

Ca⁺⁺

Glucokinase

Glucose 6-

phosphate

ATP

Insulin exocytosis

Glycolysis

Resting negative

membrane potential

Figure 11.9 Mechanism of insulin secretion. After

turn opens voltage-gated calcium channels in the

uptake, glucose is metabolized within the β-cell to

membrane allowing calcium ions to enter the cell and

generate ATP. The increase in ATP closes ATP-

be released from intracellular stores. The increase in

sensitive potassium (KIR 6.2) channels in the cell

intracellular calcium initiates insulin granule

membrane and prevents potassium ions from leaving

exocytosis. Sulphonylureas act by binding to the

the cell. This depolarizes the cell membrane, which in

SUR1 which is a component of the K⁺-ATP channel.

250 / Chapter 11: Overview of diabetes

Insulin

Ligand-binding site

Insulin

Plasma

receptor

-s-s-

membrane

Tyrosine kinase

domain

Phosphorylation of docking proteins

(IRS1, -2, -3, -4, Shc, Gab-1)

Activation of signalling pathways

(PI 3-kinase, MAP kinase)

Glucose

Glycogen

Lipogenesis

Protein

Gene

Cellular

transport

synthesis

Lipolysis

synthesis

expression growth

Figure 11.10 Insulin signalling cascade. IRS, insulin receptor substrate; PI, phosphatidylinositol; MAP,

mitogen-activated protein.

Insulin has major anabolic actions on interme-

Glucose metabolism

diate metabolism, affecting glucose, lipid and

Normally plasma glucose concentration is main-

protein metabolism. The most important insulin-

tained within a narrow range despite wide fluctua-

sensitive tissues are the liver, skeletal muscle and

tions in nutrient supply and demand. Under normal

adipose tissue. Following secretion of insulin, 60%

physiological conditions, insulin, together with its

is subsequently removed by the liver; so portal vein

principal counter-regulatory hormone glucagon, is

insulin concentrations reaching the liver are almost

the prime controller of glucose metabolism.

three-fold higher than in the peripheral circulation.

Insulin is involved in the regulation of carbohy-

Insulin plays a major role in regulating hepatic

drate metabolism at many steps (Table 11.6). As

glucose output by inhibiting gluconeogenesis and

already mentioned, insulin increases glucose uptake

promoting glycogen storage. Similarly in muscle

into key insulin-sensitive tissues. As in the β-cell

cells, insulin-mediated glucose uptake enables gly-

(see earlier), glucose is carried into cells across the

cogen to be synthesized and stored, and for carbohy-

cell membrane by glucose transporters (GLUTs).

drates, rather than fatty acids or amino acids, to be

GLUT-1 is involved in basal and non-insulin-

utilized as the immediately available energy source

mediated glucose uptake by cells, while GLUT-2 is

for muscle contraction. Adipose tissue fat break-

important in the β-cell for glucose sensing. GLUT-3

down is suppressed and fat synthesis is promoted.

is involved in non-insulin-mediated glucose

252 / Chapter 11: Overview of diabetes

Table 11.6 Insulin actions on carbohydrate metabolism

Action

Mechanism

Increases glucose uptake

Translocation of glucose transporter (GLUT)-4 to the cell surface

into cells

Increases glycogen synthesis

Activates glycogen synthase by dephosphorylation

Inhibits glycogen breakdown

Inactivates glycogen phosphorylase and its activating kinase by

dephosphorylation

Inhibits gluconeogenesis

Dephosphorylation of pyruvate kinase and 2,6-biphosphate kinase

Increases glycolysis

Dephosphorylation of pyruvate kinase and 2,6-biphosphate kinase

Converts pyruvate to acetyl

Activates the intramitochondrial enzyme complex pyruvate

CoA

dehydrogenase

phosphorylation and dephosphorylation of the

lism by the pentose phosphate pathway provides

enzymes controlling glycogenolysis and glycogen

nicotinamide adenine dinucleotide phosphate

synthesis (Figure 11.12). The rate-limiting enzymes

(NADPH), which is needed for fatty acid

are the catabolic enzyme glycogen phosphorylase

synthesis.

and the anabolic enzyme glycogen synthase. Insulin

Triglyceride synthesis is stimulated by ester

increases glycogen synthesis by activating glycogen

ification of glycerol phosphate, while triglyceride

synthase, while inhibiting glycogenolysis by

breakdown is suppressed by dephosphorylation of

dephosphorylating glycogen phosphorylase kinase.

hormone-sensitive lipase.

Glycolysis is stimulated and gluconeogenesis inhib-

Cholesterol synthesis is increased by activation

ited by dephosphorylation of pyruvate kinase (PK)

and dephosphorylation of hydroxymethylglutaryl

and 2,6-biphosphate kinase. Insulin also enhances

co-enzyme A (HMGCoA) reductase, while choles-

the irreversible conversion of pyruvate to acetyl

terol ester breakdown appears to be inhibited

CoA by activation of the intramitochondrial enzyme

by dephosphorylation of cholesterol esterase.

complex pyruvate dehydrogenase. Acetyl CoA

Phospholipid metabolism is also influenced by

may then be directly oxidized via the tricarboxylic

insulin.

acid (Krebs’) cycle, or used for fatty acid synthesis

(Figure 11.13).

Protein metabolism

Insulin stimulates the uptake of amino acid into

Lipid metabolism

cells and promotes protein synthesis in a range of

Insulin increases the rate of lipogenesis in several

tissues. There are effects on the transcription of

ways in adipose tissue and liver, and controls

specific mRNA, as well as their translation into

the formation and storage of triglyceride. The

proteins on the ribosomes (review Chapter 2 and

critical step in lipogenesis is the activation of the

Figure 2.2). Examples of enhanced mRNA tran-

insulin-sensitive lipoprotein lipase in the capillaries.

scription include glucokinase and fatty acid syn-

Fatty acids are then released from circulating

thase. By contrast, insulin decreases mRNA

chylomicrons or very low-density lipoproteins

encoding liver enzymes such as carbamoyl phos-

and taken up into the adipose tissue. Fatty acid

phate synthetase, which is a key enzyme in the urea

synthesis is increased by activation and increased

cycle. However, the major action of insulin on

phosphorylation of acetyl CoA carboxylase, while

protein metabolism is to inhibit the breakdown of

fat oxidation is suppressed by inhibition of carnitine

proteins (Figure 11.14). In this way it acts synergis-

acyltransferase

(Table

11.7). Lipogenesis is also

tically with GH and insulin-like growth factor I

facilitated by glucose uptake, because its metabo-

(IGF-I) to increase protein anabolism.

254 / Chapter 11: Overview of diabetes

Insulin

Glucagon

Stimulation

Inhibition

of adenylase

cyclase

Insulin action

Glucagon action

yields active

yields inactive

form of acetyl

cAMP-

form of acetyl

CoA carboxylase

independent

dependent

CoA carboxylase

protein

Citrate

ATP

kinase

ADP

Less active

Active (dephosphorylated)

Inactive (phosphorylated)

Monomer acetyl

Polymer acetyl CoA

CoA carboxylase

carboxylase

Phosphoprotein

Phosphatase

Long chain

acyl CoA

Stimulation of

Insulin

a factor (Fa)

Figure 11.13 Regulation of acetyl co-enzyme A

enzymes are capable of regulating the conversion of

(CoA) carboxylase by allosteric regulators and by

active polymer acetyl CoA carboxylase to the inactive

phosphorylation-dephosphorylation mechanisms.

phosphorylated form of the enzyme. The cyclic

Acetyl CoA carboxylase, which is involved in fatty

adenosine 5′-monophosphate (cAMP)-dependent

acid synthesis, exists as a monomer and in two

protein kinase may be activated by glucagon (top

polymeric forms, which are interconvertible by

right), while the cAMP-independent protein kinase is

dephosphorylation. Citrate and long-chain acyl CoA

inhibited by insulin action on the target cell (top left).

control the relative proportions of the less active

As fatty acid synthesis is increased by activation and

monomer and the active polymeric form of acetyl

increased phosphorylation of acetyl CoA carboxylase,

CoA carboxylase by allosteric mechanisms. As in the

glucagon action on the cell decreases lipogenesis,

case of glycogen synthetase, two protein kinase

while insulin stimulates fatty acid synthesis.

Glucagon

Glucagon plays an important part in preventing

significant hypoglycaemia during fasting by antago-

Glucagon is a polypeptide with a molecular weight of ∼3.5

nizing the actions of insulin. Its primary site of

kD. It is synthesized as a large precursor, pre-proglucagon,

action is the liver where it binds to specific

and is cleaved within the α-cells to the active hormone.

G-protein-coupled glucagon receptors that are

Its secretion is stimulated by a fall in blood

linked to adenylate cyclase (review Chapter 3). This

glucose and by amino acids. Release of glucagon is

leads to the mobilization of glycogen and to the

also under neural control; sympathetic adrenergic

production of glucose from non-carbohydrate pre-

activation increases glucagon release.

cursors by gluconeogenesis.

Chapter 11: Overview of diabetes / 255

Key points

IGF-I

Amino acids

• Diabetes is the commonest endocrine

condition and its prevalence is increasing

rapidly worldwide

• Diabetes is a major clinical specialty in its

Protein synthesis

own right alongside endocrinology

• The commonest types of diabetes are

type 1 and type 2 diabetes

• Diabetes is defined by elevations in blood

Protein breakdown

glucose

• Insulin is the pivotal hormone regulating

cellular energy supply and macronutrient

Insulin

balance during the fed ‘post-meal’ state

Figure 11.14 The synergistic actions of insulin,

IGF-I, and GH on protein synthesis. GH and IGF-I

stimulate protein synthesis directly, while insulin is

mainly anabolic through the inhibition of protein

breakdown. The anabolic action of both GH and

IGF-I appears to be mediated through induction of

amino acid transporters in the cell membrane. IGF-I

may act in a local autocrine or paracrine fashion as

well as in an endocrine manner.

Answers to case histories

Case history 11.1

diabetes. Epidemiologists have developed

models based on published studies that can

There is a large burden of diabetes in every

be used to estimate the burden of diabetes

community, with 20-50% of all cases of

locally. One such example is the York &

diabetes remaining undiagnosed. Diabetes

Humber Public Health Observatory (http://

prevalence varies from region to region

www.yhpho.org.uk/resource/

according to the demographics of the

view.aspx?RID=81090).

region, and therefore estimates from other

regions may be inappropriate. Any

Case history 11.2

questionnaire survey of diabetes prevalence

may significantly underestimate the true

No. Type 2 diabetes is frequently found in

prevalence as many people do not know

asymptomatic individuals. There is an

they have the disorder. Similarly,

increasing drive towards screening for type 2

extrapolation from historical publications

diabetes, especially in high-risk individuals,

may underestimate the prevalence as

which is relatively straightforward in the era

this is increasing more rapidly than

of automated biochemical testing. This man

previously.

is overweight, which increases the risk of

Establishing registers of patients with

diabetes. Hypertension is also associated

diabetes is one way of obtaining a

with an increased risk of diabetes. Symptoms

reasonable estimate of known cases of

of diabetes usually only begin when the

256 / Chapter 11: Overview of diabetes

blood glucose exceeds the renal capacity to

cysts, lipodystrophy or deafness. She is only

re-absorb glucose from the proximal tubules.

33 years old and wishes to have a family. As

Although this varies between individuals, this

well as predicting the risk to her future

is usually greater than 11 mmol/L (200 mg/

children, the management of MODY during

dL). The gradual insidious onset of diabetes

pregnancy differs from that of type 1 or type

means that people frequently are

2 diabetes. MODY should be considered

asymptomatic and may have had diabetes

when there is an autosomal dominant family

for many years before the development of

history of early-onset diabetes; when the

symptoms.

presentation or course is atypical for type 1

Again no. Even though the person with

or type 2 diabetes; when diabetes is

diabetes is asymptomatic, the

diagnosed in the

hyperglycaemia is still damaging and so

first 6 months of life; or when there are

complications can occur in people with

associated extra-pancreatic clinical

previously undiagnosed diabetes. In the UK

features. More broadly, diagnostic precision

Prospective Diabetes Study, around 50% of

is always critical for understanding

people with newly diagnosed diabetes had

epidemiological and other clinical features.

one or more diabetic complications. It is

Yes. This woman was treated with insulin

hoped that with increased awareness and

for 15 years. Diabetes caused by HNF1α

targeted screening of high-risk individuals,

mutations often responds better to

this proportion will decrease, and this is one

sulphonylureas than insulin and this would

of the major rationales for screening for

have saved her ∼20,000 injections!

diabetes.

Case history 11.4

Case history 11.3

We do not know. In order to make a

Yes. At an individual level, a precise

diagnosis of diabetes in an asymptomatic

diagnosis is important to predict clinical

person, two values above the internationally

course, explain other associated clinical

agreed criteria are required. A random blood

features, enable genetic counselling and

glucose of 11.2 mmol/L (201 mg/dL) is in the

diagnosis of family members, and guide

diagnostic range for diabetes, but a second

appropriate treatment. For instance, some

confirmatory test is required. The WHO

forms of MODY, such as inactivating

recommends that the gold standard

glucokinase mutations, tend to have a more

confirmatory test is a 75-g OGTT, although if

benign course and do not appear to be

the fasting glucose was ≥7.0 mmol/L (126 mg/

associated with the development of diabetic

dL), this would be sufficient. An alternative

complications. Some other forms have

would be to consider the use of glycated

extra-pancreatic features, such as renal

haemoglobin.

258 / Chapter 12: Type 1 diabetes

Cross-reference

■ Several hormones influence the action of insulin and exert an effect on glucose control.

These include growth hormone (see Chapter 5), cortisol and catecholamines (see Chapter 6)

■ The pathogenesis of type 1 diabetes involves a selective autoimmune destruction of the

pancreatic β-cells. Individuals with type 1 diabetes are at increased risk of other autoimmune

diseases, such as thyroid disease, which is covered in Chapter 8

■ Exercise plays an important part in the management of both type 1 and type 2 diabetes.

Exercise is discussed in greater detail in Chapter 13

■ Diabetes can lead to the development of a number of complications, which are discussed in

Chapter 14

Although type 1 diabetes only accounts for around

Box 12.1 What is autoimmunity?

10% of all cases of diabetes, its presentation, par-

ticularly in children and young adults, and acute

Under normal circumstances, the immune

complications are the most dramatic. Prior to the

system does not react against the body’s

discovery of insulin, type 1 diabetes rapidly led to

cells, tissues and organs. This is known as

the death of the patient; consequently, the use of

immune tolerance. Autoimmunity is caused

insulin to treat people with type 1 diabetes can

by a breakdown of this normal immune

rightly be considered as one of the greatest advances

tolerance of self. See Box 8.8 for other

in medicine in the 20th century. Insulin has saved

examples of organ-specific autoimmune

and transformed the lives of millions of people

diseases with shared genetic predisposition.

worldwide and continues to do so.

Box 12.2 Genetic and acquired

What is type 1 diabetes?

factors that can affect pancreatic

Type 1 diabetes is caused by an absolute deficiency

β-cell function leading to a

of insulin. In populations of white Northern

presentation of diabetes that is

European ancestry, it usually occurs as the result of

similar to autoimmune type 1

a T-cell-mediated autoimmune destruction of the

diabetes

β-cells of the pancreas (Box 12.1).

By contrast, autoimmune type 1 diabetes is

• Mitochondrial gene mutations

uncommon in non-Caucasian populations. With a

• Amylin gene mutations

better understanding of the pathogenesis of diabe-

• Maturity-onset diabetes of the young

tes, it is recognized that other genetic or acquired

(MODY)

factors affecting pancreatic β-cell function can

• Latent autoimmune diabetes of adults

result in diabetes that presents in the same way as

(LADA)

autoimmune type 1 diabetes (Box 12.2). Further-

• Viral infection

more, there may be a broad range of clinical mani-

festations that overlap between type 1 and type 2

diabetes (Chapter 13).

affect all age groups, most are diagnosed as children,

adolescents or young adults. According to a large

European study, the incidence is increasing and age

Epidemiology

of onset is becoming younger. Type 1 diabetes is rare

Approximately 20 million people have type 1 dia-

in children younger than 1 year old and if diabetes

betes worldwide. Although type 1 diabetes may

occurs at this age, maturity onset diabetes of the

Chapter 12: Type 1 diabetes / 259

young (MODY) or other monogenic cause of dia-

Worldwide the incidence and prevalence of type

betes should be considered (Box 12.3 and Table

1 diabetes increased markedly during the second

11.3). There is a steady rise in incidence throughout

half of the 20th century. Overall, the incidence rate

childhood with the peak occurring slightly earlier

increased between 3.2% and 5.3% per year during

in girls (∼11 years) than boys (∼14 years), suggest-

the 1990s, with the most pronounced increase seen

ing an influence of puberty. There is also a smaller

in pre-school children. The only global regions with

peak at the age of 4-5 years.

a decreasing trend were Central America and the

The incidence of type 1 diabetes varies dramati-

West Indies.

cally throughout the world. The highest incidence

During the 1970s, diabetes was slightly com-

rates are in northern Europe, where the rates are up

moner in European boys and in populations of

500-fold greater than in China, Pakistan or

European origin while in contrast, in African or

Venezuela (Figure 12.1). Some of this difference

Asian populations, girls were more commonly

may reflect ethnic heterogeneity between popula-

affected. However, during the 1990s the sex-specific

tions, but this does not explain all the difference,

pattern changed and the male excess has disap-

e.g. the rates of diabetes in Sardinia are three- to

peared from many but not all populations.

six-fold higher than in mainland Italy.

Pathogenesis

Box 12.3 The difference between

The pathogenesis of type 1 diabetes remains poorly

monogenic and polygenic

understood, but the most likely scenario is that an

disorders

environmental factor triggers a selective autoim-

mune destruction of the β-cells in the pancreas of

Monogenic

a genetically predisposed individual.

• Caused by a mutation in one gene

The autoimmune process develops as a result of

^ E.g. MODY and permanent neonatal

a loss of immunological tolerance and involves both

diabetes

cellular and humoral immune pathways. Histological

examination of the pancreas from an individual

Polygenic

with type 1 diabetes reveals a chronic inflammatory

• Caused by many genes

mononuclear cell infiltrate of CD4+ and CD8+ T

^ E.g. type 2 diabetes

lymphocytes and macrophages in the islets (insulitis).

Figure 12.1 Age-

standardized incidence of

type 1 diabetes in

children (per 100,000/

year).

260 / Chapter 12: Type 1 diabetes

Table 12.1 Islet cell auto-antibodies involved in the pathogenesis of type 1 diabetes

Antigen

Antibody

Function

Proportion with

Age

Gender

abbreviation

antibody at

diagnosis (%)

Glutamic acid GAD65Ab

GABA production

70-80

Frequency

Female

decarboxylase

increases with

preponderance

increasing age

if onset is <10

years

Islet antigen-2

IA-2Ab

Unknown

60-70

Frequency

Male

decreases with

preponderance

increasing age

Insulin

IAA

Regulates

Better predictive No difference

glucose

value in children

ZnT8

ZnT8Ab

Zinc transport

60-80

Better predictive No difference

transporter

and accumulation

value with age

in β-cells

The CD8+ T lymphocytes are thought to be

Case history 12.1

responsible for the selective and specific killing of

the β-cells.

A 24-year-old woman with previously

The presence of circulating islet-related auto-

well-controlled type 1 diabetes presents

antibodies in the period preceding the clinical onset

with tiredness and lethargy. She also

of diabetes adds further evidence for an autoim-

remarks that she has had many more

mune process (Table 12.1). These antibodies may

hypoglycaemic episodes than previously

be present for many months prior to the onset of

and has had to cut her insulin dose by

diabetes and have been used to predict which indi-

50%. She mentions that she often feels

viduals will develop diabetes with considerable

dizzy when she stands up and has

accuracy (up to 98%). It was previously thought

noticed that she is more ‘tanned’ than

that the development of type 1 diabetes occurred

usual.

rapidly over a period of several weeks. Having fol-

lowed individuals with islet cell antibodies, it is now

What is the possible explanation for her

known that β-cell loss can be slow and some indi-

symptoms?

viduals do not develop diabetes until many years

How would you confirm your diagnosis?

after the appearance of the auto-antibodies (Figure

12.2). Furthermore, not all individuals with auto-

Answers, see p. 283

antibodies develop diabetes, suggesting that autoim-

munity against the islet cells does not necessarily

progress to sufficient β-cell loss to cause diabetes.

The autoimmune basis for type 1 diabetes is also

suggested by its association with a number of other

Aetiology

organ-specific autoimmune diseases, such as

autoimmune thyroid disease, coeliac disease, perni-

It is apparent that both genetic and environmental

cious anaemia and Addison disease (Case history

factors are important in the development of type 1

12.1; see Box 8.8).

diabetes.

Chapter 12: Type 1 diabetes / 261

Enviromental trigger

Healthy individual

Pre-diabetes

Insulitis

Clinical onset

Type 1 diabetes

Type 2 diabetes

Time

Figure 12.2 The natural history of diabetes. β-Cell

insulin secretion is lost, followed by the development

mass increases during childhood and reaches a

of intermediate hyperglycaemia and eventually overt

peak in early adulthood. Thereafter there is a

diabetes. At the onset of diabetes, some β-cells will

progressive loss of β-cell mass of approximately 1%/

remain and their presence can be identified by the

year. In type 2 diabetes, the rate of β-cell loss is

presence of circulating C-peptide. With time,

accelerated to approximately 4%. One model for the

however, these remaining cells will also be

natural history of type 1 diabetes is that certain

destroyed, leading to absolute insulin deficiency.

individuals are genetically pre-disposed to develop

The difference between type 1 and type 2 diabetes

diabetes. Environmental factors act as triggers or

appears to be one of tempo and there has been

regulators of the autoimmune destructive process

debate recently about whether the division into two

that results in insulitis, β-cell injury and finally loss of

types is wholly justified. An alternative view is that

β-cell mass. As β-cell function falls, first-phase

they are opposite ends of a spectrum of β-cell loss.

Genetic factors

dren with type 1 diabetes will develop diabetes

themselves by the age of 15 years. However, if the

Evidence for the importance of genetic factors

HLA genotype is identical to the sibling with dia-

comes from twin and family studies. The risk of

betes, the risk of developing diabetes increases to

developing diabetes increases with the number of

16-20%, while siblings who share one HLA gene

family members with the condition. The back-

have a risk of 9% (Table 12.2).

ground risk in the population is 0.4%, but this

Recently, genome-wide association studies have

increases to around

65-70% for a monozygotic

identified a number of additional ‘non-HLA’ loci

twin whose other twin developed type 1 diabetes

that are associated with the development of type 1

under the age of 5 years (Table 12.2).

diabetes. The strongest associations seem to link to

The risk of diabetes is modified markedly by

the following nearby genes:

genes in the class II region of the human leucocyte

antigen (HLA) system (Box 12.4). Over 95% of

• INSULIN (INS), the association is particularly

white European people with type 1 diabetes have

localized to the variable number of tandem repeat

HLA-DR-3 and/or DR-4 class II HLA antigens, as

(VNTR) polymorphisms in the INS promoter (INS

compared with only 50% of individuals without

VNTR; review gene structure in Figure 2.2)

diabetes. By contrast, certain HLA haplotypes, such

• Protein tyrosine phosphatase non-receptor type 2

as HLA DQ-5 and DQ-6, may protect against dia-

(PTPN2)

betes. In Europe, around 5-6% of siblings of chil-

• Interleukin-2 receptor, α chain (IL2RA).

262 / Chapter 12: Type 1 diabetes

Table 12.2 Risk of developing type 1 diabetes

Box 12.4 What are HLA

for relatives of people with type 1 diabetes

molecules?

Family member

Risk

• HLA antigens are glycoproteins found on

the cell surface that are involved in the

Monozygotic twin

30-50% in other twin

65-70% if twin

immune process

diagnosed before

• There are two classes (I and II), which

age of 5 years

differ in their structure

• Class I molecules are found on all

Dizygotic twin

15%

nucleated cells, while class II molecules

Sibling with HLA

16-20%

are only found on antigen-presenting cells,

genotype that is

such as macrophages

identical to the affected

• Class II molecules bind foreign antigen

sibling

peptides and present them to T-helper

Sibling who shares

lymphocytes

one HLA gene

• There are three types of class II molecule

HLA non-identical

- DP, DQ and DR. Each of these is

sibling

sub-classified by numbers

Mother

Father

Box 12.5 Putative, but unproven,

Both parents

30%

environmental triggers of type 1

General population

0.4%

diabetes

• Chemicals:

• Perinatal factors:

Environmental factors

^ N-nitro

^ Maternal rubella

Although the genetic susceptibility to type 1 diabe-

compounds:

^ Blood group

tes is inherited, only 12-15% of type 1 diabetes

^ Streptozotocin

incompatibility

occurs in families with a history of diabetes and

^ Nitrosamines

^ Maternal age

only 10% of HLA-susceptible individuals develop

^ Nitrosamides

^ Pre-eclampsia

type 1 diabetes. This indicates that genetic factors

• Viruses:

^ Caesarean section

do not account entirely for the development of type

^ Mumps

^ Birth weight

1 diabetes, and several environmental triggers have

^ Rubella

^ Gestational age

been suggested (Box 12.5).

^ Cytomegalovirus

^ Birth order

How these factors affect the autoimmune

^ Enteroviruses

• Food components

response is unclear and it should be noted that none

^ Retroviruses

^ Milk protein

of the environmental factors is either necessary or

• Bacteria:

^ Wheat protein

sufficient to cause type 1 diabetes.

^ Streptomyces

^ Vitamin D

There are several overlapping hypotheses to

• Vaccination

deficiency

explain the environmental effect on the risk of

• Puberty

• High energy intake

diabetes:

• Stress

and weight gain

• An environmental trigger leads to an abnormal

production of co-stimulatory molecules and up-

• Self-antigens may be modified and become

regulation of the HLA antigens in susceptible

antigenic.

people. This may lead to self-antigens being pre-

• An immune response against a dietary or infective

sented to T-helper cells and triggering an autoim-

agent may cross-react with self-antigens, so-called

mune response.

‘molecular mimicry’.

Chapter 12: Type 1 diabetes / 263

• Reduced exposure to pathogens and their prod-

Box 12.6 Presenting features of

ucts. The ‘hygiene hypothesis’ proposes that better

type 1 diabetes

sanitation has led to a relatively immature immune

system prone to autoimmunity.

• Symptoms related to the osmotic effect of

the hyperglycaemia:

^ Increased thirst and polydipsia

Clinical features

^ Polyuria and nocturia

People with type 1 diabetes usually present with a

^ Blurred vision

short duration of illness of 1-4 weeks. Although

^ Drowsiness and dehydration

there is diversity in the clinical presentation, the

• Cutaneous candidal infection:

classical triad of thirst, polydipsia and polyuria

^ Vulva (pruritus vulvae)

together with weight loss are the commonest symp-

^ Foreskin (balanitis)

toms (Box 12.6).

• Symptoms related to the inability or

inappropriate transport of fuel substrates:

^ Extreme fatigue

Symptoms related to the osmotic effect

^ Muscle wasting through protein

of the hyperglycaemia

breakdown

Many of the presenting symptoms are linked to the

^ Weight loss

osmotic effect of the hyperglycaemia. These symp-

• Diabetic ketoacidosis

toms are common to all types of diabetes, but they

are usually more severe and the time course is

usually shorter in type 1 diabetes.

Under normal physiological conditions, the

Diabetic ketoacidosis

renal tubule re-absorbs filtered glucose in the proxi-

Diabetic ketoacidosis (DKA) occurs as a result of

mal tubule; however, once the plasma glucose

marked insulin deficiency and elevated counter-

exceeds the renal resorption capacity, glucose is

regulatory hormones. It is a potentially fatal condi-

excreted in the urine. There is considerable variabil-

tion that is a medical emergency requiring prompt

ity in the renal threshold above which glucose enters

diagnosis and treatment. In a European study, 8.6%

the urine between individuals. It averages 11 mmol/L

of people with type 1 diabetes had been admitted

(200 mg/dL) but ranges from ∼6 to 14 mmol/L

with DKA in the previous year; 25% of the cases

(110-250 mg/dL). Once present in the urine,

occurred in people without a prior history of

glucose exerts an osmotic effect that can lead to

diabetes.

profound dehydration and hypovolaemia as water

leaves the cells along the osmotic gradient, only to

be lost in the urine. Changes in osmotic pressure in

Prognosis

the eye as a result of changing intraocular and

plasma glucose concentration may distort the shape

Prior to the discovery of insulin in 1921, the devel-

of the eye and lens and cause blurred vision.

opment of type 1 diabetes meant an almost certain

death shortly after diagnosis. Since then, the prog-

nosis for people with type 1 diabetes has improved

Symptoms related to the failure of

dramatically, but despite this, type

1 diabetes

anabolism

remains associated with a two- to 10-fold increased

The profound weight loss that often accompanies

risk of premature mortality compared with the

the development of type 1 diabetes occurs because

general population.

of the loss of the anabolic actions of insulin. There

A significant proportion of early deaths are

is a failure to transport fuel substrates into the cells

attributable to DKA, while later deaths are more

and protein breakdown occurs because of the loss

commonly associated with cardiovascular disease

of insulin action.

and nephropathy

(described in more detail in

264 / Chapter 12: Type 1 diabetes

People without diabetes

People with diabetes

15-19

20-29

30-39

40-49

50-59

60-70

Age at diagnosis (years)

Figure 12.3 Life-expectancy and diabetes. Adults with diabetes have an annual mortality of about 5.4%,

double the rate for adults without diabetes. Life-expectancy is decreased by 5-10 years.

Chapter

14). Mortality rates for cardiovascular

When the clinical features are less clear-cut, it

disease are eight- to 40-fold higher in people with

may be difficult to distinguish between type 1 and

type 1 diabetes than in the general population.

type 2 diabetes (Table 12.3). The detection of islet

It used to be said that on the day that a person

auto-antibodies is indicative of type 1 diabetes but

is diagnosed with diabetes, their life-expectancy

not pathognomonic (Box 12.7). With time the

is reduced by around one-third

(Figure

12.3).

precise diagnosis usually becomes clearer, but at the

Consequently the greatest burden of diabetes falls

initial presentation is less important than the practi-

on those who are diagnosed during childhood.

cal question about whether insulin is necessary.

However, these data reflect older cohorts and there

Unlike type 2 diabetes, type 1 diabetes must be

is evidence that better control of hyperglycaemia

treated with insulin.

and other cardiovascular risk factors, such as hyper-

A catch for the unwary is the person with

tension and lipids, is being translated into improved

MODY (see Chapter 11, Table 11.3 and Case

survival.

history 11.3). These are inherited monogenic forms

It is salutary to remember that in some low-

of diabetes. As they often present in childhood, they

income countries, where there is a lack of access to

may be mistaken for type 1 diabetes. An autosomal

diagnostic equipment and basic supplies of insulin,

dominant family history of early-onset diabetes

the life-expectancy of a child with new-onset type

should alert the clinician to this possibility.

1 diabetes is only 3-4 months, similar to pre-1922

mortality rates in the developed world.

Management

Diagnosis

Type 1 diabetes is a life-long condition that is

The diagnosis of type 1 diabetes is relatively straight-

currently incurable. For most of the time, the

forward once it is considered in a person with

person with diabetes will manage their diabetes

weight loss and the classical triad of thirst, polydip-

themselves with only a minority of the time spent

sia and polyuria. As the patients have symptoms,

in contact with their healthcare professionals. As

only one plasma glucose concentration above the

such, the person with diabetes needs to be sup-

diagnostic cut-off is needed to confirm the diagno-

ported to assume much of the responsibility for

sis (review Chapter 11).

their diabetes.

Chapter 12: Type 1 diabetes / 265

Table 12.3 Comparison of presenting features of type 1 diabetes, type 2 diabetes, monogenic

diabetes and secondary diabetes

Type 1

Type 2

Monogenic

Secondary

Weight loss

Usually present

Depends on

underlying cause

Ketonuria

Usually present

No or minimal if No or minimal if

May be present

recent fasting

Duration of

Few weeks

Months

Weeks or months

symptoms

Severity of

Can be marked

Variable but

Not usually severe

Depends on

symptoms

usually mild

underlying cause

Family history Possible (see

Present in 30%

Present in almost all

Unusual unless

Table 12.2)

with onset in

with onset in early

diabetes secondary

adulthood

adulthood or (more

to conditions such as

commonly) earlier

haemochromatosis

Age

Peak incidence is

Usually after

Neonates to early

Usually middle or

during pre-school

age of 20 years,

adulthood

older age

and adolescent

but becoming

years, but can

commoner in

affect any age

children

to its introduction, people with diabetes were left

Box 12.7 Definition of

with a choice of death by DKA or death by ‘inani-

pathognomic

tion’, the exhausting condition resulting from want

or insufficiency of nourishment. People with type 1

A particular symptom or sign whose

diabetes could survive for several years on diets of

presence means that a particular disease is

∼500-700 calories/day, but had a miserable exist-

present beyond any doubt.

ence and inevitable weight loss until either the

patient broke their diet or died from starvation.

The aims of diabetes care and management are

In people without diabetes, insulin is secreted at

four-fold:

a slow basal rate throughout the day, which gives

rise to a low plasma insulin concentration between

• Life-threatening diabetes emergencies, such as

meals and during the night. Following a meal there

DKA and hypoglycaemia, should be managed effec-

is a rapid rise and peak in plasma insulin concentra-

tively, ideally by preventative measures

tion, which falls back to baseline within 2 h (Figure

• Symptoms relating to the osmotic effects of

12.5). The philosophy of managing the insulin

hyperglycaemia should be addressed

replacement in people with diabetes is to mimic this

• Long-term complications should be minimized

pattern as closely as possible (Box 12.8).

through screening and effective control of hyperg-

Although the introduction of insulin trans-

lycaemia and other cardiovascular risk factors

formed the lives of many with diabetes and is one

• Iatrogenic side-effects, such as hypoglycaemia,

of the most significant advances in medicine, it

should be avoided.

became apparent that subcutaneous insulin delivery

is not ideal and many developments have happened

Insulin

since the 1920s to allow the replacement of insulin

The discovery of insulin in 1921 transformed the

in a more physiological pattern (Box 12.9). The use

management of type 1 diabetes (Figure 12.4). Prior

of insulin should be tailored to meet individual

Chapter 12: Type 1 diabetes / 267

Box 12.9 Disadvantages of subcutaneous insulin administration compared

with endogenous insulin production from the pancreas

• Insulin must be given by injection

• Insulin is delivered into the systemic rather than portal circulation:

^ The physiological delivery of insulin to the liver is compromised resulting in lower insulin

transport to the liver while peripheral tissues such as adipose tissue receive a higher

concentration

^ Insulin has a number of actions in the liver that are not normalized by subcutaneous

administration, e.g. production of insulin-like growth factor I (IGF-I)

• Loss of normal feedback mechanism between glucose concentration and insulin secretion

• Pharmacodynamics are altered, making it difficult to match insulin supply to requirement

Insulin

analogues are

Use of animal

Animal insulin

introduced

insulin first

commercially

tested with

available

Two major

success on a

types of

14-year-old boy

diabetes

Commercial

defined:

production of

type 1 and

human insulin

type 2

1920

1930

1940

1950

1960

1970

1980

1990

2000

Figure 12.6 The timeline of the commercialization of insulin injection therapy.

from pigs or cattle but since the 1980s, insulin has

Insulin analogues

been produced biosynthetically using recombinant

Most recently, in the mid-1990s, short- and long-

DNA technology whereby the INSULIN coding

acting insulin analogues have been introduced,

sequence is inserted into bacteria such as Escherichia

allowing injections to mimic more closely the daily

coli. This technology has allowed large amounts of

changes in physiological insulin secretion. When

insulin to be produced in a highly purified manner

soluble insulin is injected subcutaneously it forms a

under ‘Good Manufacturing Practice’. Some people

hexamer that delays its absorption from the injec-

are still treated with animal insulin but the numbers

tion site. For this reason it acts more slowly than

are becoming progressively fewer.

endogenously secreted insulin. To combat this,

newer rapid-acting insulin analogues (insulin lispro,

insulin aspart, insulin glulisine) that are less likely

Protamine insulin and insulin zinc

to form hexamers were developed and consequently

suspensions

are more rapidly absorbed. Long-acting insulin ana-

Protamine insulin and insulin zinc suspensions were

logues (insulin glargine or insulin detemir) have

introduced to form isophane insulin in the 1930s

been introduced to provide a more stable basal

and 1950s respectively. These preparations prolong

plasma insulin concentration. Newer analogues in

the action of insulin to provide a sustained basal

ongoing development are likely to be introduced in

level of insulin.

the near future.

268 / Chapter 12: Type 1 diabetes

Insulin regimens

(a)

Pre-mixed

In theory any combination of insulin can be used

injection

as long as the person with diabetes achieves good

glycaemic control; however, there are several regi-

mens that are more commonly used.

One of the simplest regimens is twice-daily

mixed insulin. The mixed insulin contains both

short- and intermediate-acting insulin and is given

shortly before breakfast and the evening meal

(Figure 12.7a). While the advantage of this regimen

Breakfast Lunch

Dinner

is that only two injections a day are needed, there

are several disadvantages, such as inflexibility and

(b)

relatively poorer control. Basal bolus regimens are

Soluble

Soluble Soluble

Isophane

the treatment of choice for most individuals with

insulin

type 1 diabetes (Figure 12.7b and c; Table 12.4;

Case history 12.2).

Case history 12.2

A 35-year-old man who has had type 1

diabetes for 10 years attends the clinic

Breakfast Lunch

Dinner

Bedtime

complaining of late morning ‘hypos’. He is

(c)

currently treated with twice-daily pre-mixed

Rapid

Long-acting

insulin containing 30% soluble insulin and

insulin

70% isophane insulin. He mentions that

work is hectic and he does not always

know when he is going to eat lunch.

What possible changes to his insulin

regimen could you make?

Answer, see p. 283

Breakfast Lunch

Dinner Bedtime

Figure 12.7 Schematic representation of insulin

profiles with different regimens. (a) Pre-mixed insulin;

Injection sites and technology

(b) basal bolus regimen with soluble and isophane

Insulin is given subcutaneously by intermittent

insulin; (c) basal bolus regimen with analogue

insulin. Soluble insulin is in light blue; pre-mixed,

injection or by continuous infusion. Although it

mid blue; longer-acting insulin, dark blue.

can be injected almost anywhere if there is enough

flesh, the best sites are the front and side of the

thigh, lower abdominal wall, buttocks and upper

are portable, use a fine needle and have a simplified

arms (Figure 12.8).

procedure for measuring the insulin; the pens allow

Intermittent insulin injections may be given by

the user to dial up and dispense their required doses.

needle and syringes but more commonly insulin

The many advantages of insulin pens include con-

pen devices are used (Figure 12.9). Pens may be

venience, easier injection and less pain. Insulin

disposable with pre-filled insulin or may be re-used

pen needles were initially 12 mm in length but as

by changing the insulin cartridge when empty. They

manufacturing has improved, progressively shorter

Chapter 12: Type 1 diabetes / 269

Table 12.4 Advantages and disadvantages of insulin regimens

Twice daily insulin

Basal bolus regimen

Basal bolus regimen using

mixture

using soluble insulin

analogue insulin

Number of

Usually 4

injections

Timing

5-30 min before

20-30 min before each

5-10 min before each meal

breakfast and

meal (bolus) and

(bolus) and pre-bedtime (basal)

evening meal

pre-bedtime (basal)

Flexibility of

No - patient must

Yes - injection given

Yes - injection given before

mealtimes

eat regularly at

before meal

meal. If basal insulin is provided

pre-determined times

by long-acting analogues,

meals may be missed and

bolus insulin omitted

Variable meal

Lunch insulin is

Yes - meal doses can

Yes - meal doses can be

sizes

delivered at breakfast

be adjusted according

adjusted according to need

time, therefore little

to need

flexibility

Need for

Yes

mid-meal snack

Risk of

High

Lower

Lowest

hypoglycaemia

Glycaemic

Achievable

Better control than

Best control

control

twice-daily insulin

Insulin allergy

Possible

Reduced risk

needles have become available. The shortest avail-

able needles are now 4 mm in length and their use

is associated with fewer inadvertent intramuscular

injections than longer needles.

Continuous subcutaneous insulin infusion

(CSII) or insulin pumps are an alternative form of

insulin delivery that was first introduced over 30

years ago. CSII comprises an insulin reservoir and

delivery catheter that continuously infuses insulin

into the subcutaneous tissue (Figure 12.10). The

technology has steadily improved and allows the

user to give a basal infusion throughout the day

with boluses at mealtimes. The latest models also

include software to help the user calculate the most

appropriate insulin dose. When used by well-

motivated people, CSII leads to improved control

Figure 12.8 Sites for injection.

with fewer episodes of hypoglycaemia and improved

quality of life compared with multiple daily insulin

injections. Given these results, it is unsurprising

Chapter 12: Type 1 diabetes / 271

Box 12.10 Areas covered by

Box 12.11 Dietary advice for

diabetes education

people with diabetes

• Description of the diabetes disease

Fats

process and treatment options

• Restrict the intake of saturated fatty acids

• Diet

and trans-fats

• Physical activity

• Vegetable oils, nuts and seeds are

• Medication(s) including insulin -

preferred

effectiveness and safety

• Consume oily fish two to three times per

• Self-monitoring of blood glucose

week

• Preventing, detecting and treating acute

complications

Fibre and micronutrients

• Preventing, detecting and treating chronic

• Consume foods rich in dietary fibre and

complications

micronutrients

• Personal strategies to address

• Consume five servings of fresh fruit and

psychosocial issues and concerns

vegetables per day

• Personal strategies to promote health and

• Legumes and whole-grain products are

behaviour change

recommended

Carbohydrates

which is equally applicable to people with type 2

• Eating complex carbohydrates such as

diabetes, embraces a ‘patient-centred approach’ and

bread, potatoes, pasta and rice in

encompasses all aspects of diabetes care (Box 12.10).

moderate amounts with each meal should

Only when a person with diabetes is informed

be encouraged

about their condition and the treatment options can

• Low glycaemic index (GI) carbohydrates

they take control of their diabetes and make an

are preferred because they cause a slower

informed judgement about their care.

rise in blood glucose concentration

Although diabetes education is an on-going

• Sugar is not forbidden but excessive

process, structured educational programmes, such

intake is not desirable

as the

‘Dose Adjustment For Normal Eating

• Non-caloric sweeteners are safe

(DAFNE)’, at the time of or shortly after diagnosis

are important to equip the person with knowledge

Alcohol

and skills for their life with diabetes. Structured

• Alcoholic beverages should only be taken

education has been shown to lead to improvements

in moderation

in glycaemic control and improved quality of life.

Other

• Special diabetic foods are unnecessary

Diabetes and diet

• Meals, snacks and food choices should

match individual therapeutic needs,

It is important to encourage patterns of healthy

preferences and culture

eating (Box 12.11). Ideally 60% of total caloric

intake should be provided by carbohydrate, with no

more than 30% coming from fat. It should be

rigidity of this approach became unpopular and

recognized, however, that the real dietary limita-

was replaced by more general advice advocating

tions are dictated by the inadequacy of the available

healthy eating. The pendulum is now swinging back

insulin regimens rather than the diabetes itself.

towards the use of carbohydrate counting; however,

Historically people with diabetes were taught to

it is now being used to adjust the meal bolus of

count their carbohydrate intake so that the carbo-

insulin to match the carbohydrate intake rather

hydrate content in each meal or snack could

than vice versa. This approach promotes good gly-

be prescribed to match the insulin dose. The

caemic control while allowing flexible eating; in

272 / Chapter 12: Type 1 diabetes

effect, the aim is to mimic the response of healthy

Box 12.12 Effect of exercise on

β-cells when confronted by meals of varying size

blood glucose in people with type 1

and composition.

diabetes

Glucose concentration will tend to decrease

Diabetes and exercise

if:

Exercise is an important component of a healthy

• Too much insulin or too little carbohydrate

lifestyle and is discussed again in Chapter 13. It

is taken before exercise

brings a number of special considerations for people

• Exercise is prolonged (>30-60 min)

with type 1 diabetes because of the need to maintain

normal glucose concentration during exercise (Box

Glucose concentration will tend to remain

12.12). A reduction in insulin dose together with a

unchanged if:

snack before and during exercise may be needed.

• Exercise is short in duration or mild in

intensity

Monitoring diabetic control

• Appropriate snacks are eaten or insulin

adjustments are made before exercise

People with diabetes have to achieve a balance

between maintaining as near normal glucose con-

Glucose concentration will tend to increase if:

centration as possible to prevent the long-term

• Too little insulin or too much carbohydrate

complications of diabetes (see Chapter 14), while

is taken prior to exercise

preventing the acute complication of hypoglycae-

• The exercise is very intense: this occurs

mia (see below). As people with diabetes have lost

because high-intensity exercise increases

the normal homeostatic mechanisms to control

catecholamine (and cortisol) secretion,

glucose, it is necessary to monitor plasma glucose

which act as insulin antagonists

concentration to allow people with diabetes to

understand the nature of their disease and guide the

day-to-day adjustment of diabetes treatments.

Box 12.13 Methods of monitoring

Measurements of plasma glucose can be divided

glycaemic control

into short-term measures that provide an almost

instantaneous record of the current glucose concen-

Blood glucose (instant)

tration and long-term measures that provide an

• Intermittent capillary

assessment of average glucose concentration over

• Continuous monitoring

the preceding weeks or months (Box 12.13).

Integrated measures of long-term glycaemic

Capillary blood glucose monitoring

control (weeks, months)

)

• Glycated haemoglobin (HbA_1c

The availability of hand-held meters has allowed

• Fructosamine

people with diabetes to measure their capillary

blood glucose concentration themselves regularly

throughout the day wherever they are

(Figure

diabetes are usually advised to monitor their blood

12.11). Single blood glucose concentrations are of

glucose immediately pre-meal or approximately 2 h

little use because of their wide variability, but serial

after a meal between two and four times a day to

glucose measurements allow patterns to be recog-

assess the effectiveness of both basal and mealtime

nized and appropriate adjustment of insulin to be

bolus insulin. Although self-monitoring of blood

made according to the readings.

glucose is an important tool for achieving good

At present most blood samples are obtained by

glycaemic control, the principle that any investiga-

finger-prick but alternative site testing and non-

tion should lead to a change in management should

invasive methods are being developed. People with

be followed; therefore, if patients are unable or

Chapter 12: Type 1 diabetes / 273

Integrated measures of glycaemic

control

Glycated haemoglobin (HbA_1c) is a measure of inte-

grated glycaemic control over the preceding 2-3

months and reflects the mean lifespan of 117 days

of a normal red blood cell. Glucose becomes

attached to adult haemoglobin in a non-enzymatic

fashion that is dependent on the average concentra-

tion of blood glucose (see Figure 11.5).

The measurement and interpretation of HbA_1c

as the major longer term monitor of glycaemic

control has become the currency of most diabetolo-

gists’ daily work. The HbA_1c concentration corre-

Figure 12.11 Variety of meters used for self-

lates with the risk of development of microvascular

monitoring capillary blood glucose.

diabetic complications and clinical studies have

confirmed the direct benefits of lowering HbA_1c.

unwilling to adjust their insulin or diet then ‘testing

Target HbA_1c values are typically between 6.5% and

for testing’s sake’ should be discouraged

(Case

7.5% (48-58 mmol/mol), but this must be judged

history 12.3).

on an individual basis according to the patient’s

Urinary glucose can be used as a crude index of

clinical situation and risk of hypoglycaemia.

blood glucose but because of its lack of sensitivity,

Nevertheless HbA_1c has a number of limitations and

it should be a last resort.

so should be seen as just one of a number of tools

that can be used to improve the lives of people with

diabetes (Box 12.14). HbA_1c reduction is a means

Case history 12.3

to an end and not an end in itself.

Traditionally HbA_1c has been measured as a per-

A 47-year-old man who is being treated

centage of total haemoglobin. Until recently there

with soluble insulin three times a day and

was no international reference standard and conse-

isophane insulin before bed presents with

quently there are small numerical differences

the following set of blood results:

between assays. In order to allow comparison

between centres, the results from different assays

Before

Before Before

Before

are aligned to the results obtained during the

breakfast lunch evening

bed

Diabetes Control and Complications Trial. So,

meal

many laboratories report results as DCCT-aligned

Insulin

HbA_1c. Following the development of an interna-

dose

tional standard by the International Federation of

(units)

Clinical Chemistry and Laboratory Medicine

Home

4.0-7.8

2.3-5.2

9.4-13.0

5.0-7.8

(IFCC), it is possible to measure the quantity of

glucose

72-140

41-94

169-234

90-140

HbA_1c and so new results are being reported as

readings

mmol/mol. The conversion is shown in Table 12.5.

(mmol/L

In some countries, HbA_1c values are converted to

or mg/

provide a measure of estimated average glucose.

dL)

An alternative to HbA_1c is fructosamine which

is a measure of glycated serum proteins. It is an

What advice would you give?

index of glycaemic control over the previous 2-3

weeks, reflecting the shorter half-life of albumin

Answer, see p. 283

compared with haemoglobin. As HbA_1c assays have

274 / Chapter 12: Type 1 diabetes

Box 12.14 Limitations of HbA_1c

Table 12.5 IFCC and DCCT aligned values for

HbA_1c

Analytical variability

• Different methods for HbA_1c may give

Current DCCT aligned

IFCC HbA_1c

different results, but this has been largely

HbA_1c (%)

(mmol/mol)

addressed by reference method

4.0

standardization

5.0

• Molecular variants of haemoglobin:

^ Fetal haemoglobin

6.0

6.5

Biological variability

7.0

• Interindividual variability:

^ An individual with a mean glucose of

7.5

10 mmol/L (180 mg/dL) may have an

8.0

HbA_1c value which ranges from 6.0% to

9.0

9.0% (42-75 mmol/mol)

^ Probably reflects differences in the rates

10.0

of protein glycation

IFCC-HbA_1c (mmol/mol) = 

• Variation in erythrocyte lifespan:

[DCCT-HbA_1c(%) − 2.15] × 10.929.

^ Shortened lifespan can give spuriously

IFCC, International Federation of Clinical Chemistry and

Laboratory Medicine; DCCT, Diabetes Control and

low results

Complications Trial.

^ Haemolytic anaemia

^ Acute or chronic blood loss

^ Pregnancy

(40 mg/dL) used in the insulin tolerance test of

^ Diabetes may shorten lifespan of red

anterior pituitary function (see Table 5.4). It is the

blood cells

commonest side-effect of insulin therapy and the

major barrier to obtaining optimal glycaemic

Clinical variability

control. Most people with type 1 diabetes will expe-

• Predictive link between HbA_1c and clinical

rience several episodes of mild hypoglycaemia per

outcomes is not clear-cut

week and one to two severe episodes per year where

external help is needed. Hypoglycaemia is com-

moner in people with type 1 diabetes, where there

is absolute insulin deficiency, compared with type

improved, the use of fructosamine has declined and

2 diabetes. It occurs more frequently in young chil-

is only used rarely now; however, it may have a

dren and those receiving intensive insulin treatment

theoretical place in pregnancy, where changes in

to achieve tight glycaemic control.

average plasma glucose can occur rapidly, and in

Hypoglycaemia significantly affects the quality

those with haemoglobinopathies.

of life of people with type

1 diabetes. It may

put them at risk of harm, e.g. if they are driving

Acute metabolic emergencies

at the time, and may have physical health

consequences, e.g. cardiac arrhythmias and sudden

death. It is caused by inappropriate insulin action

Hypoglycaemia

and may result from hyperinsulinaemia or

Hypoglycaemia occurs when the blood glucose falls

an enhanced insulin effect. This may occur when

below 3.5 mmol/L (63 mg/dL). It is worth noting

there is poor matching of the insulin requirement

that this is a higher threshold for the day-to-day

to the person’s lifestyle

(Case history

12.4;

lives of people with diabetes than the 2.2 mmol/L

Box 12.15).

Chapter 12: Type 1 diabetes / 275

Case history 12.4

Box 12.15 Causes of

hypoglycaemia

A 35-year-old builder with well-controlled

• Excessive insulin administration:

type 1 diabetes was admitted to hospital

^ Error by doctor, pharmacist or person

with diarrhoea and vomiting. He was

with diabetes:

initially treated with intravenous fluids and

^ Dose

insulin but was subsequently changed

^ Type of insulin

back to his normal insulin regimen. The

^ Deliberate overdose as self-harm or from

doctors noticed that his normal doses

carer

were not controlling his glucose

• Unpredictable insulin absorption:

concentration adequately and so they

^ Insulin is absorbed more rapidly from

increased his doses substantially.

the abdomen

Two days after discharge, the man had

^ Lipohypertrophy

a severe hypoglycaemic episode and was

• Altered clearance of insulin:

admitted back to hospital.

^ Decreased insulin clearance in renal

failure

What is the most likely reason this man

• Decreased insulin requirement:

became profoundly hypoglycaemic on

^ Missed, small or delayed meals

discharge?

^ Alcohol:

Could this have been prevented?

^ Inhibits hepatic glucose output

^ Vomiting:

Answers, see p. 283

^ May occur with gastroparesis (a loss

of normal stomach motility; see

Chapter 14), a long-term complication

of diabetes

^ Weight loss

Physiological response to hypoglycaemia

^ Physical activity*:

In people without diabetes, the initial response to

^ Also increases rate of insulin

falling blood glucose is a decrease in pancreatic

absorption

insulin secretion. This occurs within the physiologi-

• Recurrent hypoglycaemia and

cal range of plasma glucose. As glucose concentra-

unawareness

tion falls below the normal range, secretion of the

insulin antagonist, glucagon, increases from the α-

*Not just exercise, such as sport; a common

cells of the pancreatic islets. At the same time, a

cause of hypoglycaemia is an increase in everyday

number of other insulin antagonists or ‘counter-

activity, e.g. from a new job.

regulatory’ hormones are released. The major ones

are norepinephrine

(noradrenaline), cortisol and

growth hormone (review Chapters 5 and 6).

with recurrent hypoglycaemia and longer duration

In diabetes these combined protective mecha-

of diabetes, the magnitude of the counter-regulatory

nisms are unavailable because of abnormal islet cell

hormone response and other sympathetic nervous

function or defective counter-regulatory hormone

system responses to hypoglycaemia become

secretion. The only circulating insulin comes from

diminished.

subcutaneous delivery that cannot be reduced in

response to hypoglycaemia. Once insulin has been

Symptoms and signs

given subcutaneously, the only way to prevent this

from entering the circulation is by surgical removal,

The physiological responses to hypoglycaemia

which is impractical in most situations. In addition,

produce a range of symptoms and signs that are

276 / Chapter 12: Type 1 diabetes

Table 12.6 Symptoms and signs of hypoglycaemia

Autonomic

Neuroglycopaenic

Non-specific

Sweating

Difficulty speaking

Nausea

Paraesthesia (pins and needles)

Loss of concentration

Hunger

Feeling hot

Drowsiness

Weakness

Shakiness

Dizziness

Anxiety

Hemiplegia

Palpitations

Fits

Pallor

Coma

Death (rare)

Figure 12.12

Onset of

Hypoglycaemia

autonomic

unawareness. The

symptoms

thresholds for

activation of

Onset of

hypoglycaemic

Onset of

brain

brain dysfunction

symptoms in

dysfunction

hypoglycaemic

Onset of autonomic

aware (normal) and

symptoms

unaware individuals

Coma/seizure

are shown.

Hypoglycaemia aware

Hypoglycaemia unaware

relieved by the restoration of plasma glucose con-

Under usual circumstances the development of

centration. The symptoms are important as they

autonomic symptoms precedes cognitive impair-

alert the individual to hypoglycaemia and prompt

ment. This is clinically important as it prompts

them to take corrective action. They can be divided

corrective action before cognitive impairment

into two main categories, autonomic and neuro-

begins; however, if these autonomic signals are

glycopaenic, although non-specific symptoms may

diminished and if the counter-regulatory hormone

be also be experienced (Table 12.6). Autonomic

response is reduced, awareness of hypoglycaemia

symptoms occur because of activation of both the

becomes impaired and the person is at risk of severe

adrenergic and cholinergic parts of the autonomic

hypoglycaemia (Figure 12.12).

nervous system, while neuroglycopaenic symptoms

result from inadequate glucose supply to the brain,

Treatment

leading to neurological dysfunction. Glucose is an

obligate fuel for the brain under physiological con-

Suspected hypoglycaemia should be treated imme-

ditions and the brain accounts for 50% of whole-

diately with oral glucose if possible. If the patient is

body glucose utilization. As the brain cannot

unconscious or unable to swallow safely, intramus-

synthesize or store glucose, it requires a constant

cular or subcutaneous glucagon or intravenous

supply of glucose from the circulation.

glucose can be administered. As glucagon causes

Chapter 12: Type 1 diabetes / 277

mobilization of hepatic glycogen stores when it is

Many factors can precipitate DKA. Infections

used to treat hypoglycaemia, these stores become

account for 30-40% of cases and new cases of dia-

diminished. So, once the patient is able to eat

betes for 10-20%. Other acute stressful illnesses,

longer-acting carbohydrate, it is also important that

such as myocardial infarction, may also trigger

they do so to replenish the glycogen stores.

DKA by increasing the production of counter-

The patient usually recovers within minutes,

regulatory hormones. Insulin errors, omissions and

after which it is important to ascertain the cause of

non-adherence are also common (15-30%) (Case

the hypoglycaemic episode to try to prevent this

history 12.6). A common mistake is for patients to

from happening in future.

stop insulin when they become unwell. Their appe-

If an individual with diabetes suffers from recur-

tite falls and they reduce the insulin in order to

rent hypoglycaemia or is experiencing ‘hypo’ una-

prevent hypoglycaemia; however, infection often

wareness, it is necessary to avoid hypoglycaemia.

increases insulin requirement, partly through the

This allows recovery of the counter-regulatory

insulin antagonistic actions of cytokines and corti-

hormone response and the patient to regain their

sol

(see Chapter 6). The challenge of matching

awareness of falling blood glucose

(Case history

insulin injection to calorie intake during illness may

12.5).

be complicated further by nausea and vomiting, and

admission may be needed for intravenous glucose

and insulin. The golden rule is never stop insulin.

Case history 12.5

A 28-year-old woman has recently tried

Case history 12.6

hard to improve her glycaemic control, but

unfortunately had a car accident when she

A 15-year-old girl with a 6-year history of

was hypoglycaemic. She mentions that

type 1 diabetes was admitted to hospital

her usual warning has disappeared and

following a short illness during which she

when you look at her glucose monitoring

had developed vomiting and general

records, you find she is having frequent

malaise. Her admission pH was 7.0,

‘hypos’.

plasma glucose 27.6 mmol/L (496 mg/dL)

and plasma ketones 5.2 mmol/L (5.6 mg/dL).

How can you help her?

She was treated appropriately and

discharged, but during the next few

Answer, see p. 284

months she was re-admitted with a similar

presentation on three separate occasions.

She had been previously well controlled

Diabetic ketoacidosis

with an HbA_1c of 7.2% (55 mmol/mol) but

Diabetic ketoacidosis is the most severe diabetic

had lost weight recently. When questioned

emergency and is still associated with a significant

she admitted that she had been feeling

mortality (∼1-2% in western countries, but par-

unhappy about her diabetes, not least

ticularly in developing countries where mortality is

because several of her schoolmates had

substantially higher). It is a state of severe uncon-

teased her about her weight.

trolled diabetes caused by insulin deficiency and

requires urgent treatment with insulin and fluids to

What was the diagnosis during her first

prevent death. DKA occurs more commonly in

admission?

younger people, but the mortality is higher in the

Why may this and the subsequent

elderly. It is estimated that 2-8% of hospital admis-

admissions have occurred?

sions in children occur because of DKA and there

are ∼5-8 episodes per year per 1000 people with

Answers, see p. 284

type 1 diabetes.

278 / Chapter 12: Type 1 diabetes

Liver

Stress homones

Adipose tissue

NEFA

HSL

Insulin

Ketone bodies

Insulin

Metabolic acidosis

Glucose

Hyperkalaemia

Kidney

Insulin

Osmotic diuresis

leads to

dehydration and

Skeletal muscle

electrolyte loss

Figure 12.13 Biochemistry of diabetic ketoacidosis.

acidosis leads to hyperkalaemia, a situation that is

Hormone-sensitive lipase (HSL) is sensitive to

worsened because insulin usually leads to transport

inhibition by insulin. Insulin deficiency leads to

of potassium into cells with glucose. Hyperglycaemia

activation of HSL and break down of adipose tissue

occurs because of a failure to inhibit hepatic glucose

triglyceride to non-esterified fatty acid (NEFA), a

output and a reduction in insulin-mediated glucose

process that is augmented by stress hormones. The

uptake. Renal gluconeogenesis is also increased.

NEFAs are transported to the liver where they are

This leads to an osmotic diuresis and profound

converted to acidosis-promoting ketone bodies. The

electrolyte loss.

esis is also enhanced in the presence of acidosis. The

Biochemistry

hyperglycaemia causes an osmotic diuresis and pro-

Diabetic ketoacidosis is characterized by hypergly-

found dehydration and loss of electrolytes. The

caemia, metabolic acidosis and hyperketonaemia

latter is worsened by the insulin deficiency which

(Figure 12.13).

impairs renal sodium re-absorption.

Hyperglycaemia - the ‘diabetic’ part of

Hyperketonaemia - the ‘keto’ part of

diabetic ketoacidosis

The absolute insulin deficiency usually leads to

The most important biochemical abnormality in

hyperglycaemia secondary to increased hepatic

DKA is uncontrolled lipolysis in adipose tissue and

glucose output and diminished peripheral insulin-

uncontrolled ketogenesis in the liver. Insulin is a

mediated glucose uptake. It should be noted that

potent inhibitor of the enzyme hormone-sensitive

DKA is predominantly caused by deranged lipid

lipase, which breaks down adipose triglycerides to

metabolism and therefore DKA may occur in

non-esterified fatty acids (NEFAs). By contrast, this

people with normal or only moderately elevated

process is accelerated by the presence of catabolic

glucose concentration.

counter-regulatory hormones. Consequently, the

Hyperglycaemia is accelerated by the presence

absence of insulin and increased counter-regulatory

of catabolic counter-regulatory stress hormones, in

hormones leads to a marked increase in lipolysis.

particular glucagon and catecholamines, but also

NEFAs are transported to the liver where they

growth hormone and cortisol. Renal gluconeogen-

are partially oxidized to acidic ketones bodies, such

Chapter 12: Type 1 diabetes / 279

as acetoacetic acid and 3-hydroxybutyric acid, and

Box 12.16 Clinical features of

acetone. This occurs because hepatic re-esterification

diabetic ketoacidosis

of NEFA to triglyceride is impaired in the absence

of insulin and presence of increased glucagon. The

• Polyuria and nocturia

ketone bodies are exported from the liver as an

• Thirst and polydipsia

alternative fuel supply, but build up in the circula-

• Nausea and vomiting

tion because of impaired uptake into peripheral

• General malaise and weakness

tissues such as muscle and brain secondary to lack

• Abdominal pain and leg cramps

of insulin. Plasma ketone body concentration is

• ‘Air hunger’ with Kussmaul breathing

commonly elevated 200-300 times above normal

(deep, sighing breathing)

fasting values.

• Odour of ketones on the breath (pear

drops or nail varnish remover)

• Altered conscious level

Acidosis - the ‘acidosis’ part of diabetic

• Postural hypotension and dehydration

ketoacidosis

Ketones bodies are strong organic acids that associ-

ate at physiological pH and generate a high concen-

tration of H⁺ ions. This rapidly exceeds the body’s

Box 12.17 Diagnosis of diabetic

buffering capacity and leads to severe metabolic

ketoacidosis

acidosis.

• Ketonaemia ≥ 3 mmol/L (31.2 mg/dL) or

In order to compensate for the acidosis, respira-

significant ketonuria (≥2 on standard urine

tory rate and depth increase (Kussmaul breathing)

sticks)

and ketone bodies may be smelt on the breath

• Blood glucose >11 mmol/L (200 mg/dL) or

(similar to nail varnish remover). Ketone bodies are

known diabetes mellitus

nauseating and many patients will vomit, worsening

• Bicarbonate (HCO3−) below 15 mmol/L

the dehydration and potassium loss. The metabolic

(15 mEq/L) and/or venous pH < 7.3

acidosis has a negative inotropic effect on the heart

and exacerbates peripheral vasodilatation. It may

also cause respiratory depression and contribute to

Making the diagnosis requires diabetes, ketosis

insulin resistance.

and acidosis (Box 12.17). Hyperglycaemia should

Metabolic acidosis leads to extracellular export

be determined by a blood sample. Ketosis can be

of potassium in exchange for hydrogen ions

detected by measuring urinary or blood ketones.

moving into the cell. This causes hyperkalaemia.

Previously, metabolic acidosis was always deter-

Insulin promotes the co-transport of potassium

mined by arterial blood gases, but the pH difference

along with glucose into cells. Thus, lack of insulin

between venous and arterial blood is only 0.02-

further exacerbates the hyperkalaemia. Significant

0.15 pH units and this is not of sufficient magni-

quantities of potassium are lost in vomit and urine.

tude to change either the diagnosis or subsequent

Therefore, although serum potassium may be ele-

management. A low venous plasma bicarbonate

vated, there is a severe whole-body potassium defi-

concentration provides further evidence of the

ciency. Potassium alterations may lead to cardiac

acidosis.

arrhythmias.

A common mistake is to describe a hyperglycae-

mic patient without ketosis as having DKA. These

two situations have different management strategies

Diagnosis

and therefore it is important to distinguish patients

Some patients’ first presentation of diabetes is DKA.

with DKA correctly.

The clinical features of DKA are similar to those of

At presentation, it is also important to measure

type 1 diabetes but tend to be more severe (Box

serum electrolytes to look for hyperkalaemia and to

12.16).

investigate the underlying cause of the DKA.

280 / Chapter 12: Type 1 diabetes

Management

and fluid and electrolyte deficiencies over the

next 24 h. It is important to treat the precipitating

The treatment of DKA is a medical emergency

cause.

and patients frequently require admission to an

The management of children differs from adults

intensive care unit or high-dependency ward

because of their increased risk of cerebral oedema;

with high clinical staff to patient ratios. It is impor-

it is particularly important to avoid too rapid fluid

tant to involve the diabetes specialist team at

replacement and overload.

the earliest opportunity. Treatment of DKA involves

Previously, guidelines for the management of

intravenous rehydration

(the most important

DKA have focused on lowering the elevated blood

first step), insulin administration and correction

glucose with fluids and insulin, together with the

of electrolytes. Treatment should be initiated

use of arterial pH and serum bicarbonate to assess

without delay with the overall goal of controlled,

the rate of metabolic improvement (Table 12.7). It

gradual correction of metabolic abnormalities

should be recognized, however, that the use of

Table 12.7 A management regimen for diabetic ketoacidosis

Fluid

Up to 10 L of fluid may be needed in the first 24 h:

1 L over first h

3 L over the next 6 h

1 L every 6-8 h depending on fluid deficit

Use isotonic (normal - 0.9%) saline

10% glucose (125 mL/h) should be administered once the blood glucose falls below 14 mmol/L

(~250 mg/dL) alongside the saline

More fluid may be needed if the patient is hypotensive on admission

Potassium replacement

On average, 40 mmol/L (40 mEq/L) KCl should be added to each litre of fluid depending on serum

potassium concentration. Saline with pre-added KCl reduces the chance of user-error

Plasma potassium

Potassium added

<3.5 mmol/L (<3.5 mEq/L)

↑ Fluid rate or ↑ KCl concentration (senior advice required)

3.5-5.5 mmol/L (3.5-5.5 mEq/L)

40 mmol/L (40 mEq/L)

>5.5 mmol/L (>5.5 mEq/L)

None

Insulin

Insulin should be given by continuous infusion at a dose of 0.1 unit/kg/h

Continue long-acting basal insulin analogue

Acidosis

50 mL 8.4% bicarbonate should only be given if there is severe acidosis (pH < 7.0) despite adequate

fluid and insulin replacement (senior advice required)

Other measures

Search for the precipitating cause

Insert nasogatric tube in those with impaired conscious level

Consider central venous pressure line, especially in the elderly or those with cardiac disease, to help

monitor circulatory status

Insert urinary catheter if no urine passed within 4 h to assess renal function accurately

Chapter 12: Type 1 diabetes / 281

blood glucose is only a surrogate marker for the

Box 12.18 Typical fluid and

underlying metabolic abnormality.

electrolytes losses in diabetic

The advent of bedside testing for blood ketones

(3β-hydroxybutyrate) allows timely and direct

ketoacidosis

monitoring of the metabolic abnormality and has

Water

100 mL/kg

led to modern guidelines moving away from the use

of glucose concentration to drive treatment deci-

Sodium

7-10 mmol/kg (7-10 mEq/kg)

sions in the management of DKA. The resolution

Chloride

3-5 mmol/kg (3-5 mEq/kg)

of DKA depends upon the suppression of ketonae-

mia; therefore, direct measurement of blood ketones

Potassium

3-5 mmol/kg (3-5 mEq/kg)

‘best practice’ for monitoring the treatment

response. If bedside ketone measurement is unavail-

able, bicarbonate concentration can be used to

Box 12.19 Crystalloids and

assess response during the first 6 h, although it may

colloids

be less reliable thereafter. Blood glucose monitoring

still remains an option.

• Crystalloids are aqueous solutions of mineral

salts or other water-soluble molecules

• Colloids contain larger insoluble molecules,

Fluid and electrolyte administration

such as gelatine; blood is also a colloid

Patients may lose up to 10% of their circulating

volume together with significant electrolytes (Box

12.18).

Dehydration in DKA may cause ‘pre-renal’ renal

The main aims of fluid and electrolyte replace-

failure, making it important to monitor urine

ment are:

output; otherwise potassium may accumulate,

leading to dangerous hyperkalaemia. There is debate

• Restoration of circulatory volume

about the need for a urinary catheter. As patients

• Promotion of ketone clearance

are significantly dehydrated on admission, it is

• Correction of the electrolyte imbalance.

unlikely that they will pass urine for several hours

Fluid should be replaced as crystalloid in the

after the initiation of fluid replacement. It therefore

first 24 h, but care should be taken not to overload

seems reasonable to delay the insertion of a urinary

the patient (Box 12.19); this is particularly impor-

catheter for up to 4 h. A central venous cannula may

tant in children, adolescents and the elderly, or

be required to monitor fluid balance in elderly

those with overt or incipient renal failure or heart

patients and those with cardiac disease.

failure.

Once insulin treatment is initiated, blood

Isotonic (normal, 0.9%) sodium chloride saline

glucose concentration will fall and care is necessary

has been used successfully for many decades, is

to prevent hypoglycaemia, which might precipitate

readily available in most clinical settings and comes

cardiac arrhythmias, acute brain injury and death.

pre-mixed with potassium (see below). Glucose and

Furthermore, it would increase secretion of counter-

compound sodium lactate (Hartmann’s solution) is

regulatory hormones that may prolong the ketosis.

an acceptable alternative, although potassium must

In order to prevent this, intravenous 10% glucose

be added to treat the potassium loss adequately.

should be initiated alongside the saline once the

DKA is associated with potassium depletion

glucose concentration has fallen below 14 mmol/L

despite the initial hyperkalaemia. As insulin is

(∼250 mg/dL).

administered, potassium concentration can fall pre-

Insulin replacement

cipitously and may cause a fatal cardiac arrhythmia

Insulin should be administered intravenously to:

if unaddressed. Therefore, serum potassium con-

centration is monitored and replaced once the

• Suppress ketogenesis

serum concentration has fallen below 5.5 mmol/L

• Reduce blood glucose

(5.5 mEq/L).

• Correct electrolyte imbalance.

282 / Chapter 12: Type 1 diabetes

A continuous intravenous insulin infusion

Box 12.20 Complications of

should be initiated at a rate of 0.1 units/kg/h as soon

diabetic ketoacidosis

as possible after the fluid replacement has been

started. Where the patient’s weight is not known,

• Cerebral oedema

this can be estimated. An initial loading dose is not

• Adult respiratory distress syndrome

needed unless there is considerable delay in setting

• Aspiration of vomit

up the infusion. Previously, the insulin dose was

• Thromboembolism

titrated according to the blood glucose

(the so-

called ‘sliding scale’). From a pragmatic perspective,

the fixed rate is simpler than the hourly dose adjust-

be continued until some form of background

ment and has been shown to be effective in the

insulin has been given and for at least 30-60 min

promotion of ketone clearance.

after the meal. For those on CSII, the basal pump

In recent years, the use of long-acting basal

rate should be re-introduced prior to discontinuing

insulin analogues has become widespread. It is rec-

the intravenous insulin infusion. For those on

ommended that these are continued during treat-

twice-daily mixed insulin, this should only be re-

ment of DKA as this will prevent rebound

introduced before breakfast or the evening meal.

hyperglycaemia when the intravenous insulin is dis-

continued and should reduce length of stay in

Complications

hospital.

Cerebral oedema is relatively uncommon in adults

Sodium bicarbonate

with DKA, but is more common in children (Box

Fluid and insulin replacement will frequently

12.20). It is potentially fatal and accounts for 70-

correct the acidosis and sodium bicarbonate should

80% of all deaths in children with DKA. The mech-

only be considered, with supervision by a senior

anisms responsible for the development of cerebral

doctor, if there is persistent acidosis (pH ≤ 7.0), as

oedema are unclear, but one possibility is cerebral

bicarbonate administration may worsen intracellu-

hypoperfusion with subsequent reperfusion. It is

lar acidosis. Sodium bicarbonate may also predis-

important to ensure that fluid replacement matches

pose to cerebral oedema, an important cause of

the patient’s losses as excessive fluid replacement

death in DKA. Repeat venous blood gas measure-

may be a further cause of cerebral oedema. If cer-

ment can be used to monitor resolution of the

ebral oedema occurs, intravenous mannitol and

acidosis.

mechanical ventilation may be used.

A common cause of death in patients with DKA

Transfer to subcutaneous insulin

is aspiration of vomit. A nasogastric tube should be

Unless there is good reason, the previous insulin

inserted to empty stomach secretions if the con-

regimen should be re-started once the acute meta-

scious level is impaired. Adult respiratory distress

bolic abnormality has been corrected and the patient

syndrome occasionally occurs in DKA. Features

is ready for a meal. It is important to know how to

include shortness of breath, central cyanosis and

do this and when to stop the intravenous insulin

hypoxaemia. The chest X-ray characteristically

infusion. Bolus insulin is given with the meal (either

shows bilateral infiltrates that resemble pulmonary

by subcutaneous injection or as part of a CSII

oedema. The management involves intermittent

regimen) and the intravenous insulin infusion

positive pressure ventilation and the avoidance of

should be continued until some form of basal

fluid overload.

insulin has been re-instituted. For those who

Thromboembolism is a further potentially fatal

remained on their long-acting basal analogue insulin

complication of DKA, which arises from dehydra-

during the episode of DKA, the insulin infusion

tion, increased blood viscosity and coagulability.

and fluids can be discontinued 30 min after the

The place of prophylactic anticoagulation remains

meal. If the long-acting insulin had been stopped,

controversial and routine anticoagulation is not

the intravenous insulin infusion and fluids should

recommended.

Chapter 12: Type 1 diabetes / 283

Key points

• Type 1 diabetes usually results from the autoimmune destruction of the β-cells in the islets of

the pancreas

• It accounts for approximately 10% of all cases of diabetes in the western world

• Treatment is based on insulin replacement as physiologically as possible

• Blood glucose concentration is determined by the previous insulin injection and so,

adjustment of insulin should be based more on the pattern of preceding blood glucose

reading rather than the current level

• Insulin treatment is not perfect and may result in hypoglycaemia if more is given than is

needed

• Diabetic ketoacidosis is the most serious acute complication of type 1 diabetes and is a

medical emergency

Answers to case histories

Case history 12.1

Case history 12.3

The most likely diagnosis is Addison disease,

Blood glucose readings are determined by

which is associated with type 1 diabetes (see

the previous insulin injection. Therefore,

Chapter 6 and Box 8.8). Tiredness, lethargy

satisfactory breakfast readings suggest that

and postural hypotension are symptoms of

his night-time insulin dose is fine. On a four

hypoadrenalism. Corticosteroids are insulin

times daily (basal bolus) regimen, getting the

antagonists; the onset of Addison disease is

breakfast glucose right is the key as this

commonly associated with increased

implies good control overnight and sets up a

frequency and severity of hypoglycaemia,

solid platform for the meal-time bolus

and necessitates a reduction in insulin dose.

injections. His readings are too low before

The increased skin pigmentation results from

lunch, implying he is taking too much soluble

loss of negative feedback from cortisol,

insulin before breakfast. Unless there are

causing overexpression of the POMC gene

major problems, it is usual to adjust the

and increased ACTH secretion, which

insulin doses by ∼10% and so, it would be

stimulates the type 1 melanocortin receptor.

sensible for him to reduce his breakfast

A short synacthen test is needed to confirm

insulin dose to 9 units. Readings before his

the diagnosis.

evening meal are too high, suggesting he is

taking too little soluble insulin before lunch. A

Case history 12.2

10% increase to 13-14 units would be

appropriate. His pre-bedtime readings are

The twice-daily regimen is not flexible

fine and so no adjustment is needed to the

enough for his lifestyle and so it would be

evening meal insulin injection.

appropriate to discuss whether he would like

to go onto a basal-bolus insulin regimen,

Case history 12.4

using four injections a day. This would give

more flexibility for the timing and quantity of

It is almost certain that this man became

food he can eat. A rapid-acting analogue

hypoglycaemic because the dose of insulin

may be better for him as this should be given

was left inappropriately increased after his

only 5-10 min before meals.

discharge from hospital. When the patient

286 / Chapter 13: Type 2 diabetes

■ Thiazolidinediones are a class of oral antidiabetes drugs that act through binding to a

nuclear hormone receptor; these receptors are described in detail in Chapter 3

■ One of the two main abnormalities in type 2 diabetes is pancreatic β-cell failure. An

understanding of normal insulin secretion is needed to appreciate the pathophysiology (see

Chapter 11)

Cross-reference

■ An overview of diabetes is given in Chapter 11

■ Dietary management plays an important part in the management of both type 1 and type 2

diabetes. Dietary management is discussed in greater detail in Chapter 12

■ Diabetes can lead to the development of a number of complications, which are discussed in

Chapter 14

■ The intrauterine environment may alter the risk of developing type 2 diabetes. The role of

steroids in fetal growth and development is described in Chapter 6

■ Sulphonylureas are a class of oral antidiabetes drugs. Some older sulphonylureas, such as

chlorpropamide, are associated with hyponatraemia because they increase the sensitivity of

the distal tubule to vasopressin (see Chapter 5)

■ Other antidiabetes drugs act by manipulating prolactin, which is discussed in Chapter 5

■ Incretins are hormones released by the gut in response to food ingestion. They augment

insulin release and include glucagon-like peptide-1 (GLP-1) and glucose-dependent

insulinotropic polypeptide (GIP). The physiology of these hormones is covered in Chapter 10.

Type 2 diabetes is the commonest type of diabetes,

Epidemiology

affecting around 285 million people worldwide. It

Type 2 diabetes accounts for around 90% of all

is a heterogeneous disorder and this chapter exam-

cases of diabetes in western Europe and the USA.

ines what causes type

2 diabetes and why it is

There are approximately

3 million people with

increasing at such an alarming rate. Although

diagnosed type 2 diabetes in the UK, with a further

insulin can be used to treat type 2 diabetes, many

800,000 estimated as having undiagnosed type 2

patients are treated with lifestyle modification alone

diabetes. The prevalence of diabetes is increasing

or in combination with oral antidiabetes drugs.

rapidly; the World Health Organization (WHO)

Some of these treatments have been used for over

has predicted that by 2030, the number of adults

50 years, but in the last 20 years there have been

with diabetes will have almost doubled worldwide,

major advances in the discovery of new drugs to

from 285 million in 2000 to 435 million. The

treat type 2 diabetes with some recently introduced

incidence of type 2 diabetes increases with age, with

and others in late phase III trials.

most cases being diagnosed after the age of 40 years.

This equates to a lifetime risk of developing diabetes

What is type 2 diabetes?

of 1 in 10. The demographics of type 2 diabetes are

Type 2 diabetes is a heterogeneous disorder that

changing, and it is now becoming increasingly

results from the interaction of genetic predisposi-

common in children and young adults. In certain

tion and environmental factors, creating a combina-

parts of the USA, the number of new cases of type

tion of insulin deficiency and insulin resistance

2 diabetes among teenagers is the same as for type

(Figure 13.1).

1 diabetes.

288 / Chapter 13: Type 2 diabetes

Table 13.1 Risk factors for type 2 diabetes

Table 13.2 Risk of developing type 2 diabetes

for UK relatives of people with type 2 diabetes

Unmodifiable

Environmental

Family member

Risk (%)

Family history - genetics

Obesity

Birth weight

Physical inactivity

Monozygotic twin

Ethnicity

Diet

Dizygotic twin

Age

Urbanization

Sibling

Past history of diabetes in

Sleep apnoea

Mother

15-20

pregnancy (gestational

diabetes)

Father

Both parents

Genetic predisposition

General population

The heritability of type 2 diabetes is greater than

for type 1 diabetes, and is estimated to account for

of diabetes can be attributed to obesity. In the UK,

40-80% of total disease susceptibility (Table 13.2).

the average body mass index (BMI) of a person with

Many patients have a family history of diabetes, and

type 2 diabetes is 30.0 kg/m², while in the USA,

monozygotic twin studies show a high concordance

67% of those with type 2 diabetes have a BMI of

rate

(60-90%). A maternal history of diabetes

greater than

27 kg/m², and

46% have a BMI

confers a higher risk of type 2 diabetes in the off-

of greater than 30 kg/m². The risk of developing

spring than a paternal history, possibly through an

type 2 diabetes increases across the whole range of

effect of maternal hyperglycaemia during preg-

BMI, such that the risk in a middle-aged woman

nancy. This may alter the intrauterine environment,

whose BMI is greater than 35 kg/m² is 93.2 times

which may in turn affect the risk of diabetes. This

greater than in a woman whose BMI is less than

is discussed further below.

22.5 kg/m² (Figure 13.3). Similar changes are also

Type 2 diabetes is a polygenic disorder

(see

seen in men.

Box 12.3), and it is clear that no single gene explains

In addition to total adiposity, the distribution

its inheritance. The advent of modern genetic

of fat is also important. For any given level of obesity,

research tools has led to the identification of several

the more visceral fat an individual has, the greater

polymorphisms in genes or nearby genes (e.g. in

their risk of developing diabetes. This is reflected

introns) that associate with increased risk of type 2

clinically by an increased waist circumference.

diabetes. Many of the genes are involved in the

The importance of obesity is discussed further

control of insulin secretion and action, or appear

in Chapter 15.

to be linked to β-cell proliferation (Table 13.3).

Other chromosomal loci have been linked with

increased risk of diabetes (review Chapter 2 for gene

Physical inactivity

and chromosomal structure).

Physical inactivity is also associated with an incr

eased risk of diabetes. People who exercise for

around 30 min/day have half the risk of developing

Environmental factors

diabetes compared to those with a sedentary lifestyle.

The most important environmental risk factors for

Although some of the difference can be explained

diabetes are obesity and physical inactivity.

by differences in adiposity, exercise itself accounts

for approximately half of the effect.

Obesity

The massive explosion in obesity rates worldwide

Intrauterine environment

has largely been responsible for the increase in dia-

The intrauterine environment is important for the

betes; it is estimated that up to 80% of all new cases

development of type 2 diabetes. Low birth weight

Chapter 13: Type 2 diabetes / 289

100

Table 13.3 Gene and chromosomal loci linked

93.2

with the development of type 2 diabetes

Specific genes

INSULIN (promoter region)

Peroxisome proliferator-activated receptor γ

KCNJ11 - encoding part of β-cell K⁺-ATP

channel

Insulin receptor substrate 1 (IRS-1)

40.3

Adiponectin

27.6

Ectonucleotide pyrophosphatase/

phosphodiesterase 1 enzyme (ENPP1)

15.8

TCF7L2 and HHEX - both encoding

8.1

transcription factors

4.3

2.9

SLC30A8 - encoding the zinc transporter ZnT8

CDKAL1 - encoding CDK5 regulatory subunit-

associated protein 1

IGF2BP2 - encoding a regulatory protein for

Body mass index (kg/m²)

IGF-2

Chromosomal regions

Figure 13.3 Risk of developing diabetes according

to body mass index in 114,281 women enrolled in

Chromosome 1

q21-q25.3

the US Nurses Health Study. Adapted from Colditz

Chromosome 2

q24.1-q31.1

GA et al. Ann Intern Med 1995;122:481-6.

q35-q37.3

Chromosome 3

q27-q29

Chromosome 6

q23.1-q24.1

Chromosome 8

p23.3-p12

the relationship between birth weight and subse-

Chromosome 9

q21.11-q21.31

quent risk of diabetes appears to be J-shaped.

Chromosome 10

q25.1-q26.3

Chromosome 14

q11.2-q21.1

Ageing

Chromosome 17

p13.3-q11.2

The changing world demographics with its ageing

Chromosome 18

p11.32-p11.21

population add a further explanation for the increase

Chromosome 19

p13.3-p13.12

in diabetes as the prevalence increases with age.

q13.32-q13.43

Chromosome 20

q11-q13.32

Pathogenesis

Chromosome 22

q11.1-q12.3

Under normal physiological conditions, plasma glu

cose concentrations are maintained within a narrow

range, despite wide fluctuations in supply and

demand, through a tightly regulated and dynamic

and thinness at birth are associated with increasing

interaction between tissue sensitivity to insulin

insulin resistance and diabetes in the offspring. In

(especially in the liver) and insulin secretion. In type

contradiction to this general observation, it appears

2 diabetes, both of these mechanisms break down

that babies born to mothers with diabetes are also at

with impaired insulin secretion through pancreatic

increased risk of diabetes, despite the fact that these

β-cell dysfunction and impaired insulin action

babies often have a high birth weight. Consequently

through insulin resistance (Box 13.1).

290 / Chapter 13: Type 2 diabetes

Box 13.1 What are insulin

Box 13.2 Consequences of insulin

sensitivity, insulin responsiveness

resistance

and insulin resistance?

Skeletal muscle

Insulin sensitivity reflects the biological effect

• Reduced insulin-mediated glucose uptake

of insulin at any given insulin concentration

and can be measured in a number of ways

Adipose tissue

to provide a dose response curve

• Failure to suppress lipolysis, leading to

increased circulating NEFA

Insulin responsiveness refers to the ability of

insulin to exert a maximal response.

Liver

• Reduced ability to inhibit hepatic glucose

Insulin resistance may be defined as existing

output

when normal insulin concentrations fail to

• Increased NEFAs stimulate

produce a normal biological response.

gluconeogenesis and glucose production,

and triglyceride synthesis

Vasculature

Insulin resistance

• Impaired endothelial function

• Increased stiffness of arteries

Insulin resistance, defined as the inability of

• Increased coagulability

insulin to produce its usual biological effects at

physiological concentrations, is a cardinal feature of

Increased sympathetic tone

type 2 diabetes (Box 13.1). It is characterized by an

• Through insulin action on the

impaired ability of insulin to inhibit hepatic glucose

hypothalamus

output and to stimulate glucose uptake into skeletal

muscle. Insulin also fails to suppress lipolysis in

Hyperuricaemia

adipose tissue, resulting in increased plasma non-

• Insulin reduces renal uric acid clearance

esterified fatty acids (NEFAs) (Box 13.2).

and this action is preserved even in the

The mechanisms leading to the development of

presence of insulin resistance.

insulin resistance are not fully understood, but may

Consequently, as insulin concentration

occur at many levels of insulin signalling (Box 13.3;

increases to meet the insulin resistance,

review tyrosine kinase-mediated signalling in

uric acid clearance falls to below normal

Chapter 3; Figure 3.6). It would appear that in type

2 diabetes, most insulin resistance is caused by

defects in post-receptor signalling.

is an integral component of the pathogenesis of type

2 diabetes.

Normal insulin secretion is biphasic in response

β-Cell dysfunction

to glucose stimulation

(review Chapter

11); an

Insulin resistance does not explain the whole story

acute first phase lasts a few minutes, followed by

because people with type 2 diabetes are no more

a sustained second phase. The major β-cell abnor

insulin resistant than the most insulin resistant

malities in type 2 diabetes are a marked reduction

quartile of the general population. Indeed, only

in first-phase insulin secretion and, in established

∼20% of those with this degree of insulin resistance

diabetes, an attenuated second phase (Figure 13.4).

develop diabetes. Abnormalities in β-cell function

By the time of diagnosis, mean β-cell function

are found early in the natural history of type 2

is already <50%, and it deteriorates further (∼4%/

diabetes and in first-degree relatives of people with

year) after diagnosis. Extrapolation from these data

type 2 diabetes, suggesting that β-cell dysfunction

suggests that loss of β-cell function begins at least

Chapter 13: Type 2 diabetes / 291

Box 13.3 Potential mechanisms

(a)

Main meals

of insulin resistance (review

800

Normal

Figure 3.6)

700

Type 2 diabetes

600

Absent or reduced number of insulin

500

receptors

400

• High circulating insulin concentration

300

reduces the number of receptors present

200

on the cell surface (down-regulation)

100

0600

1000

1400

1800

2200

0200

0600

Abnormal insulin receptor

Clock time (h)

• Failure of insulin to bind to the insulin

(b)

receptor

Normal

Type 2 diabetes

120

20g

20g glucose

• Failure of insulin binding to activate the

100

glucose

100

insulin receptor:

° No autophosphorylation

° No activation of tyrosine kinase

• Evidence for both the above points comes

-30 0

30 60 90 120

-30 0

30 60 90 120

from loss-of-function mutations of the

Time (min)

insulin receptor causing diabetes from

Figure 13.4 (a) Endogenous insulin secretion in

early life (see Box 3.4)

type 2 diabetes and under normal conditions

throughout a 24-h period. Re-drawn from O’Meara

Post-receptor signalling

NM et al. Am J Med 1990;89:11S-16S. (b) Loss of

• Down-regulation, deficiencies or subtly

early-phase insulin release in type 2 diabetes. The

lowered function from genetic

first abnormality of insulin secretion seen in type 2

polymorphisms of post-receptor signalling

diabetes is loss of the first-phase response. This is

molecules, such as tyrosine

compensated for by an exaggerated second-phase

phosphorylation of the insulin receptor,

response, which can cause hypoglycaemia 3-4 h

insulin receptor substrate (IRS) proteins or

after a meal. With time, second-phase insulin

phosphatidylinositol-3 (PI-3) kinase

secretion is also lost. Re-drawn from Ward WK et al.

Diabetes Care 1984;7:491-502.

Abnormalities of GLUT-4 translocation and

function

ing obesity, and hyperglycaemia and hyperlipidae-

mia may all accelerate the decline in β-cell function.

Accumulation of skeletal muscle triglyceride

Early-life malnutrition seems likely to programme

• So-called ‘lipotoxicity’

a diminished total β-cell number; one potential

mechanism for this is through excessive intrauterine

a decade prior to the diagnosis. The progressive

glucocorticoid levels (see Chapter 6).

decline also explains why people with diabetes find

There has been much discussion about the rela-

it increasingly hard to control their hyperglycaemia

tive roles of insulin resistance and loss of β-cell

with time and require escalations in the number and

function in the natural history of type 2 diabetes,

doses of oral antidiabetes agents, and why eventu-

since both components occur early in the disease

ally they become refractory to oral treatment and

process. One model for the development of diabetes

require insulin.

is as follows

(Figure 13.5). As insulin sensitivity

The mechanisms underlying β-cell dysfunction

falls, β-cell insulin secretion increases to compen-

appear multifactorial (Table 13.4). As well as genetic

sate and to maintain glucose concentrations within

factors, a number of environmental factors, includ-

the normal range. The maximal insulin secretory

292 / Chapter 13: Type 2 diabetes

glucose tolerance will progress to diabetes each year,

Table 13.4 Possible mechanisms of β-cell

many revert to normal. Intensive lifestyle interven-

decline and dysfunction

tion at this stage can reduce incident diabetes and

so people falling into these categories should be

Innate

Acquired

managed actively with advice about their diet and

Genetics

Glucose toxicity

exercise. Bariatric surgery to treat morbid obesity

In utero malnutrition

Lipotoxicity

may have a dramatic effect on this process (see

Chapter 15). Glucose tolerance often returns to

Obesity

normal following surgery, even in those who require

Hormonal:

insulin to treat their diabetes. Part of this effect is

• Inadequate incretin*

mediated by the dramatic loss of weight, but

stimulation

changes in glucose metabolism precede weight loss,

• Increased glucagon

suggesting a more acute effect, possibly mediated by

secretion

gut hormones.

*Incretins are hormones released by the gut in response

to food ingestion. They augment insulin release and

include glucagon-like peptide-1 (GLP-1) and glucose-

Prognosis

dependent insulinotropic polypeptide (GIP) (see Chapter

10). Drugs that mimic or augment the action of these

Type 2 diabetes is associated with premature mor-

hormones are used for the treatment of type 2 diabetes.

tality,

predominantly through cardiovascular

disease. Even after adjustment for other cardiovas-

cular risk factors, diabetes is associated with a two-

to three-fold increase in the risk of myocardial

Diagnosis

Post-prandial

infarction or stroke. Cardiovascular complications

glucose

300

Fasting glucose

are discussed in greater detail in Chapter 14.

Insulin resistance

200

Clinical features

100

Insulin concentration

Type 2 diabetes has a gradual and insidious onset,

-10 -5 0 5 10 15 20 25 30

with nearly one-third of cases identified as an

Years

incidental finding or following cardiac ischaemic

events, e.g. when an asymptomatic individual

Figure 13.5 Natural history of insulin resistance and

suffers a myocardial infarction. The diagnosis is

insulin secretion in type 2 diabetes. As insulin

often delayed, and some degree of hyperglycaemia

sensitivity falls, the β-cell compensates by increasing

may have been present for more than 20 years

insulin secretion to maintain glucose concentrations

before the diagnosis is confirmed. In the early

in the normal range. Maximal insulin secretion is

2000s, it was said that there was a ‘missing million’

eventually reached and, beyond that point, insulin

secretion declines. Blood glucose concentration

in the UK, reflecting the number of people with

rises, initially in the post-prandial period as the

undiagnosed diabetes (Figure 13.6). With greater

individual develops impaired glucose tolerance

awareness of the problem and government incen-

before the onset of diabetes.

tives to find people with undiagnosed diabetes, this

number has fallen to

∼800,000, despite overall

capacity is eventually reached and, beyond that

increasing numbers of people with diabetes.

point, insulin secretion declines. As insulin secre-

However, the proportion of people with undiag-

tion starts to fall, plasma glucose concentrations

nosed diabetes around the world remains unaccept-

rise, initially in the post-prandial period, as the indi-

ably high, with varying proportions of undiagnosed

vidual develops impaired glucose tolerance before

cases depending on the provision of local health

the onset of frank diabetes.

services. It has been estimated from the

2002

This process may, however, be reversible.

NHANES survey that one-third of the 13.3 million

Although

2-5% of individuals with impaired

US adults with diabetes were undiagnosed.

Chapter 13: Type 2 diabetes / 293

4.5% Diabetes

Box 13.4 Precipitating causes of

hyperosmolar hyperglycaemic

16.8% Impaired

state

glucose tolerance

• Infection

• Myocardial infarction

• Drugs:

° Diuretics

° Steroids

° Omission of oral hypoglycaemic drugs

78.7%

Normal

Hyperosmolar hyperglycaemic state may be

complicated by thromboembolism or rhabdomy-

Figure 13.6 Prevalence of undiagnosed glucose

olysis. The management is similar to the treatment

intolerance from the Isle of Ely Diabetes Project.

of DKA with fluid and electrolyte replacement and

1122 people aged 40-65 years without known

diabetes from one primary care setting underwent a

intravenous insulin. Heparin is usually adminis-

standard 75-g oral glucose tolerance test (review

tered because of the high risk of thromboembolic

Chapter 11; Box 11.3; Table 11.4) and were

events. Despite the dramatic presentation, follow-

classified according to WHO criteria. Williams DR

ing correction of the metabolic abnormalities, many

et al. Diabet Med 1995;12:30-5.

people may only require treatment with lifestyle

modification.

Around 50% of people with type 2 diabetes are

Prevention of diabetes

diagnosed as a result of the typical diabetic symp-

toms of polyuria, nocturia, thirst, tiredness and

One of the most exciting areas in diabetes at present

blurred vision, although these tend to be less dra-

is the possibility that type

2 diabetes can be

matic than in people with type 1 diabetes; a further

prevented or at least delayed by lifestyle and/or

16% of people are diagnosed after presenting with

pharmacological interventions (Case history 13.1).

an infection.

Case history 13.1

Hyperosmolar hyperglycaemic state

Hyperosmolar hyperglycaemic state, formerly

A 35-year-old woman developed

known as hyperosmolar non-ketotic coma, is a

gestational diabetes during her third

medical emergency and is characterized by hyperg-

pregnancy, which required treatment with

lycaemia, dehydration and uraemia without signifi-

insulin. She has a strong family history of

cant ketosis or acidosis. It occurs in middle aged or

diabetes and was significantly overweight

elderly people with type 2 diabetes and may be the

(BMI 28.2 kg/m²) prior to her pregnancy.

presenting feature in around 25% of individuals.

Afro-Caribbean individuals appear to be at a higher

What advice and treatment would you

risk of developing hyperosmolar hyperglycaemic

offer her?

state (Box 13.4). It is the type 2 diabetes equivalent

of diabetic ketoacidosis (DKA) in type 1 diabetes

Answer, see p. 309

(see Chapter 12); the biochemical differences occur

because small quantities of insulin remaining in

type 2 diabetes are able to suppress lipolysis and the

Lifestyle intervention aimed at reducing weight,

ensuing acidosis. It occurs less frequently than DKA

the amount of fat, in particular saturated fat, in the

but has a higher mortality rate (∼15%).

diet, while increasing the amount of dietary fibre

294 / Chapter 13: Type 2 diabetes

and daily physical activity, has been shown in several

Box 13.5 Groups who should be

countries to reduce new cases of type 2 diabetes by

considered for primary prevention

a half over a 3-year period. Public health policies

are urgently needed to encourage people to follow

programmes and who should be

this healthy lifestyle and prevent the development

screened for diabetes

of diabetes. Primary prevention strategies should

• White people aged over 40 years and

target individuals at especially high risk of develop-

people from black, Asian and minority

ing type 2 diabetes (Box 13.5).

ethnic groups aged over 25 years with one

In addition to lifestyle intervention, several

or more of the following risk factors:

drugs have been shown to reduce diabetes (Box

° First-degree family history of diabetes

13.6), but at present the place of pharmacological

and/or

therapy in the prevention of diabetes is not clear.

° Overweight/obese/morbidly obese

The American Diabetes Association

(ADA),

(BMI* ≥ 25 kg/m²) and/or

however, endorses the use of metformin in younger

° Sedentary lifestyle and/or

individuals who are at very high risk of developing

° Waist measurement:

diabetes.

☐

≥94 cm (≥37 inches) for white and

black men

☐

≥80 cm (≥31.5 inches) for white, black

Screening for diabetes

and Asian women

☐

≥90 cm (≥35 inches) for Asian men

The high prevalence of undiagnosed diabetes and the

• People who have ischaemic heart disease,

proportion of patients with evidence of complications

cerebrovascular disease, peripheral

at diagnosis create a strong imperative for screening

vascular disease or treated hypertension

(Figure 13.7). Many possible screening methods have

• Women who have had gestational

been shown to be feasible, acceptable and accurate,

diabetes

but there is still debate about whom to screen.

• Women with polycystic ovarian syndrome

Universal screening for diabetes is currently

who have a BMI ≥ 30 kg/m²

impractical because of the burden that would be

• People known to have impaired glucose

placed upon primary care, but there is justification

tolerance or impaired fasting glycaemia

for screening of high-risk groups in whom undiag-

• People who have severe and enduring

nosed diabetes is common (see Box 13.5).

mental health problems

Although the oral glucose tolerance test is rela-

• People who have hypertriglyceridemia

tively simple and inexpensive and is the gold stand-

not caused by alcohol excess or renal

ard test for diabetes, it is not suitable for routine

disease

screening because of the overall cost and inconven-

ience. A fasting plasma glucose has been endorsed

*Though more accurate than body weight alone,

by the WHO, ADA and Diabetes UK as a suitable

body fat may be overestimated by BMI in people

test for screening. This test is more convenient than

who are very muscular or underestimated in those

the oral glucose tolerance test but lacks sensitivity

who have lost muscle mass.

and may miss a large number of individuals with

The more risk factors that a person has, the

diabetes (Table 13.5).

higher the risk of diabetes; however, just being

Although a random plasma glucose measure-

over 40 years if white or over 25 years if black,

Asian or other ethnic origin is not necessarily a risk

ment may be unreliable, it does have certain merits.

factor in itself.

It is easy to perform and has reasonable sensitivity

Several diabetes risk scores, such as FINDRISK,

and specificity. As glycated haemoglobin (HbA_1c)

have been developed to improve the identification

has been endorsed by the WHO and ADA as a

of high-risk individuals.

diagnostic test for diabetes, this is an alternative easy

method of screening and diagnosis in countries

Chapter 13: Type 2 diabetes / 295

Box 13.6 Measures to reduce the

10 years

incidence of diabetes

Cardiovascular

Lifestyle

complications

• ↓ Weight by 5% (ideally to BMI < 25 kg/m²)

• ↓ Fat intake to <30% of energy intake

Onset of diabetes

• ↓ Saturated fat to <10% of energy intake

Onset of

• ↑ Fibre to >15 g/1000 g

symptoms

• Take at least 30 min/day of aerobic and

muscle strengthening exercise

Microvascular

complications

Pharmacological

Time

• Metformin

• Orlistat (intestinal lipase inhibitor)

Figure 13.7 The imperative for screening for type 2

• Acarbose (α-glucosidase inhibitor)

diabetes. It is estimated that many patients have

• Pioglitazone (thiazolidinedione)

diabetes for up to a decade before the onset of

• Blockade of the renin-angiotensin system

symptoms. However, diabetic complications can

(conflicting results):

progress during this period in asymptomatic

individuals. For example, approximately 20% of

° ACE inhibitors

people with newly diagnosed diabetes have

° Angiotensin receptor blockers

retinopathy at presentation and diabetes is frequently

These drugs will be considered in greater

diagnosed following myocardial infarction.

detail in the section on treatment of diabetes.

Randomized clinical trials (RCTs) have shown

that the first four drugs can reduce diabetes

but with a lesser effect than lifestyle

intervention. Post-hoc analysis suggested

that blockade of the renin-angiotensin system

may reduce diabetes but RCTs over the past

5 years have not confirmed this.

Table 13.5 Comparison of screening tests for

diabetes

Test

Specificity

Sensitivity

(%)*

(%)**

where this test is available; the limitations of HbA_1c

Fasting plasma

84-99

40-95

are shown in Box 12.14.

glucose

Screening for diabetes should be undertaken

within the community where possible. Many

Random

92-98

50-69

primary healthcare services are overstretched and

plasma

other settings may be required; e.g. an increasing

glucose

number of pharmacists in the UK are offering screen-

Glycated

79-100

35-98

ing using random blood glucose. Individuals

haemoglobin

with type 2 diabetes who are identified by any

(HbA_1c)

screening procedure differ from those who present

*Specificity: the probability that the screening test is

symptomatically. They are less likely to have estab-

negative if the person does not have diabetes. This is

lished diabetic complications and attitudes to health

also known as true negative rate.

may differ as the diagnosis is less expected. This

**Sensitivity: the probability that the screening test is

has implications for the future management of

positive if the person has diabetes. This is also known as

the true positive rate.

diabetes.

296 / Chapter 13: Type 2 diabetes

Management

people with type 2 diabetes are overweight or obese

and, therefore, their diet should have a moderate

The aims of managing type 2 diabetes are similar

calorie deficit to facilitate weight loss (Case history

to those of type 1 diabetes. Life-threatening diabetes

13.2). The management of obesity is covered in

emergencies, such as hypoglycaemia and hyperos-

greater detail in Chapter 15.

molar hyperglycaemic state, should be managed

effectively and ideally prevented. Symptoms of

hyperglycaemia, such as polyuria and polydipsia,

Case history 13.2

need to be addressed. In practice, these two aspects

of care occupy only a minority of the work under-

A 56-year-old office manager presented with

taken by diabetes healthcare professionals. The bulk

thirst, polyuria and tiredness. He admits to

of care is aimed at minimizing the long-term com-

drinking large quantities of Coca-Cola. He

plications through screening and working together

weighs 90 kg. His fasting blood glucose is

with the person with diabetes to support improved

10.0 mmol/L (180 mg/dL) and post-prandial

glycaemic control and cardiovascular risk factor

glucose is 25.6 mmol/L (461 mg/dL).

management.

Target HbA_1c levels are

∼6.5-7.5%

(48-

How would you manage this scenario?

58 mmol/mol), but these must be individualized to

Would you consider drug therapy at this time?

prevent iatrogenic side-effects of treatment (further

Answers, see p. 309

details later in this chapter and in Chapter 14).

Management of type 2 diabetes is a particular

challenge when the person has no symptoms; self-

care often requires marked lifestyle changes and

Physical activity

medications that place a considerable burden on the

People with diabetes should be encouraged to take

individual with diabetes. This includes potential

moderate exercise for at least 30 min/day to improve

side-effects, such as hypoglycaemia. As people with

glycaemic control and reduce cardiovascular risk

diabetes commonly have limited contact with

(Box 13.7). The best exercise is the one that the

healthcare professionals, it is paramount that they

person enjoys and will still be willing and able to

are involved in planning their diabetes care.

undertake many years after the diagnosis. Both

Type 2 diabetes is treated using a step-wise

aerobic and strength training are beneficial; however,

approach, starting with lifestyle modification,

physical activity is not equivalent to sport and prac-

which includes dietary changes and an increase in

tical advice should be given to help the person with

daily physical activity. These remain the cornerstone

diabetes become more physically active. Examples

of management even when treatment escalates to

include using public transport to work, alighting

include oral antidiabetes agents, initially alone but

one stop early and walking the extra distance, and

subsequently in combination. Later, injectable

using stairs rather than lifts or escalators

(Table

treatments with either long-acting glucagon-like

15.4). However, take care when advising individuals

peptide-1 (GLP-1) receptor agonists or insulin may

with peripheral neuropathy to ensure that they wear

be added to the treatment regimen.

Box 13.7 Benefits of exercise

Diet

• Improved insulin sensitivity even without

The principles of dietary changes to be adopted by

weight loss

a person with type 2 diabetes are identical to those

• Reduced blood glucose

for type 1 diabetes (Box 12.11). In brief, patients

• Reduced blood pressure

should reduce the amount of refined sugar and fat,

• Improved lipid profile

particularly saturated fat, while increasing the pro-

• Increased longevity

portion of complex carbohydrate and fibre. Many

Chapter 13: Type 2 diabetes / 297

natural fibres and well-fitting shoes to reduce the

• Inhibitors of glucose absorption from the gas-

risk of foot ulceration.

trointestinal tract:

° Acarbose

• Incretin-based therapies:

Oral antidiabetes agents

° Dipeptidyl peptidase-4 (DPP-4) inhibitors.

When diet and exercise fail to maintain normogly-

Drugs from different categories can be com-

caemia, oral antidiabetes agents are required along-

bined if needed as the diabetes progresses.

side, but not instead of, lifestyle management.

Several antidiabetes agents increase residual insulin

secretion and can only be used in type 2 diabetes as

Insulin secretagogues

they are ineffective in people with established type

1 diabetes where β-cells have been destroyed.

Insulin secretagogues, such as sulphonylureas and

There are currently four main categories of oral

meglitinides, stimulate insulin release from the pan-

agents

(Figure

13.8), although new drugs with

creas. Other than generic safety issues, the specific

novel mechanisms of action are being developed:

properties of the ideal insulin secretagogue are as

follows:

• Insulin secretagogues:

• Rapid restoration of early-phase insulin release to

° Sulphonylureas

reduce post-prandial glucose excursions

° Meglitinides

• Insulin sensitizers:

• Plasma insulin should be returned to pre-prandial

levels as soon as possible to prevent hypoglycaemia

° Metformin

between meals

° Thiazolidinediones (‘glitazones’)

Figure 13.8 Main sites of action for

Pancreas

antidiabetes agents. Different

Gliptins

(DPP4

Sulphonylureas

antidiabetes drugs target distinct

inhibitors)

meglitinides

sites as part of their primary

Incretins

mechanism for reducing

hyperglycemia. Sulphonylureas and

Intestine

meglitinides stimulate pancreatic

Insulin

Liver

insulin release. Biguanides such as

metformin primarily suppress

Metformin

hepatic glucose output. α-

Glucosidase inhibitors (acarbose)

Muscle

delay digestion and absorption of

Glitazones

carbohydrates in the gastrointestinal

Alpha-

tract. Thiazolidinediones

glucosidase

(‘glitazones’) decrease insulin

inhibitors

resistance in adipose tissue, skeletal

Adipose tissue

muscle and liver. Dipeptidyl

peptidase-4 (DPP-4) inhibitors

Blood

increase the concentration of

glucose-lowering

endogenous incretin hormones.

Reproduced from Holt RIG et al.,

eds. Textbook of Diabetes: A Clinical

Lifestyle

Approach, 4th edn. Oxford:

diet, exercise

Wiley-Blackwell, 2010, Chapter 29.

298 / Chapter 13: Type 2 diabetes

• Suitable for use in combination with treatments

poorly controlled diabetes, energy expenditure

for insulin resistance.

increases through glycosuria and an increase in basal

metabolic rate. As glycaemic control improves,

Sulphonylureas (Table 13.6)

energy expenditure decreases with the reduction in

The hypoglycaemic effects of sulphonamide antibi-

glycosuria and basal metabolic rate. Unless the

otics were first recognized during a typhoid epi-

person increases voluntary energy expenditure (by

demic in Marseilles, France in 1942. Following this

increasing physical activity) or reduces caloric

observation, further work led to the development

intake, weight gain is inevitable. As such, weight

of sulphonylureas to treat diabetes, the first agent

gain may occur with any antidiabetes agent, but

being carbutamide in 1955.

appears to be particularly marked with sulphonylu-

reas, thiazolidinediones

(‘glitazones’) and insulin.

Mechani\sm of action

Weight gain with sulphonylureas and insulin may

Sulphonylureas act mainly by increasing insulin

result from hyperinsulinaemia between meals as

release from the pancreatic β-cells (see Figure 11.9).

increased food intake may be needed to prevent

Following binding to the sulphonylurea receptor,

hypoglycaemia.

SUR1, the K⁺-ATP channel, KIR6.2, in the cell

Associated with this, the second major side-

membrane closes, leading to a rise in intracellular

effect of sulphonylureas is hypoglycaemia, which

calcium and insulin release (review Chapter 11).

occurs in 0.2 episodes per 1000 patients/year and

The in vivo potency of sulphonylureas approximates

occurs because the drug prevents the normal physi-

to their ability to inhibit the K⁺-ATP channel in

ological reduction in insulin secretion when blood

vitro. Although there is individual variability,

glucose concentration falls. Patients with severe

sulphonylureas tend to reduce HbA_1cby ∼1.5-2.0%

hypoglycaemia on sulphonylureas may need admis-

(16-22 mmol/mol).

sion to hospital for up to 48 h for observation and

glucose support until the drug has cleared from the

Side-effects

circulation. Hypoglycaemia is a particular worry in

The commonest side-effect of sulphonylureas is

the elderly in whom drug clearance is reduced

weight gain (Box 13.8). When an individual has

and the signs of hypoglycaemia may be masked.

Table 13.6 Properties of different sulphonylureas

Drug

Half-life

Duration of action

Route of elimination Active metabolite

First generation

Acetohexamide

Medium

Hepatic

Chlorpropamide

Very long

Hepatic and renal

Tolazide

Short

Medium

Hepatic

Tolbutamide

Short

Short/medium

Hepatic

Second generation

Glibenclamide

Very short

Long

Hepatic

Gliclazide

Medium

Hepatic

Glipizide

Very short

Short/medium

Hepatic

Gliquidone

Long

Hepatic

Glimepiride

Short

Medium/long

Hepatic

With the exception of tolbutamide, first generation sulphonylureas are scarcely used today. Glibenclamide, gliclazide and

glimepiride are the most commonly used.

300 / Chapter 13: Type 2 diabetes

Compared with other oral antidiabetes agents,

the action of sulphonylureas appears less durable

Guanidine

(defined as the length of time before treatment

NH₂

needs to be escalated). Accelerated β-cell loss may

result from stimulation of an already ‘exhausted

(CH₂)₂

NH NH

cell’, thereby achieving short-term control at the

Phenformin

N C

NH₂

expense of worsening long-term control.

CH₃

NH NH

Meglitinides or post-prandial regulators

Metformin

N C

NH₂

There are two drugs in the post-prandial regulator

class: nateglinide and repaglinide

(Figure

13.9).

Repaglinide is the non-sulphonylurea component

Figure 13.10 Structure of guanidine, phenformin

of glibenclamide, while nateglinide is derived from

(phenethylbiguanide) and metformin

d-phenylalanine.

(dimethylbiguanide).

Mechanism of action

These drugs also stimulate insulin release by closing

the K⁺-ATP channel, but bind to a different, but

closely related, site on the SUR1 receptor from sulpho-

• To increase glucose uptake in skeletal muscle and

nylureas. They are designed to restore early-phase

adipocytes

post-prandial insulin release without prolonged stim-

• To suppress hepatic gluconeogenesis and

ulation during subsequent periods of fasting. However,

glycogenolysis

the effect on glycaemic control with meglitinides is

• To reduce glucose absorption from the small

generally less than with other oral antidiabetes drugs.

intestine (at high concentration).

The place of meglitinides in therapeutic options,

unlike sulphonylureas, is not yet established.

Metformin appears to work through several

intracellular

insulin-dependent and insulin-

Side-effects

independent mechanisms. Recent work suggests

Hypoglycaemia may occur, but it is usually less

that metformin acts in part by stimulating

severe than with sulphonylureas because of the short

AMP kinase, an intracellular energy sensor that is

duration of action of meglitinides. This makes them

usually stimulated during exercise or hypoxia.

potentially useful in older people where hypoglycae-

Stimulation of AMP kinase leads to activation of

mia should be particularly avoided. There is also

glucose transporters and facilitates substrate uptake

less weight gain because of a reduced need to snack

into the cell. New drugs targeting AMP kinase are

between meals.

in development.

Metformin may also suppress appetite and help

achieve weight loss, which is useful in patients who

Insulin sensitizers

are overweight. Metformin may also be used in

Insulin sensitizers have no effect on insulin secretion

combination with other oral antidiabetes drugs or

but improve the effectiveness of circulating insulin.

insulin and reduces HbA_1c by

∼1.5-2% (∼16-

22 mmol/mol).

Biguanides

As well as its effect on glycaemic control, unlike

The biguanides are derived from guanidine and

sulphonylureas and insulin, metformin appears to

the only one currently available is metformin (Figure

have a cardioprotective effect. The UK Prospective

13.10). Globally, metformin is the most widely

Diabetes Study showed that metformin was associ-

prescribed antidiabetes agent. Although this drug

ated with reduced cardiovascular mortality and

has been available for many years, its mode of action

morbidity (Chapter 14). It may also protect against

is still not fully understood. Its major actions are:

cancer through its insulin-sensitizing action.

Chapter 13: Type 2 diabetes / 301

Side-effects

is significantly restricted by the US Food and Drug

The use of metformin is limited by the high preva-

Administration (Figure 13.11).

lence of gastrointestinal side-effects

(10-20%),

which include anorexia, nausea, abdominal discom-

Mechanism of action

fort and diarrhoea. The side-effects can be reduced

Thiazolidinediones (TZDs) bind to the peroxisome

by starting at low dose and gradually increasing this

proliferator-activated receptor gamma

(PPAR-γ)

until the desired therapeutic effect is achieved. A

(Figure 13.12). This receptor is part of the nuclear

slow-release preparation of metformin appears to be

hormone receptor superfamily (review Chapter 3

better tolerated.

and Figure 3.1). Its natural ligand is unclear, although

The most worrying side-effect of metformin is

fatty acids bind PPAR-γ with low affinity. After

potentially fatal lactic acidosis. Metformin tends to

binding of the TZD, PPAR-γ associates as a het-

increase lactate production by inhibiting pyruvate

erodimer with the retinoid X receptor (RXR) in the

metabolism. In situations where lactate clearance is

cell nucleus and binds to PPAR-γ response elements

impaired or anaerobic metabolism is increased, such

in regulatory elements of the insulin target genes

as in shock, lactic acidosis can result. Metformin is

(Figure 13.13; Figure 3.20).

therefore contraindicated in renal impairment,

PPAR-γ receptors are particularly abundant

cardiac failure and hepatic failure.

in adipose tissue, which is the major site of TZD

Metformin reduces gastrointestinal vitamin B₁₂

action. TZDs enhance glucose and fatty acid uptake

absorption, but it only rarely causes anaemia.

and utilization in adipocytes. They also induce

Nevertheless, it is sensible to check haemoglobin

pre-adipocyte differentiation and reduce the

annually, particularly for individuals with known or

secretion of several adipocyte cytokines that inhibit

suspected nutritional deficiencies.

insulin action. Reduced availability of fatty acids

to muscle improves insulin sensitivity in myocytes

Thiazolidinediones or ‘glitazones’

through the Randle cycle

(Box

13.9). In

Thiazolidinediones have been used clinically since

addition, TZDs reduce hepatic glucose output

2000. Pioglitazone and rosiglitazone are the two

(Figure 13.14).

available, although at the time of writing, rosiglita-

As the effect on plasma glucose is indirect,

zone has been withdrawn from Europe and its use

TZDs may take up to 3 months to reach their

Figure 13.11 Structure of

thiazolidinediones.

H3C

Pioglitazone

Troglitazone was withdrawn

because of hepatotoxicity.

Rosiglitazone was

withdrawn in Europe

because of concerns about

CH3

cardiovascular safety. Its

CH3

Troglitazone

use is restricted in the

USA.

CH3

Rosiglitazone

CH3

Chapter 13: Type 2 diabetes / 303

Figure 13.14 How

Thiazolidinedione

thiazolidinediones enhance

insulin action and normalize

blood glucose.

Thiazolidinediones enhance

Glucose uptake

glucose and fatty acid

Fatty acid uptake and utilization

Adipocytes

uptake, and utilization in

Induce differentiation of preadipocytes

adipocytes. They also

Secretion of a number of cytokines

induce differentiation of

pre-adipocytes and reduce

the secretion of a number

NEFA

of cytokines by adipocytes

that inhibit insulin action.

Reduced availability of fatty

acids to muscle increases

Skeletal muscle

Liver

glucose uptake and

utilization in muscle cells

through the Randle cycle

Glucose output

(see Box 13.9).

Glucose uptake

Thiazolidinediones also

reduce hepatic glucose

Plasma glucose

output. NEFA, non-esterified

fatty acid.

appears paradoxical because obesity is associated

Box 13.9 What is the Randle

with increased insulin resistance. However, the

cycle?

TZD-associated fat is distributed preferentially

around the hips and thighs, while the metabolically

• Cells are able to utilize either fatty acids or

more important ‘insulin resistant’ intra-abdominal

glucose and to switch from one substrate

fat is reduced.

to another depending on the supply

TZDs are associated with significant fluid reten-

• When fatty acid concentrations fall, the

tion and may precipitate overt cardiac failure in

uptake and utilization of glucose increase

those at risk. The fluid retention may also be

• When glucose concentrations fall, the

responsible for some of the weight gain and dilu-

uptake and utilization of fatty acids

tional anaemia. Rosiglitazone has been withdrawn

increase

from use in Europe because of an increased risk of

myocardial infarction.

Severe liver toxicity was specific to troglitazone,

the earliest marketed TZD, and led to its with-

drawal. This does not occur with other TZDs;

Inhibitors of glucose absorption from the

indeed recent trials have shown that they improve

gastrointestinal tract

non-alcoholic fatty liver disease.

TZDs also affect bone formation and are associ-

Guar gum has been used as an additional source of

ated with increased rates of osteoporotic fracture.

soluble fibre to reduce carbohydrate absorption

Recent epidemiological data have linked pioglita-

from a meal. Large quantities are required and the

zone with increased rates of bladder cancer.

lack of clinical benefit has limited its use.

304 / Chapter 13: Type 2 diabetes

Incretin-based therapies

Salivary amylase

Mechanism of action

Incretin hormones, the most important of which

are GLP-1 and glucose-dependent insulinotrophic

Pancreatic amylase

polypeptide (GIP), are secreted from the intestine

in response to eating (Chapter 10). One of their

chief actions is to increase glucose-induced insulin

secretion by the pancreatic islet β-cells, while sup-

a-Glucosidase

inhibited by

pressing glucagon secretion. In addition, they delay

acarbose in lumen

gastric emptying, which may reduce the post-

of small intestine

prandial rise in plasma glucose. Furthermore, they

induce satiety through their actions on the hypo

Figure 13.15 Gastrointestinal carbohydrate

thalamus, which has beneficial implications for

metabolism and site of action of acarbose.

body weight. There are also animal data suggesting

that GLP-1 increases β-cell mass and therefore

may potentially affect the disease progression of

diabetes.

Acarbose

The incretin response is reduced in people

Acarbose was designed specifically to inhibit α-

with type 2 diabetes, partly through diminished

glucosidase in the brush border of the small

GLP-1 and GIP secretion, but also through resist-

intestine and reduce glucose uptake from the gut

ance to their actions. To date, therapeutic manipu-

(Figure 13.15). Carbohydrate digestion is catalyzed

lation of GIP has not proven successful and so

by several enzymes that sequentially degrade

the currently available treatments have focussed on

complex polysaccharides, such as starch, into

GLP-1.

monosaccharides, such as glucose. Digestion

Native GLP-1 is broken down rapidly by the

begins with amylases in the saliva and from

enzyme dipeptidyl peptidase-4

(DPP-4) and so

the pancreas, and is followed in the small intes

GLP-1 per se cannot be used therapeutically.

tinal brush border by the digestion of oligosaccha-

However, inhibitors of DPP-4, which prevent

rides by β-galactosidases, such as lactase, and

the breakdown of endogenous GLP-1 and GIP,

various α-glucosidase enzymes that hydrolyze

and GLP-1 receptor agonists that are resistant

disaccharides.

to the actions of DPP-4 have been developed

Acarbose binds with higher affinity than these

successfully.

disaccharides to α-glucosidase, thereby inhibiting

dietary carbohydrate breakdown. Digestion and

absorption of glucose after a meal is slowed, and

DPP-4 inhibitors

consequently the post-prandial peak of blood

Currently, there are four DPP-4 inhibitors in clini-

glucose is reduced, leading to more stable concen-

cal use

(sitagliptin, saxagliptin, vildagliptin and

trations through the day. Its clinical utility is limited

linagliptin), although more are in development (e.g.

by its lack of efficacy and side-effects. The maximum

alogliptin). They are oral drugs that are taken once

reduction in HbA_1c is approximately half that with

or twice a day and inhibit DPP-4 by >80%, leading

metformin or sulphonylureas.

to a doubling in the concentration of GLP-1 and

GIP. DPP-4 inhibitors reduce HbA_1c by 0.6-0.9%

Side-effects

(7-10 mmol/mol). Although they can be used as

The major side-effects are gastrointestinal and

monotherapy, this is not a licensed indication in

include flatulence, abdominal distension and diar-

many countries and so their commonest use is in

rhoea, as unabsorbed carbohydrate is fermented in

combination with other oral antidiabetes drugs or

the bowel.

with insulin.

Chapter 13: Type 2 diabetes / 305

Side-effects

and is resistant to cleavage by DPP-4. Exenatide is

DPP-4 inhibitors are well tolerated, with nausea

administered by twice-daily subcutaneous injection.

being the commonest side-effect. They are not asso-

It reduces HbA_1c by

∼1% (11 mmol/mol) and

ciated with weight gain and have a low risk for

causes a mean weight loss of ∼4 kg. Some of the

hypoglycaemia. At present there are no long-term

improved glycaemic control is explained by the

safety data for these drugs.

weight loss, but there is a dissociation between

the two as weight loss continues to occur for up to

2 years after the initiation of treatment, while HbA_1c

GLP-1 receptor agonists

usually reaches a nadir after 6 months.

Currently there are two GLP-1 receptor agonists,

A once-weekly preparation of exenatide has

exenatide and liraglutide, in clinical use, but

recently been introduced into clinical practice.

other longer acting agents are in development.

Generally exenatide is well tolerated but the

Unlike DPP-4 inhibitors, these analogues achieve

main side-effect is nausea and vomiting, which

true pharmacological rather than maximum

affects up to 50% of people receiving the drug. The

physiological GLP-1 action. This leads to a larger

incidence of nausea declines with time and can be

reduction in HbA_1c and significant weight loss.

minimized by judicious meal sizes and timing.

All GLP-1 receptor agonists are injectable therapies

Despite this common side effect, only a few people

and yet, despite this, to date they are well

discontinue treatment.

tolerated and used by people with diabetes (Case

Hypoglycaemia only occurs rarely when used as

history 13.3).

monotherapy or in combination with metformin,

although hypoglycaemia occurs more frequently

when combined with either sulphonylureas or

insulin. As exenatide is a foreign protein, about

Case history 13.3

40-50% of people receiving the drug develop anti-

bodies to exenatide; however, the importance of

A 49-year-old man with type 2 diabetes

these is unknown as they do not seem to influence

presents with daytime sleepiness and

the effectiveness of the drug.

disturbed night-time sleep. His wife

Exenatide treatment has been associated with

complains that he is ‘always snoring’.

acute pancreatitis. The drug labelling warns about

He is currently treated with metformin

this possibility; however, a direct causal relationship

850 mg three times daily and gliclazide

is unclear as the incidence of pancreatitis is increased

160 mg twice daily. His BMI is 36.2 kg/m²

in people with diabetes per se. Nevertheless, exena

and his most recent HbA_1c is 10.6%

tide should be avoided in people with an increased

(92 mmol/mol).

of risk of pancreatitis, e.g. those with alcoholism,

cholecystolithiasis or hypertriglyceridemia.

What is the likely cause of his

sleepiness?

What treatment for his diabetes would

you recommend?

Liraglutide

Liraglutide is an analogue of GLP-1 and has 97%

Answers, see p. 309

amino acid homology to human GLP-1. Liraglutide

differs from native GLP-1 by an amino acid substi-

tution (arginine in place of lysine at position 34)

and attachment of a fatty acid residue to the lysine

Exenatide

at position 26. It has a longer half-life than exenatide

Exenatide is synthetic exendin-4, a molecule that

and can be administered once daily by subcutane-

was originally isolated from the saliva of the Gila

ous injection. Liraglutide is slightly more effective

monster, a lizard living in the Arizonian desert. It

than exenatide, leading to a greater reduction in

has 53% sequence homology with human GLP-1

HbA_1c.

306 / Chapter 13: Type 2 diabetes

The side-effects of liraglutide are similar to

There are differences between national and

exenatide. Overall it is well tolerated. Nausea and

international guidelines regarding the appropriate

vomiting are the commonest side-effects, but the

time to introduce metformin. The European

incidence is lower than with exenatide. Hypogly

Association for the Study of Diabetes and ADA

caemia occurs rarely when combined with either

consensus statement recommends introducing met-

sulphonylureas or insulin. Liraglutide has been asso-

formin at diagnosis, while other guidelines, such as

ciated with pancreatitis but, like exenatide, causa-

the UK National Institute of Health and Clinical

tion has not been demonstrated.

Excellence

(NICE) guidelines, advocate starting

metformin if lifestyle modification fails to achieve

adequate glycaemic control (Figure 13.16).

Which drug and when?

There is considerable debate about the most

For many years sulphonylureas were the first-line

appropriate second-line agent when metformin no

agent for people requiring more than lifestyle modifi-

longer maintains adequate glycaemic control.

cation to treat their diabetes. However, the UK

NICE recommends that sulphonylureas, thiazolid-

Prospective Diabetes Study published in 1999 showed

inediones, DPP-4 inhibitors and, in some circum-

that metformin improved longevity and reduced car-

stances, liraglutide may all be used as second-line

diovascular mortality, making this agent the first-line

treatments (Case history 13.4). There are advan-

treatment for most people (Figure 13.16).

tages and disadvantages of each of these treatments,

Usual option

Lifestyle

modification

Alternative

First line

Metformin

Sulphonylurea

drug therapy

Sulphonylurea

Thiazolidinediones

DPP-4 inhibitor

Liraglutide

Second line

Add to MTF

Add to MTF or SU

DPP-4 inhibitor

GLP-1 analogue

Insulin

Thiazolidinediones

Third line

Add to MTF and SU

±oral drugs

Add to MTFand SU

or MTF and TZD

Fourth line

Insulin

±oral drugs

Figure 13.16 The NICE stepwise management algorithm for medical treatment of type 2 diabetes. MTF,

metformin; SU, sulphonylurea; TZD, thiazolidinedione; GLP-1, glucose-dependent insulinotrophic peptide 1;

DDP-4, dipeptidyl peptidase 4.

Chapter 13: Type 2 diabetes / 307

Table 13.7 Advantages and disadvantages of second-line antidiabetes agents

Sulphonylurea

Thiazolinedione

DPP-4 inhibitor

GLP-1 analogue

Advantages

Effective HbA_1c

Well tolerated

Effective HbA_1c

reduction

reduction with

reduction

persistent glycaemic

control

Cheap

No hypoglycaemia

Weight neutral

Weight loss

Long experience

Improves

No hypoglycaemia

of use

non-alcoholic fatty

hypoglycaemia

liver disease

Disadvantages Hypoglycaemia

Slow onset of clinical

Less effective

Nausea and

effect

HbA_1c reduction

vomiting

than other agents

Weight gain

Cost

Requires injection

May hasten

Osteoporotic fracture

Lack of long-term

Cost

β-cell loss

follow-up data

Heart failure

Lack of long-term

Bladder cancer?

follow-up data

Pancreatitis?

DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; HbA_1c, glycated haemoglobin.

Case history 13.4

A 45-year-old woman has had diabetes for 8 years. Her BMI is 28 kg/m². She has been treated

with glimepiride 4 mg/day and has poor diabetic control [HbA_1c 11.0% (97 mmol/mol)]. She has

background retinopathy and mild renal impairment [serum creatinine 157 µmol/L (1.77 mg/dL)].

What would you do next?

Answer, see p. 309

and therefore the choice of agent must be individu-

or a basal bolus regimen (discussed in Chapter 12).

alized (Table 13.7). Triple therapy is needed when

There are advantages and disadvantages with each

dual therapy no longer controls glycaemia

of these approaches and therefore the insulin

adequately.

regimen must be discussed with the patient (Case

history 13.5).

Insulin is frequently used in combination with

Insulin

oral antidiabetes agents, most commonly met-

As type 2 diabetes progresses, many people ulti-

formin. Metformin acts as an insulin-sensitizing

mately require treatment with insulin. In type 2

agent and can reduce the number and severity of

diabetes, insulin is usually administered as once-

hypoglycaemic episodes, and weight gain associated

daily long-acting insulin, twice-daily mixed insulin

with insulin therapy.

308 / Chapter 13: Type 2 diabetes

weight loss through an obligate calorie loss in the

Case history 13.5

urine.

The most common adverse effect appears to be

A 72-year-old woman who lives alone

an increased incidence of urinary tract and urogeni-

attends the surgery complaining of

tal infection because the increased glucose excretion

nocturia, thirst and weight loss. She has

facilitates bacterial or fungal growth.

had diabetes for 12 years. She has a BMI

of 24.8 kg/m². She is currently treated with

metformin, tolbutamide and pioglitazone

Quick release bromocriptine

at maximally tolerated doses. Her HbA_1c

Bromocriptine is an ergot alkaloid dopamine D₂

10.2% (88 mmol/mol). She is reluctant to

receptor agonist that has been used extensively in

start insulin but wants to feel better.

the past to treat hyperprolactinaemia, galactorrhoea

What are your treatment options?

(see Chapter

5) and Parkinsonism. However,

How would you escalate treatment if your

hypothalamic hypodopaminergic states and dis-

first plan did not solve the problem?

turbed circadian rhythm are also associated with the

development of insulin resistance, obesity and dia-

Answers, see p. 310

betes in animal models and humans (see Chapter

5). When administered at daybreak, a new quick-

release formulation of bromocriptine appears to act

centrally to re-set hypothalamic dopamine circadian

rhythms and improve insulin resistance and other

Emerging antidiabetes agents

metabolic abnormalities.

Clinical studies show that quick-release bro-

There is a continuing need for new and improved

mocriptine lowers HbA_1c by 0.6-1.2% (7-13 mmol/

antidiabetes agents as current therapies neither rein-

mol) either as monotherapy or in combination with

state normal glucose homeostasis nor prevent loss

other antidiabetes medications. Quick-release

of β-cell function nor eliminate the threat of long-

bromocriptine has recently been approved in the

term complications. Furthermore, as described

USA for the treatment of type

2 diabetes.

above, many current treatments are also accompa-

Apart from nausea, the drug is well tolerated. The

nied by significant side-effects, including undesir-

diabetes treatment doses are much lower than those

able weight gain and hypoglycaemia. Many new

used in Parkinson disease, avoiding the concern

agents are in development and a brief description

over retroperitoneal fibrosis or heart valve abnor-

of some of these drugs is given below.

malities (see treatment of hyperprolactinaemia in

Chapter 5).

Sodium-glucose co-transporter 2 inhibitors

Glucose is filtered through the renal glomeruli and

Amylin analogues

almost all of it is re-absorbed in the proximal tubules

by the sodium-glucose co-transporter 2 (SGLT2)

Amylin is a 37-amino acid peptide co-secreted with

system. Inhibitors of SGLT2

(termed

‘flozins’)

insulin. It delays gastric emptying, suppresses post-

reduce hyperglycaemia by increasing urinary glucose

prandial glucagon secretion and increases satiety.

excretion. Selectivity is needed to prevent co-

Pramlintide is an analogue of amylin that is approved

inhibition of SGLT1, which is responsible for

in the USA for use in insulin-treated subjects

intestinal glucose transport. Clinical trials with

with either type 1 or type 2 diabetes. It reduces

SLGT2 inhibitors have shown improvements in

HbA_1c by 0.4-0.6% (5-7 mmol/mol) and is associ-

glucose control in people with type

2 diabetes.

ated with a small degree of weight loss (0.8-1.4 kg).

These agents may also have a place as adjunctive

It is administered by injection and the main

therapy in type 1 diabetes. SGLT2 inhibitors do

side-effects are nausea

(often transient) and

not cause hypoglycaemia and may promote

hypoglycaemia.

Chapter 13: Type 2 diabetes / 309

Key points

• Type 2 diabetes results from the

before diagnosis. This provides a strong

combination of insulin resistance and failure

imperative to screen for the disease

of the pancreatic β-cells

• Treatment is based on lifestyle modification,

• Type 2 diabetes accounts for approximately

but pharmacological treatment with oral

90% of all cases of diabetes in the western

antidiabetes agents and/or injectable

world and its prevalence is increasing rapidly

agents may be required

• It is potentially preventable by lifestyle

• Hyperosmolar hyperglycaemic state is the

modification

most serious complication of type 2

• It has an insidious onset and so patients are

diabetes and is a medical emergency

frequently asymptomatic for many years

Answers to case histories

Case history 13.1

indication to use a sulphonylurea in the short

term (<6 weeks) to improve his symptoms

This woman is at considerable risk of

while he is adjusting to his new lifestyle. The

diabetes in the future. Approximately 50% of

diet and exercise should also help him to

woman with gestational diabetes develop

lose weight.

diabetes within 10 years of the index

pregnancy (i.e. the one in which diabetes

occurred). She needs advice and support to

Case history 13.3

help change her lifestyle to minimize risk.

This man may well have developed

This includes both diet and increased

obstructive sleep apnoea as there is a

physical activity. Drug therapy at this stage is

well-established link between obesity, type 2

debatable. Although both metformin and

diabetes and obstructive sleep apnoea. As

orlistat have been shown to reduce the risk

many as 40% of people with obstructive

of diabetes, the effect size is smaller than

sleep apnoea have diabetes and almost 90%

lifestyle modification and so the emphasis

of obese people with diabetes have

should be placed on the latter. As diabetes is

obstructive sleep apnoea. Obstructive sleep

frequently asymptomatic in its earliest stages,

apnoea is an independent risk factor for

annual screening for diabetes for this woman

cardiovascular disease.

is important.

As well as specific treatments for the

obstructive sleep apnoea, weight loss is a

Case history 13.2

primary treatment strategy. A GLP-1 receptor

agonist would be an ideal treatment for this

This man presents with classical diabetic

man as it would improve his glycaemic

symptoms and has a diagnostic blood test.

control and promote weight loss. He should

Given his age and size, type 2 diabetes is

be considered for bariatric surgery.

most likely, but it is important to be aware

that type 1 diabetes or secondary diabetes

Case history 13.4

can occur in this age group. Lifestyle

modification, particularly avoidance of sugary

This woman has poor glycaemic control

drinks, is the most important aspect of this

and it is likely that improving this will make

man’s treatment, although there may be an

her feel better. She is overweight and it is

312 / Chapter 14: Complications of diabetes

To recap

■ The basic epidemiology and clinical features of type 1 and type 2 diabetes are described in

Chapters 12 and 13, respectively, while the diagnostic criteria for diabetes are given in

Chapter 11

■ The activation of several intracellular kinases is important in the development of microvascular

complications. A detailed description of intracellular signalling is given in Chapter 3

■ HMGCoA reductase inhibitors (‘statins’) reduce serum total and low-density lipoprotein

cholesterol concentration. The synthesis of the hormones from cholesterol is covered in

Chapter 2

Cross-reference

■ The risk of developing diabetes complications is strongly linked to poor glycaemic control,

which is assessed by measuring glycated haemoglobin (HbA_1c). The formation of HbA_1c is

described in Chapter 11 and its clinical application in Chapter 12.

■ The growth hormone (GH)-insulin-like growth factor (IGF) axis is believed to play a role in the

development of microvascular complications. The GH-IGF axis is covered in Chapter 5

■ Bones may be affected by diabetes, either through the effects of renal failure or through foot

infection. Bone metabolism is discussed in Chapter 9

■ Many complications could be reduced through prevention of diabetes (see Chapter 13)

Following the introduction of effective treatment

50% of patients with newly diagnosed type

with insulin that allowed people to live through the

diabetes

(Figure

14.2). With increased screening

acute metabolic consequences of diabetes, a number

for type

2 diabetes, the proportion of people

of chronic microvascular complications that affect

with complications at presentation is falling,

the eyes, kidneys and nerves became apparent.

presumably because of the earlier detection of the

Furthermore, people with diabetes have a higher inci-

disorder and consequently shorter duration of

dence of macrovascular complications, such as myo-

diabetes.

cardial infarction, stroke and peripheral vascular

disease (Figure 14.1). Diabetes is also associated with

Pathogenesis

an increased risk of certain cancers. Pregnancy out-

comes for women with diabetes are worse than in the

The pathogenesis of diabetic microvascular compli-

general population. Finally, diabetes is associated with

cations is not fully understood and is likely to

a number of psychosocial sequelae. These complica-

be multifactorial (Box 14.1). Interestingly, despite

tions of diabetes adversely affect the quality of life of

long-standing diabetes and its associated hypergly-

people with diabetes and will be considered in turn

caemia, some people seem relatively protected

together with the underlying causes and treatment.

against microvascular complications. For instance,

the concordance of complications between twins

shows the importance of genetic factors in the

Microvascular complications

aetiology of complications: some genotypes may

Microvascular complications affect over

80% of

predispose or protect against the generation of

individuals with diabetes and are present in 20-

microvascular complications.

314 / Chapter 14: Complications of diabetes

Hyperglycaemia

Each of these processes is activated by increased

mitochondrial production of reactive oxygen species

Prolonged exposure to hyperglycaemia undoubtedly

which are induced by hyperglycaemia. The develop-

predisposes to the generation of microvascular com-

ment of microvascular complications is not fully under-

plications. The cell types particularly damaged by

stood and other mechanisms may also be involved.

hyperglycaemia are those that cannot down-regulate

glucose uptake. Furthermore, in either type 1 or

type 2 diabetes, improved glycaemic control reduces

Formation of advanced glycation

the incidence of microvascular complications.

end-products

Five main underlying mechanisms appear to

If cellular proteins are exposed to increased glucose

link hyperglycaemia with the development of

over a prolonged period, glucose and its metabolites

microvascular complications (Figure 14.3):

become attached to the protein through a mecha-

• The formation of advanced glycation end-

nism that is independent of enzymatic action. Early

products (AGEs)

glycation products are reversible (Box 14.2), but

• Altered expression of the receptor for AGE

eventually the proteins undergo irreversible changes

• Increased flux of glucose through the sorbitol-

through cross-linking to form AGEs.

polyol pathway

AGEs accumulate in proportion to hyperglycae-

• Increased activation of the hexosamine pathway

mia and time. Cells are damaged by three general

• Activation of intracellular kinases and cytokines.

mechanisms:

Glucose

Aldose

reductase*

Growth

Advanced

factors

PKCβ *

Vasoactive

glycation

Sorbitol

hormones*

and products

accumulation

Angiogenesis

Cytokines

ECM cross-

Vascular

TGF β VEGF

linking

permeability

ECM

Macular

New vessel

accumulation

oedema

formation

Figure 14.3 Molecular mechanisms that may be

activation in turn lead to the secretion of a number

important in the generation of microvascular

of cytokines and growth factors that affect vascular

complications. There is no one mechanism that

permeability and angiogenesis. *Genetic factors are

explains the development of microvascular diabetic

also important in the development of microvascular

complications. Hyperglycaemia affects a number of

complications. Polymorphisms in the aldose

biochemical pathways leading to the accumulation of

reductase enzyme, PKCβ and vasoactive hormones

advanced glycation end-products (AGEs) and sorbitol

may account for some of the genetic difference.

through the polyol pathway. Hyperglycaemia also

^†Hypertension is a strong risk factor for the

activates protein kinase C β (PKCβ). AGE

development of complications. Increased tissue

accumulation leads to deposition of material in the

blood flow may affect the function of the vasoactive

extracellular matrix. This impairs the function of the

hormones. ECM, extracellular matrix; TGFβ,

tissue, e.g. the renal glomerulus. Sorbitol and PKCβ

transforming growth factor β.

Chapter 14: Complications of diabetes / 315

• Glycation directly impairs protein function

vated by pro-inflammatory proteins, which are

• AGEs promote abnormal extracellular matrix

increased by hyperglycaemia.

accumulation

• AGEs generate reactive oxygen species, which

Increased flux of glucose through the

activate nuclear factor κB (NFκB), which in turn

sorbitol-polyol pathway

activates cellular stress pathways.

In excess, glucose can be metabolized to sorbitol via

Inhibitors of the AGE reaction or antioxidants

the polyol pathway, the rate-limiting step of which is

have largely been unsuccessful at reducing the rate

catalyzed by aldose reductase

(Figure

14.4). This

of microvascular complications, possibly because

pathway depletes nicotinic acid adenine dinucleotide

the high quantity of ingested AGEs produced

phosphate (NADPH), leading to decreased forma-

during cooking swamps any effect on reducing cel-

tion of reduced glutathione. Reduced glutathione is

lular formation of AGEs.

an important scavenger of reactive oxygen species.

Hence, the knock-on consequence of increased flux

through the polyol pathway is increased reactive

Altered expression of AGE receptors

oxygen species, which damage the cell. Other mecha-

Some of the actions of AGE proteins are mediated

nisms have also been proposed to explain the damage

through specific receptors that have been identified

to the cells, including sorbitol-induced osmotic stress,

on a number of different cells, including mono-

and decreased Na⁺/K⁺-ATPase activity may also have

cytes, macrophages, glomerular mesangial cells and

an adverse effect on cellular function.

vascular endothelial cells. These receptors are acti-

This polyol pathway can be inhibited by

blocking aldose reductase. Clinical trials of aldose

Box 14.2 Glycated haemoglobin

reductase inhibitors, however, have been largely dis-

appointing and have not reduced the incidence of

• Measures the first part of glycation as a

microvascular complications. The reason for the

measure of glycaemic control (see Chapter

lack of efficacy is unclear, but may reflect the mul-

12; Figure 11.5)

tiple and redundant intracellular pathways involved

• Non-enzymatic attachment of glucose to

such that blockade of any one pathway may be

the N-terminal of the haemoglobin β-chain

insufficient to prevent damage.

Figure 14.4 Sorbitol-polyol pathway.

Toxic

Inactive

The normal function of aldose

aldehydes

alcohol

reductase is to metabolize toxic

aldehydes generated by reactive

Aldose Reductase

oxygen species to inactive alcohols.

In the presence of increased glucose

concentration, it can also reduce

Glucose

Sorbitol

Fructose

glucose to sorbitol. Both reactions

use nicotinic acid adenine

dinucleotide phosphate (NADPH) as

a co-factor. This can lead to

depletion of reduced glutathione,

NADPH

NADP

NAD⁺

NADH

increasing oxidative stress. Sorbitol

is oxidized to fructose using NAD⁺

Glutathione

reductase

as a co-factor.

Oxidized glutathione

Reduced glutathione

316 / Chapter 14: Complications of diabetes

Increased activation of the hexosamine

important than hyperglycaemia in the progression

pathway

of microvascular complications once complications

When hyperglycaemia is present, glucose metabo-

are present.

lism can be shunted into the hexosamine pathway.

The haemodynamic theory proposes that:

Excess fructose-6-phosphate is diverted from glyco-

• Through its osmotic effect, hyperglycaemia initi-

lysis to provide substrates for reactions that utilize

ates damage by swamping the normal autoregula-

UDP-N-acetylglucosamine. This activation of the

tory mechanisms that limit blood flow through a

hexosamine pathway then leads to many changes

tissue.

in both protein production, e.g. increased tumour

• Afterwards, high flow rates that are increased

necrosis factor (TNF)-β and plasminogen activator

further in patients with hypertension lead to tissue

inhibitor

(PAI)-I, and in protein function that

damage; microvascular complications result from

may contribute to the pathogenesis of diabetic

chronic abnormalities in blood flow through capil-

complications.

lary beds.

This hypothesis is supported by the observation

Activation of intracellular kinases

that retinopathy is often less severe in the eye of a

and cytokines

patient with an ipsilateral carotid artery stenosis,

Protein kinase C β (PKCβ) is an intracellular kinase

which restricts downstream blood pressure. This

belonging to a family of protein serine-threonine

hypothesis is also consistent with the observation

kinases (review Chapter 3). When glucose is metab-

that microvascular complications occur in tissues

olized to diacylglycerol, expression of PKCβ is

where there is a high capillary blood flow. Aggressive

increased. In turn, PKCβ increases production of a

treatment of blood pressure to values of less than

number of mitogenic cytokines, such as transform-

120-130/80 mmHg slows the progression of micro-

ing growth factor β(TGFβ), and vascular endothe-

vascular complications.

lial growth factor (VEGF).

Smoking increases the risk of diabetic complica-

Experiments using PKC inhibitors have shown

tions and this may be mediated through changes in

that macular oedema can be reduced in an animal

vascular function.

model of retinopathy. Clinical trials in humans are

ongoing.

The renin-angiotensin system

AGEs, hypoxia and PKCβ all increase TGFβ

Blockade of the renin-angiotensin system with

and VEGF production, which in turn increases vas-

either angiotensin-converting enzyme (ACE) inhib-

cular permeability and angiogenesis, potentially

itors or angiotensin receptor blockers slows the pro-

contributing to the macular oedema and new vessel

gression of microvascular complications to a greater

formation seen in diabetic retinopathy. Furthermore,

extent than other blood pressure lowering agents,

VEGF stimulates angiogenesis and neovasculariza-

suggesting the renin-angiotensin system may have

tion. Polymorphisms in and around the genes

a role in the generation of microvascular complica-

encoding these cytokines have been associated with

tions. The most convincing evidence is for the treat-

an increased risk of retinopathy. The genetic changes

ment of nephropathy but there are studies indicating

themselves may affect protein function, explaining

a benefit for retinopathy.

differences amongst individuals in the risk of devel-

oping microvascular complications. Recently intra-

vitreal injection of anti-VEGF drugs has been

The growth hormone-insulin-like

shown to improve diabetic macular oedema.

growth factor axis

The GH-IGF axis (see Chapter 5) has been impli-

Haemodynamic theory of diabetic

cated in the aetiology of microvascular complica-

complications

tions for a number of reasons:

Hypertension is important in the pathogenesis of

• In

1953, a woman with type 1 diabetes was

microvascular complications and may be more

described with background diabetic retinopathy,

Chapter 14: Complications of diabetes / 317

which regressed after she developed panhypopitui-

Box 14.3 Ways in which diabetes

tarism from post-partum pituitary necrosis.

can affect the eye

• In the 1960s, pituitary ablation was used to treat

diabetic retinopathy; its success was related to the

• Retinopathy

degree of GH deficiency.

• Cataract:

• People with type 1 diabetes and GH deficiency

° Diabetes increases the rate of age-

have decreased incidence and progression of

related cataract formation

retinopathy.

° There is a diabetes-specific cataract

that generally affects young people with

This area remains somewhat controversial

type 1 diabetes and may progress

because GH replacement therapy does not increase

rapidly

the incidence of retinopathy in GH-deficient

• Refractory defects:

patients with or without diabetes.

° Hyperglycaemia may alter the osmotic

In people with diabetes, the GH-IGF axis does

pressure within the lens, leading to

not function normally. The reduced portal insulin

temporary refractive defects

concentrations that inevitably accompany subcuta-

• Glaucoma:

neous administration of insulin cause reduced

° Prevalence is increased in people with

hepatic production of IGF-I. This leads to reduced

diabetes

negative feedback at the anterior pituitary soma-

• Infection

totroph and GH hyper-secretion (review Chapter

5). GH concentrations are typically up to two- to

three-fold higher in individuals with diabetes com-

pared with healthy subjects. It is possible that cor-

mated that up to one in three people with type 2

rection of the GH hyper-secretion by IGF-I

diabetes will develop sight-threatening diabetic

administration could reduce the risk of developing

retinopathy requiring laser photocoagulation

microvascular complications. Similarly, somatosta-

some time.

tin analogues or GH receptor antagonists have been

shown to produce some reduction of microvascular

complications in clinical trials.

Although effective, pituitary ablation was asso-

Case history 14.1

ciated with significant morbidity and mortality and

was superseded by retinal photocoagulation.

A 24-year-old woman presents with

classical symptoms of type 1 diabetes.

The diagnosis is confirmed when her

Clinical features

blood glucose is measured at 18.2 mmol/L

(327 mg/dL). She commences treatment

Retinopathy

with insulin and re-attends 2 weeks later.

The most important way that diabetes can affect the

She has been experiencing blurred vision

eye is the development of retinopathy, which is

and is anxious that she has developed

the commonest cause of blindness in the UK in

retinopathy and is going to go blind.

people under the age of 60 years (Box 14.3; Case

history

14.1). Historically, approximately two-

Is it likely that she has developed

thirds of people had sight-threatening retinopathy

retinopathy?

after 35 years of type 1 diabetes. With improve-

What is the cause of the blurred vision?

ments in glycaemic and blood pressure control,

What reassurance can you give her?

however, this proportion has fallen. The rate of

proliferative retinopathy is lower in type 2 diabetes

Answers, see p. 340

than in type 1 diabetes, but nevertheless it is esti-

318 / Chapter 14: Complications of diabetes

Retinopathy is also important because it devel-

will progress to sight-threatening retinopathy and,

ops in an insidious way and is almost invariably

indeed, retinopathy may regress.

asymptomatic until the patient has a catastrophic

intraocular sight-threatening haemorrhage. This is

Screening and diagnosis

a tragic situation because retinopathy is treatable

As retinopathy is asymptomatic, screening is essen-

and with adequate screening, most cases of blind-

tial in order to prevent blindness. It is recommended

ness are preventable.

that every patient receives an annual eye test that

involves a check of visual acuity and retinal (fundo-

Natural history

scopic) examination. Visual acuity should also be

Retinopathy begins with background retinopathy

checked through a pinhole to assess macula vision.

before moving to pre-proliferative retinopathy and

Traditionally, the retinal examination was per-

finally to proliferative retinopathy (Box 14.4; Figure

formed by a trained physician using an ophthalmo-

14.5). For those without retinopathy, up to 0.6%

scope through dilated pupils. More recently, this has

will progress to proliferative retinopathy over a

been replaced where possible by retinal photogra-

4-year period, while for those with background

phy as this is more reliable than traditional methods

retinopathy, there is a 6.2% risk of progression to

and provides a permanent record for comparison.

proliferative retinopathy within 1 year. However,

As pregnancy can accelerate the progression of

it is important to recognize that not all people

retinopathy, pregnant women should be screened in

Box 14.4 The different stages of diabetic retinopathy

Background retinopathy

• Intraretinal microvascular abnormalities

• Dots (micro-aneurysms):

(IRMA):

° A red spot with sharp margins <125 µm

° Clusters of irregular branched vessels

(the approximate width of a vein at disc

within the retina that may represent early

margin)

new vessel formation

• Blots (small intraretinal haemorrhages):

• Venous changes:

° A red spot with irregular margins and/or

° Beading, which appears as segmental

uneven density

dilatations

• Hard exudates:

° Loops

° Lipid exudates that often form in a circle

° Duplication

around a leaking blood vessel

° Small white or yellowish-white deposits

Proliferative retinopathy

with sharp margins

• New vessel formation:

° Caused by growth factors that are

Maculopathy

secreted in response to the retinal

• Background retinopathy that occurs within

ischaemia

one disc diameter of the macula

° These are friable and have a high

• May cause reduction in visual acuity

tendency to bleed

• May be associated with macula oedema

° Haemorrhage from these vessels can lead

• More common in type 2 diabetes

to temporary or permanent blindness

° Categorized according to whether they

Pre-proliferative retinopathy

occur at the disc (NVD) or elsewhere

• Cotton wool spots:

(NVE). NVD, new vessels at the disc; NVE,

° Fluffy white opaque areas that result from

new vessels elsewhere

retinal ischaemia

Chapter 14: Complications of diabetes / 321

Control Trial showed that by lowering glycated hae-

sign of nephropathy, and 10-fold in those with frank

moglobin (HbA_1c) by 2% (22 mmol/mol) in people

proteinuria. Approximately one-third of people with

with type 1 diabetes, the incidence of and progres-

diabetes and proteinuria die from cardiovascular

sion of retinopathy was more than halved. Similarly,

disease before they develop established renal failure.

in patients with type 2 diabetes, a reduction in

The risk is even higher in those with stage 4 chronic

HbA_1c by ∼1% (11 mmol/mol) resulted in a 21%

kidney disease.

reduction in the incidence and progression of retin-

opathy. The best results are obtained in patients who

Natural history

also have optimal blood pressure control.

Once a patient has developed pre-proliferative

The earliest effect of diabetes on the kidney is

or proliferative retinopathy or maculopathy, further

increased glomerular filtration rate

(GFR). The

treatment by laser photocoagulation is needed (see

kidney enlarges through expansion of tubular tissue,

Figure 14.5h). Laser treatment is effective in pre-

but there is no change in serum creatinine or blood

venting blindness. The principle is that by destroy-

pressure. As diabetic nephropathy progresses, there

ing peripheral parts of the retina, oxygenated blood

is a progressive increase in urinary albumin excre-

is preserved for more central regions thus reducing

tion and diminished renal function, which results

the ischaemic stimulus for new vessel formation. In

from pathological basement membrane thickening,

essence, peripheral vision is sacrificed for central

atrophy and interstitial fibrosis (Table 14.1).

vision. Intravitreal injection of anti-VEGF antibod-

The initial stage of diabetic nephropathy is

ies has recently been introduced to treat diabetic

microalbuminuria, which is defined as a higher

macular oedema.

than normal albumin excretion that cannot be

Patients may need vitrectomy

(removal of

detected by standard urine dipstick testing

(e.g.

the vitreous) if an intravitreal haemorrhage fails

Albustix), and affects approximately

30-50% of

to clear.

people with diabetes. Protein excretion returns to

Regrettably, retinopathy remains the common-

normal in ∼30% of people with microalbuminuria,

est cause of blindness in the UK in people under

while only 20-30% of people will progress to frank

the age of 60 years. After the onset of blindness,

proteinuria. These latter individuals develop inter-

patients should be advised to register as blind and

mittent overt proteinuria before developing persist-

may require additional aids to help them to monitor

ent overt proteinuria. Occasionally, protein

their diabetes. Less severe visual impairment may

excretion can reach a level that causes nephrotic

prevent the person from driving (see below).

syndrome. GFR and serum creatinine only become

abnormal after the development of frank proteinu-

ria. Hypertension affects virtually all people with

Nephropathy

persistent proteinuria and some will also develop

Diabetic nephropathy is a common cause of estab-

peripheral oedema.

lished renal failure, accounting for 20-44% of new

patients requiring renal replacement therapy. The

Screening and diagnosis

risk of developing nephropathy is lower in people

with type 2 diabetes than in those with type 1 dia-

Early identification of people with diabetic neph-

betes because of the later onset of type 2 diabetes.

ropathy allows intensification of therapy that slows

However, people with type 2 diabetes requiring

progression of kidney disease and management of

renal replacement therapy outnumber those with

the increased risk of other complications, particu-

type 1 diabetes because of the much greater preva-

larly cardiovascular disease.

lence of type 2 diabetes.

Annual assessment of urinary albumin excretion

The development of nephropathy is also associ-

and estimated GFR (eGFR) should be undertaken

ated with premature cardiovascular mortality.

(Box

14.6). Screening for microalbuminuria is

Cardiovascular disease risk is increased two- to three-

most conveniently done by assessing urinary

fold in those with microalbuminuria, the earliest

albumin:creatinine ratio, ideally with an early

322 / Chapter 14: Complications of diabetes

Table 14.1 Five stages of diabetic nephropathy

Normal

Micro-

Persistent

Renal

Stage 4 CKD

albuminuria

proteinuria

impairment

Albuminuria

<20

20-300

>300

(mg/day)

Up to 15 g/

Can fall as renal

day

function declines

GFR (mL/min)

High/

High/normal

Normal/

Decreased

Greatly

normal

decreased

Serum creatinine

Normal

High/normal

High

Very high

(µmol/L)

60-150

80-120

120-400

>400

Normal

Small increase

Increased

Signs

None

±Oedema

Uraemic

symptoms

GFR, glomerular filtration rate; BP, blood pressure; CKD, chronic kidney disease.

an inhibitor of the renin-angiotensin system (e.g.

Box 14.6 Estimated glomerular

an ACE inhibitor or angiotensin type

1 (AT1)

filtration rate (eGFR)

receptor antagonist) as these have additional bene-

eGFR = 186 × ([serum creatinine/88.4]^−1.154) ×

fits over and above their effect on blood pressure.

age (years)^−0.203

Other measures include reducing dietary protein

GFR in mL/min/1.73 m² and creatinine in

intake to 0.7-1.0 g/kg body weight/day as this may

µmol/L

slow the deterioration in renal function.

If the person is female, the result of the

It is important to manage cardiovascular risk

formula is multiplied by 0.742

factors, such as smoking and lipids, aggressively to

If the person is of black ethnicity the result

reduce the incidence of cardiovascular disease as

of the formula is multiplied by 1.21.

well as to slow the progression of nephropathy.

It is well recognized that people who are referred

as an emergency to a nephrology unit do less well

morning sample (Figure 14.6). As urinary albumin

than those whose referral is planned. An early refer-

excretion varies considerably from day to day, at

ral to the renal unit allows a structured physical and

least two of three measurements should be abnor-

psychological preparation for renal replacement

mal before a diagnosis of microalbuminuria or pro-

therapy. It is generally recommended that referral

teinuria is made.

should occur when the serum creatinine approaches

150-200 µmol/L or eGFR falls below

45 mL/

Management

min/1.73 m².

While optimal glycaemic and blood pressure control

Referral to a nephrologist should also be consid-

are important in the prevention of diabetic neph-

ered if there is increasing proteinuria without dia-

ropathy, there is little evidence that tight glycaemic

betic retinopathy because this is a sign of non-diabetic

control influences progression. By contrast, excel-

renal damage. Uncontrolled hypertension

(Case

lent blood pressure control is crucial to slow the

history 14.2), a rapid decline in renal function and

progression of nephropathy. Maintaining blood

nephritic syndrome are all indications for referral,

pressure below <125/75 mmHg reduces the annual

as are unexplained anaemia and abnormal bone

rate of decline in GFR from 10-12 mL/min/1.73 m²

chemistry (serum calcium, phosphate and parathy-

to 3-5 mL/min/1.73 m². The treatment of choice is

roid hormone; see Chapter 9).

324 / Chapter 14: Complications of diabetes

Pressure palsies

Box 14.7 Classification of diabetic

neuropathy

In diabetes, nerves are more susceptible to mechani-

cal injury at sites of compression or entrapment.

Acute reversible

The commonest is median nerve compression

• Hyperglycaemic neuropathy

(carpal tunnel syndrome), which causes paraest

hesiae and numbness in the lateral three and a

Persistent

half fingers. Most patients respond to surgical

• Symmetrical:

decompression.

° Distal symmetrical neuropathy

(peripheral neuropathy)

Mononeuropathies and radiculopathies

° Acute painful neuropathy

People with diabetes are more prone to develop

• Focal and multifocal:

mononeuropathies of the third or sixth cranial

° Pressure palsies:

nerves or trunk. Damage to nerve roots is also more

☐ Carpal tunnel syndrome (median

common. The aetiology of the mononeuropathies

nerve)

and radiculopathies is unclear, but the rapid onset

☐ Ulnar nerve compression at the elbow

suggests a vasculitic or inflammatory process at least

° Mononeuropathies:

in part.

☐ Diabetic amyotrophy (femoral nerve)

The commonest radiculopathy is femoral amyo-

☐ III and VI cranial nerves

trophy in which there is involvement of the lum-

☐ Truncal

bosacral nerve roots, plexus and femoral nerve.

• Autonomic

Patients present with continuous thigh pain, wasting

and weakness of the quadriceps, and sometimes

weight loss. The knee-jerk reflex is also lost.

Hyperglycaemic neuropathy

Recovery of the mononeuropathies or radicu-

lopathies is usually spontaneous, but may take

Hyperglycaemia slows nerve conduction and causes

many months.

uncomfortable sensory symptoms in those with

poor glycaemic control.

Management of painful diabetic neuropathy

The management of diabetic neuropathy is often

Distal symmetrical neuropathy

difficult (Figure 14.7). It is important to exclude

The commonest neuropathy is distal symmetrical

other causes of neuropathy, such as vitamin B₁₂ defi-

neuropathy, also called ‘peripheral neuropathy’. It

ciency, alcohol excess and renal dysfunction. Some

results from damage to the axon tips of the longest

patients will respond to a cradle or protective film

nerves, giving symptoms in a ‘glove and stocking’

that prevents the affected limb from being touched

distribution. The longer the nerve, the greater is the

or rubbed. Simple analgesics, such as paracetamol,

risk, explaining why tall stature is a risk factor.

aspirin and codeine phosphate, are usually ineffec-

Other risk factors include poor glycaemic control,

tive in the treatment of neuropathy but may provide

visceral obesity, duration of diabetes, hypertension,

some relief. Where these measures fail, the antide-

age, smoking, hypoinsulinaemia (i.e. patients with

pressant duloxetine is the first-line treatment. Both

β-cell failure) and dyslipidaemia.

serotonin and norepinephrine have been implicated

Sensory loss is the most obvious component,

in the mediation of endogenous analgesic mecha-

leading to numbness, but patients may also experi-

nisms via inhibitory pain pathways in the brain and

ence considerable pain or altered sensation. The pain

spinal cord. Duloxetine is a selective serotonin and

is often described as ‘burning’ or ‘an electrical shock’

norepinephrine reuptake inhibitor thereby modify-

that may be accompanied by paraesthesiae. Quality

ing pain perception. If this is contra-indicated or is

of life is reduced as pain interferes with sleep, daily

ineffective, amitriptyline is a reasonable alternative.

activities and enjoyment. Painful neuropathy is a

Pregabalin is a further alternative which can be used

risk factor for the development of depression.

alone or in addition to duloxetine or amitriptyline.

Chapter 14: Complications of diabetes / 325

Figure 14.7 NICE

Painful diabetic neuropathy

algorithm for

management of

painful neuropathy

in people with

diabetes.

Amitriptyline 10-75 mg daily

Duloxetine 60-120 mg daily

If duloxetine contraindicated

Switch to amitriptyline

Switch to pregabalin 150-600 mg daily

Add pregabalin 150-600 mg daily

Refer to pain specialist

Add tramadol up to 400 mg daily (4-h dosing)

Consider topical lidocaine

If these measures fail to control the pain, the patient

should be referred to a specialist pain clinic and

opiate analgesia may be needed. Tramadol is used

before considering more potent opiates such as mor-

phine. Topical anaesthetics may also be considered.

Autonomic neuropathy

In people with long-standing diabetes, autonomic

neuropathy may develop (Box 14.8). Symptoms are

unusual but may be distressing. Management is

often challenging and aims to relieve symptoms.

Figure 14.8 Plantar ulcer in a patient with diabetes.

The diabetic foot

Note how dry the skin appears and how the callous

Foot problems are a major cause of morbidity in

has built up around the ulcer. Image kindly provided by

people with diabetes

(Case history

14.3). Foot

Professor Cliff Shearman, University of Southampton.

ulceration is common, affecting up to

25% of

people with diabetes (Figure 14.8). Diabetes is the

commonest cause of non-traumatic lower limb

Major amputations are a tragedy because up

amputation in the developed world and in 85% of

to 85% are potentially preventable; however, this

cases amputation is preceded by foot ulceration.

requires a coordinated effort by a multidisciplinary

The rates of non-traumatic lower limb amputation

team of healthcare professionals. Strategies are

are almost 15 times higher than in people without

aimed at preventing foot ulcers and should be

diabetes. It is estimated that a leg is lost to diabetes

focused on those patients with recognized risk

somewhere in the world every 30 s. Foot ulceration

factors for the development of foot problems. These

is the commonest reason for hospitalization and the

efforts are not only clinically rewarding, but are also

most expensive complication of diabetes.

cost-effective and can even be cost-saving.

326 / Chapter 14: Complications of diabetes

Case history 14.3

Box 14.9 Cause of diabetic foot

ulcers

A 56-year-old woman develops an infected

Neuropathy

foot ulcer after a night out at a club. She

• Peripheral neuropathy results in a loss of

has had diabetes for 7 years and is

pain sensation:

treated with metformin 500 mg three times

daily and gliclazide 80 mg twice daily. Her

° Patients are unaware of injury to their

feet

HbA_1c is 9.0% (75 mmol/mol).

• Motor neuropathy leads to a characteristic

What is your immediate management?

posture of raised arch and clawed toes:

What are your long-term plans?

° Pressure is concentrated on the

metatarsal heads and heel

Answers, see p. 341

° Callus forms at these pressure points

° Haemorrhage or necrosis, which

commonly occurs within the callus, can

ulcerate

• Autonomic neuropathy:

° Reduced sweating leads to dry and

Box 14.8 Symptoms and signs of

cracked skin as a portal for infection

autonomic neuropathy

• Charcot arthropathy

Gastrointestinal

Peripheral vascular disease

• Gustatory sweating

• The reduced blood supply to the feet may

• Oesophageal dysmotility

compromise both nutrition and oxygen

• Gastroparesis

• Diabetic diarrhoea

Infection

Cardiovascular

• Postural hypotension

• Abnormal cardiovascular reflexes

• Cardiorespiratory arrest

• Neuropathic oedema

Pathogenesis of diabetic foot ulcers

• Increased peripheral blood flow

Diabetic foot ulcers are caused by a combination of

neuropathy and ischaemia and are frequently com-

Genitourinary

plicated by infection

(Box

14.9; Figure

14.8).

• Neuropathic bladder

Peripheral vascular disease (PVD) is a major con-

• Erectile dysfunction in men; sexual

tributor to the pathogenesis of foot ulcers. PVD

dysfunction in women

tends to affect distal vessels and occurs at a younger

age in people with diabetes. Although PVD rarely

Musculoskeletal

causes ulceration itself, the impaired blood supply

• Charcot arthropathy

compromises the ability to heal minor trauma or

infection. Peripheral neuropathy reduces sensation.

Metabolic

Consequently infection and trauma may not be

• Blunted counter-regulation responses to

perceived by the patient who continues to walk on

hypoglycaemia

the injured foot, causing more damage. Autonomic

neuropathy in the limbs reduces sweating and alters

Eyes

blood flow, resulting in dry skin that is prone to

• Abnormal pupillary reflexes

crack and fissure.

Chapter 14: Complications of diabetes / 327

Table 14.2 Principles of good self footcare

Box 14.10 Sites to be tested with

monofilament

Don’t

• Plantar aspect of first toe

Wash feet daily

Use corn cures

• First, third and fifth metatarsal heads

Check feet daily

Use hot water bottles

• Plantar surface of heel

Seek urgent treatment

Walk barefoot

• Dorsum of foot

of problems

Cut or file down

See a chiropodist

corns/callosities

Clinical examination can be corroborated by use of

regularly

Treat foot problems

Doppler ultrasound, which can also assess the ankle

Wear sensible shoes

yourself

to brachial blood pressure index, a further measure

Wear ill-fitting shoes

of blood flow to the feet.

Screening for foot disease

Management of diabetic foot ulcers

As the treatment of diabetic foot ulcers is difficult,

Diabetes impairs wound healing, which may be

prevention is vital. Patient education, assessment of

exacerbated by sustained pressure on the wound as

risk factors and regular examination are vital (Table

the neuropathic patient continues to walk on the

14.2).

painless ulcer. Consequently ulcers may be pro-

Screening for foot problems consists of four

longed. Offloading this pressure either by bed rest

parts:

or total contact casting will facilitate healing of the

• Enquiry about past or present ulceration

ulcer. The principle of total contact casting is that

• Inspection for abnormalities such as prominent

pressure is dispersed from the ulcer. The cast is not

metatarsal heads or clawed toes, hallux valgus,

removable, ensuring compliance. Removable casts

muscle wasting, Charcot deformity, or callus

that distribute pressure in a similar manner are

formation

available, but these are less effective than total

• Testing for neuropathy

contact casting. The casts should be removed weekly

• Palpation of foot pulses to detect ischaemia.

to inspect the ulcer, remove callus, and clean and

There has been considerable discussion about

debride the wound as necessary. Ulcers usually heal

the optimal means of testing for neuropathy.

in 6-12 weeks with this approach, but it is recom-

Examination of the feet may reveal distal loss of

mended that the cast is worn for a further 4 weeks

sensory modalities, such as vibration, touch, pin-

after healing to allow the repaired tissue to

prick and joint position sense, and temperature.

strengthen.

However, formal measurements of vibration sense

One of the first steps in managing a foot ulcer

with a biothesiometer and nerve conduction studies

is to determine whether infection is present or not.

have not been used routinely in clinical practice,

Infected ulcers are potentially medical emergencies

creating a lack of clinical standardization. More

as inattention can result in massive tissue loss and

recently, the introduction of a 10-g monofilaments

amputation. The diagnosis of infection is largely

has allowed reproducible assessments.

clinical as all bacteria colonizing an ulcer are poten-

The monofilament is applied perpendicular to

tially pathogenic. The foot should be inspected for

the foot and buckles at a force of 10 g (Box 14.10).

signs of purulent discharge, erythema, local warmth

The ability to feel that level of pressure provides

and swelling (Figure 14.9).

protective sensation against foot ulceration. The test

The severity of infection should be assessed. Mild

is repeated at various sites to detect any area where

infections are relatively superficial and limited; mod-

protective pain sensation is lost.

erate infections involve deeper tissues; while severe

Lower limb pulses, including dorsalis pedis and

infections are accompanied by systematic signs or

the posterior tibial pulse, should be palpated.

symptoms of infection or metabolic disturbances.

328 / Chapter 14: Complications of diabetes

Figure 14.9 Infected diabetic ulcer on the dorsum of

(a)

the foot. Image kindly provided by Professor Cliff

Shearman, University of Southampton.

Swabs should be taken to assess the type and sensitiv-

ity of the infecting bacteria. X-rays may help to diag-

nose osteomyelitis, although this should be assumed

if it is possible to probe the ulcer to bone. Magnetic

resonance imaging (MRI) or nuclear medicine tech-

niques may also help to confirm the diagnosis.

Antibiotics should only be used where there is

evidence of infection to reduce the selection of

(b)

antibiotic-resistant bacteria. In the case of mild

infection, ulcers can usually be treated in an out-

Figure 14.10 (a) The combination of infection and

patient clinic using oral broad-spectrum antibiotics

vascular disease puts the diabetic foot at risk of

targeted against the most likely mixture of aerobic

necrosis, as is seen in the toe of this patient. Image

and anaerobic bacteria. Treatment can be refined

kindly provided by Mr Graham Bowen, Former Chief

once the results of ulcer swabs are known and bacte-

Podiatrist, Southampton University Hospitals NHS

rial sensitivities determined.

Trust. (b) Moist gangrene. Note the difference in

More severe limb-threatening infections require

appearance between this figure and Figure 14.10 (a).

hospitalization and treatment with parenteral anti-

Image kindly provided by Professor Cliff Shearman,

biotics, while hyperglycaemia is usually treated with

University of Southampton.

intravenous insulin. Early surgical debridement is

often indicated. It may be necessary to revascularize

countries. Like many other aspects of diabetic foot

ischaemic limbs (Figure 14.10).

disease, this complication should be generally pre-

As can be appreciated above, the management

ventable. It occurs in a well-perfused foot and can

of diabetic ulcers is challenging and a number of

be divided into three phases:

novel approaches have been tried to improve healing

• Acute onset

(Box 14.11).

• Bony destruction

• Radiological consolidation and stabilization

Charcot arthropathy

Charcot arthropathy is a rare non-infective compli-

Acute onset

cation of severe neuropathy. Diabetes is the com-

Patients present with an acutely swollen hot foot

monest cause of Charcot arthropathy in developed

and about a third are painful (Figure 14.11). The

Chapter 14: Complications of diabetes / 329

Box 14.11 Novel adjuvant

Table 14.3 Features that differentiate acute

Charcot arthropathy from cellulitis

therapies used in the treatment of

diabetic foot ulcers

Charcot

Cellulitis

arthropathy

• Growth factors:

° E.g. platelet-derived growth factor

Oedema

Typical local and generalized

• Hyperbaric oxygen

may resolve

signs of infection may be present

• Negative pressure wound therapy:

with

More likely if ulcer is present,

elevation

° Utilizes a vacuum device over the wound

particularly if discharge is present

° Decreases tissue oedema

° Optimizes blood flow

° Removes pro-inflammatory cytokines

• Bioengineered skin substitutes:

casting should be continued until the swelling and

° Dorsum of foot

temperature in the foot has resolved.

Bony destruction

If treatment of the acute stage is delayed, the foot

can become deformed as bone is destroyed, often

very rapidly over a few weeks. Immobilization is the

treatment of choice. Preventing deformity is key as

this alters pressure distribution and predisposes the

foot to future ulceration, particularly on the plantar

surface as part of a ‘rocker-bottom’ deformity where

the alteration in foot architecture generates pressure

at the mid-point of the plantar surface rather than

the heel and metatarsal heads. (Figure 14.12).

Stabilization

Figure 14.11 Active Charcot arthropathy. Image

Ultimately the destructive process stabilizes after

kindly provided by Mr Graham Bowen, Former Chief

6-12 months. Rehabilitation is always necessary

Podiatrist, Southampton University Hospitals NHS

after a long period in a cast and reconstructive

Trust

surgery may be needed.

initiating event may be an injury, often trivial, that

Genitourinary and sexual problems of

causes bone fracture. Initital X-ray may be normal

diabetes

but a technetium bone scan will detect bony

Male problems

destruction.

It is important to differentiate between Charcot

Erectile dysfunction is a major sexual problem

arthropathy and cellulitis (Table 14.3). This can be

among men with diabetes (Case history 14.4). Its

difficult and so if in doubt, both conditions should

prevalence increases with age such that ∼60% of

be treated. Acute gout and deep vein thrombosis

men with diabetes over the age of 60 years are

may also masquerade as Charcot arthropathy.

affected. The overall prevalence is 35-40%.

The aim of treating Charcot arthropathy is to

In penile erection, nitric oxide relaxes vascular

prevent or minimize bony destruction. The foot is

smooth muscle of the corpus cavernosum, expand-

immobilized in a non-weight bearing cast, which

ing the cavernosal space and compressing outflow-

should be checked and replaced regularly. The

ing venules. This allows blood to flow into, but not

330 / Chapter 14: Complications of diabetes

injection into the corpus cavernosum or transure-

thrally. Apomorphine, a dopamine agonist, has

recently been introduced. Vacuum devices allow

blood to be drawn into the penis, while a constric-

tion band around the base of the penis prevents

blood leaving the penis, facilitating erection. There

is also a limited role for surgical insertion of a penile

prosthesis.

Case history 14.4

A 55-year-old man with a 10-year history

of diabetes presents with impotence. He

has no early morning erections. He

shaves normally and has a good

relationship with his wife. He drinks ½ a

Figure 14.12 Plantar ulcer in a patient with diabetes

bottle of wine daily. In addition to

whose foot has become deformed by a Charcot

diabetes, he has hypertension for which

arthropathy. Note also the amputation. Image kindly

provided by Mr Graham Bowen, Former Chief Podiatrist,

he takes atenolol and nifedipine, and

Southampton University Hospitals NHS Trust.

hypercholesterolaemia for which he takes

simvastatin.

out of, the penis. Erectile dysfunction in diabetes

What are the possible causes for his

mainly results from autonomic neuropathy and

erectile dysfunction?

endothelial dysfunction. Other contributory factors

What treatment would you suggest?

include drugs, psychological issues, and neurologi-

cal, endocrine and metabolic disorders.

Answers, see p. 341

When a man presents with erectile dysfunction,

a detailed history is needed to search for reversible

causes and to exclude wider sexual dysfunction from

Female problems

androgen deficiency (see Chapter 7). General treat-

ment includes improving glycaemic control, reduc-

Although less well described than in men, women

ing alcohol intake and substituting where possible

with diabetes may also have sexual problems,

drugs that may impair erection. First-line pharma-

including vaginal dryness and impaired sexual

cotherapy is with phosphodiesterase type 5 inhibi-

arousal. Genitourinary infections, in particular can-

tors, such as sildenafil (Viagra), vardenafil (Levitra)

didiasis, can be problematic and urinary tract infec-

and tadalafil (Cialis). These agents act by inhibiting

tions are frequent in women with poorly controlled

the breakdown of cyclic GMP, which is a second

diabetes, particularly if there is autonomic neuropa-

messenger of nitric oxide (review Chapter 3). As they

thy and bladder distension.

enhance erections following sexual stimulation, the

drugs are taken before intended sexual activity. They

are effective in

50-60% of men with diabetes.

Macrovascular disease

Phosphodiesterase type 5 inhibitors may cause severe

acute hypotension when used concomitantly with

Aetiology

nitrates and so this dual use is contra-indicated.

Other treatment options include the use of

Diabetes confers a two- to four-fold increased risk

prostaglandin E, which can be administered by

of myocardial infarction and stroke in men, and up

Chapter 14: Complications of diabetes / 331

to a

10-fold increased risk in pre-menopausal

phages, causing up-regulation of pro-coagulant and

women, who lose their normal pre-menopausal pro-

adhesive proteins.

tection against cardiovascular disease. Mortality fol-

Epidemiological studies have suggested a linear

lowing a myocardial infarction is greater in people

relationship between mean updated HbA_1c and the

with diabetes, with cardiovascular disease account-

incidence of macrovascular events, but this relation-

ing for 60-75% of all deaths in people with diabe-

ship is weaker than with microvascular events.

tes. Over the last decade, greater emphasis has been

However, in more recent studies, there appears to

placed on managing arterial risk factors.

be a ‘U-shaped’ relationship between cardiovascular

mortality and HbA_1c with a nadir at 7.5-8.0%

(58-64 mmol/mol). While there is benefit in treat-

Pathogenesis

ing marked hyperglycaemia (Figure 14.13), trials

The pathogenesis of atheroma in diabetes is consid-

attempting to normalize glucose from a baseline

ered to be the same as that in people without dia-

HbA_1c of ∼7.5% (58 mmol/mol) showed either no

betes, but it develops earlier and faster, and is more

effect or increased overall mortality. Adverse treat-

extensive and widespread (Box 14.12). There are

ment effects may have counter-balanced the benefi-

also major endothelial abnormalities, including

cial effects of reduced hyperglycaemia; for instance,

increased endothelial adhesiveness, impaired

improving glycaemic control in the type 2 diabetes

vasodilatation, enhanced haemostasis and increased

trials was associated with increased severe hypogly-

permeability.

caemia and weight gain, both of which may increase

cardiovascular risk. The duration of follow-up may

also be an issue; trials involving people with more

Hyperglycaemia

marked hyperglycaemia only found improved car-

diovascular outcomes 10 years after the end of the

There are several mechanisms by which hypergly-

trials (Figure 14.13).

caemia and AGEs might contribute to macrovascu-

It is possible that newer type 2 diabetes treat-

lar disease.

ments associated with weight loss and less hypogly-

AGEs cross-link vessel wall proteins causing

caemia may be associated with better cardiovascular

thickening and leakage, and trapping of plasma pro-

outcomes. Interestingly, reduced cardiovascular

teins in the sub-intimal layers. AGEs generate toxic

events and mortality rates were seen in people

reactive oxygen species that quench the vasodilator

treated with metformin in the UK Prospective

nitric oxide and so favour vasoconstriction. AGEs

Diabetes Study.

also interact with specific receptors on the endothe-

lium, smooth muscle cells, monocytes and macro-

Traditional cardiovascular risk factors

Traditional cardiovascular risk factors, such as

Box 14.12 Mechanisms leading to

smoking, hypertension, hyperlipidaemia and

accelerated atherosclerosis in

obesity, increase the risk of cardiovascular events in

people with diabetes

people with diabetes. In addition, with the exception

of smoking, these factors tend to cluster with higher

• Hyperglycaemia:

prevalence in those with diabetes. In the Munster

° Advanced glycation end-products

Heart study, for example, 49% of individuals with

(AGEs)

diabetes had hypertension,

24% had low high-

• Endothelial dysfunction

density lipoprotein (HDL)-cholesterol, and 37%

• Higher prevalence of traditional risk

had hypertriglyceridaemia, compared with

31%,

factors:

16% and 21%, respectively, in people without

° Hypertension

diabetes.

° Dyslipidaemia

Diabetes is associated with a dyslipidaemia

° Obesity

that is characterized by hypertriglyceridaemia, low

332 / Chapter 14: Complications of diabetes

Any DM-related

All-cause

event

Microvascular

mortality

-5

P = 0.44

-10

P = 0.04

P = 0.029

-15

P = 0.007

P = 0.014

P = 0.052

-20

-25

P = 0.001

P = 0.0099

–30

1997

2007

Figure 14.13 Lasting effect of improved glycaemic

the two groups. However, after a further follow-up

control on diabetes (DM)-related events, microvascular

period of up to 10 years (median 8.5 years), those

complications, myocardial infarction and all-cause

who had originally had intensive glycaemic control

mortality. The UK Prospective Diabetes Study

experienced not only significant reductions in

recruited 5102 individuals with newly diagnosed

microvascular complications but also improved

diabetes and randomized them to intensive or

macrovascular complications and decreased

standard glycaemic control. Over the 10-year trial, the

mortality. The implication is that early treatment of

glycated haemoglobin (HbA_1c) was on average 0.9%

hyperglycaemia has long-lasting beneficial effects

(10 mmol/mol) lower in the intensive group. At the end

both in terms of microvascular and macrovascular

of the trial, there was a significant decrease in

disease, but the benefits for macrovascular disease

microvascular events but not macrovascular events or

take a long time to be realized. MI, myocardial

mortality. After the end of the trial, just over 3000

infarction. Data adapted from Holman RR et al. N

people entered an observational study. After 6 months

Engl J Med 2008;359:1577-89.

there was no difference in glycaemic control between

HDL-cholesterol concentrations and small dense

Case history 14.5

LDL-cholesterol. These abnormalities of dyslipi-

daemia are improved, but not reversed completely,

A 67-year-old man with type 2 diabetes for 12

by tight glycaemic control. Hypertension is twice as

years was treated with gliclazide 160 mg

common in people with diabetes and occurs yet

twice daily and pioglitazone 30 mg daily as

more frequently in those who have nephropathy.

he was intolerant of metformin. HbA_1c was

This concept of clustering of cardiovascular risk

8.5% (69 mmol/mol). He has a past medical

factors is encapsulated in the concept of the meta-

history of myocardial infarction. He has

bolic syndrome (Box 14.13). The precise utility of

microalbuminuria but no other microvascular

this diagnosis is unclear, but it serves to remind clini-

complications. His weight is 120 kg, blood

cians to think of multiple rather than single risk

pressure 150/100 mmHg, serum total

factors.

cholesterol 5.1 mmol/L (197 mg/dL),

HDL-cholesterol 0.7 mmol/L (27 mg/dL) and

triglycerides 2.0 mmol/L (177 mg/dL).

Management of cardiovascular disease

What do you do now?

Management of cardiovascular complications invol

ves aggressive and systematic attention to each of

Answer, see p. 341

the risk factors (Case history 14.5).

Chapter 14: Complications of diabetes / 333

Aspirin is not licensed for the primary preven-

Box 14.13 International Diabetes

tion of vascular events, but has been used extensively

Federation criteria for the

for this purpose. Recent studies, however, have sug-

metabolic syndrome

gested that the risk of gastrointestinal haemorrhage

outweighs the potential benefit of reduced throm-

• Ethnic specific waist circumference:

boembolic events, but these may need to be recon-

° White European (≥94 cm for men

sidered in light of the most recent findings that

and ≥ 80 cm for women)

aspirin protects against cancer. Therefore, the

° Chinese and South Asian (≥90 cm for

balance of benefits and risks of aspirin should be

men and ≥ 80 cm for women)

considered carefully for each individual.

Angina in people with diabetes should be

Plus two of the following or treatment of the

managed conventionally. Cardioselective β-blockers

following:

may be particularly useful. If symptoms worsen,

• Hypertriglyceridaemia (≥1.69 mmol/L or

early consideration should be given to coronary

150 mg/dL)

angiography and revascularization. Acute coronary

• HDL-cholesterol:

syndrome and myocardial infarction have higher

° Men <1.04 mmol/L (40 mg/dL)

mortality rates among people with diabetes than

° Women <1.29 mmol/L (50 mg/dL)

within the general population, and therefore inten-

• Hypertension ≥ 130/85 mmHg

sive therapy to revascularize the lesion followed by

• High fasting glucose ≥ 6.1 mmol/L

treatment with low molecular weight heparin, a

(≥ 110 mg/dL)

β-blocker and a platelet inhibitor is needed. Strict

blood glucose control at the time of the acute coro-

Patients should be advised to quit smoking and

nary event also improves survival

(Case history

blood pressure should be tightly controlled to less

14.6).

than

130-140/70-80 mmHg. There is evidence

that the use of ACE inhibitors or angiotensin recep-

Case history 14.6

tor blockers may confer additional benefit.

HMGCoA reductase inhibitors (‘statins’; review

A 60-year-old man without a history of

synthesis of hormones from cholesterol in Chapter

diabetes presents with an uncomplicated

2, Figure 2.5) reduce the incidence of cardiovascular

acute myocardial infarction. His blood

events as either primary or secondary prevention by

glucose on admission is 11.0 mmol/L

∼30% in the general population and in people with

(198 mg/dL). His blood pressure is

diabetes. They should be offered to all people with

150/100 mmHg. Serum total cholesterol is

diabetes with pre-existing cardiovascular disease.

6.0 mmol/L (232 mg/dL), HDL-cholesterol

Statins should also be considered in those without

is 1.0 mmol/L (39 mg/dL) and triglycerides

evidence of cardiovascular disease if other risk

are 2.0 mmol/L (177 mg/dL).

factors are present, including age >40 years, the

presence of microalbuminuria or proteinuria, and

What are your immediate plans?

long duration of diabetes. The aim of treatment is

to reduce total cholesterol to less than 4.0 mmol/L

Answer, see p. 342

(∼150 mg/dL) and LDL-cholesterol to less than

2.0 mmol/L (∼75 mg/dL). The success of statins has

largely eclipsed other lipid-lowering therapy, but if

they are not tolerated or alone fail to bring the

Coronary revascularization is technically more

lipid profile to the target, there may be a place

difficult in people with diabetes because of the

for nicotinic acid, omega fish oils and ezetimibe

diffuse and distal pattern of coronary atheroma.

(a drug that inhibits the absorption of cholesterol

Coronary angioplasty with stenting is the preferred

and thereby disrupts the usual enterohepatic

procedure for accessible large-vessel disease.

circulation).

Coronary artery bypass grafting is reserved for

334 / Chapter 14: Complications of diabetes

ence every day. The knowledge of the condition and

Box 14.14 Cancers that occur

its long-term complications may affect self-esteem

more frequently in people with

and can adversely affect quality of life.

diabetes

The diagnosis of diabetes may provoke a grief

reaction and multidisciplinary support is needed

• Liver

during this period. Engagement is required to help

• Pancreas

the person with diabetes come to terms with their

• Colon and rectum

diagnosis and take control; too often, people feel

• Breast

that their diabetes or healthcare team take control

• Endometrium

of them. For some, acceptance of the diagnosis and

• Bladder

its demands may take a long time. Therefore, emo-

tional and psychological support and techniques are

required long term as well as at diagnosis.

difficult or multiple occlusions and for re-stenosis

All members of the diabetes team should be

after angioplasty.

trained to recognize and address basic psychological

issues. While much support may be gained through

healthcare professionals, it is important to recognize

Cancer

that other sources of support exist, including friends

Diabetes, particularly type 2 diabetes, is associated

and family, patient support groups and national

with an increased prevalence of a number of cancers

charities, such as Diabetes UK and the American

(Box 14.14), but reduced risk of prostate cancer.

Diabetes Association.

The underlying reason for this association is

Overall quality of life for those with diabetes is

unclear, but may relate to shared risk factors for the

similar to that of people with other chronic condi-

two diseases, such as ageing, obesity, diet and physi-

tions, such as arthritis. However, poor health-related

cal inactivity. It has been postulated that hyperin-

quality of life is associated with biomedical compli-

sulinaemia, hyperglycaemia and inflammation seen

cations, being female, physical inactivity, low

in diabetes may all increase the risk of cancer.

income and recurrent hypoglycaemia. Interventions

Recently, there has been debate about the role

to reduce psychological distress include individual

of antidiabetes treatments in the development of

psychotherapy or counselling, and group therapy.

cancer. There is some early evidence to suggest that

Despite the imperative to support the psycho-

metformin is associated with a lower risk of cancer,

logical needs of those with diabetes, the lack of

while exogenous insulin, particularly insulin

psychological support for those with diabetes is well

glargine, is associated with an increased cancer risk.

recognized, with few diabetes services having ade-

However, much more research is needed to clarify

quate access to specialist psychological support.

this, and at present cancer risk should not be a

major factor when choosing diabetes treatments.

Depression

Nevertheless, it seems appropriate that people with

diabetes should be encouraged by their diabetes

The prevalence of depression is increased two- to

team to undergo appropriate screening for cancer,

three-fold among people with diabetes, particularly

as recommended for the general population.

amongst those taking insulin or those with diabetic

complications. As well as the effects on mental well-

being, depression adversely affects diabetes care.

Psychological complications

People with depression and diabetes are less likely to

Diabetes places significant demands on those with

exercise, eat healthily, monitor glucose and take

the condition. It requires major lifestyle changes,

medication as prescribed. Their glycaemic control is

complex and frequently invasive medication regi-

worse, the incidence of both microvascular and mac-

mens, as well as monitoring by invasive blood

rovascular complications is increased, life-expectancy

testing. For many, the disorder is a continual pres-

is shortened and health costs are increased.

Chapter 14: Complications of diabetes / 335

nesses, including schizophrenia and bipolar illness,

Box 14.15 Simple screening

are associated with an increased risk of developing

questions that can be used to

of diabetes.

identify people with depression

Cognitive dysfunction

• During the past month, have you been

bothered by having little interest or

Type 1 diabetes has a modest effect on cognitive

pleasure in doing things?

function. Measures of intelligence, psychomotor

• During the past month, have you been

speed and academic achievement are the most

bothered by feeling down, depressed or

affected, with children showing greater deficits than

hopeless?

people who are diagnosed with diabetes during

• If the answer to either is ‘yes’, ask if the

adulthood. These changes occur early in the natural

patient wants help with this problem.

history of diabetes, within 2-3 years after diagnosis.

• If the answer to this is also ‘yes’, then it is

It was previously thought that hypoglycaemia was

reasonable to make a formal assessment

the main cause of the dysfunction but it appears

and offer treatment.

that it only affects cognition if it is profound and

protracted. By contrast, chronic hyperglycaemia

may be important in the aetiology of this problem.

Healthcare professionals need to be aware of the

Older adults with type 2 diabetes have memory

effects of diabetes on mental well-being. Several

deficits. Chronic hyperglycaemia and the presence

short questionnaires have been developed to iden-

of other complications, in particular retinopathy

tify those with depression and clinicians should

and peripheral neuropathy, predict this problem.

consider these during the consultation (Box 14.15).

While it is well established that treatment of depres-

How diabetes care can reduce

sion is effective at ameliorating depressive symp-

complications

toms, it has only recently been shown that both

psychological and pharmacological therapies are

High-quality diabetes care is essential for all people

also effective in improving diabetes outcomes.

with diabetes in order to achieve the best possible

Psychological therapies, such as cognitive

health outcomes. The growing numbers of people

behavioural therapy, are particularly effective, pos-

with diabetes has meant that traditional specialist

sibly because they provide the individual with

care services are oversubscribed and new models of

coping strategies to manage their diabetes more

care are being developed. No single person or setting

effectively.

can provide all that is required in diabetes care.

Children show remarkable psychological resil-

Consequently both primary and secondary sectors

ience to the diagnosis of diabetes, but nevertheless

are needed to ensure delivery of the appropriately

about one-third report some psychological distress

structured and integrated care that is the hallmark

shortly after diagnosis. This ‘adjustment disorder’ is

of a high-quality diabetes service.

characterized by symptoms of depression, anxiety,

People with diabetes should be seen as individu-

social withdrawal and sleep disturbances. A similar

als with a condition that has medical, personal and

adjustment reaction is often seen in parents, par-

social consequences, rather than passive recipients

ticularly mothers, of newly diagnosed children.

of healthcare. The person living with diabetes will

The relationship between diabetes and mental

spend the vast majority of their time managing

illness is complex. While depression was tradition-

their own diabetes and only an estimated

ally viewed as an understandable reaction to the

of their time in contact with healthcare profession-

diagnosis of a life-long condition with considerable

als. Therefore, empowering the individual with

treatment demands and complications, other bio-

the responsibility of managing diabetes is critical.

logical aspects of diabetes, such as hyperglycaemia

Contact with the diabetes healthcare team

itself, may contribute to the development of depres-

requires well-defined, clear aims and objectives

sion. Furthermore, depression and other mental ill-

delivering maximum benefit from the consultation,

336 / Chapter 14: Complications of diabetes

and providing the individual with the necessary

Box 14.16 Issues to consider

skills and coping strategies to manage their

during the diabetes consultation

diabetes.

The multidisciplinary diabetes team involves

Lifestyle

dieticians, podiatrists, pharmacists, opticians

(or

• Smoking

equivalent) and psychologists, as well as doctors and

• Driving and its legality [Driver and Vehicle

nurses. Diabetes specialist nurses play a crucial role,

Licensing Agency (DVLA) in the UK

with important duties in clinical care, counselling

(www.dvla.gov.uk)]

and advice, and education to both people with dia-

• Weight and diet (including alcohol)

betes and other healthcare professionals.

• Physical activity

Care must be structured and systematic to

• Review social situation (e.g. carers)

ensure that patients receive appropriate advice and

• Pregnancy and pre-pregnancy advice

management on the different aspects of care (Box

14.16). It is important that complications are con-

Macrovascular screening

sidered and should be sought at least annually.

• Medication review

• Lipids

• Blood pressure

Diabetes and pregnancy

• Aspirin

Diabetes is the commonest chronic medical problem

• Angina

in pregnant women, affecting 2-5% of all pregnan-

• Claudication:

cies in the UK. Gestational diabetes (GDM) is dia-

° Consider referral for intervention if

betes that is diagnosed for the first time in pregnancy

deterioration of symptoms

(see Chapter 11). Among other pregnancies com-

• Transient ischaemic attacks/

plicated by diabetes are women with pre-existing

cerebrovascular accident

type 1 diabetes and an increasing number of women

Glycaemia

with pre-existing type 2 diabetes, a combined con-

• HbA_1c

sequence of an increasing prevalence of type 2 dia-

• Hypoglycaemia

betes and women delaying pregnancy until they are

• Oral medication

older.

• Insulin:

Injection sites

Effect of diabetes on pregnancy

° Technical problems

Diabetes can affect pregnancy from conception to

Microvascular screening

birth and may have life-long consequences for the

• Retinal photography (but including other

offspring. Women with diabetes may find it harder

aspects of eyecare)

to conceive and are at increased risk of miscarriage.

• Microalbuminuria

Hyperglycaemia is teratogenic during the first tri-

• Feet

mester. There is a six- to 10-fold increased risk of

• Erectile dysfunction

all congenital malformation with heart and central

nervous system congenital abnormalities being the

Education

commonest. However, the caudal regression syn-

• Assess need for formal education

drome (sacral agenesis) is the most specific for dia-

• Promote patient charities, e.g. Diabetes

betes, being 200 times commoner in diabetic than

UK, American Diabetes Association

normal pregnancies.

During the second and third trimesters, mater-

Mental well-being

nal hyperglycaemia leads to accelerated fetal growth

• Diabetes-related distress

and macrosomia (defined as a baby whose weight

• Depression

is above the 95th centile for gestation age). This

Chapter 14: Complications of diabetes / 337

increases the risk of an operative or traumatic birth,

make informed decisions. This can only happen if

which may result in brachial plexus injury. Despite

she is educated about the risks of diabetes in preg-

their size, a baby born to a mother with diabetes

nancy and plans the pregnancy. Therefore, pre-

behaves like a premature baby in many ways; the

conception advice, education and planning should

risk of respiratory distress, jaundice and hypoglycae-

begin once a woman reaches childbearing age in

mia are all increased. In the later stages of preg-

adolescence.

nancy, pre-eclampsia and preterm labour are also

commoner in women with diabetes. The risk of

Pre-conception care

stillbirth and perinatal death is three- to five-fold

Pre-conception care is critical for good outcomes.

higher than in the general population.

Many centres run specific pre-conception clinics to

In adulthood, offspring of mothers with diabe-

allow these issues to be discussed more fully. It is

tes have a greater risk of obesity and diabetes

important to check for microvascular and macrov-

themselves.

ascular complications. Potentially harmful drugs

Tight control of blood glucose will reduce all

should be discontinued and other medical therapy

pregnancy-related complications of diabetes, but

reviewed. The insulin regimen should be adjusted

even in the best centres, the outcomes for women

to optimize glycaemic control without inducing

with diabetes and their pregnancies remain worse

hypoglycaemia. Women with pre-existing diabetes

than for the general population.

have a higher risk of neural tube defects (spina bifida

and anencephaly), and so a higher dose of folic acid

(5 mg) is recommended while trying to conceive to

Effect of pregnancy on diabetes

prevent this. Once a positive pregnancy test is

Pregnancy induces a state of insulin resistance that

obtained, fetal neurogenesis has already begun.

is maximal in the second and third trimesters.

Largely caused by placental hormones, this encour-

Antenatal care

ages nutrient transfer to the growing fetus. The

Once the pregnancy is confirmed, women should

increase in insulin resistance affects diabetes man-

attend a specialized joint antenatal diabetes clinic.

agement with insulin requirements typically going

Regular contact with the diabetes team is important

up by 50-100% in the second half of pregnancy.

to facilitate suitable adjustment to the insulin

By contrast, the insulin requirement may fall

regimen as insulin requirements change. The

in the first trimester, risking increased frequency

women should be supplied with concentrated

and severity of hypoglycaemia and hypoglycaemia

glucose solution and glucagon injections because of

unawareness.

the increased risk of hypoglycaemia and ‘hypo’ una-

Pregnancy may accelerate diabetic retinopathy

wareness. Their partners should be instructed how

and nephropathy, in part because of rapid tighten-

to use the glucagon. It is important to screen for

ing of glycaemic control and in part because of the

retinopathy regularly during the pregnancy.

pregnancy itself.

Diabetic ketoacidosis is frequently lethal to the

fetus and so women should be educated about

the early identification of this and provided with

Management of the diabetic pregnancy

the means to test for urinary or blood ketones. If

diabetic ketoacidosis occurs, the woman should be

Pre-existing diabetes

admitted and the ketoacidosis treated as an

The outcome of a diabetic pregnancy is heavily

emergency.

dependent on the optimization of glycaemic control

A detailed ultrasound scan for fetal anomalies,

from the outset of pregnancy and so management

including a four-chamber view of the fetal heart

begins well before the woman considers pregnancy.

and outflow tracts, should be offered at

18-20

Planning is the key to a successful and healthy preg-

weeks. Growth scans and other tests of fetal well-

nancy. Treatment and care should take account of

being should also be performed during the third

the woman’s needs and preferences to allow her to

trimester.

338 / Chapter 14: Complications of diabetes

Birth

Box 14.17 Major risk factors for

Most babies born to mothers with diabetes are

gestational diabetes

delivered before term because of the higher risk of

stillbirth. For many women this will involve induc-

• BMI above 30 kg/m²

tion of labour or elective caesarean section. During

• Previous macrosomic baby weighing

labour it is important that glycaemic control is

4.5 kg or above

maintained and this is usually achieved by an intra-

• Previous gestational diabetes

venous insulin and glucose infusion.

• First-degree relative with diabetes

• Family origin with a high prevalence of

diabetes:

Postnatal care

° South Asian, black Caribbean and

Following birth, the insulin requirement drops

Middle Eastern

quickly and most women will return to their pre-

conception doses. Where possible, the baby should

remain with the mother. As the baby is at increased

dence regarding the effects of milder degrees of

risk of hypoglycaemia, early feeding should be

hyperglycaemia on the fetus and the benefits

encouraged with breast-feeding being the preferred

of treating this. The International Association of

option. Maternal glucose should be monitored as

Diabetes and Pregnancy Study Groups (IADPSG)

breast-feeding may increase the risk of hypoglycae-

has recently published a consensus document rec-

mia. Neonatal glucose should also be assessed regu-

ommending that the diagnostic criteria for GDM

larly until it is clear that the pre-feeding glucose

should be changed, with the hope of achieving

levels are being maintained in the normal range.

international harmonization. While their recom-

mendations are based on sound epidemiological

findings, they have not been backed up by high-

Gestational diabetes

quality randomized controlled trials and further

GDM is defined as diabetes occurring for the first

research is needed to assess the clinical benefit and

time in pregnancy. Its importance was first recog-

cost-effectiveness of the changes.

nized around 40 years ago when it became apparent

The management of GDM begins with lifestyle

that women with GDM were more likely to develop

modification. Although the diet should provide suf-

diabetes in later life. More recently, the dangers of

ficient calories and nutrients to meet the needs of

maternal hyperglycaemia to the fetus have been

the pregnancy, micronutrient-rich foods such as

fully appreciated. It occurs in at-risk women because

fruit, vegetables and low-fat dairy products rather

their pancreatic β-cells are unable to secrete suffi-

than energy-dense high-fat foods will help control

cient insulin to meet the increased insulin require-

maternal glycaemia. The woman should be encour-

ments of pregnancy (Box 14.17). The risk factors

aged to include at least 30 min/day of physical activ-

for GDM are the same as for type 2 diabetes and

ity in her daily routine.

so, GDM can be regarded as the early unmasking

When this is insufficient to control the glucose,

of a metabolic abnormality brought on by the

pharmacotherapy is required. Although insulin is

demands of pregnancy. In a few cases, GDM may

the most commonly used means of maintaining

unmask pre-clinical type 1 diabetes.

glucose control, certain oral hypoglycaemic agents,

There is a lack of international agreement

metformin and glibenclamide (glyburide), may be

regarding diagnosis of GDM, in terms of the

used safely in pregnancy.

amount of glucose to be used (75 or 100 g) during

Approximately 50% of women with GDM will

the oral glucose tolerance test (OGTT), diagnostic

develop diabetes (mostly but not exclusively type 2)

cut-off values and number of abnormal values

within 10 years of the pregnancy. They should be

required to make the diagnosis (Table 14.4). The

targeted for lifestyle intervention to reduce their risk

discrepancies in the diagnostic criteria have arisen

and should be screened regularly for diabetes (see

largely because of the absence of high-quality evi-

Chapter 13).

Chapter 14: Complications of diabetes / 339

Table 14.4 Comparison of diagnostic criteria for gestational diabetes

Association

Glucose

Number of high

Fasting

1 h glucose

2 h glucose

load (g)

readings needed

glucose

IADPSG

≥1

5.1 mmol/L

10.0 mmol/L

8.5 mmol/L

(90 mg/dL)

(180 mg/dL)

(153 mg/dL)

WHO

≥1

7.0 mmol/L

7.8 mmol/L

(126 mg/dL)

(140 mg/dL)

Former ADA*

100

≥2

5.3 mmol/L

10.0 mmol/L

8.6 mmol/L

(95 mg/dL)

(180 mg/dL)

(155 mg/dL)

ADIPS

≥1

5.5 mmol/L

8.0 mmol/L

(100 mg/dL)

(144 mg/dL)

CDA

≥2

5.3 mmol/L

10.6 mmol/L

8.9 mmol/L

(95 mg/dL)

(190 mg/dL)

(160 mg/dL)

EASD

≥1

6.0 mmol/L

9.0 mmol/L

(108 mg/dL)

(162 mg/dL)

NZSSD

≥1

5.5 mmol/L

9.0 mmol/L

(100 mg/dL)

(162 mg/dL)

*The ADA has now adopted the IADPSG diagnostic criteria.

IADPSG, International Association of Diabetes and Pregnancy Study Groups; WHO, World Health Organization; ADA,

American Diabetes Association; ADIPS, Australasian Diabetes in Pregnancy Society; CDA, Canadian Diabetes Association;

EASD, European Association for the Study of Diabetes; NZSSD, New Zealand Society for the Study of Diabetes.

Social aspects of diabetes

Box 14.18 Advice to reduce the

risk of a road traffic accident

Diabetes affects many aspects of the daily lives of

people with the condition.

• Check blood glucose before driving and

regularly on long journeys:

Driving

° Testing kit should be available within the

vehicle

The main issues for drivers with diabetes are

• Take frequent rests with snacks and meals

hypoglycaemia and visual impairment from either

• Ensure that there is fast and longer-acting

retinopathy or cataract. Disability from leg amputa-

carbohydrate in the vehicle in case of

tion or neuropathy may also affect the ability to

hypoglycaemia

drive safely.

• Do not drive if hypoglycaemia occurs:

Drivers with diabetes must take precautions to

° Stop the car if driving

avoid hypoglycaemia while driving as this may

° Turn off the engine and remove the keys

impair motor skills and judgement (Box 14.18).

from the ignition

Although people with diabetes are not involved in

° Leave the driver’s seat

more accidents than the rest of the population,

• Do not drive for at least 45 min after the

hypoglycaemia is the commonest cause of accidents

glucose has returned to normal following

in this group. Impaired awareness of hypoglycaemia

an episode of hypoglycaemia

is a relative contra-indication to driving and these

340 / Chapter 14: Complications of diabetes

individuals need extra blood glucose testing prior to

with diabetes or others. This includes work in the

and during breaks in driving.

Armed Forces, civil aviation or emergency services.

In most countries, the licence of a driver with

Commercial driving (e.g. of public transport or

diabetes is legally restricted in duration and is

goods vehicles) or work in dangerous areas such as

subject to medical review to assess fitness to drive.

offshore or overhead working is restricted. While

In most countries, drivers with diabetes are there-

some restriction is justifiable, it is important to

fore required to inform the relevant authorities of

recognize that diabetes is not a bar to most occupa-

their diagnosis.

tions and people with diabetes should not be dis-

criminated against on the grounds of disability.

Employment

Certain employment opportunities are restricted

where hypoglycaemia may pose a risk to the worker

Key points

• Diabetes is associated with a number of

• The cause of macrovascular disease is

long-term complications

multifactorial and so a systematic review of

• These can be divided into microvascular

all cardiovascular risk factors is needed

and macrovascular

• Diabetes is associated with a number of

• Microvascular complications include:

psychological sequelae including diabetes-

° Retinopathy

related distress and depression

° Nephropathy

• Pregnancy outcomes in diabetes are worse

° Neuropathy

than in the general population, but may be

• The aetiology of microvascular

improved by assiduous glycaemic control

complications is not fully understood, but

• A systematic approach to the management

improved glycaemic control and blood

of diabetes is needed with a

pressure can slow progression

multidisciplinary team.

• The burden of myocardial infarction, stroke

• Diabetes has a number of social

and peripheral vascular disease is

implications for driving and employment

increased in people with diabetes

Answers to case histories

Case history 14.1

eye as a result of correction of the

hyperglycaemia. Prior to treatment glucose

It is highly unlikely that she has developed

equilibrates between the eye and blood.

diabetic retinopathy as this is rarely seen in

When the glucose is lowered in the blood,

the first 5 years after diagnosis in people with

this sets up an osmotic gradient between the

type 1 diabetes. In contrast, 20% of people

eye and the blood. Water flows down the

with type 2 diabetes have retinopathy at

osmotic gradient. This leads to swelling of

diagnosis. Retinopathy is frequently

the eye and in particular the lens, resulting in

asymptomatic in its earliest stages.

a refractory defect.

The most likely explanation for the blurred

With time, the glucose concentration in the

vision is a change in osmotic pressure in the

eye falls and the refractory defect corrects itself.

Chapter 14: Complications of diabetes / 341

From a clinical perspective, it is important

opportunity to assess her feet for neuropathy

to warn patients about this phenomenon to

and peripheral vascular disease. Advice and

prevent their understandable anxiety and

education about foot care and appropriate

also to advise them not to replace their

shoes should be given.

glasses during this period as their eye

prescription will undoubtedly change as the

Case history 14.4

glucose comes under control.

There are a number of reasons why this man

may have developed erectile dysfunction. It

Case history 14.2

is likely that the cause is organic because of

The combination of uncontrolled

the lack of early morning erections.

hypertension, smoking and proteinuria

Furthermore, he has a good relationship with

coupled with deterioration in renal function in

his wife. Diabetes-induced autonomic

response to ACE inhibition suggests renal

neuropathy and endothelial dysfunction are

artery stenosis. This is commoner in people

likely to be major contributors, while his

with type 2 diabetes and is a differential

antihypertensive medication, simvastatin and

diagnosis in someone with proteinuria.

excessive alcohol intake may also worsen

Clinical features may include an abdominal

the erectile dysfunction.

bruit and evidence of peripheral vascular

It is important to institute simple measures

disease (absent peripheral pulses).

such as advice to reduce his alcohol

Conventional angiography is the investigation

consumption. It may be possible to switch

of choice in many centres, but spiral

some of the antihypertensives to drugs that

computed tomography and magnetic

are less associated with erectile dysfunction.

resonance angiography have begun to

However, this must be balanced against the

replace conventional angiography. Isotope

need for cardioprotective drug treatment. The

renography can provide an estimate of renal

drug of choice for this man would be a

function but is of limited value when there is

phosphodiesterase type 5 inhibitor, such as

bilateral disease or renal function is seriously

sildenafil.

impaired. Treatment must be tailored to the

individual; it may be possible to control the

Case history 14.5

hypertension with additional antihypertensive

This man is at high risk of further

agents, but angioplasty may improve renal

cardiovascular events and all risk factors

function as well as reduce blood pressure.

should be targeted. His total cholesterol is

above the ideal and so introducing a statin is

Case history 14.3

the most important step. His HDL-cholesterol

An infected foot ulcer in a patient with

is low and nicotinic acid or fish oils may be

diabetes is potentially a medical emergency.

indicated if dyslipidaemia is not corrected by

Left untreated it can develop into a limb-

the statin. His blood pressure is above ideal

threatening condition within a few days.

and needs aggressive treatment. Although

Treatment will include debridement of the

the blood pressure target is more important

ulcer, culture of swabs and broad-spectrum

than the agent used, it is likely that an ACE

antibiotics. Pressure must be taken off the

inhibitor or angiotensin receptor blocker

foot and so bedrest should be advised.

should be included as he has

It is important to obtain good glycaemic

microalbuminuria. He is overweight and

control to improve healing and resolution of

efforts should be made to help bring down

the infection. Depending on the severity of

his weight through lifestyle modification. His

the infection, she may need insulin acutely.

glycaemic control is not ideal and the use of

Her presentation provides a good

a GLP-1 analogue is likely to be of benefit as

344 / Chapter 15: Obesity

Cross-reference

■ Obesity is a strong risk factor for type 2 diabetes. The relationship between these two

conditions is described in Chapter 13

■ Appetite is regulated by the hypothalamus, which is described in Chapter 5

■ One short-term regulator of appetite is gastrointestinal endocrine function. Various

gastrointestinal hormones are described in Chapter 10, while analogues of glucagon-like

peptide 1 (GLP-1) are discussed in Chapter 13

The global prevalence of obesity has increased dra-

Box 15.2 The WHO definitions

matically over the last 30 years. It is associated with

of underweight, overweight

a range of medical and psychological complications

and is one of the most important public health

and obesity

problems of our time. Despite this, the trend of

• Underweight - BMI < 18.5 kg/m²

obesity continues to increase, indicating that current

• Normal weight - BMI 18.5-25 kg/m²

preventative measures are failing. Although there is

• Overweight - BMI > 25 kg/m²

a high degree of heritability for obesity, the rapid

• Obese - BMI > 30 kg/m²

rise in prevalence suggests that environmental

• Morbidly obese - BMI > 40 kg/m²

factors, such as altered diet and decreased energy

expenditure, are more important factors in the

The definitions of obesity and being overweight

development of today’s epidemic.

are based on actuarial data that show that mortality

Body weight is tightly regulated; even small mis-

has a J-shaped relation to BMI, with mortality

matches of less than 100 kcal between daily energy

being lowest within the BMI range of 20-25 kg/m²,

intake and expenditure may result in massive obesity

but increasing at BMIs below and particularly above

in the long term.

this range (Box 15.2). The effect of low BMI on

Management of the individual with obesity is

mortality may have been over-estimated because of

challenging. There is much pessimism regarding

potential confounders. Smoking and intercurrent

weight reduction programmes and it has been said

illness may cause weight loss per se, while leading to

that ‘most obese people do not enter treatment, most

increased mortality (Figure 15.1).

who do fail to lose weight and most who lose weight

re-gain it’.

Why worry about weight excess?

‘Thou seest that I have more flesh than another man and

What is obesity?

therefore more frailty…’

Normal weight and degrees of either overweight or

(King Henry IV Part 1 Act III, Scene III)

underweight are classified by the World Health

It is estimated that obesity reduces life-expectancy

Organization (WHO) using body mass index (BMI)

by around 9 years and accounts for 30,000 deaths

(Box 15.1). The classification is based on data from

in the UK per annum. Overweight and obesity are

white Europeans, and for individuals of other eth-

also associated with significant morbidity via a

nicities, in particular people from South Asia, the

number of metabolic and cardiovascular complica-

upper limit of normal BMI needs to be reduced.

tions, musculoskeletal disease and several cancers

(Table 15.1). Obesity is costly both in terms of

Box 15.1 How to calculate body

the direct medical treatment costs caring for its

mass index?

complications and indirect costs through lost

Body mass index is calculated according to

productivity.

the formula:

Obesity increases the risk of diabetes, dyslipi-

Weight in kilograms/(height in metres)²

daemia and insulin resistance by more than three-

Chapter 15: Obesity / 345

Figure 15.1 Relationship

2.5

between body mass index

(BMI) and relative risk of

Men

all-cause mortality in American

All women

men and women. Note how the

Non-smoking women

with stable weight

J-shaped relationship

1.5

disappears in women when

only non-smoking women with

stable weight are considered.

0.5

BMI

Table 15.1 Health risks of obesity

Relative risk >3

Relative risk 2-3

Relative risk 1-2

Diabetes

Cardiovascular

Cancers - post-menopausal breast, endometrial, colon

disease

Gallbladder disease

Hypertension

Reproductive hormone abnormalities - polycystic

ovarian syndrome, impaired fertility, fetal defects

Dyslipidaemia

Osteoarthritis

Back pain

Insulin resistance

Hyperuricaemia

↑ Anaesthetic risk

Breathlessness

Gout

Sleep apnoea

fold, while increasing that of coronary heart disease

The limitations of body mass index

and hypertension two- to three-fold. It is estimated

As the health risks associated with obesity relate to

that up to 80% of all new cases of diabetes can be

the excess storage of body fat and in particular

attributed to obesity. The risk of developing type 2

visceral fat, certain individuals will be misclassified

diabetes increases across the normal range

(see

by BMI. For any given BMI, women have a higher

Chapter 13); however, the risk of diabetes in a

percentage of body fat than men (Box 15.3). This

middle-aged woman with a BMI of greater than

can lead to the anomalous situation where a lean

35 kg/m² is 93.2 times greater than in a woman

but heavily muscled young male bodybuilder may

whose BMI is less than 22.5 kg/m².

have a higher BMI than a middle-aged obese

There is compelling evidence that our society

discriminates against ‘fat people’ and this is damag-

ing to the psychological well-being of obese indi-

viduals. Obese women are likely to have left school

Box 15.3 Percentage body fat in

earlier, are less likely to be married and have higher

men and women

rates of household poverty than women who are not

In adult men of average weight, the expected

overweight. These findings are independent of base-

percentage body fat is 15-20%

line socioeconomic status and are not seen in people

In women of average weight, the expected

with other chronic conditions such as asthma or

percentage body fat is 25-30%

musculoskeletal disorders.

346 / Chapter 15: Obesity

Figure 15.2 Obesity in a

Scotland

number of European

England

countries based on

Czech Republic

measured height and

Austria

weight. These studies

provide a more accurate

Poland

assessment than studies

Germany

that rely on self-reported

Men

Ireland

Women

height and weight, which

France

tend to underestimate

Luxembourg

prevalence. These studies

Portugal

were undertaken in

Sweden

1997-2008 and this may

reflect some of the

Bulgaria

differences between

Netherlands

countries.

Percentage (%)

woman. Nevertheless, across populations BMI cor-

obesity levels will continue to rise in the early 21st

relates well with percentage body fat, making it an

century. The WHO MONICA project followed

easy measure of obesity.

obesity trends in

21 countries among randomly

Body fat may be preferentially located in the

selected middle-aged participants from the early

abdomen (central obesity) or surrounding the hips

1980s to the late 1990s. Mean BMI as well as the

and thighs

(peripheral obesity). Central obesity

prevalence of overweight and obesity increased in

more accurately predicts adverse health risk; for the

virtually every western European country studied

same BMI, the more visceral fat, the greater the risk

(Figure 15.2), as well as in Australia, the USA and

of developing cardiovascular and metabolic compli-

China.

cations of obesity. This may explain some ethnic

Within the UK, the prevalence of obesity in

differences in complication risks. Asians tend to

adults has almost trebled since 1980; in 2008, 24%

have greater central fat distribution than white

of men and 25% of women were obese. The preva-

Europeans and carry a higher risk of obesity com-

lence of obesity among children is lower, but the

plications for any given BMI. There are also gender

rate of increase is similar to that in adults. Obesity

differences in body fat distribution, with most

rates are higher in low social classes and in some

women developing peripheral obesity while men

ethnic minority groups.

develop central adiposity.

The Centers for Disease Control’s Behavioral

Waist measurement can be used to identify

Risk Factor Surveillance System provides dramatic

those at high risk of developing metabolic compli-

evidence of the continuing rise in the prevalence of

cations of obesity. Waist measurements in excess of

obesity in the USA. Each year, state health depart-

100-102 cm in men and 88-90 cm in women are

ments use standard procedures to collect data

independent predictors of metabolic dysfunction.

through a series of monthly telephone interviews

However, again, suitable adjustments are needed in

with US adults. In 1991, four states had a preva-

people from non-white ethnic backgrounds.

lence of obesity between 15% and 19% and no state

had a prevalence above 20%. In 2010, no state had

a prevalence of obesity less than 20%. Thirty-six

Obesity trends

states had a prevalence of 25% or more; 12 of which

An estimated 300 million people around the world

had a prevalence of 30% or more. As these data

are obese and conservative estimates suggest that

rely on self-reported height and weight, it is

Chapter 15: Obesity / 347

possible that they underestimate the true prevalence

Control of body weight

of obesity.

There are two main mechanisms regulating appetite

and body weight: a short-term control that prevents

over-eating at meals and a longer term system that

The causes of obesity

regulates body weight and energy stores, largely in

fat. These mechanisms involve the hypothalamus

The causes of obesity are multifactorial and range

(see Chapter 5). The ventromedial hypothalamus

from purely genetic conditions, such as mono

acts as a satiety centre and stimulation of this area

genic leptin deficiency, to entirely environmental

removes the drive to feed (anorexia), while lesions

conditions, as seen in sumo wrestlers. However,

lead to over-eating (Figure 15.3; see Table 5.1). By

obesity can only occur when energy intake

contrast, the lateral hypothalamus acts as a hunger

remains greater than energy expenditure for a long

(and thirst) centre. It is tonically active but is inhib-

period of time. Thus, if energy intake increases

ited transiently by the satiety centre in the post-

and/or energy expenditure decreases, an individual

prandial period. Destruction of the lateral

will gain weight. Both energy intake and expen

hypothalamus causes anorexia and cachexia.

diture are affected by internal homeostatic

Appetite is stimulated by the activation of neu-

mechanisms as well as external environmental

rones containing neuropeptide Y (NPY) or Agouti-

factors.

related protein (AGRP). It is suppressed by neurones

Given the diversity of factors affecting energy

containing α-melanocyte stimulating hormone (α-

balance, it is remarkable how well body weight

MSH) or cocaine and amphetamine-regulated tran-

is regulated. Most healthy adults are able to main-

script peptide (CART). α-MSH is derived from the

tain their body weight to within a few kilograms

protein precursor pro-opiomelanocortin (POMC)

over 40 or more years in spite of having eaten in

that also gives rise to adrenocorticotrophic hormone

excess of

20 tonnes of food. A rise of a few

(ACTH) in the anterior pituitary (see Figure 5.11

kilograms represents a gain of around

10,000-

and associated text). Several other neurotransmit-

20,000 kcal stored as fat. As the average energy con-

ters, such as orexins and brain-derived neurotrophic

sumption in western societies is approximately

factor

(BDNF), also have a role in regulating

0.75-1 million calories per year (2000-2500 kcal/

appetite.

day), such weight gain represents an energy mis-

There is considerable redundancy in the mecha-

match between intake and expenditure of much less

nisms stimulating appetite; loss of function of either

than 1%.

the AGRP or NPY gene or both genes together is

Even in individuals who become obese, the mis-

not associated with any obvious change in energy

match between energy intake and energy expendi-

metabolism or food intake. By contrast, loss-of-

ture is extremely small. Daniel Lambert earned a

function mutations in either POMC affecting

living in Leicestershire, UK, during the 18th century

α-MSH or in the gene encoding the receptor

by exhibiting himself as a natural curiosity having

through which α-MSH signals, the melanocortin 4

reached the weight of 700 pounds (320 kg). It is

receptor (MC4R), disrupt satiety and are monogenic

estimated that when he died at the age of 39 years,

causes of early-onset severe obesity.

he weighed 52 stone 11 pounds (336 kg), of which

approximately 230 kg would have been fat, contain-

Signals from the gastrointestinal tract

ing approximately 2 million kilocalories. Assuming

that there was progressive weight gain throughout

Several gastrointestinal hormones (see Chapter 10;

his life, the excess consumption would have been

Table 10.1) and neuronal signals from the afferent

only approximately 140 kcal/day; this number of

vagus nerve provide short-term information about

calories is contained in an apple.

hunger and satiety by responding to gastrointestinal

In order to understand the causes of obesity we

mechanical distension, macronutrients, pH and

need to examine the mechanisms that regulate

tonicity. Ghrelin, whose secretion by the stomach

normal body weight.

increases before meals, is the only hormone to

348 / Chapter 15: Obesity

Cortex and limbic system

“reward”

Dopamine, opioids

and endocannabinoids

Insulin

Leptin

Ghrelin PPY,

GLP-1, GIP

Vagus nerve

–

5HT_2cR

Leptin R

H₁R

Hypothalamus

POMC α-MSH

Orexin

NPY AGRP

CART

Arcuate

–

nucleus

Lateral

MC4 receptor

hypothalamus

CART receptor

Ventromedial hypothalamus

Food intake

Figure 15.3 Model of regulation of food intake.

pathway is affected by signals from the gut and

Appetite is stimulated by neurones containing

adipose tissue, as well as being influenced by the

neuropeptide Y (NPY) and Agouti-related protein

hedonistic control of food intake. PPY, peptide

(AGRP) in the lateral hypothalamic area. Food intake

YY_3-36; GLP-1, glucagon-like peptide 1; GIP,

is inhibited by α-melanocyte stimulating hormone

glucose-dependent insulinotrophic hormone;

(α-MSH) and cocaine and amphetamine-regulated

POMC, pro-opiomelanocortin; MC4,

transcript peptide (CART). Regulation of this final

melanocortin 4.

stimulate hunger, while cholecystokinin, glucagon-

leptin or its receptor cause severe obesity from over-

like peptide 1 (GLP-1) and peptide YY_3-36 (PPY) all

eating in both mouse models and rare human

reduce appetite.

patients. Where leptin is absent or non-functional

but its receptor is intact, replacing the hormone by

injection restores normal BMI to individuals with

Long-term control of fat mass - the role

early-onset severe obesity

(Figure

15.4). Under

of leptin

normal circumstances, leptin increases with increas-

The adipose tissue hormone, leptin, acts in the

ing fat mass to suppress appetite and increase basal

brain as a satiety hormone and as a negative regula-

metabolic rate, and vice versa (a classical negative

tor of fat mass. It is transported actively across the

feedback mechanism; see Figure 1.4).

blood-brain barrier to reach the hypothalamus,

These findings led to the hope that subtle

where it binds to leptin receptors located on the

abnormalities in leptin action underpin common

surface of NPY-containing neurones. Loss-of-

obesity (e.g. polymorphisms in the leptin signalling

function mutations in the genes encoding either

pathway). However, in most situations, as predicted

Chapter 15: Obesity / 349

Figure 15.4 Effects of

recombinant human leptin

treatment in a patient with

congenital leptin deficiency.

(a) Before, showing a 3-year-old

boy weighing 42 kg, and (b) after

treatment, showing

the boy now 7 years old and

weighing 72 kg. Reproduced

from Farooqi IS. Eur J Clin Invest

2011;41:451-455, with

permission.

(a)

(b)

physiologically, leptin is already increased in obesity

receptors causes a reduction in food intake and sub-

and treatment with further leptin does not lead to

sequent weight loss. This mechanism was targeted

a decrease in body weight.

by rimonabant, a drug used to treat obesity and its

associated metabolic abnormalities. The drug was

withdrawn, however, because of an increased risk of

Other mechanisms involved in

depression.

eating behaviour

Genetic factors

As well as eating for homeostasis, many of us also eat

for pleasure as part of our normal social lives. These

Why one person is better adapted than another to

hedonistic aspects of eating are controlled by a separate

withstand small mismatches in intake and expendi-

but complementary mechanism to the hypothalamic

ture is an important question, and probably has a

control of appetite. Subtle differences in this system

genetic basis. Much of the variance in BMI within

lead to less inhibited eating patterns. For instance,

a population is explained by genetic factors; twin

altered food choices are seen in overweight people.

studies have produced the most consistent and

Several hormones and neurotransmitters are

highest heritability estimates for BMI, suggesting

involved in this aspect of eating behaviour, includ-

that as much as 60-90% of variance in BMI is

ing dopamine and central opioid activity. Endo

explained by genetics.

genous endocannabinoids stimulate food intake

Over the last decade, several human genes have

through activation of cannabinoid-1 (CB1) recep-

been identified in addition to those encoding leptin

tors in the lateral hypothalamus. Blockade of CB1

and α-MSH in which loss-of-function mutations

350 / Chapter 15: Obesity

Table 15.2 Genetic causes of and associations with obesity

Genetic syndromes that feature obesity

Monogenic causes of

Polymorphisms

obesity

linked to obesity

Prader Willi

Leptin deficiency

FTO gene

Laurence Moon Biedl

Leptin receptor

Melanocortin 4

deficiency

receptor

Bardet Biedl

Pro-opiomelanocortin

deficiency

Biemond syndrome II

Melanocortin 4

receptor deficiency

Alström

Prohormone

convertase 1

deficiency*

Carbohydrate-deficient glycoprotein syndrome type 1

Neurotrophin receptor

Short stature obesity

TrkB

Albright hereditary osteodystrophy

Borjeson-Forssman-Lehmann syndrome

Fragile-X syndrome

Germinal cell aplasia Sertoli cell-only syndrome

Simpson dysmorphia

* The importance of prohormone convertase 1 in POMC and insulin processing is discussed further in Chapters 5 and 11

respectively.

have caused severe early-onset obesity; most disrupt

susceptible genotype have led to the marked increase

the normal appetite control mechanisms

(Table

in obesity prevalence.

15.2). Although they only affect a minority of

people, these monogenic causes of obesity are

Dietary intake

important because they help to identify the critical

Food and drink provide our entire energy intake

pathways regulating human energy balance and

and so changes in eating patterns have a profound

provide clues to where new therapies might be

influence on body weight. In the last 50 years, there

directed in future.

have been dramatic changes in the availability and

The possibility of other obesity-susceptibility

types of food that may have contributed to the

alleles occurring at relatively higher frequencies was

obesity epidemic.

raised by the discovery that polymorphisms in the

fat mass and obesity-associated

(FTO) gene and

Total energy intake

MC4R gene associate with increased weight and

The National Food Survey in the UK provides the

predispose to obesity.

longest running continuous survey of household

consumption in the world. This has shown that over

Environmental changes

the last 50 years food consumption within the home

Despite the important contribution of genetics to

has decreased. At first sight these data appear to be

the development of obesity, the current obesity epi-

paradoxical until it is remembered that as much as

demic cannot be explained by genetics alone given

50% of all food is now consumed outside the home;

the rapid change over the last 30 years. It is likely

the prevalence of obesity increases in people who

that changes in the environment interacting with a

live near fast-food restaurants. It is difficult to assess

Chapter 15: Obesity / 351

total energy intake but it would appear that while

rather than caloric intake. Fat contains approxi-

energy intake remained relatively stable during the

mately

9 kcal/g while carbohydrate and protein

first 80 years of the 20th century, over the last 30

contain 4 kcal/g. Short-term metabolic studies show

years, intake has increased by 10-15% or ∼300 kcal/

that when the dietary fat content increases, indi-

day, which is more than enough to account for the

viduals continue to eat the same quantity of food

50 kcal/day net (100 kcal gross) required to produce

and consequently move into positive energy balance.

1 kg weight gain each year. There are several

There is some evidence from cross-sectional and

reasons to explain this increase and these are

longitudinal studies that the proportion of energy

described below.

consumed as fat is linked to an increase in the

prevalence of obesity. More recently, however, par-

Cost of food

ticularly in the UK and USA, there has been a

Since the Second World War, in Europe and else-

decline in the proportion of energy consumed as fat,

where more food is produced than is required. This

while the prevalence of obesity continues to rise.

has led to intense competition and incentives to

This may reflect the relatively long lag phase in the

bulk buy such as ‘two for the price of one’ offers or

development of obesity and it may be many years

better value ‘jumbo’ packs. What we eat is influ-

before this recent dietary change affects the preva-

enced by the cost of food and in real terms, the cost

lence of obesity.

of food has fallen. The relative costs of certain food

The water content of a meal is important. If

types have also changed; in absolute terms the price

water is added to food, the energy density falls and

of fruit and vegetables, fish and dairy products has

total calorie intake is reduced. Drinking water at

increased much more than high energy density foods

meal times is also important as there is an inverse

containing fat and refined sugar. This is one reason

relationship between water intake and total energy

why the type of foods being consumed has changed.

intake and subsequent obesity. Since the 1970s,

there has been a shift from consumption of water

to sugary carbonated drinks. These beverages

Portion size

contain corn starch and considerable energy. When

Portion sizes have increased dramatically in the last

these soft drinks are consumed, there is little adjust-

40 years. This is apparent in a number of settings

ment to decrease energy intake from other sources

but particularly in fast-food outlets (Table 15.3).

and so overall calorie consumption increases.

Types of food

The National Food Survey indicated that there have

Physical activity

been changes in the types of food that we are eating,

with a shift from carbohydrate to fat consumption.

We have evolved to undertake vigorous physical

This is important because most individuals regulate

activity and therefore it should be unsurprising that

their meals size according to weight or volume

inactivity is associated with ill-health. Total energy

Table 15.3 Examples of how the size of commercially available portions has increased over the

last 50 years

Retailer

Then

Now

Burger King burger

2.8 oz (79 g)

1954

4.3 oz (122 g)

2004

202 kcal

310 kcal

MacDonald’s French fries

2.4 oz (68 g)

1955

7 oz (198 g)

2004

210 kcal

610 kcal

Cinema popcorn

720 ml

1950

5040 mL

2004

174 kcal

1700 kcal

352 / Chapter 15: Obesity

Table 15.4 Examples of light, moderate and vigorous physical activity

Light

Moderate

Vigorous

EE (<3.0 x BMR)

EE (3.0-6.0 x BMR)

EE (>6.0 x BMR)

Walking

Slowly

Briskly

Fast or jogging

Cycling

Slowly

Steadily or up slopes

>10 mph or up hills

Swimming

Slowly

Moderate exertion

Fast or treading water

Gym work

Stretching exercises

Sit-ups

Stair ergometer, ski machine

Housework

Vacuum cleaning

Heavier cleaning

Moving furniture

Gardening

Weeding

Mowing the lawn with a power

Hand mowing or digging

mower, sweeping, raking

EE, energy expenditure; BMR, basal metabolic rate.

expenditure is the sum of our basal metabolic rate,

pated in regular vigorous activity. Inactivity increases

dietary-induced thermogenesis, adaptive thermo-

with age but social class differences are not strong

genesis, such as shivering, and physical activity. Of

because occupational activity is often balanced with

these, physical activity offers the greatest scope for

leisure time activity. In the USA, 60% of adults are

an individual to increase their energy expenditure.

not regularly active and 25% reported no significant

Physical activity can be defined as any bodily move-

activity at all. Similarly, children are also becoming

ment produced by skeletal muscle that results in

increasingly inactive.

energy expenditure, and can be subdivided into dif-

Technological advances have also reduced our

ferent components such as exercise or sport. Activity

physical activity. Increasing car use across society has

can be also divided according to its intensity and

reduced physical activity undertaken travelling to and

duration (Table 15.4). Low-intensity activities may

from work. Household appliances are estimated to

include walking or housework, while more intense

have reduced our energy expenditure by around

activities may include running or cycling faster than

500 kcal/day. Instead, we have tended to compart-

10 mph or uphill. Sedentary behaviour, such as tel-

mentalize exercise into 30-40 min gym sessions two

evision viewing, is also significant when considering

or three times a week rather than focusing on increas-

weight gain as it constrains the opportunity to be

ing our energy expenditure throughout the day.

active and therefore reduces energy expenditure.

Physical inactivity is a major determinant of the

Psychological factors

current obesity epidemic. Several studies have

shown that physically active people have lower

There is much to be learnt from studying the eating

levels of body fat and weigh less than inactive

behaviours of people who gain weight. Overweight

people. There are also strong relationships between

individuals select more energy dense food, display

indicators of inactivity, such as television viewing

enhanced hunger traits with less satiety, and eat

and car ownership, with population trends in

larger and more frequent meals. Their eating behav-

obesity. In one study from the USA,

11-12%

iour is also less inhibited. Individuals who tend to

of children who watched television for less than

gain weight have a greater readiness to eat and will

2 h/day were overweight compared with 20-30%

eat opportunistically. There are differences in the

who watched it for more than 5 h/day.

timing of eating; obese individuals tend to eat more

Unfortunately, epidemiological studies have

in the afternoon and less in the morning, and some

shown that we are becoming progressively less

may even eat throughout the night. In contrast,

active. The Allied Dunbar National Fitness Survey

enjoyment from food is less important in those who

undertaken in 1995 indicated that 29% of men and

do not gain weight, and health rather than taste

28% of women were classed as sedentary, while only

becomes a more important factor when choosing

16% of men and 5% of women possibly partici-

food (Case history 15.1).

Chapter 15: Obesity / 353

Time spent sleeping is inversely proportional to

Case history 15.1

body weight. It is unclear why short sleepers weigh

more as sleeping is associated with physical inactiv-

A 25-year-old female secretary attends to

ity. It may relate to the seasonal and diurnal changes

ask for help with her weight (BMI 27.4 kg/

in hypothalamic control of food intake and nutrient

m²). She has read many magazines about

storage.

‘slimmer of the year’ and has tried a

commercial weight programme. She buys

Prevention

most of her food as ready prepared meals

at the supermarket. She eats her lunch

Despite the apparent simplicity of the solution to

sitting at her desk with her work

preventing obesity, there is little evidence to show

colleagues and eats her supper at home

that health education programmes within the

in front of the TV. She snacks on biscuits

general population are effective. Education alone is

while at work.

insufficient and behaviour modification is also

needed. Healthcare professionals need to take obe

What advice can you offer her?

sity seriously and must collectively support obesity

prevention strategies to avoid undermining of

Answer, see p. 358

healthy lifestyle advice.

Public health and governmental responses

are also needed to reduce the obesity epidemic. This

could include legislation or a more

‘ecological’

approach in which there is a coordinated strategy to

The prevalence of obesity is increased in people

influence the individual by education and behav-

with severe mental illness. While this partly reflects

iour change, and the

‘obesogenic’ environment

the illness and the environment in which the indi-

through economic, physical and socio-cultural

vidual lives, antipsychotics are associated with sig-

pressures.

nificant weight gain (Case history 15.2).

Management

The major aim of a weight management programme

Case history 15.2

is to improve health by reducing morbidity and

mortality associated with obesity, rather than simply

A 28-year-old man with schizophrenia

normalizing weight and adiposity. A relatively

speaks to his community psychiatric nurse

modest 10% weight loss is associated with a major

about his concerns that he has gained

reduction in death and metabolic complications of

10 kg in weight since starting treatment

obesity (Table 15.5).

with clozapine. As they are chatting, it

becomes apparent that he is eating

Table 15.5 Benefits associated with 10%

throughout the day, including at night, and

weight loss

his diet includes a high proportion of fat

Death

↓ 20-25% in premature

and sugary carbonated drinks. He usually

mortality

spends his days watching TV.

Diabetes

↓ 50% in type 2 diabetes

What advice can the psychiatric nurse

↓ 30-50% in blood glucose

offer?

Lipids

↓ 10% in total cholesterol

Are there any medications that may help?

↓ 30% in triglycerides

Blood pressure

↓ 10 mmHg in systolic BP

Answers, see p. 358

(BP)

↓ 20 mmHg in diastolic BP

354 / Chapter 15: Obesity

Patient selection

on maintaining weight can improve self-esteem and

promote long-term adherence to the programme.

Unfortunately, the scale of the problem means that

Patients should also be aware of the long-term

healthcare resources cannot treat all patients with

challenge of weight loss. In the same way that

obesity and therefore it is important to select

weight gain occurs over many years, a lifelong

patients who are likely to benefit most.

change to lifestyle is needed to reduce weight.

Characteristics of patients likely to lose weight

Patients should be encouraged not to think of

during a weight management programme are:

‘short-term fixes’. The basal metabolic rate makes

up a significant portion of our total energy expendi-

• High initial body mass

ture. If energy intake falls below the basal metabolic

• High central obesity

rate, the control mechanisms described earlier in the

• High energy intake

chapter are activated to try to maintain weight. The

• Those who have achieved initial weight loss.

patient will feel lethargic, tired and listless, and will

be unable to maintain this approach for any length

Early weight loss probably reflects the patient’s

of time. Too great a calorie deficit will therefore lead

ability to follow the weight management pro-

to failure. On the other hand, if a calorie deficit of

gramme. Patients need to be well motivated to

around 500 kcal is advocated, the patient will lose

undertake the lifestyle changes. High self-esteem

around 1 kg of weight/week, an amount that is sus-

and the acceptance of the need to change also

tainable over the long term.

predict weight loss. This is particularly challenging

in those with mental illness where obesity may well

affect the mental state of the patient.

Dietary strategies

It is important to set appropriate goals to prevent

There is a huge popular literature about diets that

disappointment and frustration during the pro-

will aid weight loss. Most of these diets fail to appre-

gramme. A 10% weight loss is an appropriate goal

ciate that nutrition is a ‘demand-led’ process and

because it is achievable, results in significant health

that any diet should meet the basic bodily require-

benefits and can be maintained. However, in one

ments. There is a need to include both fats and

study, when patients were asked how much weight

carbohydrates as energy supplies and any diet that

they would like to lose, only 1% said that they

excludes either of these components will create a

would be happy with a weight loss of less than 10%

mismatch between supply and demand. Diets need

while 63% expected to lose more than 20% of

to be sustainable over the long-term and most diets

weight. The natural history of body weight through-

that exclude many different food types, such as the

out a lifetime is gradual increase and therefore, the

‘Atkins’ or ‘Ornish’ diets, usually cannot be main-

first aim of a weight management programme is to

tained for more than several months (Box 15.4). It

prevent further weight gain before progressing to

is important, however, to recognize that individuals

weight loss (Figure 15.5). Congratulating patients

respond differently to different interventions and

any dietary recommendations should be discussed

on this basis.

Obese

The first aim of dietary advice therefore must

be to ensure that the individual eats sufficient

Weight

maintenance

food to meet their metabolic needs (Figure 15.6).

Minor weight loss

Patients should be advised to avoid extreme eating

Weight loss and in

restraints and dieting. In order to reduce calorie

risk factors

Lean

Normalization

consumption, two dietary changes should be con-

of weight

sidered: the types of food should be changed and

Time

portion sizes reduced. A systematic review of all

dietary interventions lasting longer than

1 year

Figure 15.5 What is a successful outcome?

found that there is little evidence to support the use

Chapter 15: Obesity / 355

Box 15.4 Eating and activity

Too great a deficit

500 kcal deficit

Does not meet

Meets BMR

objectives in weight management

body’s needs

requirements

programmes

Unsustainable

Sustainable

Failure

Success

Eating objectives

Activity

• Regain control (rehabilitation):

° Avoid extreme eating restraint/dieting

° Eat sufficient food to ensure metabolic

control and adequate intake of

nutrients

° Re-establish ‘normal’ eating behaviour

Basal

metabolic

and attitudes towards food

rate

Diet

° Appreciate scale of challenge

• Modest reduction in energy intake

(∼500 kcal/day)

° Eat well but with lower fat, refined sugar

and alcohol intake

Figure 15.6 Rationale of a 500-kcal deficit diet.

° Maintain sufficient energy (>BMR)

and nutrients to satisfy minimal

requirements

hypertriglyceridaemia, and high-density lipoprotein

Activity objectives

(HDL)-cholesterol in some patients.

• Decrease amount of time sitting and

Portion size is extremely important. One way of

supine

achieving this is to use a smaller plate as the same

• Aim for low-intensity activity - not what is

volume of food will appear more than on a larger

characteristically termed exercise

plate and therefore will promote reduced food

• Factor in the total time spent active; it

intake.

does not have to be a single bout of

It is important to re-establish ‘normal’ eating

continuous activity sufficiently vigorous to

behaviour and attitudes towards food. Many

cause breathlessness or heavy

people eat for reasons that have nothing to do

perspiration, i.e. 10 times for 3 min each is

with hunger. For example, people might eat

as good as once for 30 min

from boredom, to cope with sadness or to be socia-

• Activity must fit in with daily life and

ble. Encouraging healthy eating patterns can lead

functional capabilities of individual

to a reduced energy intake. It is important that

• Activity should be pleasurable

while food is consumed, the individual’s attention

is focused on the food. If the attention is divided,

such as by simultaneously working at a computer,

of diets apart from low-fat diets for weight

the reward gained from eating is reduced and

reduction. Ad libitum low-fat diets for up to 36

therefore people tend to eat more. It is important

months resulted in modest weight losses of around

that food does not become associated with

3.5 kg. The consumption of low energy dense

other activities, such as watching television, because

foods and sweeteners may also reduce meal energy

this will lead to less healthy eating behaviours.

intake. Short-term studies, however, have suggested

Patients should be advised to eat only at a dining

that weight loss on low-carbohydrate diets is com-

room or kitchen table at mealtimes. Cravings for

parable with fat-restricted diets with higher carbo-

food are often short lived and therefore, a useful

hydrate content. Low-carbohydrate diets may have

strategy can be to distract the patient with an

benefits for those with type 2 diabetes as they appear

alternative activity such as a 5-min walk when a

to have a beneficial effect on glycaemic control,

craving occurs.

356 / Chapter 15: Obesity

The value of commercial weight loss pro-

Pharmacotherapy Lifestyle modification

grammes has not been fully established, but it

appears that they may lead to greater weight loss

Modifies

than an individual’s attempts on their own. The

internal

external

environment

peer support derived from others attending the

group helps maintain motivation.

Hunger

Exposure to

foods

Food

Physical activity

preoccupation

Cues to eat

Physical activity plays an important part in a weight

Satiety

Dietary restraint

management programme (Box 15.4). While high

Nutrient

Physical

energy expenditure can outstrip energy intake and

absorption

activity

therefore promotes weight loss in its own right,

exercise particularly has a role in the prevention of

Figure 15.7 Additive effects of diet and drugs.

weight re-gain when combined with dietary inter-

ventions. It is important that patients decrease the

amount of time that they spend sitting or occupied

in sedentary activities. Low intensity activity is also

drawn. The only drug currently available is

of great importance; for example, an 80-year-old

orlistat and, when used in combination with life-

person with agitated Alzheimer disease will expend

style and behavioural modification programmes, is

more calories per day than a professional athlete

a useful adjunct in the management of obesity

because the patient with Alzheimer disease is

(Figure 15.7).

walking for nearly 24 h every day. The total time

Orlistat inhibits pancreatic and gastric lipases,

spent active is important and exercise does not need

thereby reducing hydrolysis of ingested triglyceride.

to be undertaken in a single period. Patients need

It produces a dose-dependent reduction in

to think about ways of incorporating more physical

dietary fat absorption that is near maximal at the

activity in their everyday lives. This can be achieved

currently available dose of 120 mg three times a

in many ways:

day. In clinical trials lasting up to 4 years, it leads

to modest weight loss of up to 10%. This weight

• Use the stairs rather than lifts

loss is associated with a reduction in other

• Alight the bus one stop early and walk

cardiovascular risk factors, including waist circum-

• Park at the far end of the supermarket car park

ference, blood pressure, dyslipidaemia and hyperg-

rather than right next to the door.

lycaemia. In people with impaired glucose tolerance,

Physical activity needs to fit in with daily

it reduces the risk of incident diabetes by 37% over

life and the functional capabilities of the individual.

and above the effect of lifestyle intervention alone.

Ideally, the activities should be pleasurable as

In people with pre-existing diabetes, many are able

the most appropriate type of exercise to undertake

to reduce or discontinue their oral hypoglycaemic

is the one that will still be pursued a decade

medication.

later.

The main limiting factor for the use of orlistat

is the development of gastrointestinal side-effects

secondary to fat malabsorption. These include loose

Drugs

or liquid stools, faecal urgency and anal discharge,

Pharmacological treatment of obesity has a cheq-

and can be associated with fat-soluble vitamin defi-

uered history and many physicians still regard

ciency and malabsorption. As the consumption of

these drugs with suspicion and scepticism. Indeed,

a high-fat diet will inevitably lead to severe gastroin-

in the last few years two drugs used to treat obesity

testinal side-effects, it is important that the prescrip-

(rimonabant and sibutramine) have been with-

tion of orlistat is accompanied by behavioural and

Chapter 15: Obesity / 357

dietary advice. In some people, orlistat can be

vention of diabetes in people with impaired glucose

highly effective, but it is salutary to note that only

tolerance and a 50-80% clinical resolution of diag-

around 1% of those prescribed the drug are still

nosed early type 2 diabetes. The improvement in

taking it 2 years later.

glycaemic control occurs shortly after surgery,

Several other drugs have been considered for

before the weight loss, suggesting that mechanisms

use in the management of obesity, including

other than weight loss are involved. In the long

pseudoephedrine, ephedra, sertraline, yohimbine,

term, obesity surgery decreases mortality. In the

amphetamine or its derivatives, bupropion,

Swedish Obese Subjects Study, deaths were reduced

benzocaine, threachlorocitric acid and bromocrip-

by a quarter in those who had had surgery.

tine. There is currently a paucity of data about

At present, obesity surgery is only recommended

their effectiveness and they were not recom

for those with morbid obesity (Case history 15.3).

mended in a recent Cochrane systematic database

Each patient requires an extensive preoperative

review.

assessment, which includes a psychological assess-

Of the drugs that are currently being developed

ment, as surgery will not treat an eating disorder

for the management of obesity, GLP-1 receptor

and may lead to worsening of the mental state if

agonists deserve a special mention (see Chapter 13).

patients are dependent on food.

Trials of liraglutide at higher doses than are used to

treat diabetes are on-going. The first short trial over

20 weeks demonstrated a mean

7.2-kg weight

reduction in people receiving 3 mg of liraglutide

compared with 2.8 kg with placebo and 4.1 kg with

Case history 15.3

orlistat.

A 49-year-old woman with a 10-year

history of type 2 diabetes attends her GP

Bariatric surgery

surgery for her diabetes review. She has

Bariatric surgery is currently the only long-term

been treated with pre-mixed insulin with

cure for obesity. There are two main types of

increasing doses for 2 years, currently 170

surgery; malabsorption techniques bypass part

units three times a day. She is intolerant of

of the stomach and small intestine, while restrictive

metformin. She has reduced mobility

surgery leads to reduced dietary intake by

because of markedly swollen legs as a

reducing the size of the stomach and therefore

result of venous insufficiency and two

improves satiety. Some operations utilize a

ulcers around her ankles. Her BMI is

combination of both. In some situations,

48.7 kg/m². Her HbA_1c is 13.4%

apronectomy is also needed to remove redundant

(123 mmol/mol).

abdomen skin and this may contribute to further

When the GP starts to discuss her

weight loss.

weight, she becomes distressed and

The best evidence for the long-term effects of

says that she has tried to lose weight all

bariatric surgery for obesity comes from the Swedish

her life. She has spent lots of money on

Obese Subjects Study in which the weight loss after

commercial weight programmes and

2 years was typically between 30 and 40 kg. After

has tried several medications in the

10 years, the weight losses stabilized at 25% in those

past. She does not know what else she

with bypass operations and 14-16% in those with

can try.

restrictive operations.

Quality of life improves dramatically following

What treatment options are available?

surgery and this is associated with major improve-

ments in the metabolic sequelae of obesity. Gastric

Answer, see p. 359

bypass surgery is associated with a 99-100% pre-

358 / Chapter 15: Obesity

New less invasive techniques are being developed

without altering the patient’s anatomy. Pancreatic

as alternatives to surgery, including gastrointestinal

and biliary secretions pass along the outside of the

barriers. Gastrointestinal barriers are impervious

devices and then mix with partly digested food in the

liners that prevent the duodenum and upper jejunum

upper jejunum. These liners can be inserted by an

coming into contact with partly digested food,

endoscope and left in situ for 6 months. Trials of their

thereby mimicking the foregut bypass surgery

effectiveness are currently on-going.

Key points

• The prevalence of obesity has increased

mean that there is a mismatch between

dramatically over the last two decades

energy intake and expenditure

and shows no sign of slowing

• The management of the individual with

• Obesity is associated with significant

obesity is challenging and should

morbidity and premature mortality

include lifestyle modification for all,

• Societal changes leading to a sedentary

pharmacotherapy for some and surgery

lifestyle and altered food consumption

for a few

Answers to case histories

Case history 15.1

has a sedentary job and should be encouraged

to become more physically active.

It is important to take a full dietary and

exercise history, although she has given you

Case history 15.2

clues that she has unhealthy eating

behaviours. Her expectations may be

People with schizophrenia have a two- to

unrealistic if she wants to win ‘slimmer of the

three-fold increased prevalence of obesity

year’ and she needs to know what is

compared with the general population. The

achievable. It would be better for her to eat

underlying cause is multi-factorial but it

away from her desk at lunch - partly to

seems that clozapine, a second-generation

increase her activity levels and partly

antipsychotic, has contributed to his problem.

because eating at her desk may become

This is important because weight gain can

associated with feelings of relaxation. She is

lead to discontinuation of the psychiatric

snacking on biscuits, which might be a

treatment and possible psychiatric relapse.

coping behaviour for a stressful job. Lower

Treatment of the mental illness, however, is

calorie snacks could be suggested, but

important if the man is to make lifestyle

snacking should be discouraged if possible.

changes to reduce his weight.

Cravings do not last long and so it might be

It would have been better to institute

worth suggesting she gets up and does

weight management when the treatment

something else for a few minutes when she

was initiated. People who have long-term

has the urge to eat. It is likely that eating by

problems with antipsychotic weight gain

the television will increase her calorie intake

usually experience some weight gain within

and will lead to eating outside meal times.

the first 2-3 weeks of treatment. It is

Encourage her to eat at a table where she

important to weigh people receiving

can devote all her attention to the food. She

antipsychotics weekly during the early phase

Chapter 15: Obesity / 359

of treatment to identify those who are

venous ulceration, again a result of her

developing weight gain.

obesity.

Contrary to expectation, lifestyle

Bariatric surgery would be an option

modification programmes are possible in

for her. With a bypass operation she may

people with severe mental illness and are

lose 20-30% of her body weight. This will lead

at least as successful as in the general

to improvements in her glycaemic control and

population. Longer term support may be

she may be able to stop insulin. The strongest

needed, but simple lifestyle messages

predictor of whether insulin can be stopped

can lead to significant weight loss or

post surgery is the duration of diabetes. She

prevention of weight gain. Many patients

needs to be aware that surgery will change

have never received basic health

her eating patterns for the rest of her life. It is

education.

important to exclude medical causes of

Where lifestyle modification is not

obesity, such as Cushing syndrome, but

possible, there is preliminary evidence to

these are unlikely given the duration of her

suggest that metformin is beneficial in

obesity.

reducing weight gain or promoting weight

Another option that could be used instead

gain. It also has the additional benefit in

of or prior to surgery is a GLP-1 receptor

reducing the risk of diabetes. The latter is

agonist as this may improve her glycaemic

important as this person is at increased

control and promote weight loss. The

risk of diabetes and is consuming a large

combination of GLP-1 receptor agonist and

quantity of sugary drinks.

insulin is not licensed in some countries.

The weight loss will also improve her

venous ulceration and facilitate healing

Case history 15.3

of the ulcer.

This woman has morbid obesity and has

Although surgery is expensive, when

tried all conventional means of losing

considered alongside the cost of daily

weight. She is markedly insulin resistant.

dressings and insulin, it is likely that the

Despite large doses of insulin, she has

operation would be cost-saving within a

poor glycaemic control. She also has

short period of time.

Index

Page numbers in bold refer to tables. Page numbers in italic refer to figures. Page numbers suffixed with ‘b’ refer to

boxes.

acarbose 297, 299b, 304

stimulation test

231

α subunits see Gα protein subunits

acetohexamide 298

synthetic ACTH test 88, 110,

Amadori reaction 246

acetylation of DNA 17

124

amenorrhoea 83, 151-7, 164

acetyl CoA carboxylase 252, 254

adrenoreceptors 120

American Diabetes Association,

acid labile subunit

adult respiratory distress syndrome,

classification of diabetes

acidosis

diabetic ketoacidosis

282

238-40

diabetic ketoacidosis

279, 280

advanced glycation end-products

amino acids

parathyroid hormone 196

(AGEs) 314-15

derivatives

8-9, 20-4

acromegaly 75, 77-80, 81, 97, 201

cardiovascular disease

331

growth hormone test 78

ACTH see adrenocorticotrophic

receptors

315

amiodarone 182, 184b, 189

hormone

age

AMP kinase 300

Addison disease 13, 108-11, 124,

GH and IGF-I secretion 75-6

amputations, diabetes 325

177, 231, 283

male sexuality 138

amylin analogues 308

Addisonian crisis

111

osteoporosis

206

anabolic actions

adenosine-3',5'-cyclic

AGEs see advanced glycation

growth hormone 74-6

monophosphate 37, 38

end-products

insulin

250, 251

adenylate cyclase

35, 37

Agouti-related protein

347

insulin-like growth factor I

adjustment disorder, diabetes in

AIRE gene 212

anabolic drugs

children

335

Albright hereditary osteodystrophy

osteoporosis

207-8

adrenal cortex

10, 100-19

40b, 199

anaemia

ACTH on 87

albumin

hypothyroidism 187

insufficiency

88, 108-11, 231

calcium and 191, 211-12

metformin 300-1

pigmentation 88, 124