Philip Kalra PDF

Essential
Revision Notes
for MRCP
Fourth Edition
edited by
Philip A Kalra MA MB BChir FRCP MD
Consultant and Honorary Professor of Nephrology,
Salford Royal NHS Foundation Trust and The University of Manchester
Contents
Contributors to Fourth Edition vii

Contributors toThird Edition x
Permissions xii
Preface to the Fourth Edition xiii
CHAPTER
1. Cardiology 1
J E R Davies, S Nijjer
2. Clinical Pharmacology,Toxicology and Poisoning 65
S Waring
3. Dermatology 87
H Robertshaw
4. Endocrinology 107
T Kearney, S Giritharan, M Kumar
5. Epidemiology 143
J Ritchie
6. Gastroenterology 157
S Lal, D H Vasant
7. Genetics 205
E Burkitt Wright
8. Genito-urinary Medicine and AIDS 223
B Goorney
9. Haematology 237
K Patterson
10. Immunology 279
J Galloway
11. Infectious Diseases andTropical Medicine 295
C L van Halsema
12. Maternal Medicine 329
L Byrd
v
Contents
13. Metabolic Diseases 359

S Sinha
14. Molecular Medicine 395
K Siddals
15. Nephrology 435
P Kalra
16. Neurology 493
M Jones, C Kobylecki, D Rog
17. Ophthalmology 561
K Smyth
18. Psychiatry 583
E Sampson
19. Respiratory Medicine 611
H Green
20. Rheumatology 657
M McMahon
21. Statistics 685
E Koutoumanou
Index 703
vi
Chapter 4
Endocrinology
CONTENTS
4.1 Hormone action 4.4 Hyponatraemia and SIADH

4.1.1 Types of hormone
4.1.2 Hormones that act at the cell 4.5 The thyroid gland
surface 4.5.1 Hyperthyroidism and
4.1.3 Hormones that act hypothyroidism
intracellularly 4.5.2 Causes of thyrotoxicosis
4.1.4 Hormone resistance syndromes 4.5.3 Thyroid cancer and nodules
4.5.4 Drugs and the thyroid
4.2 Speci¢c hormone physiology 4.5.5 Autoimmunity and eye signs in
4.2.1 Hormones in illness thyroid disease
4.2.2 Hormone changes in obesity 4.5.6 Thyroid function tests
4.2.3 Hormones in pregnancy
4.2.4 Investigations in endocrinology 4.6 Adrenal disease and hirsutism
4.2.5 Growth hormone 4.6.1 Cushing syndrome
4.2.6 Prolactin 4.6.2 Primary hyperaldosteronism
4.2.7 Adrenal steroids 4.6.3 Congenital adrenal hyperplasia
4.2.8 Thyroid hormone metabolism 4.6.4 Hypoadrenalism
4.2.9 Renin–angiotensin–aldosterone 4.6.5 Polycystic ovary syndrome and
4.2.10 Calcium, PTH and vitamin D hirsutism
4.2.11 Atrial natriuretic peptide
4.7 Phaeochromocytoma and
4.3 The pituitary gland multiple endocrine neoplasia
4.3.1 Anatomy syndromes
4.3.2 Pituitary tumours
4.3.3 Diabetes insipidus 4.8 Puberty/growth/intersex
4.3.4 Acromegaly 4.8.1 Normal puberty
4.3.5 Prolactinomas 4.8.2 Precocious puberty
4.3.6 Hypopituitarism and growth 4.8.3 Delayed puberty/short stature
hormone deficiency in adults 4.8.4 Intersex
107
Essential Revision Notes for MRCP
4.9 Diabetes mellitus

4.9.1 Risk factors and clinical
features of types 1 and 2
diabetes mellitus
4.9.2 Diagnostic criteria for diabetes
4.9.3 Treatment of type 1 diabetes
4.9.5 Glycated HbA1c
4.9.6 Microvascular and
macrovascular complications of
diabetes
4.9.7 Autonomic neuropathy
4.10 Hypoglycaemia
4.10.1 Hypoglycaemia in diabetes
mellitus
4.10.2 Hypoglycaemia unrelated to
diabetes
108
Endocrinology
Endocrinology
4.1 HORMONE ACTION bind to an intracellular receptor and affect gene

transcription. Glucagon is not a steroid or an amine
There are three main types of hormone:
so it must be a polypeptide hormone, which has a
• amine short circulation half-life, acts via a cell surface
• steroid receptor and probably utilises a second messenger
• peptide. (adenosine cyclic monophosphate, or cAMP, in
fact).
Knowing which category a particular hormone fits
into makes it possible to guess much of its physiol-
ogy. Thyroxine is an exception to this, as shown
below.
4.1.2 Hormones that act at the cell
surface
Peptide and amine hormones act at the cell surface
4.1.1 Types of hormone via specific membrane receptors. The signal is trans-
• Amine: catecholamines, serotonin, thyroxine mitted intracellularly by one of three mechanisms:
• Steroid: cortisol, aldosterone, androgens,
• Via cAMP
oestrogens , progestogens and vitamin D
• Via a rise in intracellular calcium
• Peptide: everything else! (made up of a series of
• Via receptor tyrosine kinases.
amino acids).
Thyroxine is chemically an amine but it acts like a If in doubt, assume the action of a peptide or amine
steroid. Vitamin D has the structure of a steroid hormone (excluding thyroxine) is via cAMP, unless
hormone and it acts like one. it is insulin or has the word ‘growth’ in its name, in
which case it is likely to act via a receptor tyrosine
kinase (Table 4.1).
Amines/peptides
• Short half-life (minutes) Cyclic AMP and G-proteins

• Secretion may be pulsatile
• Act on a cell surface receptor Hormone receptors linked to cAMP (eg thyroid-
• Often act via a second messenger stimulating hormone [TSH] receptor) typically have
seven transmembrane domains. The receptor does
not directly generate cAMP but acts via separate ‘G-
Steroids proteins’ on the cell surface which, in turn, interact
with the cAMP-generating enzyme, adenylyl
• Longer biological half-life (hours) cyclase, on the cell surface. (See Figure 14.4 in
• Act on an intracellular receptor Chapter 14, Molecular Medicine.)
• Act on DNA to alter gene expression Hormones that raise the level of cAMP intracellu-
larly (all hormones in this category except somato-
This information can be used to predict hormone statin) act via a stimulatory G-protein, ‘Gs’.
action, eg aldosterone is a steroid hormone so it Hormones that lower the level of cAMP (somato-
must have a biological half-life of several hours, statin) act via an inhibitory G-protein, ‘Gi’.
109
Table 4.1 Mechanisms of hormone action
Via cAMP Via Ca2+ Via receptor tyrosine kinases
Adrenaline (â receptors) GnRH Insulin

All pituitary hormones except GH, PRL TRH GH, PRL
Glucagon Adrenaline (Æ receptors) ‘Growth factors’: IGF-1, EGF
Somatostatin
cAMP, adenosine cyclic monophosphate; EGF, epidermal growth factor; GH, growth hormone; GnRH, gonado-
trophin-releasing hormone; IGF-1, insulin-like growth factor 1; PRL, prolactin; TRH, thyrotrophin-releasing
hormone.
G-proteins are important in endocrinology because pseudohypoparathyroidism). The dysmorphic

mutations in Gs have been found to be associated bone features are sometimes referred to as
with certain diseases: ‘Albright’s hereditary osteodystrophy’ and can be
present in either the maternally or the paternally
• Acromegaly: 40% of patients with acromegaly
inherited form.
have an activating somatic mutation of Gs in
their pituitary tumour. As a result, the cells are
always ‘switched on’ and continuously make
growth hormone (GH), resulting in acromegaly Intracellular Ca 2+
• McCune–Albright syndrome: an activating Some hormones release intracellular Ca2+ as a sec-
mutation of Gs early in embryonic development ond messenger (see Table 4.1 for examples). The
causes hyperfunction of one or more endocrine receptors for these hormones activate different G-
glands with the following sequelae: precocious proteins (eg Gq), which in turn activate the cyto-
puberty (gonad hyperfunction), acromegaly (GH plasmic enzyme phospholipase C (PLC). PLC re-
hypersecretion), Cushing syndrome (adrenal leases the small molecule inositol-1,4,5-
gland hyperfunction), thyrotoxicosis or triphosphate (IP3) from membrane phospholipids.
hyperparathyroidism. The syndrome is IP3 in turn binds to the IP3-sensitive receptor on the
associated with café-au-lait spots and endoplasmic reticulum within the cell, causing Ca2+
polyostotic fibrous dysplasia. As the mutation to be released from stores in the endoplasmic retic-
occurs after the zygote stage, affected ulum into the cytoplasm. The Ca2+ subsequently
individuals are a mosaic and different patterns affects cell metabolism by binding to the protein
of tissue involvement may be seen between calmodulin.
individuals
• Pseudohypoparathyroidism: inactivating
germline mutations in Gs result in
pseudohypoparathyroidism type 1A if maternally Receptor tyrosine kinases
inherited, with dysmorphic features (including The insulin, GH, prolactin and growth factor recep-
short fourth or fifth metacarpal) and resistance to tors do not use second messengers. The receptors
a variety of hormones that act via cAMP themselves can act as enzymes that phosphorylate
(including parathyroid hormone, TSH and (‘kinase activity’) other proteins when hormone is
gonadotrophins). Spontaneously occurring or bound at the cell surface. This is followed by a
paternally inherited mutations cause the cascade of proteins phosphorylating other proteins
dysmorphic features alone (pseudo- until gene transcription in the nucleus is modulated.
110
Endocrinology
4.1.3 Hormones that act hormone (TRH), TSH and L-thyroxine/L-triiodothyro-

intracellularly nine (T4/T3). It is orchestrated by the hypothalamus,
not by the end-organs. Hormones involved in the
Steroids, vitamin D and thyroxine are sufficiently
stress response may rise.
lipid-soluble that they do not need cell surface
receptors but can diffuse directly through the cell
membrane. They then bind to receptors in the Hormones that fall
cytoplasm, which results in shedding of heat shock
proteins that protect the empty receptor. The hor- • TSH, T4/T3a
mone–receptor complex migrates into the nucleus • LH, FSH
where it alters the transcription of a large number of • Testosterone, oestrogen
genes (see Figure 14.6 in Chapter 14, Molecular • Insulin (starvation)
Medicine).
May rise (stress hormones)
4.1.4 Hormone resistance syndromes • GH (though IGF-1 falls)

• ACTH, glucocorticoids
The following are conditions of hormone resistance
• Adrenaline
with the site of the defect shown.
• Glucagon (starvation)
• Prolactin
• Receptor defect (hormone involved)
a
• Laron’s dwarfism (GH) In this case conversion of T4 to T3 is inhibited so T3
falls more than T4
• Leprechaunism (Donahue’s syndrome,
ACTH, adrenocorticotrophic hormone; FSH, follicle-
Rabson–Mendenhall syndrome [insulin])
stimulating hormone; GH, growth hormone; IGF-1,
• Nephrogenic diabetes insipidus
insulin-like growth factor 1; LH, luteinising hormone;
(antidiuretic hormone [ADH]) T3, L-triiodothyronine; T4, L-thyroxine; TSH, thyroid-
• Androgen resistance (testicular stimulating hormone.
feminisation syndrome (testosterone))
• Vitamin-D-dependent rickets type 2 –
In starvation alone, without illness, all hormones fall
hereditary vitamin D resistance rickets
except glucagon. In anorexia nervosa there is also
(vitamin D)a
stress: all hormones fall except glucagon, GH and
• Second messenger defect
glucocorticoids.
• Pseudohypoparathyroidism
• Defect unknown
• Type 2 diabetes 4.2.2 Hormone changes in obesity
a
Vitamin D-dependent rickets type 1 is due to a failure In the absence of other diseases (eg type 2 dia-
of 1-hydroxylation of vitamin D. betes), which might develop in obese patients, the
following changes are seen in obesity:
• Hyperinsulinaemia
• Increased cortisol turnover but not
4.2 SPECIFIC HORMONE
hypercortisolism
PHYSIOLOGY
• Increased androgen levels in women
• Reduced GH
4.2.1 Hormones in illness
• Conversion of androgens to oestrogens
During illness/stress, the body closes all unneces- • A proatherogenic lipid profile develops (low
sary systems down ‘from the top’, eg the thyroid high-density lipoprotein [HDL], high low-
axis closes down by a fall in thyrotrophin-releasing density lipoprotein [LDL] and triglyceride).
111
Leptin, adipokines and other hormones Derived from tissue-specific cleavage of

involved with appetite and weight proglucagon
• Oxyntomodulin: also released from L cells and
Leptin was identified as a product of the ‘ob’ gene
derived from proglucagon; appears to act on the
in 1994. Ob/ob mice make no leptin, owing to a
same receptor as GLP-1, but with less incretin,
homozygous ob gene mutation, and are grossly
and has more of an appetite-suppressing effect
obese.
• Neuropeptide Y (NPY), from the hypothalamus
• Leptin is a polypeptide hormone, released from itself, and Agouti-related protein (AgRP) increase
fat cells, that acts on specific receptors in the appetite, whereas Æ-melanocyte-stimulating
hypothalamus to reduce appetite hormone (Æ-MSH, a melanocortin) reduces
• Circulating leptin levels are directly proportional appetite.
to fat mass, and so they tell the brain how fat an
individual is In addition to leptin, a number of other hormones
• Leptin appears to have stimulatory effects on have recently been identified as being released from
metabolic rate and levels fall in starvation fat cells. These ‘adipokines’ include adiponectin,
(appropriate change for weight homeostasis) which reduces insulin resistance, and resistin and
• Adequate leptin levels are required for the onset acylation-stimulating protein (ASP), which both in-
of puberty crease insulin resistance. Visfatin (also known as
• Persistently obese individuals appear relatively nicotinamide phosphoribosyltransferase [NAMPT]
resistant to leptin and pre-B-cell colony-enhancing factor) is released
• Congenital leptin deficiency presents in predominantly from visceral fat and has insulin-like
childhood with gross obesity and hyperphagia. actions. The role of these adipokines in the associa-
This changes dramatically with treatment of tion between obesity and insulin resistance remains
exogenous leptin. uncertain.
Several other hormones have recently been shown 4.2.3 Hormones in pregnancy
to affect appetite and weight:
As a general rule, most hormone levels rise in preg-
• Ghrelin: this was first identified as a GH- nancy. Insulin resistance develops, causing a rise in
releasing hormone. It is released from the circulating insulin levels. Insulin requirements are
stomach when subjects are fasting or in highest in the last trimester but fall slightly in the
conditions of negative energy balance and last 4 weeks of pregnancy.
triggers hunger. It stimulates gastric contraction
Other key features of hormone metabolism in preg-
and hence gastric emptying. Ghrelin levels fall
nancy are as follows:
after gastric bypass surgery, which may help
weight loss by reducing appetite • Prolactin levels rise steadily throughout
• Peptide YY (a member of the neuropeptide Y pregnancy and, in combination with oestrogen,
family): released from L cells in the small and prepare the breast for lactation. Post-partum
large bowel. Levels rise after meals and reduce surges of prolactin and oxytocin are generated
appetite. This may be the main regulator of day- by the nipple stimulation of breastfeeding.
to-day appetite However, after several weeks, prolactin levels
• Glucagon-like peptide-1 (GLP-1): also released fall almost to normal, even if breastfeeding
from L cells of the intestine after meals and continues
powerfully promotes insulin secretion in • LH/FSH from the pituitary are no longer
response to raised glucose (‘incretin effect’), as necessary after conception for continued
well as possibly reducing appetite. Inactivated pregnancy (although the pituitary may double in
by the enzyme dipeptidylpeptidase-4 (DPP-4). size) and the placenta takes over
112
Endocrinology
• Thyroid axis: thyroid-binding globulin (TBG) of which is constant and which mediates almost all
levels rise in the first trimester, causing a rise in the actions of GH, ie GH does not act directly. The
total T4 and total T3. However, human effective levels of IGF-1 are influenced by changes
chorionic gonadotrophin (hCG) from the in the level of its six binding proteins (IGF-BP 1–6).
placenta shares its Æ subunit with TSH, and very
high levels in the first trimester can cause true
mild thyrotoxicosis (not just a binding protein 4.2.6 Prolactin
rise), especially associated with hyperemesis Prolactin causes galactorrhoea but not gynaecomas-
gravidarum. Note that T4 and T3 do not cross tia (oestrogen does this). Raised prolactin levels are
the placenta very efficiently, but sufficient T4 essentially the only cause of galactorrhoea,
does cross to prevent a fetus with congenital although occasionally prolactin levels in the normal
hypothyroidism becoming hypothyroid until range can cause milk production in a sensitised
after birth. breast. Raised prolactin levels also ‘shut down’ the
gonadal axis ‘from the top’ (hypothalamic level),
4.2.4 Investigations in endocrinology resulting in low GnRH, LH and oestrogen/testoster-
one levels. Surprisingly, prolactin is a stress hor-
The plasma level of almost all hormones varies mone and can rise in various levels of stress, from
through the day (because of pulsatile secretion, anxiety about venepuncture to an epileptic fit.
environmental stress or circadian rhythms) and is
influenced by the prevailing values of the substrates Prolactin release from the pituitary is under negative
that they control. This makes it hard to define a control by dopamine from the hypothalamus. Oes-
‘normal range’, eg insulin values depend on the trogens (the pill, pregnancy) and nipple stimulation
glucose level, and GH levels depend on whether a raise prolactin.
pulse of GH has just been released or the blood
sample is taken in the trough between pulses. Prolactin is raised by
Dynamic testing is therefore frequently used, ie • Phenothiazines, haloperidol (not tricyclics)

suppression or stimulation tests. The principle is, ‘If • Antiemetics (eg metoclopramide)
you think a hormone level may be high, suppress it; • Damage to hypothalamus (eg radiation)
if you think it may be low, stimulate it’. • Pregnancy
• Suppression tests are used to test for hormone • Nipple stimulation
EXCESS, eg dexamethasone suppression for • Damage to pituitary stalk (eg pressure from
Cushing syndrome, glucose tolerance for GH in a pituitary tumour)
acromegaly • Oestrogens
• Stimulation tests are used to test for hormone • Polycystic ovary syndrome
DEFICIENCY, eg Synacthen tests for
hypoadrenalism, insulin-induced hypoglycaemia Prolactin is suppressed by
for GH deficiency and/or hypoadrenalism.
• Dopamine agonist drugs (eg bromocriptine,
cabergoline)
4.2.5 Growth hormone
This is secreted in pulses lasting 30–45 minutes
Gynaecomastia
separated by periods when secretion is undetect-
able. The majority of GH pulses occur at night This is due to a decreased androgen:oestrogen ratio
(‘children grow at night’). In response to GH pulses, in men. Gynaecomastia is unrelated to galactor-
the liver makes insulin-like growth factor 1 (IGF-1, rhoea (which is always due to prolactin). Breast
previously called somatomedin C), the plasma level enlargement is not necessary to make milk.
113
Causes of gynaecomastia: 4.2.8 Thyroid hormone metabolism

• Pubertal (normal) More than 95% of thyroid hormones are bound to
• Obesity – not true gynaecomastia plasma proteins in the circulation, predominantly
• Hypogonadism (eg Klinefelter’s syndrome, TBG and thyroid-binding prealbumin (TBPA). T4
testicular failure) (four iodine atoms per molecule) has a half-life of 7
• Cirrhosis, alcohol days (so, if a patient is in a confused state, it is
• Hyperthyroidism possible to administer his or her total weekly dose
• Drugs: including spironolactone, digoxin, of thyroxine once a week). It is converted partly in
oestrogens, cimetidine, anabolic steroids, the thyroid and partly in the circulation to T3 (three
marijuana iodine atoms per molecule), which is the active
• Tumours, including adrenal or testicular, making form and has a half-life of 1 day.
oestrogen; lung, pancreatic, gastric, making
There are three deiodinase enzymes that act on
hCG; hepatomas converting androgens to
thyroid hormones (D1–D3). D1 and D2 promote
oestrogens.
the generation of active hormone (T3) by converting
T4 to T3 (Figure 4.1). D3 opposes this by promoting
conversion of T4 to reverse T3 (rT3) and destroying
4.2.7 Adrenal steroids
T3 by conversion to T2 (inactive). The D1 and D2
These act intracellularly to alter the transcription of enzymes are inhibited by illness, propranolol, pro-
DNA to mRNA (see Section 4.1, Hormone action). pylthiouracil, amiodarone and ipodate (formerly
Surprisingly, the mineralocorticoid (aldosterone)
and glucocorticoid receptors have an equal affinity
for cortisol. However, the cellular enzyme 11-â- Figure 4.1 Metabolism of thyroid hormones,
hydroxysteroid dehydrogenase ‘protects’ the miner- D1–D3, different deiodinase enzymes that act
alocorticoid receptor by chemically modifying any on thyroid hormone.
cortisol that comes near the receptor to an inactive T3 (active form)
form, while having no effect on aldosterone itself.
Inactivating mutations of this enzyme, or inhibition D1, D2
of it by liquorice, causes ‘apparent mineralocorti-
coid excess’, because cortisol (which circulates at T4
much higher concentrations than aldosterone) is
able to stimulate the mineralocorticoid receptor. D3
The effects of adrenal steroids and their duration of rT3 (reverse T3)
action are given in Table 4.2.
Table 4.2 Adrenal steroids
Relative Relative Duration of action

glucocorticoid effect mineralocorticoid effect
Cortisol ¼ hydrocortisone 1 þ Short

Prednisolone 4 Medium
Dexamethasone 30 ÿ Long
Fludrocortisone 10 þþþ
114
Endocrinology
used as X-ray contrast medium for study of gall- Renin is released from the JGA (juxtaglomerular
bladder disease). This reduces the level of active apparatus) of the kidney in response to low Na+
hormone, T3, with little change or a rise in T4. delivery or reduced renal perfusion. Renin is an
Reverse T3 levels rise (T4 spontaneously converts to enzyme that converts angiotensinogen to angioten-
rT3 if the monodeiodinase is not available), but rT3 sin I (10 amino acids). ACE (angiotensin-converting
is not detected in laboratory tests of T3 levels. enzyme) in the lung converts angiotensin I to angio-
tensin II, which is the active form. ACE also breaks
It is said that you should ‘never measure thyroid
down bradykinin: ACE inhibitors (eg captopril) are
function tests on the intensive care unit because
believed to cause cough as a result of a build-up of
you will not be able to interpret them’. In illness,
bradykinin in the lung. The renin–angiotensin sys-
TSH and free T3 levels fall (‘sick euthyroidism’). The
tem is designed to restore circulating volume. It is
only interpretable finding in sick patients is a raised
therefore activated by hypovolaemia (Figure 4.2)
free T3 – this would almost definitely indicate
and its end product, angiotensin II, has three actions
thyrotoxicosis.
that restore volume:
• Releasing aldosterone from the adrenal (retains
4.2.9 Renin^angiotensin^aldosterone Na+, excretes K+ in the distal tubule)
Aldosterone secretion is controlled almost comple- • Vasoconstriction (powerful)
tely by the renin–angiotensin system, not by ACTH. • Induction of thirst (powerful).
The initial letters of the zones of the adrenal cortex
from outside inwards spell ‘GFR’, similar to glomer-
ular filtration rate: glomerularis, fasciculata, reticu-
4.2.10 Calcium, PTH and vitamin D
laris. Aldosterone is the ‘outsider hormone’ and is
made on the ‘outside’ (zona glomerulosa). (See also Chapter 13, Metabolic Diseases.)
Figure 4.2 The renin–angiotensin system.
Low Na1 delivery Angiotensinogen
Renal perfusion RENIN

reduced Release Angiotensin I
Angiotensin-converting
β-adrenoreceptor enzyme (ACE) in the lung
stimulates Also inactivates bradykinin
α-adrenoreceptor
inihibits Angiotensin II
Aldosterone
Thirst
secretion
Retain Na1 Vasoconstriction

Excrete K1/H1
(distal tubule)
115
Plasma calcium is tightly regulated by parathyroid • Natriuretic: it causes a natriuresis (urinary

hormone (PTH) and vitamin D, acting on the kidney excretion of sodium). It thereby reduces
(PTH), bone (PTH) and gut (vitamin D). circulating volume (opposite of renin–
angiotensin). As you would predict, therefore, it
PTH controls Ca2+ levels minute to minute by
is secreted in conditions of hypervolaemia – via
mobilising Ca2+ from bone and inhibiting Ca2+
stretch of the right atrial and ventricular walls. It
excretion from the kidney. Vitamin D has a more
also antagonises the other actions of angiotensin
long-term role, predominantly by promoting Ca2+
II by causing vasodilatation and reduced thirst/
absorption from the gut. Its actions on the kidney
salt craving
and bone are of lesser importance. Ca2+ levels are
• Peptide: it is a peptide hormone (which acts via
sensed by a specific calcium-sensing receptor on
cAMP).
the parathyroid glands. Mutations that reduce the
activity of this receptor result in a resetting of There are two other natriuretic peptides, B-type and
calcium and PTH to higher levels (familial hypocal- C-type natriuretic peptides (BNP and CNP). BNP is
ciuric hypercalcaemia, FHH). Activating mutations similar to ANP, and is produced from the heart,
can also occur, which result in a picture almost especially in heart failure. Serum levels are more
indistinguishable from hypoparathyroidism, with a stable than those of ANP, and BNP is proving to be
low Ca2+ (autosomal dominant hypocalcaemia with a useful test of heart failure. CNP is produced by
hypercalciuria). It is important to identify these con- the vascular endothelium rather than cardiac myo-
ditions because they run a benign course and only cytes.
attempted treatment causes problems (eg raising the
serum Ca2+ in autosomal dominant hypocalcaemia
will predispose to renal stone formation).
4.3 THE PITUITARY GLAND
Precursor vitamin D, obtained from the diet or
synthesised by the action of sunlight on the skin, 4.3.1 Anatomy
requires activation by two steps:
The anatomical relations of the pituitary (Figure 4.3)
• 25-hydroxylation in the liver are important because enlarging pituitary tumours
• 1-hydroxylation in the kidney. may press on surrounding structures.
PTH can promote 1-hydroxylation of vitamin D in • Above: optic chiasma (classically causing
the kidney, ie it can activate vitamin D, thereby bitemporal hemianopia if compressed, but any
indirectly stimulating Ca2+ absorption from the gut. visual field defect may occur), pituitary stalk,
Calcitonin (from the C cells of the thyroid) behaves hypothalamus, temporal lobes
almost exactly as a counter-hormone to PTH • Below: sphenoid sinus (in front and below to
(secreted by high Ca2+, acts to lower serum Ca2+ by allow trans-sphenoidal surgery), nasopharynx
inhibiting Ca2+ release from bone), but its physio- • Lateral: cavernous sinus, internal carotid
logical importance is in doubt (thyroidectomy does arteries, III, IV, V , and V and VI cranial nerves.
not affect Ca2+ levels if the parathyroid glands are Expanding pituitary tumours may also compromise
undisturbed). remaining anterior pituitary function, but rarely af-
fect posterior pituitary hormones.
4.2.11 Atrial natriuretic peptide
Atrial natriuretic peptide (ANP) physiology can be 4.3.2 Pituitary tumours
predicted from its name:
A microadenoma is a pituitary tumour ,10 mm in
• Atrial: it is synthesised by the myocytes of the size. The size and frequency of pituitary tumours
right atrium and ventricle are related.
116
Endocrinology
Figure 4.3 Schematic sagittal section through the pituitary to show its relation to surrounding
structures.
Supraoptic recess
Hypothalamus
Optic chiasm
Suprasellar
cistern Pituitary stalk
Cavernous
sinus Temporal lobe
III
IV
V1
V2 Internal carotid
artery
Sphenoid sinus
Pituitary gland
Sphenoid bone
Pituitary tumours excessive ACTH production from the pituitary gland

(usually by a microadenoma). They are in them-
• Large – non-secreting (typically selves rare.
chromophobe): 50% of all tumours
• Large – prolactinomas in men: 25% of all For further discussion about Cushing syndrome
tumours diagnosis and management, please see Section
• Medium – acromegaly (typically 4.6.1.
‘acidophil’, 70% are about 1 cm): 12% of Excessive secretion of GH from the pituitary gland
all tumours in adults is termed ‘acromegaly’. There is a prepon-
• Small – Cushing’s disease (often derance to macroadenomas with blunting of the
undetectable on CT/MRI, typically normal pulsatile GH secretion.
basophil): 5–10% of all tumours
• Small – TSH secreting: 1% (very rare) Pituitary apoplexy is sudden enlargement of the
pituitary by haemorrhage into a tumour, typically
causing the combination of headache, neck stiffness
The most common tumours are small, non- and sudden blindness associated with cardio-
functioning microadenomas, which have been re- vascular collapse due to hypopituitarism. Treatment
ported to occur in up to 20% of people post is with steroid replacement and urgent surgery for
mortem. visual loss (to decompress optic chiasma). In pitui-
tary failure the only two hormones that must be
Prolactinomas are the most common functioning
replaced for survival are T4 and hydrocortisone. It is
pituitary tumours. Microprolactinomas are more fre-
important to ensure that the patient is adequately
quent than macroprolactinomas.
replaced with glucocorticoids before starting
True Cushing’s disease is used to describe pituitary- replacement of T4, because levothyroxine increases
dependent Cushing syndrome. This is caused by glucocorticoid clearance.
117
Craniopharyngiomas are benign tumours that arise Causes of nephrogenic DI

from remnants of Rathke’s pouch. Two-thirds arise
in the hypothalamus itself (suprasellar) and a third Reduced action of ADH on the kidney can
in the sella. They are usually cystic, frequently have several causes:
calcify, often recur after aspiration and, although • Primary
they represent an embryonic remnant, they not • Childhood onset: X-linked/dominant
infrequently present in adulthood. abnormality in tubular ADH receptor
• Secondary (common)
• Hypercalcaemia
4.3.3 Diabetes insipidus
• Hypokalaemia
ADH (also called vasopressin or arginine–vasopres- • Renal disease (particularly if it involves
sin, AVP) is synthesised in the hypothalamus and the medullary interstitium)
transported to the posterior pituitary, along with • Lithium
oxytocin, for storage and release. Diabetes insipidus • Demeclocycline
(DI) is caused either by a failure to secrete vasopres-
sin from the posterior pituitary (central or cranial DI)
or resistance to the action of vasopressin in the Water deprivation test
kidney (nephrogenic DI). To cause cranial DI, the A water deprivation test (Table 4.3) is used to
hypothalamic nuclei (supraoptic and paraventricular) identify the cause of polydipsia and/or polyuria. It is
need to be damaged – it is not sufficient simply to worth confirming polyuria (urine output .3000 mL/
compress the posterior pituitary, because vasopressin 24 h) before proceeding to a water deprivation test.
can be secreted directly from the hypothalamus Major metabolic causes should first be excluded (eg
itself. Pituitary tumours therefore rarely cause Dl. hyperglycaemia, hypercalcaemia, hypokalaemia,
chronic renal failure). The patient is then deprived
Major causes of cranial diabetes of water (from the night before if polyuria is not
insipidus excessive) and hourly urine and plasma osmolality
are measured until 3% of the body weight is lost.
• Idiopathic The patient is then given an injection of DDAVP (a
• Craniopharyngiomas synthetic analogue of ADH).
• Infiltrative processes of the hypothalamus
(eg sarcoid, histiocytosis X) Interpretation of the water deprivation test
• Trauma
• Pituitary surgery • Primary polydipsia (compulsive water drinking):
• Lymphocytic hypophysitis in this condition the patient is not dehydrated
• Dysgerminomas but water overloaded in the resting state (Na+
,140 mmol/l). Chronic polydipsia in this
118
Endocrinology
Table 4.3 Interpretation of the water deprivation test
Initial plasma Final urine osmolality Urine osmolality Final plasma ADH
osmolality (mosmol/kg) post-DDAVP
(mosmol/kg)
Normal Normal .600 .600 High

Cranial Dl High ,300 .600 Low
Nephrogenic Dl High ,300 ,300 High
Primary polydipsia Low 300–400 (approx.) 400 (approx.) Moderate
Partial cranial Dl High 300–400 400–600 Relatively low
ADH, antidiuretic hormone; DI, diabetes insipidus.
condition can result in washout of the renal 4.3.4 Acromegaly

medullary-concentrating gradient so that, even if
The common features of acromegaly are well
the patient does become dehydrated, with a rise
known (hand and foot enlargement, coarse facial
in ADH, urine cannot be concentrated
features, overbite of the lower jaw, splaying of the
• Cranial DI: in this condition there is failure to
teeth) but the following also occur (see box).
concentrate urine due to lack of ADH. This is
observed with a high plasma osmolality and a
relatively low urine osmolality throughout the Features of acromegaly
test. Administration of DDAVP allows the
kidneys to concentrate urine, thus raising the • Diabetes
osmolality. If the thirst mechanism is intact, • Arthropathy – often pseudogout
patients attempt to compensate by increasing • Sleep apnoea
their fluid intake orally. If, however, this • Carpal tunnel syndrome
mechanism is disrupted (patient is unconscious • Multinodular goitre
or has intracerebral lesion rendering the patient • Increase in malignancies, especially colonic
adipsic), there is a significant risk of becoming polyps
dehydrated very quickly • Hypertension
• Partial cranial DI: in this condition there is • Twofold increase in death from
weak ADH production. There is a similar effect cardiovascular disease
on the renal medullary-concentrating gradient to • Cardiomyopathy
that seen in primary polydipsia, and so the two • Left ventricular hypertrophy
conditions cannot be differentiated unless a • Enlarged testes
post-hydration serum ADH level is obtained • Renal stones (hypercalciuria)
• Nephrogenic diabetes inspidus: despite • Raised phosphate
adequate circulating ADH, there is renal • Raised prolactin, galactorrhoea, menstrual
resistance to the action of ADH, resulting in an change
inability to concentrate urine. Therefore urine • Raised triglycerides
osmolality does not improve on administration
of DDVAP during the water deprivation test. Acromegaly is almost always due to a GH-secreting
Treatment is by correcting the underlying cause pituitary tumour. Rarely, the condition is due to
and ensuring adequate hydration. Sometimes ectopic GH-releasing hormone (GHRH) secretion
high doses of DDAVP can be used. from a tumour (typically carcinoid) which stimulates
119
the normal pituitary (no discrete tumour seen on cases, with shrinkage of the tumour in about 85%.
MRI). Biochemical tests usually reveal a raised Surgery is usually reserved for patients who are
serum IGF-1 level (above the age- and gender- intolerant or resistant to dopamine agonists.
specific normal range). The diagnosis is confirmed
by failure to suppress GH to a nadir of 0.4 ng/mL
on an oral glucose tolerance test. 4.3.6 Hypopituitarism and growth
hormone de¢ciency in adults
First-line treatment is trans-sphenoidal surgery to
resect the pituitary tumour (or transcranial surgery if Panhypopituitarism can be caused by enlarging
there is a large suprasellar extension of the tumour). pituitary tumours, cranial irradiation (including
The cure rate is very variable (40–80%), and is specific pituitary radiotherapy), pituitary apoplexy,
dependent on the extent of lateral and superior Sheehan’s syndrome (infarction after post-partum
extension and the skill of the surgeon. Alternative haemorrhage), and then by any of the conditions
therapies are dopamine agonists (bromocriptine, that can cause cranial diabetes insipidus (see box
cabergoline, quinagolide, pergolide, which reduce on p. 118).
GH secretion in approximately 20% of cases), so-
Patients present with a soft, smooth ‘baby’ skin,
matostatin analogues (octreotide, which inhibit GH
‘crows’ feet’ lines around the eyes and features
secretion), GH antagonists (pegvisamant, which
related to their specific hormonal deficiencies –
blocks GH) and pituitary radiotherapy (may take
hypotension in relation to ACTH deficiency, weight
years to take effect and may result in hypopituitar-
gain in relation to TSH deficiency, etc.
ism). After successful treatment of acromegaly most
physical features do not regress, although some soft- Typically, hormone loss follows a common pattern,
tissue effects do. Features of active disease are in- with GH deficiency being most common, followed
creased sweating and oedema, together with evi- in order by LH, FSH, ACTH and TSH deficiency.
dence of metabolic effects such as poor glycaemic Secondary hypothyroidism is suggested by a low
and hypertensive control. free T4 (fT4) in the context of a low or inappropri-
ately normal TSH. ACTH deficiency is diagnosed by
an insulin stress test or glucagon test or, if long-
4.3.5 Prolactinomas
standing, may be suggested by a failed short
Prolactinomas are the most common functioning Synacthen test with low or inappropriately normal
pituitary tumours. They present with galactorrhoea, ACTH levels, although this test depends on the
gonadal dysfunction (amenorrhea, oligomenor- presence of adrenal atrophy subsequent to ACTH
rhoea, poor libido, erectile dysfunction, subfertility) deficiency. The following points should be noted:
and symptoms of mass effect (headache and dete-
• Only replacement therapy with corticosteroids
rioration in visual fields). Diagnosis is based on
and T4 is essential for life
raised serum prolactin concentrations and demon-
• In suspected hypopituitarism, the steroids should
stration of a pituitary lesion on MRI. Microadeno-
be given first and certainly before thyroid
mas can be hard to detect on imaging and may
replacement therapy. This is because correction
appear as gland asymmetry, but generally speaking
of hypothyroidism will accelerate cortisol
the size of the lesion is proportional to the prolactin
metabolism and would precipitate a
level.
hypoadrenal crisis (if T4 is given before
Treatment is aimed at normalising the prolactin exogenous steroids)
level, restoring gonadal function and reducing the • If the pituitary is damaged, GH production is
size of the lesion. The first-line treatment of prolacti- lost early, so that most patients are GH-deficient
nomas is medical management. Dopamine agonists (see below)
such as cabergoline and bromocriptine suppress • Despite conventional hormone replacement
prolactin levels to normal in approximately 95% of therapy (T4, glucocorticoid and sex steroids),
120
Endocrinology
mortality rates are increased in hypopituitarism ADH will be secreted even if the osmolality is low.
due to cardiovascular events or malignancy. The This explains the hyponatraemia seen in renal,
potential for GH therapy to reverse this trend is cardiac and liver failure, as well as after excessive
currently undergoing research. sodium loss (eg diarrhoea). Other stimuli can also
commonly override control of ADH secretion by
GH de¢ciency osmolarity (see Syndrome of inappropriate ADH
secretion [SIADH] below).
The main role for GH in children is growth; how-
ever, in adults GH is required for musculoskeletal,
Syndrome of inappropriate ADH secretion
metabolic and possibly psychological wellbeing.
Many common stimuli override the control of os-
Adult GHD is associated with the following:
molality and cause inappropriate amounts of ADH
• Reduced muscle tone and power, increased fat to be secreted, causing hyponatraemia. Sodium
mass, easy fatigability, poor exercise tolerance concentration should be high in the urine (exclud-
• Low mood, poor concentration and memory ing hypovolaemia), renal, adrenal and thyroid func-
• Osteoporosis tion should be normal, and diuretic therapy needs
• Increased cardiovascular risk (impaired to be excluded before SIADH is diagnosed. Treat-
endothelial function, proatherogenic lipid ment is by fluid restriction or, if necessary, oral
profile, impaired left ventricular function). demeclocycline.
Based on guidance of the National Institute for
Health and Care Excellence (NICE), GH replace- Causes of inappropriate secretion of
ment in adults is indicated for impaired quality of ADH include
life in patients with severe GH deficiency (defined
as a peak GH response ,9 mU/L [3 ng/mL] during • Nausea
a stimulation test). These symptoms are reassessed • Pain
after a 9-month period of treatment. • Fits
• Pneumonia
Treatment is with recombinant GH given nightly by • Other central nervous system/lung insults
subcutaneous injection. Longer-acting preparations • Smoking
are currently under review • Chlorpropamide
• Carbamazepine
• Head injury
4.4 HYPONATRAEMIA AND SIADH • Cerebrovascular accidents (CVAs)
• Tumours making ectopic ADH (eg
ADH (or vasopressin) is synthesised in magnocellu- bronchus)
lar neurons in the supraoptic and paraventricular
nuclei of the hypothalamus and stored in the poster-
If a tumour is the cause, it is usually obvious: a
ior pituitary. ADH is released in response to rising
search for malignancy beyond a chest radiograph is
plasma osmolality and acts on the distal tubule and
not required in SIADH. Smoking makes you pass
renal collecting ducts to increase water permeabil-
less urine (releases ADH); drinking (alcohol) makes
ity. Water is reabsorbed and the urine becomes
you pass more (inhibits ADH secretion).
more concentrated. When the ADH system is work-
ing normally, ‘the urine should reflect the blood’, ie
Causes of hyponatraemia
concentrated urine should occur when the plasma
osmolality is high, and vice versa. Hyponatraemia can be divided into three cate-
gories:
However, hypovolaemia is also a strong signal for
ADH release, and in the presence of hypovolaemia, • ‘Real’ (low serum osmolality)
121
• Pseudohyponatraemia: high triglycerides, high features. ‘Recognised’ features of the two major
protein (eg myeloma) (normal serum osmolality) thyroid syndromes are summarised in Table 4.5.
• Dilutional: high glucose, ethanol, mannitol
(serum osmolality may be raised).
If hyponatraemia is confirmed to be ‘real’ (low Features of hyper- and hypothyroidism

plasma osmolality, glucose not raised, and no sug-
gestion of ethanol or mannitol in blood), then the Amenorrhoea may be associated with hyperthyroid-
following clinical and laboratory pointers must be ism because of associated weight loss. In hypothyr-
considered: oidism, everything slows down except the periods!
The menorrhagia can cause a microcytic anaemia
• Careful history for drug use (especially diuretics) in contrast to the more usual macrocytosis. In both
and of fluid loss (eg diarrhoea) conditions there may be subfertility. In the gastro-
• Examination for circulatory volume status intestinal tract, the symptoms of hyperthyroidism are
(oedema, postural hypotension and skin turgor) almost indistinguishable from those of anxiety. The
• Measurement of urinary sodium concentration diarrhoea is actually more like the increased bowel
(Table 4.4). frequency before an examination.
Hypoadrenalism is the most important diagnosis not • Both hyperthyroidism (if Graves’ disease) and
to be missed, because untreated, it can result in hypothyroidism can cause periorbital oedema
death. (see note in Section 4.5.5 on eye signs in
thyrotoxicosis)
• The leukopenia of thyrotoxicosis can be
misdiagnosed: thionamide drugs (eg
4.5 THE THYROID GLAND
carbimazole) used as treatment also commonly
cause a lymphopenia. Both of these are separate
4.5.1 Hyperthyroidism and
from the agranulocytosis that rarely occurs with
hypothyroidism
thionamide drugs
The common features of hyperthyroidism (eg weight • In hyperthyroidism the urticaria due to the
loss, tremor, palpitations) and hypothyroidism (eg disease itself can cause confusion with the
weight gain, lethargy, dry skin) are well known but maculopapular rash, which develops in 10% of
questions are often asked on the more unusual patients treated with thionamide drugs.
Table 4.4 Causes of hyponatraemia
Urine sodium (mmol/L) Hypovolaemia present Euvolaemia/Hypervolaemia 6 oedema
.20 Diuretics SIADH

Hypoadrenalism Hypothyroidism
Salt-losing nephropathy Renal failure
,10 Vomiting, diarrhoea Congestive cardiac failure, cirrhosis, nephrotic

syndrome
Loss of other fluid
SIADH, syndrome of inappropriate antidiuretic hormone secretion.
122
Endocrinology
Table 4.5 Features of hyper- and hypothyroidism
Features Hyperthyroidism Hypothyroidism
General Weight gain (rarely) Weight gain

Gynaecomastia Serous effusions (pleural, pericardial, ascites,
Occult in elderly people joint)
Hair loss Hair loss
Gynaecological Raised sex hormone-binding globulin Amenorrhoea, menorrhagia

(SHBG) Infertility
Gastrointestinal Raised alkaline phosphatase (derived Diarrhoea

from liver and bone) Constipation
Vomiting
Muscle Proximal myopathy Raised creatine kinase

Periodic paralysis (especially Chinese) Chest pain (muscular)
Muscle cramps
Cardiovascular Atrial fibrillation with high stroke rate Dyspnoea

system High-output cardiac Hypercholesterolaemia
Ischaemic heart disease
failure
Bone Osteoporosis
Hypercalcaemia
Neurological ‘Apathetic thyrotoxicosis’ Deafness

Ataxia, confusion, coma
Eyes Eye signs (see Section 4.5.5) Periorbital oedema
Blood Leukopenia Macrocytic anaemia

Microcytic anaemia Microcytic, if menorrhagia
Skin Urticaria Dry, orange (carotenaemia)
123
Side-e¡ects of anti-thyroid drugs be presumed to be benign. In order of increasing

(carbimazole, propylthiouracil) malignancy and decreasing frequency, the thyroid
epithelial cancers are:
• Common • papillary
• Rash • follicular
• Leukopenia • anaplastic.
• Rare
• Agranulocytosis Lymphomas occur in Hashimoto’s disease. Medul-
• Aplastic anaemia lary thyroid cancer is from the C cells (calcitonin),
• Hepatitis not from the thyroid epithelium. Serum calcitonin is
• Fever a tumour marker for this cancer, which often occurs
• Arthralgia in families, sometimes as part of the multiple endo-
• Vasculitis (propylthiouracil) crine neoplasia type 2 syndrome (see Section 4.7).
(See also Chapter 2, Clinical Pharmacology, Toxi- 4.5.4 Drugs and the thyroid
cology and Poisoning)
• Lithium
4.5.2 Causes of thyrotoxicosis • Inhibits T4 release from the gland,
causing hypothyroidism
The three common causes of thyrotoxicosis are: • Oestrogens
• Graves’ disease • Raised TBG and hence ‘total’ T4 /T3
• toxic multinodular goitre • Amiodarone
• toxic (hot) nodule. • Inhibits T4 to T3 conversion, increasing
reverse T3
In all these conditions all or part of the gland is • High iodine content can cause hyper- or
overactive and the gland takes up a normal or hypothyroidisma
increased amount of radioiodine. • Iron – if taken at the same time as
In the following conditions, there is thyrotoxicosis thyroxine, can reduce its absorption
• Interferon
without increased production of new hormone by
• Induces anti-thyroid autoantibodies and
the thyroid gland itself, ie radioiodine uptake is
suppressed: hypothyroidism (usually transient)
a
Note on amiodarone-induced hyperthyroidism. This
• Excess thyroxine ingestion
may be due to drug-induced damage (thyroiditis) or to
• Thyroiditis: post-viral (de Quervain’s), post- the excess iodine in amiodarone, and can be very
partum or silent thyroiditis resistant to treatment.
• Ectopic thyroid tissue, eg lingual thyroid or
ovary (struma ovarii)
• Iodine administration: gland is actually still
active, but cold iodine competes with 4.5.5 Autoimmunity and eye signs in
radioiodine during scanning. thyroid disease
In areas such as the UK, where there is relatively
little iodine deficiency, more than 90% of sponta-
4.5.3 Thyroid cancer and nodules
neous hypothyroidism is due to autoimmunity. Anti-
Only 5–10% of thyroid nodules are malignant (the thyroglobulin autoantibodies are present in 60% of
rest are adenomas). Thyroid cancer virtually never cases and anti-microsomal antibodies (now identi-
causes hyperthyroidism, so ‘hot nodules’ can usually fied as anti-thyroid peroxidase antibodies) are
124
Endocrinology
present in up to 90%. Antibodies that block the Conditions that alter thyroid-binding
TSH receptor may also be present. Similar anti- globulin (TBG)
bodies are present in Graves’ disease, but the anti-
TSH receptor antibodies are stimulatory, causing the Raised TBG Low TBG
thyrotoxicosis. Pregnancy Nephrotic syndrome
Oestrogen Congenital TBG
The eye signs in thyroid disease are shown in the
Hepatitis abnormality
box (see also Chapter 17, Ophthalmology). Retro-
Congenital TBG
orbital inflammation and swelling of the extraocular
abnormality
muscles are only seen in Graves’ disease.
Note that each of the features listed can occur
separately in thyroid eye disease (eg diplopia with- Interpretation of thyroid function tests
out exophthalmos) and, surprisingly, disease of the This is generally straightforward in ambulant out-
two eyes is usually asymmetrical. The target of the patients if the causes of different patterns of thyroid
antibody or T-cell reaction causing this inflamma- function tests (TFTs) are known (Table 4.6). Special
tion is not known for certain, and eye disease care in interpretation should be taken in the follow-
activity can occur in the absence of thyrotoxicosis ing circumstances:
and even with hypothyroidism.
• Known or suspected pituitary disease (TSH is
Thyrotoxicosis from any cause misleading and should NOT be used as a test)
• Acutely ill patients (eg in intensive care) – TSH
• Lid retraction often low with low free T3 (fT3)
• Lid lag • Patients taking T3 supplements alone.
Graves’ disease only

4.6 ADRENAL DISEASE AND
• Soft-tissue signs: periorbital oedema, HIRSUTISM
conjunctival injection, chemosis
• Proptosis/exophthalmos 4.6.1 Cushing syndrome
• Diplopia/ophthalmoplegia Cushing syndrome refers to the sustained over-pro-
• Optic nerve compression causing visual duction of cortisol (hypercortisolism), which causes
failure the following:
• centripetal obesity with moon face
• ‘buffalo hump’
4.5.6 Thyroid function tests
• hirsutism
TSH is the most sensitive measure of thyroid status • recurrent infections
in patients with an intact pituitary. T4 and T3 are • osteoporosis
over 95% protein-bound, predominantly to TBG. • oligomenorrhoea
The conditions in the box alter TBG levels and • hypokalaemia
hence total, but not free, hormone levels. • striae
125
Table 4.6 Thyroid function tests
TSH
Low Normal Raised
Raised fT4 /fT3 Thyrotoxicosis Rare: (applies to both normal and raised)
• TSH-secreting pituitary tumour
(TSHoma)
• Thyroid hormone resistance
(receptor defect)
• Hypoadrenalism
• Acute psychiatric illness
• Intermittent T4 therapy (poor
compliance)
• T4 acute overdose (TSH normal)
• Interfering anti-T4/T3 antibody
(TSH normal)
• Familial dysalbuminaemic
hyperthyroxinaemia (TSH normal)
Normal fT4 /fT3 Subclinical thyrotoxicosis: Normal Subclinical

• Excess thyroxine hypothyroidism:
• Steroid therapy • Poor compliance with
• Non-thyroidal illness T4 therapy
• Dopamine infusion • Interfering (heterophile)
antibody
• Recovery from non-
thyroidal illness
• Hypoadrenalism
Low fT4/fT3 Non-thyroidal illness: (applies to both low and normal) Hypothyroidism
• Pituitary failure
• Recent (excessive)
treatment for
hyperthyroidism
• acne genic Cushing syndrome secondary to steroid use,

• proximal muscle weakness Cushing syndrome is rare. Other endocrine causes
• hyperglycaemia of obesity should be excluded:
• psychiatric disturbances
• hypothyroidism
• hypertension.
• leptin deficiency
If untreated, the mortality rate is high (59% within 5 • hypothalamic tumours (hyperphagia)
years), and death is usually due to cardiovascular • Prader–Willi syndrome
disease or infection. Fortunately, apart from iatro- • GH deficiency.
126
Endocrinology
Possible causes of Cushing syndrome are: of the pituitary causing Cushing’s disease are
often too small to see and, second, incidental
• Adrenal tumour
tumours of both the pituitary and adrenal are
• Pituitary tumour (Cushing’s disease)
common and may not be functional. Tests used
• Ectopic production of ACTH – either from
to identify the causes of Cushing syndrome are
cancer (eg small-cell cancer of lung) or from a
shown in Table 4.7
bronchial adenoma (often very small)
• Inferior petrosal sinus sampling (IPSS) is an
• Ectopic production of corticotrophin-releasing
invasive radiological technique in which blood
hormone (CRH) (very rare).
samples are drawn from the sinuses, draining
The diagnosis of Cushing’s is made in three phases. the left and right sides of the adrenal gland, and
also from the periphery. By looking at the ACTH
Screening tests gradients between samples, localisation may be
determined. However, due to cross-drainage
• Loss of diurnal variation (midnight cortisol
and difficulties in cannulating the sinuses,
similar to morning cortisol)
results may be difficult to interpret.
• Overnight dexamethasone suppression test
(1 mg at midnight then 9am cortisol). Cortisol
should suppress to ,50 nmol/L Treatment of Cushing syndrome
• Raised urinary free cortisol (24-hour collection).
The aim of treatment is to normalise cortisol levels.
Primary treatment is therefore surgical resection of
Diagnostic tests
the tumour with either pituitary or adrenal surgery.
• Low-dose dexamethasone suppression test
(0.5 mg four times daily for 48 hours). Cortisol Surgery
should suppress to ,50nmol/l
Pituitary
• ACTH will be inappropriately normal/raised in
Cushing’s disease is primarily treated with trans-
pituitary (Cushing’s disease) or ectopic ACTH
sphenoidal surgery (successful in approximately
secretion, both of which are referred to as
60% of cases). ‘Biochemical cure’ is achieved if
‘ACTH-dependent Cushing syndrome’
post-operative cortisol levels are undetectable, as
• ACTH will be suppressed in adrenal disease
non-tumorous pituitary tissue will have been dor-
(Cushing syndrome or ‘non-ACTH-dependent
mant in the presence of the ACTH-producing
Cushing syndrome’).
tumour and may remain dormant for up to 2 years
If one or more of these are positive then one can post-operatively. During this time, the patient will
proceed to localisation. Note that depression or require cortisol replacement therapy. Sometimes re-
alcoholism can cause cortisol overproduction covery never occurs and the patient remains perma-
(‘pseudo-Cushing syndrome’). If these conditions nently ACTH-deficient.
are present, further investigation is very difficult.
If surgical cure has not been achieved, due to
incomplete resection of the tumour, then pituitary
Localisation studies
radiotherapy or medical treatment may be offered.
• High-dose/low-dose dexamethasone
suppression test (2 mg four times daily for 48 Adrenal
hours). ACTH levels suppress by 50% in 50% of Adrenal cortisol-secreting tumours are usually treated
people with pituitary disease, but not with with laparoscopic resection, although occasionally
ectopic production. Many have now abandoned this is not possible due to the large size. The whole
this test due to lack of sensitivity adrenal is resected and cortisol levels should be
• MRI of the adrenal or pituitary alone cannot be undetectable post-operatively, as the contralateral
relied on to localise the cause. First, the tumours adrenal gland will be dormant due to lack of ACTH
127
Table 4.7 Tests used to identify causes of Cushing syndrome
Adrenal Pituitary Ectopic
ACTH Suppressed Mid-range High

High-dose No change in cortisol Suppression of cortisola No change
dexamethasone
suppression
CRH stimulation test No change Rise in ACTH and No change

cortisola
Metyrapone Rise in 11-deoxycortisol Rise in 11-deoxycortisol Rise in 11-deoxycortisol

,220-fold .220-folda ,220-fold
Petrosal sinus sampling Equals peripheral level Higher than peripheral Equals peripheral level
ACTHb level
a
’Under pressure’ (ie at high doses), pituitary adenomas behave like a normal pituitary in dynamic endocrine
testing, whereas adrenal or ectopic sources do not. A positive response to high-dose suppression (2 mg four times
daily for 48 h) is .10% suppression of plasma cortisol or 24-hour urinary free cortisol.
b
In a petrosal sinus sampling, a catheter is placed in the draining sinus of the pituitary gland, via a femoral or
jugular venous approach. The ACTH level is compared with that in the peripheral blood before and after CRH
injection.
stimulation. Recovery of this adrenal gland may take Medical therapy

up to 2 years, although, as with the pituitary gland, Where surgery is not possible, normalisation of
this may never occur and the patient will remain cortisol levels can be sought with metyrapone
cortisol-dependent. Failure to cure because of incom- (although long-term complications include hirsuit-
plete resection may be treated medically. ism and hypertension) and more recently SOM230,
which also inhibits cortisol production. Ketocona-
Occasionally, bilateral adrenalectomy is performed
zole, previously used with a similar intent, has
when it is not possible to normalise ACTH secretion
recently been withdrawn because of concerns of
(source unknown, or pituitary surgery/radiotherapy
hepatotoxicity. Mitotane can be used in patients
has been ineffective). This causes cortisol deficiency
with adrenal cortical carcinoma as adjunct chemo-
but may result in Nelson’s syndrome: loss of sup-
therapy. However, medical therapies rarely normal-
pression (provided by the previously high cortisol
ise cortisol levels long term.
levels) may allow a pre-existing pituitary adenoma
to grow very rapidly, years later, causing local
damage and generalised pigmentation.
4.6.2 Primary hyperaldosteronism
Radiotherapy Primary hyperaldosteronism comprises hyper-
Pituitary irradiation may reduce ACTH production tension, hypokalaemia (80% of cases), hypomagne-
and reduce tumour growth. It is insidious in onset saemia and metabolic alkalosis. Patients can,
but can be effective for up to 15 years. however, have a serum potassium within the normal
128
Endocrinology
range. Primary hyperaldosteronism is now thought (See Chapter 1, Cardiology, Section 1.9.3 Systemic
to account for 1–3% of all cases of hypertension. hypertension. See also Chapter 15, Nephrology,
Section 15.3.4 for differential diagnoses of hypoka-
• Symptoms (if present) relate to hypokalaemia:
laemia.)
weakness, muscle cramps, paraesthesiae,
polyuria and polydipsia. Patients rarely develop
peripheral oedema (‘sodium escape’ 4.6.3 Congenital adrenal hyperplasia
mechanism)
Two enzyme defects account for 95% of all CAH:
• Causes: aldosterone-secreting adenoma (Conn’s
syndrome is almost never caused by a • 21-hydroxylase (90%)
malignancy), idiopathic bilateral adrenal • 11-hydroxylase (5%).
hyperplasia, unilateral hyperplasia (rare)
• Investigations (not standardised): the The block caused by these enzyme defects leads to
aldosterone:renin ratio (ARR) should be reduced production of cortisol, but increased pro-
assessed to confirm high aldosterone levels in duction of other intermediates in steroid metabolism,
the presence of low renin. Ideally, the ratio including androgenic steroids. 17-hydroxylase,
should be assessed after the patient has ceased 3-â-hydroxysteroid dehydrogenase and cholesterol
antihypertensive drugs (â blockers reduce renin side-chain cleavage enzyme defects are very rare
levels and therefore increase the ARR, giving a causes of congenital adrenal hyperplasia (CAH) and
false-positive result. Spironolactone, calcium have different effects (see the box).
channel blockers, ACE inhibitors and
angiotensin antagonists increase renin levels Features of congenital adrenal
causing a lowering of ARR and therefore a false- hyperplasia
negative result. Alpha blockers (eg doxazosin)
have the least effect. Ideally, where possible, • Autosomal recessive
these agents should be stopped to allow a • Both gene deletions and point mutations
washout period of between 4 and 6 weeks. If can occur
hyperaldosteronism is confirmed, a CT or MR • Plasma ACTH is high (renin is high if salt-
scan of the abdomen may identify a unilateral losing)
adrenal adenoma. However, the tumours are • Can cause male precocious puberty (not
usually ,2 cm in diameter and so, if imaging is 17-hydroxylase or side-chain enzyme); can
negative, adrenal vein sampling may be cause ambiguous genitalia in females (not
required in order to distinguish unilateral 17-hydroxylase or side-chain enzyme)
hypoplasia or a tiny adenoma from idiopathic • Treat with glucocorticoids
bilateral hyperplasia mineralocorticoids at night
• Treatment: spironolactone and amiloride are • Can have a minor, late-onset form
often successful treatments when the cause is resembling polycystic ovary syndrome
bilateral hyperplasia. Eplerenone is a selective • Surgery may be required to correct
aldosterone antagonist that can be used in ambiguous genitalia/cliteromegaly
patients who develop gynaecomastia or breast • Antenatal steroid therapy to the mother has
soreness with spironolactone. An adenoma or been used
unilateral adrenal hyperplasia may be surgically
removed; hypertension may persist if this was It is possible to distinguish between the different
previously long-standing. enzyme defects in CAH (Table 4.8).
129
Table 4.8 Differentiating features in congenital adrenal hyperplasia
21-hydroxylase 11-hydroxylase 17-hydroxylase/

side-chain enzyme
Frequency 90% cases 5% cases Very rare
Presentation in females Virilising, intersex 70% salt-losinga Virilising, Non-virilising

hypertension, low K+ (intersex in boys)
Biochemistry Raised 17-hydroxylase, progesterone Raised 11-

dehydroxycortisol
a
Salt-losing individuals can have Addisonian crises soon after birth.
4.6.4 Hypoadrenalism corticoids continue to be secreted via the renin–

angiotensin–aldosterone system.
In the UK, spontaneous hypoadrenalism is most
commonly due to autoimmune destruction of the The gold standard in diagnosing hypoadrenalism is
adrenal glands (Addison’s disease – adrenal by failure of plasma cortisol to rise above 550 nmol/
autoantibodies present in 70% of cases). Vitiligo is L at 30 or 60 min after intramuscular or intravenous
present in 10–20% of cases and can be associated injection of 250 g synthetic ACTH (short Synacthen
with other autoimmune diseases. Other causes of 1 test).
primary adrenal insufficiency include tuberculosis
Treatment is with steroid replacement, and this is
(TB), HIV or haemorrhage into the adrenal glands.
most commonly done with oral hydrocortisone.
Secondary hypoadrenalism is due to ACTH defi- Patients are told to double their steroid doses in
ciency, most commonly caused by a pituitary times of stress or intercurrent illness. It is imperative
lesion. Hypoadrenalism after withdrawal of long- that steroid replacement is not stopped, and there-
standing steroid therapy is similar to secondary fore if patients are unable to take their tablets for
hypoadrenalism. any reason (ie vomiting), they are told to seek
medical attention.
The following are ‘recognised’ features of hypo-
adrenalism:
• Biochemical: raised urea, hypoglycaemia,
hyponatraemia, hyperkalaemia, raised TSH, Acute adrenal failure (Addisonian crisis)
hypercalcaemia Acute adrenal failure is one of the few endocrine
• Haematological: eosinophilia, lymphocytosis, emergencies. Addisonian crisis presents with hypo-
normocytic anaemia volaemia, hyponatraemia, hyperkalaemia (if primary
• Clinical features: weight loss, abdominal pain, adrenal failure), hypoglycaemia and cardiovascular
psychosis, loss of pubic hair in women, collapse, which can be fatal. A mildly raised TSH
hypotension, auricular cartilage calcification, may also be seen even in the absence of thyroid
increased pigmentation. disease. Urgent treatment is necessary, and this
includes intravenous fluid and electrolyte replace-
ment as well as, most importantly, steroid replace-
Hyperkalaemia and increased pigmentation are ment. All patients with hypoadrenalism are advised
absent in secondary hypoadrenalism, because there to wear/carry a MedicAlert bracelet with them at all
are low levels of circulating ACTH and mineralo- times.
130
Endocrinology
4.6.5 Polycystic ovary syndrome and oligo-/amenorrhoea and subfertility. The following
hirsutism are recognised associations of PCOS:
Hirsutism (Table 4.9) is the increased growth of • Clinical features: obesity, acanthosis nigricans,
terminal (dark) hairs in androgen-dependent areas. oligomenorrhoea, polycystic ovaries, subfertility,
Virilisation is temporal hair recession (male pattern), hypertension, premature balding in male
breast atrophy, voice change, male physique and relatives, hirsutism
(most important) cliteromegaly. Hirsutism and acne • Biochemical: insulin resistance and
are invariably also present. hyperinsulinaemia, raised testosterone, raised
LH/FSH ratio, raised prolactin, low HDL.
A serum testosterone 4.5 nmol/L (normal
,1.8 nmol/L), recent onset of hirsutism and signs of Treatment: metformin will lower insulin resistance
virilisation in women should prompt a search for and it has been shown to promote ovulation, im-
other causes (eg a tumour). Dehydroepiandrostene- prove conception rates and reduce hirsutism.
dione (DHEA) is a weak androgen produced in the Weight loss may also be beneficial. Separate speci-
adrenal only. fic treatments are available for hirsutism (eg fluta-
• Measure the 17-hydroxyprogesterone level after mide, cyproterone, finasteride, topical creams) and
stimulation with ACTH to check for late-onset infertility (ovulation induction).
21-hydroxylase deficiency (partial enzyme
deficiency)
• Other than androgens, the drugs listed strictly
4.7 PHAEOCHROMOCYTOMA AND
cause hypertrichosis, an increase in vellus hair,
MULTIPLE ENDOCRINE
rather than an increase in androgen-sensitive
NEOPLASIA SYNDROMES
terminal hairs (see Chapter 3, Dermatology).
Phaeochromocytomas are rare tumours of the adre-
nal medulla or ganglia of the sympathetic nervous
Polycystic ovary syndrome system. They are the ‘tumour of 10%’:
There is no widely recognised definition, and up to • 10% are outside the adrenal glands –
20% of women have a degree of hirsutism. In prac- paragangliomas (including organ of
tice, the three main presenting complaints in poly- Zuckerkandl)
cystic ovarian syndrome (PCOS) are hirsutism/acne, • 10% are multiple (eg bilateral)
Table 4.9 Causes of hirsutism
Ovarian Adrenal Drugs
PCOS (.90% of cases) CAH (may be late onset) Minoxidil

Virilising tumour Cushing syndrome/adrenal carcinoma Phenytoin
Diazoxide
Ciclosporin
Androgens
CAH, congenital adrenal hyperplasia; PCOS, polycystic ovarian syndrome.
131
• 10% are malignant Important features of

• 10% are familial. phaeochromocytomas
The most sensitive and specific test for the diagnosis • 70% have persistent rather than episodic
of phaeochromocytoma is the measurement of hypertension
plasma or urinary fractionated metanephrines. This • The triad of headache, sweating and
is not available in all centres and measurement palpitations is said to be .90% predictive
of urinary catecholamines is an alternative • Extra-adrenal tumours do not make
(measurement of urinary catecholamine metabolites adrenaline (they secrete noradrenaline/
– 3-methoxy-4-hydroxymandelic acid or vanillyl- dopamine)
mandelic acid [VMA] – has now been superseded). • Hypotension or postural hypotension may
As is the case with most endocrine tumours, the occur, particularly if adrenaline is produced
histology is not a reliable guide to the malignant • They give characteristically a ‘bright’ (white)
potential in phaeochromocytomas. The diagnosis of signal on T2-weighted MRI
malignancy is made by the presence of metastases. • MIBG (m-iodobenzylguanidine) scanning
may help localisation
• Phaeochromocytomas may produce
chromogranin A
• Preoperative preparation is with
Familial phaeochromocytomas occur in Æ-adrenergic blockade
(eg phenoxybenzamine) before â blockade
• Multiple endocrine neoplasia type 2 (see
below)
• Spontaneously in some families (not
associated with a syndrome) Causes of episodic sweating and/or £ushing
• Von Hippel–Lindau syndrome (retinal and
cerebral haemangioblastomas and renal • Oestrogen/testosterone deficiency (eg
cystic carcinomas) menopause, castration)
• Von Recklinghausen’s disease • Carcinoid syndrome (flushing, diarrhoea,
(neurofibromatosis) – 1–2% wheeze)
• Carney’s triad: gastric leiomyosarcoma, • Phaeochromocytoma (sweat but do not flush)
pulmonary chondroma, Leydig’s testicular • Hypoglycaemia (in diabetes)
tumour • Thyrotoxicosis (not usually episodic)
• Paraganglioma syndromes (PGL types 1–4): • Systemic mastocytosis (histamine release)
associated with head and neck • Allergy.
paragangliomas and phaeochromocytomas.
Mutations in one of the four succinate Multiple endocrine neoplasia (MEN) syndromes are
dehydrogenase subunits (SDH), especially syndromes with multiple benign or malignant endo-
SDHD (PGL1) and SDHB (PGL 4) crine neoplasms (Table 4.10). They should not
be confused with polyglandular autoimmune
132
Endocrinology
Table 4.10 Classification of multiple endocrine neoplasia (MEN)
MEN-1 MEN-2A MEN-2B
Genetics The menin gene The ret gene The ret gene
Chromosome 11 Chromosome 10 Chromosome 10
Tumours Parathyroid Parathyroid Parathyroid
Pituitary Phaeochromocytoma Phaeochromocytoma
Pancreas (carcinoid) Medullary thyroid cancer Medullary thyroid cancer
(Adrenal adenomas) Marfanoid
Mucosal neuromas
syndromes which relate to autoimmune endocrine 4.8 PUBERTY/GROWTH/INTERSEX

diseases.
4.8.1 Normal puberty
• MEN-1 was formerly known as Werner’s
syndrome. MEN-2A was known as Sipple’s In 95% of children, puberty begins between the
syndrome. All MEN syndromes are autosomal ages of 8 and 13 years in females and 9 and 14
dominant. Genetic (DNA-based) screening is years in males. The mean age of menarche is 12.8
available for both MEN-1 and MEN-2. The years. The events of puberty occur in a particular
MEN-2 mutation in ret activates the protein. order, although the later stages overlap with the
Inactivating mutations of ret are seen in earlier ones.
Hirschsprung’s disease
• All MEN syndromes can be associated with Order of events in normal puberty
hypercalcaemia. This is usually due to (earliest events listed ¢rst)
hyperplasia of all four parathyroids, not a single
parathyroid adenoma as with sporadic • Male
hyperparathyroidism. Hypercalcaemia is often • Scrotal thickening (age 9–14)
the first manifestation in MEN-1 • Testicular enlargement (.2 mL)
• Gastrinomas and insulinomas are the most • Pubic hair
common pancreatic tumours in MEN-1. Of the • Phallus growth
pituitary tumours, prolactinomas are the most • Growth spurt (age 10–16) + increasing
common, followed by acromegaly and bone age
Cushing’s disease. • Female
• Breast development (age 8–13)
• Growth spurt
• Pubic hair
Medullary thyroid cancer (MTC) is always malig- • Menstruation (age 10–16) + increasing
nant, secretes calcitonin and is preceded by C-cell bone age
hyperplasia. Prophylactic thyroidectomy in patients
with genetically confirmed MEN-2 should be per-
formed to prevent this most serious manifestation.
4.8.2 Precocious puberty
The exact site of the ret gene determines the age at
which thyroidectomy should be performed, in many True precocious puberty is rare. It is diagnosed if
cases under the age of 2 years. multiple signs of puberty develop before age 8 in
133
females and age 9 in males, accompanied by in- Causes of delayed puberty/short stature
creased growth rate, accelerated bone age and
raised sex steroid levels. Isolated premature breast • General causes
development (thelarche) or the appearance of pubic • Overt systemic disease
hair alone (from adrenal androgens – adrenarche) • Social deprivation
are both benign conditions if no other stages of • Anorexia, excess exercise
puberty are entered. • Chemotherapy/gonadal irradiation
• Cranial irradiation
Causes of precocious puberty • Syndromes causing delayed puberty/short
stature
• True ‘central’ gonadotrophin-dependent • Turner’s syndrome (XO)
precocious puberty • Noonan’s syndrome (‘male Turner’s
• Idiopathic syndrome’)
• Other CNS disease (eg hydrocephalus, • Prader–Willi syndrome
encephalitis, trauma) • Occult systemic disease
• CNS hamartoma (eg pineal) • Renal failure/renal tubular acidosis
• Other causes (gonadotrophin-independent) • Crohn’s/coeliac disease
• Adrenal, ovarian tumour • Hypothyroidism
• CAH (males) • Asthma
• Testotoxicosis (males) • Anterior pituitary disease
• Exogenous oestrogen (females) • Hyperprolactinaemia
• McCune–Albright syndrome • Isolated GH deficiency
• Follicular cysts (females) • Syndromes causing delayed puberty but
• Profound hypothyroidism normal stature
• Androgen insensitivity (testicular
McCune–Albright syndrome is more common in feminisation – XY female)
girls (see Section 4.1.2 on activating G-protein mu- • Polycystic ovary syndrome (delayed
tations). menarche only)
• Kallman’s syndrome (XY), anosmia
• Klinefelter’s syndrome (XXY) – males
4.8.3 Delayed puberty/short stature
Short stature in children is often due to delayed In Turner’s syndrome, Noonan’s syndrome, andro-
puberty and hence the two problems are usually gen insensitivity and Klinefelter’s syndrome, raised
grouped together. Three per cent of children are LH and FSH are present. Kallman’s syndrome is due
‘statistically delayed’, ie for girls no breast develop- to failure of GnRH-secreting neurons migrating to
ment by age 13 or menses by age 15, and for boys the hypothalamus. LH and FSH levels, as well as
no testicular enlargement by age 14. The majority sex steroids, are low and patients typically have
will have ‘constitutional delay’ and will later enter associated anosmia. Mutations in at least five genes
puberty spontaneously. However, there is no endo- can cause the syndrome, the best recognised being
crine test that can reliably distinguish constitutional the classic X-linked locus (KAL-1 also known as
delay from other organic causes of delayed puberty. anosmin-1 – the syndrome associated with anosmia)
and the autosomal loci fibroblast growth factor
In investigation, systemic diseases or syndromes that
receptor 1 (FGFR1, a syndrome associated with
can cause delayed puberty should be excluded
orofacial clefting and hypodontia).
before considering pituitary testing. A karyotype (for
Turner’s syndrome) should always be requested in However, gene mutations account for only around
girls (see following text). 40% of cases of idiopathic hypogonadotrophic
134
Endocrinology
hypogonadism. There is no biochemical test that Causes of intersex

can currently distinguish Kallman’s syndrome from
constitutional delay of puberty, and therefore a • Virilised female (XX)
clinical diagnosis is made when delayed puberty is • CAH (21-OH or 11-OH)
associated with anosmia. • Maternal androgen ingestion
Turner’s syndrome (XO) (see Chapter 7, Genetics) • Non-masculinised male (XY)
occurs in 1 in 2500 live births. The typical features • Unusual CAH (17-OH/side-chain/3-â-
(abnormal nails, neonatal lymphoedema, web neck, OH)
widely spaced nipples, wide carrying angle) may be • Androgen resistance:
absent. A karyotype should always be requested in • Receptor defect (‘testicular
girls with short stature/delayed puberty because the feminisation’)
final height can be increased by early treatment • 5Æ-reductase deficiency
with high doses of growth hormone. Other impor-
tant complications which may occur in Turner’s
syndrome include aortic root dilatation (often the
cause of death) or coarctation, renal abnormalities, Mothers who have a virilised daughter with CAH
abnormal liver function tests and deafness. Women can be treated antenatally with steroids in subse-
with Turner’s syndrome are generally infertile, but in quent pregnancies in order to suppress androgen
some cases will have relatively minor X deletions production by the fetus. Steroids are continued until
and/or chimaerism with cells of a normal karyotype, the sex of the baby can be established by chorionic
so both menstruation and pregnancy can occur. villous sampling.
Klinefelter’s syndrome (XXY) (see Chapter 7, Genet-

ics) occurs in 1 in 1000 live births (by meiotic non-
disjunction), but is usually undiagnosed until adult-
hood. Testosterone production is around 50% of
4.9 DIABETES MELLITUS
normal, but is sufficient to allow secondary sexual
characteristics and normal height to develop. Diabetes may be defined as chronic hyperglycaemia
Patients usually come to attention because of small at levels sufficient to cause microvascular complica-
testes, gynaecomastia or infertility. tions:
• 10% of cases are due to type 1 diabetes where
there is autoimmune destruction of the
4.8.4 Intersex
pancreatic islets of Langerhans
(See also Chapter 7, Genetics.) Ambiguous genitalia • Around 85% are due to type 2 diabetes
at birth require urgent diagnosis with steroid profile characterised by insulin resistance and relative
and karyotype to assign the appropriate sex of rear- deficiency of insulin secretion
ing and identify the risk of a salt-losing crisis (CAH). • The remaining 5% of cases are due to a
Causes can be grouped as shown in the box. collection of secondary causes
135
4.9.1 Risk factors and clinical and is actually more strongly inherited than type 1
features of types 1 and 2 diabetes, despite being ‘adult-onset’.
diabetes mellitus
Maturity onset diabetes of the young (MODY) is a
Table 4.11 summarises the differences between type term used to describe a group of disorders describ-
1 and type 2 diabetes mellitus. Note that type 2 ing autosomal dominantly inherited monogenic dia-
diabetes is more common in non-Caucasian races betes. It causes 1–2% of diabetes and there is
Table 4.11 Comparison between type 1 and type 2 diabetes mellitus
Type 1 Type 2
Genetics Both parents affected: up to 30% risk Both parents affected: 75% risk for child
for child Identical twins: up to 90% concordance
Identical twins: 64% concordance by
60 years Asian, Black, Hispanic, Native Americans
Over 20 genes have been identified that
Caucasians increase susceptibility
Increased risk conferred by over 15 gene

loci identified so far, the more of these
present, the greater the risk
Autoantibodies In new type 1 diabetics: No antibody association

60–75% have insulin antibodies
70–80% have GAD (glutamic acid
decarboxylase) antibodies
65–75% have IA-2 (islet antigen-2)
antibodies
70–80% have ZnT8 (zinc transporter-8)
antibodies
Incidence Approximately 1/10 000 per year and Approximately 1/200 per year
rising
Prevalence Approximately 1/1000 Approximately 5/100
Clinical features Age ,40 Age usually .20 but increasing numbers of
paediatric patients
Insidious onset
Weight loss Overweight
Ketosis prone Usually ketone negative
Insulin deficient Insulin resistant
Autoimmune aetiology (other Acanthosis nigricans
autoimmune disorders may be present) Associated with metabolic syndrome (with
obesity, hypertension, dyslipidaemia)
136
Endocrinology
usually a family history. Age of onset of diabetes is • HbA1c >48 mmol/mol or 6.5%
usually less than 25 years and the condition is • Without symptoms: fasting glucose .7.0
caused by beta cell dysfunction. Treatment depends mmol/L or random glucose 11.1 mmol/L on
on the underlying gene defect (Table 4.12). 2 occasions
• Impaired glucose tolerance is defined by a
2 hour OGTT value of 7.8–11.1 mmol/L
4.9.2 Diagnostic criteria for diabetes
• Impaired fasting glucose is a value .5.6 but
This remains an area of ongoing debate. There have ,7.0 mmol/L.
been recent changes to the diagnostic criteria for
*Values are based on venous rather than capillary blood
diabetes with the official addition of the use of values.
HbA1c for diagnosis rather than to solely look at
glycaemic control. The current practical use of the
OGTT (oral glucose tolerance test) is for those
patients with a fasting glucose level between 6.0 Impaired fasting glucose (IFG) and impaired glucose
and 7.0 mmol/L, or in the diagnosis of gestational tolerance (IGT) are two conditions of ‘pre-diabetes’.
diabetes. IGT confers increased cardiovascular risk. Twenty
percent of patients with IGT will progress to type 2
Diagnoses of diabetes and pre-diabetes* diabetes within 5 years. A number of interventions
have been identified that can reduce the risk of this
• With symptoms: fasting glucose occurring or slow the progression. A programme of
.7.0 mmol/L or random glucose over 11.1 diet and exercise, weight loss (any cause including
mmol/L or glucose over 11.1 mmol/L 2 bariatric surgery), and drugs including metformin,
hours into an OGTT acarbose, thiazolindenediones and orlistat have all
been shown to be effective.
Table 4.12 Classification of MODY (maturity-onset diabetes of young people) disorders
Gene Percentage of Classification

MODY cases
Glucokinase 20 MODY 2 – mild, complications are rare

HNF-1Æ 60 MODY 3 – progressive beta cell failure but very sensitive to
sulphonylureas
HNF-4Æ 1 MODY 1 – neonatal hyperinsulinism
HNF 1â 1 MODY 5 – associated renal anomalies or cysts
IPF-1 1 MODY 4 – very rare
,1 MODY 6–11
Unknown 15 MODY X
SUR1, Kir6.2 ,1 Hyperinsulinism in infancy and â cell failure in adulthood
137
Classi¢cation of diabetes glycaemic control reduces the risk of complications.

Subcutaneous insulin administration can vary from
• Type 1 diabetes two to five injections per day. Multiple dose regimes
• Type 2 diabetes with a combination of basal insulin (intermediate or
• Genetic disorders usually long acting) and varying doses of rapid-
• MODY acting insulin meals according to capillary glucose
• Mitochondrial disorders eg MELAS, levels, carbohydrate intake and exercise, allow
MIDD greater flexibility and improve control. In the UK,
• Exocrine pancreas disease eg NICE has licensed continuous subcutaneous insulin
• Pancreatitis infusions (CSII, insulin pumps) for type 1 diabetics
• Pancreatectomy in whom multiple dose regimes of insulin have not
• Haemochromatosis improved control sufficiently (HbA1c over 8.5%,
• Cystic fibrosis 69mmol/mol) or led to disabling hypoglycaemic
• Neoplasm episodes. Additional treatments include islet cell
• Drugs eg corticosteroids, antipsychotics transplantation and whole pancreas transplantation,
• Endocrine disorders eg which may be indicated in patients with recurrent
• Cushings severe hypoglycaemia despite best medical treat-
• Acromegaly ment. In addition, cardiovascular risk factor man-
• Thyrotoxicosis agement is also indicated in all patients. Types of
• Phaeochromocytoma insulin are shown in Table 4.13.
• Other genetic syndromes eg
• Down’s syndrome
• Klinefelter’s syndrome 4.9.4 Treatment of type 2 diabetes
• Turner’s syndrome
There are a number of drug categories available to
• Wolfram syndrome (also known as
treat patients with type 2 diabetes (Table 4.14), and
DIDMOAD – diabetes insipidus,
drug choice needs to be based on a number of
diabetes Mellitus, optic atrophy and
factors including glycaemic control, patient prefer-
deafness)
ence, side effects and associated comorbidities. A
• Gestational diabetes mellitus
gradual decline in insulin reserves leads to an in-
creasing requirement for medication and around
30% of type 2 diabetics ultimately need insulin
therapy to achieve glycaemic targets. Weight loss
Insulin replacement is essential in type 1 diabetes. (whether by diet and exercise, medication or baria-
There is ample evidence to show that improved tric surgery) is an important adjunct to medication
Table 4.13 Types of insulin
Examples Peak (hours) Duration (hours)
Rapid Aspart, Lispro 1 3–4

Short Regular 2–4 6–8
Intermediate NPH 4–8 12–16
Long Detemir – 18–24
Glargine – 20–24
Mixed Insuman Comb 25 Varies depending on type – combined intermediate and
Humulin M3 rapid acting insulin
138
Endocrinology
Table 4.14 Drugs used in the glucose control of type 2 diabetes
Drug Action/comments
Sulphonylureas Increase insulin secretion; risk of hypoglycaemia, weight gain
Biguanides (eg metformin) Reduced insulin resistance (lower hepatic glucose production). GI side effects.
Rare risk of lactic acidosis (usually in the context of concurrent illness and
reduced GFR)
Æ-Glucosidase inhibitors Slows carbohydrate absorption. Unacceptable flatus production for most
(eg acarbose) patients
Thiazolindenediones (eg Activate intracellular PPAR-ª thereby reducing insulin resistance. Can cause
pioglitazone) fluid retention, osteoporosis and link with bladder cancer
Insulin Used frequently in combination with other drugs; causes weight gain
Glucagon-like peptide Increase secretion of endogenous insulin, suppress glucagon, reduce appetite
agonists (eg exenatide) and promote weight loss. Injected
Dipeptidyl peptidase IV Increase secretion of endogenous insulin. No weight gain

inhibitors (eg sitagliptin)
SGLT-2 inhibitors (eg Allow glycosuria by blocking glucose reabsorption in the kidneys. Some weight
dapagliflozin) loss. Increased risk of urinary tract infections
to improve glycaemic control, and in some cases

can cause the remission of diabetes. In addition, Abnormally low HbA1c
cardiovascular risk reduction with control of hyper-
tension, lipids and the use of aspirin are important • Haemolysis
for management. • Increased red cell turnover
• Blood loss
• HbS or HbC
4.9.5 Glycated HbA1c Abnormally high HbA1c

Red cell haemoglobin is non-enzymatically gly-
cated at a low rate according to the prevailing level • Persistent HbF
of glucose. The percentage of glycated haemoglobin • Thalassaemia
provides an accurate estimate of mean glucose • Uraemia (carbamylated haemoglobin)
levels over the preceding 2–3 months and correlates
with the risk of microvascular complications. Mod- One thing this does highlight is the potential pitfall
ern assays for HbA1c are rarely misleading but a of using HbA1c in the diagnosis of diabetes – care
few considerations should be made if home glucose must be taken if there is a high red cell turnover or
monitoring results don’t correlate well: if symptoms are of a rapid onset.
139
4.9.6 Microvascular and amputation (0.5–1%). Some patients with

macrovascular complications of neuropathy develop Charcot’s osteoarthropathy
diabetes with collapse of the bony architecture of the
foot and development of deformity.
Long-term diabetic complications are due to vascu-
lar damage. Damage to the microvasculature and its
consequences correlate well with levels of glycae-
mic control and can be delayed or prevented by Micro- and macrovascular complications
maintaining near-normal glucose levels. Microvas- of diabetes
cular complications usually take a minimum of 5
years to develop, even with poor glycaemic control. • Microvascular
In paediatric cases, the changes in hormones during • Retinopathy (90%)*
puberty lead to acceleration of risk as compared to • Neuropathy (70–90%)*
pre-puberty. Complications may be apparent at • Nephropathy (30–40%)*
diagnosis in type 2 diabetes due to delayed diag- • HbA1c dependent
nosis. Neuropathy (70–90%) and retinopathy (90%) • Macrovascular
occur in virtually all patients with suboptimal con- • Ischaemic heart disease (accounts for up
trol and longer duration of diabetes. Thirty to forty to 70% of deaths in diabetes)
per cent of patients will develop diabetic nephro- • Peripheral Vascular disease
pathy, usually within 20 years of onset of diabetes. • Cerebrovascular disease
• Less HbAC1c-dependent
The incidence of microvascular complications was
reduced in type 1 diabetics by around 50% in the *Approximate percentages of diabetics who will have
Diabetes Control and Complications Trial (DCCT) this complication to some degree during their lifetime
by tight glycaemic control. (data from retrospective studies).
In contrast, macrovascular disease, which is respon-

sible for most of the increased mortality in diabetes,
does not appear to be as closely related to the level
of glycaemic control. The increased risk of macro- 4.9.7 Autonomic neuropathy
vascular disease is partly explained by a combina-
tion of hypertension, lower HDL and higher Autonomic complications of diabetes may occur in
triglyceride levels. Treatment of hypertension re- long-standing diabetes, especially in the context of
duces not only cardiovascular risk but also the risk poor control. Complications can be very difficult to
of neuropathy and retinopathy (especially the use of treat and there is high morbidity, reduced quality of
ACE inhibitors). life and increased mortality.
• Note that chest pain due to ischaemic heart

disease is often absent or atypical in diabetes Manifestations of diabetic autonomic
and easily missed neuropathy
• Proteinuria is a strong risk factor for ischaemic
heart disease in diabetes, presumably as a • Postural hypotension
marker of endothelial dysfunction. Individuals • Gastroparesis
with microalbuminuria or proteinuria should • Gustatory sweating
have more aggressive blood pressure control. • Generalised sweating
• Peripheral neuropathy predisposes to foot • Cardiac arrhythmia (‘dead in bed’)
ulceration (occurs in 10% of patients) and, • Diarrhoea, constipation
particularly in combination with peripheral • Reduced appreciation of cardiac pain
vascular disease, increases the risk of
140
Endocrinology
4.10 HYPOGLYCAEMIA 4.10.2 Hypoglycaemia unrelated to

diabetes
4.10.1 Hypoglycaemia in diabetes
True hypoglycaemia unrelated to diabetes is rel-
mellitus
atively rare. Whipple’s triad consists of symptoms
Autonomic symptoms of hypoglycaemia (sweating, consistent with hypoglycaemia, measured hypogly-
tremor) appear when the blood glucose is ,3.5 caemia and resolution of symptoms with correction
mmol/L, but can also occur at higher levels when of the low glucose. A supervised 72-hour fast can be
diabetics have poorer glycaemic control, or when used to precipitate and document an episode, parti-
there is a rapid drop in glucose levels. Neurogyco- cularly to diagnose an insulinoma (where there will
paenic symptoms (impaired cerebral function, be inappropriately elevated insulin and C-peptide
coma, seizures) occur when glucose levels drop levels in conjunction with a low glucose level).
,2.5 mmol/L. In patients on insulin, failure of the
normal counter-regulatory responses (sympathetic Causes of hypoglycaemia
nervous system activation, adrenaline and glucagon
release) may develop in long-standing diabetes, • Fasting
particularly in the context of frequent hypoglycae- • Insulinoma
mic episodes. This results in hypoglycaemic • Tumour (IGF-2 mediated)
unawareness. With no warning of impending neuro- • Hypoadrenalism
logical impairment, the patient cannot take appro- • Alcohol
priate action. More frequent hypoglycaemic • Severe liver failure
episodes result, exacerbating the problem – ‘hypos • Factitious (insulin or sulphonylurea)
beget hypos’. Hypoglycaemic awareness can be • Drugs
restored by relaxing control to allow a prolonged • Anti-insulin antibodies (delayed post-
hypoglycaemia-free period. prandial release of insulin)
• Post prandial
• Post-gastrectomy/bariatric surgery
• Reactive
• Idiopathic (rare)
141

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Essential

Contributors to Fourth Edition vii

13. Metabolic Diseases 359

4.1 Hormone action 4.4 Hyponatraemia and SIADH

4.9 Diabetes mellitus

4.1 HORMONE ACTION bind to an intracellular receptor and affect gene

• Short half-life (minutes) Cyclic AMP and G-proteins

Table 4.1 Mechanisms of hormone action

Via cAMP Via Ca2+ Via receptor tyrosine kinases

Adrenaline (â receptors) GnRH Insulin

G-proteins are important in endocrinology because pseudohypoparathyroidism). The dysmorphic

4.1.3 Hormones that act hormone (TRH), TSH and L-thyroxine/L-triiodothyro-

4.1.4 Hormone resistance syndromes • GH (though IGF-1 falls)

Leptin, adipokines and other hormones Derived from tissue-specific cleavage of

Dynamic testing is therefore frequently used, ie • Phenothiazines, haloperidol (not tricyclics)

Causes of gynaecomastia: 4.2.8 Thyroid hormone metabolism

Table 4.2 Adrenal steroids

Relative Relative Duration of action

Cortisol ¼ hydrocortisone 1 þ Short

Figure 4.2 The renin–angiotensin system.

Low Na1 delivery Angiotensinogen

Renal perfusion RENIN

Retain Na1 Vasoconstriction

Plasma calcium is tightly regulated by parathyroid • Natriuretic: it causes a natriuresis (urinary

Pituitary tumours excessive ACTH production from the pituitary gland

Craniopharyngiomas are benign tumours that arise Causes of nephrogenic DI

Table 4.3 Interpretation of the water deprivation test

Normal Normal .600 .600 High

condition can result in washout of the renal 4.3.4 Acromegaly

If hyponatraemia is confirmed to be ‘real’ (low Features of hyper- and hypothyroidism

Table 4.4 Causes of hyponatraemia

Urine sodium (mmol/L) Hypovolaemia present Euvolaemia/Hypervolaemia 6 oedema

.20 Diuretics SIADH

,10 Vomiting, diarrhoea Congestive cardiac failure, cirrhosis, nephrotic

Table 4.5 Features of hyper- and hypothyroidism

Features Hyperthyroidism Hypothyroidism

General Weight gain (rarely) Weight gain

Gynaecological Raised sex hormone-binding globulin Amenorrhoea, menorrhagia

Gastrointestinal Raised alkaline phosphatase (derived Diarrhoea

Muscle Proximal myopathy Raised creatine kinase

Cardiovascular Atrial fibrillation with high stroke rate Dyspnoea

Neurological ‘Apathetic thyrotoxicosis’ Deafness

Eyes Eye signs (see Section 4.5.5) Periorbital oedema

Blood Leukopenia Macrocytic anaemia

Skin Urticaria Dry, orange (carotenaemia)

Side-e¡ects of anti-thyroid drugs be presumed to be benign. In order of increasing

Graves’ disease only

Table 4.6 Thyroid function tests

Low Normal Raised

Normal fT4 /fT3 Subclinical thyrotoxicosis: Normal Subclinical

• acne genic Cushing syndrome secondary to steroid use,

Table 4.7 Tests used to identify causes of Cushing syndrome

Adrenal Pituitary Ectopic

ACTH Suppressed Mid-range High

CRH stimulation test No change Rise in ACTH and No change

Metyrapone Rise in 11-deoxycortisol Rise in 11-deoxycortisol Rise in 11-deoxycortisol

stimulation. Recovery of this adrenal gland may take Medical therapy

Table 4.8 Differentiating features in congenital adrenal hyperplasia

21-hydroxylase 11-hydroxylase 17-hydroxylase/