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Metabolic and endocrine disorders
Table33.2 Causes of hypocalcaemia
Mechanism Example
Reduced calcium intake Dietary deficiency,
Reduced vitamin D
intake/production
Reduced activation of
vitamin D
Increased inactivation of
vitamin D
Reduced production of
PTH
Resistance to PTH Pseudohypoparathyroidism
Hypoalbuminaemia Shock
PTH, Parathyroid hormone.
malabsorption
Dietary deficiency,
malabsorption, reduced
sunlight exposure
Renal disease, liver disease
Enzyme induction by
anticonvulsants
Surgical removal of
parathyroid glands,
autoimmune, congenital
(DiGeorge syndrome)
Investigations
Serum calcium level is low, phosphate level is high and alkaline phosphatase level is normal. Additional tests include
serum urea and creatinine levels, serum PTH level, parathyroid antibodies and vitamin D metabolite levels. Serum
PTH level will be low in hypoparathyroidism but raised in
pseudohypoparathyroidism. Investigations for other endocrinopathies may be required in certain cases.
X-rays of the hands show short fourth metacarpals in
pseudohypoparathyroidism.
Management
Emergency treatment of hypocalcaemia is with 10 mL
of 10% calcium gluconate IV, repeated as necessary (see
Chapter31). IV magnesium chloride may also be required if
there is concurrent hypomagnesaemia. Calcium levels will
be difficult to correct in the context of low serum magnesium levels.
Long-term treatment is with alfacalcidol or calcitriol.
Serum calcium level should be monitored to prevent
hypercalcaemia.
Aetiology
Primary hyperparathyroidism (overproduction of PTH
in the absence of other abnormalities) is usually due to a
single benign adenoma. This is common, particularly in
postmenopausal women. Less frequently it can be due to
multiple adenomas, carcinoma or hyperplasia. It may be associated with other endocrine abnormalities as part of the
multiple endocrine neoplasia (MEN) syndromes. Ectopic
PTH production is very rare; more commonly, cancers
of the lung or breast produce PTH-related protein, which
causes a similar picture.
Secondary hyperparathyroidism occurs when PTH levels are persistently and appropriately raised to maintain
calcium concentrations in the face of a disorder that lowers
calcium levels. Causes include chronic renal failure and deficiency of vitamin D.
Tertiary hyperparathyroidism is the continued secretion of excess PTH after prolonged secondary hyperparathyroidism. The parathyroids act autonomously and cause
hypercalcaemia, despite correction of the original cause of
the secondary hyperparathyroidism. This occurs in some
patients with end-stage renal failure.
Clinical features
Hyperparathyroid bone disease can cause osteopenia and
osteoporosis. This may result in fractures causing bone
pain. In addition, all the features associated with hypercalcaemia may be present (see Chapter31).
Investigations
In primary hyperparathyroidism, serum calcium level is
raised. Serum phosphate level is low and alkaline phosphatase level is high, reflecting increased bone turnover.
In secondary hyperparathyroidism of renal failure, serum
calcium level is low or normal and phosphate level is normal
or high, resulting in an appropriate rise in PTH production.
In tertiary hyperparathyroidism, serum calcium level is
high and PTH level is inappropriately high.
In patients with hyperparathyroidism a dual energy
X-ray absorptiometry scan can show evidence of bone
involvement. Pathognomonic X-ray features include subperiosteal resorption of the phalanges and salt and pepper
degranulation of the skull. Imaging of the renal tract may
show renal calculi. Imaging of the neck is used only to plan
surgery and is not used for diagnosis.
Hyperparathyroidism
Hyperparathyroidism results from excess circulating PTH.
PTH acts to increase serum calcium levels by increasing mobilization of calcium from bone and increasing
calcium reabsorption from the kidney. Also, in the kidney it increases the hydroxylation of vitamin D to active
1,25-dihydrovitamin D3. This acts to increase calcium absorption from the small bowel. PTH also increases phosphate release from bone and increases renal phosphate
excretion, with the overall effect of lowering phosphate
concentrations.
318
CLINICAL NOTES
Perform a 24-hour urinary collection to look for
familial benign hypocalciuric hypercalcaemia. This
condition can present with a hypercalcaemia and
an inappropriately raised parathyroid hormone
level; in this case parathyroidectomy will be
ineffective.
Pituitary disorders
3333
Management
Parathyroidectomy is indicated for symptomatic disease. The
decision is more difficult in asymptomatic patients, many of
whom will progress to overt disease. Guidelines suggest surgery when there is persistent hypercalcaemia with a calcium
level greater than 0.25 mmol/L above normal, renal impairment, renal calculi, bone mineral density (BMD) T score
below −2.5, vertebral fracture or age younger than 50years.
The parathyroid glands may be localized by CT scan,
single photon emission CT scan or a technetium (
sestamibi scan, which can detect adenomas. The operative
procedure may be a full bilateral exploration (if multiple
adenomas are present and in certain other situations) or a
minimally invasive endoscopic procedure with intraoperative PTH monitoring (when a single adenoma is seen on
imaging). All abnormal glands are removed.
If all the glands are hyperplastic, three and a half are usually removed, leaving the last half in situ.
COMMON PITFALLS
Serum calcium and magnesium levels should be
monitored very carefully postoperatively as removal
of the glands may lead to rapid and prolonged
hypocalcaemia and hypomagnesaemia as the
‘hungry bones’ recover the minerals lost during the
period of hyperparathyroidism. This often warrants
frequent intravenous administration of calcium.
If surgery is contraindicated, bisphosphonates or
calcimimetics (e.g. cinacalcet) may be useful.
99m
Tc)
PITUITARY DISORDERS
sarcoidosis), pituitary infarction (Sheehan syndrome) or
haemorrhage and metastatic lesions.
RED FLAGS
Sudden haemorrhage or infarction of the pituitary
causes headache, diplopia and hypopituitarism
and is known as ‘pituitary apoplexy’. This is an
emergency and requires intravenous fluids and
steroids.
Clinical features
These can be related to the size of the adenoma, which can
cause headaches and affect vision, classically causing a bitemporal hemianopia through pressure on the optic chiasm (see later).
Otherwise, the features of hypopituitarism relate to
which pituitary hormones are being affected. GH and gonadotrophins are often affected first:
• Suppressed GH: fatigue, increased abdominal adiposity
and reduced muscle strength and exercise capacity.
• Suppressed LH and FSH: in women, there is
oligomenorrhoea, infertility, dyspareunia, breast
atrophy, loss of pubic and axillary hair and hot flushes;
in men, there is loss of libido, impotence, infertility,
flushes, regression of secondary sexual characteristics,
soft testes and fine wrinkles on the face.
• Suppressed TSH: fatigue, muscle weakness, sensitivity
to cold, constipation, apathy, weight gain and dry skin.
• Suppressed ACTH: fatigue, anorexia, weight loss,
postural hypotension, weakness, nausea and vomiting,
hypoglycaemia, apathy, reduced libido and loss of pubic
and axillary hair.
• Suppressed prolactin: inability to lactate.
Hypopituitarism
The anterior pituitary produces six hormones: adrenocorticotrophic hormone (ACTH), growth hormone (GH),
follicle-stimulating hormone (FSH), luteinizing hormone
(LH), TSH and prolactin (PRL). Hypopituitarism may be
associated with loss of all or some of these hormones. The
clinical and biochemical presentation will depend on which
hormones are deficient and to what extent.
Aetiology
The most common cause of hypopituitarism is from the
mass effect of a pituitary adenoma (which, if functional,
may cause features of hypersecretion of a specific hormone;
see later), with additional loss of pituitary function after
surgery and pituitary irradiation.
Other causes include hypothalamic tumours and
cysts, peripituitary tumours (e.g. gliomas and meningiomas, craniopharyngiomas), infiltrative diseases (e.g.
CLINICAL NOTES
The symptoms of hypopituitarism are nonspecific
but must not be dismissed. A high index of
suspicion may be required to make the diagnosis.
Investigations
Dynamic tests involving stimulation are occasionally
needed to assess ACTH or GH levels; otherwise basal levels
provide all the necessary information.
HINTS AND TIPS
Most pituitary hormones are secreted in a pulsatile
fashion, and therefore random levels are not very
useful.
319
Metabolic and endocrine disorders
• Serum thyroxine (T4) and thyroid stimulating
hormone: a low T4 level together with a low or
normal TSH level is suggestive of secondary
hypothyroidism.
• To assess adrenocorticotrophic hormone
(ACTH), cortisol level should be measured
between 8 a.m. and 9 a.m. If the level is
low or intermediate, serum ACTH should be
measured; the sample needs to be taken at
9a.m. into a cold tube and immediately
put on ice.
• Follicle-stimulating hormone (FSH) and
Luteinizing hormone (LH): these should be
measured in the morning with a simultaneous
measurement of serum testosterone level in
men and serum oestradiol level in women.
• Growth hormone (GH): as basal levels of GH
fluctuate greatly, if deficiency is suspected, an
insulin tolerance test is required; the normal
response is GH release as glucose levels
decrease. Insulin-like growth factor 1 levels will
also be low in GH deficiency.
• Prolactin: raised levels would signify a
prolactinoma.
• Investigate with CT/MRI/visual field assessment:
(see section Pituitary tumours: investigations.
Management
Hormone replacement involves the use of multiple hormones. Hydrocortisone is given for adrenal failure, T4
for hypothyroidism, testosterone for hypogonadal men
and oestrogen for hypogonadal premenopausal women.
Recombinant human GH is given by injection to patients
with significant symptoms. Careful instruction and patient
adherence are mandatory for long-term recovery.
Pituitary tumours
Pituitary tumours are generally benign and curable.
They can result in problems by excessive hormone production, local effects of the tumour or inadequate hormone production by the remaining pituitary gland.
Nonfunctioning and PRL-secreting tumours are the most
common. Pituitary tumours account for around 20% of
all intracranial neoplasms. PRL- and ACTH-secreting
tumours occur most commonly in 25–35-year-olds, GHsecreting tumours occur most commonly in those aged
35–50years, and nonfunctioning tumours usually present
after the age of 60years. They can also be classified by
their size as microadenoma (<1 cm diameter) or macroadenoma (>1 cm).
Clinical features
Pressure effects cause headaches, and there may be
compression of the optic chiasm causing bitemporal
hemianopia. Seizures, other cranial nerve signs and hydrocephalus may occur with large masses. Extension into
the hypothalamus affects appetite, sleep and temperature
regulation.
The effects of functioning tumours depend on the
hormone secreted. They may cause acromegaly via GH,
amenorrhoea–galactorrhoea syndrome via PRL, or Cushing
disease via ACTH. Secondary thyrotoxicosis is rare. The
features of hypopituitarism were described earlier.
Investigations
Endocrinological assessment is performed as described earlier. MRI scan is the best modality with which to assess the
anatomy of the tumour. Formal visual field assessment is
important as many of these tumours have effects on the visual pathways, particularly at the optic chiasm.
Management
Management may be medical, surgical or with radiotherapy. Aside from prolactinomas, surgical resection
is the treatment of choice in most cases. The surgical
approach is usually transsphenoidal, but with larger
masses a transfrontal approach may be necessary. Drug
therapy includes dopamine receptor agonists (e.g. cabergoline, bromocriptine) for prolactinoma; these inhibit
PRL release and induce shrinkage of the tumour in more
than 90% of cases. Somatostatin analogues inhibit GH
release and induce less tumour shrinkage in most GHsecreting adenomas. They are usually used after surgery
in acromegaly.
Acromegaly
Acromegaly is an insidious disease resulting from excessive
circulating levels of GH in adults. GH stimulates the production of insulin-like growth factor-1 (IGF-1), which is
produced in the liver and is the main tissue mediator of the
actions of GH. Diagnosis is often made years after symptoms first occur.
Acromegalic gigantism results from acromegaly in
young individuals before epiphyseal fusion, and is very
uncommon.
Aetiology
The commonest cause is a benign pituitary tumour secreting GH. Pituitary carcinoma and carcinoid tumours that secrete hypothalamic GH-releasing hormone are uncommon
causes.
Clinical features
The clinical features of acromegaly are summarized in
Fig 33.5.
320
Brain
— Skin coarse and thickened
Skull
— Enlar
Hands
— Lar
— Carpal tunnel
syndrome
Large bowel
— T
Liver and kidneys
— Enlar
Blood
— 1 in 10 are
— 1 in 4 have glucose
are diabetic
Eyes
— Loss of peripheral vision
Heart
— Enlar
ged head circumference
due to pituitary tumour
compressing optic nerve
ged (predisposed
to cardiomyopathy)
ged organs
hypercalcaemic
intolerance, some
ge, square
and spade-like
umours (benign
or malignant)
Pituitary disorders
— Mental disturbances
— Insomnia
Face
resulting in prominent
nasolabial folds and
supraorbital ridge
— Large lower jaw
(prognathism)
— Spaces between lower
teeth due to jaw growth
(interdental spacing)
— Large nose
— Large tongue
(macroglossia)
— Frontal bone prominence
Blood pressure
— 1 in 3 are hypertensive
(predisposed to
ischaemic heart disease)
Bones
— Predisposed to
osteoarthritis owing to
increased body size and
altered bone structure
Skin
— Increased greasy sweating
— Temperature intolerance
3333
Fig.33.5 Signs and symptoms of acromegaly (caused by excessive growth hormone secretion in adults).
HINTS AND TIPS
The diagnosis of acromegaly may become more
obvious on comparison of old photographs of
the patient with the present appearance. Ask the
patient about changes in hat, glove or shoe size.
Cardiovascular problems are often the cause of death.
Coronary artery disease, hypertension and diabetes are more
common than in the normal population. Cardiomyopathy
may occur.
Headaches, visual field defects and cranial nerve palsies
may occur because of the mass effect of the pituitary tumour.
Feet
—Large and wide
Hyperprolactinaemia (due to compression of the pituitary
stalk and therefore loss of tonic inhibitory dopamine from
hypothalamus—see later) is common. Hypopituitarism can
also occur. Sleep apnoea occurs in up to 50% of individuals
because of an enlarged tongue and soft tissues of the upper
pharynx.
Investigations
IGF-1 is recommended as the initial screen for suspected
acromegaly. If the level is raised, GH level is measured following a glucose tolerance test. In healthy individuals, GH
level falls to below 1 ng/mL in the 2 hours following a 75-g
glucose load. If the glucose load fails to reduce the GH concentration to below this level, a diagnosis of acromegaly can
be made.
321
Metabolic and endocrine disorders
Other investigations include:
• Assessment of other pituitary hormones.
• Assessment of visual fields: bitemporal hemianopia.
• Skull X-ray and MRI of the brain.
• Hand X-ray: tufting of the terminal phalanges and
increased joint spaces due to hypertrophy of the
cartilage. The heel pad is usually thickened.
• CXR, ECG and echocardiogram: left ventricular
hypertrophy and cardiomyopathy.
• CT scan to investigate the patient for ectopic GH
production (e.g. from lung, ovarian, pancreatic or
adrenal tumours).
Management
The aim of treatment is to relieve symptoms, reverse somatic
changes and reverse metabolic abnormalities. Treatment is
by surgery, radiotherapy or drugs.
Surgery
Surgery is the first-choice treatment. The transsphenoidal route is usually used. Up to 90% of microadenomas
are cured, but the success rate is lower for larger tumours.
Complications include hypopituitarism, meningitis and intraoperative bleeding.
Radiotherapy
This is often used for refractory disease, as an adjuvant
for large invasive tumours and when surgery is contraindicated. The outcome is less good with radiotherapy.
Hypopituitarism is a common complication.
Medical therapies
The most effective treatment is with octreotide, a somatostatin analogue. Somatostatin inhibits GH secretion. Side
effects include colicky abdominal pain and diarrhoea, but
this usually settles with continued treatment. Gallstones occur in approximately one-third of patients.
Prognosis
Untreated, the mortality rate is approximately twice that
in healthy individuals because of cardiovascular and cerebrovascular disease. There is also an increased risk of colon
cancer and thyroid cancer.
Prolactin disorders
Aetiology
Prolactin is the hormone most commonly secreted by pituitary tumours. They are generally benign tumours, and
more common in women. Secretion of prolactin is under
constant negative control by the action of dopamine produced in the hypothalamus and transported down the pituitary stalk. In this way, high levels of prolactin may be caused
directly, by a prolactin-secreting tumour, or indirectly, by a
nonsecreting tumour that prevents dopamine from reaching the normal prolactin-producing cells. Other causes of a
raised prolactin level are summarized in Table33.3.
Table33.3 Causes of hyperprolactinaemia
Cause Examples
Physiological Pregnancy, lactation, stress
Drugs Antiemetics (e.g.
metoclopramide,
prochlorperazine)
Phenothiazines
Tricyclic antidepressants
Primary hypothyroidism
Pituitary tumours Prolactinoma
Growth hormone-secreting
tumours
Nonfunctioning tumours
Polycystic ovary syndrome
Uncommon Sarcoidosis
Hypothalamic lesions Langerhans cell
histiocytosis
Hypothalamic tumours
Chest wall stimulation Repeated self-examination
of breasts
After herpes zoster
Liver or renal failure
CLINICAL NOTES
A prolactinoma may occur in association with the
clinical syndrome multiple endocrine neoplasia
type 1. This is an autosomal dominant genetic
disorder where pituitary adenomas (most often
prolactinomas) occur in association with tumours
of the parathyroid and pancreatic islet cells.
Clinical features
In premenopausal women the most common symptoms are oligomenorrhoea and infertility (through raised prolactin level inhibiting gonadotrophin secretion of FSH and LH). Prolactinomas
can also cause galactorrhoea and occasionally hirsutism. In men,
symptoms include reduced libido, hypogonadism, impotence,
infertility and galactorrhoea. Symptoms caused by large tumour
size are more common in men and postmenopausal women, and
include headache, visual field defects and cranial nerve palsies.
Various degrees of hypopituitarism may be present.
RED FLAG
Large prolactinomas can be complicated by
pituitary apoplexy. This presents with sudden
headache, visual symptoms and altered mental
state and hormonal dysfunction due to acute
haemorrhage or infarction of the gland.
322
Adrenal disorders
3333
Investigations
Elevated PRL levels should be confirmed on repeated testing. Other blood tests include thyroid function tests, renal
and liver function tests and a pregnancy test in women. The
drug history should always be taken carefully.
Radiological assessment of the pituitary tumour should
be performed with skull X-rays and MRI scan of the brain.
Full assessment of pituitary function should be undertaken
if an adenoma is suspected, and visual fields should be
assessed.
Management
Microprolactinomas are smaller than 10 mm on MRI.
Dopamine agonist therapy (bromocriptine, cabergoline)
should be the first-line therapy as this is effective in most
cases. Transsphenoidal surgery is usually successful for resistant cases, but there is a small recurrence rate. Prolactin
levels are monitored and scans are repeated if there is
evidence of tumour growth (e.g. headache, visual field
defects).
Macroprolactinomas are larger than 10 mm on MRI.
They can be treated with drugs, but if there are pressure
effects, visual symptoms or pregnancy is considered (25%
expand in pregnancy), surgery is usually performed.
Diabetes insipidus
This occurs from a primary deficiency in vasopressin (also
called ‘antidiuretic hormone’) in the case of cranial diabetes
or in a lack of response in the kidney to vasopressin, which
is called ‘nephrogenic diabetes insipidus’.
A similar clinical picture can occur with primary polydipsia or excessive drinking. Clinically, the patient presents
with polyuria, nocturia and polydipsia. Investigations are
outlined in Chapter15.
Cranial diabetes insipidus
The causes of acquired cranial diabetes insipidus (CDI) are
given in Table 33.4. The most common type is idiopathic
CDI, which may be due to an autoimmune process. Familial
CDI is inherited as an autosomal dominant trait or as part
of the DIDMOAD syndrome (diabetes insipidus, diabetes
mellitus, optic atrophy and deafness).
Table33.5 Causes of acquired nephrogenic diabetes
insipidus
Metabolic: hypokalaemia, hypercalcaemia
Chronic renal failure
Lithium toxicity
Obstructive uropathy
Diabetes mellitus
Nephrogenic diabetes insipidus
Familial nephrogenic diabetes insipidus is X-linked recessive or autosomal recessive. It is rare and is due to mutations of the genes encoding arginine vasopressin receptor 2
(AVR2) or aquaporin 2 (AQP2) channel protein.
Causes of acquired nephrogenic diabetes insipidus are
given in Table33.5.
Management
For cranial diabetes insipidus, desmopressin (a vasopressin
analogue) is the treatment of choice. It may be administered
orally, intranasally or parenterally.
For nephrogenic diabetes insipidus, any metabolic and
electrolyte disturbances should be corrected, and any potential drug causes should be reviewed. In familial forms,
thiazide diuretics are occasionally used to drive thirst or
indomethacin, a nonsteroidal antiinflammatory, is used,
which can reduce urine output by up to 50%.
For patients with primary polydipsia, water restriction and
treatment of any associated psychiatric disorder is required.
RED FLAG
In patients with cranial diabetes insipidus it is vital
that they receive their desmopressin medication.
Without this they are at risk of severe dehydration
and hypernatraemia and ultimately death.
Particularly vulnerable groups are those who
have impaired thirst drive or access to water (e.g.
elderly people, children, patients after a general
anaesthetic or patients on the intensive care unit).
Table33.4 Causes of acquired cranial diabetes insipidus
Cause Example
Idiopathic No known cause – likely to be
autoimmune
Trauma Head injury and neurosurgery
Tumours Craniopharyngioma or secondary
tumours
Granulomas Tuberculosis, sarcoid, histiocytosis
Infections Encephalitis or meningitis
ADRENAL DISORDERS
Histologically, the adrenal glands are divided into the medulla, which secretes adrenaline and noradrenaline, and the
cortex, which is divided into three zones:
• The inner zone, or zona reticularis, produces sex
hormones.
• The middle zone, or zona fasciculata, produces cortisol.
Production is stimulated by ACTH released by the
pituitary gland. In a negative feedback loop, cortisol
323
Metabolic and endocrine disorders
Free plasma
Stress
+
Hypothalamus
−
+
pituitary gland
Fig.33.6 Control of cortisol production via the
hypothalamus–pituitary–adrenal axis. ACTH,
Adrenocorticotrophic hormone; CRH, corticotrophinreleasing hormone.
Anterior
+
Adrenal
cortex
CRH
−
ACTH
cortisol
reduces both corticotrophin-releasing hormone (CRH)
production in the hypothalamus and pituitary release
of ACTH (Fig 33.6).
• The outer zona glomerulosa produces aldosterone,
which is regulated through the renin–angiotensin
system.
CLINICAL NOTES
‘Cushing disease’ describes excessive
adrenocorticotrophic hormone production from the
pituitary (e.g. from a pituitary adenoma). All other
causes of raised cortisol levels are referred to as
‘Cushing syndrome’.
Clinical features
The clinical features of Cushing syndrome are demonstrated in Fig 33.7. Psychiatric disturbance may range from
anxiety to psychosis, and cognitive problems such as shortterm memory loss are common.
Investigations
The following investigations are important in Cushing
syndrome:
• Plasma cortisol measurement: the level will vary
throughout the day in normal individuals, being lowest at
midnight and highest at 9 a.m. With Cushing syndrome
both the midnight and the 9 a.m. cortisol level will be high
and there will be loss of the normal diurnal variation.
• Twenty-four-hour urinary free cortisol measurement.
• Plasma ACTH measurement: this will be high in
Cushing disease and ectopic ACTH production, and
very low in adrenal cortisol hyperproduction.
• Dexamethasone suppression tests and corticotroph
function tests are outlined at the end of the chapter.
• Imaging of the adrenal glands (with CT scan) and the
pituitary (with MRI).
A 24-hour urinary free cortisol measurement or a low-dose
dexamethasone suppression test is the best screening tool.
Cushing syndrome
Cushing syndrome is the result of long-term exposure to
excess glucocorticoid. This is most commonly iatrogenic,
secondary to glucocorticoid administration given to treat
inflammatory diseases (i.e. exogenous glucocorticoid). The
causes of endogenous Cushing syndrome include:
• ACTH-dependent disease:
◦ Cushing disease: ACTH hypersecretion by a
pituitary adenoma or corticotroph hyperplasia
(70%);
◦ Ectopic ACTH syndrome caused by a variety of
ACTH-secreting nonpituitary tumours such as
small cell lung carcinoma (10%–15%).
• Non–ACTH-dependent disease (i.e. unregulated
cortisol production):
• Primary adrenocortical tumours (15%–20%).
The annual incidence of spontaneous Cushing syndrome is
approximately 1 in 100,000. Cushing syndrome due to adrenal tumours, or Cushing disease (from a pituitary tumour),
is around four times more common in women.
324
CLINICAL NOTES
Pseudo-Cushing syndrome is where the clinical
features of Cushing syndrome occur along with
high cortisol levels but without a pituitary–adrenal
axis problem. Causes include poorly controlled
diabetes, obesity, severe anxiety/depression and
excess alcohol consumption.
Management
This is dependent on the cause of the raised cortisol level.
Cushing disease
Transsphenoidal surgery is the first line of treatment and is
curative in approximately 80% of patients. Pituitary radiotherapy or drugs are used if surgery fails. Metyrapone inhibits steroidogenesis and is the drug of choice. Ketoconazole
or mitotane may be used. Rarely, bilateral adrenalectomy
is necessary, although there is a risk of causing Nelson
n
Infections
Abdominal striae
Hypertension
Osteoporosis
Hirsutism (in females)
Skin
— Thin
— Easy bruising
— Poor healing
— Infections
Proximal muscle wasting
Blood
— Hypernatraemia
— Hypokalaemia
— Impaired glucose
tolerance/diabetes
Centripetal fat distributio
— Face
— Buffalo hump
— Tunnel obesity
— Amenorrhoea/infertility
(females)
— Impotence (males)
Adrenal disorders
3333
Fig.33.7 Symptoms and signs of Cushing syndrome.
syndrome, a rapidly enlarging pituitary tumour associated
with hyperpigmentation.
Adrenocortical tumours
Surgical removal of a benign adrenocortical tumour is curative. Bilateral adrenalectomy necessitates replacement therapy
with cortisol and fludrocortisone daily. Carcinomas may recur.
Ectopic adrenocorticotrophic hormone syndrome
Surgical resection of the tumour cures the hypercortisolism,
although this is often not possible, and medical therapy is
used to control cortisol levels.
CLINICAL NOTES
Patients with incompletely controlled Cushing
syndrome have a fivefold excess mortality, from
cardiovascular disease and complications of
uncontrolled diabetes.
— Psychiatric disturbance
— Cognitive dysfunction
Lower limb oedema
Addison disease
Addison disease is primary adrenocortical failure. The annual incidence is about 1 in 10,000 people.
Aetiology
The causes of Addison disease include:
• Autoimmune adrenal destruction: this accounts for
up to 90% of cases in developed countries. Women are
affected two to three times more often than men. Up
to 50% of patients have other autoimmune endocrine
deficiencies (see later).
• Infections: worldwide, tuberculosis is a common cause.
• Adrenal haemorrhage/infarction: this may be
associated with sepsis, particularly meningococcal
septicaemia – Waterhouse–Friderichsen syndrome.
The presentation is usually acute.
• Metastatic carcinoma: especially from the breast
andlung.
• Infiltrative causes: sarcoidosis, amyloidosis and
haemochromatosis.
325
Metabolic and endocrine disorders
Brain
— Letha
— Nausea
Muscles
— Skeletal muscle
Blood pressure
— Postural hypotension
Adipose tissu
— W
Blood
— Hyponatraemia
— Hyperkalaemia
—
Skin
— General increase in
• Inherited disorders: there are several familial disorders
of adrenal function, which are all rare.
• Iatrogenic causes (e.g. following surgery, bilateral
nephrectomies for renal cell carcinoma).
• Trauma.
Clinical features
The symptoms and signs of Addison disease are predominantly caused by cortisol deficiency, although deficiencies
of aldosterone and adrenal androgen will also be present
to various extents (Fig 33.8). The main symptoms are insidious and nonspecific: fatigue, weight loss, orthostatic
dizziness and anorexia. Patients may present with gastrointestinal symptoms (e.g. abdominal pain, nausea, vomiting
and diarrhoea). Hyperpigmentation of the skin and mucous
membranes may occur because of high β-lipotrophin levels
(Box33.9).
rgy
weakness, fatigue
(shock in addisonian
crisis due to circulatory
collapse)
e
eight loss
pigmentation (due to
increased ACTH),
especially in skin fold,
mucous membranes,
recent scars, pressure
areas
Tendency for hypoglycaemia
and hypercalcaemia
Fig.33.8 Symptoms and signs of adrenal insufficiency.
ACTH, Adrenocorticotrophic hormone.
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Addisonian crisis may occur with sudden onset adrenal failure (such as in haemorrhage) or increased cortisol
requirements (such as in concurrent infection, surgery or
trauma). There is hypovolaemic shock, often with acidosis
and hypoglycaemia.
HINTS AND TIPS
The adrenocorticotrophic hormone (ACTH)
precursor, proopiomelanocortin, is cleaved
to ACTH and β-lipotrophin, which acts on
melanocytes, increasing pigmentation.
Investigations
The following are important investigations in patients with
Addison disease:
• Serum cortisol concentration: low.
• Adrenal autoantibodies: these are detected in
approximately 50% of patients (antibodies against
steroid 21-hydroxylase).
• Serum ACTH levels: raised in Addison disease and low
in secondary failure.
• Serum electrolytes: in an impending crisis there may
be hyponatraemia, hyperkalaemia and raised blood
urea level.
• Glucose level: bedside capillary blood glucose
monitoring, watch for hypoglycaemia.
• Short and long Synacthen tests (described in
‘Endocrine investigations’ later).
• Screening for other autoimmune diseases such as
autoimmune thyroid disease.
Management
Maintenance therapy is with hydrocortisone, usually in
split doses throughout the day. The dose of hydrocortisone should be increased during intercurrent illnesses and
during surgery. Enzyme-inducing drugs (e.g. phenytoin
and rifampicin) may also increase patient requirements for
hydrocortisone. Fludrocortisone is used to replace aldosterone because aldosterone taken orally undergoes first-pass
metabolism in the liver. The dose is adjusted to maintain
blood pressure and potassium levels.
RED FLAG
It is essential that the patient always has the
maintenance dose. If this is omitted or the dose
is not increased appropriately with surgery/
intercurrent illness, an Addisonian crisis can
Adrenal disorders
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occur. Occasionally the first presentation of
Addison disease is with a crisis. Treatment is
with intravenous administration of saline and
hydrocortisone (100 mg) every 6 hours. Electrolyte
abnormalities should be corrected, and any
precipitating factor (e.g. underlying infection)
should be treated. Seek senior help.
Addison disease can coexist with thyroid deficiency,
when it is important to replace glucocorticoid before
replacement of thyroid hormones, otherwise an
Addisonian crisis can be precipitated.
Conn syndrome (primary hyperaldosteronism)
This is due to a unilateral adrenocortical adenoma in 75% of
cases. Other causes include adrenal carcinoma or bilateral
hyperplasia of the zona glomerulosa.
Clinical features
The clinical features are due to excess production of aldosterone. Resistant hypertension is the principal feature, along with
hypokalaemia (although this is often not present). Sodium
level tends to be mildly raised but there is usually no oedema.
HINTS AND TIPS
In phaeochromocytoma, 90% are benign and 90%
are unilateral.
Clinical features
The symptoms and signs are due to the release of adrenaline
and noradrenaline. The clinical features are very variable.
The most common are headache, sweating and hypertension,
which may be episodic. Others include pallor, tachycardia
and palpitations, nausea, tremor, visual blurring and chest
pain. The blood pressure may rise to very high levels and may
precipitate a stroke, myocardial infarction or hypertensive
encephalopathy.
RED FLAG
Be suspicious: phaeochromocytomas are rare and
the diagnosis can be easily missed. If they are
untreated, excessive catecholamine release can
cause life-threatening arrhythmias and shock. They
can occasionally present as mimics of cardiogenic
shock, septic shock or an acute coronary event.
Once they have been diagnosed, they can be
cured.
Investigations
Measure serum electrolyte levels: serum potassium level
is often low, serum sodium level may be raised and there
is usually a metabolic alkalosis. Measure paired renin and
aldosterone serum levels. In primary hyperaldosteronism
aldosterone level will be very high with a suppressed renin
level (increased aldosterone-to-renin ratio). Imaging of the
adrenals is required following a positive test result.
Secondary hyperaldosteronism is a result of high circulating renin levels. The most common cause is renal artery
stenosis, although renin-producing tumours, coarctation of
the aorta, congestive heart failure and hepatic and nephrotic
syndrome are differentials.
Management
Tumours should be resected. Spironolactone is an aldosterone antagonist that can be given in primary or secondary
aldosteronism.
Phaeochromocytoma
This is a rare tumour arising from the chromaffin tissues
of the adrenal medulla, producing catecholamines. Similar
tumours may arise from the cells of the sympathetic ganglia,
and are often then referred to as ‘paragangliomas’. It may be
associated with medullary carcinoma of the thyroid, parathyroid adenoma and neurofibromatosis.
Investigations
Urine is collected for 24 hours for measurement of adrenaline and noradrenaline and metanephrines. An abdominal
CT scan may show the tumour. PET–CT or scintigraphy is
occasionally used.
Management
This is by surgical removal of the tumour. The patient
must be fully α-blocked with phenoxybenzamine or phentolamine, and β-blocked with propranolol before surgery
to prevent the consequences of release of catecholamines
during an operation. Changes in pulse and blood pressure
should be monitored closely. α-Blockade must be achieved
before β-blockade to prevent unopposed α-agonism causing
severe hypertension.
Hypothalamus–pituitary–adrenal axis
Fig.33.6 summarizes the control of cortisol levels via the
hypothalamus–pituitary–adrenal axis. These tests are used
to diagnose diseases of glucocorticoid excess (Cushing disease, ectopic ACTH production, adrenal hyperproduction
of cortisol) and glucocorticoid deficiency (pituitary hypoproduction of ACTH and hypoadrenalism).
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