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Endocrine hypertension

450 pmol/litre (check reference ranges with the local endocrine

Confirmation of primary aldosteronism is achieved by showing
that plasma aldosterone fails to decrease following salt loading with
saline, 2 litres i.v. over 4 hours or 300 mmol/day p.o. for 3 days,
or administration of fludrocortisone, 0.1 mg q.d.s. for 4 days plus
high salt intake.

Paul M Stewart

Prevalence of endocrine hypertension

The true prevalence of endocrine hypertension (Figures 1 and 2) is
unknown, but recent data suggest that it might account for up to
10% of all cases of essential hypertension, which in turn affects
10% of the population. A high index of suspicion and appropriate
investigations are required to make the diagnosis. Recognition of
the condition is important, because it may predispose to increased
mortality from cerebrovascular disease, and is often reversible with
targeted therapy. The molecular basis for some forms of endocrine
hypertension has been described, providing new mechanisms that
may be important in the pathogenesis of hypertension.

Aldosterone response
to angiotensin II



Increasing aldosterone:renin ratio

The apparent increase in the prevalence of primary aldosteronism results
from increased reliance on the aldosterone:renin ratio for its diagnosis,
which principally detects cases of bilateral adrenal hyperplasia.

Primary aldosteronism
Primary aldosteronism is the most common cause of mineralocorticoid hypertension; based on a high plasma aldosterone:renin
ratio, the prevalence is 710% in hypertensive patients. Most
cases are caused by bilateral adrenal hyperplasia; the sensitivity of the zona glomerulosa to angiotensin II is increased such
that aldosterone production is greater for the prevailing level of
plasma renin. Rarely, patients have a solitary, small (0.52 cm)
aldosterone-producing adenoma of the adrenal gland (Figure 3a).
The condition is more common in women than in men (3:1). More
rarely, glucocorticoid-suppressible hyperaldosteronism (GSH) is
the cause.

Causes of endocrine hypertension

Mineralocorticoid excess states
Low renin, high aldosterone primary aldosteronism
Aldosterone-producing adenoma (Conns syndrome)
Bilateral adrenal hyperplasia
Glucocorticoid-suppressible hyperaldosteronism
Rarely, adrenal carcinoma, unilateral hyperplasia
Low renin, low aldosterone
Congenital adrenal hyperplasia
11-hydroxylase deficiency
17-hydroxylase deficiency
Liddles syndrome
Apparent mineralocorticoid excess
Liquorice or carbenoxolone ingestion

Clinical features: most hypertensive patients are asymptomatic.

Tiredness, muscle weakness, thirst, polyuria and nocturia may
occur in those who are hypokalaemic (< 50%).
Diagnosis: serum electrolytes should be measured in all patients
with hypertension. Spontaneous hypokalaemia (< 3.5 mmol/litre)
is uncommon in untreated hypertension; when it is found in a
patient taking diuretics, these should be withdrawn, potassium
stores replenished, and serum potassium re-measured 2 weeks
later. All patients with refractory hypertension and those with a
strong family history of hypertension and/or cerebral haemorrhage
should be investigated, irrespective of potassium levels. The most
sensitive diagnostic screening test is a high plasma aldosterone:
renin ratio, with a plasma aldosterone concentration of more than

Mineralocorticoid/glucocorticoid excess states

Cushings syndrome (particularly ectopic adrenocorticotrophic
hormone syndrome)
Corticosteroid therapy (glucocorticoid/mineralocorticoid

Paul M Stewart is Professor of Medicine at the University of Birmingham,

UK. He qualified from the University of Edinburgh, and trained in
internal medicine, endocrinology and diabetes in Edinburgh, Dallas,
USA and Birmingham. His research interests include corticosteroids and
hypertension, hormone action and pituitaryadrenal disease. Conflicts of
interest: none.


Primary hyperparathyroidism


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cases, malignant in 10% and familial in up to 30%. Familial

tumours include multiple endocrine neoplasia type 2 (primary
hyperparathyroidism, medullary carcinoma of the thyroid), neurofibromatosis, Von HippelLindau disease (cerebellar or retinal
haemangioblastomas, renal carcinoma), and mutations in genes
encoding subunits of the mitochondrial succinate dehydrogenase

Clinical features: symptoms are often paroxysmal, and include:

headache (80% of cases)
sweating (70%)
palpitations (70%)
pallor (40%) (note that patients with phaeochromocytoma do
not flush)
nausea (40%)
tremor (30%)
weakness (30%)
anxiety (20%)
epigastric pain (20%)
chest pain and dyspnoea (20%)
constipation (10%).
Signs include paroxysmal or sustained hypertension, often with
a postural decrease in blood pressure caused by reduced plasma
volume, and tachycardia. Patients may present with myocardial
ischaemia or heart failure.

Adrenal tumours showing a the characteristic
lipid-laden appearance of an aldosterone-secreting
adenoma and, in contrast, b a typical haemorrhagic

Diagnosis of phaeochromocytoma requires a high index of suspicion. The diagnosis is made biochemically by measuring free
noradrenaline and adrenaline in an acidified urine collection.
False-positive results can occur in patients who are taking interfering medications such as -blockers or methyldopa. Tumours
are localized by MRI of the abdomen or by scintigraphy using
iodine-131 meta-iodobenzylguanidine.

Differential diagnosis of adrenal adenoma, hyperplasia and

Imaging adrenal adenomas are a common incidental finding; therefore, adrenal CT or MRI should be performed only when
biochemical tests have confirmed primary aldosteronism.
Measurement of intermediary glucocorticoid metabolites (e.g.
18-hydroxycortisol, 18-oxocortisol/corticosterone) in plasma or
urine is helpful. Metabolite levels are lowest in hyperplasia, higher
in adenoma and much higher in GSH.
Adrenal vein sampling may be required to confirm unilateral
(rather than bilateral) adrenal aldosterone secretion.
Gene sequencing studies can be performed to confirm the
diagnosis of GSH.

Management is usually surgical, but inadequate medical preparation can result in precipitous hypertension during surgery and
severe hypotension postoperatively. All patients must therefore be
given both -blockade (phenoxybenzamine, up to 200 mg/day)
and -blockade (propranolol, up to 240 mg/day) for a minimum
of 23 weeks before surgery.

Single-gene defects causing mineralocorticoid hypertension

GSH is an autosomal dominant condition characterized by
aldosterone excess under the control of adrenocorticotrophic
hormone (ACTH) rather than the normal principal secretagogue,
angiotensin II. Normally, two closely related enzymes coordinate the final pathway of glucocorticoid (11-hydroxylase) and
mineralocorticoid (aldosterone synthase) synthesis from the
adrenal gland. In GSH, a hybrid enzyme is formed that contains
proximal components of 11-hydroxylase and distal components
of aldosterone synthase. This enzyme can synthesize aldosterone,
but is under the control of ACTH. The treatment of choice is

Management: adrenal adenoma is treated with surgical excision,

usually by laparascopic adrenalectomy. Medical treatment with
mineralocorticoid receptor antagonists such as spironolactone
and the newer, more selective antagonist eplerenone is indicated
in patients unsuitable for surgery. Surgery is never indicated
in patients with bilateral hyperplasia or GSH, who should be
treated medically with mineralocorticoid receptor antagonists or
dexamethasone, respectively.


Liddles syndrome is an autosomal dominant form of hypertension

caused by mutations in the apical sodium pump that result in
constitutive activation of sodium reabsorption. Amiloride or triamterene is the treatment of choice.

Tumours of chromaffin tissue are most commonly found in the

adrenal medulla (Figure 3b), and result in hypertension as a
consequence of secretion of large amounts of catecholamines
(noradrenaline, adrenaline). The tumour is bilateral in 10% of



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Apparent mineralocorticoid excess is an autosomal recessive

condition caused by a defect in 11-hydroxysteroid dehydrogenase
type 2 (11-HSD2). This enzyme inactivates cortisol in the kidney,
allowing aldosterone to bind to the mineralocorticoid receptor. In
apparent mineralocorticoid excess, a mutated 11-HSD2 enzyme
cannot inactivate cortisol, which then acts as a potent mineralocorticoid. Liquorice ingestion inhibits kidney 11-HSD2, explaining
its mineralocorticoid and hypertensinogenic activity. Appropriate
therapy is dexamethasone to suppress endogenous cortisol, or
high-dose spironolactone/amiloride.

Bravo E L, Tagle R. Phaeochromocytoma: state-of-the-art and future
prospects. Endocr Rev 2003; 24: 53953.
Kaplan N M. The current epidemic of primary aldosteronism: causes and
consequences. J Hypertens 2004; 22: 8639.
Neumann H P, Bausch B, McWhinney S R et al. Germ-line mutations
in nonsyndromic pheochromocytoma. N Engl J Med 2002; 346:
Stewart P M. Mineralocorticoid hypertension. Lancet 1999; 353:
Young W F. Primary aldosteronism changing concepts in diagnosis and
treatment. Endocrinology 2003; 144: 220813.

Practice points
Primary aldosteronism may account for up to 10% of all
patients with essential hypertension
Serum electrolytes should be measured in all patients with
Endocrine hypertension should be excluded in all patients
with unexplained hypokalaemia, refractory hypertension or a
strong family history of hypertension or stroke
A random plasma aldosterone:renin ratio should be the initial
diagnostic screening test
Patients with phaeochromocytoma must be adequately treated
with both -blockers and -blockers for 23 weeks before
The molecular basis of some forms of endocrine hypertension
has been elucidated



2005 The Medicine Publishing Company Ltd