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Endocrine hypertension
ADRENAL
Endocrine hypertension
Causes of endocrine hypertension
Paul M Stewart
Mineralocorticoid excess states Low renin, high aldosterone e primary aldosteronism C Aldosterone-producing adenoma (Conn’s syndrome) C Bilateral adrenal hyperplasia C Glucocorticoid-suppressible hyperaldosteronism C Rarely, adrenal carcinoma, unilateral hyperplasia
Abstract Up to 10% of patients with ‘essential’ hypertension have a secondary cause and this usually has an endocrine base. Most causes relate to inappropriate sodium retention in the kidney that gives rise to mineralocorticoid excess; here primary aldosteronism is the commonest example. Tumours of chromaffin tissue (phaeochromocytoma, paraganglioma) result in often severe and paroxysmal hypertension because of catecholamine excess. Establishing a diagnosis is important because it may lead to effective surgery and/or targeted medical therapy.
Keywords adrenal adenomas; mineralocorticoid excess; gangliomas; phaeochromocytoma; primary aldosteronism
Low renin, low aldosterone C Congenital adrenal hyperplasia C 11b-hydroxylase deficiency C 17a-hydroxylase deficiency C Liddle’s syndrome C Apparent mineralocorticoid excess C Liquorice or carbenoxolone ingestion
paraMineralocorticoid/glucocorticoid excess states C Cushing’s syndrome (particularly ectopic adrenocorticotrophic hormone syndrome) C Corticosteroid therapy (glucocorticoid/mineralocorticoid activity)
The true prevalence of endocrine hypertension 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 (Table 1). 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.
Phaeochromocytoma Others C Acromegaly C Primary hyperparathyroidism Table 1
a patient taking diuretics, these should be withdrawn, potassium stores replenished and serum potassium re-measured 2 weeks later. All patients with refractory hypertension, those with a strong family history of hypertension and/or cerebral haemorrhage, and patients with an underlying adrenal ‘incidentaloma’ 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 450 pmol/litre (check reference ranges with the local endocrine laboratory).
Primary aldosteronism Primary aldosteronism is the most common cause of mineralocorticoid hypertension, that is, inappropriate sodium retention with suppression of plasma renin activity. Based on a high plasma aldosterone:renin ratio, the prevalence is 7e10% 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 (Figure 1). Rarely, patients have a solitary, small (0.5e2 cm) aldosterone-producing adenoma of the adrenal gland (Figure 2a). The condition is more common in women than in men (3:1). More rarely, glucocorticoid-suppressible hyperaldosteronism (GSH) is the cause.
Increased prevalence of primary aldosteronism
Aldosterone response to angiotensin II
Clinical features Most hypertensive patients are asymptomatic. Tiredness, muscle weakness, thirst, polyuria and nocturia may occur in patients who are hypokalaemic (<30% of the total).
Bilateral adrenal hyperplasia
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
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.
Paul M Stewart MBChB FRCP FMedSci is Professor of Medicine at the University of Birmingham, UK. Competing interests: none declared.
MEDICINE 37:8
Essential hypertension
Low-renin essential hypertension
Figure 1
420
Ó 2009 Elsevier Ltd. All rights reserved.
ADRENAL
Confirmation of primary aldosteronism is achieved by showing that plasma aldosterone fails to decrease to <140 pmol/litre 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.
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.
Differential diagnosis of adrenal adenoma, hyperplasia and GSH Imaging: adrenal adenomas are a common incidental finding. Adrenal computed tomography (CT) or magnetic resonance imaging (MRI) should therefore be performed only when biochemical tests have confirmed primary aldosteronism (CT yields better definition of adrenocortical lesions than MRI).
Diagnosis 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 a-blockers or methyldopa. Diagnostic sensitivity is increased to approximately 95% by measuring urinary total fractionated metanephrines, and many centres are changing routine assays accordingly. Tumours are localized by MRI of the abdomen or by scintigraphy using iodine-131 meta-iodobenzylguanidine.
Adrenal vein sampling may be required to confirm unilateral (rather than bilateral) adrenal aldosterone secretion in patients wishing surgery. Gene sequencing studies can be performed to confirm the diagnosis of GSH. Management Adrenal adenoma is treated with surgical excision, usually by laparoscopic 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.
Management Management is usually surgical, but inadequate medical preparation can result in precipitous hypertension during surgery and
Phaeochromocytoma and paragangliomas Tumours of chromaffin tissue are found in the adrenal medulla (Figure 2b) or extra-adrenal chromaffin tissue (phaeochromocytoma or extra-adrenal phaeochromocytoma, respectively) or ganglia of the sympathetic trunk (paragangliomas), and result in hypertension as a consequence of secretion of large amounts of catecholamines (noradrenaline, adrenaline). Phaeochromocytomas are bilateral in 10% of cases, extra-adrenal in 10%, malignant in 10% and familial in up to 30%. Familial tumours include multiple endocrine neoplasia type 2 (primary hyperparathyroidism, medullary carcinoma of the thyroid) due to mutations in the RET proto-oncogene, neuro-fibromatosis, von HippeleLindau disease (cerebellar or retinal haemangioblastomas, renal carcinoma), and mutations in genes encoding subunits of the mitochondrial respiratory chain enzyme, succinate dehydrogenase (SDH). Mutations in the SDHB subunit are associated with extraadrenal tumours and an increased malignancy risk. Those with mutations in the SDHC and D subunits tend to be paragangliomas. 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%)
MEDICINE 37:8
Adrenal tumours showing a the characteristic lipid-laden appearance of an aldosterone-secreting adenoma and, in contrast, b a typical haemorrhagic phaeochromocytoma. Figure 2
421
Ó 2009 Elsevier Ltd. All rights reserved.
ADRENAL
Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2008; 93: 3266e81. Kaplan NM. The current epidemic of primary aldosteronism: causes and consequences. J Hypertens 2004; 22: 863e9. Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002; 346: 1459e66. Phaeochromocytoma, new genes and screening strategies. Clin Endocrinol (Oxf) 2006; 65: 699e705. Quinkler MO, Stewart PM. Hypertension and the cortisol - cortisone shuttle. J Clin Endocrinol Metab 2003; 88: 2384e92. Young WF. Primary aldosteronism e changing concepts in diagnosis and treatment. Endocrinology 2003; 144: 2208e13.
severe hypotension postoperatively. All patients must therefore be given both a-blockade (phenoxybenzamine e incremental doses commencing with 10 mg t.d.s up to 200 mg/day) and b-blockade (propranolol e incremental doses commencing with 40 mg b.d. up to 240 mg/day) for a minimum of 2e3 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 (11b-hydroxylase) and mineralocorticoid (aldosterone synthase) synthesis from the adrenal gland. In GSH, a hybrid enzyme is formed that contains proximal components of 11b-hydroxylase and distal components of aldosterone synthase. This enzyme can synthesize aldosterone, but is under the control of ACTH. The treatment of choice is dexamethasone. Liddle’s 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. Apparent mineralocorticoid excess is an autosomal recessive condition caused by a defect in 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2). This enzyme inactivates cortisol in the kidney, allowing aldosterone to bind to the mineralocorticoid receptor. In apparent mineralocorticoid excess, a mutated 11b-HSD2 enzyme cannot inactivate cortisol, which then acts as a potent mineralocorticoid. Liquorice ingestion inhibits kidney 11b-HSD2, explaining its mineralocorticoid and hypertensinogenic activity. Appropriate therapy is dexamethasone to suppress endogenous cortisol or high-dose spironolactone/amiloride. A
Practice points C
C
C
C
C
C
FURTHER READING Bravo EL, Tagle R. Phaeochromocytoma: state-of-the-art and future prospects. Endocr Rev 2003; 24: 539e53.
MEDICINE 37:8
422
Primary aldosteronism may account for up to 10% of all patients with essential hypertension Serum electrolytes should be measured in all patients with hypertension 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 a-blockers and b-blockers for 2e3 weeks before surgery The molecular basis of some forms of endocrine hypertension has been elucidated
Ó 2009 Elsevier Ltd. All rights reserved.
Endocrine hypertension
Causes of endocrine hypertension
Paul M Stewart
Mineralocorticoid excess states Low renin, high aldosterone e primary aldosteronism C Aldosterone-producing adenoma (Conn’s syndrome) C Bilateral adrenal hyperplasia C Glucocorticoid-suppressible hyperaldosteronism C Rarely, adrenal carcinoma, unilateral hyperplasia
Abstract Up to 10% of patients with ‘essential’ hypertension have a secondary cause and this usually has an endocrine base. Most causes relate to inappropriate sodium retention in the kidney that gives rise to mineralocorticoid excess; here primary aldosteronism is the commonest example. Tumours of chromaffin tissue (phaeochromocytoma, paraganglioma) result in often severe and paroxysmal hypertension because of catecholamine excess. Establishing a diagnosis is important because it may lead to effective surgery and/or targeted medical therapy.
Keywords adrenal adenomas; mineralocorticoid excess; gangliomas; phaeochromocytoma; primary aldosteronism
Low renin, low aldosterone C Congenital adrenal hyperplasia C 11b-hydroxylase deficiency C 17a-hydroxylase deficiency C Liddle’s syndrome C Apparent mineralocorticoid excess C Liquorice or carbenoxolone ingestion
paraMineralocorticoid/glucocorticoid excess states C Cushing’s syndrome (particularly ectopic adrenocorticotrophic hormone syndrome) C Corticosteroid therapy (glucocorticoid/mineralocorticoid activity)
The true prevalence of endocrine hypertension 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 (Table 1). 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.
Phaeochromocytoma Others C Acromegaly C Primary hyperparathyroidism Table 1
a patient taking diuretics, these should be withdrawn, potassium stores replenished and serum potassium re-measured 2 weeks later. All patients with refractory hypertension, those with a strong family history of hypertension and/or cerebral haemorrhage, and patients with an underlying adrenal ‘incidentaloma’ 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 450 pmol/litre (check reference ranges with the local endocrine laboratory).
Primary aldosteronism Primary aldosteronism is the most common cause of mineralocorticoid hypertension, that is, inappropriate sodium retention with suppression of plasma renin activity. Based on a high plasma aldosterone:renin ratio, the prevalence is 7e10% 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 (Figure 1). Rarely, patients have a solitary, small (0.5e2 cm) aldosterone-producing adenoma of the adrenal gland (Figure 2a). The condition is more common in women than in men (3:1). More rarely, glucocorticoid-suppressible hyperaldosteronism (GSH) is the cause.
Increased prevalence of primary aldosteronism
Aldosterone response to angiotensin II
Clinical features Most hypertensive patients are asymptomatic. Tiredness, muscle weakness, thirst, polyuria and nocturia may occur in patients who are hypokalaemic (<30% of the total).
Bilateral adrenal hyperplasia
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
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.
Paul M Stewart MBChB FRCP FMedSci is Professor of Medicine at the University of Birmingham, UK. Competing interests: none declared.
MEDICINE 37:8
Essential hypertension
Low-renin essential hypertension
Figure 1
420
Ó 2009 Elsevier Ltd. All rights reserved.
ADRENAL
Confirmation of primary aldosteronism is achieved by showing that plasma aldosterone fails to decrease to <140 pmol/litre 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.
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.
Differential diagnosis of adrenal adenoma, hyperplasia and GSH Imaging: adrenal adenomas are a common incidental finding. Adrenal computed tomography (CT) or magnetic resonance imaging (MRI) should therefore be performed only when biochemical tests have confirmed primary aldosteronism (CT yields better definition of adrenocortical lesions than MRI).
Diagnosis 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 a-blockers or methyldopa. Diagnostic sensitivity is increased to approximately 95% by measuring urinary total fractionated metanephrines, and many centres are changing routine assays accordingly. Tumours are localized by MRI of the abdomen or by scintigraphy using iodine-131 meta-iodobenzylguanidine.
Adrenal vein sampling may be required to confirm unilateral (rather than bilateral) adrenal aldosterone secretion in patients wishing surgery. Gene sequencing studies can be performed to confirm the diagnosis of GSH. Management Adrenal adenoma is treated with surgical excision, usually by laparoscopic 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.
Management Management is usually surgical, but inadequate medical preparation can result in precipitous hypertension during surgery and
Phaeochromocytoma and paragangliomas Tumours of chromaffin tissue are found in the adrenal medulla (Figure 2b) or extra-adrenal chromaffin tissue (phaeochromocytoma or extra-adrenal phaeochromocytoma, respectively) or ganglia of the sympathetic trunk (paragangliomas), and result in hypertension as a consequence of secretion of large amounts of catecholamines (noradrenaline, adrenaline). Phaeochromocytomas are bilateral in 10% of cases, extra-adrenal in 10%, malignant in 10% and familial in up to 30%. Familial tumours include multiple endocrine neoplasia type 2 (primary hyperparathyroidism, medullary carcinoma of the thyroid) due to mutations in the RET proto-oncogene, neuro-fibromatosis, von HippeleLindau disease (cerebellar or retinal haemangioblastomas, renal carcinoma), and mutations in genes encoding subunits of the mitochondrial respiratory chain enzyme, succinate dehydrogenase (SDH). Mutations in the SDHB subunit are associated with extraadrenal tumours and an increased malignancy risk. Those with mutations in the SDHC and D subunits tend to be paragangliomas. 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%)
MEDICINE 37:8
Adrenal tumours showing a the characteristic lipid-laden appearance of an aldosterone-secreting adenoma and, in contrast, b a typical haemorrhagic phaeochromocytoma. Figure 2
421
Ó 2009 Elsevier Ltd. All rights reserved.
ADRENAL
Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2008; 93: 3266e81. Kaplan NM. The current epidemic of primary aldosteronism: causes and consequences. J Hypertens 2004; 22: 863e9. Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002; 346: 1459e66. Phaeochromocytoma, new genes and screening strategies. Clin Endocrinol (Oxf) 2006; 65: 699e705. Quinkler MO, Stewart PM. Hypertension and the cortisol - cortisone shuttle. J Clin Endocrinol Metab 2003; 88: 2384e92. Young WF. Primary aldosteronism e changing concepts in diagnosis and treatment. Endocrinology 2003; 144: 2208e13.
severe hypotension postoperatively. All patients must therefore be given both a-blockade (phenoxybenzamine e incremental doses commencing with 10 mg t.d.s up to 200 mg/day) and b-blockade (propranolol e incremental doses commencing with 40 mg b.d. up to 240 mg/day) for a minimum of 2e3 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 (11b-hydroxylase) and mineralocorticoid (aldosterone synthase) synthesis from the adrenal gland. In GSH, a hybrid enzyme is formed that contains proximal components of 11b-hydroxylase and distal components of aldosterone synthase. This enzyme can synthesize aldosterone, but is under the control of ACTH. The treatment of choice is dexamethasone. Liddle’s 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. Apparent mineralocorticoid excess is an autosomal recessive condition caused by a defect in 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2). This enzyme inactivates cortisol in the kidney, allowing aldosterone to bind to the mineralocorticoid receptor. In apparent mineralocorticoid excess, a mutated 11b-HSD2 enzyme cannot inactivate cortisol, which then acts as a potent mineralocorticoid. Liquorice ingestion inhibits kidney 11b-HSD2, explaining its mineralocorticoid and hypertensinogenic activity. Appropriate therapy is dexamethasone to suppress endogenous cortisol or high-dose spironolactone/amiloride. A
Practice points C
C
C
C
C
C
FURTHER READING Bravo EL, Tagle R. Phaeochromocytoma: state-of-the-art and future prospects. Endocr Rev 2003; 24: 539e53.
MEDICINE 37:8
422
Primary aldosteronism may account for up to 10% of all patients with essential hypertension Serum electrolytes should be measured in all patients with hypertension 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 a-blockers and b-blockers for 2e3 weeks before surgery The molecular basis of some forms of endocrine hypertension has been elucidated
Ó 2009 Elsevier Ltd. All rights reserved.