Primary hyperaldosteronism overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

In 1955, Dr Jerome W. Conn, the American endocrinologist, first described the condition and named it Conn's syndrome. Primary hyperaldosteronism may be classified into five groups, include adrenal carcinoma, familial hyperaldosteronism type I and II, Idiopathic hyperaldosteronism (IH), primary adrenal hyperplasia, and aldosterone producing adenoma (APA), which is either renin-responsive or renin-unresponsive. Conn's syndrome (primary hyperaldosteronism) features overproduction of aldosterone despite suppressed plasma renin activity (PRA). The resulting sodium retention produces hypertension, and elevated potassium excretion may cause hypokalemia. Patients with Conn's syndrome due to primary hyperaldosteronism may have an aldosterone producing adrenocortical adenoma (APA); classically referred to as Conn's syndrome, a unilateral hyperplasia, idiopathic hyperaldosteronism (IHA, also known as bilateral adrenal hyperplasia), familial forms (familial hyperaldosteronism types I, II, and III) have also been described, ectopic secretion of aldosterone. Common causes of primary hyperaldosteronism are aldosterone-secreting adenoma, bilateral hyperplasia of the adrenal glands, and ectopic secretion of aldosterone from ovaries and kidneys. Primary hyperaldosteronism must be differentiated from other diseases that cause hypertension and hypokalemia, such as renal artery stenosis, cushing's syndrome, congenital adrenal hyperplasia, Liddle's syndrome, diuretic use, licorice ingestion, and renin-secreting tumors. Patients with primary hyperaldosteronism usually appear well. Physical examination of patients with primary hyperaldosteronism is usually remarkable for high blood pressure, tachycardia, and an S4 maybe heard on auscultation of the precordium suggesting left ventricular hypertrophy secondary to increased afterload due to hypertension. Laboratory findings consistent with the diagnosis of primary hyperaldosteronism include plasma aldosterone to renin activity ratio (PAC/PRA) > 30, serum aldosterone value > 6 ng/dl, and simultaneous plasma renin activity levels < 1.0 ng/ml/hour after fludrocortisone suppression test or a plasma aldosterone > 10 ng/dl on saline infusion test or on oral sodium loading test, the post-test 24-hour urinary aldosterone excretion < 12 μg/day and a urinary sodium excretion of more than 200 mMol/day. The adrenal venous sampling test is gold standard for subtype classification of primary hyperaldosteronism. The optimal therapy for primary hyperaldosteronism depends on the etiology of hyperaldosteronism. Medical therapy is indicated for bilateral adrenal hyperplasia, and all ambiguous causes of primary hyperaldosteronism. Surgery is the mainstay of treatment for unilateral adrenal hyperplasia, aldosterone producing adenomas (APAs), adrenal carcinoma, ectopic ACTH, renin, and deoxycorticosterone secreting tumors.

Historical Perspective

Primary hyperaldosteronism (Conn's syndrome) was described for the first time by the Polish internist, Michał Lityński. In 1955, Dr Jerome W. Conn, the American endocrinologist, first described the condition and named it Conn's syndrome. Over the last few decades other more rare type of primary hyperaldsoteronism have also been described. From 1960s to early 1970s, techniques of diagnosis and treatment were greatly improved by the availability of spironolactone, realization of the renin-angiotensin-aldosterone system, and progress in laboratory tests and adrenal venous sampling.

Classification

Primary hyperaldosteronism may be classified into five groups, including adrenal carcinoma, familial hyperaldosteronism type I and II, Idiopathic hyperaldosteronism (IH), primary adrenal hyperplasia, and aldosterone producing adenoma (APA), which is either renin-responsive or renin-unresponsive.

Pathophysiology

Conn's syndrome (primary hyperaldosteronism) features overproduction of aldosterone despite suppressed plasma renin activity (PRA). The resulting sodium retention produces hypertension, and elevated potassium excretion may cause hypokalemia. Patients with Conn's syndrome due to primary hyperaldosteronism may have an aldosterone producing adrenocortical adenoma (APA); classically referred to as Conn's syndrome, a unilateral hyperplasia, idiopathic hyperaldosteronism (IHA, also known as bilateral adrenal hyperplasia), familial forms (familial hyperaldosteronism types I, II, and III) have also been described, ectopic secretion of aldosterone (the ovaries and kidneys are the 2 organs described in the literature that, in the setting of neoplastic disease, can be ectopic sources of aldosterone, but this is a rare occurrence).

Causes

Common causes of primary hyperaldosteronism are aldosterone-secreting adenoma, bilateral hyperplasia of the adrenal glands, and ectopic secretion of aldosterone from ovaries and kidneys. Less common causes of primary hyperaldosteronism are familial hyperaldosteronism types I-III, pure aldosterone-producing adrenocortical carcinomas, and unilateral hyperplasia of the adrenal gland.

Differentiating Primary Hyperaldosteronism from other Diseases

Primary hyperaldosteronism must be differentiated from other diseases that cause hypertension and hypokalemia, such as renal artery stenosis, cushing's syndrome, congenital adrenal hyperplasia, Liddle's syndrome, diuretic use, licorice ingestion, and renin-secreting tumors.

Epidemiology and Demographics

Prevalence of primary hyperaldosteronism is from 1,400-32,000 (median 8,800) per 100,000 individuals around the world. Primary hyperaldosteronism incidence among patients with newly diagnosed hypertension is 11,200 of per 100,000 individuals. The case-fatality rate of primary hyperaldosteronism is approximately 23.4 per 1,000 individual-years. Patients of all age groups may develop primary hyperaldosteronism. There is no racial predilection for primary hyperaldosteronism.

Risk Factors

The only risk factors in the development of primary hyperaldosteronism are age of hypertension onset and serum potassium level.

Screening

There is insufficient evidence to recommend routine screening for primary hyperaldosteronism but according to the Endocrine Society Clinical Practice Guideline, screening for hyperaldosteronism is recommended for resistant hypertension by checking the plasma aldosterone to renin ratio (PAC/PRA).

Natural History, Complications and Prognosis

If left untreated, patients with primary hyperaldosteronism may progress to develop stroke, coronary artery disease, and renal insufficiency with associated proteinuria. Aldosterone producing adenomas (APAs) continue to grow slowly over time. The aldosterone production likely correlates with the size of the adenoma. It is a progressive disease and its common complications include left ventricular hypertrophy due to chronic hypertension, atrial fibrillation, myocardial infarction, stroke, proteinuria, and metabolic syndrome. The prognosis of primary hyperaldosteronism is good with treatment. Without treatment, primary hyperaldosteronism will result in hypertension with resultant hypertension-related complications, which may be a major cause of morbidity and mortality among patients. 

Diagnosis

History and Symptoms

The hallmark of primary hyperaldosteronism is resistant hypertension. A positive history of spontaneous or unprovoked hypokalemia and treatment-resistant (refractory) hypertension are suggestive of primary hyperaldosteronism. The most common symptoms of primary hyperaldosteronism include headaches, facial flushing, vision changes, and weakness.

Physical Examination

Patients with primary hyperaldosteronism usually appear well. Physical examination of patients with primary hyperaldosteronism is usually remarkable for high blood pressure, tachycardia, and an S4 maybe heard on auscultation of the precordium suggesting left ventricular hypertrophy secondary to increased afterload due to hypertension.

Laboratory Findings

Laboratory findings consistent with the diagnosis of primary hyperaldosteronism include plasma aldosterone to renin activity ratio (PAC/PRA) > 30, serum aldosterone value > 6 ng/dl, and simultaneous plasma renin activity levels < 1.0 ng/ml/hour after fludrocortisone suppression test or a plasma aldosterone > 10 ng/dl on saline infusion test or on oral sodium loading test, the post-test 24-hour urinary aldosterone excretion < 12 μg/day and a urinary sodium excretion of more than 200 mMol/day. The adrenal venous sampling test is gold standard for subtype classification of primary hyperaldosteronism.

CT scan

Adrenal CT scan may be helpful in the diagnosis of primary hyperaldosteronism. Findings on CT scan suggestive of primary hyperaldosteronism are signal intensity near to <10 HU, no contrast enhancement, and non-calcified lesion in adrenal gland.

MRI

Adrenal MRI may be helpful in the diagnosis of primary hyperaldosteronism when the attenuation on CT is < 30 HU. 

Other Imaging Findings

Iodocholesterol scintigraphy (NP-59 scan) may be helpful in the diagnosis of primary aldosteronism. Findings on an Iodocholesterol scintigraphy (NP-59 scan) suggestive of primary aldosteronism is increased uptake of the adrenal glands.

Other Diagnostic Studies

There are no other diagnostic studies associated with primary hyperaldosteronism.

Treatment

Medical Therapy

The optimal therapy for primary hyperaldosteronism depends on the etiology of hyperaldosteronism. Medical therapy is indicated for bilateral adrenal hyperplasia, and all ambiguous causes of primary hyperaldosteronism.

Surgery

Surgery is the mainstay of treatment for unilateral adrenal hyperplasia, aldosterone producing adenomas (APAs), adrenal carcinoma, ectopic ACTH, renin, and deoxycorticosterone secreting tumors.

Primary Prevention

There is no primary prevention for primary hyperaldosteronism.

Secondary Prevention

There is no secondary prevention for primary hyperaldosteronism.