Primary hyperaldosteronism

Other Names: Primary aldosteronism; Conn syndrome; Mineralocorticoid excess

Primary hyperaldosteronism is a disorder caused by excess production of the hormone aldosterone by the adrenal glands.

If primary hyperaldosteronism is caused by an adenoma, it is known as Conn’s syndrome. The condition may also be caused by enlarged adrenal glands without adenomas (adrenal hyperplasia).

Epidemiology

Primary hyperaldosteronism occurs worldwide, and no evidence suggests that there are more cases of primary hyperaldosteronism in certain areas of the world. Aldosterone-producing adenomas occur more frequently in women than in men. Reports are that there may be a higher prevalence in African Americans or persons from African origin; this is demonstrated more in the idiopathic adrenal hyperplasia variant of the disease.

Cause

The most prevalent cause of primary hyperaldosteronism is aldosterone-producing adenomas. Other causes include aldosterone-producing adrenal carcinoma, ectopic aldosterone secretion from the kidneys or ovaries, and bilateral zona glomerulosa hyperplasia. There are familial causes as well.

Type I is glucocorticoid-remediable hyperaldosteronism that results from the formation of a chimeric gene containing the regulator portion of 11B-hydroxylase (usually regulated by ACTH) and the synthetic region of aldosterone synthase; as a result, ACTH stimulates aldosterone synthase and hence aldosterone production.

Type II causes are unclear; it correlates to a gene on 7p22 (band 11q13), and histologic findings are consistent with hyperplasia or adenomas. Type III results from a mutation in KCNJF which is a potassium channel coding gene. This mutation causes increased calcium ion availability into the glomerulosa cells leading to increased aldosterone synthesis.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

In some cases, primary hyperaldosteronism is inherited in an autosomal dominant manner, but in most cases the exact cause of the disease is unknown (idiopathic).

Signs and symptoms

The main symptom of primary hyperaldosteronism is high blood pressure (hypertension), but other symptoms may include headaches, weakness, swelling (edema), and muscle spasms (tetany). A patient with suspected primary hyperaldosteronism will present with uncontrolled hypertension and will typically be young. They can also have a family history of early-onset hypertension or cerebral vascular disease at a younger age. Patients may have severe muscle weakness, palpitations, fatigue, or muscle cramps due to symptoms related to hypokalemia. Polydipsia and polyuria are present due to nephrogenic diabetes insipidus likely secondary to hypokalemia.

Diagnosis

Hypokalemia has been considered one of the hallmark signs in the diagnosis of primary aldosteronism; however, estimates are now that less than 37 percent of patients who have primary hyperaldosteronism will present with hypokalemia.

Even though patients typically do not present with hypokalemia; the diagnosis should be considered in a patient with drug-resistant hypertension and hypokalemia in a patient starting a low dose of diuretic.

There are no physical exam characteristics that will lead to a diagnosis of primary hyperaldosteronism. However, due to excessive hypertension and stress on the heart, left ventricular hypertrophy can occur leading to an S4 heart sound secondary to blood trying to enter a noncompliant stiff ventricle during atrial contraction. Other findings related to longstanding hypertension can arise throughout the body affecting the heart (heart failure), kidneys (proteinuria), eyes (hypertensive retinal changes), vasculature (carotid bruits/stroke symptoms), muscle weakness, and mental status changes secondary to hypertensive encephalopathy.

Suspect primary aldosteronism when a patient presents with hypertension at an early age with hypokalemia and poorly controlled blood pressure despite medical therapy. The next step is to obtain a morning plasma aldosterone and renin activity. If the ratio of morning aldosterone to plasma renin activity is higher than 20 to 1; then the excess aldosterone can be attributed to the adrenal gland as the primary source. Next, any of the four confirmatory tests may follow: 1) oral sodium loading 2) saline infusion 3) fludrocortisone suppression 4) captopril challenge, should suppress aldosterone; however, in a patient with primary aldosteronism, there will be a lack of aldosterone suppression. Once primary aldosteronism is confirmed all suspected patients are recommended to undergo Adrenal computed tomography scan as the initial study and to exclude possible adrenocortical carcinoma. It is then recommended for the patient to have an adrenal venous sampling.

The best diagnostic test involves the measurement of cortisol and aldosterone in bilateral adrenal venous effluent and a peripheral vein before and during an ACTH infusion. Cortisol will be used to evaluate the catheter placement in the adrenal veins, as levels from the two sides should be similar. When an adenoma is present, the aldosterone-to-cortisol ratio on one side is usually at least five times greater than the other indicating suppression.

Bilateral hyperplasia tends to produce similar values on each side. If the study points towards a unilateral adenoma, then laparoscopic adrenalectomy is the preferred treatment. If the patient declines surgery or is not a surgical candidate, medical therapy is the recommended route. If the study points towards a bilateral cause, then medical treatment with a mineralocorticoid antagonist is warranted.

Treatment

Treatment for primary hyperaldosteronism includes laparoscopic resection for adenomas. This procedure will usually resolve the hypokalemia, but hypertension can persist in up to 65% of patients post adrenalectomy. Surgery is the preferred treatment for patients with unilateral aldosterone-producing adenoma. After unilateral adrenalectomy, almost all patients have the resolution of hypokalemia and moderate improvement in blood pressure control.

In those who are unable to undergo surgery or have bilateral adrenal hyperplasia, mineralocorticoid antagonists such as [[[spironolactone]] or eplerenone are an option. In a randomized study, the antihypertensive effects between spironolactone and eplerenone in patients with primary hyperaldosteronism were studied showing that spironolactone was more effective than eplerenone in controlling blood pressure.

Amiloride, a sodium channel blocker, may be helpful in the treatment and other antihypertensive agents can be continued as needed to optimize blood pressure control. Spironolactone is considered the first line agent for patients who cannot undergo surgical resection.

Prognosis

Studies show that morbidity and mortality of those with primary hyperaldosteronism are directly related to chronic elevated hypertension leading to increased risk of cardiovascular disease including CAD, stroke, and congestive heart failure secondary to left ventricular hypertrophy.

Other studies point to the increased risk of cardiac arrhythmias secondary to persistent hypokalemia in those with primary hyperaldosteronism. Research has shown in individual studies that surgical correction by adrenalectomy leads to a better prognosis by a significant reduction in hypertension and hypokalemia when compared to those with medical therapy.

NIH genetic and rare disease info

• NIH info on Primary hyperaldosteronism

Primary hyperaldosteronism is a rare disease.

Primary hyperaldosteronism Resources
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