Friday, June 11, 2021

Primary aldosteronism: an update


Here's an update on this topic recently published in Cardiology in Review.

The original Conn syndrome was described in 1956 as a case report of a young woman with hypertension and severe hypokalemia who was found to have an adrenal adenoma and was cured after adrenalectomy. Subsequently we've found that primary aldosteronism is much more common than previously thought. It's certainly not a rare cause of secondary hypertension but it is markedly under-diagnosed.

The mechanism of action of aldosterone is described in the paper thusly:

Aldosterone, which is synthesized in the adrenal zona glomerulosa, acts primarily at the renal collecting tubule where it binds to mineralocorticoid receptors leading to an increased number of open epithelial sodium channels (ENaC) in the luminal membrane4 and increased Na-K-ATPase expression.5 Reabsorbed sodium leaves the luminal cell via the Na-K-ATPase pump. Subsequent intraluminal electronegativity triggers potassium secretion through membrane potassium channels. Additionally, aldosterone has been found to act at the second part of the distal convoluted tubule, where both the thiazide-sensitive sodium chloride cotransporter and ENaC are expressed. By regulating the function of these transporters, aldosterone is thought to have effects on sodium and chloride balance and blood pressure (BP) control.6

Hypokalemia is characteristic but only a minority of patients exhibit it at presentation.

Regarding the different etiologies, again, from the paper:

The most common cause of primary hyperaldosteronism is bilateral idiopathic hyperplasia (IHA), accounting for 60% of cases. An aldosterone-producing adenoma (APA) is seen in 30%, primary (unilateral) adrenal hyperplasia in 2%, aldosterone-producing adrenocortical carcinoma in less than 1%, familial hyperaldosteronism (FH) type 1 (glucocorticoid-remediable) in less than 1%, FH type 2 (APA or IHA) in less than 6%, and FH type 3 (germline KCNJ5 mutations) in less than 1%.9 Although germline mutations of KCNJ5 are quite rare, causing FH type 3 PA, somatic mutations of KCNJ5 are relatively common, and in one study was seen in 38% of patients with APA. These mutations are believed to increase expression of CYP11B2, the aldosterone synthase gene.10Glucocorticoid-remediable aldosteronism, which is inherited as an autosomal dominant trait, usually presents in childhood with moderate to severe hypertension. The pathophysiology involves ectopically synthesized aldosterone in the zona fasciculata under adrenocorticotropin control.

Patients with primary hyperaldosteronism have a higher cardiovascular risk then do those with comparable degrees of essential hypertension. This is believed to be due to direct extrarenal damaging effects of of aldosterone such as endothelial damage and myocardial fibrosis.

The two big questions are who should be screened and how to work it up. Guidelines are fairly aggressive in their recommendations for screening. They are covered in the paper. In brief, things that should trigger a workup include severity of hypertension (levels persistently exceeding 150 / 100), resistant hypertension which could be translated to mean failure to control the hypertension on 3 drugs or essentially any patient who is on four drugs even if controlled and hypokalemia whether spontaneous or diuretic associated. Additional candidates would include those with family history, those with early onset, and those with an adrenal incidentaloma. In addition those with sleep apnea are candidates. There is a somewhat poorly understood connection between sleep apnea and hyperaldosteronism.

It has been estimated that if these criteria or fully applied around 50% of hypertensive patients in primary care would be candidates for screening. This is straight out of of the Endocrine Society guidelines. This may seem like over testing and will certainly rule out the disorder in a substantial number of patients but it is promulgated in guidelines and published recommendations due to a substantially under-diagnosed disease burden.

Diagnosis starts with simultaneous measurement of renin and aldosterone. The renin measurement can either be plasma renin activity or renin concentration. Preferably these are done in the morning, seated for 5 to 15 minutes. The patient should be potassium and sodium replete and have diuretics discontinued. Unless the aldosterone to renin ratio is very high or spontaneous hypokalemia is observed further confirmatory testing is likely to be necessary followed by testing for the etiology of hyperaldosteronism. This includes ruling out glucocorticoid responsive hyperaldosteronism. Imaging is generally required followed often by adrenal vein sampling. Once one is past the initial screening test help from an endocrinologist or hypertension specialist might be warranted.

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