primary aldosteronism

**Pathophysiology** - Excess aldosterone acts on principal cells of the distal tubule and collecting duct. It upregulates ENaC and the Na+/K+-ATPase. - This increases Na+ and water reabsorption, causing volume expansion and hypertension. - It increases K+ secretion, causing hypokalemia. - It increases H+ secretion by alpha-intercalated cells, causing metabolic alkalosis. - Volume expansion suppresses renin, so renin is low and aldosterone is high (high aldosterone-to-renin ratio, ARR). - **Aldosterone escape:** Natriuretic mechanisms (e.g., ANP, pressure natriuresis) limit Na+ retention. As a result, there is NO significant peripheral edema, and hypernatremia is typically mild or absent (high-normal Na+).

**Etiologies** - Bilateral idiopathic adrenal hyperplasia (most common). - Aldosterone-producing adenoma (Conn syndrome), usually unilateral. Common somatic mutations are in KCNJ5, plus ATP1A1, ATP2B3, and CACNA1D. - Rare causes: - Unilateral adrenal hyperplasia. - Adrenal carcinoma. - Familial hyperaldosteronism type I (glucocorticoid-remediable aldosteronism). A chimeric CYP11B1/CYP11B2 gene puts aldosterone synthase under ACTH control. It is autosomal dominant and is treated with dexamethasone. - Familial hyperaldosteronism types II-IV (e.g., type III from a germline KCNJ5 mutation).

**Clinical features** - Resistant or early-onset hypertension. Think of it in hypertension with hypokalemia, hypertension with an adrenal incidentaloma, or resistant hypertension on ≥3 drugs. - Hypokalemia can cause muscle weakness, cramps, polyuria (nephrogenic DI-like), and palpitations or arrhythmias. Many patients are normokalemic. - Metabolic alkalosis, and mild hypomagnesemia. - There is higher cardiovascular risk (LVH, AF, stroke) than in essential hypertension at the same BP.

**Diagnosis (stepwise)** 1. Screen with morning plasma aldosterone concentration and plasma renin activity (ARR). Correct hypokalemia first, because low K+ suppresses aldosterone secretion and causes false negatives. Interfering drugs: - Beta-blockers, central α2-agonists, and NSAIDs lower renin and can cause false positives. - ACE inhibitors, ARBs, diuretics, and DHP CCBs raise renin and can cause false negatives. 2. Confirm with a failure of aldosterone suppression: oral or IV saline infusion, captopril challenge, or fludrocortisone suppression. 3. Subtype with an adrenal CT. Then do adrenal vein sampling (AVS) if the patient is a surgical candidate. This distinguishes unilateral from bilateral disease, and AVS is the gold standard.

**Treatment** - Unilateral adenoma: laparoscopic adrenalectomy. Hypertension often improves, and it can be cured. - Bilateral hyperplasia or non-surgical patients: mineralocorticoid receptor antagonists. Spironolactone is first-line, and eplerenone is more selective. Spironolactone can cause gynecomastia, impotence, and menstrual irregularities. Eplerenone has fewer of these effects. Also give amiloride (ENaC blocker) and a low-sodium diet. - Glucocorticoid-remediable aldosteronism: low-dose dexamethasone. - After adrenalectomy, the contralateral zona glomerulosa may be suppressed, so monitor for transient hyperkalemia.

**High-yield differentials (hypertension + hypokalemia)** - **Secondary hyperaldosteronism** (renal artery stenosis, renin-secreting tumor, CHF, cirrhosis): high renin and high aldosterone. - **Cushing syndrome, Liddle syndrome** (ENaC gain-of-function), **apparent mineralocorticoid excess** (11β-HSD2 deficiency, licorice ingestion), **congenital adrenal hyperplasia** (11β-hydroxylase and 17α-hydroxylase deficiency): these have low renin and LOW aldosterone.

**Board pearls** - Hypertension + hypokalemia + metabolic alkalosis + low renin + high aldosterone = primary aldosteronism. - No edema, because of aldosterone escape. - The most common cause is bilateral hyperplasia, but a classic vignette shows a unilateral adenoma (Conn syndrome). - Adrenal vein sampling is used to localize disease. A CT alone is not enough, since incidental nonfunctioning adenomas are common, especially in older patients. - Spironolactone is the drug of choice for medical management. - Histology of an adenoma: a golden-yellow, lipid-rich lesion composed of zona glomerulosa-like and fasciculata-like cells.