Primary Hyperaldosteronism (Conn Syndrome)

Primary hyperaldosteronism is an autonomous overproduction of aldosterone by the adrenal glands that suppresses plasma renin activity (PRA), leading to hypertension and hypokalemia. This disorder accounts for approximately 5-10% of all hypertension cases and is present in up to 20% of resistant hypertension, making it the most common secondary cause of hypertension. The condition primarily affects individuals in the 4th-6th decades of life with a slight female predominance. Recognition is clinically critical because primary hyperaldosteronism is surgically curable when caused by aldosterone-producing adenoma (APA), and identification improves cardiovascular outcomes through specific therapy rather than empiric antihypertensive regimens.

In primary hyperaldosteronism, excessive aldosterone secretion occurs independently of the normal regulatory axis. Unlike secondary hyperaldosteronism where elevated renin activates the renin-angiotensin-aldosterone system (RAAS), primary disease is characterized by inappropriately elevated aldosterone with suppressed plasma renin activity (<1 ng/mL/hr). This autonomous production reflects loss of normal feedback inhibition at the level of the zona glomerulosa, the outermost layer of the adrenal cortex responsible for mineralocorticoid synthesis.

Approximately 40-60% of primary hyperaldosteronism cases result from unilateral aldosterone-producing adenomas. Recent molecular studies have identified somatic mutations in genes regulating ion channel function and cellular calcium signaling that drive autonomous aldosterone synthesis. The most common mutations include KCNJ5 (potassium channel gene, ~40-50% of APAs), ATP1A1 (sodium-potassium pump, ~10%), ATP2B3 (calcium ATPase, ~5%), and CACNA1D (calcium channel, ~5%). These mutations increase intracellular calcium concentration, which directly activates the steroidogenic enzyme aldosterone synthase (CYP11B2), leading to constitutive aldosterone production regardless of circulating ACTH or angiotensin II levels.

The remaining 35-60% of cases result from bilateral idiopathic hyperaldosteronism (IHA), characterized by widespread hyperplasia of aldosterone-producing cells throughout both adrenal glands. This form is associated with increased responsiveness to ACTH and angiotensin II, explaining why some patients with IHA show modest responses to these stimulus changes. The underlying defect in IHA remains partially unclear but involves altered cellular proliferation regulation and enhanced steroidogenic sensitivity.

Elevated aldosterone acts on mineralocorticoid receptors (MR) in the principal cells of the collecting duct. Aldosterone increases expression of the epithelial sodium channel (ENaC) and Na-K-ATPase, enhancing sodium reabsorption and potassium secretion. This leads to sodium retention and volume expansion, which chronically elevates blood pressure through increased intravascular volume. Simultaneously, potassium wasting produces hypokalemia, with magnitude correlating to aldosterone excess severity. The osmotic effect of retained sodium increases distal delivery of fluid, prompting compensatory kaliuresis.

Initial hypertension results from sodium retention and plasma volume expansion (volume-dependent mechanism), explaining why salt restriction and diuretics (before hypokalemia develops) initially lower blood pressure. However, prolonged aldosterone excess produces volume-independent hypertension through direct effects on vascular smooth muscle. Aldosterone increases expression of NAD(P)H oxidase, promoting vascular reactive oxygen species (ROS) production, which impairs endothelial nitric oxide (NO) availability and increases vascular stiffness. Additionally, aldosterone promotes vascular remodeling through increased collagen synthesis and inflammatory cell infiltration, mediated by MR activation in fibroblasts and immune cells.

While hypokalemia is the hallmark electrolyte disturbance, aldosterone excess impairs glucose tolerance through multiple mechanisms: reduced insulin secretion (mediated by hypokalemia), increased hepatic glucose production, and impaired glucose uptake in peripheral tissues. Patients demonstrate increased prevalence of metabolic syndrome and diabetes mellitus independent of obesity.

APAs account for 35-40% of surgically confirmed primary hyperaldosteronism and represent true benign neoplasms of zona glomerulosa cells. These are typically small (<2 cm diameter), lipid-rich adenomas that are rarely visible on standard imaging and almost never cause mass effects. APAs are more common in younger patients (mean age 40-50 years) and disproportionately affect women. The presence of severe hypokalemia (<3.0 mEq/L) and marked aldosterone elevation (>20 ng/dL) suggests APA over bilateral disease.

IHA comprises 50-60% of primary hyperaldosteronism cases and results from bilateral adrenal zona glomerulosa hyperplasia without discrete nodules. IHA is more common in older patients, shows less severe biochemical abnormalities, and rarely responds to surgical intervention. The condition is characterized by enhanced sensitivity to ACTH, explaining why diurnal ACTH variation may partially drive aldosterone secretion. IHA has autosomal dominant inheritance patterns in rare familial cases.

Three rare autosomal dominant forms exist:

Extremely rare (<1% of cases), these malignant tumors produce severe aldosterone excess and often present with signs of malignancy (rapid progression, large tumor size >4 cm, elevated cortisol or androgens). Poor prognosis with frequent metastases.

Larger adrenal masses (>3-4 cm) with aldosterone excess should raise concern for carcinoma; imaging characteristics (heterogeneity, hemorrhage, invasion) help distinguish from benign adenoma.

Hypertension is the cardinal manifestation, typically moderate to severe (SBP 160-180 mmHg), developing before age 40 in many cases. The hypertension is notably resistant to conventional therapy (requiring ≥3 antihypertensive classes in nearly 50% of patients). Patients often report a long history of difficulty controlling blood pressure despite multiple medications. The mechanism combines both volume expansion (responsive to salt restriction and diuretics initially) and increased vascular resistance from chronic aldosterone-induced vascular remodeling.

Hypokalemia occurs in 50-70% of primary hyperaldosteronism and ranges from mild (3.5-3.8 mEq/L) to severe (<2.5 mEq/L). Serum potassium <3.0 mEq/L suggests APA rather than IHA. Symptoms result from impaired neuromuscular function: muscle weakness, fatigue, myalgia, muscle cramps, and palpitations. Severe hypokalemia may cause rhabdomyolysis or cardiac arrhythmias (including atrial fibrillation and ventricular ectopy). Hypokalemia-induced metabolic alkalosis (from increased ammoniagenesis and urinary H+ loss) may paradoxically reduce symptoms despite worsening hypokalemia, creating diagnostic delay.

Most patients develop metabolic alkalosis (serum bicarbonate >28 mEq/L) from urinary potassium and hydrogen ion loss. This alkalosis is characteristically resistant to saline administration ("saline-resistant metabolic alkalosis") because the primary stimulus is ongoing aldosterone-mediated sodium reabsorption in the collecting duct, not volume depletion. Urinary chloride is typically low (<10-15 mEq/L) because all reabsorbed sodium is coupled to potassium/hydrogen secretion rather than chloride reabsorption, creating "chloride-responsive" component; however, the primary aldosterone excess maintains ongoing alkalosis despite normalization of other factors.

Unlike secondary hyperaldosteronism (heart failure, cirrhosis, nephrotic syndrome), primary hyperaldosteronism characteristically does NOT produce edema despite sodium retention. This reflects "aldosterone escape"—the phenomenon where initial sodium retention increases blood pressure and glomerular filtration, with the rise in ANP and pressure natriuresis limiting further sodium accumulation. This distinguishes primary from secondary causes and explains why diuretics are generally avoided as monotherapy (they cause further hypokalemia without sustained blood pressure reduction).

Many patients are diagnosed incidentally when screening resistant hypertension, with up to 50% having no symptoms attributable to aldosterone excess. Hypertension alone may be the only finding in mild cases or bilateral IHA.

Some patients are identified through workup of an incidentally discovered adrenal mass on imaging, with biochemical testing then revealing autonomous aldosterone production.

The aldosterone-to-plasma renin activity ratio (ARR) is the primary screening test for all patients with hypertension and ≥1 of the following: (1) hypertension onset before age 40, (2) resistant hypertension (requiring ≥3 drugs), (3) hypertension with spontaneous hypokalemia, (4) hypertension with adrenal mass, or (5) family history of early hypertension or stroke. An ARR >20-30 (with aldosterone in ng/dL and PRA in ng/mL/hr) suggests primary hyperaldosteronism, though cutoffs vary by laboratory and clinical context. Higher specificity is achieved with ARR >20 AND aldosterone >15 ng/dL AND PRA <1 ng/mL/hr. The test requires standardized conditions: seated position for ≥5 minutes before phlebotomy, morning timing (9-11 AM), and ideally discontinuation of interfering medications (ACE inhibitors, ARBs, potassium-sparing diuretics) for 4-6 weeks, though this may be impractical in patients with severe hypertension.

Elevated ARR alone is insufficient due to false positives; confirmation requires demonstration of autonomous aldosterone production with suppressed renin responsiveness. The saline suppression test is the gold standard: 2 liters of normal saline IV over 4 hours in the supine position (morning study) should suppress aldosterone to <5-6 ng/dL in healthy individuals. Failure to suppress aldosterone (<10 ng/dL or <6 ng/dL depending on institutional cutoff) confirms autonomous production. The captopril challenge test (25 mg PO, measuring aldosterone at 30-60 minutes) represents an alternative, with failure to suppress aldosterone by ≥30% suggesting primary disease. The fludrocortisone suppression test (0.1 mg QID for 4 days with high sodium diet, measuring morning aldosterone) is less commonly used but highly specific; aldosterone <6 ng/dL after suppression excludes primary hyperaldosteronism.

Once primary hyperaldosteronism is confirmed, determining the subtype (APA vs. IHA) guides treatment decisions since only APA is surgically curable. The adrenal vein sampling (AVS) is the gold-standard test but is invasive, technically challenging, and not universally available. AVS involves selective cannulation of bilateral adrenal veins with simultaneous measurement of aldosterone and cortisol to determine the aldosterone-to-cortisol ratio (selectivity index >2-4 confirms successful adrenal vein cannulation). A >4-fold lateralization ratio (ipsilateral:contralateral aldosterone/cortisol) suggests unilateral APA. AVS is indicated in candidates for adrenalectomy or those with equivocal imaging.

High-resolution CT or MRI is often performed as initial subtype differentiation before considering AVS. Key imaging findings in APA: discrete unilateral nodule <2 cm, homogeneous appearance, lipid-rich composition (low Hounsfield units <10 on non-contrast CT or high T2 signal on MRI). However, "incidentalomas" (incidental adrenal masses on imaging) are present in 1-4% of the general population; many are non-functional. Conversely, absence of visible mass does not exclude APA (30-40% of APAs are <1 cm and not visualized on imaging). Bilateral macronodular or micronodular appearance suggests IHA. Imaging is essential to exclude aldosterone-producing carcinoma (larger size >3-4 cm, heterogeneity, invasion, necrosis/hemorrhage).

KCNJ5 genetic testing may be considered in younger patients (<40 years) with severe primary hyperaldosteronism or those with family history, as KCNJ5 mutations are associated with APAs responsive to sodium-potassium-chloride cotransporter inhibitors (thiazides). Familial Hyperaldosteronism screening with dexamethasone suppression test (low-dose dexamethasone 0.5 mg QID for 4 days; aldosterone <4 ng/dL and suppressed cortisol suggest GRA) is indicated in very young patients or those with family history of early hypertension/stroke.