Hyperaldosteronism

Overview

Definition

Hyperaldosteronism is defined as an increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex.

• Primary hyperaldosteronism: autonomous (renin-independent) secretion of aldosterone
• Secondary hyperaldosteronism: physiological oversecretion of aldosterone that occurs in response to overstimulation of the RAAS, triggered by decreases in renal blood flow.

Epidemiology

• Prevalence of primary hyperaldosteronism: 0.5%‒2% in most populations:
  • Approximately 40% of cases are due to aldosterone-producing adenomas
  • Approximately 60% of cases are due to bilateral adrenal hyperplasia
  • Other causes are rare
• Prevalence of secondary hyperaldosteronism: unknown
• Association of primary hyperaldosteronism with hypertension:
  • Found in 10% of patients with hypertension
  • Most common cause of hypertension, which is due to an endocrinopathy
• Typically diagnosed in adults; rare in children

Etiology

Pathophysiology

The primary role of aldosterone is to increase BP, which occurs by an increase in sodium and, thus, increased water reabsorption from the kidneys, while excreting potassium and hydrogen ions.

Physiology review

• Aldosterone synthesis is stimulated directly by:
  • Angiotensin II
  • Hyperkalemia
• RAAS:
  • Renin (secreted by the macula densa cells within the kidneys) → converts angiotensinogen (secreted by hepatocytes) to angiotensin I
  • ACE (secreted by pulmonary vascular endothelium) → converts angiotensin I to angiotensin II
  • Angiotensin II → stimulates the release of aldosterone (secreted by zona glomerulosa in the adrenal cortex)
• Factors that normally trigger the RAAS (and thus ↑ aldosterone):
  • ↓ Renal perfusion:
    • ↓ BP
    • ↓ Effective blood volume
  • ↓ Sodium delivery to the kidney
  • ↑ Sympathetic tone
• Effects of aldosterone: 
  • Stimulates production of the following proteins within the principal cells in the distal renal tubules:
    • Na⁺/K⁺ ATPase on the basolateral side
    • Epithelial sodium channel (ENaC) on the lumen side: allows Na⁺ reabsorption from the lumen into the principal cells
    • Renal outer medullary potassium (ROMK) channel on the lumen side: allows excretion of K⁺ into the urine
  • Stimulates Na⁺ reabsorption from the renal tubules:
    • Water follows the Na⁺.
    • Creates a negative electrical gradient across the lumen promoting the secretion of K⁺ and H⁺ into the urine
• End result of ↑ aldosterone: 
  • ↑ BP (↑ water reabsorption from the kidneys)
  • ↑ Serum Na⁺ (↓ urinary excretion of Na⁺)
  • ↓ Serum K⁺ (↑ urinary excretion of K⁺)
  • ↑ Serum pH (↑ urinary excretion of H⁺)

Primary hyperaldosteronism

• Unregulated (autonomous) secretion of aldosterone:
  • Secondary hypertension
  • Hypokalemia
  • Metabolic alkalosis
• Leads to a compensatory ↓ in renin
• Aldosterone escape mechanism:
  • Body senses ↑ blood volume and attempts to correct it
  • Secretion of atrial natriuretic peptide (ANP) → diuresis
  • Result is that edema is typically not present in primary hyperaldosteronism.

Secondary hyperaldosteronism

• ↓ Renal blood flow due to other diseases
• Leads to a compensatory ↑ in renin → ↑ aldosterone:
  • Secondary hypertension
  • Hypokalemia
  • Hypernatremia
  • Metabolic alkalosis
• ↑ Na⁺ and water reabsorption occurs because of regulated mechanisms → no aldosterone escape → pitting edema

Clinical Presentation

• Treatment-resistant hypertension:
  • Headaches
  • Fatigue
  • Visual impairment
• Hypokalemia:
  • Found in approximately 10%‒35% of patients with primary hyperaldosteronism
  • Can present as:
    • Cardiac arrhythmias
    • Muscle weakness
    • ↓ Deep-tendon reflexes
    • GI symptoms (e.g., constipation)
• Metabolic alkalosis
• Additional exam findings in secondary hyperaldosteronism:
  • Pitting edema
  • Signs/symptoms consistent with the underlying etiology:
    • Abdominal bruits (renal artery stenosis)
    • Cardiac findings
    • Signs of severe liver disease

Diagnosis

The diagnoses of primary and secondary hyperaldosteronism are made based on biochemical testing. Imaging is required to identify the etiology in cases of primary hyperaldosteronism.

Biochemical tests

• Who should be tested:
  • All patients with hypertension and hypokalemia
  • Patients with drug-resistant hypertension
  • Individuals with hypertension with an incidentally discovered adrenal mass
  • Individuals with hypertension and atrial fibrillation
  • All 1st-degree relatives of patients with primary hyperaldosteronism
• 1st-line screening serum tests:
  • Plasma aldosterone concentration (PAC): ↑ (> 15 ng/dL) in hyperaldosteronism in general
  • Plasma renin activity: 
    • ↓ In primary hyperaldosteronism
    • ↑ In secondary hyperaldosteronism
  • Aldosterone-renin ratio: ↑ PAC/plasma renin activity (> 20‒30) in primary hyperaldosteronism 
  • Summary:
    • Primary hyperaldosteronism: ↑ PAC, ↓ plasma renin activity, ↑ PAC/plasma renin activity ratio
    • Secondary hyperaldosteronism: ↑ PAC, ↑ plasma renin activity
• Confirmatory tests: 
  • Assess the patient’s response to a salt load (which normally should suppress aldosterone secretion as the body tries to eliminate the excess Na+ and water):
    • Non-suppressed 24-hour urine aldosterone after oral salt loading
    • Non-suppressed PAC after IV saline infusion
  • Adrenal vein sampling: 
    • Interventional radiological procedure used to measure aldosterone in adrenal venous blood
    • Performed to determine if an adenoma is functional (e.g., secreting aldosterone) prior to surgical excision
    • Look for a 5-fold increase in PAC on the side of the adenoma.
    • Technically challenging procedure

Imaging

Imaging is used to differentiate a unilateral adrenal adenoma from bilateral adrenal hyperplasia once a biochemical diagnosis of primary hyperaldosteronism is made.

• CT scan of the adrenal gland: 
  • Test of choice due to similar efficacy as MRI, but with lower cost
  • Can differentiate between:
    • Adenoma: a unilateral hypodense solitary mass with normal contralateral morphology
    • Carcinoma: unilateral mass > 4 cm
    • Bilateral hyperplasia: bilateral gland thickening or micronodular changes
• MRI of the adrenal gland (rarely needed)

Management

Medical management

• Aldosterone receptor antagonists:
  • Options:
    • Spironolactone
    • Eplerenone
  • Indicated in:
    • Bilateral adrenal hyperplasia
    • Pre-treatment for surgical patients
• Management of hypertension
• Monitor and manage sodium and potassium levels:
  • Salt restriction
  • Potassium repletion
• Optimizing the management of underlying etiologies in secondary hyperaldosteronism (e.g., heart failure, cirrhosis)

Surgical management

• Excise any hormone-secreting tumors (adrenalectomy).
• Indicated in unilateral sources:
  • Adrenal adenomas
  • Adrenal carcinoma

Complications

• Cardiovascular complications due to hypertension:
  • Hypertrophy
  • Dilation
  • MI
  • Cerebrovascular events
  • Peripheral artery disease
• Renal disease due to hypertension:
  • Renal sclerosis
  • Renal insufficiency
• Impaired insulin secretion due to chronic hypokalemia → diabetes mellitus

Clinical Relevance

• Primary hypertension: elevated BP that is not a result of an appropriate physiological response to regulatory mechanisms. Although very common, the pathogenesis remains poorly understood and is likely multifactorial. Causes of secondary hypertension should be excluded. Complications include cardiovascular and renal diseases. Management includes lifestyle modifications and treatment with antihypertensive drugs.
• Other causes of secondary hypertension: There are a number of other conditions that can lead to an increase in BP, including medication use, primary kidney disease, obstructive sleep apnea, pheochromocytoma, Cushing’s syndrome, and coarctation of the aorta. Signs and symptoms suggestive of these conditions should prompt appropriate work-up.
• Hypokalemia due to other causes: defined as plasma potassium levels < 3.5 mEq/L. Hypokalemia may result from potassium loss due to renal tubular acidosis, salt-wasting nephropathies (e.g., Bartter’s and Gitelman’s syndromes), increased cortisol, and non-reabsorbable anions. Other causes of hypokalemia include GI losses, transcellular shifts, poor dietary intake, and hypomagnesemia. Diagnosis is aided by assessing pH status, BP, and magnesium levels. Management involves replacing the potassium deficit and treating the underlying cause.