Evaluation of Rare Non‑Aldosterone Mediated Causes of Mineralocorticoid Hypertension

Diagnostic Approach

When renin remains suppressed despite maximal mineralocorticoid‑receptor blockade, confirm that the case is not surgically curable unilateral primary aldosteronism by performing adrenal vein sampling to exclude a unilateral aldosterone‑producing adenoma; bilateral disease can be managed medically with high‑dose spironolactone (300–400 mg/day) whereas unilateral disease requires adrenalectomy for optimal outcomes【2】【3】【4】.
Measure plasma aldosterone while the patient is on spironolactone:
After a suppressed aldosterone result, assess deoxycorticosterone (DOC) and cortisol levels:

Suspect this condition in patients with a family history of early‑onset hypertension or stroke (≤ 40 years) and hypertension onset at ≤ 20 years with normal adrenal imaging【2】.
The disorder is caused by a chimeric CYP11B1/CYP11B2 gene that places aldosterone synthesis under ACTH control, leading to aldosterone that paradoxically rises after ACTH stimulation【5】.
Genetic testing for the chimeric gene confirms the diagnosis, and low‑dose dexamethasone (0.25–1 mg daily) can normalize aldosterone production and blood pressure【3】【4】.

Hereditary AME results from autosomal‑recessive 11β‑hydroxysteroid dehydrogenase type 2 deficiency; the acquired form is caused by chronic ingestion of licorice (glycyrrhizic acid) which inhibits the same enzyme【6】.
Both forms allow cortisol to activate mineralocorticoid receptors, producing hypertension with low renin and low aldosterone levels【6】.

DOC‑secreting adrenal tumors (benign or malignant) and congenital adrenal hyperplasia due to 11β‑hydroxylase or 17α‑hydroxylase deficiency generate excess DOC, leading to hypertension with suppressed renin and aldosterone【6】.

An autosomal‑dominant disorder causing constitutive activation of epithelial sodium channels, presenting with severe early‑onset hypertension and hypokalemia; both renin and aldosterone are suppressed【6】.
The condition does not respond to spironolactone but improves with ENaC blockers such as amiloride (5–30 mg daily) or triamterene【6】.

Evaluate for cortisol excess when patients exhibit central obesity, muscle weakness, and purple striae; some adrenal tumors co‑secrete aldosterone, but plasma aldosterone is usually low unless co‑secretion occurs【6】.

A rare familial disorder characterized by low‑renin hypertension, hyperkalemia (distinguishing it from other mineralocorticoid excess states), and variable aldosterone levels (low, normal, or paradoxically high)【6】.

Do not assume that all suppressed‑renin hypertension on high‑dose spironolactone represents refractory bilateral primary aldosteronism without first excluding surgically curable unilateral disease【2】【1】.
Hypokalemia is absent in approximately 72 % of primary aldosteronism patients and should not be used to rule out the diagnosis【7】.
Spironolactone is ineffective for Liddle syndrome, apparent mineralocorticoid excess, and DOC excess because these conditions bypass the mineralocorticoid receptor or involve alternative pathways【6】.