What causes increased mineralocorticoid precursors leading to hypertension and hypokalemia?

Increased Mineralocorticoid Precursors Causing Hypertension and Hypokalemia

The primary causes of increased mineralocorticoid precursors leading to hypertension and hypokalemia are specific enzyme deficiencies in the adrenal steroidogenesis pathway—most notably 11β-hydroxylase deficiency and 17α-hydroxylase deficiency in congenital adrenal hyperplasia—as well as iatrogenic causes from medications that inhibit cortisol synthesis, particularly osilodrostat and metyrapone. 1

Congenital Adrenal Hyperplasia: Primary Genetic Causes

11β-Hydroxylase Deficiency

• This enzyme deficiency causes accumulation of 11-deoxycorticosterone (DOC) and 11-deoxycortisol, both potent mineralocorticoid precursors that activate mineralocorticoid receptors. 1
• Clinical presentation includes virilization (due to elevated androgens), hypertension, and hypokalemia. 1, 2
• The diagnostic pattern shows hypertension and hypokalemia with low or normal aldosterone and renin levels—this suppression occurs because the excess mineralocorticoid precursors activate receptors, causing negative feedback. 1, 3
• Laboratory confirmation reveals elevated deoxycorticosterone (DOC), 11-deoxycortisol, and androgens. 1

17α-Hydroxylase Deficiency

• This deficiency blocks both glucocorticoid and sex steroid synthesis while shunting precursors toward mineralocorticoid pathways. 1, 4
• Clinical features include incomplete masculinization in males (presenting as male pseudohermaphroditism) and primary amenorrhea with absent secondary sexual development in females. 1, 4
• Patients present with severe hypertension and hypokalemia, often in adolescence or early adulthood when the lack of sexual development becomes apparent. 4
• Diagnostic findings show elevated ACTH, FSH, and LH with low basal levels of all steroid hormones requiring 17-hydroxylation, plus elevated deoxycorticosterone and corticosterone. 1, 4
• Hypertension and hypokalemia resolve with glucocorticoid replacement therapy, which suppresses ACTH and reduces precursor accumulation. 4

Iatrogenic Causes: Adrenal Steroidogenesis Inhibitors

Osilodrostat

• Osilodrostat inhibits 11β-hydroxylase and aldosterone synthase, causing accumulation of 11-deoxycortisol and 11-deoxycorticosterone. 1, 5
• These accumulated precursors activate mineralocorticoid receptors, causing hypokalemia, edema, and hypertension in 42% of treated patients. 1, 5
• Hypokalemia occurred in 17% of patients in the 48-week clinical study and requires correction with potassium supplementation and/or mineralocorticoid antagonists (spironolactone). 1, 5
• Hypokalemia should be corrected prior to initiating osilodrostat, and patients require ongoing monitoring for worsening hypertension and edema. 5
• The FDA label explicitly warns about this mechanism: "Elevated 11-deoxycorticosterone levels may activate mineralocorticoid receptors and cause hypokalemia, edema and hypertension." 5

Metyrapone

• Metyrapone blocks 11β-hydroxylase, causing similar accumulation of androgenic and mineralocorticoid precursors. 1
• Adverse effects include hirsutism, hypertension, and hypokalemia from precursor accumulation. 1
• The mechanism is identical to osilodrostat—blocking the final step in cortisol synthesis causes upstream precursor buildup. 1

Diagnostic Algorithm for Mineralocorticoid Precursor Excess

When evaluating a patient with hypertension and hypokalemia, measure plasma aldosterone and renin to calculate the aldosterone-to-renin ratio (ARR). 3

If Both Aldosterone and Renin Are Low or Suppressed:

• This pattern indicates mineralocorticoid receptor activation by non-aldosterone substances—either precursors or cortisol itself. 1, 3
• Screen for Cushing's syndrome with overnight 1-mg dexamethasone suppression test and 24-hour urinary free cortisol. 1, 2
• If hypercortisolism is excluded, consider congenital adrenal hyperplasia with measurement of specific precursors:
  • For 11β-hydroxylase deficiency: Measure 11-deoxycortisol, DOC, and androgens (all elevated). 1
  • For 17α-hydroxylase deficiency: Measure DOC and corticosterone (elevated) with decreased androgens and estrogens; check for absent secondary sexual characteristics. 1, 4
• Obtain detailed medication history, specifically asking about osilodrostat or metyrapone use for Cushing's disease treatment. 1, 5

If Aldosterone Is Elevated with Suppressed Renin:

• This indicates primary aldosteronism, not mineralocorticoid precursor excess. 3

If Both Aldosterone and Renin Are Elevated:

• This suggests renovascular hypertension or secondary hyperaldosteronism, not precursor-mediated disease. 3

Critical Clinical Pitfalls

• Do not assume all mineralocorticoid hypertension is due to primary aldosteronism—precursor-mediated disease requires different diagnostic and therapeutic approaches. 6, 7
• In patients taking osilodrostat or metyrapone for Cushing's disease, hypokalemia may develop or worsen despite improving hypercortisolism, requiring addition of potassium supplementation and mineralocorticoid antagonists rather than dose reduction of the steroidogenesis inhibitor. 1, 5
• Cross-reactivity of 11-deoxycortisol with cortisol in routine immunoassays can falsely elevate cortisol measurements in patients on osilodrostat or metyrapone, complicating assessment of treatment adequacy. 1
• In congenital adrenal hyperplasia, early diagnosis and treatment with glucocorticoid replacement prevents end-organ damage from chronic hypertension and hypokalemia, including left ventricular hypertrophy, renal failure, and hypertensive retinopathy. 4, 8

Management Principles

• For congenital adrenal hyperplasia: Glucocorticoid replacement (hydrocortisone or dexamethasone) suppresses ACTH, reducing precursor production and resolving hypertension and hypokalemia. 4
• For osilodrostat- or metyrapone-induced precursor excess: Add potassium supplementation (oral or IV based on severity) and consider mineralocorticoid antagonists (spironolactone) if hypokalemia persists despite supplementation. 1, 5
• Dose reduction or discontinuation of the steroidogenesis inhibitor may be necessary if precursor-related adverse effects cannot be controlled with adjunctive therapy. 1, 5