What is apparent mineralocorticoid excess?

Apparent Mineralocorticoid Excess Syndrome

Apparent mineralocorticoid excess (AME) is a rare genetic disorder characterized by severe hypertension, hypokalemia, and suppressed renin-angiotensin-aldosterone system due to deficiency of the 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) enzyme, which normally prevents cortisol from activating mineralocorticoid receptors. 1, 2

Pathophysiology

• The 11βHSD2 enzyme normally converts cortisol to inactive cortisone, protecting mineralocorticoid receptors from cortisol activation 2, 3
• In AME, defective 11βHSD2 enzyme activity allows cortisol to bind to mineralocorticoid receptors, causing sodium retention, potassium excretion, and hypertension 2, 4
• AME is characterized by low aldosterone and renin levels despite hypertension and hypokalemia 4
• Two types have been identified:
  • Type I (classic): Increased ratio of tetrahydrocortisol (THF) + allo-THF/tetrahydrocortisone (THE) in urine 4
  • Type II: Normal THF/THE ratio but elevated free urinary cortisol/cortisone ratio 2, 4

Clinical Presentation

• Early-onset hypertension, often severe and resistant to conventional therapy 1
• Hypokalemia or hyperkalemia with associated arrhythmias 1
• Low aldosterone and renin levels 1
• Pre- and postnatal growth failure 3
• End-organ damage affecting kidneys, retina, heart, and central nervous system 3, 5

Diagnosis

• Screening tests show low aldosterone and renin levels 1
• Confirmatory tests include urinary cortisol metabolites and genetic testing 1
• Elevated ratio of urinary cortisol to cortisone metabolites (THF+allo-THF/THE) in Type I AME 4
• Genetic testing reveals mutations in the HSD11B2 gene located on chromosome 16q22 4
• Infusion of tritiated cortisol shows minimal release of tritiated water, indicating failure of cortisol to cortisone conversion 3

Differential Diagnosis

• Other mineralocorticoid excess syndromes 1
• Liddle syndrome (constitutive activation of epithelial sodium channel) 4
• Congenital adrenal hyperplasia 1
• Cushing syndrome 1, 6
• Licorice ingestion (which inhibits 11βHSD2 activity) 4

Management

• Spironolactone or eplerenone (mineralocorticoid receptor antagonists) are first-line treatments to normalize blood pressure and correct hypokalemia 6, 5
• Low-dose dexamethasone can be considered to suppress ACTH-driven cortisol production, though response may be variable 5, 4
• Other antihypertensive medications may be required for long-term blood pressure control 2, 5
• Early and vigilant treatment is crucial to prevent or improve end-organ damage 3, 5
• Renal transplantation has been reported to cure AME in severe cases with renal failure 5

Prognosis

• Without treatment, AME can lead to significant morbidity and mortality due to severe hypertension and end-organ damage 3, 5
• Early diagnosis and appropriate treatment can significantly improve outcomes 3, 5
• Long-term follow-up studies show that with proper treatment, end-organ damage can improve in many patients 3
• Some patients may develop progressive renal failure despite treatment 5, 7

Genetic Considerations

• AME is typically inherited in an autosomal recessive pattern 3, 4
• Multiple mutations in the HSD11B2 gene have been identified 3, 4
• Heterozygous carriers typically have normal steroid profiles 7
• Genotype-phenotype correlations are difficult to establish due to the rarity of the condition 3