Apparent mineralocorticoid excess (AME): a rare genetic cause of hypertension

Cortisol, the body's main stress hormone, can switch on the same receptor as aldosterone, the mineralocorticoid receptor in the kidney that tells the body to hold on to salt and lose potassium. To prevent that, kidney cells contain an enzyme, 11-beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2), that converts active cortisol to inactive cortisone. A published review explains that this enzyme mediates the ligand selectivity of aldosterone for the receptor.

In AME this enzyme is deficient. Cortisol accumulates and over-stimulates the receptor, leading to sodium retention, potassium loss and low renin, even though aldosterone itself is low, which is why the condition is called apparent mineralocorticoid excess. The review says the clinical features were first reported in 1974 in a 3-year-old girl with low birth weight, delayed growth, polydipsia, polyuria and hypertension, and that over 50 deleterious HSD11B2 mutations have since been identified.

AME usually presents in infancy or childhood, though a milder non-classic form has been described. A case series of three children found that all were small for gestational age and had severe hypokalaemia, metabolic alkalosis, hypertension, nephrocalcinosis (calcium deposits in the kidneys) and hypercalciuria, with a normal glomerular filtration rate. Another source describes low birth weight, developmental delay, low-renin hypertension, hypokalaemia and increased risk of chronic kidney disease.

The case reports describe excessive thirst and passing a lot of urine, delayed growth and failure to thrive, in addition to hypertension and low potassium. The review records a history of hypokalaemic paralysis in some patients. The long-term data it quotes, from a series of 36 patients with classic AME, include cardiovascular mortality of 19%, persistent nephrocalcinosis in 89% and kidney failure in 15%, which illustrate the stakes of early diagnosis.

The suspicion arises when a child has severe or resistant hypertension with low potassium and low renin. The review says the biochemical profile includes low renin and aldosterone and a raised ratio of cortisol to cortisone metabolites in the urine. A precise diagnosis depends on genetic testing for HSD11B2 variants, and the case series concludes that early genetic testing in patients suspected of having AME is beneficial.

Other causes of low-renin, hypokalaemic hypertension need to be considered by the specialist team. The review also stresses taking a detailed personal and medication history when identifying acquired forms, because excessive ingestion of exogenous 11β-HSD2 inhibitors such as liquorice and azole antifungals can cause mineralocorticoid-receptor-induced hypertension.

Treatment targets the abnormal receptor activation. The review states that a mineralocorticoid receptor antagonist, spironolactone or eplerenone, combined with potassium-sparing diuretics, is strongly recommended with satisfactory curative effects, and that spironolactone blocks the hyperactivated receptors while amiloride blocks the epithelial sodium channel. In the three-child case series, oral spironolactone and potassium chloride normalised both blood pressure and serum potassium in all patients.

Management is long term and specialist-led, usually by paediatric or adult endocrinology and nephrology teams, with monitoring of blood pressure, potassium and kidney function. The case series was small and cannot define a standard regimen, so doses and drug choices are individualised.

AME is autosomal recessive, so a child is affected only when both copies of HSD11B2 carry a disease-causing variant. Parents are usually healthy carriers, and the case series notes that the three children were born to non-consanguineous parents, although the first families described had parents who were related. Each pregnancy of two carrier parents has a one in four chance of an affected child.

Genetic counselling through a clinical genetics service can explain the pattern, testing for relatives and options in future pregnancies. Because the diagnosis depends on genetics, confirming the specific variants is helpful for the whole family.

Children with persistent high blood pressure, excessive thirst and urination, failure to grow or muscle weakness need assessment by a doctor, and severe headache, vomiting, confusion or weakness with high blood pressure needs urgent care through NHS 111, 999 or A&E. For adults with unexplained hypertension and low potassium, a doctor will consider the acquired causes, and you should tell them about any regular use of liquorice products or antifungal medicines.