The Syndrome of Apparent Mineralocorticoid Excess (AME) is a rare disorder causing the body to exhibit effects of mineralocorticoid overactivity, such as high blood pressure and electrolyte imbalances. The condition is called “apparent” because the primary mineralocorticoid, aldosterone, is present at low levels. Instead of true overproduction, AME results from the failure of a protective mechanism that normally regulates salt and water balance. AME can be inherited due to a genetic defect or acquired through the ingestion of certain substances.
The Underlying Biological Mechanism
The syndrome’s “apparent” nature stems from the function of the enzyme 11-beta hydroxysteroid dehydrogenase type 2 (11β-HSD2). This enzyme is specifically located in the cells of the kidney and other tissues that possess the mineralocorticoid receptor (MR). The mineralocorticoid receptor (MR) is the cellular switch that, when activated by aldosterone, promotes sodium retention and potassium excretion.
Cortisol, the body’s main stress hormone, circulates in the blood at concentrations hundreds of times higher than aldosterone. Cortisol has a natural ability to bind to and activate the mineralocorticoid receptor (MR) with an affinity similar to aldosterone. To prevent this high-concentration cortisol from constantly over-stimulating the receptor, the 11β-HSD2 enzyme acts as a local shield.
The 11β-HSD2 enzyme rapidly converts active cortisol into its inactive form, cortisone, at the mineralocorticoid receptor site. This inactivation ensures that only aldosterone effectively binds to the receptor under normal conditions. In AME, however, the 11β-HSD2 enzyme is either absent or its activity is severely impaired.
When this protective enzyme fails, high levels of circulating cortisol are left unchecked, flooding the mineralocorticoid receptors in the kidney. This unhindered binding mimics a state of true mineralocorticoid excess. Continuous receptor activation drives excessive sodium and water reabsorption and increased potassium excretion, leading to the syndrome’s characteristic clinical features.
Key Clinical Manifestations
Unchecked mineralocorticoid receptor activation profoundly disturbs the body’s electrolyte and fluid balance. A primary feature of AME is early-onset hypertension, which is often resistant to conventional treatments. This high blood pressure is a direct result of the kidneys retaining too much sodium and water due to the constant stimulation of the mineralocorticoid receptor.
Patients commonly develop hypokalemia (low blood potassium). The over-activation of the receptor causes the kidney to excrete potassium at an excessive rate. Low potassium can lead to muscle weakness, fatigue, and heart rhythm abnormalities.
The combination of excessive potassium loss and resulting changes in acid-base balance often leads to metabolic alkalosis. In this state, the blood becomes less acidic than normal due to an increase in bicarbonate levels. Children with severe cases may also experience complications such as growth retardation, failure to thrive, and damage to organs like the heart, retina, and kidneys from sustained high blood pressure.
Distinguishing Between Forms of AME
The syndrome is broadly categorized into two forms based on its cause: hereditary and acquired. Hereditary AME is a genetic disorder typically transmitted in an autosomal recessive pattern. This form is caused by mutations in the HSD11B2 gene, which provides the instructions for making the 11β-HSD2 enzyme.
The severity of hereditary AME can vary, but it usually presents as a severe condition in infancy or early childhood because the enzyme’s function is significantly reduced or completely absent. The specific mutation dictates the amount of residual enzyme activity, which accounts for the spectrum of clinical presentation. This form requires lifelong management to control blood pressure and electrolyte levels.
Acquired AME occurs when the 11β-HSD2 enzyme is inhibited by an external substance. The most common cause is the excessive consumption of licorice, which contains the active compound glycyrrhizic acid. This compound acts as a potent inhibitor of the 11β-HSD2 enzyme, functionally mimicking a genetic deficiency.
Other substances, such as the drug Carbenoxolone, are also known to inhibit the enzyme and can cause acquired AME. A key difference from the hereditary form is that acquired AME is generally reversible. The symptoms, including hypertension and hypokalemia, typically resolve once the inhibiting substance is removed or discontinued.
Diagnosis and Management Strategies
The diagnosis of AME is strongly suggested by the combination of clinical signs and specific laboratory findings. A hallmark feature is the discovery of low levels of both plasma renin activity and aldosterone, despite the presence of high blood pressure and signs of mineralocorticoid excess. This biochemical profile confirms that the problem is not true primary aldosteronism but an “apparent” excess.
Confirmatory testing involves analyzing steroid metabolites in the urine, specifically the ratio of cortisol to cortisone. Because the protective conversion is impaired, AME results in an elevated ratio of cortisol metabolites (Tetrahydrocortisol) to cortisone metabolites (Tetrahydrocortisone). For the hereditary form, genetic testing can definitively confirm the diagnosis by identifying mutations in the HSD11B2 gene.
The management of AME focuses on counteracting the mineralocorticoid-like effects of cortisol and controlling the resulting high blood pressure. For the acquired form, the primary treatment is the removal of the inhibiting substance, such as stopping licorice consumption. This action allows the 11β-HSD2 enzyme activity to recover naturally.
For the hereditary form, long-term treatment involves medications that block the mineralocorticoid receptor, such as spironolactone, which competes with cortisol to prevent receptor activation. Another strategy is the use of sodium channel blockers, like amiloride, which inhibit the epithelial sodium channel (ENaC) to reduce sodium and water reabsorption. In some cases, low-dose corticosteroids like dexamethasone may be administered to suppress the body’s natural production of cortisol, thereby reducing the amount of substrate available to activate the mineralocorticoid receptor.