Apparent mineralocorticoid excess syndrome

Lore & Background

The clinical symptoms of AME were first reported in 1974 by Professor Edmond A Werder from Switzerland in a 3-year-old girl with low birth weight, delayed growth, polydipsia, polyuria, and hypertension. Stanley Ulick in New York studied a similar patient in 1964, finding low aldosterone secretory rate but increased secretion of 18-hydroxycorticosterone. Ulick proposed that two distinct enzymes act in succession on corticosterone. Later, a young Native American girl was referred to Dr. Maria New, who identified patients with similar symptoms and characterized their biochemical profiles. The description of the syndrome was published in 1977, and the first coinage of 'Apparent Mineralocorticoid Excess' was used in a second paper in 1979. The syndrome was initially known as 'Ulick syndrome' in honor of researcher Ulick.

Reader's Guide

Apparent mineralocorticoid excess syndrome is significant as a model disorder illustrating the critical role of 11β-hydroxysteroid dehydrogenase type 2 in protecting the mineralocorticoid receptor from cortisol. Its discovery and characterization by researchers including Werder, Ulick, New, and Funder elucidated a fundamental mechanism of blood pressure regulation. The identification of HSD11B2 mutations in 1995 by Robert Wilson confirmed the genetic basis. The syndrome's pathophysiology—where cortisol at high concentrations activates the mineralocorticoid receptor due to non-selectivity—explains the hypertension, hypokalemia, and hypernatremia seen in patients. Diagnosis relies on the ratio of free urinary cortisol to free urinary cortisone, which is elevated in AME. Treatment involves aldosterone antagonists like spironolactone, and renal transplant is curative. The condition can also be temporarily induced by licorice consumption, which inhibits the same enzyme. AME remains a rare but instructive example of how enzyme defects can mimic hormonal excess.

Did You Know?

• Liquorice consumption can inhibit the enzyme and cause a temporary form of AME.
• A renal transplant has been attempted in some cases but is not considered curative; the underlying genetic defect remains systemic.

The Molecular Defect and Its Downstream Consequences

AME arises from a loss-of-function mutation in the HSD11B2 gene, which produces the kidney-specific form of 11β-hydroxysteroid dehydrogenase type 2. In healthy individuals, this enzyme converts circulating cortisol into its much less active metabolite, cortisone, effectively keeping cortisol levels low in the kidney. When the enzyme is absent or nonfunctional, cortisol accumulates locally in aldosterone-sensitive renal tissues. Because the mineralocorticoid receptor is inherently non-selective, it readily binds cortisol at these elevated concentrations, triggering the same downstream signaling that aldosterone would normally produce. The result is a constellation of aldosterone-like effects: the kidney retains sodium, excretes potassium, and drives blood pressure upward, producing the hallmark triad of hypertension, hypernatremia, and hypokalemia. Paradoxically, serum measurements of both aldosterone and renin come back low, because the body's feedback loops sense the mineralocorticoid activity and suppress their own production. The condition is inherited in an autosomal recessive pattern, meaning a child must receive a defective copy of the gene from each parent to manifest the disease, while typically asymptomatic carriers pass the mutation silently to the next generation.

Clinical Picture and the Challenge of Diagnosis

AME mimics primary hyperaldosteronism so closely that initial laboratory workup can be misleading. Patients typically present with severe, often childhood-onset hypertension accompanied by hypokalemia, metabolic alkalosis, and suppressed plasma renin activity. The sustained pressure damage produces end-organ complications including left ventricular hypertrophy, retinal and renal vascular changes, neurological vascular injury, growth retardation, and failure to thrive. Because serum aldosterone and renin are both low, the picture does not fit the classic hyperaldosteronism template. Definitive diagnosis hinges on measuring the ratio of free urinary cortisol to free urinary cortisone; in AME patients the ratio is markedly elevated because the defective enzyme produces far less cortisone. An alternative diagnostic approach involves administering a potassium-sparing diuretic and observing the response. Liddle's syndrome, a key mimic, responds only to agents that block the ENaC channel, whereas AME patients will respond to diuretics targeting either ENaC or the mineralocorticoid receptor itself. This pharmacological distinction helps clinicians separate the two conditions when biochemical profiles overlap.

From Mystery to Named Syndrome: The Discovery Story

The clinical entity now known as AME emerged from a patchwork of observations spanning continents and decades. In 1964, Stanley Ulick in New York examined a child with severe hypertension yet paradoxically low aldosterone secretion, using an isotopic dilution technique that measured radioactivity of urinary metabolites after injecting radiolabeled aldosterone. He noted elevated 18-hydroxycorticosterone and proposed that two distinct enzymes acted in succession on corticosterone. A few years later, Swiss professor Edmond A. Werder described a three-year-old girl with low birth weight, polydipsia, polyuria, and hypertension in 1974. A young Native American girl was subsequently referred to pediatric endocrinologist Maria New in New York, where she and Ulick conducted extensive investigations, sending samples to John Baxter in San Francisco and a center in Melbourne, both of which could not identify the cause. The syndrome was formally described in 1977, and the name Apparent Mineralocorticoid Excess was coined by Dr. New in a 1979 publication. It had previously been informally called Ulick syndrome. The causative HSD11B2 mutation was not identified until 1995, when Robert Wilson found it in siblings from a consanguineous Iranian family.

Management, Rarity, and the Liquorice Connection

Because AME is exceedingly rare, with fewer than one hundred cases documented worldwide, most clinicians will never encounter a patient. Treatment centers on controlling blood pressure with an aldosterone antagonist such as spironolactone, which simultaneously reverses the hypokalemic metabolic alkalosis, alongside additional antihypertensive agents as needed. In the most severe or refractory cases, renal transplantation has proven curative in nearly all reported instances, effectively replacing the enzyme-deficient kidney with a healthy organ that can properly metabolize cortisol. The genetic architecture of the disorder means that both parents must be silent carriers of one defective HSD11B2 allele for a child to be affected, making recurrence in a family a matter of Mendelian probability. Interestingly, the same enzymatic pathway can be pharmacologically disrupted by dietary means: consumption of liquorice inhibits 11β-hydroxysteroid dehydrogenase type 2, transiently raising local cortisol and producing a reversible, temporary form of the syndrome. Cessation of liquorice intake resolves the condition, underscoring how a single enzyme's activity sits at the crossroads of genetics, diet, and renal physiology.