Apparent mineralocorticoid excess (AME) is an autosomal recessive form of low-renin hypertension caused by deficiency of the 11β-hydroxysteroid dehydrogenase type 2 enzyme (11β -HSD2). New and co-authors first described this syndrome in 1977 in a young female child who presented with hypertension associated with significant hypokalemia, metabolic alkalosis, low renin and low serum aldosterone. (13) The exploration and elucidation demonstrated that the specificity of the mineralocorticoid receptor (MR) function depends on a metabolic enzyme rather than the receptor itself, a new concept in receptor biology. (14) The 11β -HSD2 enzyme is co-expressed with the MR in renal tubular cells. This enzyme functions to protect the MR by inactivating cortisol to its inactive metabolite cortisone (Figure 4), thereby enabling aldosterone to occupy the MR in vivo. (15, 16) Aldosterone is not metabolized by 11β -HSD2 because it forms a C11–C18 hemi-ketal group in aqueous solution. The MR is non-selective in vitro and cannot distinguish between the glucocorticoid cortisol and its natural ligand, aldosterone. (17, 18) Therefore, lack of receptor protection by the defective enzyme allows cortisol, which has higher circulating levels than aldosterone, to bind to the MR and to act as an offending mineralocorticoid. AME has defined an important "pre-receptor" pathway in the analysis of corticosteroid hormone action. (19)

It is a rare disorder, having been identified in only approximately 60 patients over the past 20 years. Analysis of the gene for HSD11B2, which was mapped to human chromosome 16q22 (20), has demonstrated that most patients with AME are homozygous for one of the different mutations. This suggests endogamy or a founder effect in origin. (21)

AME usually presents in early life with low birth weight and postnatal failure to thrive, hypertension, and persistent polyuria and polydipsia. The disorder is characterized by hypokalemic alkalosis, hyporeninemia and undetectable serum concentrations of aldosterone. End-organ damage secondary to hypertension is common, even at a young age. Thirteen out of fourteen AME patients demonstrated damage of one or more organs (kidney, heart, retina or central nervous system.) In addition, most had hypercalcuria with nephrocalcinosis. (21)

Biochemical diagnosis of AME is made by measuring the ratio of cortisol to cortisone by the ratios of their urinary metabolites. Three metabolite ratios are calculated, each reflecting a different aspect of enzyme function: (1) 5β -tetrahydrocortisol (THF) and allo-THF to tetrahydrocortisone (THE), reflecting global function of HSD (22); (2) allo-THF to THF ratio, reflecting defect in 5β -reductase activity (23); (3) urinary free cortisol (UFF) to urinary free cortisone (UFE), reflecting kidney HSD function. (24)

In 1998, the first patient with a mild form of AME was described. Mutations that attenuated 11β -HSD2 enzyme activity were reported. (25) The patient lacked the typical features of low birth weight, failure to thrive, polyuria and polydipsia, hypokalemia, nephrocalcinosis and other significant end organ damage. Her hypertension was not severe. Subsequently, more patients with mild forms of AME have been reported. (26) Identification of mild-form AME suggests a link of impaired enzyme activity to diverse conditions that share moderate characteristics of typical AME patients. The conditions with such intermediate phenotype that may be related to the genetic defect in AME include essential hypertension, pre-eclampsia, intrauterine growth retardation (IUGR), renal disease, and cirrhosis. (27-31)

The treatment of AME is primarily directed at the correction of hypokalemia and hypertension. Cortisol acts as the offending mineralocorticoid in AME, hence blockage of its binding to the MR reverses excess mineralocortocoidism. Spironolactone, an MR receptor antagonist, is the medication of choice: it binds competitively and protects the receptors against any mineralocorticoid in excess. A reduction in dietary sodium and supplemental potassium can be beneficial. Patients with nephrocalcinosis require additional thiazide diuretic. Follow-up studies of AME patients treated with spironolactone revealed significant improvement in clinical symptoms. These outcomes demonstrate the importance of early diagnosis and adequate treatment. (14, 21) Another approach utilizing dexamethasone to suppress cortisol secretion demonstrated variable results. Normalization of blood pressure occurred in approximately 60% of cases. (32) The low effectiveness of this treatment is not surprising based on theoretical grounds: in vitro data suggest that putative physiologic ligands to non-selective MR in the kidney include dexamethasone, as well as cortisol and other mineralocorticoids. (17) Therefore administering dexamethasone to suppress cortisol secretion, which is already lowered in AME, may supply an additional MR ligand to aggravate mineralocorticoid excess.

Additional antihypertensive medications, such as thiazides or amiloride, may be required during disease progression. Cure of AME was reported in one patient after kidney transplantation due to the normal 11β-HSD2 activity of the transplanted kidney. (33, 34) Advances in enhancing or inhibiting11βHSD2 activity by some medications may provide novel treatments for AME. (31, 35)