The syndrome of apparent
mineralocorticoid excess (
AME) is an inherited form of
hypertension. This disorder results from an inability of the
enzyme 11beta-hydroxysteroid dehydrogenase (11beta-OHSD) to inactivate
cortisol to
cortisone. The diagnosis of
AME is usually based on an elevated ratio of
cortisol to
cortisone reduced metabolites in the urine [
tetrahydrocortisol plus
allotetrahydrocortisol to
tetrahydrocortisone (THF+alloTHF/THE)]. The principal site of "A" ring reduction is the liver, but
AME arises from mutation in the gene encoding 11beta-OHSD2 in the kidney. We used a gas chromatographic/mass spectrometric method to measure the urinary free
cortisol (UFF) and free
cortisone (UFE) in 24 patients affected by the two variants of
AME [19 with the classical form (type I) and 5 with the mild form called
AME type II] in order to provide a more reproducible in vivo measure of the renal enzymatic activity. Type I patients were divided into two groups: children under 12 and adults. UFF levels (microg/24 h) did not differ between under-12 controls and
AME type I children (mean+/-SD, 9+/-4 and 15+/-12, respectively), but was significantly higher in affected adults compared to controls: (62+/-32 vs 29+/-8, p<0.01). No differences were found between adult controls and
AME type II patients (29+/-8 and 37.0+/-14, respectively). UFE was undetectable in 63% of
AME type I and significantly lower in
AME type II (p<0.05). As a consequence UFF/UFE ratio was significantly higher in
AME type I patients both in children and adults compared to controls (
AME children: 5.1+/-2.6; normal children: 0.43+/-0.2, p<0.01;
AME type I adults: 17.7+/-19.6; normal adults: 0.54+/-0.3 p<0.01). For
AME type II, where UFE was detectable in every case, the UFF/UFE ratio was significantly higher than adult controls (2.75+/-1.5 vs 0.54+/-0.3, p<0.01). In conclusion, our study indicates that UFE and UFF/UFE ratio are sensitive markers of 11beta-OHSD2, directly reflecting the activity of the renal
isozyme and readily identifying patients with
AME. The presence of an altered UFF/UFE ratio in both types of
AME, although with different degree of severity, calls for re-evaluation and the classification of
AME as a single disorder.