Abstract
The syndrome of apparent mineralocorticoid excess (AME) is an inherited form of hypertension. This disorder results from an inability of the enzyme 11β-hydroxysteroid dehydrogenase (11β-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 11β-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 (μg/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 11β-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.
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Shimojo M., Stewart P.M. Apparent mineralocorticoid excess syndrome. J. Endocrinol. Invest. 1995, 51: 518–532.
Shackleton C.H.L. Stewart P.M. The hypertension of apparent mineralocorticoid excess (AME) syndrome. In: Biglieri E.G, Melby J.C. (Eds.), Endocrine hypertension. Raven Press, New York, 1990, pp. 155–173.
Stewart P.M., Wallace A.M., Valentino R., Burt D., Shackleton C.H.L., Edwards C.R.W. Mineralocorticoid activity of licorice: 11beta-hydroxysteroid dehydrogenase comes of age. Lancet ii: 1987, 2: 821–824.
Edwards C.R.W., Walker B.R., Benediktsson R., Seckl J.R. Congenital and acquired syndrome of apparent mineralocorticoid excess. J. Steroid Biochem. Mol. Biol. 1983, 45: 1–5.
Arriza J.L., Weinberger C., Cerelli G., Gasler T.M., Handelin B.L.J., Housman D.E., Evans R.M. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science 1987, 237: 268–274.
Stewart P.M., Mason J.I. Cortisol to cortisone: glucocorticoid to mineralocorticoid. Steroids 1995, 60: 143–146.
Ulick S., Chan C.K., Rao K.N., Mantero F. A new form of the syndrome of apparent mineralocorticoid excess. J. Steroid Biochem. 1989, 32: 209–212.
Moore C.C.D., Mellon S.H., Murai J., Siiteri P.K., Miller W.L. Structure and function of the hepatic form of 11β- hydroxysteroid dehydrogenase in the squirrel monkey, An animal model of glucocorticoid resistance. Endocrinology 1993, 133: 368–375.
Stewart P.M. 11β-hydroxysteroid dehydrogenase: implications for clinical medicine. Clin. Endocrinol. 1996, 44: 483–499.
Stewart P.M., Boulton A., Kumar S., Clark P.M., Shackleton C.H.L. Cortisol metabolism in human obesity: impaired cortisone-cortisol conversion in subjects with central obesity. J. Clin. Endocrinol. Metab. 1999, 84: 1022–1027.
Kenouch S., Alfaidy N., Bonvalet J.P., Farman N. Expression of 11β-hydroxysteroid dehydrogenase along the nephron of mammals and humans. Steroids 1994, 59: 100–104.
Krozowski Z.S., Maguire J.A., Stein-Oakley A.N., Dowling J., Smith R.E., Andrews R.K. Immunohistochemical localization of 11β-hydroxysteroid dehydrogenase type 2 enzyme in human kidney and placenta. J. Clin. Endocrinol. Metab. 1995, 80: 2203–2209.
Brown R.W., Chapman K.E., Edwards C.R.W., Seckl J.R. Human placental 11β-hydroxysteroid dehydrogenase: evidence for and partial purification of a distinct NAD-dependent isoform. Endocrinology 1993, 132: 2614–2621.
Mune T., Rogerson F.M., Nikkila H., Agarwal A.K., White P.C. Human hypertension caused by mutation in the kidney isozyme of 11β-hydroxysteroid dehydrogenase. Nat. Genet. 1995, 10: 394–399.
Li A., Tedde R., Krozowski Z.S., Pala A., Li K.X., Shackleton C.H.L., Mantero F., Palermo M., Stewart P.M. Molecular basis for hypertension in the “type 2 variant” of apparent mineralocorticoid excess. Am. J. Hum. Genet. 1998, 63: 370–379.
Ulick S., Tedde R., Mantero F. Pathogenesis of type 2 variant of the syndrome of apparent mineralocorticoid excess. J. Clin. Endocrinol. Matab. 1990, 70: 200–206.
Mantero F., Tedde R., Opocher G., Dessì Fulgheri P., Arnaldi P., Ulick S. Apparent mineralocorticoid excess type 2. Steroids 1994, 59: 80–83.
Shackleton C.H.L. Mass spectrometry in the diagnosis of steroid related disorder and in hypertension research. J. Steroid Biochem. Mol. Biol. 1993, 45: 127–140.
Palermo M., Gomez-Sanchez C., Roitman E. and Shackleton C.H.L. Quantitation of cortisol 3-oxo-4-ene steroids in urine using gas chromatography/mass. Spectrometry with stable isotope-labeled internal standard. Steroids 1996, 61: 583–589.
Ulick S., Tedde R., Wang J.Z. Defective ring A reduction of cortisol as the major metabolic error in the syndrome of apparent mineralocorticoid excess. J. Clin. Endocrinol. Metab. 1992, 74: 593–599.
Mantero F., Palermo M., Petrelli M.D., Tedde R., Stewart P.M., Shackleton C.H.L. Apparent minaralocorticoid excess: type I and type II Steroids 1996, 61: 193–196.
Palermo M., Cossu M., Shackleton C.H.L. Cure of apparent mineralocorticoid excess by kidney transplantation. N. Engl. J. Med. 1998, 339: 1787–1788.
Nikkila H., Tannin G.M., New M.I., Taylor N.F., Kalaitzoglou G., Monder C., White P.C. Defect in the HSD 11 gene encoding 11β-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxo reductase deficiency. J. Clin. Endocrinol. Metab. 1993, 77: 687–691.
Wilson R.C., Krozowski Z.S., Li K., Obeyesekere V.R., Razzaghy-Azar M., Harbison M.D., Wej J.Q., Shackleton C.H.L., Funder J.W., New M.I. A mutation in HSD11β2 gene in a family with apparent mineralocorticoid excess. J. Clin. Endocrinol. Metab. 1995, 80: 2263–2266.
Wilson R.C., Dave-Sharma S., Wei J.Q., Obeyesekere V.R., Li K., Ferrari P., Krozowsky Z.S., Shackleton C.H.L., Bradlow L., Wiens T., New M.I. A genetic defect resulting in mild low-renin hypertension. Proc. Natl. Acad. Sci. USA 1998, 18; 95: 10200–10205.
Shackleton C.H.L., Artega J.R.E., Lopez J.M., Winter J.S.D. Congenital 11β-hydroxysteroid dehydrogenase deficiency associated with juvenile hypertension: corticosteroid metabolite profile of four patients and their families. Clin. Endocrinol. 1985, 22: 701–712.
Nunez B.S., Rogerson F.M., Mune T., Igarashi Y., Nakagawa Y., Phillipov G., Moudgil A., Travis L.B., Palermo M., Shackleton C.H.L., White P.C. Mutans 11beta-hydroxysteroid dehydrogenase (11-HSD2) with partial activity: improved correlations between genotype and biochemical phenotype in apparent mineralocorticoid excess. Hypertension 1999, 34: 638–642.
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Palermo, M., Delitala, G., Mantero, F. et al. Congenital deficiency of 11β-hydroxysteroid dehydrogenase (apparent mineralocorticoid excess syndrome): Diagnostic value of urinary free cortisol and cortisone. J Endocrinol Invest 24, 17–23 (2001). https://doi.org/10.1007/BF03343803
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DOI: https://doi.org/10.1007/BF03343803