Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)
- Norman M Kaplan, MD
Norman M Kaplan, MD
- Editor-in-Chief — Nephrology
- Section Editor — Hypertension
- Clinical Professor of Internal Medicine
- University of Texas Southwestern Medical Center
- William F Young, Jr, MD, MSc
William F Young, Jr, MD, MSc
- Professor of Medicine
- Mayo Clinic College of Medicine
The syndrome of apparent mineralocorticoid excess (AME), a genetic disorder, and chronic ingestion of licorice (the root of glycyrrhiza glabra) or licorice-like compounds (such as carbenoxolone) can result in findings similar to those in primary aldosteronism: hypertension, hypokalemia, metabolic alkalosis, and low plasma renin activity. However, plasma aldosterone levels are low in these disorders, rather than elevated, as in primary aldosteronism. (See "Diagnosis of primary aldosteronism" and "Pathophysiology and clinical features of primary aldosteronism".)
The pathogenesis of these disorders has been elucidated. Summarized briefly, renal mineralocorticoid receptors bind aldosterone and cortisol with similar affinity. Although the plasma concentration of cortisol is approximately 100-fold higher than aldosterone, activation of mineralocorticoid receptors by cortisol is normally limited due to its conversion to inactive cortisone at the sites of aldosterone action by the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (11-beta-HSD2) . This conversion is impaired in AME because of a mutation in the 11-beta-HSD2 gene and with licorice ingestion because of a compound in licorice (glycyrrhetinic acid) that inhibits the enzyme . (See 'Pathogenesis' below.)
SYNDROME OF APPARENT MINERALOCORTICOID EXCESS
Clinical manifestations — The syndrome of apparent mineralocorticoid excess (AME) is a rare form of severe juvenile hypertension that is usually transmitted as an autosomal recessive trait . AME is characterized by low birth weight, failure to thrive, onset of severe hypertension in early childhood with extensive target organ damage, hypercalciuria and nephrocalcinosis from an unknown mechanism, and renal failure . These manifestations are accompanied by all of the findings of primary aldosteronism (hypertension, hypokalemia, metabolic alkalosis, and low plasma renin activity) except for the low plasma aldosterone concentration. Affected patients may also have polyuria due to nephrogenic diabetes insipidus that is presumably induced by the chronic hypokalemia [4,6]. (See "Pathophysiology and clinical features of primary aldosteronism" and "Clinical manifestations and causes of nephrogenic diabetes insipidus", section on 'Hypokalemia'.)
- Quinkler M, Stewart PM. Hypertension and the cortisol-cortisone shuttle. J Clin Endocrinol Metab 2003; 88:2384.
- Stewart PM. Tissue-specific Cushing's syndrome, 11beta-hydroxysteroid dehydrogenases and the redefinition of corticosteroid hormone action. Eur J Endocrinol 2003; 149:163.
- Ulick S, Wang JZ, Blumenfeld JD, Pickering TG. Cortisol inactivation overload: a mechanism of mineralocorticoid hypertension in the ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab 1992; 74:963.
- Dave-Sharma S, Wilson RC, Harbison MD, et al. Examination of genotype and phenotype relationships in 14 patients with apparent mineralocorticoid excess. J Clin Endocrinol Metab 1998; 83:2244.
- Morineau G, Sulmont V, Salomon R, et al. Apparent mineralocorticoid excess: report of six new cases and extensive personal experience. J Am Soc Nephrol 2006; 17:3176.
- Bockenhauer D, van't Hoff W, Dattani M, et al. Secondary nephrogenic diabetes insipidus as a complication of inherited renal diseases. Nephron Physiol 2010; 116:p23.
- Lavery GG, Ronconi V, Draper N, et al. Late-onset apparent mineralocorticoid excess caused by novel compound heterozygous mutations in the HSD11B2 gene. Hypertension 2003; 42:123.
- Wilson RC, Dave-Sharma S, Wei JQ, et al. A genetic defect resulting in mild low-renin hypertension. Proc Natl Acad Sci U S A 1998; 95:10200.
- Funder JW. 11 beta-Hydroxysteroid dehydrogenase: new answers, new questions. Eur J Endocrinol 1996; 134:267.
- Mune T, Rogerson FM, Nikkilä H, et al. Human hypertension caused by mutations in the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase. Nat Genet 1995; 10:394.
- Carvajal CA, Gonzalez AA, Romero DG, et al. Two homozygous mutations in the 11 beta-hydroxysteroid dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess. J Clin Endocrinol Metab 2003; 88:2501.
- Palermo M, Delitala G, Mantero F, et al. Congenital deficiency of 11beta-hydroxysteroid dehydrogenase (apparent mineralocorticoid excess syndrome): diagnostic value of urinary free cortisol and cortisone. J Endocrinol Invest 2001; 24:17.
- Antonelli G, Artusi C, Marinova M, et al. Cortisol and cortisone ratio in urine: LC-MS/MS method validation and preliminary clinical application. Clin Chem Lab Med 2014; 52:213.
- Palermo M, Shackleton CH, Mantero F, Stewart PM. Urinary free cortisone and the assessment of 11 beta-hydroxysteroid dehydrogenase activity in man. Clin Endocrinol (Oxf) 1996; 45:605.
- Ulick S, Tedde R, Wang JZ. 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.
- Speiser PW, Riddick LM, Martin K, New MI. Investigation of the mechanism of hypertension in apparent mineralocorticoid excess. Metabolism 1993; 42:843.
- Palermo M, Cossu M, Shackleton CH. Cure of apparent mineralocorticoid excess by kidney transplantation. N Engl J Med 1998; 339:1787.
- Khattab AM, Shackleton CH, Hughes BA, et al. Remission of hypertension and electrolyte abnormalities following renal transplantation in a patient with apparent mineralocorticoid excess well documented throughout childhood. J Pediatr Endocrinol Metab 2014; 27:17.
- Farese RV Jr, Biglieri EG, Shackleton CH, et al. Licorice-induced hypermineralocorticoidism. N Engl J Med 1991; 325:1223.
- Franzson L, Manhem K, Ragnarsson J, et al. Liquorice-induced rise in blood pressure: a linear dose-response relationship. J Hum Hypertens 2001; 15:549.
- Whorwood CB, Sheppard MC, Stewart PM. Licorice inhibits 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid levels and potentiates glucocorticoid hormone action. Endocrinology 1993; 132:2287.
- de Klerk GJ, Nieuwenhuis MG, Beutler JJ. Hypokalaemia and hypertension associated with use of liquorice flavoured chewing gum. BMJ 1997; 314:731.
- Torpy DJ, Mullen N, Ilias I, Nieman LK. Association of hypertension and hypokalemia with Cushing's syndrome caused by ectopic ACTH secretion: a series of 58 cases. Ann N Y Acad Sci 2002; 970:134.
- Walker BR, Campbell JC, Fraser R, et al. Mineralocorticoid excess and inhibition of 11 beta-hydroxysteroid dehydrogenase in patients with ectopic ACTH syndrome. Clin Endocrinol (Oxf) 1992; 37:483.
- CHRISTY NP, LARAGH JH. Pathogenesis of hypokalemic alkalosis in Cushing's syndrome. N Engl J Med 1961; 265:1083.