Diagnosis of late-presenting 11β-hydroxysteroid dehydrogenase Type 2 (11βHSD2) deficiency by gas-chromatography/mass-spectrometric profiling of urinary cortisol metabolites Joseph Montalto1, Nilika Wijeratne1, 2, Jan Awadallah1, David Mitchell1, Anthony Boers3, Alan McNeil1 1Dorevitch Pathology, Heidelberg , 2 Department of Medicine, Monash University, Clayton, 3Latrobe Regional Hospital , Traralgon; Vic, Australia Joseph.Montalto@dorevitch.com.au 11βHSD2 deficiency, also known as Apparent Mineralocorticoid Excess Syndrome (AME) is a rare, autosomal recessive genetic disorder, typically causing severe hypertension, hypokalaemia, metabolic alkalosis, low renin and low aldosterone. AME usually manifests early in life with low birth weight, severe hypertension, failure to thrive, polydipsia and polyuria. Its biochemical hallmark is the presence of an abnormal urine steroid pattern, revealing an elevated ratio of tetrahydrocortisol (THF) plus 5α-tetrahydrocortisol (5α-THF) to tetrahydrocortisone (THE). Additionally, chronic licorice ingestion may inhibit 11βHSD2,resulting in an acquired form of AME. DISCUSSION The syndrome of AME is a form of low- renin hypertension, which is caused by a deficiency of 11βHSD2 enzyme. This results in reduced oxidation of cortisol to inactive cortisone and thus to excess cortisol binding to the mineralocorticoid receptor(MR). The resultant MR activation produces Na+ retention, volume expansion, hypokalaemia and suppression of plasma renin and aldosterone. Usually patients present in early life, however, a late-onset syndrome has been reported in adults with heterozygous mutations with milder phenotype. Chronic ingestion of licorice or licorice-like substances (eg: Carbenoxolone) may result in an acquired form of AME syndrome. The hallmark of the disease is a state of mineralocorticoid excess in the absence of aldosterone and the presence of an abnormal urine steroid profile with an increased urinary cortisol to cortisone metabolite ratio (THF + 5α-THF / THE) (Figure 1 -4). Patients with AME syndrome usually treated with mineralocorticoid receptor blockers. SUMMARY Hypertensive adults and children presenting with significantly reduced renin and aldosterone should be screened for AME. A detailed clinical history may be helpful to identify acquired AME syndrome. Biochemical diagnosis can be made by an elevated ratio of (THF + 5αTHF) to THE by GC-MS analysis. CASE Presentation: A 60 y old female admitted to the hospital with conscious collapse, dizziness, declining mobility and weight loss. Background history revealed fatigue, palpitations, poor appetite, nausea with diarrhoea for two months, hypertension over 20 years and thyroidectomy for hyperthyroidism. No history of diuretic, laxative or licorice abuse. Family history of hypertension noted. On admission, her blood pressure was 230/120. She was on Irbesartan and Metoprolol. Investigations: Figure.1 Figure: 2 Analyte Result Unit Reference Interval Sodium 142 mmol/L 135 - 145 Potassium 3.3* 3.5 - 5.0 Creatinine 69 umol/L 40 - 80 pH 7.45* 7.38 – 7.43 PCO2 39 mmHg 35 - 45 HCO3 27 22 - 31 Cortisol 833* nmol/L 119 - 618 Renin 3* mIU/L 10 - 50 Aldosterone <50* pmol/L 100 - 950 Urine Metanephrine 1.1 umol/24hr 0.2 – 1.5 Normetanephrine 2.8* 0.3 – 2.0 Figure: 3 Urine steroid profile: REFERENCES White PC, Mune T, Agarwal AK. 11β-Hydroxysteroid Dehydrogenase and the Syndrome of Apparent Mineralocorticoid Excess. Endocr Rev 1997;18:135-156 Ulick S, Levine LS, Gunczler P, Zanconato G, Ramirez LC, Rauh W, Rosler A, Bradlow HL, New MI. A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. J. Clin Endocrinol Metab 1979;49:757-764 Palermo M, Quinkler M, Stewart PM. Apparent Mineralocorticoid Excess Syndrome: An Overview. Arq Bras Endocrinol Metab 2004;48:687-696 Wilson RC, Nimkarn S, New MI. Apparent mineralocorticoid excess. Trends Endocrinol Metab 2001;12:104-111 Figure: 4