Journal of Clinical Endocrinology & Metabolism, Vol 76, 748-751, Copyright © 1993 by Endocrine Society

ARTICLES

11 beta-Hydroxysteroid dehydrogenase deficiency and glucocorticoid status in patients with alcoholic and non-alcoholic chronic liver disease

PM Stewart, P Burra, CH Shackleton, MC Sheppard and E Elias
Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom.

11 beta-Hydroxysteroid dehydrogenase (11 beta HSD), found predominantly in liver and kidney, is responsible for the shuttling of active cortisol to cortisone. A defect in this shuttle mechanism, e.g. after liquorice ingestion, results in an increase in the ratio of urinary cortisol [tetrahydrocortisol (THF)] to cortisone [tetrahydrocortisone (THE)] metabolites. The plasma cortisol half-life is prolonged, but concentrations remain normal because of a concomitant fall in cortisol production. Alcohol-induced pseudo-Cushing's syndrome is an ill defined cause of Cushing's syndrome. Because many of the documented cases have abnormal liver function tests, we have investigated whether abnormal hepatic 11 beta HSD activity may play a role in the pathogenesis of the condition. Fourteen patients with alcoholic (ALD) and 14 patients with non-alcoholic (CLD) chronic liver disease had marked deficiency of 11 beta HSD [5 alpha-THF + THF/THE: ALD, 1.94 +/- 0.38 (+/- SEM); CLD, 1.82 +/- 0.20] compared to controls (0.94 +/- 0.04; P < 0.01 and 0.001, respectively). In the CLD group, the daily cortisol production rate (as assessed by summation of principal cortisol metabolites) was reduced appropriately [median, 3,510; range, 1,101-8,940 micrograms/24 h; controls, 5,492 (range, 3,818-14,996) micrograms/24 h; P < 0.001], and normal 0900 h plasma cortisol and urinary free cortisol levels were maintained. However, in the ALD group, there was no concomitant fall in the cortisol production rate (sum of cortisol metabolites, 5,043 micrograms/24 h; range, 520-27,344). As a consequence, 0900 h plasma cortisol in the ALD group was significantly elevated (633 +/- 52 nmol/L) compared to values in the CLD group (487 +/- 48 nmol/L; P < 0.05) and controls (432 +/- 27 nmol/L; P < 0.001). Our findings of glucocorticoid excess in patients with chronic ALD may indicate that alcohol-induced pseudo-Cushing's syndrome develops as a result of continuing normal cortisol secretion in the face of impaired cortisol metabolism. The latter is mediated by defective hepatic 11 beta HSD activity; the former by either abnormal glucocorticoid feedback or stimulation of cortisol secretion at the level of the hypothalamus/pituitary.

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