CORTISOL METABLOISM IN CIRRHOSIS

The production and peripheral metabolism of cortisol were studied in 10 cirrhotics and 11 controls after [intravenous] tracers of cortisol-14C. Total urinary excretion of radioactivity was normal (81% of the dose) but a decreased fraction was present as glucosiduronates: 18-47% of the dose (average 34%) compared to a normal average of 54%. There was a distinctively abnormal pattern of cortisol metabolites, not previously observed in other illnesses: tetrahydrocortisone was decreased to 14% of the enzyme hydrolysate (normal 26%); cortolones were increased to 34% (normal 19%), owing entirely to an increase in cortolone (20[alpha]) formation, since [beta] -cortolone (20[beta]) was not significantly increased; Reichstein''s substances U and epi-U were increased, averaging 2.6% for the former and 4.7% for the latter; tetrahydrocortisol, allotetrahydro-cortisol and cortols were normal. This pattern was independent of the degree of decreased glucosiduronate formation and also independent of the presence or absence or a protacaval shunt. Cortisol production, determined by isotope dilution, was normal in 6 cirrhotic patients. Cirrhotic patients have decreased A-ring reduction of cortisone to tetrahydrocortisone and correspondingly increased 20-ketone reduction of cortisone to Reichstein''s substances U and epi-U and then to the cortolones. Intrahepatic cholestasis, a regular pathophysiological feature of cirrhosis, may be responsible for the observed abnormal cortisol metabolite pattern in this disease. The slowed metabolic turnover rate of cortisol in cirrhosis may be due to decreased trans -port and/or binding of cortisol to its intracellular metabolic sites rather than to abnormalities of any specific metabolizing enzymes.