Adrenocortical Steroid Metabolism and Adrenal Cortical Function in Liver Disease

Abstract. The production and peripheral metabolism of cortisol have been studied in 10 cirrhotics and 11 controls after i.v. tracers of cortisol-'4C. The findings were as follows: (a) 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%. (b) 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 (20a) formation, since fl-cortolone (20,8) 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, allotetrahydrocortisol and cortols were normal. This pattern was independent of the degree of decreased glucosiduronate formation and also independent of the presence or absence of a portacaval shunt. (c) Cortisol production, determined by isotope dilution, was normal in each of six cirrhotic patients. From these data, taken in conjunction with our previously reported findings concerning the influence of norethandrolone on cortisol metabolism, the following conclusions were drawn: (a) 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. (b) Intrahepatic cholestasis, a regular pathophysiological feature of cirrhosis, may be responsible for the observed abnormal cortisol metabolite pattern in this disease. (c) The slowed metabolic turnover rate of cortisol in cirrhosis may be due to decreased tranpsort and/or binding of cortisol to its intracellular metabolic sites rather than to abnormalities of any specific metabolizing enzymes. IntroductionDisturbances of cortisol metabolism in liver disease have been described by many investigators.

Section: Introductioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cortisol Metabolism in Cirrhosis*

Zumoff¹,

Bradlow²,

Gallagher³

et al. 1967

“…It is tentatively concluded that the abnormal clearance and decreased glucuronide conjugation of D3-3H observed in the cirrhotic patients (Table II) reflect the importance of the liver in the regulation and metabolism of circulating vitamin D and its metabolites in man. This defect in the capacity of the cirrhotic liver to metabolize sterols appears relatively specific, since abnormal metabolic schemes have also been documented for testosterone (25) and cortisol (26) but not for corticosterone, cortisone, and aldosterone (26).…”

Section: Discussionmentioning

confidence: 97%

Metabolism of Vitamin D3-3H in Human Subjects: Distribution in Blood, Bile, Feces, and Urine*

Avioli¹,

Lee²,

McDonald³

et al. 1967

163

Summary. Vitamin D8-3H has been administered intravenously to seven normal subjects, three patients with biliary fistulas, and four patients with cirrhosis. Plasma D3-3H half-times normally ranged from 20 to 30 hours. in vivo evidence that a metabolic transformation of vitamin D occurs was obtained, and a polar biologically active vitamin D metabolite was isolated from plasma.Urinary radioactivity averaged 2.4% of the administered dose for the 48-hour period after infusion, and all the excreted radioactivity represented chemically altered metabolites of vitamin D. The metabolites in urine were mainly water-soluble, with 26% in conjugated form.From 3 to 6% of the injected radioactivity was excreted in the bile of subjects with T-tube drainage and 5% in the feces of patients having no T-tube. The pattern of fecal and biliary radioactivity suggested that the passage of vitamin D and its metabolites from bile into the intestine represents an essential stage for the fecal excretion of vitamin D metabolites in man.Abnormally slow plasma disappearance of vitamin D3-3H in patients with cirrhosis was associated with a significant decrease in the quantity and rate of glucuronide metabolite excretion in the urine.

“…Ten or 20 ,sc (7 to 21 pug) of the d,l-form of randomly ring-labeled H3-aldosterone, with a specific activity ranging from 1.0 to 3.0 MAc per 1ug was injected intravenously; the efficiency of the liquid scintillation spectrometer was approximately 25 per cent. The concentration of true H3-aldosterone in peripheral plasma was measured at intervals of 5, 10,15,20, 30, 45, 60, and 90 minutes. In the dogs with thoracic inferior vena caval constriction, large volumes of ascitic fluid formed and sodium retention was almost complete.…”

Section: Methodsmentioning

confidence: 99%

THE EFFECTS OF CHRONIC HEPATIC VENOUS CONGESTION ON THE METABOLISM OF d,l-ALDOSTERONE AND d-ALDOSTERONE*

Ayers¹,

Davis²,

Lieberman³

et al. 1962

In 1950 Deming and Luetscher demonstrated increased salt-retaining activity in urine from patients with congestive heart failure (1). In 1953 aldosterone was isolated (2), and subsequently the urinary excretion of this hormone was found to be elevated in nearly all the clinical states associated with edema. Two possible mechanisms could lead to an increase in the plasma level of aldosterone and thus to an increase in urinary aldosterone excretion: 1) hypersecretion of aldosterone, and 2) a decreased rate of metabolism of the hormone. In 1957, it was demonstrated that a sixfold increase in aldosterone secretion occurred in dogs with experimental right heart failure and in dogs with thoracic inferior vena caval constriction (3). The possibility of decreased metabolism of aldosterone was suggested by Yates, Urquhart and Herbst (4) who found a decrease in the 4,5-steroid reductase activity for inactivation of aldosterone by liver tissue from rats subjected to chronic passive venous congestion. They suggested that a decreased rate of reduction of ring A of aldosterone might increase the plasmal level of the hormone in these animals. The primary purpose of the present study was to evaluate the possibility of a decreased rate of metabolism of aldosterone by the congested liver. The disappearance of H3-aldosterone from plasma was studied in dogs with chronic hepatic venous congestion secondary to thoracic inferior vena caval constriction and in normal animals. In addition, several aspects of the metabolism of dl-aldosterone were studied including the urinary and biliary excretion of * Reported in preliminary form to the Endocrine Society, June, 1960, and at the Laurentian Hormone Conference, Sept., 1960. total tritium radioactivity, the disappearance of total methylene chloride-extractable radioactivity from the plasma, the effect of hepatectomy on the biological half-life (ti) of aldosterone, and binding of H3-aldosterone to plasma protein. At the time these studies were performed tritiated d-aldosterone was not available; recently, d-aldosterone has been tritiated and additional observations have been made with the natural hormone. METHODSStudies with d,l-aldosterone. The disappearance of H3-d,l-aldosterone from peripheral plasma was determined in 9 normal dogs before and after constriction of the thoracic inferior vena cava, and in one additional dog after caval constriction. Ten or 20 ,sc (7 to 21 pug) of the d,l-form of randomly ring-labeled H3-aldosterone, with a specific activity ranging from 1.0 to 3.0 MAc per 1ug was injected intravenously; the efficiency of the liquid scintillation spectrometer was approximately 25 per cent. The concentration of true H3-aldosterone in peripheral plasma was measured at intervals of 5, 10,15,20, 30, 45, 60, and 90 minutes. In the dogs with thoracic inferior vena caval constriction, large volumes of ascitic fluid formed and sodium retention was almost complete. In a preliminary experiment it was found that equilibration of H3-aldosterone between ascitic fluid and plasma was v...