C. Cooper Bell

Bile Acid Metabolism in Patients with Cirrhosis: II. Cholic and chenodeoxycholic acid metabolism

Primary bile acid kinetics and pool sizes were determined in 12 patients with cirrhosis and 10 patients without liver disease. Labeled bile acids (14C-cholic and 14C-chenodeoxycholic acids) were administered to each patient. Patients with cirrhosis were found to have a total bile acid pool about one-half that of the group of patients without cirrhosis. The diminished total bile acid pool was the result of marked reductions in the cholic and deoxycholic acid pools, whereas the chenodeoxycholic acid pool was not significantly altered. The daily synthesis of cholic acid in patients with cirrhosis was about one-fourth that of the group with no liver disease, whereas chenodeoxycholic acid synthesis was reduced by only 30%. The fractional turnover rate of cholic acid was significantly reduced in patients with cirrhosis, but the rate of turnover of chenodeoxycholic acid was similar in both groups of patients. As a consequence of these alterations in the fractional turnover rate of the primary bile acids, chenodeoxycholic acid turned over more rapidly than cholic acid in cirrhotic patients. Changes in the conversion of cholic to deoxycholic acid could account for the decreased cholic acid turnover rate in patients with cirrhosis. The findings of this report suggest that there is a marked impairment in the cholesterol to cholic acid pathway in patients with cirrhosis, possibly due to a deficiency of the enzyme system which converts the dihydroxy intermediate to the trihydroxy precursor of cholic acid.

Bile Acid Pools, Kinetics and Biliary Lipid Composition before and after Cholecystectomy

Abstract Bile acid pools, kinetics and biliary lipid composition were determined in 10 patients with cholesterol gallstones before and after cholecystectomy. The determinations of post-cholecystect...

Bile acid metabolism in patients with cirrhosis. I. Kinetic aspects of cholic acid metabolism.

Labeled cholic acid was administered orally to 8 patients with cirrhosis and no ascites. Bile-rich duodenal fluid was obtained at daily intervals for periods up to 7 days, and bile acid composition and cholic acid specific activity were determined. The total and component bile acid pools, cholic acid production, and half-life were estimated from the data and compared with a group of our patients without liver disease previously reported. The total and component bile acid pools were markedly reduced in patients with cirrhosis. The total bile acid pool was 46% smaller in cirrhotic patients than the control patients (1.3 g versus 2.4 g). There was a virtual absence of biliary deoxycholic acid in 7 of 8 patients with cirrhosis. Cholic acid production in the cirrhotic patients was approximately one-third that of the normal group. A prolongation of the cholic acid turnover time was also noted in 3 of the 8 cirrhotic patients. It is suggested that in patients with cirrhosis the failure of the liver to produce adequate amounts of bile acids is responsible for the diminished bile acid pool. The nonpancreatogenic steatorrhea observed in some patients with cirrhosis might be attributed in part to a lack of sufficient bile salts in the intestine.

Bile acids and lipid metabolism: III. Influence of bile acids on phospholipids in liver and bile of the isolated perfused dog liver

Abstract The isolated perfused dog liver was used to study the effect of bile acids on the excretion of biliary phospholipids and [32P]phospholipids and the 32P-labeling of the individual plasma, liver, and biliary phospholipids. Although high amounts of [32P]phospholipids were found in the liver, none was excreted in the bile unless taurocholate was infused. Biliary phospholipid excretion continued to increase throughout the taurocholate infusion period. The liver was the source of the biliary phospholipids. However, during the taurocholate infusion the specific activity of the biliary phospholipids greatly exceeded the liver phospholipids which suggests that a specific phospholipid is secreted into the bile by the liver or that biliary phospholipids are derived from a specific pool in the liver. There was a marked heterogeneity in the labeling pattern of the plasma, liver, and biliary phospholipids. The bile [32P]phosphatidyl choline fraction accounted for over 95% of the total [32P]phospholipids. Marked differences between the composition of the liver and plasma [32P]phospholipids were noted. The data support the view that the stimulatory effect of bile acids on biliary phospholipid excretion is related to the formation of a biliary micellar complex, and that highly selective mechanisms are involved in the formation of plasma and biliary phospholipids.

Cholic acid synthesis as an index of the severity of liver disease in man

Bile acid pool size and kinetics were determined in 17 patients with cirrhosis and 11 patients without liver disease and correlated with the severity of liver disease as determined by the usual clinical and laboratory criteria. In order to assess the severity of liver disease, a grading system was devised which assigned numerical values to various clinical signs and laboratory results. The total clinical score and the patients were divided into two groups of advanced (7-18 points) or mild (1-6 points) cirrhosis. The clinical rating was then correlated with the various aspects of bile acid metabolism. Cholic acid synthesis was markedly reduced in the early stages of cirrhosis and continued to decrease with the advancement of the liver disease. There was an inverse correlation between synthesis of cholic acid and the severity of cirrhosis. Nine of the 10 patients with advanced cirrhosis and a very low cholic acid synthetic rate (average 68 mg per day) died within one to 13 months from the start of the study. Patients with mild cirrhosis also had significantly reduced cholic acid synthesis (average 152 mg per day) but they all were well and alive three to 23 months after the study. In contrast, chenodeoxycholic acid synthesis was not markedly affected in either patients with mild or advanced cirrhosis. There was also a high degree of correlation between the fractional daily turnover rate of cholic acid and the severity of liver disease. The fractional daily turnover rate of cholic acid was greatly reduced (50%) in patients with advanced cirrhosis. Deoxycholic acid was reduced in patients with mild cirrhosis and virtually absent from the bile of patients with advanced cirrhosis. The findings of the present report provide evidence that cholic acid synthesis is a sensitive indicator of the hepatocellular damage, whereas chenodeoxycholic acid synthesis is relatively unaffected by cirrhosis. The selective alteration in cholic acid synthesis probably resides in a deficiency of one or more enzymes regulating the formation of the 3-keto, 7 alpha, 12 alpha-dihydroxy precursor of cholic acid.

Relationship of bile acid pool size to the formation of lithogenic bile in female Indians of the southwest.

Bile acid kinetics and pool size were determined in 18 female American Indians of the Southwest. Eleven patients had a lithogenic bile and 7 patients had a normal bile. Eight of the patients with a lithogenic bile had cholesterol gallstones which were confirmed both at surgery and by analysis of the gallstones; the remaining 3 patients in this group had no radiological evidence of gallstones. The group of 7 patients with a normal bile had no evidence of gallstones by oral cholecystogram. The patients were administered orally 14C-cholic and 14C-chenodeoxycholic acids. The primary and total bile acid pools were found to be significantly smaller in patients with a lithogenic bile than in patients with a normal bile (1.1 g versus 1.6 g). The 3 patients with a lithogenic bile and no gallstones also had greatly diminished bile acid pools (under 1 g). The primary bile acids of patients with a lithogenic bile turned over at a faster rate than in patients with a normal bile. There was no significant difference in the daily production of the primary bile acids between the two groups. The production of primary bile acids in the female Indian averaged 350 mg per day. The data suggest that the diminished bile acid pool in the female Indians with a lithogenic bile resulted from an inability of the liver to synthesize adequate amounts of bile acids to compensate for bile acid excretion. Biliary lipid excretion was estimated from the total bile acid pool size and biliary lipid composition. Although there was a slight decrease in phospholipid and a slight increase in cholesterol excretion in the patients with a lithogenic bile, these differences were not significant. However, these alterations in biliary lipid excretion were of sufficient magnitude when coupled with the reduction in the bile acid pool to tip the bile out of the micellar zone. Based on the findings of this and earlier reports, it is suggested that a diminished bile acid pool could be responsible for the development of a bile supersaturated with cholesterol and subsequent cholesterol gallstone formation.

Abnormal metabolism of secondary bile acids in patients with cirrhosis.

The composition of bile acids in human bile was determined in bile-rich duodenal fluid on four consecutive days in a group of seven patients with cirrhosis and eight control patients with no liver disease. There was a marked reduction of secondary biliary bile acids in cirrhotic patients. Possible mechanisms for these changes are discussed.

Bile-rich duodenal fluid as an indicator of biliary lipid composition and its applicability to detection of lithogenic bile

A comparison was made of the lipid composition of duodenal and gallbladder bile in 10 patients with cholesterol gallstones and in 11 patients without. The lipid composition of duodenal and gallbladder bile was found to be similar in each patient. A phase diagram plot of the biliary lipid composition data showed that duodenal bile is also a valid indicator of the presence or absence of lithogenic bile. Also, based on the analysis of the duodenal lipids, a distinction could be made between the presence of calcium bilirubinate and that of cholesterol gallstones. Analysis of the lipids of duodenal bile should serve as a useful tool in studying the effect of various agents and factors on the metabolism of the biliary lipids.

Bile Acid Metabolism in Cirrhosis: III. Biliary lipid secretion in patients with cirrhosis and its relevance to gallstone formation

Abstract Biliary lipid secretion and bile acid pools were determined in 10 patients without and 13 patients with cirrhosis. Patients with cirrhosis were found to have a greatly diminished total bile acid pool. This alteration in the bile acid pool was associated with a significantly decreased phospholipid secretion, and a very marked decrease in biliary cholesterol secretion. The concentration of the biliary lipids in duodenal bile paralleled the changes in biliary lipid secretion. A triangular phase diagram plot of the biliary lipid composition data indicated that the bile of patients with cirrhosis was entirely normal (no insoluble cholesterol) and had a greater cholesterol holding capacity than the bile of control subjects. These findings indicate that cirrhotic patients are not predisposed to develop cholesterol gallstones. The reported high incidence of gallstones in cirrhotic patients may be related to an abnormality in bilirubin metabolism since a high proportion of the stones in these patients have been reported to be of the pigmented type.

Influence of bile acids on biliary lipid excretion in man. Implications in gallstone formation.

Bile salts orally administered to a human subject, who had a short-arm Ttube in his common bile duct, markedly increased the concentrations of bile acids, phospholipid, and cholesterol in the hepatic bile. The increase in phospholipid was proportionately greater than that of cholesterol. When administration of oral bile acids was stopped, there was a decrease in the bile acids and phospholipid levels, and in the phospholipid to cholesterol ratio. These data provide evidence that biliary lipid excretion is regulated by the availability of bile acids.