Serum concentrations of bile acid glucuronides in hepatobiliary diseases

Bile acid glucuronides in the serum in various hepatobiliary diseases (36 cases) were quantitated by mass fragmentography and their clinical significance was discussed. Serum was added to defined amounts of deuterium-labeled bile acids and their glucuronide and sulfate derivatives, and the bile acids were separated into unconjugated, glucuronidated and sulfated groups after enzymatic cleavage of amide bonds. The liberated bile acids were quantitated by mass fragmentography. Bile acid glucuronides comprised about 7-8% of the total bile acids in the serum of various patients. Chenodeoxycholic acid was the major glucuronidated bile acid while cholic acid was mostly unconjugated. Lithocholic acid was almost all either sulfated or glucuronidated. In patients with obstructive jaundice, glucuronidated bile acids also comprised about 5%, although their absolute amounts were increased. In patients with liver cirrhosis, bile acid glucuronides were decreased, especially in decompensated cases, possibly as a result of hepatocellular dysfunction.     

Urinary excretion of bile acid glucosides and glucuronides in extrahepatic cholestasis

Recently the formation of bile acid glucosides has been described as a novel conjugation mechanism in vitro and in vivo. In 10 patients with extrahepatic cholestasis caused by carcinoma of the head of the pancreas we investigated excretion rates and profiles of urinary bile acid glucosides. Urinary bile acid glucosides and, for comparison, bile acid glucuronides were extracted and characterized according to established methods. In controls total urinary bile acid glucoside excretion was 0.22 +/- 0.03 mumol/24 hr (mean +/- S.E.M.)-in the range of bile acid glucuronide excretion (0.41 +/- 0.06 mumol/24 hr; mean +/- S.E.M.). A gas chromatography-mass spectrometry-characterized trihydroxy bile acid glucoside of still-unknown hydroxyl positions accounted for 65% of total urinary bile acid glucosides. In extrahepatic cholestasis total urinary bile acid glucoside excretion was 0.52 +/- 0.13 mumol/24 hr (mean +/- SEM), yet significantly lower than bile acid glucuronide excretion (1.53 +/- 0.13 mumol/24 hr; mean +/- SEM; p less than 0.001). In cholestasis the primary bile acid derivatives cholic and chenodeoxycholic acid glucosides amounted to 90%, whereas the trihydroxy bile acid glucoside had decreased to 5% of total bile acid glucoside excretion, indicating its alteration during enterohepatic circulation. The data establish the composition and quantity of urinary bile acid glucosides in healthy controls and cholestasis and constitute a quantitative comparison with another glycosidic conjugation reaction, bile acid glucuronidation.     

Intestinal absorption of bile acid glucuronides in rats

While the intestinal absorption of taurine, glycine, and sulfate conjugates of bile acids has been studied extensively, nothing is known about the absorption of bile acid glucuronides. In the present study, the intestinal phase of the enterohepatic circulation of two bile acid glucuronides was examined. [3-³ H]cholic acid 3-O--d-glucuronide or [3^–3 H]lithocholic acid 3-O--d-glucuronide was perfused through isolated segments of ileum or jejunum with intact blood supply in rats prepared with a biliary fistula. [¹⁴C]Taurocholic acid was perfused simultaneously with each glucuronide to compare glucuronide absorption with that of an actively transported bile acid. Intestinal absorption was determined by measuring the rate of secretion of labeled bile acid in bile. The absorption of [³H]cholic acid glucuronide by the ileum and jejunum was one fortieth and one eighth, respectively, that of [¹⁴C]taurocholic acid. Comparison of the two glucuronides show that [³H]lithocholic acid glucuronide absorption was 18 and 10 times greater than [³H]cholic acid glucuronide absorption from the jejunum and ileum, respectively. Collectively, the above observations suggest that glucuronidation of bile acids markedly reduces absorption from the small intestine.This work was supported in part by the National Institutes of Health, grant HD-14198, and the March of Dimes Foundation, grant G-305.     

Cell-kinetic study of proliferating bile ductules in various hepatobiliary diseases

ABSTRACT— Aims and Methods: Proliferat bile ductules are classifiable histologically into typical and atypical types. To clarify their histogenesis and regulation, we examined their phenotype, proliferating and degrading characteristics, using liver sections from 58 patients with various hepatobiliary diseases. Results: Typical ductules were found in all cases. Atypical ductules were also frequently found in extrahepatic biliary obstruction (EBO), chronic hepatitis (CH), as well as in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Typical ductules completely expressed biliary-type cytokeratins, while atypical ductules lacked complete biliary-type cytokeratins and often connected with periportal hepatocytes. Proliferative indices of typical ductules in diseased livers were higher than those in normal livers, while those of atypical ductules were low in PBC and PSC and high in EBO and CH. Apoptosis was detected in typical and atypical ductules. Perforin was preferably expressed on typical and atypical ductules, compared with CD95. Conclusions: These findings suggest that typical ductules reflect active proliferation of preexisting ductules. Atypical ductules might be classifiable into two categories: those in PBC and PSC primarily reflect ductular transformation (metaplasia) of periportal hepatocytes, while those in EBO and CH reflect active proliferation and transformation of hepatocytes. Apoptosis via perforin/granzyme B pathway may be involved in the maintenance of homeostasis in ductular proliferation as degrading fraction.     

Immunohistochemical study on bile ductular proliferation in various hepatobiliary diseases

ABSTRACT- Proliferation of the two types of bile ductules, typical and atypical, in the portal and periportal areas was examined in various liver diseases other than cirrhosis to determine any difference in their immunohistochemical properties and presumed histogenesis. While the typical ductules with a well-formed lumen were frequently seen in a large spectrum of diseases, atypical ductules with a poorly defined lumen were encountered much more frequently in prolonged biliary diseases, including primary biliary cirrhosis and primary sclerosing cholangitis, than in nonbiliary hepatic diseases. Immunocytochemically, cytoplasmic keratin was intensively positive in typical ductules, and the degree of its intensity and extent was variable in atypical ductules. Simultaneously, some of the periportal hepatocytes revealed weak staining for keratin. Luminal borders of typical ductules usually revealed an expression of both carcinoembryonic antigen and epithelial membrane antigen, while atypical ductules and periportal hepatocytes lacked epithelial membrane antigen. The atypical ductules, together with the adjoining hepatocytes, appeared on occasion to form anastomosing cords in prolonged biliary diseases. Thus, atypical ductules seem likely to originate from ductular transformation of the periportal hepatocytes and the typical ductules might result from the proliferation of preexisting interlobular bile ducts and ductules.     

Urinary bile acid sulfate levels in patients with hepatitis C virus-related chronic liver diseases

Aim:  Urinary bile acids are mainly conjugated with sulfuric acid, and urinary sulfated bile acid (USBA) levels in hepatobiliary diseases have been reported. However, the relationship between USBA and fasting serum total bile acid (TBA) has not been studied in hepatobiliary diseases. In the present study, we measured USBA levels in patients with hepatitis C virus-related chronic liver diseases, and the relationship between TBA and various laboratory tests was studied.
Methods:  USBA was measured using an automatic assay kit in 66 patients with chronic hepatitis and 28 patients with liver cirrhosis, and its relationship between TBA and various laboratory tests was studied.
Results:  The median USBA level was 10.7 µmol/g creatinine in patients with chronic hepatitis and 41.1 µmol/g creatinine in liver cirrhosis ( P  = 0.000). More patients with chronic hepatitis had elevated USBA levels (61%) compared to TBA level (39%) ( P  = 0.002). USBA level was well correlated with TBA (r_s = 0.680), and negatively correlated with albumin (r_s = −0.488), prothrombin time (r_s = −0.385) and platelet counts (r_s = −0.394). In patients with liver cirrhosis, USBA was significantly elevated in Child–Pugh class B compared to Child–Pugh class A ( P  = 0.036).
Conclusion:  Although the metabolic pathways of USBA and TBA are different, these levels correlated very well, and USBA is considered to be a useful indicator of hepatic function like TBA in patients with chronic hepatitis C.     

Diagnostic value of serum bile acids and routine liver function tests in hepatobiliary diseases

Total serum bile acids measured by enzymatic fluorometry and routine liver function tests were determined in a large population including 97 healthy subjects, 138 patients free of hepatobiliary diseases but affected by other diseases, and 344 patients with mild or severe hepatobiliary diseases. In order to define the diagnostic value and some operational characteristics of serum bile acids, sensitivity, specificity, and several predictive value tables for increasing cutoff levels of serum bile acids were calculated by means of a computer program. Serum bile acids and aspartate aminotransferase were found to be similar in sensitivity, specificity, and predictive value. Serum aspartate aminotransferase was found to be more suitable than serum bile acids in detecting mild hepatobiliary diseases, whereas serum bile acids were more sensitive than routine liver tests in the evaluation of severe hepatobiliary diseases. In view of its ability to detect severe hepatobiliary diseases, serum bile acids test may play a decisive role in clinical practice (eg, decision to perform a liver biopsy).     

Duodenal bile acid output in gastroenterologic diseases

The biliary secretion of bile acids was measured with the modified secretin-pancreozymin test in 50 patients with various gastroenterological diseases and in a control group. In the control group the highest bile acid output and the lowest G/T quotient was estimated. In comparison to the control group, the bile acid output in the patients with gastroenterological disorders was reduced significantly to a varying degree. Except in postcholecystectomy patients, it was proved that the G/T quotient was significantly increased compared to that in the control group. The estimation of bile acid output and the G/T quotient presented here shows an easier extension of the validity of the secretin-pancreozymin test which does not indice any additional burden to the patients.     

胆汁酸代谢及相关进展

胆汁酸在肝脏南胆同醇合成，是机体类同醇物质的主要清除途径，胆汁酸代谢在维持机体的胆同醇稳态中起重要的作用。本文就胆汁酸合成的机制、生理功能、肝肠循环、胆汁酸障碍相关疾病及胆汁酸合成的调节等方面的一些进展作一简要综述。