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Biomedical subjects

A F Hofmann

Publications and source records attributed to A F Hofmann.

370 records · Page 21Linked to original sources
PubMedDate not supplied

Normal fasting-state levels of serum cholyl-conjugated bile acids in Gilbert's syndrome: an aid to the diagnosis.

Fasting levels of cholic acid conjugates were determined by radioimmunoassay in the serum of 24 patients with extensively documented Gilbert's syndrome and in 98 healthy controls without unconjugated hyperbilirubinemia. The Gilbert's syndrome patients studied included all three subtypes, as determined from studies of the plasma disappearance kinetics of sulfobromophthalein and indocyanine green. Although patients with structural liver disease severe enough to produce hyperbilirubinemia almost invariably have elevated fasting serum levels of cholic acid conjugates, values were normal in each of the Gilbert's syndrome patients, including patients with metabolic abnormalities in sulfobromophthalein and indocyanine green transport. It is concluded that the measurement of fasting serum levels of cholic acid conjugates is a useful adjunct to the diagnosis of Gilbert's syndrome.

Cholic Acids↗
PubMedDate not supplied

Chemistry and enterohepatic circulation of bile acids.

A brief review is given of the chemistry of bile acids, emphasizing the relationship between chemical structure, physical properties and enterohepatic cycling of the major primary and secondary bile acids. Features of the enterohepatic circulation of primary and secondary bile acids in man are summarized. The effects of bile acid feeding on the composition of the enterohepatic circulation in man are reviewed. Methods for characterizing the enterohepatic circulation of bile acids in man are tabulated.

Animals↗
PubMedDate not supplied

Animal models of calcium cholelithiasis.

Bile contains four calcium anions which are readily precipitated by calcium: bilirubinate, "palmitate", carbonate and phosphate. Precipitation of insoluble calcium salts is common in calculous biliary disease. All animal models of calcium cholelithiasis probably share a common pathogenesis--an increased concentration of a calcium-sensitive anion. In calcium bilirubinate cholelithiasis, an increased concentration of bilirubinate occurs. In mice, this occurs in animals having a genetic hemolytic anemia; in rats, it may be induced by an essential fatty acid in combination with diet modification; in dogs, by a low-taurine, low-protein diet; and in prairie dogs, by ileal resection which probably increases the bilirubinate/bile acid ratio in bile. In the two models of calcium-bile acid cholelithiasis, an increased biliary concentration of a calcium-sensitive glycine conjugated bile acid is induced by administration of a suitable precursor. In the rabbit, gallstones composed mostly of calcium allodeoxycholyl glycine are induced by the feeding of 5 beta-cholestan-3 beta-ol. In the taurine-deficient rat, the feeding of lithocholate leads to formation of gallstones which contain a mixture of calcium lithocholyl glycine and 3 alpha, 6 beta-dihydroxy cholanoyl glycine. These animal models may be of value in testing agents designed to lower calcium activity in bile.

Animals↗
PubMedDate not supplied

Effect of side chain length on bile acid conjugation: glucuronidation, sulfation and coenzyme A formation of nor-bile acids and their natural C24 homologs by human and rat liver fractions.

The effect of side chain length on bile acid conjugation by human and rat liver fractions was examined. The rate of conjugation with glucuronic acid, sulfate and coenzyme A of several natural (C24) bile acids was compared with that of their corresponding nor-bile acids. The rate of coenzyme A ester formation by nor-bile acids was much lower than that of the natural bile acids. In human liver microsomes, the rate of coenzyme A formation was less than 8% of the rate for the corresponding C24 bile acid. Rat liver microsomes formed the coenzyme A ester of nor-bile acids less than 20% of the rate of their corresponding C24 homologs. Glucuronidation rates were greater than sulfation rates in both species. With human liver microsomes, nor-bile acids were glucuronidated more rapidly than their corresponding C24 homologs, whereas with rat liver microsomes the reverse was true. Purified 3 alpha-OH androgen UDP-glucuronyltransferase catalyzed the glucuronidation of both nor-bile acids and bile acids. Human liver cytosol sulfated nor-bile acids more slowly than the corresponding bile acids. Rat liver cytosol, however, sulfated nor-bile acids more rapidly than the corresponding bile acids. The highest rate was seen with lithocholylglycine. The results indicate that the novel biotransformation of nor-bile acids seen in vivo--sulfation and glucuronidation rather than amidation--is most likely explained as a consequent of defective amidation, to which the rate of coenzyme A formation contributes. Thus, side chain and nuclear structures as well as species differences in conjugating enzyme activity are determinants of the pattern of bile acid biotransformation by the mammalian liver.

Animals↗
PubMedDate not supplied

Computer simulation of portal venous shunting and other isolated hepatobiliary defects of the enterohepatic circulation of bile acids using a physiological pharmacokinetic model.

The effect of three isolated defects in the enterohepatic circulation of bile acids on the size and distribution of the bile acid pool, plasma bile acid levels and bile acid secretion into the intestine was simulated using a linear multicompartmental physiological pharmacokinetic model previously used to simulate these aspects of bile acid metabolism in healthy man. Stepwise increases in portal-systemic shunting (with a reciprocal decrease in hepatic blood flow) caused an exponential increase in systemic plasma concentrations of bile acids, but no other major changes in bile acid metabolism. When the effect of varying fractional hepatic extraction was simulated, it was found that the greater the fractional hepatic extraction, the greater the elevation observed for systemic plasma bile acid levels for a given degree of portal-systemic shunting. When total hepatic blood flow was restored to normal by simulating "arterialization," systemic plasma levels of bile acids decreased strikingly, yet remained elevated. For cholate with a fractional hepatic extraction of 0.9 and 100% portal-systemic shunting, arterialization caused a decrease from a 20-fold elevation to a 5-fold elevation. This simulation thus defined the effect of the presence of the portal venous system per se on plasma bile acid levels and also quantified the circulatory route by which substances reach the liver when portal-systemic shunting is present. An isolated defect in hepatic uptake of bile acids caused little change in overall bile acid metabolism other than modestly increased plasma levels. Loss of bile acid storage by the gallbladder caused the majority of the bile acid pool to move from the gallbladder compartments to the proximal small intestine during fasting but had little effect on the dynamics of the enterohepatic circulation during eating. The results of these novel simulations of isolated defects in bile acid transport should aid in the interpretation of the more complex changes in bile acid metabolism which are likely to occur in hepatic or biliary disease.

Bile Acids and Salts↗
PubMedDate not supplied

Bile acid absorption after near-total proctocolectomy in dogs: ileal pouch vs. jejunal pouch-distal rectal anastomosis.

Bile acid malabsorption is often present in patients after near-total proctocolectomy and ileal pouch-anal canal anastomosis, suggesting ileal dysfunction. Experiments were performed in dogs to compare bile acid absorption after a modified procedure, in which a jejunal pouch was interposed between the terminal ileum and the distal rectum, with that after a conventional ileal pouch operation. Fecal bile acid output (equivalent to hepatic bile acid biosynthesis) and composition were determined by gas chromatography/mass spectrometry in five jejunal pouch dogs and in five ileal pouch dogs more than 6 months after operation. Fecal bile acid output in the jejunal pouch dogs (mean +/- standard deviation) was 215 +/- 59 mg/day (10.1 +/- 2.7 mg/kg-day), a value similar to that obtained in the ileal pouch dogs (261 +/- 46 mg/day [12.8 +/- 3.1 mg/kg-day]; P >0.05). These values were also similar to those reported by others for healthy unoperated dogs, indicating that increased bile acid biosynthesis occurring in response to bile acid malabsorption was not present. Fecal bile acids in pouch dogs were completely deconjugated and extensively 7-dehydroxylated (jejunal pouch = 90.4% dehydroxylated; ileal pouch = 88.6% +/- 6.6% dehydroxylated) and consisted predominantly of deoxycholic acid derivatives. We conclude that when either a jejunal pouch or an ileal pouch is used as a rectal substitute in dogs, an anaerobic pouch flora develops that efficiently deconjugates and dehydroxylates bile acids, rendering them membrane permeable. The resultant passive absorption of unconjugated bile acids appears to compensate for any loss of active ileal absorption of conjugated bile acids, and bile acid malabsorption does not occur.

Absorption↗