deoxycholic-acid and Liver-Diseases

Routine and research techniques are outlined for the analysis of bile acids in serum. The basis of these techniques is the use of liquid-solid extraction and liquid-gel chromatography coupled with the measurement of bile acids by gas chromatography using high resolution glass capillary columns and mass spectrometry which provides increased sensitivity compared with conventional methods of measurement. Problems associated with the isolation and purification of bile acids from serum are discussed and rapid and flexible methods for their metabolic profiling are described. The advantages and applicability of these procedures are illustrated with examples of profiles of bile acids in the serum from normal subjects, patients with liver disease and a patient with an ileal resection.

Topics: Adult; Aged; Bile Acids and Salts; Bile Ducts; Chenodeoxycholic Acid; Child; Child, Preschool; Cholic Acids; Chromatography, Gas; Chromatography, Gel; Deoxycholic Acid; Female; Gas Chromatography-Mass Spectrometry; Humans; Ileum; Lithocholic Acid; Liver Cirrhosis, Biliary; Liver Diseases; Male; Middle Aged

Topics: Bile; Bile Acids and Salts; Biological Transport, Active; Chenodeoxycholic Acid; Child; Child, Preschool; Cholestasis; Cholesterol; Cholic Acids; Deoxycholic Acid; Humans; Infant; Infant Nutrition Disorders; Infant, Newborn; Lithocholic Acid; Liver; Liver Diseases; Malabsorption Syndromes; Surface Properties

Disposition profiles of ursodeoxycholic acid (UDCA) were studied by using a radioimmunoassay measuring serum UDCA after the single i.v. and oral 50 mg dose in five healthy subjects and in five patients with chronic liver disease. The healthy subjects also received single oral doses of 25, 100 and 300 mg of UDCA in a random order. The fasting pre-treatment UDCA concentrations were frequently higher in patients compared with the overall range of values in healthy subjects. The post-treatment concentrations were much higher in patients than in healthy subjects receiving the same i.v. and oral doses. A dose-dependent increase in AUC and Cmax after the oral UDCA doses was observed in normal subjects. The mean UDCA clearance in normal subjects was estimated to be much smaller than that expected and was apparently incompatible with the reported value for the hepatic extraction ratio of UDCA. This discrepancy was explained by an enterohepatic circulation which exists even in the fasting condition. The relationship between the hepatic extraction ratio and a substantial magnitude of enterohepatic circulation was formulated by using two newly defined concepts, hepatic extraction clearance and single path recirculating fraction.

Topics: Administration, Oral; Adult; Aged; Deoxycholic Acid; Enterohepatic Circulation; Female; Humans; Injections, Intravenous; Liver; Liver Diseases; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Radioimmunoassay; Ursodeoxycholic Acid

Golgi protein 73 (GP73) is upregulated in a variety of liver diseases, yet the detailed mechanism is poorly characterized. We analyzed GP73 in a retrospective cohort including 4211 patients with chronic liver disease (CLD) or hepatocellular carcinoma (HCC). The effect of deoxycholic acid (DCA) and nuclear factor-kappa B (NF-κB) on expression and release of GP73 in Huh-7 and SMMC7721 cells were studied. A mouse study was used to confirm our findings in vivo. A positive correlation was found between serum GP73 and total bile acid (TBA) in cirrhotic patients (

Topics: Adult; Animals; Bile Acids and Salts; Carcinoma, Hepatocellular; Cell Line, Tumor; Chronic Disease; Deoxycholic Acid; Female; Fibrosis; Gene Expression Profiling; Humans; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Middle Aged; NF-kappa B p50 Subunit; Phosphoproteins; Retrospective Studies; Up-Regulation

Clinicians sometimes encounter difficulty in choosing a therapeutic strategy due to the uncertainty regarding the type of liver injury. In particular, cholestasis is difficult to diagnose by conventional markers at an early stage of disease. The aim of this study was to identify promising biomarkers for distinguishing the symptom-based types of liver injury (e.g. hepatocellular injury, cholestasis), which was derived from a rigorously statistical perspective. The associations between diagnostic biomarkers (e.g. bile acid components, oxidative stress markers and liver fibrosis markers) and the liver injury types were assessed by a multiple logistic regression analysis using 304 blood samples from patients with liver disease. As a result, reductions in the lithocholic acid (LCA) and deoxycholic acid (DCA) levels, and elevation of the serum sulfated bile acid (SSBA), liver fibrosis marker IV collagen (type IV collagen), hyaluronic acid (HA) and reactive oxygen species (ROS) levels were all significantly associated with cholestasis. On the other hand, elevations in the LCA and type IV collagen levels, and a reduction in the ursodeoxy cholic acid (UDCA) level, were significantly associated with hepatocellular injury. The receiver operating characteristic (ROC) analyses showed that the largest area under the ROC curve (AUC) was found for ROS, followed by DCA, HA, LCA, SSBA and type IV collagen in the cholestatic-type cases. These results indicated that ROS, the secondary bile acid levels such as DCA and LCA, and SSBA are promising biomarkers for cholestasis and for classifying the type of liver injuries. This comprehensive approach will allow for an accurate diagnosis, which will facilitate the selection of an appropriate therapy at the onset of disease.

Topics: Aged; Bile Acids and Salts; Biomarkers; Cholestasis; Collagen Type IV; Deoxycholic Acid; Female; Humans; Hyaluronic Acid; Lithocholic Acid; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Oxidative Stress; Reactive Oxygen Species; Sulfates

To evaluate the fasting and postprandial serum bile acid composition in patients with cystic fibrosis-associated liver disease (CFLD) after chronic administration of ursodeoxycholic acid (UDCA) (20 mg/kg/day). The aim was to specifically focus on the extent of biotransformation of UDCA to its hepatotoxic metabolite, lithocholic acid, because of recent concerns regarding the safety of long-term, high-dose UDCA treatment for CFLD.. Twenty patients with CFLD (median age 16 years, range: 2.4-35.0) prescribed UDCA therapy for at least 2 years were studied. Total and individual serum bile acids were measured by stable-isotope dilution mass spectrometry, in fasting and 2-hour postprandial samples taken during chronic UDCA (20 mg/kg/day) administration.. During chronic UDCA administration (median duration 8 years, IQR: 6-16), UDCA became the predominant serum bile acid in all patients (median, IQR: 3.17, 1.25-5.56 μmol/L) and chenodeoxycholic acid concentrations were greater than cholic acid (1.86, 1.00-4.70 μmol/L vs 0.40, 0.24-2.71 μmol/L). The secondary bile acids, deoxycholate and lithocholate, were present in very low concentrations in fasted serum (<0.05 μmol/L). After UDCA administration, 2-hour postprandial concentrations of both UDCA and chenodeoxycholic acid significantly increased (P < .01), but no significant changes in serum lithocholic acid concentrations were observed.. These data do not support recent suggestions that enhanced biotransformation of UDCA to the hepatotoxic secondary bile acid lithocholic occurs when patients with CFLD are treated with relatively high doses of UDCA.

Topics: Adolescent; Adult; Bile Acids and Salts; Biotransformation; Child; Child, Preschool; Cystic Fibrosis; Deoxycholic Acid; Female; Humans; Lithocholic Acid; Liver Diseases; Male; Tandem Mass Spectrometry; Ursodeoxycholic Acid; Young Adult

Total plasma gamma-glutamyltransferase (GGT) activity is a sensitive, non-specific marker of liver dysfunction. Four GGT fractions (b-, m-, s-, f-GGT) were described in plasma and their differential specificity in the diagnosis of liver diseases was suggested. Nevertheless fractional GGT properties have not been investigated yet. The aim of this study was to characterize the molecular nature of fractional GGT in both human plasma and bile. Plasma was obtained from healthy volunteers; whereas bile was collected from patients undergoing liver transplantation. Molecular weight (MW), density, distribution by centrifugal sedimentation and sensitivity to both detergent (deoxycholic acid) and protease (papain) were evaluated. A partial purification of b-GGT was obtained by ultracentrifugation. Plasma b-GGT fraction showed a MW of 2000 kDa and a density between 1.063-1.210 g/ml. Detergent converted b-GGT into s-GGT, whereas papain alone did not produce any effect. Plasma m-GGT and s-GGT showed a MW of 1,000 and 200 kDa, and densities between 1.006-1.063 g/ml and 1.063-1.210 g/ml respectively. Both fractions were unaffected by deoxycholic acid, while GGT activity was recovered into f-GGT peak after papain treatment. Plasma f-GGT showed a MW of 70 kDa and a density higher than 1.21 g/ml. We identified only two chromatographic peaks, in bile, showing similar characteristics as plasma b- and f-GGT fractions. These evidences, together with centrifugal sedimentation properties and immunogold electronic microscopy data, indicate that b-GGT is constituted of membrane microvesicles in both bile and plasma, m-GGT and s-GGT might be constituted of bile-acid micelles, while f-GGT represents the free-soluble form of the enzyme.

Topics: Bile; Cholesterol; Deoxycholic Acid; Detergents; Exosomes; gamma-Glutamyltransferase; Humans; Immunohistochemistry; Lipoproteins; Liver Diseases; Liver Failure; Molecular Weight; Papain; Peptide Hydrolases; Ultracentrifugation

To investigate the effects of (dietary) glycine against oxidant-induced injury caused by bile duct ligation (BDL).. Either a diet containing 5% glycine or a standard diet was fed to male Sprague-Dawley (SD) rats. Three days later, BDL or sham-operation was performed. Rats were sacrificed 1 to 3 d after BDL. The influence of deoxycholic acid (DCA) in the presence or absence of glycine on liver cells was determined by measurement of calcium and chloride influx in cultivated Kupffer cells and lactate dehydrogenase (LDH) activity was determined in the supernatant of cultivated hepatocytes.. Serum alanine transaminase levels increased to about 600 U/L 1 d after BDL. However, enzyme release was blunted by about two third in rats receiving glycine. Release of the alkaline phosphatase and aspartate aminotransferase was also blocked significantly in the group fed glycine. Focal necrosis was observed 2 d after BDL. Glycine partially blocked the histopathological changes. Incubation of Kupffer cells with DCA led to increased intracellular calcium that could be blocked by incubation with glycine. However, systemic blockage of Kupffer cells with gadolinium chloride had no effects on transaminase release. Incubation of isolated hepatocytes with DCA led to a significant release of LDH after 4 h. This release was largely blocked when incubation with glycine was performed.. These data indicate that glycine significantly decreased liver injury, most likely by a direct effect on hepatocytes. Kupffer cells do not appear to play an important role in the pathological changes caused by cholestasis.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Calcium; Cells, Cultured; Chlorides; Cholagogues and Choleretics; Cholestasis; Deoxycholic Acid; Diet; Disease Models, Animal; Glycine; Glycine Agents; Hepatocytes; Kupffer Cells; L-Lactate Dehydrogenase; Ligation; Liver Diseases; Male; Rats; Rats, Sprague-Dawley

In previous work acute toxic effects of amphotericin B (AB) were reduced in both in vitro and in vivo tests when AB was associated with a triglyceride-rich emulsion (AB-emulsion). The present paper compares the severity of the histopathological alterations as determined by morphometry produced in the target tissues (kidneys, liver, and lungs) by AB-emulsion with those produced by the conventional formulation AB-deoxycholate (DOC) following subacute AB treatment. No morphological alterations were seen in the spleen and heart following both AB-DOC and AB-emulsion treatment. Although the alterations in the liver, kidneys and lungs are basically the same for both formulations, the intensity of the changes varies considerably. AB-emulsion always caused statistically decreased severity of morphologic alterations, compared to AB-DOC by stereological measurements, for the three treatment regimes of AB-administration. These three treatment regimens consisted of 1 mg AB/kg of body weight every 48 hours for 20 days, 2 mg AB/kg of body weight every 48 hours for 12 days, and 2 mg AB/kg of body weight for 4 consecutive days. Thus, these regimens consisted of total doses varying from 8-12 mg/kg of body weight. Specifically, these morphological changes included proximal and distal tubular edema, inflammation and tubular cell degeneration in the kidney and a moderate inflammation of the portal region in the liver. Vacuolization of hepatocytes only occurred for AB-DOC treatment. In addition, acute interstitial inflammation was observed in the lungs prior to interstitial and alveolar edema. The intensity of the histopathological damage increase with the dose and with the reduction in the time interval between AB administrations. Abnormal serum biochemical parameters were observed for serum urea which was higher for both treated AB-groups, as compared to control, and for iron which was lower for the AB-DOC group. In conclusion, the decreased severity of the morphological alterations in the kidneys, liver, and lungs following subacute treatment with AB-emulsion, as compared to AB-DOC formulation, confirms our previous results consisting of acute toxic effects induced by in vitro and in vivo tests with AB-emulsion treatment.

Topics: Amphotericin B; Animals; Antifungal Agents; Chemical and Drug Induced Liver Injury; Deoxycholic Acid; Fat Emulsions, Intravenous; Kidney; Kidney Diseases; Liver; Liver Diseases; Lung; Lung Diseases; Male; Myocardium; Rats; Rats, Wistar; Triglycerides

Modifying effects of fibrosis or a cirrhotic state, caused by treatment with swine serum (SS), on the induction of preneoplastic focal lesions were assessed in a rat medium-term liver bioassay model for the detection of environmental carcinogens, in which the test compound is administered during the promotion phase after initiation with diethylnitrosamine. In experiment I, repeated intraperitoneal administration of SS concomitantly with the hepatopromoting agent deoxycholic acid (DCA) or phenobarbital (PB) resulted in a cirrhotic state and a significant increase in the number or size of preneoplastic glutathione S-transferase placental form (GST-P)-positive liver cell foci as compared to the corresponding DCA or PB alone groups. In experiment II, SS was given prior to commencement of the same medium-term bioassay system, in which a known hepatopromoting agent, DCA, 17-alpha-ethynylestradiol, or 2-acetylaminofluorene, was applied. In this case, the liver did not show obvious cirrhotic change and, rather than any enhancement, slight inhibition of promotion occurred. The results indicate that a coexisting, but not a pre-existing, cirrhotic condition acts to increase growth pressure on GST-P+ preneoplastic foci, and suggest that concomitant administration of SS with the promoting agent could be applied to improve the sensitivity of the assay protocol.

Topics: 2-Acetylaminofluorene; Animals; Blood; Chemical and Drug Induced Liver Injury; Cocarcinogenesis; Deoxycholic Acid; Ethinyl Estradiol; Glutathione Transferase; Injections, Intraperitoneal; Liver; Liver Cirrhosis, Experimental; Liver Diseases; Male; Organ Size; Phenobarbital; Precancerous Conditions; Rats; Rats, Inbred F344; Swine

We evaluated the effect of ursodeoxycholic acid on the defective natural killer activity in primary biliary cirrhosis. Administration of ursodeoxycholic acid (600 mg daily) for one month significantly increased natural killer activity in patients with primary biliary cirrhosis (P < 0.05). Ursodeoxycholic acid also enhanced the in vitro natural killer activity of lymphocytes from healthy volunteers, while other hydrophobic bile acids depressed it. Furthermore, ursodeoxycholic acid reduced the prostaglandin E2 concentration in culture supernatants of lymphocytes from healthy volunteers to a lower level than that in culture incubated with chenodeoxycholic acid (P < 0.05) or control cultures (P < 0.01). Urosdeoxycholic acid normalized the defective natural killer activity in primary biliary cirrhosis by reducing the levels of other hydrophobic bile acids and inhibiting prostaglandin E2 production, suggesting that it may be a useful immunomodulating agent for primary biliary cirrhosis.

Topics: Adult; Aged; Cells, Cultured; Chenodeoxycholic Acid; Cholic Acid; Cholic Acids; Chronic Disease; Deoxycholic Acid; Dinoprostone; Female; Hepatitis C; Humans; Indomethacin; Killer Cells, Natural; Liver Cirrhosis, Biliary; Liver Diseases; Male; Middle Aged; Ursodeoxycholic Acid

We examined the effects of feeding deoxycholic acid (1% and 0.4% of diet), alone and in combination with ursodeoxycholic acid, on serum and biliary bile acid concentrations, hepatic morphology, and the activities and steady-state messenger RNA (mRNA) levels of HMG-CoA reductase and cholesterol 7 alpha-hydroxylase in the rat. Feeding 1% deoxycholic acid increased serum bile acid concentrations (cholestasis), produced portal triad inflammation, bile duct proliferation, and severe hepatocyte necrosis with nuclear pleomorphism. Hepatic damage was prevented when ursodeoxycholic acid (1%) was combined with the deoxycholic acid (1%), or when deoxycholic acid intake was reduced to 0.4%. HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities were markedly inhibited (-56% and -55%, respectively) with either 1% or 0.4% deoxycholic acid. Ursodeoxycholic acid alone produced an insignificant decline in HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities, and when combined with 1% deoxycholic acid did not lessen the inhibitory effect of the latter. Steady-state mRNA levels increased 20-fold for HMG-CoA reductase and 53-fold for cholesterol 7 alpha-hydroxylase in rats fed 1% deoxycholic acid. In contrast, 0.4% deoxycholic acid decreased HMG-CoA reductase mRNA levels 76%, and cholesterol 7 alpha-hydroxylase mRNA levels 82%. Ursodeoxycholic acid alone did not affect HMG-CoA reductase or cholesterol 7 alpha-hydroxylase steady-state mRNA levels. Steady-state mRNA levels and activities of sterol 27-hydroxylase, a key enzyme in the alternative acidic pathway of bile acid synthesis, did not change with either high or low doses of deoxycholic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bile; Bile Acids and Salts; Cell Nucleus; Chemical and Drug Induced Liver Injury; Cholagogues and Choleretics; Cholestanetriol 26-Monooxygenase; Cholesterol 7-alpha-Hydroxylase; Cytochrome P-450 Enzyme System; Deoxycholic Acid; Diet; Hydroxymethylglutaryl CoA Reductases; Liver; Liver Diseases; Male; Necrosis; Rats; Rats, Sprague-Dawley; RNA, Messenger; Steroid Hydroxylases; Ursodeoxycholic Acid

The aim of this study was to define whether N-acetylglucosaminidation is a selective conjugation pathway of structurally related bile acids in humans. The following bile acids released enzymatically from N-acetylglucosaminides were identified: 3 alpha,7 beta-dihydroxy-5 beta-cholanoic (ursodeoxycholic), 3 beta, 7 beta-dihydroxy-5 beta-cholanoic (isoursodeoxycholic), 3 beta,7 beta-dihydroxy-5 alpha-cholanoic (alloisoursodeoxycholic), 3 beta,7 beta-dihydroxy-5-cholenoic, 3 alpha,7 beta,12 alpha-trihydroxy-5 beta-cholanoic, and 3 alpha,6 alpha,7 beta-trihydroxy-5 beta-cholanoic acids. The selectivity of conjugation was studied by administration of 0.5 g ursodeoxycholic (UDCA) or hyodeoxycholic (HDCA) acids, labeled with 13C, to patients with extrahepatic cholestasis, and of 0.5 g of 13C-labeled chenodeoxycholic acid (CDCA) to patients with extra- or intrahepatic cholestasis. After administration of [24-13C]-CDCA, labeled glucosides, and the glucuronide of CDCA were excreted in similar amounts. Labeled N-acetylglucosaminides of UDCA and isoUDCA were also formed. When [24-13C]-UDCA was given, 13C-label was detected in the N-acetylglucosaminide, the glucosides, and the glucuronide of UDCA, and in the N-acetylglucosaminide of isoUDCA. In the patient studied, 32% of the total UDCA excreted in urine was conjugated with N-acetylglucosamine. In contrast, 96% of the excreted amount of [24-13C]HDCA was glucuronidated, and 13C-labeled glucosides but no N-acetylglucosaminide were detected. The selectivity of N-acetylglucosaminidation towards bile acids containing a 7 beta-hydroxyl group was confirmed in vitro using human liver and kidney microsomes and uridine diphosphate glucose (UDP)-N-acetylglucosamine. These studies show that N-acetylglucosaminidation is a selective conjugation pathway for 7 beta-hydroxylated bile acids.

Topics: Acetylglucosamine; Administration, Oral; Bile Acids and Salts; Chenodeoxycholic Acid; Cholestasis; Deoxycholic Acid; Glycosides; Humans; Hydroxylation; Liver Diseases; Mass Spectrometry; Ursodeoxycholic Acid

The biliary bile acid composition was determined for patients with cystic fibrosis and associated liver disease before and after the administration of ursodeoxycholic acid (10 to 15 mg/kg body wt/day). Bile acids were analyzed by fast atom bombardment ionization-mass spectrometry, high performance liquid chromatography and gas chromatography-mass spectrometry after individual bile acids were separated according to their mode of conjugation using the lipophilic anion exchanger, diethylaminohydroxypropyl Sephadex LH-20. More than 50 individual bile acids were identified in the bile of cystic fibrosis patients and these acids were predominantly secreted as glycine and taurine conjugates. Small proportions (less than 8% of the total) of unconjugated and sulfate conjugates were present. Of interest was the identification of two side-chain-elongated (C25) bile acids, homocholic and homochenodeoxycholic acids. After ursodeoxycholic acid was administered, duodenal bile became enriched with the conjugated species of ursodeoxycholic acid (accounting for 11.9% to 32.5% of the total biliary bile acids), but to a lesser extent than reported previously for patients with other liver diseases or gallstones who received comparable doses of ursodeoxycholic acid, and this presumably occurs because of bile acid malabsorption that is a feature of cystic fibrosis. The mean glycine/taurine ratio increased from 2.4 before ursodeoxycholic acid administration to 5 after ursodeoxycholic acid administration even though these patients also received taurine. Despite the relatively low enrichment of the bile by ursodeoxycholic acid, biochemical indices of liver function all improved in these patients after ursodeoxycholic acid administration.

Topics: Adolescent; Bile Acids and Salts; Child; Chromatography, High Pressure Liquid; Cystic Fibrosis; Deoxycholic Acid; Female; Gas Chromatography-Mass Spectrometry; Humans; Liver Diseases; Male; Mass Spectrometry; Ursodeoxycholic Acid

The hydrophilic bile acid ursodeoxycholic acid (UDCA) has recently been shown to improve indexes of liver function in adult patients with various liver diseases. The clinical and biochemical responses to UDCA administration (10 to 15 mg/kg body weight per day) were therefore investigated in nine patients with cystic fibrosis and evidence of liver disease. All patients were receiving pancreatic enzymes and taurine supplementation. Liver function tests were done and serum bile acid concentrations and biliary bile acid composition were determined before and during UDCA therapy; fat balance studies and fecal bile acid excretion were carried out before and 6 months after UDCA treatment. After 2 months of bile acid therapy, biliary bile acid composition was enriched in UDCA from approximately 5% before treatment to 25%, at the expense of cholic and chenodeoxycholic acids, thus making the pool more hydrophilic. This enrichment is lower than that reported for adults with chronic liver diseases. Serum concentrations of UDCA increased significantly but variably. UDCA became the predominant fecal bile acid excreted (12% to 67%), indicating a variable absorption of the administered bile acid. Liver function improved in all patients after 2 to 6 months of therapy, although the degree of improvement (aspartate aminotransferase, -34%; alanine aminotransferase, -41%; gamma-glutamyltranspeptidase, -41% alkaline phosphatase, -19%) was lower than that observed in adults with chronic liver diseases. Mean coefficient of fat absorption and growth rate were, on average, unaffected by UDCA therapy, although an improvement was noted for three patients with greater severity of steatorrhea. The study indicates that UDCA can be used safely in this patient population but that higher doses of UDCA may be of greater benefit in the treatment of the liver disease associated with cystic fibrosis.

Topics: Adolescent; Bile Acids and Salts; Child; Cystic Fibrosis; Deoxycholic Acid; Female; Humans; Liver Diseases; Liver Function Tests; Male; Taurine; Ursodeoxycholic Acid

Effects of the administration of heat treated cells of intestinal lactic acid bacteria were examined in rats fed a deoxycholic acid (DCA) diet. Male Wistar rats were given a 0.25% DCA diet with or without the heat treated cells of Enterococcus faecalis AD 1001 (EFH-1) or Lactobacillus reuteri AD 0002 (LRH-2) for 4 weeks. Abnormal increases in serum GOT, GPT, UN and lipoproteins were observed in the rats fed the DCA diet. Furthermore, severe lesions in the kidney as well as in the liver were found in these rats. On the contrary, the increases in serum GOT, UN, VLDL and LDL were significantly suppressed, and markedly fewer lesions in the liver and the kidney were observed in the rats fed the DCA diet plus EFH-1 or LRH-2.

Topics: Animal Feed; Animals; Chemical and Drug Induced Liver Injury; Deoxycholic Acid; Enterobacteriaceae; Hot Temperature; Kidney Diseases; Lactobacillus; Liver Diseases; Male; Rats; Rats, Inbred Strains

Topics: Bile Acids and Salts; Cholic Acids; Chromatography, Gas; Chromatography, High Pressure Liquid; Deoxycholic Acid; Humans; Intestines; Liver Diseases; Radioimmunoassay; Reference Values; Specimen Handling

Canalicular transport of bilirubin diglucuronide, dibromosulfophthalein and several glutathione conjugates is deficient in mutant TR- rats. In contrast, transport of cholyltaurine (taurocholate), a conjugated bile acid, is normal. Previous studies using normal rats have shown that C23 nor-dihydroxy bile acids are conjugated with sulfate or glucuronide during hepatic transport in contrast to the natural C24 bile acids, which are amidated with glycine or taurine. Studies were performed to test the hypothesis that (a) in the TR- rat, nordeoxycholate would be conjugated with glucuronate or sulfate just as in the normal rat, and (b) that such conjugates would have defective biliary secretion. [C23-14C]Nordeoxycholate was administered intravenously to bile fistula rats (TR- and normal), and the biliary recovery of metabolites was assessed by chromatography and mass spectrometry. In both groups of rats, the major biotransformation product of nordeoxycholate was the side chain (23-ester) glucuronide. Conjugation on the nucleus with sulfate and glucuronide at the 3-position (ethereal linkage) also occurred, as well as amidation at the C23 carboxylic acid group. In the mutant rats, biliary secretion of the 3-sulfate and 3-glucuronide conjugates was less than 10% and 1%, respectively, of that of normal rats, whereas biliary secretion of the 23-ester glucuronide and the 23-taurine amidate, as well as unchanged nordeoxycholate, was not decreased. Canalicular secretion of nor-bile acid 3-ether glucuronides and 3-sulfates appears to involve the "bilirubin transport system," which is deficient in mutant rats. Canalicular secretion of unconjugated, amidated or esterified nordeoxycholate is mediated via another pathway, probably the "bile acid transport system."(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bile Canaliculi; Bile Ducts, Intrahepatic; Biliary Tract; Biological Transport; Biotransformation; Deoxycholic Acid; Liver; Liver Diseases; Male; Rats; Rats, Mutant Strains

Topics: Adult; Biliary Tract; Chronic Disease; Deoxycholic Acid; Female; Humans; Liver; Liver Diseases; Male; Middle Aged; Organometallic Compounds; Organotechnetium Compounds; Pyridoxal; Radionuclide Imaging; Tryptophan; Ursodeoxycholic Acid

Topics: Bile Acids and Salts; Chronic Disease; Deoxycholic Acid; Glucagon; Humans; Liver Cirrhosis; Liver Diseases; Liver Function Tests; Predictive Value of Tests; Ursodeoxycholic Acid

Nor-ursodeoxycholate, the C23 analogue of ursodeoxycholate, is a potent choleretic agent in rodents when given acutely but, to be used in humans, chronic toxicity studies are required. In the rabbit, ingestion of ursodeoxycholate or chenodeoxycholate leads to accumulation of lithocholate, its major bacterial metabolite, in biliary bile acids, which causes inflammation in portal tracts of the liver and bile duct proliferation. To test whether chronic administration of nor-ursodeoxycholate would cause an analogous accumulation of nor-lithocholate and hepatotoxicity, rabbits were fed a Chow diet containing nor-ursodeoxycholate (5 or 50 mg/day): control groups received Chow alone, and "disease control" groups received Chow plus ursodeoxycholate or Chow plus chenodeoxycholate. After 3 wk, animals were killed, liver sections were interpreted by a pathologist, and the steroid moiety of the glycine (and taurine) conjugates of gallbladder bile acids were analyzed by high-pressure liquid chromatography. Ingestion of nor-ursodeoxycholate did not cause hepatotoxicity, and neither it nor its presumed metabolite, nor-lithocholate, accumulated in biliary bile acids. To explain this unexpected finding, the hepatic metabolism of nor-ursodeoxycholate was investigated in biliary fistula rabbits. Nor-ursodeoxycholate was well absorbed from the intestine and secreted in the bile as a glucuronide as well as the unchanged compound, but conjugation with glycine and taurine was not observed. As glucuronides are poorly absorbed from the gut, it is proposed that the hepatic biotransformation of nor-ursodeoxycholate to a glucuronide rather than to a glycine amidate in the liver prevented its accumulation in the bile acid pool. Thus, shortening the side chain of ursodeoxycholate by a single carbon atom resulted in a bile acid with novel metabolism, which when administered chronically, does not accumulate in the enterohepatic circulation and does not cause hepatotoxicity.

Topics: Animals; Bile Acids and Salts; Deoxycholic Acid; Liver; Liver Diseases; Rabbits; Ursodeoxycholic Acid

Topics: Adolescent; Adult; Aged; Bile Acids and Salts; Deoxycholic Acid; Diagnosis, Differential; Evaluation Studies as Topic; Female; Humans; Liver Diseases; Liver Function Tests; Male; Middle Aged; Ursodeoxycholic Acid

Topics: Bile Acids and Salts; Biological Availability; Deoxycholic Acid; Diagnosis, Differential; Hepatitis; Humans; Liver Cirrhosis; Liver Diseases; Liver Function Tests; Ursodeoxycholic Acid

Portal-systemic spill-over of unconjugated ursodeoxycholic acid (UDCA) was assessed in ten healthy subjects, six patients with mild chronic liver disease and eight patients with cirrhosis. Following oral administration of UDCA (1.5 mg/kg body weight), serum concentrations of unconjugated UDCA were measured during 2 h using a capillary gas-liquid chromatographic method. Peak time of UDCA varied from 15 to 30 min, but was not significantly different in the three groups studied. Peak concentration was increased up to two-fold in patients with mild, and up to three-fold in patients with cirrhotic liver disease. Since, in addition, plasma disappearance rate (k) was markedly impaired in cirrhotics (1.7 +/- SD 0.5%/min, compared to 2.8 +/- 0.6 in healthy controls), the calculated area under the curve (AUC) was on the average five-fold that in controls. In two healthy and four cirrhotic subjects, the data obtained after oral administration were compared with those after i.v. loading with the same UDCA dose. The k-values after the two routes of administration were practically identical. Calculated systemic availability was 50% in normals, 78-87% in cirrhotics, 90 and 136% in two patients with surgical porta-caval shunt. It is concluded that the portal-systemic spill-over of UDCA in patients with liver disease is increased primarily due to portal-systemic shunting. Since in the normal liver hepatic extraction of conjugated, endogenous bile acids is greater than 80%, diminished first-pass elimination is expected to augment systemic concentrations even more, particularly when measured after a meal.

Topics: Adult; Bile Acids and Salts; Chronic Disease; Deoxycholic Acid; Female; Humans; Kinetics; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Ursodeoxycholic Acid

Topics: Bile Acids and Salts; Deoxycholic Acid; Humans; Liver Diseases; Ursodeoxycholic Acid

The hepatotoxic effects of cholelitholytic bile acids, ursodeoxycholic and chenodeoxycholic acids, were compared with each other and with those of lithocholic acid, a known hepatotoxic bile acid, in the rabbit. Male New Zealand white rabbits were fed regular laboratory chow containing ursodeoxycholic, chenodeoxycholic, or lithocholic acid at a concentration of 0.5 per cent (w/w) for 14 days. The control group was fed the chow without added bile acids. The mortality rate was highest (six of 12) in the lithocholate group, intermediate (two of eight) in the chenodeoxycholate group, and lowest (none of six) in the ursodeoxycholate group. Light microscopy of the liver revealed fibrosis, inflammation, and bile duct proliferation in the portal regions in the three experimental groups; however, the lesions in the lithocholate and chenodeoxycholate groups were more severe and often associated with periportal extension of fibrosis and focal necrosis of the parenchyma. In addition, electron microscopy revealed distortion of bile canaliculi, conspicuous bundles of intermediate-sized filaments, expansion of pericanalicular cytoplasmic matrix due to apparent accumulation of microfilaments, prominence of lysosomes, and fragmentation of cisternae of the rough endoplasmic reticulum. These ultrastructural changes were less marked and often absent in the ursodeoxycholate group. The serum L-alanine aminotransferase activity increased 5- to 6-fold in the lithocholate and chenodeoxycholate groups, whereas it remained less than 2-fold of the control level in the ursodeoxycholate group on day 14. The serum lithocholate concentration was markedly elevated to comparable levels in all three groups, whereas ursodeoxycholate was highly increased in the ursodeoxycholate group but undetectable in the other groups at the time of sacrifice. It is concluded that (1) although the oral administration of three bile acids induces hepatic injuries in the rabbit, ursodeoxycholate causes less severe injury than do the other two, (2) the advantage of ursodeoxycholate versus chenodeoxycholate is probably relative rather than absolute, (3) lithocholate formed through metabolic conversion from ursodeoxycholate may be responsible for the most part for hepatotoxicity, and (4) it is possible that the concurrent presence of ursodeoxycholate may mitigate lithocholate's hepatotoxicity.

Topics: Animals; Bile Canaliculi; Body Weight; Chemical and Drug Induced Liver Injury; Chenodeoxycholic Acid; Cytoskeleton; Deoxycholic Acid; Lithocholic Acid; Liver; Liver Diseases; Prognosis; Rabbits; Ursodeoxycholic Acid

Topics: Bile Acids and Salts; Deoxycholic Acid; Drug Tolerance; Humans; Liver Diseases

Topics: Biliary Tract Diseases; Deoxycholic Acid; Drug Tolerance; Humans; Liver Diseases; Radioimmunoassay; Ursodeoxycholic Acid

The plasma cholic acid, chenodesoxycholic acid and desoxycholic acid levels were studied by spectrofluoremetry in 153 cases. The values of 67 controls with no evidence of hepatobiliary or intestinal disease were compared with those of 86 patients with liver and biliary tract disease. The fasting values failed to provide more diagnostic information than did conventional laboratory assays. Plasma bile acid concentrations exceeding 2.5 mu mol/l are conclusive of liver or biliary disease. A cholic acid/chenodesoxycholic acid quotient higher than 1.0 is a sign of cholestasis. Estimation of bile acids after food intake was found more informative. The plasma cholic acid- and chenodesoxycholic acid levels underwent a considerable increase 1 to 2 hours after meals. A more marked increase of chenodesoxycholic acid than of cholic acid (the ratio of the two being in excess of 1.0) is indicative of cholestasis and is most marked in primary biliary cirrhosis.

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholestasis; Cholic Acids; Deoxycholic Acid; Diagnosis, Differential; Humans; Liver Cirrhosis, Biliary; Liver Diseases; Spectrometry, Fluorescence

Topics: Administration, Oral; Bile Acids and Salts; Deoxycholic Acid; Fasting; Humans; Liver Diseases; Ursodeoxycholic Acid

During the last years bile acids have gained more and more clinical importance. They play a decisive part in intestinal fat resorption. Increased bile acid content in the colon will result in diarrhea. By determination of serum bile acids the liver function can be judged exactly. It seems probable that bile acids take part in the pathogenesis of gastritis gastric ulcer and colonic cancer. By administration of chenodeoxycholic acid and ursodeoxycholic acid dissolution of cholesterol stones within the gall bladder is possible.

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Colonic Neoplasms; Deoxycholic Acid; Gastritis; Humans; Intestinal Absorption; Liver Diseases; Oxalates; Stomach Ulcer

Individual serum bile acids were analysed by an improved gas liquid chromatography method in 12 patients with primary hyperlipidaemia. Total serum bile acid concentrations were raised in 10 subjects. Ursodeoxycholic acid was found in all 12 patients. It was present in significantly greater concentrations, accounted for a greater proportion of the total serum bile acids, and occurred more frequently than in patients with various forms of hepatobiliary disease. Patients with hyperlipidaemia had proportionately less deoxycholic acid than controls but more than patients with liver disease. There was proportionately less chenodeoxycholic acid in patients with hypercholesterolaemia, in whom the primary bile acid ratio was raised.

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholic Acids; Deoxycholic Acid; Humans; Hyperlipidemias; Liver Diseases

The level of the four major bile acids was measured in the plasma using gas liquid chromatography. The enhancement of the level of the primary bile acids was well known during bile duct obstruction. In the case of hepatic diseases, the chenodesoxycholiccholic acid concentration ratio (CDC/C) was equal or lower than unity when cholestasis occurred rather than hepatic deficiency. When hepatic deficiency developed, the ratio CDC/C was higher than unity. Plasma bile acid fractionnation exhibits also a prognostic value. When the ratio CDC/C is very high, it is significant of progressive hepatic deficiency. A high level of lithocholic acid is also a sign of unfavourable prognosis.

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholic Acids; Chromatography, Gas; Deoxycholic Acid; Hepatitis, Viral, Human; Humans; Lithocholic Acid; Liver Cirrhosis; Liver Diseases

The value of serum bile acids (SBA) in the diagnosis of hepatobiliary disease has been investigated. A modified GLC method was used, with an overall coefficient of variation of +/- 11% in the control range. Serum was obtained after a 12 hour fast, and two hours after a fatty meal from 73 patients and 14 control subjects. In controls the total fasting SBA of 2.17 +/- 0.86 mumol/l increased significantly (p less than 0.001) to 3.81 +/- 1.14 mumol/l after a meal. All icteric patients had raised SBA, but in 23 anicteric patients there was no significant difference in the detection of chronic liver disease by fasting SBA, postprandial SBA, AST, or gamma GTP. Compared with controls, serum in patients contained proportionately less deoxycholic acid (p less than 0.001), there was proportionately more cholic acid in extrahepatic obstruction (p less than 0.001), and proportionately more chenodeoxycholic acid in patients with cirrhosis, viral hepatitis, and neoplasia (p less than 0.001). In control subjects, the fasting cholic:chenodeoxycholic acid ratio ranged from 0.5-1.0, and differed significantly (p less than 0.001) from patients with extrahepatic obstruction 0.96-3.6, and cirrhosis 0.1-0.5. It is concluded that serum bile acids measured by sensitive methods can provide useful diagnostic information.

Topics: Bile Acids and Salts; Biliary Tract Diseases; Chenodeoxycholic Acid; Cholic Acids; Deoxycholic Acid; Humans; Liver Diseases; Liver Function Tests

To investigate the possibility that bowel-related liver disease is due to accumulation of abnormal bile acids in the enterohepatic circulation, bile acids have been measured in gall-bladder bile and portal blood of patients with chronic bowel disease, none of whom had liver disease. There was no difference in the composition and concentration of bile acids in bile and portal blood compared with control patients. In a second study, serum bile acid composition and concentrations were similar in two groups of patients with liver disease, whether they had bowel disease or not. In a further study, post-prandial serum bile acid concentrations were not elevated in a group of patients with chronic bowel disease, making it unlikely that subcliical liver disease was present. No evidence has been found to support the hypothesis that bowel-related liver disease in man results from the action of abnormal bile acids.

Topics: Adult; Aged; Bile; Bile Acids and Salts; Cholangitis; Cholic Acids; Chronic Disease; Colitis, Ulcerative; Crohn Disease; Deoxycholic Acid; Enterohepatic Circulation; Female; Humans; Lithocholic Acid; Liver Cirrhosis; Liver Diseases; Male; Middle Aged

A sensitive radioimmunoassay for cholylglycine, chenodeoxycholylglycine, deoxycholylglycine, and sulfolithocholylglycine was established using antibodies obtained from rabbits injected with albumin conjugates of these bile acids. Glycine-conjugated bile acid levels were measured in sera from 25 control subjects and 110 patients who had hepatic disease (alcoholic cirrhosis, hepatitis, cholestasis, and hepatic malignancy). Sulfolithocholylglycine was elevated in the sera of all 110 patients with hepatic disease. Cholylglucine was within normal range in only three. Chenodeoxycholylglycine was elevated in most sera of patients who had hepatitis, cholestasis, or hepatic malignancy. It was normal in most sera of patients who had alcoholic cirrhosis, suggesting that chenodeoxycholic acid may be subject to further biotransformations in these patients. Deoxycholylglycine was elevated in a minority of patients, none of whom had cholestasis. The data suggest that serum bile acids, particularly sulfolithocholylglycine, are a highly sensitive index for hepatic dysfunction.

Topics: Alcoholism; Biliary Tract Diseases; Chenodeoxycholic Acid; Cholestasis; Cholic Acids; Deoxycholic Acid; Glycocholic Acid; Hepatitis; Humans; Lithocholic Acid; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Radioimmunoassay

Large amounts of bile acid sulfate were found in the urine of patients with hepatobiliary diseases. In patients with acute hepatitis, daily excretion of bile acid into urine was 68.24 plus or minus 51.80 mumoles per day, and the percentage of sulfated bile acid was 83.4 plus or minus 16.7%. In patients with chronic hepatitis and cirrhosis, a slight increase of urinary bile acid was observed (2.89 plus or minus 2.69 and 5.27 plus or minus 4.28 mumoles per day, respectively), and the percentage of sulfated bile acid was 73.9 plus or minus 28.6 and 44.6 plus or minus 30.4%, respectively. In patients with obstructive jaundice, a moderate increase of urinary bile acid was found (32.62 plus or minus 18.35 mumoles per day), and the percentage of sulfated bile acid was 58.3 plus or minus 22.6%. In patients with hepatobiliary diseases, the elevation of both levels of sulfated and nonsulfated bile acids in serum was observed. The percentage of sulfated bile acid was 9% in normal serum, and varied from zero to 82.8% in pathological sera. A remarkable increase of sulfated bile acid was found in patients with obstructive juandice and acute hepatitis, while a slight elevation was found in patients with chronic hepatitis and cirrhosis. Sulfated bile acid in bile was nonexistent or below 0.5% of total bile acid. According to these findings, the increased bile acid in serum of patients with hepatobiliary diseases might be more easily excreted into the urine as sulfated bile acid.

Topics: Bile Acids and Salts; Biliary Tract Diseases; Carbon Radioisotopes; Chenodeoxycholic Acid; Cholestasis; Cholic Acids; Chromatography, Gas; Deoxycholic Acid; Female; Hepatitis; Humans; Liver Cirrhosis; Liver Diseases; Male; Sulfates

Topics: Adult; Bile; Bile Acids and Salts; Bilirubin; Chenodeoxycholic Acid; Cholic Acids; Deoxycholic Acid; Fatty Liver; Female; Glycine; Humans; Ileum; Jejunum; Lithocholic Acid; Liver; Liver Cirrhosis; Liver Diseases; Male; Obesity; Postoperative Complications; Protein Deficiency; Sulfuric Acids; Taurine

Topics: Acute Disease; Adolescent; Adult; Bile; Bile Acids and Salts; Biliary Fistula; Chenodeoxycholic Acid; Cholic Acids; Deoxycholic Acid; Glycocholic Acid; Hepatitis A; Humans; Liver; Liver Cirrhosis; Liver Diseases; Middle Aged; Taurocholic Acid

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.

Topics: Adult; Aged; Ascites; Bile Acids and Salts; Chenodeoxycholic Acid; Cholic Acids; Deoxycholic Acid; Hepatic Encephalopathy; Humans; Kinetics; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Varicose Veins

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholestasis; Cholic Acids; Chronic Disease; Deoxycholic Acid; Hepatic Encephalopathy; Hepatitis; Humans; Lithocholic Acid; Liver Cirrhosis; Liver Diseases

Topics: Adult; Aged; Bile Acids and Salts; Biliary Tract Diseases; Chenodeoxycholic Acid; Cholestasis; Cholic Acids; Chromatography, Gel; Chromatography, Ion Exchange; Deoxycholic Acid; Female; Glycocholic Acid; Humans; Liver Diseases; Liver Function Tests; Male; Middle Aged; Sulfuric Acids; Taurocholic Acid

Topics: Cholesterol; Deoxycholic Acid; Flocculation Tests; Liver Diseases; Liver Function Tests; Phosphatidylethanolamines