deoxycholic-acid and Cholestasis--Intrahepatic

Topics: Cholestasis, Intrahepatic; Chronic Disease; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Basis on study through integrated comparative assessment of clinical, biochemical survey data revealed that in patients with impaired metabolism of uric acid in a greater percentage of common biliary sludge, a violation of the rheological properties of bile, a violation of cholate-cholesterol ratio index, which indicates an increased risk of bile stones. The study found that despite the high levels of uric acid there is a violation of the spectrum of bile acids, cholic and deoxycholic growth acid reduction taurocholic acid. Thus, application of ursodeoxycholic acid, rosuvastatin and allopurinol in these study patients with NAFLD dosages in combination with hyperuricemia improves the clinical symptoms and normalization of biochemical parameters and normalizes the spectrum of biliary acids.

Topics: Adult; Allopurinol; Bile; Cholagogues and Choleretics; Cholestasis, Intrahepatic; Cholesterol; Cholic Acid; Deoxycholic Acid; Drug Therapy, Combination; Duodenoscopy; Female; Fluorobenzenes; Humans; Hyperuricemia; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Pyrimidines; Rosuvastatin Calcium; Sulfonamides; Taurocholic Acid; Uric Acid; Ursodeoxycholic Acid

The total bile acid (TBA) concentration criterion for diagnosing intrahepatic cholestasis of pregnancy varies in the published literature. The purpose of this study was to establish pregnancy-specific reference ranges for the TBA concentration among Latina women.. Self-identified Latina women (n = 211) over 18 years of age with a singleton pregnancy were recruited and had random serum samples drawn during the second and third trimesters. The total and fractionated bile acid concentrations were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and reference ranges were calculated. Laboratory-provided general reference ranges from a general population of adult men and nonpregnant women were used for comparison.. The TBA reference range for our Latina pregnant population (<8.5 µmol/L) was markedly lower than the laboratory-provided reference range (4.5 to 19.2 µmol/L).. These data suggest that the upper TBA concentration reference range in our Latina pregnant population is 8.5 µmol/L, based on LC-MS/MS measurements.

Topics: Adult; Bile Acids and Salts; Case-Control Studies; Chenodeoxycholic Acid; Cholestasis, Intrahepatic; Cholic Acid; Chromatography, Liquid; Deoxycholic Acid; Female; Hispanic or Latino; Humans; Male; Pregnancy; Pregnancy Complications; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Reference Values; Tandem Mass Spectrometry; Young Adult

Progressive familial intrahepatic cholestasis type 2 (PFIC2) is caused by hereditary mutations of bile salt export pump (BSEP), such as E297G BSEP, which is a folding-defective mutant that is unable to traffic beyond the endoplasmic reticulum (ER). 4-Phenylbutyric acid (4-PBA) enhances the cell surface expression and transport capacity of E297G BSEP, but has a relatively high dose (1mM or more) is required to show the effect. Here, we show that bile acids possibly act as pharmacological chaperones, promoting the proper folding and trafficking of E297G BSEP. We also describe the discovery and structural development of non-steroidal compounds with potent pharmacological chaperone activity for E297G BSEP.

Topics: Amino Acid Substitution; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Biological Transport; Cell Line; Cholestasis, Intrahepatic; Dogs; Drug Evaluation, Preclinical; Endoplasmic Reticulum; Gene Expression; Isoxazoles; Mutation; Phenylbutyrates; Structure-Activity Relationship

ICP (intrahepatic cholestasis of pregnancy) is characterized by pruritus and biochemical cholestasis, including raised SBAs (serum bile acids) and, usually, elevated aminotransferases levels. However, AHP (asymptomatic hypercholanaemia of pregnancy) is defined as the presence of total SBA levels above the cut-off value (11 microM) in healthy pregnant women, thus elevation of total SBAs do not necessarily reflect an ICP condition. The aim of the present study was to describe clinical, obstetric, perinatal and biochemical findings, as well as the SBA profile, in pregnant women studied in the third trimester of pregnancy in order to define characteristic patterns of individual bile acids that enable women with ICP to be distinguished from AHP and healthy pregnancies. Free and conjugated ursodeoxycholic (UDCA), cholic (CA), lithocholic (LCA), deoxycholic (DCA) and chenodeoxycholic (CDCA) acids were evaluated by CE (capillary electrophoresis) in 41 patients (15 of them simultaneously by HPLC), in 30 healthy pregnant women and in 10 non-pregnant women. A highly significant correlation between CE and HPLC for total SBAs (r=0.990) and for individual SBAs was found. Normal pregnant women had higher total SBA levels than non-pregnant women (due to an increase in taurine-conjugated dihydroxy SBAs). Women with ICP had higher levels of total SBAs, the free/conjugated ratio, LCA, CA, CDCA and DCA than normal pregnant women. Newborns from women with ICP had lower birth weight and gestational age. Women with AHP had higher levels of conjugated dihydroxy SBAs than normocholanaemic patients, without any evidence of a clinical difference. In conclusion, the present study has shown a clear difference in SBA profiles between ICP and normal pregnancies (including AHP), involving a shift towards a characteristic hydrophobic composition in women with ICP.

Topics: Adult; Bile Acids and Salts; Biomarkers; Birth Weight; Case-Control Studies; Chenodeoxycholic Acid; Chi-Square Distribution; Cholestasis, Intrahepatic; Cholic Acid; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Deoxycholic Acid; Electrophoresis, Capillary; Female; Gestational Age; Humans; Infant, Newborn; Lithocholic Acid; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Trimester, Third; Ursodeoxycholic Acid

Bile salts (BSs) stimulate cholangiocyte proliferation in vitro and in vivo in normal rats. In this study, we evaluated the effects of BS-enriched diets on cholangiocyte proliferative activity already triggered by partial bile-duct ligation (pBDL), a surgical model that induces mild cholestatic conditions, focusing our attention on ursodeoxycholate (UDC).. Animals (n=45) were fed either a standard diet, or a 0.2% deoxycholate- or 0.2% UDC-enriched diet for 4 weeks. Then, in each group, ten animals underwent pBDL and five underwent sham operation. Serum and biliary BS levels, serum cholestasis and cytolysis indexes, as well as liver conventional histology, apoptosis and proliferative activity were evaluated 48 h after the operation.. Animals that underwent pBDL showed sustained proliferative response compared with sham-operated rats. BS-enriched diets did not influence cholangiocyte proliferation in sham-operated rats. However, significantly increased proliferation was observed in pBDL rats fed a UDC-enriched diet. The evaluation of humoral and histological parameters excluded the possibility that the increased proliferation induced by UDC-enriched diet could be related to concomitant liver cell damage.. A UDC-enriched diet is able to amplify the magnitude of the cholangiocyte hyperplastic process, which occurs by a stimulatory mechanism after partial bile-duct ligation.

Topics: Administration, Oral; Animals; Bile Ducts; Cell Division; Cholagogues and Choleretics; Cholestasis, Extrahepatic; Cholestasis, Intrahepatic; Deoxycholic Acid; Diet; Disease Models, Animal; Ligation; Liver; Liver Function Tests; Proliferating Cell Nuclear Antigen; Rats; Rats, Inbred F344; Ursodeoxycholic Acid

The efficiency of bile acid conjugation before and during therapy with 600 mg/day of ursodeoxycholic acid was measured in seven adult patients with early chronic cholestatic liver disease (6 with primary biliary cirrhosis; 1 with primary sclerosing cholangitis). Duodenal bile samples were obtained by aspiration and the proportion of unconjugated bile acids was determined using lipophilic anion exchange chromatography to separate bile acid classes, followed by analysis of individual bile acids by gas chromatography-mass spectrometry. The proportion of conjugated bile acids was determined by high-performance liquid chromatography. Use of a (99m)Tc-HIDA recovery marker permitted the absolute mass of unconjugated bile acids in the gallbladder to be calculated. Unconjugated bile acids comprised 0.4% of total biliary bile acids before and 0.2% during ursodeoxycholic acid therapy, indicating highly efficient conjugation of bile acids. During therapy, percentage unconjugated ursodeoxycholic acid significantly increased from (mean +/- S.D.) 13 +/- 13% to 54 +/- 12%; P < 0.002. When the unconjugated and conjugated fractions of bile acids were compared, there was an enrichment in unconjugated fraction for cholic acid and ursodeoxycholic acid and a depletion for chenodeoxycholic acid both in basal condition and during ursodeoxycholic acid therapy, suggesting that hydrophilic bile acids were conjugated less efficiently. During therapy, the conjugation efficiency significantly increased for cholic acid and ursodeoxycholic acid. The pretreatment mass of total unconjugated bile acids in the gallbladder was (mean +/- S.D.) 4.4 +/- 3.2 mumol, and was not significantly changed by ursodeoxycholic acid therapy (6.2 +/- 3.5 mumol). However, ursodeoxycholic acid therapy caused a significant increase in the mass of unconjugated ursodeoxycholic acid. It is concluded that endogenous bile acids and exogenous ursodeoxycholic acid when given at the usual dose are efficiently conjugated in patients with early cholestatic liver disease. Despite showing increased biliary unconjugated ursodeoxycholic acid during its oral administration, our data do not lend support to the occurrence of hypercholeresis due to cholehepatic shunting of bile acids.

Topics: Adult; Bile Acids and Salts; Chenodeoxycholic Acid; Cholestasis, Intrahepatic; Cholic Acid; Cholic Acids; Chromatography, High Pressure Liquid; Deoxycholic Acid; Gallbladder; Gas Chromatography-Mass Spectrometry; Humans; Imino Acids; Organotechnetium Compounds; Technetium Tc 99m Lidofenin; Ursodeoxycholic Acid

Topics: Adult; Arteriosclerosis; Cholestasis, Intrahepatic; Chronic Disease; Deoxycholic Acid; Female; Humans; Lipoprotein(a); Lipoproteins; Male; Middle Aged; Risk Factors; Ursodeoxycholic Acid

Topics: Bile Acids and Salts; Bilirubin; Cholestasis, Intrahepatic; Deoxycholic Acid; Follow-Up Studies; Humans; Liver Cirrhosis, Biliary; Liver Function Tests; Peptide Fragments; Procollagen; Ursodeoxycholic Acid

Topics: Adult; Cholestasis, Intrahepatic; Deoxycholic Acid; Female; Humans; Recurrence; Ursodeoxycholic Acid

Ursodeoxycholic acid (UDCA) was administered to 16 intrahepatic cholestasis patients with severe jaundice, and its clinical effects were studied. As a result, it was remarkably effective in 6 patients, significantly effective in 5 patients, slightly effective in 2 patients and unchanged in 3 patients. As for the dose, when 600 mg/day was administered, it was effective in all patients, but even when only 150 mg/day was administered, it was effective in one patient (50%). Duration of treatment was 15 to 177 days with a mean of 55.3 days. These results suggested that while there is no adequate treatment for intrahepatic cholestasis with severe jaundice, UDCA should be considered as a possible method of treatment.

Topics: Adult; Aged; Aged, 80 and over; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Deoxycholic Acid; Dose-Response Relationship, Drug; Female; Humans; Jaundice; Male; Middle Aged; Ursodeoxycholic Acid

When a lymphokine, the cholestatic factor, is intravenously injected into rats through a mesenteric vein, remarkable reductions in bile flow and bile acid excretion are observed. Using this experimentally-induced intrahepatic cholestasis model, the choleretic effects of ursodeoxycholic acid (UDCA) were studied. When UDCA was injected with the cholestatic factor, the reductions in bile flow and bile acid excretion were significantly suppressed. Remarkable choleretic effects were also noted, when UDCA was administered to normal rats. These results suggested that UDCA may be effective in the treatment of intrahepatic cholestasis.

Topics: Animals; Bile; Bile Acids and Salts; Cholagogues and Choleretics; Cholestasis, Intrahepatic; Deoxycholic Acid; Guinea Pigs; Male; Rats; Rats, Inbred Strains; Ursodeoxycholic Acid

Topics: Cholestasis, Intrahepatic; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Topics: Adult; Aged; Bilirubin; Cholestasis, Intrahepatic; Deoxycholic Acid; Drug Resistance; Female; Half-Life; Humans; Male; Middle Aged; Prednisolone; Ursodeoxycholic Acid

Topics: Adult; Aminopyrine; Cholestasis, Intrahepatic; Deoxycholic Acid; Dipyrone; Humans; Male; Ursodeoxycholic Acid

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholestasis, Intrahepatic; Cholic Acids; Deoxycholic Acid; Female; Humans; Liver Function Tests; Pregnancy; Pregnancy Complications

Nineteen patients suffering from the intrahepatic cholestasis (IHC) of pregnancy were studied. Twelve of them were treated with phenobarbital (100 mg/day) and seven with cholestyramine (18 g/day). The overnight fasting levels of serum cholic acid (CA), chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) were measured by radioimmunoassay. The activities of serum transaminases, gamma-glutamyltranspeptidase, alkaline phosphatase and total and conjugated bilirubins were also analyzed. It was found that there was no correlation between the itching symptom and the serum bile acid levels. During phenobarbital treatment serum bile acid concentrations did not change. Also, the other measured parameters as well as the CA/CDCA ratio did not change significantly. Transaminases had, however, a slight tendency to decrease. The therapy successfully relieved itching in half of the cases. There was no relationship between the relief of the itching and the change in the bile acid concentrations. Cholestyramine treatment did not decrease the CA level significantly, but that of the CDCA decreased (P less than 0.05) and the ratio of CA/CDCA increased (P less than 0.05). In the other analyzed liver function test results, an increase (P less than 0.05) occurred only in the concentrations of conjugated bilirubin. The itching was relieved in five of the seven cases during the first week of treatment, but after that the symptom tended to reappear. There was a slight correlation between the decrease in the CDCA level and in the relief of the itching. The two drugs did not cause any particular side effects.

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholestasis, Intrahepatic; Cholestyramine Resin; Cholic Acids; Deoxycholic Acid; Female; Humans; Liver Function Tests; Phenobarbital; Pregnancy; Pregnancy Complications; Pruritus

Topics: Animals; Bile; Bile Ducts; Cholestasis, Intrahepatic; Deoxycholic Acid; Graft Rejection; Histocompatibility Antigens; Liver Transplantation; Postoperative Complications; Swine; Ursodeoxycholic Acid

Two primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), and one secondary bile acid, deoxycholic acid (DCA), were measured by radioimmunoassay in pregnancy serum from 30 healthy women, 49 women with itching and 45 with intrahepatic cholestasis of pregnancy. All subjects were studied serially from between 16 and 20 weeks gestation until 35-60 days post partum. In healthy pregnant women, serum CA and DCA levels did not change significantly at any time. The mean CDCA level rose significantly towards term. In women with intrahepatic cholestasis, serum levels of CA and CDC were increased ten- and five-fold, respectively, at the time of appearance of clinical symptoms and the CA/CDCA ratio rose from 1/1 to 2/1; there was also a moderate increase in the serum concentration of DCA. In 4 of 8 women studied prospectively an increase in serum bile acid levels preceded the appearance of symptoms or other laboratory evidence of intrahepatic cholestasis. Nine of the women with itching with normal routine liver function test results had increases in serum CA and CDCA concentrations suggesting mild cholestasis.

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholestasis, Intrahepatic; Cholic Acids; Deoxycholic Acid; Female; Humans; Postpartum Period; Pregnancy; Pregnancy Complications; Pruritus

The metabolism of 14C-labeled chenodeoxycholic, cholic, and deoxycholic acids was studied in patients with intrahepatic cholestasis. Radioactively labeled metabolites were isolated from urine and were identified by gas-liquid chromatography-mass spectrometry. About 5% of the radioactivity was recovered in urine after administration of labeled chenodeoxycholic acid to a patient with mild intrahepatic cholestasis. In urine collected 0-24 hr after the injection, 20% of the radioactivity appeared in the combined glycine and taurine conjugate fractions, and the predominant metabolite in these fractions was identified as hyocholic acid. Eighty percent of the activity was eluted in the sulfate fraction presumably representing mainly sulfated chenodeoxycholic acid conjugates. Twenty percent of the radioactivity was recovered in urine following administration of labeled cholic acid to a patient with biliary cirrhosis and severe cholestasis. In urine collected on the fifth day, half of this radioactivity appeared in the glycine and taurine conjugate fractions, and 10% of this activity was present as tetrahydroxycholanoates. The major metabolites in this fraction were 3 alpha, 6 alpha, 7 alpha, 12 alpha-tetrahydroxy-5 beta- and 1 xi, 3 alpha, 7 alpha, 12 alpha-tetrahydroxy-5 beta-cholanoic acids. The former compound constituted about 50% of the tetrahydroxycholanoates. Three additional minor tetrahydroxy bile acids were present, one of which was tentatively identified as 6 beta-hydroxycholic acid. About 5% of the radioactivity appeared in urine after oral administration of labeled deoxycholic acid to a patient with mild intrahepatic cholestasis. Twenty-two percent of the activity appeared in the glycine and taurine conjugate fractions isolated from urine collected on the second day after the administration. About 75% of this activity was associated with trihydroxycholanoates. The main metabolite was 1 beta-hydroxydeoxycholic acid with small amounts of, tentatively, 6 alpha-hydroxydeoxycholic acid.

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholestasis, Intrahepatic; Cholic Acids; Deoxycholic Acid; Female; Gas Chromatography-Mass Spectrometry; Humans; Hydroxylation; Male