Ursodeoxycholic Acid (ursodeoxycholic + acid)

Distribution by Scientific Domains
Distribution within Medical Sciences

Selected Abstracts

Ursodeoxycholic acid treatment of idiopathic thrombocytopenic purpura with liver dysfunction

Michiaki Koike
Abstract: Ursodeoxycholic acid (UDCA) is known to reduce immunoglobulin from B cells and cytokine production from T cells. We found that UDCA increased the platelet count in two idiopathic thrombocytopenic purpura (ITP) patients who have liver dysfunction. UDCA was tolerated and did not cause diarrhea in the amounts used. Further investigation is needed to evaluate the effectiveness of UDCA in ITP patients. [source]

Induction of avian musculoaponeurotic fibrosarcoma proteins by toxic bile acid inhibits expression of glutathione synthetic enzymes and contributes to cholestatic liver injury in mice,

HEPATOLOGY, Issue 4 2010
Heping Yang
We previously showed that hepatic expression of glutathione (GSH) synthetic enzymes and GSH levels fell 2 weeks after bile duct ligation (BDL) in mice. This correlated with a switch in nuclear anti-oxidant response element (ARE) binding activity from nuclear factor erythroid 2,related factor 2 (Nrf2) to c,avian musculoaponeurotic fibrosarcoma (c-Maf)/V-maf musculoaponeurotic fibrosarcoma oncogene homolog G (MafG). Our current aims were to examine whether the switch in ARE binding activity from Nrf2 to Mafs is responsible for decreased expression of GSH synthetic enzymes and the outcome of blocking this switch. Huh7 cells treated with lithocholic acid (LCA) exhibited a similar pattern of change in GSH synthetic enzyme expression as BDL mice. Nuclear protein levels of Nrf2 fell at 20 hours after LCA treatment, whereas c-Maf and MafG remained persistently induced. These changes translated to ARE nuclear binding activity. Knockdown of c-Maf or MafG individually blunted the LCA-induced decrease in Nrf2 ARE binding and increased ARE-dependent promoter activity, whereas combined knockdown was more effective. Knockdown of c-Maf or MafG individually increased the expression of GSH synthetic enzymes and raised GSH levels, and combined knockdown exerted an additive effect. Ursodeoxycholic acid (UDCA) or S-adenosylmethionine (SAMe) prevented the LCA-induced decrease in expression of GSH synthetic enzymes and promoter activity and prevented the increase in MafG and c-Maf levels. In vivo knockdown of the Maf genes protected against the decrease in GSH enzyme expression, GSH level, and liver injury after BDL. Conclusion: Toxic bile acid induces a switch from Nrf2 to c-Maf/MafG ARE nuclear binding, which leads to decreased expression of GSH synthetic enzymes and GSH levels and contributes to liver injury during BDL. UDCA and SAMe treatment targets this switch. (HEPATOLOGY 2010.) [source]

Nuclear translocation of UDCA by the glucocorticoid receptor is required to reduce TGF-,1,induced apoptosis in rat hepatocytes,

HEPATOLOGY, Issue 4 2005
Susana Solá
Ursodeoxycholic acid (UDCA) inhibits classical mitochondrial pathways of apoptosis by either directly stabilizing mitochondrial membranes or modulating specific upstream targets. Furthermore, UDCA regulates apoptosis-related genes from transforming growth factor ,1 (TGF-,1),induced hepatocyte apoptosis by a nuclear steroid receptor (NSR),dependent mechanism. In this study, we further investigated the potential role of the glucocorticoid receptor (GR) in the antiapoptotic function of UDCA. Our results with short interference RNA (siRNA) technology confirmed that UDCA significantly reduces TGF-,1,induced apoptosis of primary rat hepatocytes through a GR-dependent effect. Immunoprecipitation assays and confocal microscopy showed that UDCA enhanced free GR levels with subsequent GR nuclear translocation. Interestingly, when a carboxy-terminus deleted form of GR was used, UDCA no longer increased free GR and/or GR translocation, nor did it protect against TGF-,1,induced apoptosis. In co-transfection experiments with GR response element reporter and overexpression constructs, UDCA did not enhance the transactivation of GR with TGF-,1. Finally, using a flourescently labeled UDCA molecule, the bile acid appeared diffuse in the cytosol but was aggregated in the nucleus of hepatocytes. Both siRNA assays and transfection experiments with either wild-type or mutant forms of GR showed that nuclear trafficking occurs through a GR-dependent mechanism. In conclusion, these results further clarify the antiapoptotic mechanism(s) of UDCA and suggest that GR is crucial for the nuclear translocation of this bile acid for reducing apoptosis. (HEPATOLOGY 2005;42:925,934.) [source]

Ursodeoxycholic acid and primary biliary cirrhosis with features of autoimmune hepatitis

HEPATOLOGY, Issue 4 2002
Olivier Chazouillčres M.D.
No abstract is available for this article. [source]

Role of mitogen-activated protein kinases in tauroursodeoxycholic acid-induced bile formation in cholestatic rat liver

Gerald Ulrich Denk
Aim:, Ursodeoxycholic acid exerts anticholestatic effects in various cholestatic disorders and experimental models of cholestasis. Its taurine conjugate (TUDCA) stimulates bile salt secretion in isolated perfused rat livers (IPRL) under physiological, non-cholestatic conditions, in part by mitogen-activated protein kinase (MAPK)-dependent mechanisms. The role of MAPK in the anticholestatic effect of TUDCA, however, is unclear. Therefore, we studied the role of MAPK in the anticholestatic effect of TUDCA in IPRL and isolated rat hepatocytes (IRH) in taurolithocholic acid (TLCA)-induced cholestasis. Methods:, Bile flow, biliary levels of 2,4-dinitrophenyl-S-glutathione (GS-DNP) as a marker of hepatobiliary organic anion secretion and activity of lactate dehydrogenase (LDH) in hepatovenous effluate as a marker of hepatocellular damage in IPRL perfused with TUDCA and/or TLCA were determined in the presence or absence of MAPK inhibitors. In addition, phosphorylation of Erk 1/2 and p38MAPK induced by TUDCA and/or TLCA was studied by Western immunoblot in IPRL and IRH. Results:, TUDCA-induced bile flow was impaired by the Erk 1/2 inhibitor PD98059 in normal livers (,28%), but not in livers made cholestatic by TLCA. GS-DNP secretion was unaffected by PD98059 under both conditions. TUDCA-induced bile formation and organic anion secretion both in the presence and absence of TLCA were unaffected by the p38MAPK inhibitor SB202190. Erk 1/2 phosphorylation in liver tissue was unchanged after bile salt exposure for 70 min, but was transiently enhanced by TUDCA in IRH. Conclusion:, MAPK do not mediate the anticholestatic effects of TUDCA in TLCA-induced cholestasis. [source]

Ursodeoxycholic acid: Mechanism of action and novel clinical applications

Tadashi Ikegami
Ursodeoxycholic acid (UDCA) is used in the treatment of cholestatic liver diseases, gallstone dissolution, and for patients with hepatitis C virus infection to ameliorate elevated alanine aminotransferase levels. The efficacy of UDCA treatment has been debated and the mechanisms of action in humans have still not defined. Suggested mechanisms include the improvement of bile acid transport and/or detoxification, cytoprotection, and anti-apoptotic effects. In this review, we summarize the proposed molecular mechanisms for the action of UDCA, especially in hepatocytes, and also discuss the putative future clinical usage of this unique drug. [source]

Ursodeoxycholic acid and artesunate in the treatment of severe falciparum malaria patients with jaundice

Sombat Treeprasertsuk
Abstract Background and Aims:,Plasmodium falciparum (PF) infection can lead to severe complications. Ursodeoxycholic acid (UDCA) is increasingly used for the treatment of cholestatic liver diseases. The present study aims to determine the effects of combined UDCA and artesunate compared to placebo and artesunate on the improvement of liver tests in severe PF jaundiced patients. Methods:, All severe PF jaundiced patients, aged , 15 years and diagnosed as having severe malaria according to WHO 2000 criteria, were enrolled. Patients with evidence of biliary obstruction, other cholestatic liver diseases and those who were pregnant were excluded. Patients were randomized to receive either oral UDCA or placebo for 2 weeks in additional to artesunate. All patients were admitted for at least 14 days to monitor the result of the treatment. Results:, Seventy-four severe PF malaria patients with jaundice were enrolled. Both groups had similar demographic and laboratory tests, with the exception being more males in the UDCA group than in the placebo group (P = 0.04). The median of percentage change of total bilirubin and aminotransferase levels at the end of weeks 1, 2, 3 and 4 showed no difference between the two groups. Only the median of percentage change of alkaline phosphatase at the end of week one compared with the baseline values showed less increment in the UDCA group than in the placebo group (P = 0.04). No serious adverse events were seen during the 4 weeks of follow up. Conclusions:, In severe PF malaria patients with jaundice, combined therapy with UDCA and artesunate is safe, but does not significantly improve liver tests compared to placebo and artesunate. [source]

Bioequivalence of a new liquid formulation of ursodeoxycholic acid (Ursofalk suspension) and Ursofalk capsules measured by plasma pharmacokinetics and biliary enrichment

K. D. R. Setchell
Summary Background:, Ursodeoxycholic acid is an approved therapy for hepatobiliary disorders but in infants and children compliance is compromised because it is formulated exclusively as capsules, or tablets. Aim:, To determine the pharmacokinetics and bioequivalence of a new liquid formulation of ursodeoxycholic acid (Ursofalk suspension) with a standard capsule (Ursofalk) in a randomized, unblinded, crossover designed study of 24 healthy adults. Methods:, Equivalence was based on single bolus oral plasma pharmacokinetics and biliary ursodeoxycholic acid enrichments after repeat doses. Biliary bile acid composition and hydrophobicity index were also compared. Ursodeoxycholic acid was measured in duodenal bile by high-performance liquid chromatography and in plasma by mass spectrometry. Results:, The mean percentage biliary ursodeoxycholic acid enrichment after administration of the suspension was not significantly different from that obtained with capsules (44.2 ± 11.7% vs. 46.9 ± 10.2%, respectively). The equivalence ratio was 0.94 (95% CI: 0.8,1.1), establishing bioequivalence between suspension and capsules. Both formulations reduced the biliary hydrophobicity index and no differences in bile acid composition were observed between formulations. The plasma pharmacokinetics of both formulations was similar and the tolerability of the suspension was excellent. Conclusions:, A new liquid formulation of ursodeoxycholic acid suitable for paediatric patients is pharmacologically bioequivalent to capsules when given as single, or repeated oral doses. [source]

Review: low caloric intake and gall-bladder motor function

D. Festi
Summary Cholelithiasis is the primary expression of obesity in the hepatobiliary system. In obese subjects the risk of developing gallstones is increased due to a higher cholesterol saturation of gall-bladder bile. During weight reduction with very low calorie diets (VLCD) the incidence of gallstones increases, but the mechanism for gallstone formation is not completely understood and several pathogenetic mechanisms have been suggested: increased saturation of bile, increased gall-bladder secretion of mucin and calcium, increased presence of prostaglandins and arachidonic acid. Alterations in gall-bladder motility may contribute to gallstone formation, but few studies have addressed the issue of gall-bladder motility during rapid weight loss and its possible role in gallstone formation. VLCD have been associated with a gall-bladder stasis, as a consequence of reduced gall-bladder stimulation by low fat content of the diets. A threshold quantity of fat (10 g) has been documented to obtain efficient gall-bladder emptying. Ursodeoxycholic acid administered during VLCD seems to have a protective role in developing a biliary cholesterol crystals. Gall-bladder emptying was lower in response to low fat meals with respect to relative higher fat meals, before as well as during the VLCD. This may account the possibility of an adaptative response of the gall-bladder motility to a given diet regimen. Adequate fat content of the VLCD may prevent gallstone formation, maintaining adequate gall-bladder motility and may be more economic and physiologically acceptable than administration of a pharmacological agent. [source]

Hereditary spherocytosis in an elderly woman with periodic attacks of jaundice

Hiroyuki Fukuhara
Hereditary spherocytosis is a disease with chronic hemolytic anemia found mostly in childhood. We encountered a rare case of sporadic hereditary spherocytosis in a 68-year-old woman who developed periodic jaundice caused by hemolytic crises. Since the hemolytic crises were caused by cholelithiasis-related biliary inflammation, administration of ursodeoxycholic acid was useful for the prevention of the hemolytic crises. In the differential diagnosis of periodic increases in indirect bilirubin, the possibility of hemolytic diseases, including hereditary ones, should be considered, even if the patients are elderly. [source]

Biliary physiology and disease: Reflections of a physician-scientist,

HEPATOLOGY, Issue 4 2010
Gustav Paumgartner
A review is presented of Gustav Paumgartner's five decades of research and practice in hepatology focusing on biliary physiology and disease. It begins with studies of the excretory function of the liver including hepatic uptake of indocyanine green, bilirubin, and bile acids. The implications of these studies for diagnosis and understanding of liver diseases are pointed out. From there, the path of scientific research leads to investigations of hepatobiliary bile acid transport and the major mechanisms of bile formation. The therapeutic effects of the hydrophilic bile acid, ursodeoxycholic acid, have greatly stimulated these studies. Although ursodeoxycholic acid therapy for dissolution of cholesterol gallstones and some other nonsurgical treatments of gallstones were largely superseded by surgical techniques, ursodeoxycholic acid is currently considered the mainstay of therapy of some chronic cholestatic liver diseases, such as primary biliary cirrhosis. The major mechanisms of action of ursodeoxycholic acid therapy in cholestatic liver diseases are discussed. An attempt is made to illustrate how scientific research can lead to advances in medical practice that help patients. (HEPATOLOGY 2010:51:1095,1106.) [source]

Influence of ursodeoxycholic acid on the mortality and malignancy associated with primary biliary cirrhosis: A population-based cohort study,

HEPATOLOGY, Issue 4 2007
Hannah Jackson
There is debate over the mortality and malignancy risk in people with primary biliary cirrhosis (PBC) and whether this risk is reduced by use of ursodeoxycholic acid. To investigate this issue, we identified 930 people with PBC and 9,202 control subjects from the General Practice Research Database in the United Kingdom. We categorized regular ursodeoxycholic acid as treatment with 6 or more prescriptions and nonregular treatment as less than 6. We found a 2.7-fold increase in mortality for the PBC cohort compared with the general population [adjusted hazard ratio (HR), 2.69; 95% CI, 2.35,3.09]. In those having regular ursodeoxycholic acid (43%), the mortality increase was 2.2-fold (HR, 2.19; 95% CI, 1.66,2.87) and in those not treated 2.7-fold (HR, 2.69; 95% CI, 2.18,3.33). This apparent reduction in mortality was not explained by less severe disease in the ursodeoxycholic acid,treated group. The increased risk of primary liver cancer in ursodeoxycholic acid,treated patients was 3-fold (HR, 3.17; 95% CI, 0.64,15.62), in contrast to an 8-fold increase in those not treated (HR, 7.77; 95% CI, 1.30,46.65). Conclusion: We found that people with PBC had a 3-fold mortality increase when compared with the general population, which was somewhat reduced by regular treatment with ursodeoxycholic acid. However, the observed effect of ursodeoxycholic acid was not statistically significant. (HEPATOLOGY 2007.) [source]

Endogenous ursodeoxycholic acid and cholic acid in liver disease due to cystic fibrosis

HEPATOLOGY, Issue 6 2004
Jeffery L. Smith
Focal biliary cirrhosis causes significant morbidity and mortality in cystic fibrosis (CF). Although the mechanisms of pathogenesis remain unclear, bile acids have been proposed as potential mediators of liver injury. This study examined bile acid composition in CF and assessed altered bile acid profiles to determine if they are associated with incidence and progression of liver injury in CF-associated liver disease (CFLD). Bile acid composition was determined by gas,liquid chromatography/mass spectrometry in bile, urine, and serum samples from 30 children with CFLD, 15 children with CF but without liver disease (CFnoLD), and 43 controls. Liver biopsies from 29 CFLD subjects were assessed histologically by grading for fibrosis stage, inflammation, and disruption of the limiting plate. A significantly greater proportion of endogenous biliary ursodeoxycholic acid (UDCA) was demonstrated in CFnoLD subjects vs. both CFLD subjects and controls (2.4- and 2.2-fold, respectively; ANOVA, P = .04), and a 3-4 fold elevation in endogenous serum UDCA concentration was observed in both CFLD subjects and CFnoLD subjects vs. controls (ANOVA, P < .05). In CFLD, there were significant correlations between serum cholic acid and hepatic fibrosis, inflammation, and limiting plate disruption as well as the ratio of serum cholic acid/chenodeoxycholic acid to hepatic fibrosis, inflammation, and limiting plate disruption. In conclusion, elevated endogenous UDCA in CFnoLD suggests a possible protective role against liver injury in these patients. The correlation between both cholic acid and cholic acid/chenodeoxycholic acid levels with histological liver injury and fibrosis progression suggests a potential monitoring role for these bile acids in CFLD. (HEPATOLOGY 2004;39:1673,1682.) [source]

Primary sclerosing cholangitis in children: A long-term follow-up study

HEPATOLOGY, Issue 1 2003
Ariel E. Feldstein
Primary sclerosing cholangitis (PSC) is increasingly diagnosed in children and adolescents, but its long-term prognosis remains uncertain. The aim of this longitudinal, cohort study was to determine the long-term outcome of children with PSC. Fifty-two children with cholangiography-proven PSC (34 boys and 18 girls; mean age 13.8 ± 4.2 years; range, 1.5-19.6 years) who were seen at our institution over a 20-year period were followed-up for up to 16.7 years. Two thirds presented with symptoms and/or signs of PSC and 81% had concomitant inflammatory bowel disease (IBD). Twenty-five percent had total alkaline phosphatase activity within the normal range for the age group, but all of them had elevated ,-glutamyl transpeptidase levels. Autoimmune hepatitis overlapping with PSC was present in 35% of children. A positive but transient clinical and/or biochemical response occurred under therapy with ursodeoxycholic acid, alone or in combination with immunosuppressive medications. During follow-up, 11 children underwent liver transplantation for end-stage PSC and 1 child died. The median (50%) survival free of liver transplantation was 12.7 years. Compared with an age- and gender-matched U.S. population, survival was significantly shorter in children with PSC (P < .001). In a Cox regression model, lower platelet count, splenomegaly, and older age were associated with shorter survival. Presence of autoimmune hepatitis overlapping with PSC (P = .2) or medical therapy (P = .2) did not affect survival. In conclusion, PSC significantly decreases survival in this child population. Although pharmacologic therapy may improve symptoms and liver test results initially, it does not seem to impact the long-term outcome. [source]

Guidelines for the treatment of chronic hepatitis and cirrhosis due to hepatitis C virus infection for the fiscal year 2008 in Japan

Hiromitsu Kumada
In the 2008 guidelines for the treatment of patients with chronic hepatitis C, pegylated interferon (Peg-IFN) combined with ribavirin for 48 weeks are indicated for treatment-naive patients infected with hepatitis C virus (HCV) of genotype 1. Treatment is continued for an additional 24 weeks (72 weeks total) in the patients who have remained positive for HCV RNA detectable by the real-time polymerase chain reaction at 12 weeks after the start of treatment, but who turn negative for HCV RNA during 13,36 weeks on treatment. Re-treatment is aimed to either eradicate HCV or normalize transaminase levels for preventing the development of hepatocellular carcinoma (HCC). For patients with compensated cirrhosis, the clearance of HCV RNA is aimed toward improving histological damages and decreasing the development of HCC. The recommended therapeutic regimen is the initial daily dose of 6 million international units (MIU) IFN continued for 2,8 weeks that is extended to longer than 48 weeks, if possible. IFN dose is reduced to 3 MIU daily in patients who fail to clear HCV RNA by 12 weeks for preventing the development of HCC. Splenectomy or embolization of the splenic artery is recommended to patients with platelet counts of less than 50 × 103/mm3 prior to the commencement of IFN treatment. When the prevention of HCC is at issue, not only IFN, but also liver supportive therapy such as stronger neo-minophagen C, ursodeoxycholic acid, phlebotomy, branched chain amino acids (BCAA), either alone or in combination, are given. In patients with decompensated cirrhosis, by contrast, reversal to compensation is attempted. [source]

Matrine improves 17,-ethinyl estradiol-induced acute cholestasis in rats

Ying Zhao
Aim:, To explore the effects of matrine (MT) on acute intrahepatic cholestasis induced by 17,-ethinyl estradiol (EE) in rats. Methods:, Acute intrahepatic cholestasis in rats were induced by EE, and the effects of MT on acute intrahepatic cholestasis were explored and compared with ursodeoxycholic acid (UDCA) by serum biochemical determination and bile excretion experiments. Results:, The serum biochemical and bile biochemical results indicated that MT and UDCA had notable hepatoprotective effects by counteracting cholestasis induced by EE. The bile flow and the bile excretion of glycocholic acid (GC, a substrate of bile salt export pump [Bsep]), ketoprofen glucuronide (KPG) and rhodamine 123 (Rh123, a substrate of multidrug resistance protein 1 [MDR1]) decreased by EE, were significantly improved after administration of MT. Conclusion:, MT exhibited potential protection against EE-induced acute intrahepatic cholestasis. [source]

Fibrate for treatment of primary biliary cirrhosis

Shinji Iwasaki
Recent studies of the effectiveness of ursodeoxycholic acid (UDCA) therapy in patients with primary biliary cirrhosis (PBC) reported that UDCA therapy did not necessarily stop the progression of liver fibrosis in all patients, even those with early stage PBC. Thus, there is a need for more effective treatments that could prevent asymptomatic PBC from progressing to the icteric stage. Bezafibrate is effective in approximately two-thirds of non-icteric patients who have not shown a complete response to UDCA. Serum bilirubin, aspartate aminotransferase and ,-guanosine 5,-triphosphate levelswere significantly lower in patients who responded to additional bezafibrate on univariate analysis. The putative mechanism by which bezafibrate acts in cholestasis is by increasing phospholipid output into bile, which forms micelles with the hydrophobic bile acid that reduces its toxicity. [source]

Chemoprophylaxis of colorectal cancer in inflammatory bowel disease: Current concepts

Jonathan S. Levine MD
Abstract Ulcerative colitis and Crohn's disease both confer an increased risk of developing colorectal cancer. The use of 5-aminosalicylate as a remission-inducing agent has been long accepted. Its use as a potential chemoprophylactic agent has been proposed and is used by some practitioners. This review examines the most recent data on 5-aminosacilycylate as a chemoprophylactic drug as well as ursodeoxycholic acid, folic acid, azathioprine, and 6-mercaptopurine. (Inflamm Bowel Dis 2007) [source]

One-Pot Multienzymatic Synthesis of 12-Ketoursodeoxycholic Acid: Subtle Cofactor Specificities Rule the Reaction Equilibria of Five Biocatalysts Working in a Row

Daniela Monti
Abstract The hydroxysteroid dehydrogenases (HSDHs)-catalyzed one-pot enzymatic synthesis of 12-ketoursodeoxycholic acid (3,,7,-dihydroxy-12-oxo-5,-cholanoic acid), a key intermediate for the synthesis of ursodeoxycholic acid, from cholic acid has been investigated. This goal has been achieved by alternating oxidative and reductive steps in a one-pot system employing HSDHs with different cofactor specificity, namely NADH-dependent HSDHs in the oxidative step and an NADPH-dependent 7,-HSDH in the reductive one. Coupled in situ regeneration systems have been exploited not only to allow the use of catalytic amounts of the cofactors, but also to provide the necessary driving force to opposite reactions (i.e., oxidation and reduction) acting on different sites of the substrate molecule. Biocatalysts suitable for the set-up of this process have been selected and their kinetic behaviour in respect of the reactions of interest has been evaluated. Finally, the process has been studied employing the enzymes both in free and compartmentalized form. [source]

Protective effect of n-3 polyunsaturated fatty acid on primary culture of rat hepatocytes

Ryoichi Sohma
Abstract Background and Aim:, Recently, we reported on the beneficial clinical effects of eicosapentaenoic acid (EPA) in patients with primary biliary cirrhosis (PBC) who were unresponsive to ursodeoxycholic acid (UDCA). In this study we examined the effect of EPA on rat hepatocytes in primary culture. Methods:, Hepatocytes were isolated from rat liver by perfusion of collagenase and cultured with or without EPA. Cell damage induced by chenodeoxycholic acid (CDCA) was assessed by WST-8 assay and lactate dehydrogenase (LDH) release. PGE2 and LTB4 concentrations in the culture medium were measured by enzyme-linked immunosorbent assay (ELISA). cDNA was made from total RNA that was extracted from hepatocytes, and TaqMan polymerase chain reaction (PCR) was performed to assess the expression of CuZn and Mn superoxide dismutase (SOD) mRNA. Results:, When rat hepatocytes were cultured in the presence of EPA, the damage caused by CDCA was significantly decreased compared with cells cultured without EPA. Cytotoxicity significantly decreased in the presence of EPA. Furthermore, SOD mRNA expression was increased by adding EPA. These findings indicated that EPA protects cells by scavenging superoxide radicals (,O2,) mediated by SOD production. Conclusion:, EPA has a direct protective effect on rat hepatocytes, which is in agreement with the clinical efficacy of EPA in PBC patients. [source]

17,-estradiol prevents cytotoxicity from hydrophobic bile acids in HepG2 and WRL-68 cell cultures

Matteo Ricchi
Abstract Background:, Epidemiological and clinical studies suggest the possibility that estrogens might have a cytoprotective effect on the liver. The aim of the present study was to test the hypothesis that 17,-estradiol (E2) prevents hepatocellular damage induced by deoxycholic acid (DCA), a hydrophobic bile acid. Methods:, HepG2 cells were exposed for 24 h to DCA (350 µmol/L). Cell viability, aspartate aminotransferase and lactate dehydrogenase activity and apoptosis were measured as indices of cell toxicity. The effect of DCA was compared to that observed using either a hydrophilic bile acid, ursodeoxycholic acid (UDCA; 100 µmol/L), or E2 at different concentrations (1 nmol/L, 10 nmol/L, 50 nmol/L and 50 µmol/L) or mixtures of E2/DCA or UDCA/DCA. The same experiments were performed using WRL-68 cells that, at variance with HepG2, express a higher level of nuclear estrogen receptor. Results:, High concentrations of E2 and UDCA prevented DCA-induced decrease in cell viability, increase in enzyme activity and apoptosis evaluated both by 4,,6-diamidino-2-phenylindole dihydrochloride (DAPI) and TdT-mediated dUTP nick-end labeling (TUNEL) assays. In addition, DCA-related apoptosis, assessed by caspase activity, was also prevented by E2 (P < 0.01) in physiological (1,10 nmol/L) doses. The cytoprotective effects of E2 and UDCA was also observed in the WRL-68 cell line. Conclusions:, 17,-Estradiol prevents DCA-induced cell damage in HepG2 and WRL-68 cell lines to an extent comparable to UDCA. The hypothesis that the protective effect of E2 may be mediated by a mechanism that is nuclear estrogen receptor independent, deserves further verification. [source]

Tumor necrosis factor- , and transforming growth factor- , reflect severity of liver damage in primary biliary cirrhosis

Abstract Background and Aims The pathogenesis of primary biliary cirrhosis (PBC) is unknown. The role of cytokines such as tumor necrosis factor-, (TNF-,) and transforming growth factor-, (,GF-,), and the effect of ursodeoxycholic acid (UDCA) in modifying the cytokine environment in patients with PBC has remained largely unstudied. Our aims were to determine: (i) the relationship between serum levels of TNF-, and TGF-, and the severity of PBC; and (ii) the effects of UDCA therapy on TNF-, and TGF-, levels in patients with PBC. Methods We studied 90 patients who had been treated with UDCA (53 patients) or placebo (37 patients) for 2 years as part of a randomized, double-blind, controlled trial. Patients were divided into histological stage I/II or stage III/IV disease. Serum TNF-, and TGF-, levels were quantified by enzyme-linked immunoabsorbent assay. Results Baseline levels of TNF-, were significantly greater in patients with stage III/IV compared to stage I/II disease. After 2 years of treatment with UDCA, patients showed a significantly greater decrease in TNF-, levels and progression risk score compared to placebo-treated patients. TNF-, and TGF-, levels were significantly reduced compared to baseline levels in the UDCA-treated group after 2 years, while there was no significant change in the levels of placebo-treated patients. Conclusions Serum TNF-, and TGF-, levels may reflect severity of disease in patients with PBC. The beneficial effects of UDCA therapy may be explained by lowering serum levels of these two cytokines. [source]

Elevated plasma bile acid concentrations in two sisters with tyrosinaemia type I

JO Sass
Abstract: A 21-month-old girl suffering from tyrosinaemia type I and undergoing treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) presented with pruritus which rapidly ceased with administration of high doses of ursodeoxycholic acid. Determination of plasma bile acids revealed clearly elevated levels both in samples taken before and after the onset of NTBC therapy, thus indicating, that the increase was not related to the administration of this drug. This result is corroborated by data from the first patient's newborn sister, diagnosed with the same disease, who showed elevated plasma bile acid concentrations in all samples examined, except for the cord plasma. This is the first report on altered bile acid concentrations in tyrosinaemia type I, and underlines the need for thorough investigation of bile acid metabolism in this disease. [source]

Effect of ursodeoxycholic acid treatment on the expression and function of multidrug resistance-associated protein 2 in rat intestine

Ryoko Yumoto
Abstract Effect of ursodeoxycholic acid (UDCA) treatment on the expression and function of intestinal multidrug resistance-associated protein (Mrp) 2 was examined in rats. When rats were orally administered 0.5% UDCA solution for 6 days, mRNA and protein levels of Mrp2 in the intestine were increased about twofold compared with those in untreated rats. In in vitro everted sac study, Mrp2-mediated efflux of 2,4-dinitrophenyl-S-glutathione (DNP-SG) to the mucosal surface was shown to be increased by UDCA treatment. In vivo intestinal exsorption clearance of DNP-SG was also increased by UDCA treatment. In addition, in situ intestinal absorption of methotrexate, a substrate of Mrp2, was decreased by the treatment. These results indicate that the expression and function of intestinal Mrp2 is up-regulated by oral administration of UDCA. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2822,2831, 2009 [source]

Apoptosis in hepatitis C

J. Kountouras
Summary. The apoptotic process appears to be a host defence mechanism against viral infections and tumourigenesis. However, many viral genomes encode proteins, which repress apoptosis so as to escape from immune attack by the host. Therefore, virus,host interactions may determine viral persistence, extent and severity of liver inflammation and possibly viral hepatocarcinogenesis. Apoptosis of liver cells may play a significant role in the pathogenesis of hepatitis C. Pathomorphologic features of increased apoptosis include shrinkage and fragmentation of nuclei/cytoplasm in piecemeal necrosis areas, acidophilic bodies, and focal cell dropout in the liver lobule. The hepatitis C virus (HCV) core protein exhibits both proapoptotic or antiapoptotic actions. Modulation of apoptosis may involve binding of HCV core protein to the intracellular signal transducing portion of death receptors and displacement of signalling molecules. Apoptosis may occur in the absence of significant transaminase elevation, thereby explaining the lack of correlation between biochemical activity and liver cell histological injury. Monitoring caspase activation might provide a reliable tool to estimate the efficacy of HCV therapy, and might open challenging therapeutic strategies in HCV infection. The antiviral effect of interferon may be mediated through induction of apoptosis. Lastly, administration of the antiapoptotic ursodeoxycholic acid in HCV infection is compatible with the notion that apoptosis may represent a mechanism for viral shedding rather than for viral elimination, thereby raising the concept that inhibition of apoptosis could ameliorate hepatitis C. [source]

Bioequivalence of a new liquid formulation of ursodeoxycholic acid (Ursofalk suspension) and Ursofalk capsules measured by plasma pharmacokinetics and biliary enrichment

K. D. R. Setchell
Summary Background:, Ursodeoxycholic acid is an approved therapy for hepatobiliary disorders but in infants and children compliance is compromised because it is formulated exclusively as capsules, or tablets. Aim:, To determine the pharmacokinetics and bioequivalence of a new liquid formulation of ursodeoxycholic acid (Ursofalk suspension) with a standard capsule (Ursofalk) in a randomized, unblinded, crossover designed study of 24 healthy adults. Methods:, Equivalence was based on single bolus oral plasma pharmacokinetics and biliary ursodeoxycholic acid enrichments after repeat doses. Biliary bile acid composition and hydrophobicity index were also compared. Ursodeoxycholic acid was measured in duodenal bile by high-performance liquid chromatography and in plasma by mass spectrometry. Results:, The mean percentage biliary ursodeoxycholic acid enrichment after administration of the suspension was not significantly different from that obtained with capsules (44.2 ± 11.7% vs. 46.9 ± 10.2%, respectively). The equivalence ratio was 0.94 (95% CI: 0.8,1.1), establishing bioequivalence between suspension and capsules. Both formulations reduced the biliary hydrophobicity index and no differences in bile acid composition were observed between formulations. The plasma pharmacokinetics of both formulations was similar and the tolerability of the suspension was excellent. Conclusions:, A new liquid formulation of ursodeoxycholic acid suitable for paediatric patients is pharmacologically bioequivalent to capsules when given as single, or repeated oral doses. [source]

Biochemical markers of liver fibrosis and lymphocytic piecemeal necrosis in UDCA-treated patients with primary biliary cirrhosis

Christophe Corpechot
Abstract: Background/Aim: We have previously shown that the histological stage and severity of lymphocytic piecemeal necrosis (LPN) are independent predictive factors of cirrhosis development in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cirrhosis (PBC). Our aim during this study was to determine whether biochemical parameters classically used in PBC management and measured under UDCA could be considered as reliable surrogate markers for these histological prognostic indices in clinical practice. Method: The study included 153 patients with PBC who had undergone a control liver biopsy after 2 years of UDCA therapy. The relationships between histological and biological features were assessed by variance analysis and logistic regression. The diagnostic value of independent markers was assessed in terms of their sensitivity, specificity, positive predictive value (PPV) and negative value (NPV) and receiver-operating characteristic curves. Results: Two variables were independently associated with extensive fibrosis (i.e. advanced histological stages): serum levels of bilirubin and hyaluronic acid (HA). A fibrosis index ([bilirubin (,mol/l)/14]+[HA (,g/l)/143]) higher than 1.5 exhibited good PPV and specificity (>74%) but rather poor NPV and sensitivity (<64%) regarding a diagnosis of extensive fibrosis. The only independent marker of LPN was aspartate aminotransferase (AST) activity. AST activity of more than twice the upper limit of normal showed acceptable PPV (>70%) but very low sensitivity (<25%) for a diagnosis of LPN. Conclusions: Serum bilirubin and HA levels measured under UDCA therapy are of acceptable diagnostic value for extensive fibrosis, but none of the biochemical tests commonly employed in the management of PBC can be considered as surrogate markers of LPN. Taken together with our previous results, these findings suggest that liver biopsy may be necessary to screen UDCA-treated patients who might require additional therapies. [source]

Tumor necrosis factor-, and interferon-, directly impair epithelial barrier function in cultured mouse cholangiocytes

Hanada Shinichiro
Abstract:Background/Aims: In primary biliary cirrhosis (PBC), cytokines from CD4 + T lymphocytes were suggested to contribute to the intralobular bile duct damage together with cellular immunity by CD8 + T lymphocytes. Recently, we reported that immunolocalization of 7H6 , a tight junction (TJ)-associated protein , was significantly diminished in cholangiocytes in the PBC liver. In this study, we examined the direct effects of several cytokines , tumor necrosis factor-, (TNF-,), interferon-, (IFN-,), interleukin-2 and 4 (IL-2 and 4) , on TJ in immortalized mouse cholangiocytes. Moreover, we examined the inhibitory effect of ursodeoxycholic acid (UDCA)on cytokine-induced changes in paracellular permeability. Methods: Barrier function of TJ was evaluated by measuring transepithelial electrical resistance (TER) and 3H-inulin flux. We also performed immunostaining and immunoblotting for TJ-associated proteins , claudin-1 and -3, occludin, zonula occluden-1 (ZO-1) and 7H6. Results: TNF-, and IFN-,, but neither IL-2 nor IL-4, significantly decreased TER (P < 0.005). 3H-inulin flux studies confirmed IFN-,-induced increases in paracellular permeability of cholangiocytes (P < 0.001). In immunostaining and immunoblotting studies, TJ-associated proteins were well preserved in TNF-,- or IFN-,-treated cells. Ursodeoxycholic acidhas been found to have no inhibitory effect on increased paracellular permeability induced by TNF-, or IFN-,. Conclusion: These findings show that TNF-, and IFN-, disrupt barrier function of TJ in cholangiocytes without major structural changes to TJ and suggest that disruption of TJ function and subsequent leakage of the bile constituents may influence the aggravation of cholestasis in PBC. [source]

Expression of uncoupling protein-2 in biliary epithelial cells in primary biliary cirrhosis

Eitaro Taniguchi
Abstract:Background/Aims: Uncoupling proteins are thought to protect cells from oxidative stresses. Because uncoupling protein-2 is expressed in liver and reactive oxygen species are involved in pathogenesis of various liver diseases, this protein may protect liver cells from disease-associated oxidative stress. However, uncoupling protein-2 expression in human liver has not been examined. Methods: We investigated hepatic uncoupling protein-2 distribution in various liver diseases including primary biliary cirrhosis, autoimmune hepatitis, chronic viral hepatitis, and histologically normal liver by immunohistochemistry.Results: Uncoupling protein-2 was expressed in some hepatocytes, however, the degree of hepatocytic uncoupling protein-2 expression did not differ significantly among liver diseases and normal liver. Uncoupling protein-2 was abundant in biliary epithelial cells in primary biliary cirrhosis but not in other liver specimens. Enhanced uncoupling protein-2 expression in biliary epithelial cells was specific for primary biliary cirrhosis and did not result simply from cholestasis. The percentage of uncoupling protein-2 positive bile ducts in primary biliary cirrhosis patients treated with ursodeoxycholic acid was significantly lower than in untreated patients.Conclusions: These results suggest that uncoupling protein-2 is involved in the pathogenesis of primary biliary cirrhosis. [source]

Hepatic graft-versus-host disease resembling acute hepatitis: additional treatment with ursodeoxycholic acid

Tetsuhiro Chiba
Abstract: Hepatic graft-versus-host disease (GVHD) is a frequent complication after bone-marrow transplantation (BMT). The disease is often refractory to immunosuppressive therapy. We present a 30-year-old Japanese male, who developed an abrupt elevation of aminotransferases, on day 135 after allogeneic BMT. A liver biopsy specimen revealed degeneration of the small bile ducts and portal fibrosis, and the diagnosis of chronic hepatic GVHD was confirmed. No manifestation of chronic GVHD was observed except liver dysfunction. The administration of prednisolone (PSL) and cyclosporin (CsA) ameliorated laboratory data to a degree, but they did not return to normal. Treatment with ursodeoxycholic acid (UDCA), subsequently added to the immunosuppressive therapy, apparently normalized the levels of biliary tract enzyme and total bilirubin. His liver function test completely returned to normal on day 260. We believe that it is worthwhile to administer UDCA as an additional treatment for not only common hepatic GVHD but also atypical cases presenting as acute hepatitis. [source]