Increase of sulfated ursodeoxycholic acid in the serum and urine of patients with chronic liver disease after ursodeoxycholic acid therapy

The present study was undertaken in order to investigate the influence of ursodeoxycholic acid (UDCA) on the composition of sulfate-conjugated bile acids in the serum and urine of patients with chronic active hepatitis and compensated liver cirrhosis. After a 12 week UDCA treatment (600 mg/day), total serum bile acid concentration increased two-fold in patients with compensated liver cirrhosis and increased slightly in patients with chronic active hepatitis. The percentage of sulfated bile acids significantly increased in patients with both compensated liver cirrhosis and chronic active hepatitis. UDCA made up 63% of the total serum bile acids in compensated liver cirrhosis and 61% in chronic active hepatitis after UDCA treatment. Of the serum bile acids after UDCA treatment, 35.2 and 53.9% of UDCA was sulfate conjugated in compensated liver cirrhosis and chronic active hepatitis, respectively. Urinary excretion of total bile acid and UDCA after UDCA treatment in compensated liver cirrhosis were higher than in chronic active hepatitis. UDCA made up 68% of the total urinary bile acids in compensated liver cirrhosis and 64% in chronic active hepatitis after UDCA treatment. Of the urinary bile acids after UDCA treatment, 51.8 and 54.8% of UDCA was sulfate conjugated in compensated liver cirrhosis and chronic active hepatitis, respectively. UDCA treatment for compensated liver cirrhosis was less effective than for chronic active hepatitis. We found that sulfate conjugation is one of the major metabolic pathways for UDCA after UDCA treatment in chronic liver diseases.     

Ursodeoxycholic acid in the treatment of primary biliary cirrhosis: A short-term, randomized, double-blind controlled, cross-over study with long-term follow up

Abstract In order to evaluate the efficacy of ursodeoxycholic acid (UDCA) in the treatment of Chinese patients with primary biliary cirrhosis, a short-term, randomized, double-blind controlled, cross-over study was done with long-term follow up. In the first part of the study, 12 patients were randomly chosen to receive either UDCA 600 mg/day for 3 months followed by a placebo for 3 months or a placebo for 3 months followed by UDCA for 3 months. The clinical symptoms of pruritus improved when the patients were receiving UDCA but became worse when receiving a placebo. Mean serum levels of alkaline phosphatase (ALPase), γ-glutamyl transferase (γ-GT), total bilirubin, cholesterol, alanine aminotransferase (ALT) and aspartate aminotransferase all decreased below the baseline values when receiving UDCA treatment and all increased above the baseline values when receiving the placebo. The difference was statistically significant. In the second part of the study, 19 patients received long-term UDCA treatment (mean 20 months). The clinical symptoms of pruritus improved in 90% of the pruritic patients. Serum levels of ALPase, γ-GT and ALT fell significantly from the pretreatment values 6, 12 and from the mean 20 months after UDCA treatment. Serum levels of total bilirubin fell significantly 6 and 12 months after UDCA treatment but did not reach statistical significance at the last follow up. No patient lost antimitochondrial antibody and elevated immunoglobulin levels did not improve significantly, but the Mayo clinical risk score improved significantly after long-term UDCA treatment. Treatment failure was noted in three patients: two patients in the histologic stage IV with clinical overt jaundice died of complications 4 and 5 months after UDCA treatment, respectively; another patient underwent a liver transplantation 1 year after the UDCA treatment due to progressive jaundice. No severe adverse reaction was noted during UDCA treatment, only one patient suffered from a mild allergic reaction. In conclusion, UDCA is safe and effective in the treatment of Chinese PBC patients in stages I—III.     

Methotrexate improves biochemical tests in patients with primary biliary cirrhosis who respond incompletely to ursodiol.

BACKGROUND & AIMS: Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of presumed autoimmune etiology. Ursodeoxycholic acid (UDCA), methotrexate, and colchicine each have shown promise in its treatment. The value of combining 2 or 3 of these drugs is uncertain. The aim of this study was to determine whether addition of methotrexate to the treatment regimen improves results of liver biochemical tests in patients with antimitochondrial antibody-positive PBC who responded incompletely to treatment with UDCA and colchicine. METHODS: Methotrexate was added to the treatment regimen of 10 consecutive patients with antimitochondrial antibody-positive PBC who had an incomplete response to therapy with UDCA alone or in combination with colchicine. The primary end point was biochemical response. Symptoms and histological changes were also recorded. RESULTS: Addition of methotrexate to the UDCA plus colchicine regimen was associated with a significant reduction in serum alkaline phosphatase (ALP) levels beyond those found with UDCA and colchicine alone or in combination. Median ALP concentration was 389 IU (range, 247-1013 IU) at baseline, 300 IU (range, 155-467 IU) after treatment with UDCA plus colchicine, and 120 IU (range, 66-351 IU) after treatment with methotrexate. CONCLUSIONS: Addition of methotrexate to a regimen of UDCA and colchicine may be beneficial for patients with PBC who respond incompletely to treatment with UDCA and colchicine.     

Efficacy and safety of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy

Background and aims. Patients with intrahepatic cholestasis of pregnancy (ICP) benefit from ursodeoxycholic acid (UDCA) treatment. Since there is still certain reluctance to use UDCA in pregnant women, mainly due to warnings in the official SPC information in respective drug leaflets, our objective was to assess the efficacy and safety of UDCA during pregnancy.Material and methods. Our retrospective multicentric study was performed on 191 consecutive pregnant women with ICP treated with UDCA. Any maternal and/or fetal complications of the UDCA treatment were searched for; healthy pregnant women (n = 256) served as controls.Results. The UDCA treatment improved liver disease status in the majority of the affected women (86.1%). This treatment was well tolerated, with only negligible skin reactions (0.5%) and mild diarrhea (4.7%). No complications attributable to UDCA treatment were detected during the fetal life, delivery, or the early neonatal period.Conclusion. We confirmed the good efficacy and safety of UDCA treatment in pregnancy for both mothers and fetuses/neonates.     

Effect of ursodeoxycholic acid administration on biliary lipid composition and bile acid kinetics in cholesterol gallstone patients

The effect of ursodeoxycholic acid (UDCA) on bile lipid composition and bile acid kinetics was evaluated in seven cholesterol gallstone patients following one month of UDCA administration (12 mg/kg/day). UDCA administration induces a significant reduction in the cholesterol saturation index (SI). After UDCA treatment, UDCA becomes the predominant biliary bile acid while chenodeoxycholic, cholic, and deoxycholic acid are significantly reduced. UDCA pool significantly increases, and chenodeoxycholic, cholic, and total bile acid pools significantly decrease. The reduction in bile lithogenicity during UDCA administration suggests that UDCA may be useful for cholesterol gallstone treatment in man.     

Best-buy regimen of ursodeoxycholic acid for patients with gallstones

Bedtime administration has been advocated as a strategy for reducing minimum effective dose, side effects, and costs of chenodeoxycholic acid treatment of cholesterol gallstones, but little information is available for ursodeoxycholic acid (UDCA). We prospectively determined the minimum effective dose of bedtime UDCA in 44 patients with radiolucent gallstones treated with a range of UDCA doses (4.6-17.0 mg/kg/day). The average minimum effective dose for reducing the cholesterol saturation index (SI) of gallbladder bile to a value of 0.8 was 8.4 mg/kg/day for bedtime UDCA. The greater potency of the bedtime regimen was confirmed in seven individual patients by comparison with a mealtime regimen. Cholesterol SI was reduced from 1.25 during placebo to 0.73 during 7 mg/kg/day for bedtime UDCA and to 0.81 during 10 mg/kg/day for mealtime UDCA. The effect of the bedtime regimen was not enhanced by a repeated-release tablet formulation of UDCA by comparison with UDCA in 15 patients. We conclude that the bile acid dose is reduced during bedtime UDCA administration by comparison with mealtime UDCA in individual patients and that the best-buy regimen is 8.4 mg/kg/day UDCA given at bedtime for patients with gallstones as a group. With this dose, gallstone dissolution can be supported by unsaturated gallbladder bile at minimum risk of dose-related side effects and at minimum treatment costs.     

Additive improvement induced by bezafibrate in patients with primary biliary cirrhosis showing refractory response to ursodeoxycholic acid

Background and Aim: Ursodeoxycholic acid (UDCA) has been widely used in the treatment of patients with primary biliary cirrhosis (PBC). However, some patients are refractory to UDCA. The aim of this study is to clarify the additive improvement induced by bezafibrate in patients refractory to UDCA. Methods: This study was a prospective analysis of 37 consecutive PBC patients. All patients were treated first for 6 months with UDCA, and then with bezafibrate, if their alkaline phosphatase (ALP) levels did not decrease more than 40% or within the normal range after 6 months' treatment with UDCA. Clinical parameters were monitored for the subsequent 24 months. Result: Twenty‐two patients (59%) achieved improvement of ALP levels after the treatment with UDCA. Those patients (Group A) had significantly lower levels of ALP at diagnosis than those with abnormal ALP levels after 6 months' treatment with UDCA (Group B; P = 0.020). They continued UDCA monotherapy, and maintained normal ALP levels at subsequent follow ups. However, immunoglobulin M (IgM) levels remained abnormal in eight patients, whose IgM levels at the time of diagnosis were significantly higher than those whose IgM were normalized after 6 months' treatment with UDCA (P = 0.026). Those in Group B were treated additionally with bezafibrate, and 12 patients (80%) achieved normal ALP and IgM levels within 12 months of commencement of therapy. Conclusion: Higher ALP level at diagnosis is one of the predictors for UDCA failure. Combination treatment of bezafibrate in addition to UDCA may be an effective treatment for PBC patients refractory to UDCA.     

Effects of chenodeoxycholic and ursodeoxycholic acids on interferon-γ production by peripheral blood mononuclear cells from patients with primary biliary cirrhosis

Ursodeoxycholic acid (UDCA) administration can obtain marked improvement of primary biliary cirrhosis (PBC). Recently, UDCA has been demonstrated to have a direct effect on immunological reactions in patients with PBC in that the aberrant expression of major histocompatibility complex (MHC) class I molecules was markedly reduced after UDCA treatment. To understand the immunological effect of UDCA, we analyzed interferon (IFN)-γ production in peripheral blood mononuclear cells (PBMCs) from 29 patients with PBC treated with UDCA (group 1), 19 patients with PBC who were not treated with UDCA (group 2), 11 healthy subjects (group 3), and 12 patients with chronic viral hepatitis (group 4). IFN-γ production was investigated because the excess production of this cytokine is associated with the aberrant expression of MHC molecules. Whereas IFN-γ production in the patients in group 2 was significantly increased, the level of production in group 1 was similar to that in the control groups (groups 3 and 4). There was significant improvement in IFN-γ production in 6 patients with PBC after UDCA treatment. The effect of UDCA and chenodeoxycholic acid (CDCA) on IFN-γ production in PBMCs from 12 normal subjects was also analyzed. IFN-γ was produced dose-dependently according to concentrations of CDCA ranging from 0.1 to 10 μM, but the increase in production was markedly suppressed by the addition of UDCA. We conclude that low doses of CDCA enhance IFN-γ production and may therefore lead to the aberrant hepatic expression of MHC molecules, and that the increase in IFN-γ production is suppressed by UDCA.     

Efficacy of colchicine in patients with primary biliary cirrhosis poorly responsive to ursodiol and methotrexate

OBJECTIVE: Approximately 20-30% of patients with primary biliary cirrhosis (PBC) respond fully to treatment with ursodeoxycholic acid (UDCA). The rest have progressive disease and eventually develop cirrhosis and liver failure. More effective treatment is needed. Methotrexate improved biochemical tests of liver function and liver histology in patients with PBC who had failed to respond to UDCA in one report and induced sustained biochemical and histological remission in another. The role of colchicine in PBC is unclear. We describe three patients with symptomatic PBC who responded very well to the addition of colchicine after they had failed to respond to UDCA alone and in combination with methotrexate. We suggest that colchicine should be tried in PBC patients who clearly fail to respond to UDCA. METHODS: Three patients with symptomatic biopsy-proven, antimitochondrial antibody-positive PBC failed to respond to UDCA and then to the addition of methotrexate. Colchicine was eventually added to the regimen. Symptoms, biochemical tests of liver function, and percutaneous liver biopsies were done at baseline, after treatment with UDCA, UDCA plus methotrexate, and UDCA plus methotrexate plus colchicine. RESULTS: All three patients responded after colchicine was added to UDCA and methotrexate. Symptoms, biochemical tests of liver function, and liver histology improved in all, and blood tests normalized in two. CONCLUSIONS: Colchicine may be effective treatment in some symptomatic patients with PBC who respond incompletely to UDCA alone or in combination with methotrexate. Colchicine may be tried in such patients.     

Case Report: Three paediatric cases of primary sclerosing cholangitis treated with ursodeoxycholic acid and sulphasalazine

We present here three paediatric patients with primary sclerosing cholangitis. In case 1, the serum γ-glutamyl transpeptidase was decreased only temporarily by ursodeoxycholic acid (UDCA) treatment and 34 months later, sulphasalazine was added because of microscopic colitis. The enzyme level decreased with dual therapy. Similarly, in case 3, first diagnosed as autoimmune hepatitis, the transpeptidase levels remained elevated for 18 months during treatment with UDCA, prednisolone and mizoribin. The enzyme decreased only after a diagnosis of primary sclerosing cholangitis complicated with ulcerative colitis was established and sulphasalazine was introduced. Case 2 also had Crohn's colitis and was put on UDCA and sulphasalazine from the start. The enzyme level was normalized within 1 month and has remained normal for the following 5 years. Liver biopsies were analysed repeatedly in these three patients. In case 1, periductal fibrosis remained unchanged while being treated by UDCA. There appeared to be no progression in liver cirrhosis in case 3 while being treated by UDCA, prednisolone, and mizoribin. In case 2, who has been treated with both UDCA and sulphasalazine from the start, periductal fibrosis and portal fibrosis were remarkably improved 45 months later. We suggest that sulphasalazine in addition to UDCA might be a viable treatment for children with primary sclerosing cholangitis.     

Does ursodeoxycholic acid mediate immunomodulatory and anti-inflammatory effects in patients with primary sclerosing cholangitis?

BACKGROUND AND OBJECTIVES: Therapy with ursodeoxycholic acid (UDCA) has been reported to be associated with improvements in abnormal serum biochemical liver tests in patients with primary sclerosing cholangitis (PSC). To evaluate further the effects of UDCA on this disease, we evaluated immunological markers and indices of inflammation during a one-year, prospective, open-label trial of UDCA therapy in patients with PSC. PATIENTS AND METHODS: Seventeen PSC patients were enrolled for one year of treatment with UDCA 12-15 mg/kg/day. Serum biochemical variables, immunological markers and indices of inflammation were compared before and at the end of therapy and 4 months after treatment had been withdrawn. Liver histology and immunohistochemistry for human leucocyte antigen (HLA) class I/II and intercellular adhesion molecule 1 (ICAM-1) expression were compared before and at the end of therapy. RESULTS: UDCA treatment was associated with significant improvements in serum biochemical liver tests, immunoglobulin levels and blood coagulation factors. Tumour necrosis factor alpha (TNF-alpha) production after in vitro whole-blood phytohaemagglutinin (PHA) stimulation was increased, but unaltered by UDCA therapy. Baseline serum levels of interleukin-6 (IL-6) and soluble IL-2 receptor were normal, and serum IL-8 levels were increased, but none of these variables was significantly affected by UDCA therapy. Liver histological stage/grade and HLA class I/II and ICAM-1 expression on biliary epithelial cells and hepatocytes were not markedly altered by UDCA therapy. CONCLUSIONS: UDCA therapy in PSC patients was associated with a decrease in cholestasis, but no consistent improvement in hepatic inflammation, fibrosis or histological stage of the disease. Immunomodulatory effects of UDCA in PSC do not appear to be HLA-restricted.     

Ursodeoxycholic acid decreases the serum transaminase levels of chronic liver disease patients treated with glycyrrhizin

The effects of ursodeoxycholic acid (UDCA) on the liver function test values were investigated in patients with chronic hepatitis (CH) and liver cirrhosis (LC) in whom treatment with glycyrrhizin (SNMC) for more than 6 months had failed to improve serum transaminase levels. Twenty-six patients treated with Stronger neo minophagen C (SNMC), 60 ml, i.v., three times/week) for more than 6 months were given UDCA (Urso, 600 mg/day) in addition (SNMC + UDCA group) and 22 patients were given UDCA (Urso, 600 mg/day) alone (UDCA group). The mean AST, ALT, γ-GTP and total bile acid (TBA) values during the 3 months before UDCA treatment and the 3 months after the start of UDCA treatment were compared in each case. The results showed that AST, ALT and γ-GTP were improved by 28, 34 and 46%, respectively in the 24 patients with CH, type C in the SNMC + UDCA group, and 27, 30 and 39%, respectively in the 14 patients with CH, type C in the UDCA group. UDCA was also effective in improving AST and ALT in the patients in the SNMC + UDCA group who were resistant to interferon therapy. The percentages of improvement in AST, ALT and γ-GTP in the 10 LC patients were lower than in the CH patients in both SNMC + UDCA and UDCA group. In conclusion, UDCA is useful in decreasing the serum transaminase levels of patients with CH, even when they are being treated with SNMC.     

Effect of long term simvastatin administration as an adjunct to ursodeoxycholic acid: evidence for a synergistic effect on biliary bile acid composition but not on serum lipids in humans

BACKGROUND: Stimulated bile acid synthesis preferentially utilises newly synthesised cholesterol, raising the possibility that combination of simvastatin (an inhibitor of cholesterol synthesis) with ursodeoxycholic acid (UDCA; a stimulator of bile acid synthesis) may result in reduced bile acid synthesis and greater enrichment of the pool with UDCA than that achieved with UDCA treatment alone. AIMS: To investigate the effect of simvastatin and UDCA given alone and in combination on serum and biliary lipid and biliary bile acid composition. METHODS: Eighteen patients with primary non-familial hypercholesterolaemia were studied during treatment with simvastatin 20 mg/day, UDCA 10 mg/kg/day, and a combination of the two drugs. Each regimen was given in random order for three months following a three month lead in period. RESULTS: Simvastatin significantly reduced serum low density lipoprotein (LDL) cholesterol but biliary cholesterol concentration remained unchanged. Combination of the two drugs had no synergistic effect on serum cholesterol concentration, but significantly increased the proportion of UDCA in the bile acid pool from 35% during UDCA to 48% during combination treatment (p<0.04). CONCLUSIONS: Results showed that: (1) simvastatin reduces serum LDL cholesterol but has no effect on biliary cholesterol concentration, supporting the concept that newly synthesised cholesterol is not the preferential source for biliary cholesterol; and (2) combination of simvastatin with UDCA has the predicted effect of enhancing the proportion of UDCA in the pool. This effect may be of benefit in the treatment of cholestatic liver diseases.     

Effect of ursodeoxycholic acid on liver iron stores and distribution in rats with normal or iron-supplemented diet

Abstract: Iron excess is a potential liver-damaging factor, and bile salts can increase iron digestive absorption and iron biliary excretion. The aim of this study was to investigate in rats the effect of ursodeoxycholic acid, a bile salt used in the treatment of chronic liver disease, on the hepatic iron stores in normal and iron-overload conditions. UDCA was administered by gavage to Sprague-Dawley rats. Iron hyperabsorption and overload were obtained by 5% carbonyl iron addition in diet. Hepatic iron stores and distribution were evaluated by liver iron concentration measurement and histologic assessment, respectively. Whatever the iron content of the diet, liver iron concentration was not modified by UDCA administration compared with the control groups. Iron distribution was not modified by UDCA in rats with normal diet. The total iron score was only transiently lowered by UDCA in iron supplemented rats compared with the control group at 1 month. In conclusion, chronic UDCA administration does not modify liver iron stores and distribution in rats with both normal or increased digestive iron absorption. These data suggest that UDCA is unlikely to increase hepatic iron stores in treated patients and that the benefit of UDCA treatment is probably not related to a decreasing effect of liver iron content.     

Gallstone dissolution with ursodeoxycholic acid in patients with chronic active hepatitis and two years follow-up

Chemical dissolution of cholesterol gallstones using ursodeoxycholic acid (UDCA) in six patients with histologically confirmed HBsAg-negative chronic active hepatitis was started after a minimum of one year of therapy with steroids, azathioprine, or chloroquine and a treatment-free period of 8-15 months. The treatment with UDCA lasted 3-20 months with a daily dose of 8-11 mg/kg. Four patients served as controls. A decrease in transaminases (P less than 0.05) occurred in all patients during the UDCA therapy. After completion of the treatment, the figures rose again, but did not return to the initial value. The stones dissolved in five patients. A second liver biopsy was carried out in two patients after UDCA therapy, and this showed no detectable deterioration. Four patients refused biopsy because the laboratory parameters had improved under UDCA. A stone recurred in one patient six months after the end of therapy; the others have remained free of stones for up to 24 months.     

Clinical studies on dissolution of gallstones using ursodeoxycholic acid

Ursodeoxycholic acid (UDCA), 7beta hydroxy epimer of chenodeoxycholic acid (CDCA), has been used as a choleretica for 20 years in Japan. Recent report showing increased excretion of UDCA in bile after CDCA administration may suggest the possibility that UDCA has similar effects to CDCA on bile cholesterol unsaturation and on gallstone dissolution. The present paper describes the clinical usefulness of UDCA for gallstone patients during the past two years. Seventy-four gallstone patients with functioning gall-bladders, 19 men and 55 women with a mean age of 48 years, have been treated for 6 months or more. UDCA, supplied in tablets (Ursosan), was given 450 mg per day. The disappearance or the reduction of stone size or number, or both (dissolution effect) was recognized in 32 out of 74 patients (43%). In case of radiolucent stones, the overall effective rate was estimated for 24 of 46 patients (52%). There may be no significant difference in dissolution effect between CDCA and UDCA treatment, however, the merit of UDCA treatment seems to have its few side effects.     

Improvement of biliary enzyme levels and itching as a result of long-term administration of ursodeoxycholic acid in primary biliary cirrhosis

Ursodeoxycholic acid (UDCA) was administered to 10 patients diagnosed as having primary biliary cirrhosis (PBC) after liver biopsy. Eight patients were anicteric, and two were icteric cases. One patient was in stage I, seven were in stage II, one in stage I-III, and one in stage III-IV of Scheuer's classification. Six hundred milligrams of UDCA were administered orally after meals three times daily to all of the patients for more than 1 yr. The period of UDCA administration ranged from 6 to 41 months. The major findings are as follows: 1) in six out of seven patients with pruritus, itching disappeared 1 month after administration of UDCA; 2) both serum alkaline phosphatase and gamma-glutamyltranspeptidase levels began decreasing significantly the first month after the onset of UDCA treatment, and continued decreasing throughout the treatment; 3) GOT and GPT levels also decreased significantly during the administration of UDCA, compared with before-treatment levels; 4) in one icteric patient with portal hypertension, although serum biliary enzyme levels improved after treatment, serum bilirubin level got worse, and the patient died of esophageal variceal hemorrhage. In another icteric case, biliary and bilirubin levels improved slightly after treatment; 5) antimitochondrial antibody titer decreased in four cases, but IgM levels and other immunological parameters were not changed; 6) serum UDCA increased significantly during UDCA treatment; in particular, glyco-UDCA occupied up to 40% of the total bile acid and CDC decreased to 25%; 7) portal inflammation activity decreased in all five patients who had undergone follow-up liver biopsy, more than 1 yr after UDCA administration--bridging fibrosis decreased in three cases; and 8) no side effects were observed in any of the cases. Although large-scale, randomized, controlled, double-blind tests are necessary, it is speculated that the long-term administration of UDCA is a safe and effective treatment for the improvement of biliary enzyme levels and pruritus in anicteric PBC.     

Ursodeoxycholic acid improves insulin sensitivity and hepatic steatosis by inducing the excretion of hepatic lipids in high-fat diet-fed KK-Ay mice

Type 2 diabetes mellitus is frequently accompanied by fatty liver/nonalcoholic fatty liver disease. Hence, accumulation of lipids in the liver is considered to be one of the risk factors for insulin resistance and metabolic syndrome. Ursodeoxycholic acid (UDCA) is widely used for the treatment of liver dysfunction. We investigated the therapeutic effects of UDCA on type 2 diabetes mellitus exacerbating hepatic steatosis and the underlying mechanisms of its action using KK-A(y) mice fed a high-fat diet. KK-A(y) mice were prefed a high-fat diet; and 50, 150, and 450 mg/kg of UDCA was orally administered for 2 or 3 weeks. Administration of UDCA decreased fasting hyperglycemia and hyperinsulinemia. Hyperinsulinemic-euglycemic clamp analyses showed that UDCA improved hepatic (but not peripheral) insulin resistance. Hepatic triglyceride and cholesterol contents were significantly reduced by treatment with UDCA, although the genes involved in the synthesis of fatty acids and cholesterol, including fatty acid synthase and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, were upregulated. Fecal levels of bile acids, neutral sterols, fatty acids, and phospholipids were significantly increased by UDCA treatment. The gene expression levels and protein phosphorylation levels of endoplasmic reticulum stress markers were not changed by UDCA treatment. These results indicate that UDCA ameliorates hyperglycemia and hyperinsulinemia by improving hepatic insulin resistance and steatosis in high-fat diet-fed KK-A(y) mice. Reduction of hepatic lipids might be due to their excretion in feces, followed by enhanced utilization of glucose for the synthesis of fatty acids and cholesterol. Ursodeoxycholic acid should be effective for the treatment of type 2 diabetes mellitus accompanying hepatic steatosis.     

Effects of ursodeoxycholic acid on synthesis of cholesterol and bile acids in healthy subjects

BACKGROUND/AIMS: Ursodeoxycholic acid (UDCA) decreases biliary secretion of cholesterol and is therefore used for the dissolution of cholesterol gallstones. It remains unclear whether these changes in biliary cholesterol excretion are associated with changes in cholesterol synthesis and bile acid synthesis. We therefore studied the activities of rate-limiting enzymes of cholesterol synthesis and bile acid synthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cholesterol 7alpha-hydroxylase, respectively, in normal subjects during UDCA feeding. METHODS: UDCA was given to 8 healthy volunteers (5 men, 3 women; age 24-44 years) in a single dose of 10-15 mg/kg body weight for 40 days. Before and during (days 3, 5, 10, 20, 30 and 40) UDCA treatment, urinary excretion of mevalonic acid and serum concentrations of 7alpha-hydroxy-4-cholesten-3-one (7alpha-HCO) were determined as markers of cholesterol and bile acid synthesis, respectively. The Wilcoxon signed rank test and Spearman's rank correlation coefficient were used for statistical analysis. RESULTS: Cholesterol synthesis and serum lipid concentrations remained unchanged during UDCA treatment for 40 days. However, synthesis of bile acids increased during long-term treatment with UDCA as reflected by an increase in 7alpha-HCO serum concentrations from 39.7 +/- 21.3 ng/ml (median 32.8 ng/ml) before treatment to 64.0 +/- 30.4 ng/ml (median 77.5 ng/ml) at days 30-40 of UDCA treatment (p < 0.05). CONCLUSIONS: UDCA treatment does not affect cholesterol synthesis in the liver, but does increase bile acid synthesis after prolonged treatment. This may represent a compensatory change following decreased absorption of endogenous bile acids as observed with UDCA therapy.     

Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver

BACKGROUND/AIM: The aim of this study was to assess the efficacy of ursodeoxycholic acid (UDCA) for primary biliary cirrhosis in a randomized, double-blind placebo-controlled trial. METHODS: Consecutive patients (n=192) were randomized to receive 14-16 mg UDCA/kg/day or placebo. Patients underwent a complete history, physical examination, liver chemistries, immunological determinations and liver biopsy at entry and at the end of the trial, which lasted for at least 2 years. Patients were seen every 3 months and the median follow-up was 3.4 years (range 0.3 to 6.1 years). RESULTS: Patients receiving UDCA (99) or placebo (93) were comparable with regard to age, sex, biochemical parameters and liver histology. UDCA treatment was associated with decreases in alkaline phosphatase, gammaglutamyl transferase, alanine aminotransferase, and cholesterol levels, effects which were conspicuous after 3 months of treatment and remained similar during the follow-up. During the study 31 patients (10 receiving UDCA and 21 placebo) discontinued the trial because of noncompliance (n=11), voluntary withdrawal (n=19) or adverse effects (n=1). Treatment failure (death or liver transplantation) was observed in 17 patients receiving UDCA and in 11 patients receiving placebo. Times to death or liver transplantation and to clinical complications were not significantly different in patients receiving UDCA or placebo. Histological analysis indicates that UDCA improved portal inflammation and prevented histological stage progression. By contrast, histological stage as well as ductular proliferation and ductopenia progressed in patients receiving placebo. CONCLUSIONS: Although UDCA treatment did not significantly affect time to death or liver transplantation and to clinical complications, the effects on both cholestasis and liver histology suggest that UDCA is safe and may be useful for preventing the progression of primary biliary cirrhosis.