Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis

BACKGROUND & AIMS: Long-term ursodeoxycholic acid (UDCA) therapy slows the progression of primary biliary cirrhosis. This study examined the effect of UDCA therapy on survival free of liver transplantation in a large group of patients. METHODS: Data from three clinical trials were combined in which patients with primary biliary cirrhosis were randomly assigned to receive UDCA (n = 273) or placebo (n = 275). After 2 years, patients from French and Canadian studies received UDCA for up to 2 years. Patients from the American study remained on their assigned treatment for up to 4 years. RESULTS: Survival free of liver transplantation was significantly improved in the patients treated with UDCA compared with the patients originally assigned to placebo (P < 0.001; relative risk, 1.9; 95% confidence interval, 1.3-2.8). Subgroup analyses showed that survival free of liver transplantation was significantly improved in medium- and high-risk groups (serum bilirubin level, 1.4 to 3.5 or > 3.5 mg/dL; P < 0.0001 and P < 0.03, respectively) and histological stage IV subgroup (P < 0.01). CONCLUSIONS: Long-term UDCA therapy improves survival free of liver transplantation in patients with moderate or severe disease. An effect in patients with mild disease is probably not found because they do not progress to end-stage disease in 4 years.     

Peroxide biosensors and mediated electrochemical regeneration of redox enzymes

BACKGROUND/AIMS/METHODS: Apolipoprotein E polymorphism, affecting intestinal absorption and biliary secretion of bile acids, might also contribute to the variable course and response to drug treatment of primary biliary cirrhosis. To test this possibility, we studied the apo E gene frequency, and the expression and response to drug therapy in different apo E isoforms of 88 patients with primary biliary cirrhosis, randomized to ursodeoxycholic acid, colchicine or placebo treatments for 2 years. RESULTS: The frequency of the epsilon2 allele was 2.4 times higher (p<0.01) in the patients with primary biliary cirrhosis compared with the Finnish population. At entry the patients with the epsilon4 allele were significantly younger (p<0.01) than those with other epsilon alleles, while the severity of primary biliary cirrhosis was similar in the three apolipoprotein E phenotypes. Liver enzymes, acute hepatic inflammation, serum total and low density lipoprotein cholesterol were decreased by ursodeoxycholic acid only in the patients with the epsilon4 and homozygous epsilon3 alleles, but not in those with the epsilon2 allele. Improvements of liver enzyme tests by ursodeoxycholic acid were more marked in the patients with the epsilon4 than other epsilon alleles. CONCLUSIONS: The present data show that in primary biliary cirrhosis the epsilon2 allele is overrepresented, and suggest that the expression of primary biliary cirrhosis and response of the disease to ursodeoxycholic acid treatment are closely related to the apo E polymorphism.     

Triple therapy with ursodeoxycholic acid, prednisone and azathioprine in primary biliary cirrhosis: a 1-year randomized, placebo-controlled study

BACKGROUND/AIMS: Treatment with ursodeoxycholic acid has been shown to decrease the rate of disease progression in patients with primary biliary cirrhosis, although the effect is modest. Since primary biliary cirrhosis has many features of an autoimmune disorder, immunosuppressives added to ursodeoxycholic acid may be of value in the treatment of primary biliary cirrhosis. METHODS: A 1-year randomized, double-blind, placebo-controlled trial was carried out in 50 patients with primary biliary cirrhosis, who had already been treated with ursodeoxycholic acid for at least 1 year, but had not achieved complete disease remission. Patients were randomized to additional prednisone (30 mg per day initially, tapered to 10 mg daily after 8 weeks) and azathioprine (50 mg daily) or placebo. A subgroup of patients received cyclical etidronate and calcium. The principal aim of the study was to assess the short-term benefits and risks of the combined bile acid and low-dose immunosuppressive regimen. Primary endpoints were effects on symptoms, liver biochemistry, liver histology, bone mass and the occurrence of adverse events. RESULTS: Pruritus (p=0.02), alkaline phosphatase, aspartate aminotransferase, IgM and procollagen-III-propeptide improved significantly (all p<0.002) in the combined treatment group as compared to the placebo group. Histological scores for disease activity and disease stage decreased significantly within the combination treatment group (p<0.001). CONCLUSIONS: In patients with primary biliary cirrhosis receiving ursodeoxycholic acid, there is an additional beneficial effect of 1-year treatment with prednisone and azathioprine on symptoms and biochemical, fibrogenetic and histological parameters. These results strongly encourage the evaluation of this triple treatment regimen in long-term controlled trials of adequate size to document its effect on clinical events.     

Effect of morphine on gastroesophageal reflux and transient lower esophageal sphincter relaxation

BACKGROUND: Results from animal studies and preliminary data from pilot studies in patients with primary biliary cirrhosis suggest that tauro-ursodeoxycholic acid has metabolic properties that may favour its long-term use as an alternative to ursodeoxycholic acid for patients with chronic cholestatic liver diseases. No direct comparison of tauro-ursodeoxycholic and ursodeoxycholic acids have yet been carried out in primary biliary cirrhosis. METHODS: The effects of ursodeoxycholic and tauro-ursodeoxycholic acids were compared in 23 patients with primary biliary cirrhosis according to a crossover design. Both drugs were administered at the daily dose of 500 mg. in a randomly assigned sequence for two 6-month periods separated by a 3-month wash-out period. RESULTS: Serum liver enzymes related to cholestasis and cytolysis consistently improved, as compared to baseline values, during the administration of both ursodeoxycholic and tauro-ursodeoxycholic acids, but no significant difference between these two bile acids was found. Both treatments were well tolerated and no patient complained of side effects. CONCLUSION: In the short-term, tauro-ursodeoxycholic acid appears to be safe and at least as effective as ursodeoxycholic acid for the treatment of primary biliary cirrhosis.     

An EIA method on single donor solubilized HLA antigens for the identification of anti-HLA antibodies

Primary biliary cirrhosis (PBC) is an immunologically mediated disease in which activated T lymphocytes attack and destroy epithelial cells in the small intralobular bile ducts of genetically susceptible patients. This article reviews the results of treatment of PBC with immunomodulatory agents. Results with drugs such as glucocorticoids, azathioprine, and chlorambucil have been disappointing because of either limited efficacy (azathioprine), toxicity (chlorambucil), or both (glucocorticoids). Colchicine improved tests of liver function in three prospective studies and was associated with improved survival for up to 4 years. However, survival benefits were lost at 8 years. Colchicine appears to slow the rate of progression of PBC but not to stop it. Preliminary results suggest that colchicine may have synergistic effects if used together with ursodeoxycholic acid, particularly in patients who are only partially responsive to ursodeoxycholic acid. Results with cyclosporine have been disappointing because of limited efficacy and predictable toxicity. The modest improvement in tests of liver function and survival are counterbalanced by the development of hypertension in some and worsening renal function in most. There is little beneficial effect on symptoms or histology. Results with methotrexate are promising. There are improvements in symptoms and tests of liver function that are equal to those seen with ursodeoxycholic acid and significant improvement in liver histology. Some patients, particularly those with striking inflammation and granulomas in portal triads, appear to have achieved sustained remission while on methotrexate. The effects of methotrexate are additive to those of ursodeoxycholic acid in patients whose blood tests have responded only partially to ursodeoxycholic acid. The most effective treatment of PBC will most likely use a combination of drugs such as ursodeoxycholic acid, colchicine, and methotrexate.     

Relationship between biliary and serum bile acids and response to ursodeoxycholic acid in patients with primary biliary cirrhosis

OBJECTIVE: Ursodeoxycholic acid (UDCA) improves liver biochemistries and enriches the bile with UDCA in patients with primary biliary cirrhosis. The aim of this study was to determine whether the degree of enrichment of bile correlated with that of serum and whether either of these measures correlated with improvement in measures of liver disease. METHODS: In a randomized study, biliary and serum bile acid analyses were performed at entry and after 2 yr of UDCA or placebo. RESULTS: The percentage of ursodeoxycholic acid in bile increased by 42% in the UDCA group (n = 61) compared with 8% in the placebo group (n = 57) (p < 0.0001). Measurement of serum bile acids in 32 patients (18 ursodeoxycholic acid, 14 placebo) indicated that at 2 yr, ursodeoxycholic acid comprised 65% of serum bile acids in the treated group and 7% in the placebo group. Agreement between bile and serum was fair (r = 0.75, p < or = 0.00002) because in some patients, plasma but not biliary bile acids were enriched with UDCA. Changes in biliary ursodeoxycholic acid correlated significantly but weakly with the changes in serum alkaline phosphatase, AST, bilirubin, and in Mayo risk score. Correlations between changes in serum bile acid composition and biochemical measures of disease activity were even weaker. CONCLUSION: The measurement of biliary bile acids is superior to that of serum bile acids for assessing the compliance and changes in the circulating bile acids in patients receiving ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Furthermore, measures to further increase the proportion of ursodeoxycholic acid in circulating bile acids should be explored.     

Ursodeoxycholic acid corrects defective natural killer activity by inhibiting prostaglandin E2 production in primary biliary cirrhosis

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

Increased serum IgM class anti-lipid A antibody and therapeutic effect of ursodeoxycholic acid in primary biliary cirrhosis

BACKGROUND/AIMS: There is as yet no explanation for the increased serum IgM level observed in patients with primary biliary cirrhosis. METHODOLOGY: The serum IgM class anti-lipid A antibody was determined in patients with primary biliary cirrhosis using Elisa and Western blot techniques. RESULTS: Using enzyme-linked immunosorbent assay, we found the concentration of serum IgM class anti-lipid A antibody was the highest in 21 patients with PBC as compared to 29 patients with other liver diseases and 19 controls. Using western blotting, IgM class anti-lipid A antibody was detected as a clear band in patients with primary biliary cirrhosis. The level of this antibody correlated significantly (p < 0.005) with that of total IgM. Treatment with ursodeoxycholic acid improved not only the routine biochemical profile but also the level of IgM class anti-lipid A antibody (p < 0.005). CONCLUSIONS: Since the lipid A plays a primary role in the biological activities of lipopolysaccharide (a component of gram-negative bacteria), bacterial antigen may participate in the elevation of serum IgM levels in patients with primary biliary cirrhosis. Ursodeoxycholic acid treatment may improve the cholestasis, and this may have altered the response to stimulation by gut derived bacterial antigens.     

Unusual diagnosis in recurrent arthritis, erythema nodosum and arrhythmia

HISTORY AND ADMISSION FINDINGS: A 42-year-old woman, with recurrent arthritis of the large joints and erythema nodosum for 7 years, was admitted because of recent onset of bouts of rapid heart rate. A 2/6 systolic murmur at Erb's point was the only contributory finding on physical examination. INVESTIGATIONS: The transaminases and gamma-GT were elevated, as were total cholesterol, LDL fraction, IgM, total protein, gamma-globulin and IgM. Antimitochondrial antibodies, especially anti-M2, were positive, while rheumatoid factor and C-reactive protein were negative. ANA, ANCA and antibodies against double-strand DNA were not demonstrated. ENA screening was negative. Abdominal computed tomography showed discrete intrahepatic cholestasis. Liver biopsy revealed chronic destructive cholangitis, i.e. the early stage of primary biliary cirrhosis. TREATMENT AND COURSE: On treatment with ursodeoxycholic acid (10 mg/kg daily) the patient has remained free of symptoms for 3 years and laboratory tests no longer showed evidence of impaired liver function. CONCLUSION: Primary biliary cirrhosis should be included in the differential diagnosis of recurrent arthritis and erythema nodosum, as early treatment with ursodeoxycholic acid can favourably influence its course.     

Ursodeoxycholic acid does not improve the clinical course of primary sclerosing cholangitis over a 2-year period

BACKGROUND: Ursodeoxycholic acid has been shown to be a useful agent in the clinical management of patients with primary biliary cirrhosis and autoimmune chronic active hepatitis. Its efficacy is presumed to be based upon its ability to act as a detergent and to incite a choleresis. Recent additional data suggest it also reduces HLA antigen expression on liver and biliary epithelial cells and impairs T cell reactivity. METHODS: A randomized controlled study of 59 patients with primary sclerosing cholangitis was performed over a 24 months period with 3 groups being studied. Group I consisted of 20 patients who were given ursodeoxycholic acid 300 mg orally twice a day; group II consisted of 19 patients who were given colchicine 0.6 mg orally BID; and group III was an untreated medical control group. All three groups were seen at regular 3-month intervals and had quarterly, annual and terminal studies performed to assess their disease status. RESULTS: No difference between groups was evident after two full years of therapy when parameters of liver injury, liver function, liver size and hepatic copper content were compared between groups. Similarly, no difference in ERCP findings was evident between groups either at entry or after two years of therapy. CONCLUSIONS: These data suggest that ursodeoxycholic acid is no better than colchicine or simple medical follow-up. Thus, neither ursodeoxycholic acid or colchicine can be considered to be effective therapies for primary sclerosing cholangitis.     

Guided bone regeneration in the treatment of periimplantitis

Immunological abnormalities frequently observed in patients with primary biliary cirrhosis are considered to be related to the pathogenesis of this disease. We performed a prospective trial to evaluate whether immune mechanisms play a role in the effectiveness of ursodeoxycholic acid (UDCA) therapy. Fifteen female patients with primary biliary cirrhosis were followed for 1 year and were then treated with UDCA (600 mg/day) for another year. Laboratory tests, including peripheral blood lymphocyte subsets assessed by dual colour fluorescence analysis using monoclonal antibodies against respective T cell markers, were evaluated at the beginning of the study, at the start of therapy and at the end of therapy. In primary biliary cirrhosis, the proportion of cytotoxic T cells, suppressor inducer T cells and alpha beta-receptor bearing T cells were significantly lower than in healthy controls. No significant changes were observed in the proportions during the year before the therapy. These reductions, however, recovered to normal ranges after 1 year of UDCA therapy. These changes were associated with an improvement in the serum levels of aspartate aminotransferase, alkaline phosphatase, gamma-globulin and IgM. The close correlation between the improvement in the imbalance of lymphocyte subsets after the therapy and the clinical status suggests that an immunological process may play a role in the effectiveness of therapy in primary biliary cirrhosis.     

Primary biliary cirrhosis associated with mixed type autoimmune hemolytic anemia and sicca syndrome: a case report and review of literature

A case presenting with an unusual association of primary biliary cirrhosis and mixed type autoimmune hemolytic anemia plus sicca syndrome is described. The 49-yr-old female primary biliary cirrhosis patient had a confirmed sicca syndrome and presented with jaundice and life-threatening anemia. Laboratory tests revealed positive Coombs' test with coexisting cold and warm autoantibodies. She was successfully treated by blood transfusion with packed red cells lacking any red cell antigens corresponding to serum alloantibodies and pulse methylprednisolone therapy. The patient remained stable under maintenance treatment using oral steroids and ursodeoxycholic acid. This case is probably the first reported showing an association between primary biliary cirrhosis and mixed type autoimmune hemolytic anemia plus sicca syndrome and was probably induced by heterogenous and complicated autoimmune reactions.     

Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group

BACKGROUND: There is no satisfactory medical therapy for patients with primary sclerosing cholangitis. Ursodiol (ursodeoxycholic acid) benefits patients with primary biliary cirrhosis, another cholestatic liver disease. METHODS: From May 1989 to July 1995, we enrolled 105 patients with well-documented primary sclerosing cholangitis in a randomized, double-blind study comparing ursodiol (13 to 15 mg per kilogram of body weight per day in divided doses) with placebo. The primary outcome was the time to treatment failure, defined as death; liver transplantation; histologic progression by two stages (of four) or progression to cirrhosis; the development of varices, ascites, or encephalopathy; sustained quadrupling of the serum bilirubin concentration; marked worsening of fatigue or pruritus; inability to tolerate the drug; or voluntary withdrawal from the study. RESULTS: We analyzed data on the 51 patients in each group with at least 3 months of follow-up; the median follow-up was 2.2 years. There was no significant difference between the groups in time to treatment failure (relative risk of treatment failure in the ursodiol group, 1.01; 95 percent confidence interval, 0.6 to 1.7). During the first two years of follow-up, treatment was unsuccessful in 17 of 32 patients (53 percent) in the placebo group and 16 of 31 (52 percent) in the ursodiol group. There were also no differences in time to treatment failure for patients with early-stage disease or in time to liver transplantation. Ursodiol, but not placebo, was associated with improvement in serum alkaline phosphatase, aspartate aminotransferase, bilirubin, and albumin levels at one and two years. CONCLUSIONS: In a group of patients with well-defined primary sclerosing cholangitis, ursodiol provided no clinical benefit.     

Primary sclerosing cholangitis--an ulcerative colitis-associated illness with surgical consequences

Primary sclerosing cholangitis (PSC) is generally associated with ulcerative colitis (UC). The disease typically progresses slowly, but ultimately, and leads to cirrhosis, liver failure or bile duct cancer. PSC patients with simultaneous ulcerative colitis are also at higher risk for colorectal cancer. At the present time, there is no effective treatment for PSC, although preliminary data show encouraging results after treatment with ursodeoxycholic acid. However, there are no data concerning the delay or prevention of progress of the disease with this drug, because follow-up time is not yet long enough. Isolated bile duct strictures should be treated endoscopically. The possible effect of proctocolectomy on the course of PSC is controversial. Liver transplantation is the therapy of choice for PSC in its final stage. The 5-year survival rate (89%) is significantly better than after transplantation for other indications. Patients with ulcerative colitis have to be followed up by lifelong colonoscopy. Although the course of UC after transplantation is mostly asymptomatic, these patients are at higher risk for colorectal cancer.     

Organic nitrates--new perspectives on an old drug group

A quarter of patients with erythropoietic protoporphyria develop mild to severe cholestatic liver disease. The determination of early indicators of hepatobiliary involvement are of pivotal importance to select patients for choleretic therapy. Porphyrin parameters were studied during ursodeoxycholic acid treatment in eight patients with protoporphyrin-associated liver disease and eight patients with liver failure before and after liver transplantation. The patients with intrahepatic cholestasis exhibited excessive protoporphyrinemia (27 mumol/l) compared with controls (normal < 0.64 mumol/l). Fecal protoporphyrin excretion decreased in patients with deterioration of liver function, whereas urinary coproporphyrin increased up to 2290 nmol/24 h (normal < 119 nmol/24 h). Coproporphyrin isomer I proportion increased to 71 +/- 10% (mean +/- SD, n = 8) in patients with terminal liver failure (normal < 31%). During therapy with ursodeoxycholic acid biochemical improvement occurred but without clinical remission in most cases. Eight patients underwent liver transplantation between 1987 and 1997. One patient died of liver failure. Two transplant recipients are in a good condition since 8 and 9 years, respectively. All explanted livers revealed micronodular cirrhosis and high protoporphyrin levels of about 25,000-fold (mean, n = 3). Immediately after liver transplantation protoporphyrin in erythrocytes decreased to 46-96% of pre-operative values. Coproporphyrin remained moderately elevated due to post-operative cholestasis. A post-operative rise in fecal protoporphyrin elimination reflected sufficient biliary clearence of protoporphyrin by the transplant. In conclusion, moderate coproporphyrinuria with isomer I is the earliest sign of liver complications in erythropoietic protoporphyria. Progression of protoporphyrin induced toxic liver injury is indicated by excessive protoporphyrinemia and coproporphyrinuria with an isomer I proportion > 71 +/- 10%, and reduction of fecal protoporphyrin excretion. Results suggest that therapy of intrahepatic cholestasis with ursodeoxycholic acid is only effective in the initial stages of liver disease in erythropoietic protoporphyria. In patients with severe cholestatic hepatic failure, liver transplantation is the treatment of choice.     

Effects of ursodeoxycholic acid on hepatic inflammation and histological stage in patients with primary biliary cirrhosis

OBJECTIVES: Ursodeoxycholic acid (UDCA) has been reported to be of benefit in the treatment of primary biliary cirrhosis; however, the effects of UDCA on the histological features of primary biliary cirrhosis are uncertain. The goal of this study was to determine the histological effects of 2 yr of treatment with UDCA compared to placebo in a prospective randomized trial of primary biliary cirrhosis. We also sought to correlate the changes in inflammation and histological stage with changes in serum bilirubin, Mayo Risk Score, and the percentage of UDCA in bile in these patients. METHODS: Sixty-one patients (32 receiving UDCA, 29 receiving placebo) who had initial and 2-yr biopsies were studied. Biopsy specimens were evaluated by a single pathologist under coded identification. The degree of inflammation and histological stage were graded on a scale of 0 to 4. RESULTS: There was no significant difference in the degree of inflammation with UDCA treatment when compared to the placebo group at 2 yr. There was a significant but weak indirect association between degree of enrichment of UDCA and changes in inflammation (r = -0.34, p = .02). There was no detectable change in stage in either the UDCA-treated or placebo group when comparing pre- and posttreatment specimens. There were no associations with changes in serum bilirubin or Mayo Risk Score and degree of inflammation. CONCLUSIONS: No significant changes in the degree of inflammation or histological stage were apparent after 2 yr of treatment with UDCA or in the placebo group. A tendency toward improvement in inflammation was noted with greater degrees of biliary UDCA enrichment. Longer term studies will be necessary to determine whether UDCA has a beneficial effect on histological stage.     

Antibodies to pyruvate dehydrogenase in primary biliary cirrhosis: correlation with histology

Antimitochondrial antibodies to pyruvate dehydrogenase are the hallmark of primary biliary cirrhosis. Their pathogenic role has not been proven, although antibodies to pyruvate dehydrogenase are bound to biliary epithelium. The aim of this study was to characterize serum IgA antibodies to pyruvate dehydrogenase and to evaluate their response to different treatment regimens. We also compared the level of antibodies with severity of histological lesions and the data of biochemical liver tests. Serum samples were collected at baseline and after 24 months from 61 primary biliary cirrhosis patients, whereas 23 patients were treated with ursodeoxycholic acid, 20 with colchicine, and 18 with placebo. ELISA was used to detect antibodies to pyruvate dehydrogenase. IgA and IgG were separated with jacalin and protein-A, respectively. Capacity of immunoglobulins to inhibit enzymatic activity was detected by spectrophotometric observation of the rate of enzyme reaction. 49 (80.3%) of the 61 patients possessed IgA antibodies to pyruvate dehydrogenase. Significant decrease in IgA antibodies was observed only in the ursodeoxycholic acid group (p<0.05). 15 of 18 IgA preparations and all 24 IgG preparations of patients' sera were inhibitory towards pyruvate dehydrogenase (mean inhibitory percent +/-SD: 42+/-33.4% and 79+/-22.4%, respectively, at a protein concentration of 100 microg/ml). The level of serum antibodies to pyruvate dehydrogenase correlated with several histological parameters (fibrosis, inflammatory infiltrate), but not with biochemical parameters. Our data reveal that IgA antibodies to pyruvate dehydrogenase inhibit enzyme function. The correlation between antibodies to pyruvate dehydrogenase and histological parameters might suggest the pathogenic role of these antibodies.     

Ursodeoxycholic acid treatment in cholesterol gallstone disease: effects on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, biliary lipid composition, and plasma lipid levels

The present study was undertaken to characterize the effects of ursodeoxycholic acid on biliary lipid metabolism in man. Fifteen gallstone patients were treated with ursodeoxycholic acid at a daily dosage of 15 mg per kg body weight for about 4 weeks before cholecystectomy. At operation a liver biopsy, together with gallbladder and hepatic bile, were obtained. Eighteen untreated gallstone patients undergoing cholecystectomy served as controls. During treatment with ursodeoxycholic acid, hepatic bile became unsaturated with cholesterol in all patients investigated. The total biliary lipid concentration remained unchanged. The hepatic cholesterol concentration decreased by about 20%. No significant change in the microsomal HMG CoA reductase activity was observed (38.5 +/- 6.7 pmol . min-1 . mg protein-1 vs 38.3 +/- 4.7 pmol . min-1 . mg protein-1 in the controls; means +/- SEM). Plasma concentrations of total cholesterol were reduced by about 10%, and those of high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol by about 15%. Plasma triglyceride levels remained essentially unchanged during treatment. We conclude that, similar to chenodeoxycholic acid therapy, ursodeoxycholic acid treatment results in unsaturation of fasting hepatic bile. In contrast to the changes seen during chenodeoxycholic acid feeding, however, the unsaturation of hepatic bile during ursodeoxycholic acid treatment is not primarily related to a decreased hepatic HMG CoA reductase activity. Furthermore, while chenodeoxycholic acid tends to increase plasma LDL levels, such changes are not seen during ursodeoxycholic acid treatment.     

Detection of retroviral antibodies in primary biliary cirrhosis and other idiopathic biliary disorders

BACKGROUND: Retroviruses have been implicated in the aetiology of various autoimmune diseases. We used immunoblots as a surrogate test to find out whether retroviruses play a part in the development of primary biliary cirrhosis. METHODS: We did western blot tests for HIV-1 and the human intracisternal A-type particle (HIAP), on serum samples from 77 patients with primary biliary cirrhosis, 126 patients with chronic liver disease, 48 patients with systemic lupus erythematosus, and 25 healthy volunteers. FINDINGS: HIV-1 p24 gag seroreactivity was found in 27 (35%) of 77 patients with primary biliary cirrhosis, 14 (29%) of 48 patients with systemic lupus erythematosus, 14 (50%) of 28 patients with chronic viral hepatitis, and nine (39%) of 23 patients with either primary sclerosing cholangitis or biliary atresia, compared with only one (4%) of 24 patients with alcohol-related liver disease or alpha1-antitrypsin-deficiency liver disease, and only one (4%) of 25 healthy volunteers (p=0.003). Western blot reactivity to more than two HIAP proteins was found in 37 (51%) of patients with primary biliary cirrhosis, in 28 (58%) of patients with systemic lupus erythematosus, in 15 (20%) of patients with chronic viral hepatitis, and in four (17%) of those with other biliary diseases. None of the 23 patients with either alcohol-related liver disease or alpha1-antitrypsin deficiency, and only one of the healthy controls showed the same reactivity to HIAP proteins (p<0.0001). Our results showed a strong association between HIAP seroreactivity and the detection of autoantibodies to double-stranded DNA. HIAP seroreactivity was also strongly associated with the detection of mitochondrial, nuclear, and extractable nuclear antigens. INTERPRETATION: The HIV-1 and HIAP antibody reactivity found in patients with primary biliary cirrhosis and other biliary disorders may be attributable either to an autoimmune response to antigenically related cellular proteins or to an immune response to uncharacterised viral proteins that share antigenic determinants with these retroviruses.     

Screening patients with celiac disease for primary biliary cirrhosis and vice versa

BACKGROUND: An association between celiac disease and primary biliary cirrhosis has been reported in a few cases, mainly as individual case reports. OBJECTIVES: To screen adult patients with celiac disease for primary biliary cirrhosis and patients with primary biliary cirrhosis for intestinal celiac involvement. METHODS: The celiac group consisted of 336 adults (218 women and 118 men; mean age, 36 yr; range 18-74 yr) with celiac disease diagnosed by serological and histological tests, 38 with newly diagnosed celiac disease and 298 with previously diagnosed celiac disease who were consuming a gluten-free diet. The mean follow-up period was 6 yr (range, 1-16 yr). Liver function parameters and autoantibody levels were determined, and, when indicated, histological tests were performed. The biliary cirrhosis group consisted of 65 subjects (58 women and seven men) (mean age, 59 yr; range, 35-67 yr) with primary biliary cirrhosis diagnosed 1-17 years previously (mean, 7 yr) on the basis of the usual biochemical, serological, and histological criteria. Antigliadin and antiendomysium antibody levels were determined, and two biopsy specimens from the distal duodenum obtained during endoscopy were evaluated. RESULTS: In patients with celiac disease, impairment of liver function was frequently found at diagnosis (16 of 38, or 44%), but primary biliary cirrhosis was diagnosed in only one case. In patients with primary biliary cirrhosis, no cases of celiac disease, as currently defined, were found. CONCLUSIONS: Our findings indicate that celiac disease and primary biliary cirrhosis are rarely associated and support the hypothesis that the intestinal lesions per se are not responsible for the liver disease.