Therapy For Primary Biliary Cirrhosis Research Articles

New treatments/targets for primary biliary cholangitis.

SummaryPrimary biliary cholangitis (PBC) is an autoimmune, cholestatic, chronic liver disease that ultimately progresses towards cirrhosis and liver failure if untreated. While ursodeoxycholic acid has been established as standard of care for PBC in the last few decades, significant advances in second-line treatment options have recently been made and new therapeutic developments are currently under evaluation. The purpose of this article is to provide the clinician with an overview of the current treatment options and future opportunities for patients with PBC.

Exercise therapy in primary biliary cirrhosis: the importance of moving while sitting on a surgical waiting list—a case study

BackgroundIt is being increasingly recognised that reduced cardiorespiratory fitness is associated with poorer outcomes after major surgery. Exercise limitation and reduced aerobic capacity are common in people with end-stage liver...

SAT-398 - Vitamin D Supplementation Therapy for Primary Biliary Cirrhosis: A Retrospective Clinical Study

SAT-398 - Vitamin D Supplementation Therapy for Primary Biliary Cirrhosis: A Retrospective Clinical Study

Therapy of Primary Biliary Cirrhosis: Novel Approaches for Patients with Suboptimal Response to Ursodeoxycholic Acid

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease of presumed autoimmune pathogenesis, characterized by the inflammation and damage of the intrahepatic intermediate and small bile ducts, which eventually results in cirrhosis. A number of randomized and observational and pilot studies using several agents were carried out in the 80s, but no clear results or even harmful effects were reported. Over the past 2 decades, increasing evidence indicates that ursodeoxycholic acid (UDCA) - 13 to 16 mg/kg/day - is the treatment of choice for patients with PBC. Biochemical response to UDCA, assessed at 1 year, clearly predicts the long-term outcome, since in UDCA, responders survival is similar to that estimated for the matched control population. However, about 40% of patients have incomplete biochemical response and increased risk of progression and decreased survival free of transplantation. Patients with suboptimal biochemical response to UDCA outline the group in whom further single or combined treatments with UDCA are needed. Accordingly, data on the effect of fibrates alone or in combination with UDCA, and budesonide in combination with UDCA have been reported. The combined treatment of UDCA and fibrates in patients without optimal biochemical response to UDCA improves the degree of cholestasis and may minimize the long-term management of these patients. The results of the combined therapy of UDCA with budesonide are appealing but they should be established in large randomized trials. The effect of new agents such obeticholic acid are promising, since the addition of this farnesoide-X-receptor agonist bile acid in patients with stable UDCA dosage and increased alkaline phosphatase levels results in an improvement of cholestasis as compared to placebo, with a parallel decrease of aminotransferases and immunoglobulin M, as well as one surrogate marker of bile acid synthesis. New molecular therapies are currently being investigated.

Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is a progressive autoimmune disease of the liver. It is the most common cause of chronic intrahepatic cholestatic liver disease in adults. This review addresses the epidemiology, etiology and genetics, pathophysiology and pathogenesis, diagnosis, differential diagnosis, treatment, complications, and prognosis of PBC. Figures show the pathogenesis and natural history of PBC and histologic features of the four stages of PBC. Tables list diagnostic criteria for PBC via the American Association for the Study of Liver Diseases, differential diagnosis for PBC, medications used to treat PBC, secondary therapy for PBC, and follow-up of patients with PBC. This review contains 2 highly rendered figures, 5 tables, and 45 references.

Fenofibrate is effective adjunctive therapy in the treatment of primary biliary cirrhosis: A meta-analysis

Fenofibrate is a potential novel therapy for primary biliary cirrhosis (PBC). We performed a systematic review and a meta-analysis of studies of fenofibrate in PBC. Electronic database search was performed for relevant studies. A search of abstracts presented in the main scientific meetings in the field and articles in press was also performed. Random effect model was used to pool the effect size across studies for changes in alkaline phosphatase, GGT, bilirubin and IgM levels before and after treatment and the overall rate of complete response to fenofibrate therapy. Six studies with 102 patients met the inclusion criteria. All studies were case series and in all, patients who had no or incomplete response to UDCA had fenofibrate added at a dose of 100-200mg daily. Treatment duration ranged from 8-100weeks. Treatment with fenofibrate was associated with a significant decrease in alkaline phosphatase (-114IU/L, 95% CI: -152 to -76, P<0.0001); a significant decrease in GGT level (-92IU/L, 95% CI: -149 to -43; P=0.0004); significant decrease in total bilirubin (-0.11mg/dL, 95% CI: -0.18 to -0.08; P=0.0008); and a significant decrease in IgM level (-88mg/dL, 95% CI: -119 to -58; P<0.0001). The complete response rate was 69% (95% CI: 53-82%) with an odds ratio of 82.8 (95% CI: 21.6-317.2; P=0.024) while on fenofibrate. Fenofibrate at doses of 100-200mg daily appears to be effective adjunctive therapy in PBC patients who had no or incomplete response to UDCA. There is a critical need for larger scale randomized trials to determine its effect on liver-related morbidity and mortality (or progression towards end-stage disease).

Network Meta-Analysis of Randomized Controlled Trials

Major ursodeoxycholic acid (UDCA)-based therapies for primary biliary cirrhosis (PBC) include UDCA only, or combined with either methotrexate (MTX), corticosteroids (COT), colchicine (COC), or bezafibrate (BEF). As the optimum treatment regimen is unclear and warrants exploration, we aimed to compare these therapies in terms of patient mortality or liver transplantation (MOLT) and adverse events (AE).PubMed, the Cochrane Library, and Scopus were searched for randomized controlled trials up to August 31, 2014. We estimated the hazard ratios (HRs) for MOLT and odds ratios (ORs) for AE. A sensitivity analysis based on the dose of UDCA was also executed.Thirty-one eligible articles were included. Compared with COT plus UDCA, UDCA (HR 0.38, 95% confidence interval [CI] 0.09-1.39), BEF plus UDCA (HR 0.29, 95% CI 0.02-4.83), COC plus UDCA (HR 0.39, 95% CI 0.07-2.25), MTX plus UDCA (HR 0.28, 95% CI 0.05-1.63), or OBS (HR 0.49, 95% CI 0.11-2.01) all provided an increased risk of MOLT. With respect to drug AE profile, although not differing appreciably, BEF plus UDCA was associated with more AEs compared with UDCA (OR 3.16, 95% CI 0.59-20.67), COT plus UDCA (OR 2.27, 95% CI 0.15-33.36), COC plus UDCA (OR 1.00, 95% CI 0.09-12.16), MTX plus UDCA (OR 2.03, 95% CI 0.23-17.82), or OBS (OR 3.00, 95% CI 0.53-20.75). The results of sensitivity analyses were highly consistent with previous analyses.COT plus UDCA was the optimal UDCA-based regimen for both MOLT and AEs. BEF plus UDCA was most likely to cause AEs, whereas monotherapy with UDCA and coadministriation of COT plus UDCA appeared to be associated with the fewest AEs for PBC treatment.

New therapies for primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a rare inflammatory liver disease for which ursodeoxycholic acid (UDCA) is the only therapy approved by the U.S. Food and Drug Administration. Patients with a biochemical response to UDCA therapy have a similar survival rate compared to the general population. However, up to 40% of PBC patients do not achieve a complete response to UDCA, have an increased risk of liver-related death and liver transplantation, and represent a persistent medical need for new therapies. Several novel drugs have recently been studied and show potential efficacy in PBC. Obeticholic acid, a farnesoid X receptor agonist, has been tested in phase II trials and initial results after 1 year in a phase III international trial suggest that it may be effective in achieving a biochemical response in approximately 40% of patients who do not completely respond to UDCA. Several small studies on fibrates have suggested that they may have efficacy, but larger studies are needed. Surprisingly, results of immunomodulators and biologics have not yet been able to demonstrate efficacy, but new approaches have shown promise in animal models and their translation to human clinical trials are awaited.

Old and novel therapies for primary biliary cirrhosis.

Despite the presumed immunological pathogenesis of primary biliary cirrhosis, no clear or even harmful consequences resulted from some specific treatments addressed to modify the immunological condition. However, ursodeoxycholic acid (UDCA; 13-16 mg/kg/d) has clear favorable effects not only by improving biochemical cholestasis, but also by delaying the histological progression. Long -term treatment with UDCA is associated with excellent survival, free of transplantation in cases showing biochemical response at one year. In the remaining patients, data on the effect of fibrates, budesonide, or obeticholic acid are encouraging. Pruritus is usually managed using resins; further steps are needed in resistant cases with the use of rifampicin, naltrexone, sertraline, or invasive procedures such as albumin dialysis. Osteoporosis, which is highly prevalent in patients with deep and prolonged cholestasis, improves with bisphosphonates; current data indicate that both weekly alendronate and monthly ibandronate increase bone mass in patients with osteoporosis. Nutritional and fat-vitamin supplementation is also mandatory in patients with severe cholestasis.

Innate immunity drives xenobiotic-induced murine autoimmune cholangitis

Although primary biliary cirrhosis (PBC) is considered a model autoimmune disease, it has not responded therapeutically to traditional immunosuppressive agents. In addition, PBC may recur following liver transplantation, despite the absence of major histocompatibility complex (MHC) matching, in sharp contrast to the well-known paradigm of MHC restriction. We have suggested previously that invariant natural killer T (iNK T) cells are critical to the initiation of PBC. In this study we have taken advantage of our ability to induce autoimmune cholangitis with 2-octynoic acid, a common component of cosmetics, conjugated to bovine serum albumin (2-OA-BSA), and studied the natural history of pathology in mice genetically deleted for CD4 or CD8 following immunization with 2-OA-BSA in the presence or absence of α-galactosylceramide (α-GalCer). In particular, we address whether autoimmune cholangitis can be induced in the absence of traditional CD4 and CD8 responses. We report herein that CD4 and CD8 knock-out mice immunized with 2-OA-BSA/PBS or 2-OA-BSA/α-GalCer develop anti-mitochondrial antibodies (AMAs), portal infiltrates and fibrosis. Indeed, our data suggest that the innate immunity is critical for immunopathology and that the pathology is exacerbated in the presence of α-GalCer. In conclusion, these data provide not only an explanation for the recurrence of PBC following liver transplantation in the absence of MHC compatibility, but also suggest that effective therapies for PBC must include blocking of both innate and adaptive pathways.

Editorial for ‘Randomized controlled trial assessing the effect of simvastatin in primary biliary cirrhosis’

Editorial for ‘Randomized controlled trial assessing the effect of simvastatin in primary biliary cirrhosis’

Cost and health consequences of treatment of primary biliary cirrhosis with ursodeoxycholic acid

Long-term use of ursodeoxycholic acid (UDCA) is the recommended therapy in primary biliary cirrhosis (PBC). The lifetime effectiveness and cost-effectiveness of UDCA in PBC have, however, not been assessed. To estimate the health outcomes and lifetime costs of a Norwegian cohort of PBC patients on UDCA. Norwegian PBC patients (n = 182) (90% females; mean age 56.3 ± 8.9 years; Mayo risk score 4.38) who were included in a 5-year open-label study of UDCA therapy were subsequently followed up for up to 11.5 years. The lifetime survival was estimated using a Weibull survival model. The survival benefit from UDCA was based on a randomised clinical trial from Canada, comparing the effect of non-UDCA and UDCA. Survival and costs of standard care vs. standard care plus UDCA were simulated in a Markov model with death and liver transplantation as major events, invoking transition of a patient's state in the model. The gain in life expectancy for a PBC patient on UDCA compared with standard care was 2.24 years (1.19 years discounted). The lifetime treatment costs were EUR 151,403 and EUR 157,741 (EUR 102,912 and EUR 115,031 discounted) for patients with and without UDCA respectively. A probabilistic sensitivity analysis indicated an 82% probability that UDCA entails both greater life expectancy and lower costs than standard care. The results of this study indicate that UDCA therapy is a dominant strategy as it confers reduced morbidity and mortality, as well as cost savings, compared with standard therapy.

Therapeutic Equivalence of Ursodeoxycholic Acid Tablets and Ursodeoxycholic Acid Capsules for the Treatment of Primary Biliary Cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic cholestatic, progressive inflammatory liver disease with a suspected autoimmunological pathogenesis. The disease is typically diagnosed in women at an age between 30 and 65 years and has a prevalence of up to 1 in 1000 women over the age of 40. The only approved medical therapy for PBC is ursodeoxycholic acid (UDCA) in a recommended dose of 13–15mg/kg/day. UDCA is a hydrophilic dihydroxy bile acid (3a,7bdihydroxy-5b-cholanoic acid). In humans, UDCA accounts for up to 4% of the bile acid pool. Following oral administration, approximately 30–60% of UDCA is absorbed in the gut. After intestinal absorption, UDCA enters the portal circulation and is then taken up by the hepatocytes via specific bile acid transporters. Within the hepatocyte, UDCA is conjugated to glycine or taurine and is subsequently transported into the bile ducts by the bile salt export pump (BSEP). In bile, UDCA concentration peaks 1 3 h following oral administration. In humans, the biological half-life of UDCA is 3.5–5.8 days and the predominant route of elimination is by feces. UDCA exerts its beneficial effects at the level of hepatocytes and cholangiocytes. It stimulates hepatocyte secretion by mostly post-transcriptional mechanisms, including insertion of transporters like BSEP and the anion exchanger AE2. In addition, UDCA exerts antiapoptotic effects in hepatocytes and protects cholangiocytes against endogenous toxic bile acids by modifying micelle formation. UDCA consistently improves the biochemical parameters of cholestasis, delays the histological progression and the time to liver transplantation in patients suffering from PBC. Both, UDCA 250mg capsules and UDCA 500mg tablets (“Ursofalk1”), are registered in Germany and other European countries for the treatment of PBC. UDCA 500mg tablets were developed to facilitate medication intake compared to the standard UDCA 250mg capsule preparations. Tablets are considerably smaller, but contain twice as much active pharmaceutical ingredient compared to the capsule preparation, which might improve the compliance of patients and thereby increase its therapeutic efficacy. Ursofalk tablets were registered in Germany on the basis of bioequivalence studies comparing tmax, Cmax, and AUC values of UDCA between capsules and tablets. Cmax values of UDCA in plasma are probably of only limited clinical relevance for the efficacy and safety of UDCA. Aim of this trial was to assess if the therapeutic efficacy of UDCA 500mg tablets is equivalent to that of UDCA 250mg capsules (both at 14 2mg/kg BW/day once daily) in patients with PBC. Therapeutic efficacy was measured by comparing the liver enzyme parameters alkaline phosphatase (AP), g-glutamyl transferase (gGT), and alanine aminotransferase (ALT) under both treatments. The secondary objectives were to assess the safety Clinical Pharmacology in Drug Development XX(XX) 1–6 © The Author(s) 2013 DOI: 10.1002/cpdd.24

No more pilots, a phase III trial of fibrates in primary biliary cirrhosis is long overdue!

No more pilots, a phase III trial of fibrates in primary biliary cirrhosis is long overdue!

Latest and emerging therapies for primary biliary cirrhosis and primary sclerosing cholangitis.

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the two most common causes of chronic cholestatic liver disease in adults. In PBC, therapy with ursodeoxycholic acid (UDCA) is safe and has been associated with tangible biochemical, histologic, and survival benefits. However, a need for different or adjuvant therapies remains for specific subsets of PBC patients, including those who do not respond to UDCA and those who have advanced histologic disease at presentation. Similarly, beneficial therapies for disease-related symptoms that do not typically respond to UDCA (eg, fatigue and pruritus) are still needed. In contrast to PBC, no medical therapy of proven benefit has been identified for patients with PSC. In PBC and PSC, adequate management of complications of chronic cholestasis is important. For both diseases, liver transplantation is the only curative option.

Increased Granulysin Expression in Peripheral Blood Cells of Patients with Primary Biliary Cirrhosis and Its Clinical Implications

Granulysin is a cytotoxic molecule involved in cellular immune reactions. The levels of granulysin mRNA in the peripheral blood and serum granulysin of patients with primary biliary cirrhosis (PBC) were determined by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The expression of granulysin mRNA and serum protein in PBC was increased compared to the controls. The expression of granulysin mRNA or serum protein showed close associations, respectively, with natural killer cell population in PBC patients. Serum granulysin was down-regulated by steroid and ursodeoxycholic therapy for PBC according to the improvement of severity of PBC. In addition, the expression of serum granulysin were related to serum total bilirubin and Mayo Clinic risk score. The serum granulysin reflected the cellular immune status of patients with PBC, and the expression correlated with the severity of PBC. Therefore, there is a clinical benefit to monitoring granulysin as a biomarker of the prognosis of patients with PBC.

The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: A prospective, multicenter study

Treatment with ursodeoxycholic acid (UDCA) improves the survival of stage I and II primary biliary cirrhosis (PBC) patients. However, new therapeutic options are needed for patients who are refractory to UDCA and for those whose disease is at an advanced stage. Bezafibrate could be useful in PBC treatment, since it increases phospholipid output into the bile and reduces the cytotoxicity of hydrophobic bile acids, which are increased with cholestasis. We conducted two prospective, multicenter randomized open studies in non-cirrhotic patients with PBC to evaluate the efficacy of bezafibrate. One study compared UDCA and bezafibrate monotherapy (study 1: 45 patients [37 females], mean age 55.9 years), and the other evaluated the addition of bezafibrate to patients who were refractory to UDCA (study 2: 21 patients [18 females], mean age 54.1 years). Study 1 demonstrated that bezafibrate monotherapy was as effective as UDCA and study 2 revealed that bezafibrate combined with UDCA was effective in improving and maintaining biliary enzymes where the ineffectiveness of long-term treatment with UDCA was confirmed. This multicenter, randomized, open study revealed that combination therapy of bezafibrate and UDCA improved biliary enzymes in non-cirrhotic Japanese patients with PBC refractory to UDCA. Further studies are needed to evaluate whether combination therapy improves histological staging and prognosis.

Prevalence and Predictors of Esophageal Varices in Patients With Primary Biliary Cirrhosis

Esophageal varices and bleeding are among the most feared complications of primary biliary cirrhosis (PBC). We aimed to determine the prevalence of esophageal varices in patients with PBC, to evaluate noninvasive markers of esophageal varices in this population, and to validate the results in an independent set of patients. Data were collected on all patients with PBC seen for the first time at the University of Florida (study group) and at Case Western Reserve University hospitals (cross-validation group) during 7 consecutive years. Logistic regression analysis was used to identify independent predictors of esophageal varices. The best cut-off values were calculated based on receiver operating characteristic curves. The diagnostic accuracy of the independent predictors of esophageal varices identified in the study group were retested in the cross-validation group. Of 210 patients with PBC seen at the University of Florida, 113 had an endoscopy and 49.6% (56 of 113) were found to have esophageal varices. After excluding 22 patients with a history of variceal bleeding, data on 91 patients were analyzed. Thirty-four patients had esophageal varices (37%). Multivariate analysis revealed that a platelet count of less than 140,000 (odds ratio, 7.6; 95% confidence interval, 1.6-37) and a Mayo risk score of 4.5 or greater (odds ratio, 10.6; 95% confidence interval, 1.8-62) were independent predictors of esophageal varices. The diagnostic accuracy of these predictors was confirmed in an independent set of patients. Among patients with PBC, a platelet count of less than 140,000 and/or a Mayo risk score of 4.5 or greater appears to identify those patients more likely to benefit from a screening endoscopy.

Risk of Lymphoma in Primary Biliary Cirrhosis

A number of immunosuppressive therapies have not been associated with clinical benefit in primary biliary cirrhosis (PBC). The use of more potent immunomodulatory therapies, however, could raise concerns over the risk of adverse effects such as the development of lymphoma. Therefore, we sought to describe the frequency, clinical spectrum, and outcomes among patients with PBC and a concomitant diagnosis of lymphoma. Patients with PBC evaluated at the Mayo Clinic between January 1, 1976-December 31, 1997 comprised the study cohort. Medical records were abstracted for demographic and clinical information including the temporal relationship between diagnoses and potential risk factors for lymphoma. From a total of 2192 patients, the frequency of lymphoma was observed at 0.6% (13 cases). The majority of patients (54%) had PBC before they were diagnosed with lymphoma, whereas 23% of cases were diagnosed in conjunction with PBC. Non-Hodgkin's lymphoma (69%) was observed in most cases with disease involvement above the diaphragm (38%). Treatment in the form of chemotherapy (n = 3), radiation (n = 2), and surgery (n = 6) was provided for 11 patients. Seven (54%) patients did not have evidence for recurrent disease, whereas 3 (23%) patients died of progressive lymphoma. The baseline risk for lymphoma in patients with PBC is estimated at <1%. Clinical trials with potent immunosuppressive therapies for PBC should not be prohibited on the basis of concerns regarding a baseline predisposition for lymphoma in this population.

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic, cholestat-ic liver disease that is characterized by progressive immune mediated destruction of the intrahepatic bile ducts. Over time, fibrosis extends out of the portal tracts and progresses to cirrhosis. Neither the etiology nor the pathogenesis are well understood; however, most of the current evidence suggests that it is an autoimmune condition that may be triggered by environmental stimuli in genetically predisposed individuals. Since the precise mechanisms involved in the pathogenesis of PBC have not been elucidated, curative therapy has not been identified and the focus has been on preventing disease progression. Ursodeoxycholic acid (UDCA), the only approved therapy for PBC, improves histology and retards disease progression. Future studies will likely combine UDCA with anti-inflammatory, immunosuppressive, immunomodulatory or antimicrobial agents. Once the etiology and pathogenesis of PBC are better delineated, more definitive therapy can be designed with curative intent.