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Annals of Hepatology 2006Primary biliary cirrhosis (PBC) is a chronic, cholestatic liver disease that is characterized by progressive immune mediated destruction of the intrahepatic bile ducts....
Primary biliary cirrhosis (PBC) is a chronic, cholestatic 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.
Topics: Adult; Autoimmune Diseases; Cholagogues and Choleretics; Female; Humans; Liver Cirrhosis, Biliary; Pregnancy; Ursodeoxycholic Acid
PubMed: 17060882
DOI: No ID Found -
Best Practice & Research. Clinical... Oct 2010Primary biliary cirrhosis (PBC) is an idiopathic chronic autoimmune liver disease that primarily affects women. It is believed that the aetiology for PBC is a... (Review)
Review
Primary biliary cirrhosis (PBC) is an idiopathic chronic autoimmune liver disease that primarily affects women. It is believed that the aetiology for PBC is a combination between environmental triggers in genetically vulnerable persons. The diagnosis for PBC is made when two of the three criteria are fulfilled and they are: (1) biochemical evidence of cholestatic liver disease for at least 6 month's duration; (2) anti-mitochondrial antibody (AMA) positivity; and (3) histologic features of PBC on liver biopsy. Ursodeoxycholic acid (UDCA) is the only FDA-approved medical treatment for PBC and should be administered at a recommended dose of 13-15 mg/kg/day. Unfortunately despite adequate dosing of UDCA, approximately one-third of patients does not respond adequately and may require liver transplantation. Future studies are necessary to elucidate the role of environmental exposures and overall genetic impact not only in the development of PBC, but on disease progression and variable clinical response to therapy.
Topics: Animals; Disease Management; Disease Progression; Environmental Exposure; Humans; Liver; Liver Cirrhosis, Biliary; Liver Transplantation; Major Histocompatibility Complex; Mitochondria, Liver; Treatment Failure; Ursodeoxycholic Acid
PubMed: 20955967
DOI: 10.1016/j.bpg.2010.07.006 -
Seminars in Liver Disease Aug 2014Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by selective destruction of intrahepatic cholangiocytes. Mechanisms underlying the... (Review)
Review
Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by selective destruction of intrahepatic cholangiocytes. Mechanisms underlying the development and progression of the disease are still controversial and largely undefined. Evidence suggests that PBC results from an articulated immunologic response against an immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2); characteristics of the disease are also the presence of disease-specific antimitochondrial autoantibodies (AMAs) and autoreactive CD4 and CD8 T cells. Recent evidence suggests that cholangiocytes show specific immunobiological features that are responsible for the selective targeting of those cells by the immune system. The immune reaction in PBC selectively targets small sized, intrahepatic bile ducts; although a specific reason for that has not been defined yet, it has been established that the biliary epithelium displays a unique heterogeneity, for which the physiological and pathophysiological features of small and large cholangiocytes significantly differ. In this review article, the authors provide a critical overview of the current evidence on the role of cholangiocytes in the immune-mediated destruction of the biliary tree that characterizes PBC.
Topics: Animals; Apoptosis; Autoimmunity; Bile Ducts, Intrahepatic; Cell Proliferation; Disease Models, Animal; Epithelial Cells; Humans; Liver Cirrhosis, Biliary; Signal Transduction
PubMed: 25057951
DOI: 10.1055/s-0034-1383727 -
Gut Sep 1991
Review
Topics: Humans; Liver; Liver Cirrhosis, Biliary; Liver Transplantation; Prognosis
PubMed: 1916473
DOI: 10.1136/gut.32.suppl.s73 -
Journal of Autoimmunity Nov 2015Primary biliary cirrhosis (PBC), a classic autoimmune liver disease, is characterised by a progressive T cell predominant lymphocytic cholangitis, and a serologic... (Review)
Review
Primary biliary cirrhosis (PBC), a classic autoimmune liver disease, is characterised by a progressive T cell predominant lymphocytic cholangitis, and a serologic pattern of reactivity in the form of specific anti-mitochondrial antibodies (AMA). CD4+ T cells are particularly implicated by PBC's cytokine signature, the presence of CD4+ T cells specific to mitochondrial auto-antigens, the expression of MHC II on injured biliary epithelial cells, and PBC's coincidence with other similar T cell mediated autoimmune conditions. CD4+ T cells are also central to current animal models of PBC, and their transfer typically also transfers disease. The importance of genetic risk to developing PBC is evidenced by a much higher concordance rate in monozygotic than dizygotic twins, increased AMA rates in asymptomatic relatives, and disproportionate rates of disease in siblings of PBC patients, PBC family members and certain genetically defined populations. Recently, high-throughput genetic studies have greatly expanded our understanding of the gene variants underpinning risk for PBC development, so linking genetics and immunology. Here we summarize genetic association data that has emerged from large scale genome-wide association studies and discuss the evidence for the potential functional significance of the individual genes and pathways identified; we particularly highlight associations in the IL-12-STAT4-Th1 pathway. HLA associations and epigenetic effects are specifically considered and individual variants are linked to clinical phenotypes where data exist. We also consider why there is a gap between calculated genetic risk and clinical data: so-called missing heritability, and how immunogenetic observations are being translated to novel therapies. Ultimately whilst genetic risk factors will only account for a proportion of disease risk, ongoing efforts to refine associations and understand biologic links to disease pathways are hoped to drive more rational therapy for patients.
Topics: Animals; B-Lymphocyte Subsets; Epigenesis, Genetic; Epistasis, Genetic; Gene Expression Regulation; Genetic Loci; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; HLA Antigens; Humans; Immunogenetics; Liver Cirrhosis, Biliary; Phenotype; Selection, Genetic; Signal Transduction; T-Lymphocyte Subsets
PubMed: 26250073
DOI: 10.1016/j.jaut.2015.07.004 -
Drug Design, Development and Therapy 2015Ursodeoxycholic acid (UDCA) is the standard treatment for primary biliary cirrhosis (PBC), but not all cases respond well. Evidence has shown that combination therapy of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIM
Ursodeoxycholic acid (UDCA) is the standard treatment for primary biliary cirrhosis (PBC), but not all cases respond well. Evidence has shown that combination therapy of UDCA with bezafibrate significantly improved liver function. A meta-analysis was performed to assess the efficacy and safety of UDCA and bezafibrate combination therapy in the treatment of PBC.
RESULTS
Nine trials, with a total of 269 patients, were included in the analysis. The bias risk of these trials was high. Compared with UDCA alone, the combination with bezafibrate improved the Mayo risk score (mean difference [MD], 0.60; 95% confidence interval [CI], 0.25-0.95; P=0.0008) and liver biochemistry: alkaline phosphatase (MD, -238.21 IU/L; 95% CI, -280.83 to -195.60; P<0.00001); gamma-glutamyltransferase (MD, -38.23 IU/L; 95% CI, -50.16 to -25.85; P<0.00001); immunoglobulin M (MD, -128.63 IU/L; 95% CI, -151.55 to -105.71; P<0.00001); bilirubin (MD, -0.20 mg/dL; 95% CI, -0.33 to -0.07; P=0.002); triglycerides (MD, -26.84 mg/dL; 95% CI, -36.51 to -17.17; P<0.0001); total cholesterol (MD, -21.58 mg/dL; 95% CI, -30.81 to -12.34; P<0.0001), and serum alanine aminotransferase (MD, -10.24 IU/L; 95% CI, -12.65 to -78.5; P<0.00001). However, combination therapy showed no significant differences in the incidence of all-cause mortality or pruritus, and may have resulted in more adverse events (risk ratio [RR], 0.22; 95% CI, 0.07-0.67; P=0.008).
CONCLUSION
Combination therapy improved liver biochemistry and the prognosis of PBC, but did not improve clinical symptoms or incidence of death. Attention should be paid to adverse events when using bezafibrate.
Topics: Bezafibrate; Biomarkers; Chi-Square Distribution; Drug Therapy, Combination; Humans; Liver; Liver Cirrhosis, Biliary; Odds Ratio; Risk Factors; Treatment Outcome; Ursodeoxycholic Acid
PubMed: 26491252
DOI: 10.2147/DDDT.S92041 -
World Journal of Gastroenterology May 2014Primary biliary cirrhosis is a multifactor autoimmune disease characterized by hepatic and systemic manifestations, with immune system dysregulation and abnormalities in... (Review)
Review
Primary biliary cirrhosis is a multifactor autoimmune disease characterized by hepatic and systemic manifestations, with immune system dysregulation and abnormalities in the hepatic metabolism of bile salts, lipids, and nutrients, as well as destruction of membrane lipids and mitochondrial dysfunction. Both oxidative and nitrosative stress are associated with ongoing manifestations of the disease. In particular, abnormalities in nitric oxide metabolism and thiol oxidation already occur at early stages, thus leading to the hypothesis that these biochemical events play a pathogenic role in primary biliary cirrhosis. Moreover, the association of these metabolic abnormalities with the progression of the disease may indicate some biochemical parameters as early diagnostic markers of disease evolution, and may open up the potential for pharmacological intervention to inhibit intra- and extra-cellular stress events for resuming hepatocellular functions. The following paragraphs summarize the current knowledge by outlining molecular mechanisms of the disease related to these stress events.
Topics: Animals; Bile Acids and Salts; Glutathione; Humans; Inflammation; Liver; Liver Cirrhosis, Biliary; Mitochondria; Nitric Oxide; Nitrogen; Oxidation-Reduction; Oxidative Stress; Sulfhydryl Compounds; Thioredoxins
PubMed: 24914336
DOI: 10.3748/wjg.v20.i19.5746 -
British Medical Journal (Clinical... Jun 1982
Review
Topics: Aged; Antibodies; Antigen-Antibody Complex; Cholecalciferol; Copper; Humans; Immunoglobulin M; Liver Cirrhosis, Biliary; Liver Transplantation; Mitochondria, Liver; Osteomalacia; Penicillamine
PubMed: 6282386
DOI: 10.1136/bmj.284.6333.1898 -
Revista de Gastroenterologia de Mexico... 2019
Topics: Autoimmune Diseases; Cohort Studies; Humans; Liver Cirrhosis, Biliary; Mexico
PubMed: 30541671
DOI: 10.1016/j.rgmx.2018.07.005 -
Bailliere's Best Practice & Research.... Aug 2000Pruritus is experienced by about 80% of patients with primary biliary cirrhosis. It can have a marked negative impact on the quality of life of patients, and it can be... (Review)
Review
Pruritus is experienced by about 80% of patients with primary biliary cirrhosis. It can have a marked negative impact on the quality of life of patients, and it can be an indication for liver transplantation. There is evidence to suggest that the pruritus of cholestasis is mediated, at least in part, by endogenous opioids. A central component has been proposed. Behavioural data have shed light on the pathogenesis of this form of pruritus. Fatigue affects the majority of patients with primary biliary cirrhosis. It interferes with work performance and family life. An idea is emerging that suggests that fatigue in primary biliary cirrhosis also may be mediated centrally. Research tools need to be developed to study fatigue objectively in patients with primary biliary cirrhosis.
Topics: Fatigue; Female; Humans; Liver Cirrhosis, Biliary; Male; Opioid Peptides; Pruritus; Quality of Life; Serotonin
PubMed: 10976020
DOI: 10.1053/bega.2000.0109