obeticholic-acid and Autoimmune-Diseases

Primary biliary cholangitis is a cholestatic, chronic autoimmune liver disease with a wide individual variation in disease progression. The diagnosis is predominantly based on chronic elevation of alkaline phosphatase and the presence of anti-mitochondrial antibodies or other specific antinuclear antibodies (i.e. anti-gp210 and anti-sp100). Even in early-stage disease, health-related quality of life can be severely impaired by symptoms such as pruritus, fatigue, and sicca syndrome and metabolic bone disease should be assessed and treated. The prognosis of the disease is, however, largely determined by the development of cirrhosis and its complications. Ursodeoxycholic acid is associated with an improved prognosis and should be initiated and continued in all patients. Clinical outcome is related to the biochemical response to ursodeoxycholic acid, but the prognosis of those with an incomplete response is still better than those who remain untreated. Obeticholic acid was recently approved as second-line treatment and bezafibrate may serve as an adequate off-label alternative, particularly in patients with pruritus. Preliminary data suggest an additive effect of triple therapy with ursodeoxycholic acid, obeticholic acid, and bezafibrate, whereas other promising drugs are being evaluated in clinical trials.

Topics: Autoantigens; Autoimmune Diseases; Bezafibrate; Biomarkers; Biopsy; Chenodeoxycholic Acid; Cholagogues and Choleretics; Disease Progression; Drug Therapy, Combination; Elasticity Imaging Techniques; End Stage Liver Disease; Fatigue; Female; Humans; Immunoglobulin M; Liver; Liver Cirrhosis, Biliary; Liver Function Tests; Liver Transplantation; Middle Aged; Off-Label Use; Prognosis; Pruritus; Quality of Life; Severity of Illness Index; Sjogren's Syndrome; Survival Rate; Treatment Outcome; Ursodeoxycholic Acid

Primary biliary cholangitis is an autoimmune liver disease that predominantly affects women. It is characterised by a chronic and destructive, small bile duct, granulomatous lymphocytic cholangitis, with typical seroreactivity for antimitochondrial antibodies. Patients have variable risks of progressive ductopenia, cholestasis, and biliary fibrosis. Considerations for the cause of this disease emphasise an interaction of chronic immune damage with biliary epithelial cell responses and encompass complex, poorly understood genetic risks and environmental triggers. Licensed disease-modifying treatment focuses on amelioration of cholestasis, with weight-dosed oral ursodeoxycholic acid. For patients who do not respond sufficiently, or patients with ursodeoxycholic acid intolerance, conditionally licensed add-on therapy is with the FXR (NR1H4) agonist, obeticholic acid. Off-label therapy is recognised as an alternative, notably with the pan-PPAR agonist bezafibrate; clinical trial agents are also under development. Baseline characteristics, such as young age, male sex, and advanced disease, and serum markers of liver injury, particularly bilirubin and ALP, are used to stratify risk and assess treatment responsiveness. Parallel attention to the burden of patient symptoms is paramount, including pruritus and fatigue.

Topics: Autoimmune Diseases; Biomarkers; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Fatigue; Humans; Pruritus; Risk Factors; Ursodeoxycholic Acid

Primary Biliary Cholangitis (PBC) is an uncommon, chronic, cholangiopathy of autoimmune origin and unknown etiology characterized by positive anti-mitochondrial autoantibodies (AMA), female preponderance and progression to cirrhosis if left untreated. The diagnosis is based on AMA- or PBC-specific anti-nuclear antibody (ANA)-positivity in the presence of a cholestatic biochemical profile, histologic confirmation being mandatory only in seronegative cases. First-line treatment is ursodeoxycholic acid (UDCA), which is effective in preventing disease progression in about two thirds of the patients. The only approved second-line treatment is obeticholic acid. This article summarizes the most relevant conclusions of a meeting held in Lugano, Switzerland, from September 23rd-25th 2018, gathering basic and clinical scientists with various background from around the world to discuss the latest advances in PBC research. The meeting was dedicated to Ian Mackay, pioneer in the field of autoimmune liver diseases. The role of liver histology needs to be reconsidered: liver pathology consistent with PBC in AMA-positive individuals without biochemical cholestasis is increasingly reported, raising the question as to whether biochemical cholestasis is a reliable disease marker for both clinical practice and trials. The urgent need for new biomarkers, including more accurate markers of cholestasis, was also widely discussed during the meeting. Moreover, new insights in interactions of bile acids with biliary epithelia in PBC provide solid evidence of a role for impaired epithelial protection against potentially toxic hydrophobic bile acids, raising the fundamental question as to whether this bile acid-induced epithelial damage is the cause or the consequence of the autoimmune attack to the biliary epithelium. Strategies are needed to identify difficult-to-treat patients at an early disease stage, when new therapeutic approaches targeting immunologic pathways, in addition to bile acid-based therapies, may be effective. In conclusion, using interdisciplinary approaches, groundbreaking advances can be expected before long in respect to our understanding of the etiopathogenesis of PBC, with the ultimate aim of improving its treatment.

Topics: Antibodies, Antinuclear; Autoimmune Diseases; Chenodeoxycholic Acid; Cholagogues and Choleretics; Congresses as Topic; Female; Humans; Liver; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by biliary destruction, progressive cholestasis, and potentially liver cirrhosis. Patients develop a well-orchestrated immune reaction, both innate and adaptive, against mitochondrial antigens that specifically targets intrahepatic biliary cells. A puzzling feature of PBC is that the immune attack is predominantly organ specific, although the mitochondrial autoantigens are found in all nucleated cells. The disease results from a combination of genetic and environmental risk factors; however, the exact pathogenesis remains unclear. Serologically, PBC is characterized by presence of antimitochondrial antibodies, which are present in 90-95 % of patients and are often detectable years before clinical signs appear. Like other complex disorders, PBC is heterogeneous in its presentation, symptomatology, disease progression, and response to therapy. A significant number of patients develop end-stage liver disease and eventually require liver transplantation. Recent studies from large international cohorts have better identified prognostic factors, suggesting a change in patient management based on risk stratification. Therapeutic options are changing. In this review we discuss data on the autoimmune responses and treatment of the disease.

Topics: Anti-Inflammatory Agents; Autoimmune Diseases; Biopsy; Budesonide; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Fibric Acids; Humans; Immunosuppressive Agents; Liver; Prognosis; Ursodeoxycholic Acid

Autoimmune liver diseases are a group of abnormal autoimmune-mediated inflammatory hepatobiliary injuries, mainly including autoimmune hepatitis(AIH), primary biliary cholangitis(PBC), and primary sclerosing cholangitis (PSC). The diagnosis and treatment of autoimmune liver diseases, an important type of non-viral liver disease, have become a prominent issue in hepatology. In 2016, many new advances have been achieved in the clinical and basic research on autoimmune liver diseases, including the phase 3 clinical trial of obeticholic acid, the proposal of UK-PBC risk score, and the research on gut microbiota associated with PSC. This article reviews the research advances in the diagnosis and treatment of autoimmune liver diseases in 2016.. 自身免疫性肝病是一组由异常自身免疫介导的肝胆炎症性损伤，主要包括自身免疫性肝炎、原发性胆汁性胆管炎及原发性硬化性胆管炎等。作为非病毒性肝病的重要成员，自身免疫性肝病的诊断与治疗日益成为肝病领域的突出问题之一。2016年，自身免疫性肝病在临床和基础研究方面又有了许多新进展，包括奥贝胆酸的临床III期试验，UK-PBC危险评分的提出，以及原发性硬化性胆管炎相关的肠道微生态研究等。现就自身免疫性肝病2016年的诊疗与研究进展进行介绍。.

Topics: Autoimmune Diseases; Biomedical Research; Chenodeoxycholic Acid; Cholangitis; Cholangitis, Sclerosing; Clinical Trials, Phase III as Topic; Hepatitis, Autoimmune; Humans; Liver Cirrhosis, Biliary; Liver Diseases

Primary biliary cholangitis (PBC) is an autoimmune disease of the liver characterized by destruction and inflammation of the intrahepatic bile ducts. The disease affects mainly women. The disease is often discovered through abnormal alkaline phosphatase (ALP) activity, and is confirmed when anti-mitochondrial antibodies (AMA) are present. The etiology of PBC is poorly understood. Cigarette smoking, immune dysregulation, nail polish, urinary tract infections, and low socioeconomic status have been implicated but none have been confirmed. Genome wide association studies (GWAS) have disclosed strong associations between certain human leukocyte antigen (HLA) alleles and PBC. PBC can progress to cirrhosis and end-stage liver disease. Hepatocellular carcinoma (HCC) develops in up to 3.5% of PBC patients. Ursodeoxycholic acid (UDCA) is the only medication approved for the treatment of PBC. The use of UDCA in PBC delays histological progression and extends the transplant-free survival. 40% of PBC patients do not respond adequately to UDCA, and these patients are at high risk for serious complications. Therefore, there is a critical need for more effective therapies for this problematic disease. Multiple other agents have either been or are currently being studied as therapeutic options in UDCA non-responder PBC patients. Six-ethyl chenodeoxycholic acid (6-ECDCA), a potent farnesoid X receptor (FXR) agonist, has shown anti-cholestatic activity in rodent models of cholestasis. Obeticholic acid (OCA, 6-ECDCA, or INT-747), a first-in-class FXR agonist, has been examined in PBC patients with inadequate response to UDCA, and shown promising results. Particularly, initial clinical trials have demonstrated that the use of OCA (in addition to UDCA) in PBC patients with inadequate response to UDCA led to significant reduction of serum alkaline phosphatase (ALP, an important prognostic marker in PBC). More recently, the results of a randomized clinical trial of OCA monotherapy in PBC reported significant reduction of ALP in the treatment group compared to placebo.. This review covers the preclinical and clinical studies of OCA in PBC. In addition, other alternative therapies that are currently being examined in PBC patients will also be discussed in this review. A literature search was carried out using the PubMed database.. If approved by the U.S. FDA, OCA will likely be an important alternative add-on therapy in PBC patients who have inadequate response to UDCA.

Topics: Animals; Autoimmune Diseases; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Cholestasis; End Stage Liver Disease; Genome-Wide Association Study; Humans; Liver Cirrhosis, Biliary; Randomized Controlled Trials as Topic; Ursodeoxycholic Acid

Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease mostly seen in middle-aged women characterized by progressive nonsuppurative destruction of small bile ducts resulting in intrahepatic cholestasis, parenchymal injury and ultimately end-stage liver disease. Despite major breakthroughs in our understanding of PBC, there remains only one FDA-approved agent for treatment: ursodeoxycholic acid (UDCA) to which one-third of patients are unresponsive.. Biochemical response to treatment with UDCA is associated with excellent survival rates in PBC patients. However, there is a need for alternative treatments for nonresponders. Results from human epidemiological and genetic studies as well as preclinical studies in PBC animal models have provided a strong impetus for the development of new therapeutic agents. In this review, we discuss the recent advances in translational research in PBC focusing on promising therapeutic approaches, namely immune-based targeted therapies and agents targeting the synthesis and circulation of bile acids.. We are in a new era for the development of novel therapies for PBC. Data on fibrates, budesonide and obeticholic acid offer encouragement for nonresponders to UDCA.

Topics: Autoimmune Diseases; Bile Acids and Salts; Budesonide; Chenodeoxycholic Acid; End Stage Liver Disease; Female; Fibric Acids; Humans; Liver; Liver Cirrhosis, Biliary; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Treatment Failure; Ursodeoxycholic Acid

Primary biliary cirrhosis (PBC) is a chronic, autoimmune, cholestatic liver disease. It is characterized by slow destruction of small intrahepatic bile ducts, impaired biliary secretion and stasis of toxic endogenous bile acids within the liver with progression to liver fibrosis and cirrhosis. It has an increasing prevalence worldwide. It occurs more commonly in women than men at a ratio of 10:1. In most cases, diagnosis relies on a positive antimitochondrial antibody in the context of chronic cholestasis, without the need for a liver biopsy. Ursodeoxycholic acid improves survival even in patients with advanced liver disease. Certain findings such as fatigue, anti-nuclear antibodies, anti-centromere antibodies and the GP210 antinuclear antibody predict a poor outcome. Up to 40% of patients do not respond satisfactorily to ursodeoxycholic acid therapy and should be considered for adjunctive therapies. Several adjunctive and newer therapies are being tested and some appear promising. We provide a review of PBC with a focus on advances in therapies that may impact the management of PBC in the near future.

Topics: Adult; Autoimmune Diseases; Chenodeoxycholic Acid; Cholagogues and Choleretics; Humans; Liver Cirrhosis, Biliary; Receptors, Cytoplasmic and Nuclear; Ursodeoxycholic Acid