obeticholic-acid and Cholangitis--Sclerosing

Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are immune-mediated chronic liver diseases. PSC is a rare disorder characterized by multi-focal bile duct strictures and progressive liver diseases that ultimately results in the need for liver transplantation in most patients. Imaging studies, such as MRCP, have an essential role in the diagnosis of most cases of PSC. PSC is usually accompanied by inflammatory bowel disease, and there is a high risk of cholangiocarcinoma and colorectal cancer in PSC. No medical therapies have been proven to delay the progression of PSC. Endoscopic intervention for tissue diagnosis or biliary drainage is frequently required in cases of PSC with a dominant stricture, acute cholangitis, or clinically suspected cholangiocarcinoma. PBC is a chronic inflammatory autoimmune cholestatic liver disease, which, when untreated, will culminate in end-stage biliary cirrhosis requiring liver transplantation. A diagnosis is usually based on the presence of serum liver tests indicative of cholestatic hepatitis in association with circulating antimitochondrial antibodies. Patient presentation and course can be diverse in PBC, and risk stratification is important for ensuring that all patients receive a personalized approach to their care. Medical therapy using ursodeoxycholic acid or obeticholic acid has an important role in reducing the progression to end-stage liver disease in PBC.

Topics: Alkaline Phosphatase; Chenodeoxycholic Acid; Cholangitis, Sclerosing; Humans; Liver Cirrhosis, Biliary; Prognosis; Risk Factors; Ursodeoxycholic Acid

Cholestatic liver diseases encompass a broad spectrum of pathologies, with the core injury occurring at the level of cholangiocytes and progressing to hepatic fibrosis and liver dysfunction. Primary biliary cholangitis and primary sclerosing cholangitis are the most significant progressive cholangiopathies in adults. Although rare, they commonly evolve to liver failure and need for liver transplantation. Despite recent advances in the basic knowledge of these cholangiopathies, the pathogenesis is still elusive. Targeted treatments to prevent disease progression and to preclude malignancy are not yet available. This review will address the general clinical features of both diseases, analyze their commonalities and differences, and provide a state-of-the art overview of the currently available therapeutics.

Topics: Adult; Biliary Tract; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis, Sclerosing; Cholestasis; Clinical Trials as Topic; Disease Progression; Drug Therapy, Combination; End Stage Liver Disease; Humans; Immunologic Factors; Life Expectancy; Prevalence; Prognosis; Treatment Outcome; Ursodeoxycholic Acid

Farnesoid X nuclear receptor is involved in the regulation of lipid and glucose metabolism, though mainly in the homeostasis of bile acids. Indeed, the agonists of farnesoid X nuclear receptor represent promising drugs. Areas covered: Obeticholic acid, a novel semisynthetic analogue of the naturally occurring bile acid, has led to encouraging preliminary results in both cholestatic and metabolic liver disease. In patients with primary biliary cholangitis, obeticholic acid determines a significant biochemical improvement although the effects on liver fibrosis are lacking. Obeticholic acid has been suggested for the treatment of nonalcoholic liver disease with good laboratory results. In cirrhotic animal models, the drug seems to reduce both portal hypertension and gut bacterial translocation. Expert commentary: The use of obeticholic acid for the treatment of primary biliary cholangitis shows satisfying results. However, some open questions remain unresolved. Herein, we provide an overview of the current knowledge about the use of obeticholic acid in the field of nonviral chronic liver diseases. We tried to give a global point of view using a translational approach.

Topics: Animals; Chenodeoxycholic Acid; Cholangitis, Sclerosing; Disease Models, Animal; Humans; Hypertension, Portal; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Treatment Outcome

While bile acids are important for both digestion and signalling, hydrophobic bile acids can be harmful, especially when in high concentrations. Mechanisms for the protection of cholangiocytes against bile acid cytotoxicity include negative feedback loops via farnesoid X nuclear receptor (FXR) activation, the bicarbonate umbrella, cholehepatic shunting and anti-inflammatory signalling, among others. By altering or overwhelming these defence mechanisms, cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) can further progress to biliary cirrhosis, end-stage liver disease and death or liver transplantation. While PBC is currently treated with ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), many fail treatment, and we have yet to find an effective therapy for PSC. Novel therapies under evaluation target nuclear and surface receptors including FXR, transmembrane G-protein-coupled receptor 5 (TGR5), peroxisome proliferator-activated receptor (PPAR) and pregnane X receptor (PXR). Modulation of these receptors leads to altered bile composition, decreased cytotoxicity, decreased inflammation and improved metabolism. This review summarizes our current understanding of the role of bile acids in the pathophysiology of cholestatic liver diseases, presents the rationale for already approved medical therapies and discusses novel pharmacologic therapies under investigation.

Topics: Bile Acids and Salts; Budesonide; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis, Sclerosing; Cholestasis; Drug Therapy, Combination; Elasticity Imaging Techniques; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis, Biliary; Receptors, Cytoplasmic and Nuclear; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most frequent chronic cholestatic liver diseases and serve as model diseases to discuss the management of cholestasis in 2017 in the lecture that is summarized in this report. PBC and PSC are characterized by inflammation and fibrosis of small intrahepatic (PBC) or larger intra- and/or extrahepatic (PSC) bile ducts. Bile duct damage leads to cholestasis and can progress to liver fibrosis and even cirrhosis. Various genetic, environmental and endogenous factors may contribute to the development of chronic cholestatic liver diseases, but the exact pathogenesis of PBC and PSC has not been clarified. Ursodeoxycholic acid (UDCA) is the standard treatment of PBC and is used also for other cholestatic conditions including PSC, and it exerts anticholestatic effects at adequate doses. Novel anticholestatic therapeutic options for patients not adequately responding to UDCA are under development or have, like obeticholic acid, already been proven to have efficacy when combined with UDCA in the treatment of PBC. The future role of immunomodulating/immunosuppressive drug regimens must be critically reviewed.

Topics: Bile Acids and Salts; Bile Ducts; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis, Sclerosing; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Randomized Controlled Trials as Topic; Ursodeoxycholic Acid

The only currently approved treatment for primary sclerosing cholangitis (PSC) is liver transplantation, with a median time to transplant of 12-18 years after diagnosis. There are a number of emerging drugs that have the potential to meet this critically unmet need that will be summarized and discussed herein.. Although the cause of PSC is unknown, there are a number of novel therapeutics under development. These drugs target presumed pathogenic mechanisms largely extrapolated from ex-vivo and in-vivo preclinical models, as well as translational observations.. Future therapeutic strategies for PSC may include a multitude of complex pathogenic mechanisms encompassing pathways of immunomodulation, the microbiome and inflammation-related fibrosis.

Topics: Anti-Bacterial Agents; Chenodeoxycholic Acid; Cholangitis, Sclerosing; Clinical Trials as Topic; Fecal Microbiota Transplantation; Fibric Acids; Gastrointestinal Microbiome; Humans; Immunologic Factors; Molecular Targeted Therapy; Organic Anion Transporters, Sodium-Dependent; Probiotics; Symporters; 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

Topics: Chenodeoxycholic Acid; Cholangitis, Sclerosing; Humans

Topics: Chenodeoxycholic Acid; Cholangitis, Sclerosing; Hope; Humans; Life Expectancy; Liver Cirrhosis, Biliary; Receptors, Cytoplasmic and Nuclear; Ursodeoxycholic Acid