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      Update on pharmacotherapies for cholestatic liver disease

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      Author(s): 1 , 2 , 1 , 3 ,
      Publication date (Electronic):
      Journal: Hepatology Communications
      Publisher: John Wiley and Sons Inc.

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          Abstract

          Cholestatic liver diseases are conditions with impaired bile formation and/or flow due to genetic, immunologic, environmental, or other causes. Unless successfully treated, this can lead to chronic liver injury and end‐stage liver disease. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) embody the most prominent adult cholestatic liver diseases with regard to incidence, morbidity, and mortality. A considerable proportion of patients with PBC and PSC experience progressive liver disease and ultimately liver‐related death due to a paucity of effective pharmacotherapy; however, novel pharmacologic developments offer substantial promise in this regard. Here, we provide a brief review and update on current and emerging pharmacotherapies for PBC and PSC. (H epatology C ommunications 2017;1:7–17)

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          Primary biliary cirrhosis.

          Elizabeth J Carey, Ahmad Ali, Keith D. Lindor (2015)
          Primary biliary cirrhosis is a chronic cholestatic liver disease characterised by destruction of small intrahepatic bile ducts, leading to fibrosis and potential cirrhosis through resulting complications. The serological hallmark of primary biliary cirrhosis is the antimitochondrial antibody, a highly disease-specific antibody identified in about 95% of patients with primary biliary cirrhosis. These patients usually have fatigue and pruritus, both of which occur independently of disease severity. The typical course of primary biliary cirrhosis has changed substantially with the introduöction of ursodeoxycholic acid (UDCA). Several randomised placebo-controlled studies have shown that UDCA improves transplant-free survival in primary biliary cirrhosis. However, about 40% of patients do not have a biochemical response to UDCA and would benefit from new therapies. Liver transplantation is a life-saving surgery with excellent outcomes for those with decompensated cirrhosis. Meanwhile, research on nuclear receptor hormones has led to the development of exciting new potential treatments. This Seminar will review the current understanding of the epidemiology, pathogenesis, and natural history of primary biliary cirrhosis, discuss management of the disease and its sequelae, and introduce research on new therapeutic options.
          Article 0 comments Cited 185 times – based on 0 reviews     Review now
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            Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid.

            Llorenç Caballeria, Albert Pares, J Rodés (2006)
            Because the efficacy of UDCA on long-term outcome of primary biliary cirrhosis (PBC) has not been completely elucidated, we have assessed the course and survival of patients with PBC treated with UDCA and compared with the survival predicted by the Mayo model and the estimated survival of a standardized population. (One hundred ninety-two patients [181 women] with PBC treated with UDCA [15 mg/kg per day] for 1.5-14 years.) Response to treatment was defined by an alkaline phosphatase decrease greater than 40% of baseline values or normal levels after 1 year of treatment. The predicted survival was obtained by the Mayo model and the estimated survival was taken from the standardized matched Spanish population. Seventeen patients died or fulfilled criteria for liver transplantation (8.9%). The observed survival was higher than that predicted by the Mayo model and lower than that of the control population (P < .001). One hundred seventeen patients (61%) responded to treatment. The survival of responders was significantly higher than that predicted by the Mayo model and similar to that estimated for the control population (P = .15). By contrast, the survival of patients without biochemical response was lower than that estimated for the Spanish population (P < .001) although higher than that predicted by the Mayo model. Biochemical response to UDCA after 1 year is associated with a similar survival to the matched control population, clearly supporting the favorable effects of this treatment in PBC. The suboptimal survival of nonresponders identifies the group for further treatments.
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              Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.

              Konstantinos Lazaridis, Rou-Gang Xie, Cameron Ghent … (2009)
              Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary cirrhosis, but the susceptibility loci are unknown. To identify genetic loci conferring a risk for primary biliary cirrhosis, we carried out a genomewide association analysis in which DNA samples from 2072 Canadian and U.S. subjects (536 patients with primary biliary cirrhosis and 1536 controls) were genotyped for more than 300,000 single-nucleotide polymorphisms (SNPs). Sixteen of the SNPs most strongly associated with primary biliary cirrhosis were genotyped in two independent replication sets. We carried out fine-mapping studies across three loci associated with primary biliary cirrhosis. We found significant associations between primary biliary cirrhosis and 13 loci across the HLA class II region; the HLA-DQB1 locus (encoding the major histocompatibility complex class II, DQ beta chain 1) had the strongest association (P=1.78x10(-19); odds ratio for patients vs. controls, 1.75). Primary biliary cirrhosis was also significantly and reproducibly associated with two SNPs at the IL12A locus (encoding interleukin-12alpha), rs6441286 (P=2.42x10(-14); odds ratio, 1.54) and rs574808 (P=1.88x10(-13); odds ratio, 1.54), and one SNP at the IL12RB2 locus (encoding interleukin-12 receptor beta2), rs3790567 (P=2.76x10(-11); odds ratio, 1.51). Fine-mapping analysis showed that a five-allele haplotype in the 3' flank of IL12A was significantly associated with primary biliary cirrhosis (P=1.15x10(-34)). We found a modest genomewide association (P<5.0x10(-5)) with the risk of disease for SNPs at the STAT4 locus (encoding signal transducer and activator of transcription 4) and the CTLA4 locus (encoding cytotoxic T-lymphocyte-associated protein 4) and 10 other loci. Our data show significant associations between primary biliary cirrhosis and common genetic variants at the HLA class II, IL12A, and IL12RB2 loci and suggest that the interleukin-12 immunoregulatory signaling axis is relevant to the pathophysiology of primary biliary cirrhosis. (ClinicalTrials.gov number, NCT00242125.) 2009 Massachusetts Medical Society
              Article 0 comments Cited 157 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Keith D. Lindor: keith.lindor@asu.edu
                Journal
                Journal ID (nlm-ta): Hepatol Commun
                Journal ID (iso-abbrev): Hepatol Commun
                Journal ID (doi): 10.1002/(ISSN)2471-254X
                Journal ID (publisher-id): HEP4
                Title: Hepatology Communications
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2471-254X
                Publication date (Electronic): 21 December 2016
                Publication date Collection: February 2017
                Volume: 1
                Issue: 1 ( doiID: 10.1002/hep4.v1.1 )
                Pages: 7-17
                Affiliations
                [ 1 ] Division of Gastroenterology and Hepatology Mayo Clinic Scottsdale AZ
                [ 2 ] Division of Gastroenterology and Hepatology University of California, Davis Medical Center Sacramento CA
                [ 3 ] College of Health Solutions Arizona State University Phoenix AZ
                Author notes
                [*] [* ]ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:

                Keith Lindor, M.D.

                Dean, College of Health Solutions

                Arizona State University

                550 N 3 rd Street

                Phoenix, AZ 85004

                E‐mail: keith.lindor@ 123456asu.edu

                Tel.: + 1‐602‐496‐0789

                Potential conflict of interest: Dr. Lindor is an unpaid advisor for Intercept Pharmaceuticals Inc. and Shire Plc. Drs. Tabibian and Ali have nothing to disclose.

                Author information
                http://orcid.org/0000-0001-9104-1702
                Article
                Publisher ID: HEP41013
                DOI: 10.1002/hep4.1013
                PMC ID: 5747033
                PubMed ID: 29404429
                SO-VID: b41f8c5d-4bdb-417a-a07e-3c477f8bcf52
                Copyright © © 2016 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.
                License:

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 19 October 2016
                Date accepted : 30 October 2016
                Page count
                Figures: 1, Tables: 2, Pages: 11, Words: 6862
                Categories
                Subject: Review Article
                Subject: Review Articles
                Custom metadata
                source-schema-version-number 2.0
                component-id hep41013
                cover-date February 2017
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.7 mode:remove_FC converted:08.12.2017

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