Primary Biliary Cirrhosis

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Eric M Gershwin - One of the best experts on this subject based on the ideXlab platform.

  • obeticholic acid for the treatment of Primary Biliary Cirrhosis
    Expert Review of Clinical Pharmacology, 2016
    Co-Authors: Palak J Trivedi, Gideon M. Hirschfield, Eric M Gershwin
    Abstract:

    Primary Biliary Cirrhosis (PBC) is characterized by progressive nonsuppurative destruction of small bile ducts, resulting in intrahepatic cholestasis, fibrosis and ultimately end-stage liver disease. Timely intervention with ursodeoxycholic acid is associated with excellent survival, although approximately one-third of all patients fail to achieve biochemical response, signifying a critical need for additional therapeutic strategies. Obeticholic acid (OCA) is a potent ligand of the nuclear hormone receptor farnesoid X receptor (FXR). Activation of FXR inhibits bile acid synthesis and protects against toxic accumulation in models of cholestasis and facilitates hepatic regeneration in preclinical studies. Data from recent Phase II and III controlled trials suggest a therapeutic impact of OCA in PBC biochemical nonresponders, as evidenced by change in proven laboratory surrogates of long-term outcome. Dose-dependent pruritus is a common adverse effect, but may be overcome through dose-titration. Longer term studies are needed with focus on safety and long-term clinical efficacy.

  • the diagnosis of Primary Biliary Cirrhosis
    Autoimmunity Reviews, 2014
    Co-Authors: Christopher L Bowlus, Eric M Gershwin
    Abstract:

    Primary Biliary Cirrhosis (PBC) is a chronic liver disease characterized by the immune mediated destruction of small intrahepatic bile duct epithelial cells leading to cholestasis and Cirrhosis. The autoimmune basis of PBC is supported by the highly specific anti-mitochondrial antibodies (AMAs) and autoreactive T cells, the former being the basis for diagnosis in the vast majority of cases. Although a rare disease, the incidence rates of PBC have been increasing, possibly due to increased testing and diagnosis as opposed to a true increase in disease incidence. Presently, most cases are asymptomatic and only suspected based upon routine liver tests. Those with symptoms typically complain of pruritus and fatigue. The diagnosis of PBC is based on the presence of at least 2 of 3 key criteria including a persistently elevated serum alkaline phosphatase, the presence of serum AMAs, and liver histology consistent with PBC. Anti-nuclear antibodies specific to PBC are useful in cases in which AMAs are not detected and may indicate a more aggressive course. Ursodeoxycholic acid is the only proven therapy for PBC and in most cases can delay or prevent disease progression. However, a subgroup of patients does not adequately respond to ursodeoxycholic acid and for whom new therapies are needed.

  • Primary Biliary Cirrhosis and the nuclear pore complex
    Autoimmunity Reviews, 2012
    Co-Authors: Carolina Duarterey, Dimitrios P Bogdanos, Chenyen Yang, Krista Roberts, Patrick S C Leung, Juanmanuel Anaya, Howard J Worman, Eric M Gershwin
    Abstract:

    Experimental models of autoimmune diseases have led to the conclusion that an immune response to nuclear antigens is a sentinel marker for loss of tolerance and potential tissue damage. Various proteins are targets of antinuclear antibodies in a variety of autoimmune diseases, ranging from systemic rheumatologic disorders to diseases affecting specific organs such as the liver. Autoantibodies against specific nuclear constituents have also been used as probes to understand the structure and the function of the targeted components and their relevance to disease pathogenesis. Approximately a quarter of patients with Primary Biliary Cirrhosis (PBC) have antibodies targeting proteins of the nuclear pore complex (NPC), a multi-protein structure that mediates molecular transport across the nuclear envelope. Autoantibodies against the integral membrane glycoprotein gp210 and nucleoporin p62 appear to be highly specific for PBC, an autoimmune disease characterized by progressive destruction of intrahepatic Biliary epithelial cells. This review discusses the diagnostic and clinical relevance of anti-NPC antibodies in PBC and the possibility that this autoimmune response may arise as a result of molecular mimicry.

  • Primary Biliary Cirrhosis and sjogren s syndrome autoimmune epithelitis
    Journal of Autoimmunity, 2012
    Co-Authors: Carlo Selmi, Pier Luigi Meroni, Eric M Gershwin
    Abstract:

    Abstract Primary Biliary Cirrhosis (PBC) has been often coined a model autoimmune disease based on the homogeneity amongst patients, the frequency and similarity of antimitochondrial antibodies, including the highly directed immune response to pyruvate dehydrogenase (PDC-E2). A significant number of patients with PBC suffer from sicca and amongst these, there are patients who also have classic Sjogren’s syndrome. Indeed, both PBC and Sjogren’s syndrome are characterized by inflammation of target epithelial elements. Both diseases can be considered on the basis of a number of other related clinical aspects, including proposed unique apoptotic features of the target tissue, the role of secretory IgA, and the frequency with which both diseases overlap with each other. Indeed, PBC may be considered a Sjogren’s syndrome of the liver, whereas Sjogren’s syndrome can be equally discussed as PBC of the salivary glands. Dissection of the genetic predispositions for both diseases and especially the molecular basis of effector mechanisms, will become critical elements in developing new therapies.

  • the x and why of xenobiotics in Primary Biliary Cirrhosis
    Journal of Autoimmunity, 2007
    Co-Authors: Roman Rieger, Eric M Gershwin
    Abstract:

    Primary Biliary Cirrhosis (PBC) is a chronic autoimmune liver disease characterized by inflammation and destruction of intrahepatic Biliary epithelial cells, ultimately leading to liver failure. The serological hallmark of PBC is the presence of high-titer antimitochondrial antibodies (AMA) against the inner lipoyl domain of E2 subunits of 2-oxo-acid dehydrogenase complexes, in particular the E2 component of the pyruvate dehydrogenase complex (PDC-E2). The initiating events triggering the autoimmune response are not yet identified but the hypothesis of molecular mimicry is a widely proposed mechanism for the development of autoimmunity in PBC. Several candidates, including bacteria and viruses, have been suggested as causative agents, but also environmental factors, such as chemical xenobiotics, have been implicated in the pathogenesis of Primary Biliary Cirrhosis. In this review, we will discuss our current knowledge of the immunoreactivity of xenobiotically modified PDC peptide antigens. In addition, we will provide a working hypothesis how xenobiotic modification of antigens might occur that ultimately leads to the breaking of self-tolerance and the induction of PBC.

Keith D. Lindor - One of the best experts on this subject based on the ideXlab platform.

  • Current management of Primary Biliary Cirrhosis and Primary sclerosing cholangitis
    2015
    Co-Authors: Cynthia Levy, Keith D. Lindor
    Abstract:

    Primary Biliary Cirrhosis (PBC) is a chronic, cholestatic autoimmune liver disease characterized by inflammation and progressive destruction of interlobular bile ducts, ulti-mately leading to Biliary Cirrhosis. Population based studies have estimated the incidence of PBC as 19.1–251/ 1 000 000 in the general population [1,2]. The etiology of PBC is attributed to autoimmunity mainly due to the association with antimitochondrial antibodies, present in 95 % of PBC patients, but genetic and environ-mental factors are thought to contribute as well. In a large epidemiologic study conducted in the United States a survey was sent to 241 patients with PBC using standardized ques-tions drawn from the National Health and Nutrition Exam-ination Survey in an attempt to identify risk factors for the disease; 83.3 % of the patients returned the questionnaire

  • efficacy of obeticholic acid in patients with Primary Biliary Cirrhosis and inadequate response to ursodeoxycholic acid
    Gastroenterology, 2015
    Co-Authors: Gideon M. Hirschfield, Kris V Kowdley, Andrew L. Mason, Keith D. Lindor, Velimir A Luketic, Catherine Vincent, Stuart C Gordon, Marlyn J Mayo, Henry C Bodhenheimer
    Abstract:

    Background & Aims We evaluated the efficacy and safety of obeticholic acid (OCA, α-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with Primary Biliary Cirrhosis who had an inadequate response to ursodeoxycholic acid therapy. Methods We performed a double-blind study of 165 patients with Primary Biliary Cirrhosis (95% women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The Primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year. Results OCA was superior to placebo in achieving the Primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study ( P P P P Conclusions Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, γ-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with Primary Biliary Cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial. ClinicalTrials.gov ID: NCT00550862.

  • novel therapeutic targets in Primary Biliary Cirrhosis
    Nature Reviews Gastroenterology & Hepatology, 2015
    Co-Authors: Jessica K Dyson, Gideon M. Hirschfield, Keith D. Lindor, Ulrich Beuers, David H Adams, Derek A Mann, David Jones
    Abstract:

    Primary Biliary Cirrhosis (PBC) leads to progressive cholestasis, Biliary fibrosis and Cirrhosis and characteristic symptoms with a marked effect on quality of life. Evolution in our understanding of disease mechanisms in PBC is rapidly leading to the advent of new and re-purposed therapeutic agents targeting key processes. This Review provides a current perspective on potential approaches to PBC treatment, and highlights the challenges faced in evaluating and implementing those treatments.

  • treatment of Primary Biliary Cirrhosis therapy with choleretic and immunosuppressive agents
    Clinics in Liver Disease, 2008
    Co-Authors: Marina G Silveira, Keith D. Lindor
    Abstract:

    Primary Biliary Cirrhosis (PBC) is a chronic cholestatic liver disease of presumed autoimmune etiology affecting predominantly middle-aged women; it is a slowly progressive disease causing loss of intrahepatic bile ducts, resulting in advanced fibrosis, Cirrhosis, and liver failure. Many drugs have been studied for treatment, including agents with choleretic and immunosuppressive properties. Ursodeoxycholic acid (UDCA) has been evaluated most widely. After liver failure, the only effective treatment is liver transplantation. Effective therapy reduces the need for transplantation and improves life expectancy. For advanced liver disease or incomplete response to UDCA, new therapies to cure or retard the progression of disease in PBC are needed.

  • ursodeoxycholic acid for the treatment of Primary Biliary Cirrhosis
    The New England Journal of Medicine, 2007
    Co-Authors: Keith D. Lindor
    Abstract:

    A 52-year-old woman receives a diagnosis of Primary Biliary Cirrhosis. Treatment with ursodeoxycholic acid is recommended. Therapy with this drug appears to prolong transplantation-free survival, although the mechanism of benefit is unclear.

Paolo Muratori - One of the best experts on this subject based on the ideXlab platform.

Francesco B Bianchi - One of the best experts on this subject based on the ideXlab platform.

Jenny E Heathcote - One of the best experts on this subject based on the ideXlab platform.

  • baseline ductopenia and treatment response predict long term histological progression in Primary Biliary Cirrhosis
    The American Journal of Gastroenterology, 2010
    Co-Authors: Teru Kumagi, Jenny E Heathcote, Maha Guindi, Sandra Fischer, Tamara Arenovich, Rupert Abdalian, Catalina Coltescu, Gideon M. Hirschfield
    Abstract:

    Baseline Ductopenia and Treatment Response Predict Long-Term Histological Progression in Primary Biliary Cirrhosis

  • management of Primary Biliary Cirrhosis
    Hepatology, 2000
    Co-Authors: Jenny E Heathcote
    Abstract:

    Primary Biliary Cirrhosis (PBC) is a presumed autoimmune disease of the liver, which predominantly affects women once over the age of 20 years. Most cases are diagnosed when asymptomatic (60%). The antimitochondrial antibody is present in serum in most, but not in all, patients with PBC. The disease generally progresses slowly but survival is less than an age- and gender-matched general population. The symptomatic patient may have fatigue, generalized pruritus, portal hypertension, osteoporosis, skin xanthomata, fat soluble vitamin deficiencies, and/or recurrent asymptomatic urinary tract infections. Many nonhepatic autoimmune diseases are found in association with PBC and may prompt initial presentation. To date, immunosuppressive therapy has not been shown to prolong survival in PBC. The hydrophilic bile acid, ursodeoxycholic acid (UDCA), has been shown when given in a dose of 13 to 15 mg/kg daily for up to 4 years to delay the time to liver transplantation or death. This therapy also causes a significant improvement of all the biochemical markers of cholestasis but has no beneficial effects on any of the symptoms or associated disorders. Treatment with UDCA does not obviate the need for liver transplantation. Therapies to prevent complications arising from malabsorption, portal hypertension, and/or osteoporosis are required as well. Good control of pruritus can be achieved in most patients. PBC is diagnosed with increasing frequency, but the agent(s) responsible for this slowly progressive destruction of the interlobular bile ducts remains elusive and hence a specific therapy remains unavailable.

  • Primary Biliary Cirrhosis
    Hepatology, 1998
    Co-Authors: Keith D. Lindor, Eric M Gershwin, Raoul Poupon, Nora V. Bergasa, Marshall M Kaplan, Jenny E Heathcote
    Abstract:

    During the last few years, understanding of the natural history of Primary Biliary Cirrhosis (PBC) has undergone considerable revision, with realisation of the great variability of presentation and progression. The majority of patients are middle-aged women who present with a history of gradual onset of pruritus, increasing skin pigmentation and subsequently signs and symptoms of cholestatic liver disease. Others will present with a history of portal hypertension with gastrointestinal haemorrhage, or as a consequence of hypersplenism. Others, with a poorer prognosis, present with signs of decompensated liver disease. It is becoming increasingly recognised that there is a substantial pool of patients, who present either with some of the associated conditions of PBC (such as sicca syndrome, sclerodactyly or Raynaud’s phenomenon) or who are truly asymptomatic and who are detected because of abnormal liver function tests or antimitochondrial antibodies (AMA) on routine screening. Most, but not all, present with early histological disease; some, at presentation, have an established Cirrhosis. In this asymptomatic group, life expectancy is probably not significantly different from that of a normal, matched population [6, 11]. Thus, despite the lack of proven effective specific treatment for the disease, due to recognition of patients at an earlier stage there has been an apparent improvement in prognosis from 5 years twenty-five years ago [14] to over 10 years currently [2].

  • the canadian multicenter double blind randomized controlled trial of ursodeoxycholic acid in Primary Biliary Cirrhosis
    Hepatology, 1994
    Co-Authors: Jenny E Heathcote, Pina Michieletti, Gerald Y Minuk, K Cauchdudek, Valery Walker, Robert J Bailey, Laurence M Blendis, Cameron N Ghent, Chris S Pappas, Linda Scully
    Abstract:

    Ursodeoxycholic acid, a dihydroxyl bile acid normally present in human beings in minimal amounts, becomes incorporated into the bile salt pool when taken orally. In cholestasis, bile acids are retained in the liver and are hepatotoxic. Ursodeoxycholic acid is the least-known hepatotoxic bile acid, has choleretic properties and is reported to benefit patients with chronic cholestasis. In a nationwide Canadian controlled trial, 222 patients with Primary Biliary Cirrhosis were treated with ursodeoxycholic acid (14 mg/kg/body wt/day) or placebo for 24 mo. Only patients with a diagnosis confirmed by liver biopsy and serum positive for antimitochondrial antibodies were enrolled; 88% were symptomatic on entry. The Primary outcome measure was percent change in total serum bilirubin from baseline to final follow-up. Treated patients (111) and controls (111) were comparable with regard to age, gender, biochemical parameters and liver histological condition. Although treatment was not associated with any improvement in symptoms, ursodeoxycholic acid therapy caused the bilirubin to fall significantly within the first 3 mo of therapy (p < 0.001). Significant falls in serum alkaline phosphatase, aminotransferases, cholesterol and IgM levels were also noted in the treated group. Improvement in some histological features was observed but there was no difference between the groups in the number of patients who reached the endpoints of death or liver transplantation. Ursodeoxycholic acid, given to patients with Primary Biliary Cirrhosis, leads to an improvement in serum markers of cholestasis. A larger sample size is needed to determine whether ursodeoxycholic acid therapy has a beneficial effect on the survival of patients with Primary Biliary Cirrhosis.

  • the canadian multicenter double blind randomized controlled trial of ursodeoxycholic acid in Primary Biliary Cirrhosis
    Hepatology, 1994
    Co-Authors: Jenny E Heathcote, Pina Michieletti, Gerald Y Minuk, K Cauchdudek, Valery Walker, Robert J Bailey, Laurence M Blendis, Cameron N Ghent, Chris S Pappas, Linda Scully
    Abstract:

    Ursodeoxycholic acid, a dihydroxyl bile acid normally present in human beings in minimal amounts, becomes incorporated into the bile salt pool when taken orally. In cholestasis, bile acids are retained in the liver and are hepatotoxic. Ursodeoxycholic acid is the least-known hepatotoxic bile acid, has choleretic properties and is reported to benefit patients with chronic cholestasis. In a nationwide Canadian controlled trial, 222 patients with Primary Biliary Cirrhosis were treated with ursodeoxycholic acid (14 mg/kg/body wt/day) or placebo for 24 mo. Only patients with a diagnosis confirmed by liver biopsy and serum positive for antimitochondrial antibodies were enrolled; 88% were symptomatic on entry. The Primary outcome measure was percent change in total serum bilirubin from baseline to final follow-up. Treated patients (111) and controls (111) were comparable with regard to age, gender, biochemical parameters and liver histological condition. Although treatment was not associated with any improvement in symptoms, ursodeoxycholic acid therapy caused the bilirubin to fall significantly within the first 3 mo of therapy (p<0.001). Significant falls in serum alkaline phosphatase, aminotransferases, cholesterol and IgM levels were also noted in the treated group. Improvement in some histological features was observed but there was no difference between the groups in the number of patients who reached the endpoints of death or liver transplantation. Ursodeoxycholic acid, given to patients with Primary Biliary Cirrhosis, leads to an improvement in serum markers of cholestasis. A larger sample size is needed to determine whether ursodeoxycholic acid therapy has a beneficial effect on the survival of patients with Primary Biliary Cirrhosis. (HEPATOLOGY 1994;19:1149–1156.)

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