Primary Biliary Cirrhosis Pietro Invernizzi, MD, PhD1,2 1 Liver Unit and Center for Autoimmune Liver Diseases, Humanitas

Clinical and Research Center, Rozzano (MI), Italy 2 Division of Rheumatology, Allergy and Clinical Immunology,

University of California at Davis, Davis, California

Despite the fact that the liver was one of the earliest recognized targets for autoimmunity, primary biliary cirrhosis (PBC), the most paradigmatic autoimmune liver disease, still presents several controversial issues in diagnosis, causation, and therapy. This issue of Seminars in Liver Disease is timely; we are indeed witnessing an enormous increase in our basic knowledge of the disease with an initial translation in clinical practice. These advances are described by the expert contributors to this dedicated issue. Ten review articles address several key open questions in PBC, such as the reasons for female preponderance, why only small-size bile ducts are affected, the real role of genetics and epigenetics in its development, why there are large geographical variations in disease frequency, and what causes disabling symptoms such as fatigue. In addition, new theories on potential environmental triggers, such as chemical xenobiotics, are critically reviewed and contextualized within the unique immunological milieu of the liver that leads to the breaking of self-tolerance. Five of the 10 articles in this issue focus on the progress in our understanding of the pathogenesis of this enigmatic disease. Dr. Lleo and colleagues critically discuss recent evidence suggesting that cholangiocytes show specific immunobiological features that are responsible for the selective targeting of cholangiocytes by the immune system. Although the specific reason why in PBC the immune reaction targets only small intrahepatic bile ducts is still unknown, it has been established that the unique heterogeneity of the biliary epithelium plays a key role. Drs. L. Wang, F-S. Wang, Chang, and Gershwin describe the disruption of control mechanisms (i.e., central tolerance, peripheral anergy, a “liver tolerance effect,” and the action of T-regulatory cells) that lead to the breach of tolerance with the consequent development of PBC.

Dr. Bianchi et al present new data on genetic architecture coming from recent high-throughput studies, sex chromosome defects, and epigenetic abnormalities that they critically summarize, together with the implications for novel therapeutics in PBC. Juran and Lazaridis focus on the evidence supporting the role of environmental factors, whereas Wang et al describe the limits and strengths of the number of PBC animal models that are now available. Five articles focus specifically on the clinical aspects of PBC. Based on the encouraging data on the effects of novel drugs, such as fibrates or obeticholic acid, that are given in addition to ursodeoxycholic acid, a review by Dr. Parés is dedicated to old and novel therapies for the disease. Therapeutic novelties in the management of general complications of cholestasis, such as osteoporosis and pruritus, are also summarized and discussed. A relevant review by Dr. Nakamura on diagnostic serology in PBC, specifically focusing on the clinical significance of the PBC-specific serum autoantibodies, is also included. Drs. Floreani, Franceschet, and Cazzagon focus on the particular aspects of the coexistence of PBC with other autoimmune conditions affecting both the liver or extrahepatic organs. Patients with overlap syndromes are indeed a difficult-to-treat subset of PBC patients. Finally, Griffiths, Dyson, and Jones deal with the epidemiology and Imam and Lindor with the natural history of the disease. The prevalence of PBC is known to vary both on an international and a regional level, suggesting the existence of substantive geographical differences in terms of genetic susceptibility and environmental factors. We believe this series is a timely and “state-of-the-art” conspectus of PBC, emanating from centers highly considered for their many contributions to the knowledge and practice of PBC.

Address for correspondence Issue Theme Primary Biliary Pietro Invernizzi, MD, PhD, Liver Cirrhosis; Guest Editor, Pietro Unit and Center for Autoimmune Invernizzi, MD, PhD Liver Diseases, Humanitas Clinical and Research Center, Via A. Manzoni 56, 20089 Rozzano (MI), Italy (e-mail: pietro. [email protected]).

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DOI 10.1055/s-0034-1383724. ISSN 0272-8087.

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Semin Liver Dis 2014;34:253–254.

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Primary biliary cirrhosis. Foreword.

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