Primary Biliary Cirrhosis

Recognition of the continuity of the gallbladder and cystic and common bile ducts by the Babylonians in 2000 to 3000 B.C., led to centuries of controversy regarding the biliary tract and the origin and function of bile. Although Malpighi demonstrated that bile was formed in the liver, rather than the gallbladder, in the 17th century, it was not until the 19th century that Kiernan observed intrahepatic bile ducts in portal tracts and Hering identified their connection to canals that drain the canaliculi of hepatocytes. Mechanical obstruction of the distal biliary tract was long recognized as the cause of what was termed secondary biliary cirrhosis. Yet is was only in the mid-20th century that patients with biliary cirrhosis due to inflammatory destruction of proximal, intrahepatic bile ducts were identified, and their disease designated as primary biliary cirrhosis (PBC). Subsequent recognition of the nearly universal association with antimitochondrial autoantibodies (AMAs) and PBC-specific autoantigens led to the categorization of PBC as a prototypic autoimmune disease and fostered the search for predisposing host and environmental factors responsible for the break in self-tolerance. Appreciation of nonsuppurative destructive cholangitis as the T-cell-mediated, histopathological process in PBC was later confounded by recognition of similar pathology in the alloimmune diseases chronic graft-versus-host disease (GVHD) and hepatic allograft rejection (HAR).

The current pace of research in PBC has been catalyzed by opportunities afforded by important advances in research technologies, epidemiology, immunogenetics, autoimmunity, cholangiocyte pathophysiology, immunological mechanisms of tissue injury, and new therapeutic options for the treatment of autoimmune- and immune-mediated inflammatory diseases. This issue of Seminars in Liver Disease provides comprehensive reviews of our current understanding of PBC and identifies key priorities for future research.

Mackay sets the stage by summarizing current concepts of the etiopathogenesis of autoimmunity. Fava et al detail often unappreciated information about the contributions of cholangiocytes to both innate and adaptive immune responses. Selmi et al summarize knowledge of both genetics and geoepidemiology, providing new theories and directions for research. Adams and Afford describe important insights into immunopathogenesis of bile duct destruction gained from studies of the mechanisms responsible for nonsuppurative destructive cholangitis in GVHD and HAR. Invernizzi et al review PBC-specific antinuclear autoantibodies and their prognostic significance. Beurers and Rust examine the complexity of overlap syndromes occurring among the hepatobiliary autoimmune diseases: PBC, autoimmune hepatitis, and primary sclerosing cholangitis. Lee and Kaplan revisit the natural history of PBC in an era of better access to diagnostic tests and routine treatment with ursodeoxycholic acid. Leung et al evaluate the newest provocative findings in the search for the etiological triggers that break tolerance to autoantigens in PBC. Ishibashi et al analyze the nature of the immune responses of both B cells and T cells to mitochondrial autoantigens. Finally, Vierling assesses future treatment options, emphasizing those that interdict immunopathogenetic mechanisms involved in PBC.

In the popular section, Diagnostic Problems in Hepatology, two provocative case reports are presented. Stanca et al illustrate the problem of determining the mechanisms of liver failure in a patient with both AMA-positive PBC and hepatic sarcoidosis. Tsuji et al then intrigue us with a report of a PBC patient who developed de novo autoimmune hepatitis in an auxiliary allograft, while continuing to exhibit PBC in the native liver.

We are indebted to our colleagues who have provided these authoritative articles and case reports. It is our hope that the content of this issue will not only inform readers about our current knowledge of PBC, but also prepare them to assimilate future findings and encourage the curious to become involved in research aimed at solving the puzzle of PBC.