Recent Advances in Basic Science Pathogenesis of Primary Biliary Cirrhosis

Correspondence to: Professor David E J Jones, Liver Research Group, Institute of Cellular Medicine, 4th Floor William Leech Building, The Medical School, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK; d.e.j.jones@ ncl.ac.uk __________________________ P rimary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that affects up to one in 700 women in western populations (female to male ratio is approximately 10 to 1, with the disease typically presenting over the age of 40 years). 2 PBC is characterised histologically by damage to, and eventual loss of, the biliary epithelial cells (BEC) lining small intrahepatic bile ducts. BEC loss is typically accompanied by a significant portal tract inflammatory infiltrate that is mixed in phenotype (T cells (CD4 and CD8, with the latter predominating in the periductal areas), B cells, macrophages, eosinophils and natural killer cells). 4 Early descriptions of PBC emphasised the predominant role played by the progression of bile duct loss, accompanied by increasing portal tract and linking fibrosis leading to biliary cirrhosis, in the clinical expression of PBC, and described an aggressive and uniformly fatal condition. Increased awareness of the condition and, in particular, the availability of diagnostic tools such as serology has led to broader and earlier diagnosis. This has had the effect that we now recognise PBC far more frequently than was previously the case, and typically do so at an earlier stage in the disease process. Broadening of the diagnostic base has, in addition, led us to appreciate that there is a significant subgroup within the PBC population who have a low risk of disease progression and who are unlikely to develop end-stage liver disease during a normal lifetime (but who remain at risk of developing the often life-altering symptoms of the disease such as fatigue, which are seemingly unrelated to the severity of the underlying liver disease). 7 8 The factors that determine individual risk of disease progression remain unclear, precluding us, at present, from targeting disease-modifying therapies at ‘‘high-risk’’ patients. Study of the pathogenesis of PBC has focused, until relatively recently, almost entirely on immunological aspects of the disease. PBC was one of the first conditions in which the presence of autoantibodies in the serum was identified, and was one of the first conditions in which the antigen specificity of this autoreactive response was characterised. This led, quite naturally, to the view that PBC is an autoimmune disease. This led, again not unreasonably (but largely unsuccessfully), to a focus on developing and applying therapies aimed at modifying this increasingly well-characterised autoreactive immune response. More recently, however, the true complexities of the processes seemingly contributing to PBC pathogenesis have begun to be appreciated and the exclusively autoimmune disease model has been challenged.