For personal use. Only reproduce with permission from The Lancet SEMINAR THE LANCET • Vol 362 • July 5, 2003 • www.thelancet.com 53 Primary biliary cirrhosis is a chronic cholestatic liver disease of unknown cause. Progressive bile-duct injury from portal and periportal inflammation could result in progressive fibrosis and eventual cirrhosis. Evidence to date suggests that immunological and genetic factors might cause the disease. Affected individuals are typically middle-aged women with asymptomatic rises of serum hepatic biochemical variables. Fatigue, pruritus, or unexplained hyperlipidaemia at initial presentation might also suggest a diagnosis of primary biliary cirrhosis. Serum antimitochondrial antibody positivity is nearly diagnostic of the disease. Disease identification is important because effective medical treatment with ursodeoxycholic acid can halt disease progression and extend survival free of liver transplantation. Mathematical models that accurately characterise the natural history of primary biliary cirrhosis may also assist in determining the optimum timing for liver transplantation when indicated. Epidemiology Primary biliary cirrhosis affects all races, yet seems to cluster within specific geographical areas. 1 Women are mainly affected, with a female/male ratio of 9/1. The median age of disease onset is 50 years, but varies between 20 and 90 years. Estimates of annual incidence 2,3 and prevalence 3,4 range from 2 to 24 cases per million and 19 to 240 cases per million population, respectively. Data from Olmsted County, Minnesota, USA, 4 suggest a stable incidence rate over the past 25 years but a higher prevalence than described in Canada. 5 Differences in methodology and case definitions have impeded comparisons between series. The worldwide variation in disease prevalence suggests that environmental factors are needed for phenotypic expression of primary biliary cirrhosis. From a population- based study in northern England 6 and a large case-control US investigation, 7 presence of tobacco use and extrahepatic autoimmune disorders have been associated with the disease when compared with controls. First-degree relatives of people with primary biliary cirrhosis are also known to have at least a two-fold increased risk of autoimmune diseases. A high rate of urinary-tract infections in smokers with the disease has raised the possibility of an infectious cause. 8 Data of the association between gravidity and primary biliary cirrhosis are conflicting. 9,10 Genetics Genetic predisposition to autoimmunity in primary biliary cirrhosis has been associated with alleles from MHC loci. However, class 2 MHC loci, including DR8, DQA1*0102, and DQ/1*0402, have only been reported in selected patients with the disorder. 11–13 The haplotypes DR3, DR8, and DR4 are more frequent in white populations by contrast with DR2 and DR8 haplotypes in Japanese patients. 11 Conflicting results, however, are noted for the observation between the DQA1*0102 haplotype and disease resistance. 14 Presence of a raised familial risk for primary biliary cirrhosis could be an indirect link to a genetic component for disease susceptibility. Results of studies have estimated frequency of the disease among first-degree relatives of index cases to be between 1·3% and 6%. 15,16 A positive family history of primary biliary cirrhosis, using population-based epidemiological methods, was identified in 6·4% of instances. 16 The overall prevalence in offspring of patients with the disease was 1·2%, with a 2·3% rate in Primary biliary cirrhosis Jayant A Talwalkar, Keith D Lindor Primary biliary cirrhosis is a chronic cholestatic liver disease of adults. This disorder is characterised histologically by chronic non-suppurative destruction of interlobular bile ducts leading to advanced fibrosis, cirrhosis, and liver failure. The precise aetiopathogenesis of primary biliary cirrhosis remains unknown, although dysregulation of the immune system and genetic susceptibility both seem to be important. Affected patients are typically middle-aged women with abnormal serum concentrations of alkaline phosphatase. Presence of antimitochondrial antibody in serum is almost diagnostic of the disorder. Identification of primary biliary cirrhosis is important, because effective treatment with ursodeoxycholic acid has been shown to halt disease progression and improve survival without need for liver transplantation. However, therapeutic options for disease-related complications—including fatigue and metabolic bone disease—remain unavailable. Mathematical models have been developed that accurately predict the natural history of primary biliary cirrhosis in individuals. Despite advances in understanding of the disease, it remains one of the major indications for liver transplantation worldwide. Lancet 2003; 362: 53–61 Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA (J A Talwalkar MD, K D Lindor MD) Correspondence to: Dr Keith D Lindor (e-mail: lindor.keith@mayo.edu) Search strategy and selection criteria Sources including published reports and abstracts, reference books, and selected references from affiliated bibliographies provided the material for this Seminar. Peer-reviewed publications were identified by computerised search of the MEDLINE database (1966–present) with the terms “primary biliary cirrhosis” and “biliary cirrhosis”. Clinical trials were included if they had been published as peer-reviewed manuscripts or in abstract form. Randomised controlled trials examining survival, treatment failure, or both were specifically identified. Seminar