rimary biliary cirrhosis is a slowly progressive autoimmune disease of the liver that primarily affects women. Its peak incidence occurs in the fifth decade of life, and it is uncommon in persons under 25 years of age. Histopathologically, primary biliary cirrhosis is characterized by portal inflammation and immune-mediated destruction of the intrahepatic bile ducts. These changes occur at different rates and with varying degrees of severity in different patients. The loss of bile ducts leads to decreased bile secretion and the retention of toxic substances within the liver, resulting in further hepatic damage, fibrosis, cirrhosis, and eventually, liver failure. Serologically, primary biliary cirrhosis is characterized by the presence of antimitochondrial antibodies, which are present in 90 to 95 percent of patients and are often detectable years before clinical signs appear. A puzzling feature of primary biliary cirrhosis, as of several other autoimmune diseases, is that the immune attack is predominantly organ-specific, although the mitochondrial autoantigens are found in all nucleated cells. These mitochondrial antigens have been a major focus of research on primary biliary cirrhosis, which has led to their precise identification. 1 Indeed, since primary biliary cirrhosis was last reviewed in the Journal, 2 considerably more data have become available on both the autoimmune responses involved and the treatment of the disease. Primary biliary cirrhosis is now diagnosed earlier in its clinical course than it was in the past; 50 to 60 percent of patients are asymptomatic at diagnosis. 3,4 Fatigue and pruritus are the most common presenting symptoms, 5 occurring in 21 percent and 19 percent of patients, respectively, in two studies. 6,7 Overt symptoms develop within two to four years in the majority of asymptomatic patients, although one third of patients may remain symptom-free for many years. 4,6 Fatigue has been noted in up to 78 percent of patients and can be a significant cause of disability. 8,9 The degree of severity of the fatigue is independent of the degree of severity of the liver disease, and there is no proven treatment for the fatigue. Pruritus, which occurs in 20 to 70 percent of patients, can be the most distressing symptom. 10 The onset of pruritus usually precedes the onset of jaundice by months to years. The pruritus can be local or diffuse. It is usually worse at night and is often exacerbated by contact with wool, other fabrics, or heat. Its cause is unknown, but endogenous opioids may have a role. Unexplained discomfort in the right upper quadrant occurs in approximately 10 percent of patients. 11 Other common findings in primary biliary cirrhosis include hyperlipidemia, hypothyroidism, osteopenia, and coexisting autoimmune diseases, including Sjögren's syndrome and scleroderma. 12 Portal hypertension does not usually occur until later in the course of the disease. Malabsorption, deficiencies of fat-soluble vitamins, and steatorrhea are uncommon except in advanced disease. Rarely, patients pr...

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There have been significant advances in our understanding of human autoimmunity that have led to improvements in classification and diagnosis and, most importantly, research advances in new therapies. The importance of autoimmunity and the mechanisms that lead to clinical disease were first recognized about 50 years ago following the pioneering studies of Macfarlane Burnett and his Nobel Prize‐winning hypothesis of the ‘forbidden clone’. Such pioneering efforts led to a better understanding not only of autoimmunity, but also of lymphoid cell development, thymic education, apoptosis and deletion of autoreactive cells. Contemporary theories suggest that the development of an autoimmune disease requires a genetic predisposition and environmental factors that trigger the immune pathways that lead, ultimately, to tissue destruction. Despite extensive research, there are no genetic tools that can be used clinically to predict the risk of autoimmune disease. Indeed, the concordance of autoimmune disease in identical twins is 12–67%, highlighting not only a role for environmental factors, but also the potential importance of stochastic or epigenetic phenomena. On the other hand, the identification of cytokines and chemokines, and their cognate receptors, has led to novel therapies that block pathological inflammatory responses within the target organ and have greatly improved the therapeutic effect in patients with autoimmune disease, particularly rheumatoid arthritis. Further advances involving the use of multiplex platforms for diagnosis and identification of new therapeutic agents should lead to major breakthroughs within the next decade.

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