PRIMARY BILIARY CIRRHOSIS: NEW PERSPECTIVES* WILLIS C. MADDREY PHILADELPHIA Primary biliary cirrhosis (PBC) is a chronic, usually progressive, cho- lestatic liver disease of unknown etiology which is found predominantly in middle-aged females and is characterized by the progressive destruc- tion and disappearance of small interlobular hepatic bile ducts (1-4). The extrahepatic bile ducts are not affected. The diagnosis of PBC is most often established between the ages of 30 and 70 years. There is no evidence that the course of PBC occurring in a male differs from that found in females (5). The diagnosis of PBC should be prominently considered in the evaluation of an adult patient with chronic cholestasis. PBC must be distinguished from extrahepatic bile duct obstruction and several other established causes of chronic cholestasis including chronic drug-induced cholestasis, primary sclerosing cholangitis, and cholestatic chronic active hepatitis. The clinical manifestations of PBC result from the destruction and subsequent loss of bile ducts, thereby leading to a diminished flow of bile and subsequent development of a biliary (portal to portal) cirrhosis. In the majority of patients with PBC, there is no evidence of cirrhosis at the time of diagnosis, and the term chronic destructive intrahepatic cholangitis is a more appropriate designation. Early descriptions of PBC emphasized the clinical and histologic features of patients with advanced disease and cirrhosis. With increasing aware- ness of PBC over the past three decades, the diagnosis is being made earlier in the course of the illness, and many patients are being identified in whom there are no signs or symptoms of liver disease and the only abnormalities detected are an elevated serum alkaline phosphatase level and presence of antimitochondrial antibodies. SPECULATIONS REGARDING ETIOLOGY The etiology of PBC remains unknown. The disorder has been detected in more than one member of a family suggesting a genetic predisposition (6-8). Furthermore, family members of patients with PBC have an increased incidence of circulating autoantibodies as well as an apparent increase in occurrence of other autoimmune disorders (9). No definite association with any specific HLA type has been found in patients with * From the Department of Medicine, Jefferson Medical College, Philadelphia, Pennsyl- vania 19107. 142 PRIMARY BILIARY CIRRHOSIS 143 PBC. There are many features of PBC which suggest that there may be an underlying immunologic basis for the disorder (3). Autoantibodies including those directed against mitochondrial as well as nuclear and thyroid antigens are found in increased frequency in patients with PBC. PBC is found in association with a number of other disorders with presumed immunologic bases including Sjogren's syndrome, thyroiditis, rheumatoid arthritis, and the CREST syndrome (10-12). In an occasional patient, there is the apparent coexistence of sarcoidosis and PBC (13). The antimitochondrial antibody system has been extensively studied in patients with PBC (14-16). Antimitochondrial antibodies (AMAs) are found in greater than 95% of these patients and testing for the presence of AMAs is important in diagnosis. The role of the AMAs in the pathogenesis of PBC is uncertain. The AMAs are neither organ nor species specific. There is no apparent correlation between the titer of AMAs and disease activity. It has been suggested that there is cross reactivity between the antimitochondrial antibodies found in PBC and structural proteins found in R mutants of enterobacteriaceae thereby suggesting an infectious etiology for PBC (17). There is no evidence PBC results from deposition of immune complexes such as had been suggested earlier using less specific assays (3). Patients with PBC have been demonstrated to have an impaired sulfoxidation pathway similar to that implicated in the pathogenesis of chlorpromazine-induced liver injury (18, 19). Sulfoxide metabolites of chlorpromazine are less cholestatic and hepatotoxic than are hydroxyl metabolites. Because of the similarities between chlorpromazine-induced liver injury and PBC, the status of the sulfoxidation pathway was evaluated and found to be impaired (19, 20). It has been suggested that the inability to sulfoxidize a variety of compounds including such potent cholestatic agents as D-ring estrogen derivatives may promote intracel- lular accumulation of toxic products. The defect in sulfoxidation in patients with PBC was corrected by liver transplantation. CLINICAL FEATURES Most often, patients with PBC are females (90%) in mid-life who complain of progressive loss of energy and malaise. Unexplained weight loss may be found early in the illness. Late in the course, weight loss may be accelerated by the development of steatorrhea with diarrhea secondary to decreased delivery of bile salts to the intestine. Pruritus is an important early symptom. The exact pruritogen has not been identi- fied. Once pruritus appears in a patient with PBC, it rarely spontaneously remits. In addition, the skin may become thickened and hyperpigmented. An enlarged liver is found in more than half of patients with PBC at the 144 WILLIS C. MADDREY time of diagnosis. Abdominal pain is unusual. Splenomegaly may be detected even in asymptomatic patients. Bone pain especially severe in the back is frequent and results from osteoporosis which may be debili- tating and associated with fractures (21-23). Once a patient enters the progressive phase of the illness, the level of serum bilirubin begins to rise, xanthelasma and xanthomata develop in patients in whom there is a retention of lipids. Evidence of hepatocellular failure along with portal hypertension, ascites, and hepatic encephalopathy are late manifesta- tions. However, occasionally a patient with PBC will present with bleed- ing from esophagogastric varices in the absence of manifestations of cholestasis (24). BIOCHEMICAL AND SEROLOGIC FINDINGS The usual biochemical tests of the liver in patients with PBC reveal evidence of cholestasis. The serum alkaline phosphatase level is almost invariably increased as are the 5' nucleotidase and gammaglutamyl transpeptidase (GGTP) levels. Serum bilirubin may be normal or only slightly elevated early in the course of PBC. Serum cholesterol levels are elevated in the majority of patients with symptomatic disease. Early in the course of PBC, the HDL cholesterol level is increased and subse- quently falls as the disorder progresses (25). The combination of a falling serum cholesterol level in a patient with advanced PBC associated with an increasing serum bilirubin and a decreasing serum albumin is an ominous sign indicating failure of hepatic synthesis. Aminotransferase levels are usually only slightly increased. In some patients there is evidence of coexistent pancreatic insufficiency (26). The serum IgM level is increased in approximately 75% of patients with PBC (3). There is evidence that the IgM in these patients is highly immunoreactive and contains cryoproteins. The immunoreactive IgM is produced by a small population of B cells and production presumably results from a defect in T-suppressor cell regulation (27, 28). Further- more, the immunoreactive IgM has been shown to promote spontaneous conversion ofcomplement C3 to C3b and C3c by activation ofthe classical complement pathway thereby inducing hypercatabolism of complement in patients with PBC (29, 30). The discovery of antimitochondrial antibodies (AMAs) and recognition of the high (approximately 95%) incidence of these antibodies in patients with PBC was a milestone in the development of knowledge regarding the disorder (14-16). AMAs are rarely found in patients with mechanical obstruction of the biliary tract. However, these antibodies are found in 5-15% of patients with idiopathic chronic active hepatitis, and occasion- ally the differentiation of the disorders is difficult. Over the past several PRIMARY BILIARY CIRRHOSIS 145 years, it has been determined that the antimitochondrial antibody system is composed of several antigens with varying disease specificities. Several antigens have been identified within the mitochondria which are targets for the AMAs. The most prevalent AMA in PBC is designated M2 and is directed against a polypeptide found in the inner membrane of the mitochondria (15, 16). In addition to the M2 antigen, patients with PBC often have antibodies to antigens designated M4 and M8. It has been noted that patients who have anti-M2 as the sole AMA detected are generally asymptomatic and have a good prognosis, whereas patients in whom antibodies to M2 are found in association with antibodies to M4 and M8 more often have evidence of progressive disease. Therefore, the subtype pattern of AMAs, while not yet in widespread use, may prove to be important in predicting the course of PBC and in the separation of PBC from other disorders. More recently, an AMA designated M9 has been identified and associated with an antigenic site on submitochondrial particles (31). Anti-M9 is often found in patients with early PBC and is generally not found in later stages of the disorder. Of note has been the detection of anti-M9 AMA in 50% of 70 relatives of eleven patients with PBC as well as in 63% of technicians who were working in an immuno- pathologic laboratory testing blood from patients with PBC (15). These observations further increase interest in a possible infectious etiology for PBC. Another antibody found in patients with PBC is an anticentromere antibody originally described in patients