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Primary biliary cirrhosis (PBC) is a disease characterized by inflammatory destruction of the small bile ducts within the liver. PBC eventually leads to cirrhosis of the liver. The cause of PBC is unknown, but because of the presence of autoantibodies, it is generally thought to be an autoimmune disease. Other etiologies, such as infectious agents, have not been completely excluded. PBC has a worldwide prevalence of approximately 5/100,000 and an annual incidence of approximately 6/1,000,000. The prevalence and incidence appear to be similar in different regions of the world. About 90% of patients with PBC are women. Most commonly, the disease is diagnosed in patients between the ages of 40 and 60 years. Most patients with PBC present with pruritus (itching). After pruritus, jaundice (yellow skin caused by bilirubin retention) is the most common presenting symptom. Several patients also present with complaints related to chronic portal hypertension (increased blood pressure in the veins that go to the liver that can lead to symptoms such as bleeding in the esophagus or fluid retention in the abdomen). Some patients are discovered to have PBC during workup of another illness. Since the widespread use of routine serum biochemical analysis, many patients present for evaluation of an elevated serum alkaline phosphatase activity that was detected on laboratory examination.

Patients with PBC have abnormalities in several blood tests. In essentially all patients, the serum alkaline phosphatase and gamma-glutamyltranspeptidase activities are markedly elevated (these are enzymes present in the bile ducts). Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities are usually moderately elevated (these are enzymes made by hepatocytes, the predominant liver cell type). The serum bilirubin concentration is normal early in the disease and rises as the disease progresses (which causes jaundice or yellow skin). Most patients have an elevated serum cholesterol concentration, which is largely contained in an abnormal lipoprotein, termed lipoprotein X, which is produced in patients with bile duct obstruction. The total gamma-globulin concentration is usually normal until late in the disease when cirrhosis develops. Almost all patients with PBC have an elevated serum IgM concentration (a type of antibody). The prothrombin time (a measure of blood clotting) and serum albumin concentration (the major protein in blood that is made in the liver) are normal until cirrhosis develops later in the course of disease.

Serum autoantibodies are of primary importance in the diagnosis of PBC. Antibodies against mitochondria are characteristic of PBC and found in about 90% of patients. About 50% of patients with PBC also have antinuclear antibodies. Antibodies against mitochondrial and nuclear proteins are found in several diseases besides PBC, but the cDNA cloning of several mitochondrial proteins has shown that antibodies against specific antigens are virtually diagnostic of PBC. The same has been shown to be true for antibodies against nuclear proteins in about 25% of patients. Because of the presence of specific autoantibodies, PBC is thought to be an autoimmune disease. Several laboratories around the world are actively involved in determining how the immune response relates to the bile ducts destruction characteristic of the disease. In addition to clinical and laboratory abnormalities and the presence of specific autoantibodies, histological examination (looking at tissue under the microscope) of liver tissue is of central importance in the diagnosis of PBC. Tissue for this purpose is obtained by liver biopsy, which is generally an outpatient procedure. Histologically, PBC is classified into four stages. Stage I is referred to as the florid duct lesion or nonsuppurative destructive cholangitis and is characterized by mononuclear inflammatory cells surrounding a small bile duct. In stage II, there is proliferation of small bile ductules. Stage III is characterized by fibrosis or scarring. Stage IV is cirrhosis. These histological stages demonstrate the progression of the disease from destruction of the intrahepatic bile duct to fibrosis and cirrhosis. Histological features of more than one stage can be seen on one liver biopsy. Because of sampling differences, the stages can also vary in liver biopsies done at different times on the same patient. In general, however, there is a gradual progression over years from the histological features of stage I to stage IV.

The diagnosis of PBC must be based on a combination of historical, laboratory, serological and histological criteria. In general, patients are middle-aged women who present with pruritus early and jaundice late. Patients that present late in the course of disease may also have signs and symptoms of cirrhosis and hepatic failure. Many patients are referred for evaluation of an isolated elevated serum alkaline hosphatase
activity on laboratory testing for other purposes. Essentially all patients have elevated serum alkaline phosphatase and gamma-glutamyltranspeptidase activities. The serum IgM concentration is almost always elevated. About 90% of patients have autoantibodies against specific mitochondrial proteins (the E2 subunits of the oxo-acid dehydrogenase complexes). Approximately 50% of patients have antinuclear antibodies, sometimes against very specific proteins (nuclear pore membrane protein gp210, transcriptional activator Sp100, inner nuclear membrane protein LBR). The absence of an elevated serum IgM concentration and/or specific autoantibodies should place the diagnosis of PBC in doubt. Patients with PBC must have a consistent liver biopsy. The histological findings alone are frequently not diagnostic as the florid duct lesion is often not seen and other features, such as ductular proliferation, fibrosis and biliary cirrhosis, can be seen in other liver diseases.

PBC is a progressive disease that leads to cirrhosis and liver failure. The time from diagnosis to end-stage liver disease can range from a few months to 20 years depending upon when the diagnosis is first made. Several mathematical models based on clinical, laboratory and histological criteria have been devised to predict disease progression. In general, the development of portal hypertension indicates a poor prognosis. The serum bilirubin concentration is the best prognostic indicator of all laboratory values. Once the serum bilirubin concentration reaches 6 mg/dl, the average life expectancy is about 2 years. At this time, patients should be evaluated for possible liver transplantation.

Despite extensive studies, medical therapy has not been shown to have a significant impact in slowing the progression of PBC. Patients with PBC should take vitamins and calcium to help prevent osteoporosis (loss of bone), a common complication of this disease. Colchicine may play a role in inhibiting liver fibrosis and improves laboratory values but not signs or symptoms. D-penicillamine has been studied in several series but the results have shown it to be ineffective and possibly toxic. Various immunosuppressive agents have been studied in patients with PBC. Corticosteroids are probably not effective and may aggravate the osteoporosis commonly present in patients with PBC. Azathioprine (Imuran), methotrexate and cyclosporin A have been examined in several studies and are still being investigated, but these agents will not likely produce radical improvements in clinical course. Ursodiol (Actigall or Urso), a bile acid, has been shown to improve the laboratory and clinical parameters in patients with PBC and the results of one study suggest that it may slow the progression of the disease. Orthotopic liver transplantation is highly successful in patients with end-stage liver disease resulting from PBC.