Clinical Pathology: Clinical Chemistry, General Principles, Hematology & Coagulation, Immunology & Histocompatibility, Lab Management, Microbiology, Transfusion Medicine, Urinalysis, Body Fluids, Clinical Microscopy

• Primary biliary cirrhosis (PBC) is an autoimmune disorder characterized by progressive destruction of small and medium-sized intrahepatic bile ducts, portal inflammation, and progressive liver fibrosis leading to cirrhosis and hepatic failure.

• PBC primarily affects middle-aged women and can present with cholestasis (e.g., jaundice, pruritus, xanthomas), hepatomegaly, and cirrhosis with portal hypertension, ascites, and gastrointestinal bleeding. PBC is often associated with other autoimmune disorders such as Sjögren syndrome, arthropathy, CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia), and autoimmune thyroiditis.

• In developed countries, most cases are asymptomatic at presentation and detected by abnormal liver function test (LFT) results. Most commonly, markers of cholestasis, such as elevation of alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (GGT), are seen. Less commonly, the patient presents with jaundice and conjugated hyperbilirubinemia. When the disease progresses to marked liver fibrosis and cirrhosis, markers of hepatocyte damage, such as mildly elevated aminotransferases, can be detected. With the development of hepatic insufficiency, hypoalbuminemia, prolonged prothrombin time, and elevated conjugated and unconjugated bilirubin can be seen. Hyperbilirubinemia is a sign of advanced or severe disease and an indicator for the possibility of liver transplantation.

• Antimitochondrial antibodies (M2, M4, M8, M9) are present in all patients with PBC and remain a pathognomonic hallmark of the diagnosis. Anti-M2 antibodies are directed against the pyruvate decarboxylase complex (PDC) in the inner mitochondrial membrane, and M4, M8, and M9 bind to the outer membrane. In 90% to 95% of cases, autoantibodies directed against the lipoyl domain of the E2 subunit of mitochondrial PDC are present. Anti-M2 antibodies can also be directed against other members of the PDC complex, including the E2 subunit of the branched-chain 2-oxoacid dehydrogenase complex, the E2 subunit of the 2-oxoglutarate dehydrogenase complex, E1t α-subunits of PDC, and E3-binding protein (protein X). Other mitochondrial targets of autoantibodies present in PBC include the β- and γ-subunits of F1F0-adenosine triphosphatase and sulfite oxidase (M4).

• Although antimitochondrial antibodies are very sensitive for the diagnosis of PBC, they are not entirely specific. First, they can present many years in advance of significant hepatic disease, although in this case they can serve as a predictor for development of PBC. Second, they can be present in other autoimmune disorders, including Sjögren syndrome, scleroderma, autoimmune hepatitis, and infectious diseases such as viral hepatitis and tuberculosis.

• The pathogenesis of PBC implicates liver-infiltrating autoreactive T cells against the dominant PDC-E2 autoantigen. Levels of antimitochondrial antibodies reflect the B-cell response and do not correlate with the severity of disease.

• Antinuclear antibodies, directed against pore glycoprotein 210, nuclear protein p62, sp100 proteins, promyelocytic leukemia protein, NDP52, and sp140 proteins, can be positive in about 50% of the minority of patients (5% to 10%) without detectable antimitochondrial antibodies.

Hu CJ, Zhang FC, Li YZ, et al: Primary biliary cirrhosis: what do autoantibodies tell us? World J Gastroenterol 2010;16(29): 3616–3629.

Miyachi K, Hankins RW, Matshushima H, et al: Profile and clinical significance of anti-nuclear envelope antibodies found in patients with primary biliary cirrhosis: a multicenter study. J Autoimmun 2003;20(3):247–254.

Leuschner U: Primary biliary cirrhosis: presentation and diagnosis. Clin Liver Dis 2003;7(4) 741–758.

* = Required 
* Note Title
* Note