Clinical Information

Autoimmune liver disease (ALD) collectively refers to diseases that result from immune-mediated damage to hepatocytes, cholangiocytes, or both.(1-3) The disease entity includes autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and their overlaps.(1) Testing for liver-related autoantibodies is usually included in the workup of patients with hepatitis or cholestasis of unknown origin.(1-5) However, it is important to note that these autoantibodies are not specific and must be interpreted in contest of risk factors. In addition, efforts to standardize how these tests should be performed and reported are not well established.

Autoimmune hepatitis is a multifaceted liver disease characterized by the presence of diverse autoantibodies, increased concentrations of specific liver enzymes, hypergammaglobulinemia and abnormalities in liver histology.(1,2 4-6) AIH can be stratified into two main subtypes based on the presence of specific autoantibodies and patient’s age, these include AIH-type 1 (AIH-1) or AIH-type 2 (AIH-2).(2,4-6) Patients with AIH-1 are positive for antinuclear autoantibodies (ANA), smooth muscles antibodies associated with anti-filamentous-actin IgG antibody, or both. While patients with AIH-2 have detectable anti-liver kidney microsomal type-1, or rarely anti-liver kidney microsomal type-3, or anti-liver cytosol type-1 antibodies. Antibodies against soluble liver antigens/liver pancreas autoantigen can also be detected in AIH-1 patients.(6) Compared to AIH-2, which generally occurs in children with a more moderated or severe disease course, AIH-1 occurs in all age groups and has a relatively mild course that is responsive to timely treatment with steroids and azathioprine.(4)

Primary biliary cholangitis is a rare cholangiopathic ALD characterized by predominantly anti-mitochondrial autoantibodies (AMA), female preponderance and progression to liver damage, if left untreated.(1,3) In some cases, patients with these diseases may present asymptomatically, with increases in various liver enzymes being identified incidentally during an unrelated clinical evaluation. On the other end of the spectrum are patients who present with clinical evidence of liver disease, including fatigue, hepatomegaly, ascites, esophageal varices, and jaundice. The serological hallmark of PBC is the presence of AMA characterized by cytoplasmic reticular/AMA staining pattern on HEp-2 substrate by indirect immunofluorescence assay (IFA). In addition, autoantibodies associated with the HEp-2 IFA nuclear patterns have been reported in a subset of patients with PBC who are seronegative for AMA or may be positive for AMA but have uncertain clinical or phenotypic attributes.(1,3, 7-9) The HEp-2 IFA nuclear patterns in PBC include multiple nuclear dots (MND or AC-6) and punctate nuclear envelope (AC-12), which are associated with anti-Sp100 and anti-gp210 antibodies, respectively.(1,3) The diagnosis of PBC can be established if 2 out of the 3 following criteria are met: 1) sustained elevated levels of alkaline phosphatase (ALP); 2) evidence AMA or ANA (anti-Sp100 and anti-gp210 antibodies); and 3) diagnostic liver histology.(3) Based on these criteria, a biopsy can be avoided in case of high ALP levels and detection of these PBC-specific autoantibodies.(1,3,5) In a recent study, the prevalence of AMA and levels of ALP were both reported to vary by race/ethnicity.(10) Highlighting the need to incorporate the ANA PBC-specific autoantibodies and HEp-2 IFA in disease evaluation.

In association with chronic cholestasis after exclusion of known causes of liver disease, AMA are strongly suggestive of a diagnosis of PBC.(6) AMA have a variable prevalence in other autoimmune diseases that can also be found in some apparently healthy individuals.(7,8) AMA are found in more than 90% of patients with PBC, with a specificity of greater than 95%. AMA are included in the clinical practice guidelines for PBC, which were developed through an international collaborative effort.(9)

For more information see First-Line Screening for Autoimmune Liver Disease Algorithm.