Clinical Information

Primary biliary cholangitis (PBC) is a chronic and progressive autoimmune liver disease characterized by the destruction of the small intrahepatic bile ducts and a variable clinical course, which may include fatigue and pruritus. Untreated patients with PBC have a high risk of liver cirrhosis and related complications, liver failure, and death.(1,2) The serological hallmark of PBC is the presence of anti-mitochondrial antibody (AMA) characterized by cytoplasmic reticular/AMA (anti-cell 21 [AC-21] based on the International Consensus on Antinuclear Antibody Patterns [ICAP] nomenclature) staining pattern on HEp-2 substrate by indirect immunofluorescence assay (IFA).(3) 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.(1,2,4,5) 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.(3) The diagnosis of PBC can be established if two out of the three following criteria are met: sustained elevated levels of alkaline phosphatase (ALP), evidence AMA or specific antinuclear antibody (ANA) (anti-Sp100 and anti-gp210 antibodies) and diagnostic liver histology.(2) Based on these criteria, a biopsy can be avoided in case of high ALP levels and detection of these PBC-specific autoantibodies.(1,2) Therefore, reliable and accurate serologic determination of PBC-specific autoantibodies play a critical role in disease evaluation.

 

Of the PBC-specific antibodies, the AMA is the most common, with the M2-type AMA (AMA-M2) the dominant target of the 9 subunits of the mitochondrial antigenic complex.(1,2) In addition to AMA, anti-gp210 IgG antibodies can be found in PBC patients who are seropositive or seronegative for AMA. In the context AMA-negative PBC, the presence of anti-gp210 IgG antibody associated with clinical and laboratory features of disease is of diagnostic significance.(1,2) The likelihood of PBC is also increased in at-risk or asymptomatic patients who test positive for both AMA and anti-gp210 IgG antibodies.(5) In addition to the diagnostic relevance of anti-gp210 IgG antibody, a few studies have suggested a role for their use in the risk stratification and prognosis in PBC, however, the significance of these remain contentious. In one study, the presence of anti-gp210 antibodies was reported to pose a significant risk for hepatic failure type progression, more severe interface hepatitis and lobular inflammation compared to those with centromere antibodies who had relatively higher ductular reaction.(6)

Anti-gp210 antibodies can be detected and/or quantified using solid-phase immunoassays (SPA), such as enzyme-linked immunosorbent assay line blot immunoassay, and dot immunoassay.(4-8) Although anti-gp210 antibodies have been reported be associated with a positive punctate nuclear envelope (AC-12) HEp-2 IFA pattern, a recent investigation by the Antibody Immunology Laboratory at Mayo Clinic showed no positive correlation between anti-gp210 IgG and the punctate nuclear envelope pattern. These observations suggest testing for anti-gp210 IgG antibodies in the absence of a positive punctate nuclear envelope pattern when clinical suspicion for PBC is high. While HEp-2 IFA is not reliable for the detection of anti-gp210 IgG antibodies, it offers the possibility to identify patients at-risk for PBC who may present with coexisting systemic autoimmune rheumatic diseases (systemic lupus erythematosus, systemic sclerosis, and Sjogren syndrome) or autoimmune liver disease (autoimmune hepatitis) through additional pattern recognition. The use of SPA for ANA testing do not provide these additional diagnostic insights.