Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis

Abstract

Background & Aims: Detection of autoantibodies is a mainstay of diagnosing autoimmune hepatitis (AIH). However, conventional autoantibodies for workup of AIH lack either sensitivity or specificity leading to substantial diagnostic uncertainty. We aimed to identify more accurate serological markers of AIH with a protein macro-array. Approach & results: During the search for more precise autoantibodies to distinguish AIH from non-AIH liver diseases, IgG antibodies with binding capacities to many human and foreign proteins were identified with a protein macroarray and confirmed with solid phase ELISAs in AIH patients. Subsequently, polyreactive IgG (pIgG) were exemplarily quantified by reactivity against human huntingtin-interacting protein 1related protein in bovine serum albumin blocked ELISA (HIP1R/BSA). Diagnostic fidelity of HIP1R/BSA binding pIgG to diagnose AIH was assessed in a retrospective training, a retrospective multicenter validation and a prospective validation cohort, in cryo-conserved samples from 1568 adults from ten centers from eight countries. Reactivity against HIP1R/BSA had a 25% and 14% higher specificity to diagnose AIH than conventional anti-nuclear and antismooth muscle antibodies, a significantly higher sensitivity than liver kidney microsomal antibodies and anti-soluble liver antigen/liver pancreas antigen and a 12-20% higher accuracy than conventional autoantibodies. Importantly, HIP1R/BSA reactivity was present in up to 88 % of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy pIgG returns to background levels of non-AIH liver diseases. Conclusions: pIgG could be used as a new promising marker to improve the diagnostic workup of liver diseases with a higher specificity for AIH compared to conventional autoantibodies and a utility in autoantibody negative AIH. Likewise, pIgG could be a major source of assay interference in untreated AIH.

Genome‐wide meta‐analysis identifies susceptibility loci for autoimmune hepatitis type 1

“…[20] Only patients with a pretreatment score of 10 points or more were classified as AIH and included. [21,22] Patients were excluded from this study if they had any other cause of chronic liver disease, including primary biliary cholangitis (PBC), primary sclerosing cholangitis, Wilson's disease, hemochromatosis, drug-induced liver disease, alcoholic liver disease, and chronic viral hepatitis B or C. In addition, patients with positive LKM-1 and/or LC-1 antibodies (AIH type 2) were excluded. Healthy controls were recruited from Anhui Medical University and the China-Japan Friendship Hospital and matched to cases by age and gender.…”

Recent advances in the diagnosis and management of autoimmune hepatitis

“…Additionally, the new test showed 12-20% higher accuracy than conventional autoantibodies [61]. Of interest, pIgG reactivity identified the majority of patients with autoantibodies negative AIH (88%) and most of AIH patients with normal IgG (71%) [61]. Moreover, after response to immunosuppression, pIgG returned to those levels of patients with non-AIH liver diseases.…”

“…This polyreactive IgG (pIgG) demonstrated 25% and 14% greater specificity for diagnosing AIH than conventional ANA and SMA testing, respectively, and a considerably higher sensitivity than anti-LKM and anti-SLA/LP. Additionally, the new test showed 12-20% higher accuracy than conventional autoantibodies [61]. Of interest, pIgG reactivity identified the majority of patients with autoantibodies negative AIH (88%) and most of AIH patients with normal IgG (71%) [61].…”

“…IgG antibodies with high capacity to bind to several proteins (human and non-human) were recently discovered utilizing a protein microarray and verified using ELISAs in AIH patients [61]. This polyreactive IgG (pIgG) demonstrated 25% and 14% greater specificity for diagnosing AIH than conventional ANA and SMA testing, respectively, and a considerably higher sensitivity than anti-LKM and anti-SLA/LP.…”

“…Moreover, after response to immunosuppression, pIgG returned to those levels of patients with non-AIH liver diseases. The authors stressed that quantifying pIgG will not eliminate the necessity for a liver biopsy in AIH patients, but its better specificity could aid to the enhance preselection for a liver biopsy and deferring or cancelling the procedure in those with a low pretest probability of AIH [61].…”