• Richard Taubert, Bastian Engel, Jana Diestelhorst, Katharina Luise Hupa-Breier, Patrick Behrendt, Niklas T Baerlecken, Kurt-Wolfram Sühs, Maciej K Janik, Kalliopi Zachou, Marcial Sebode, Christoph Schramm, María-Carlota Londoño, Sarah Habes, UK-AIH Consortium, Ye H Oo, Claudine Lalanne, Simon Pape, Maren Schubert, Michael Hust, Stefan Dübel, Mario Thevis, Danny Jonigk, Julia Beimdiek, Falk F R Buettner, Joost Ph Drenth, Luigi Muratori, David H Adams, Jessica K Dyson, Amédée Renand, Isabel Graupera, Ansgar W Lohse, George N Dalekos, Piotr Milkiewicz, Martin Stangel, Benjamin Maasoumy, Torsten Witte, Heiner Wedemeyer, Michael P Manns, and Elmar Jaeckel.
• Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
• Hepatology. 2021 Sep 2.

Background & AimsDetection 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 & ResultsDuring 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 macro-array and confirmed with solid phase ELISAs in AIH patients. Subsequently, polyreactive IgG (pIgG) were exemplarily quantified by reactivity against human huntingtin-interacting protein 1-related 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 anti-smooth 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.ConclusionspIgG 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.This article is protected by copyright. All rights reserved.

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