Update on Autoimmune Hepatitis

Abstract

Autoimmune hepatitis (AIH), a liver disorder affecting both children and adults, is characterized by inflammatory liver histology, elevated transaminase levels, circulating nonorganspecific autoantibodies, and increased levels of immunoglobulin G, in the absence of a known etiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or antinuclear antibody define AIH type 1 and antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2. AIH type 1 affects both adults and children, while AIH type 2 is mainly a paediatric disease, though it does occasionally affects young adults. AIH should be considered during the diagnostic workup of any patient with increased liver enzyme levels. AIH is exquisitely responsive to immunosuppressive treatment with prednisolone with or without azathioprine, with symptom free long-term survival for the majority of patients. For those who do not respond to standard treatment, or who are difficult-to-treat, mycophenolate mofetil and, in the absence of a response, calcineurin inhibitors should be tried in addition to steroids. The pathogenesis of AIH is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4 T-cells, although recent studies support the involvement of diverse populations, including Th17 cells. A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigenspecific regulatory T-cells, which ultimately aim at restoring tolerance to liver-derived antigens.

Keywords: Autoantibodies; Autoimmune hepatitis; Immunogenetics; Immunosuppresion; Regulatory T cells.

Fig. 1. Autoimmune attack to the liver cell.

An autoantigenic peptide is presented to an uncommitted T helper (Th0) lymphocyte within the HLA class II molecule of an antigen-presenting cell (APC). Th0 cells become activated and, according to the cytokines present in the microenvironment and the nature of the antigen, differentiate into Th1, Th2, or Th17 cells, initiating a series of immune reactions determined by the cytokines they produce: Th2 secrete mainly IL-4, IL-10, and IL-13 and direct autoantibody production by B lymphocytes; Th1 secrete IL-2 and IFN-γ, which stimulate cytotoxic T lymphocytes (CTL), enhance expression of class I, and induce expression of class II HLA molecules on hepatocytes and activate macrophages; activated macrophages release IL-1 and tumor necrosis factor alpha (TNF-α). If regulatory Tcells do not oppose, a variety of effector mechanisms are triggered: liver cell destruction could derive from the action of CTL; cytokines released by Th1 and recruited macrophages; complement activation; or engagement of Fc receptor-bearing cells, such as natural killer (NK) lymphocytes, by the autoantibody bound to the hepatocyte surface. The role of the recently described Th17 cells, which arise in the presence of transforming growth factor beta (TGF-γ) and IL-6, is under investigation.

Fig. 2. Histology of autoimmune hepatitis.

The portal and periportal inflammatory infiltrate characteristic of autoimmune hepatitis is composed of lymphocytes, monocytes/macrophages, and plasma cells (interface hepatitis, arrows). Hematoxylin & eosin staining (Picture kindly provided by Dr. Alberto Quaglia, Institute of Liver Studies, King’s College Hospital).