Autoimmune hepatitis: new paradigms in the pathogenesis, diagnosis, and management

Abstract

Autoimmune hepatitis (AIH), primary biliary cirrhosis, and primary sclerosing cholangitis are the three major autoimmune diseases affecting the liver, and of these three, AIH is the most typical autoimmune disease being characterized by a T-cell-rich infiltrate, raised circulating γ-globulins, autoantibodies, HLA associations, and links with other autoimmune diseases. It is the only one, of the three diseases, that responds well to immunosuppressive therapy. AIH is caused by dysregulation of immunoregulatory networks and the consequent emergence of autoreactive T cells that orchestrate a progressive destruction of hepatocytes leading untreated to liver failure. T cells play a major role in the immunopathogenesis, and both CD4(+) and CD8(+) T cells are involved together with effector responses mediated by NK cells, γδ T cells, and macrophages. A number of triggering factors have been proposed including viruses, xenobiotics, and drugs, but none have been conclusively shown to be involved in pathogenesis.

Keywords: Autoimmune liver disease; Lymphocytes; Mycophenolate mofetil; Recruitment; Regulatory T cell; Th17.

Fig. 1

Histological features of autoimmune hepatitis. a A dense plasma cell-rich portal mononuclear inflammatory infiltrate is associated with moderate interface hepatitis. b Interface hepatitis with ballooning and rosetting of entrapped periportal hepatocytes. c A plasma cell-rich centrilobular mononuclear inflammatory infiltrate is associated with confluent and bridging hepatocyte necrosis

Fig. 2

Immunopathogenesis of AIH. A specific autoantigenic peptide is presented to an uncommitted naive T lymphocyte within the HLA class II molecule of dendritic cells/antigen-presenting cell (APC). Naive T cells will differentiate into different T-cell lineages, Th1, Th2, or Th17, depending on cytokine milieu (IL-12 for Th1, IL-4 for Th2, and IL-1β, IL-6, and IL-23, and TGF-β for Th17) and these cells recruit T-cytotoxic (Tc) cells and B cells to initiate a series of immune reactions. Regulatory T cells (Treg) control these effector T cells to prevent excessive damage and they differentiate from naive T cells by TGF-β. Th1 cells secrete TNF-α and IFN-γ, which stimulate Tc lymphocytes. Th2 cells secrete IL-4, IL-5, IL-10, and IL-13 and direct autoantibody production by B lymphocytes. Th17 cells secrete IL17A&F, IL-22, TNF-α, IFN-γ, and CCL20. Regulatory T cells suppress these effector cells to maintain immune homeostasis. If regulatory T cells do not intervene, a variety of effector mechanisms are triggered and hepatocytes destruction/autoimmune hepatitis occur. Th17 cells, which play a major role in murine models of autoimmune disease, may also be involved in autoimmune liver diseases. In some cases, this leads to uncontrolled inflammation and fulminant hepatic failure. Treg could also transform to Th17 cells in inflamed hepatic microenvironment under the influence of inflammatory cytokines

Fig. 3

Algorithm for adjusting therapy in patients with autoimmune hepatitis