Autoimmmune hepatitis

Abstract

Autoimmune hepatitis (AIH) is a T-cell mediated, inflammatory liver disease affecting all ages and characterized by female preponderance, elevated serum transaminase and immunoglobulin G levels, positive circulating autoantibodies, and presence of interface hepatitis at liver histology. AIH type 1, affecting both adults and children, is defined by positive anti-nuclear and/or anti-smooth muscle antibodies, while type 2 AIH, affecting mostly children, is defined by positive anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. While the autoantigens of type 2 AIH are well defined, being the cytochrome P4502D6 (CYP2D6) and the formiminotransferase cyclodeaminase (FTCD), in type 1 AIH they remain to be identified. AIH-1 predisposition is conferred by possession of the MHC class II HLA DRB1*03 at all ages, while DRB1*04 predisposes to late onset disease; AIH-2 is associated with possession of DRB1*07 and DRB1*03. The majority of patients responds well to standard immunosuppressive treatment, based on steroid and azathioprine; second- and third-line drugs should be considered in case of intolerance or insufficient response. This review offers a comprehensive overview of pathophysiological and clinical aspects of AIH.

Keywords: Autoimmune Hepatitis; Genetic Predisposition; Immunopathophysiology; Treatment.

Fig. 1. Autoimmune attack to the liver cell.

An autoantigenic peptide (Ag) is presented to the T cell receptor (TCR) of uncommitted T helper (Th0) lymphocytes within the HLA class II (HLA II) molecule of an antigen-presenting cell (APC) either in the regional lymph nodes or within the liver itself. Activated Th0 cells differentiate into Th1 or Th2 cells in the presence of interleukin (IL)-12 or IL-4, respectively, and according to the nature of the antigen. This triggers a cascade of immune reactions determined by the cytokines they produce. Th1 cells secrete IL-2 and interferon (IFN)-γ, cytokines that stimulate cytotoxic T lymphocytes (CTL), enhance expression of class I HLA (HLA I) molecules, induce expression of class II HLA molecules on the liver cells and activate macrophages (MΦ). MΦ release IL-1 and tumour necrosis factor (TNF). Th2 cells secrete mainly IL-4, IL-13 and IL-21, and stimulate autoantibody production by B lymphocytes, which mature into plasma cells. Regulatory T cells (Tregs) derive from Th0 in the presence of transforming growth factor (TGF)-β. If Tregs are defective in number and/or function, hepatocyte destruction follows from the engagement of damaging effector mechanisms, including CTL, cytokines released by Th1 and by activated MΦ, complement activation, or adhesion of natural killer (NK) cells to autoantibody-coated hepatocytes through their Fc receptors. Th17 cells produce the inflammatory cytokines IL-17, IL-22 and TNF, and derive from Th0 cells in the presence of TGF-β and IL-6. The hepatocyte releases IL-6 which further stimulates Th17. Positive signal: Negative signal

Fig. 2. Autoantibodies detected by indirect immunofluorescence on rodent liver tissue.

Autoimmune hepatitis type 1: Panel A: anti-nuclear antibody (ANA) homogenous pattern on liver tissue. Panel B: anti-smooth muscle antibody (SMA) on kidney tissue showing staining of vessels (V), glomeruli (G) and tubules (T), VGT pattern. Panel C: combined ANA and SMA patterns. Autoimmune hepatitis type 2: anti-liver-kidney microsomal type 1 (LKM-1) antibody pattern on liver (D) and kidney (E) tissue

Fig. 3. Interface hepatitis in a patient with autoimmune hepatitis type 1.

Lymphocytes and plasma cells infiltrate the portal and periportal area, extending to and disrupting the parenchymal limiting plate. Hematoxylin & eosin staining; original magnification x100. Courtesy of Professor Yoh Zen, Institute of Liver Studies, King’s College Hospital, London, UK

Fig. 4. Overview of the mode of action of initial and second/third-line pharmacological treatments used in autoimmune hepatitis.

Glucocortisteroids bind to the cytosolic glucocorticosteroid receptor, which migrates to the cell nucleus leading to repression of pro-inflammatory genes and activation of anti-inflammatory genes. Azathioprine and mycophenolate mofetil inhibit the synthesis of purines, the substrates for RNA and DNA synthesis during the S phase of the cell cycle, thus causing cell death of the rapidly dividing cells, including lymphocytes. Calcineurin inhibitors act mainly by suppressing the synthesis of IL-2, which is essential to T cell proliferation. Sirolimus and everolimus act on the mammalian target of rapamycin (mTOR), a serine/threonine-specific protein regulating cellular metabolism, growth, and proliferation. Anti-tumor necrosis factor (TNFα) antibodies act by binding to soluble or membrane-bound TNFα preventing its binding to the cognate receptor