Autoimmune Hepatitis-Immunologically Triggered Liver Pathogenesis-Diagnostic and Therapeutic Strategies

Abstract

Autoimmune hepatitis (AIH) is a severe liver disease that arises in genetically predisposed male and female individuals worldwide. Diagnosis of AIH is made clinically applying diagnostic scores; however, the heterotopic disease phenotype often makes a rapid determination of disease challenging. AIH responds favorably to steroids and pharmacologic immunosuppression, and liver transplantation is only necessary in cases with acute liver failure or end-stage liver cirrhosis. Recurrence or development of de novo AIH after transplantation is possible, and treatment is similar to standard AIH therapy. Current experimental investigations of T cell-mediated autoimmune pathways and analysis of changes within the intestinal microbiome might advance our knowledge on the pathogenesis of AIH and trigger a spark of hope for novel therapeutic strategies.

Figure 1

Pathogenesis of autoimmune hepatitis. HLA and non-HLA molecules as well as environmental triggers such as viruses, toxins, and the microbiome have been suggested as key components for a T cell-mediated immune response. The presentation of autoantigenic peptide (AG) to naïve CD4⁺ T helper cells (TH0) by antigen-presenting cells (APC, dendritic cells (DC)) leads to a secretion of proinflammatory cytokines (IL-12, IL-6, and TGF-B) who give rise to the development of Th1, Th2, and TH17 cells. TH1 cells secrete IL-2 and IFN-y, which stimulate CD8⁺ cells to induce expression of HLA class I and HLA class II molecules on hepatocytes. Tregs and Th2 cells secrete IL-4, Il-10, and IL-13 thereby stimulating the maturation of B cells and plasma cells which themselves produce autoantibodies. TH17 cells, which increased number correlates with the degree of liver fibrosis, secrete proinflammatory cytokines and suppress T regulatory cells (Treg). The numerical decrease of Tregs leads to impaired tolerance to autoantigens which subsequently results in the initiation and perpetuation of autoimmune liver damage. The histological characteristics of interface hepatitis comprise an inflammatory cell infiltrate consisting of lymphocytes and plasma cells which is located around the portal tracts.

Figure 2

Example of histological features of autoimmune hepatitis (a, b), virus hepatitis C (c, d), and drug-induced liver injury (DILI) (e, f). Haematoxylin and Eosin (H&E) staining: (a, c, e) 20-fold magnification; (b, d, f) 40-fold magnification. (a, b) Interface hepatitis. Liver biopsy histology of a patient with autoimmune hepatitis typically reveals a dense portal and periportal mononuclear cell infiltrate including several plasma cells. The infiltration of lymphocytes and plasma cells in the central and periportal areas reflecting interface hepatitis occurs during the acute phase of AIH but is rather not present during acute hepatitis caused by hepatitis C virus (c, d) and drug-induced liver injury (e, f).

Figure 3

Proposed treatment strategy for indeterminate acute severe hepatitis based on the authors' experience. Patients with diagnosis of acute severe hepatitis receive early steroid treatment. Evaluation after 3 days is aimed at assessing a possible steroid response. If no response is seen, steroid therapy is stopped and alternative treatment strategies are considered. In case of therapy response, steroids are tapered accordingly. After steroid withdrawal, reevaluation may allow for discrimination between autoimmune hepatitis (AIH) and drug-induced liver injury (DILI), since early steroid tapering in AIH is commonly accompanied by a disease relapse.

Figure 4

ALT values (a) and response rates in % (b) (indicated as ranges of upper limits of normal, ULN) of AIH patients who received early corticosteroid treatment at our institution. ALT < 0.85 μkat/l for male and <0.58 μkat/l for female patients were considered normal and hence classified as full response (green). ALT levels > 0.85 and <1.7 μkat/l for male and >0.58 μkat/l and <1.16 μkat/l for female were considered as partial response (yellow), and ALT > 1.7 μkat/l for male and >1.16 μkat/l for female were considered as no response (blue).