What causes a patient to develop autoimmune hepatitis?

How Autoimmune Hepatitis Develops

Autoimmune hepatitis develops when environmental triggers, genetic predisposition, and a failure of immune tolerance mechanisms converge to initiate a T cell-mediated immune attack against liver antigens in susceptible individuals. 1

Pathogenic Mechanism

The disease reflects a multistep breakdown in self-tolerance where the immune system inappropriately targets hepatocyte autoantigens 1:

• Autoreactive CD4 and CD8 T cells break self-tolerance to hepatic autoantigens due to environmental triggers and the inability of regulatory T cells (both natural and inducible Tregs) to prevent autoreactivity 1
• Autoreactive B cells produce autoantibodies in the absence of effective B regulatory cell inhibition 1
• Professional antigen-presenting cells present autoantigenic peptides to T cell receptors on naive CD4+ helper T cells and CD8+ T cells, activating them 1
• This creates a self-perpetuating cycle of inflammation with portal lymphocytic/lymphoplasmacytic infiltrates causing progressive hepatic necroinflammation and fibrosis 1, 2

Genetic Predisposition

HLA associations are the primary genetic risk factors 1:

• The disease clusters within the conserved 8.1 ancestral haplotype, particularly HLA-DRB103:01, DRB104:01, and DRB1*13:01 alleles 1
• These HLA class II alleles determine which autoantigenic peptides can be presented to autoreactive T cells 1
• Female sex is strongly associated with AIH (gender ratio 3.6:1), suggesting hormonal influences on autoimmunity, though exact mechanisms remain unclear 1, 3

Environmental Triggers

Several factors have been identified as potential triggers in genetically susceptible individuals 3:

Viral Infections

• Hepatitis A, hepatitis C, and other viral infections have been documented as potential triggers through molecular mimicry between viral epitopes and liver autoantigens 1, 3, 4
• The development of AIH has been reported after acute hepatitis A virus infection and during/after interferon-alpha treatment for hepatitis C 1, 4

Drug-Induced AIH

• Certain medications can trigger classical AIH or induce liver disease with autoimmune features, including tumor necrosis factor-alpha antagonists (infliximab, adalimumab) and immune checkpoint inhibitors 1, 3
• This represents a genuine autoimmune process rather than simple drug toxicity, as patients require ongoing immunosuppression after drug withdrawal 1

Other Environmental Factors

• Alcohol consumption, vitamin D deficiency, and altered intestinal microbiome composition have been studied as contributing factors 3
• Intestinal dysbiosis and circulating gut-derived lipopolysaccharides with weakening of the intestinal mucosal barrier have been described in AIH patients 1

Ethnic and Demographic Variations

Clinical manifestations vary significantly among ethnic groups, suggesting different environmental exposures or genetic backgrounds 1:

• African-American patients present more frequently with cirrhosis 1
• Alaskan natives exhibit higher frequency of acute icteric disease 1
• Middle Eastern patients commonly have cholestatic features 1
• Asian patients typically present with late-onset, mild disease 1
• South American patients are commonly children with severe inflammation 1

Special Circumstances

De Novo AIH Post-Transplant

• AIH can develop after liver transplantation performed for other liver diseases, termed "de novo AIH" or "post-transplant immune hepatitis" 1
• This occurs when the immune system attacks the transplanted liver, which is not strictly "self" 1

Pregnancy-Related Development

• AIH may manifest in the postpartum period due to immune reconstitution following delivery 1
• The disease rarely presents during pregnancy itself but should be strongly considered in postpartum liver dysfunction with hypergammaglobulinemia 1

Critical Pitfall

The exact triggering event often cannot be identified in individual patients 1. The disease represents a complex interaction between multiple factors rather than a single identifiable cause, making prevention strategies challenging 1. What matters clinically is recognizing the syndrome early through its characteristic features (hypergammaglobulinemia, autoantibodies, interface hepatitis) rather than identifying the specific trigger 1, 5.