What is autoimmune hepatitis and what are its types?

Definition of Autoimmune Hepatitis

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by immune-mediated hepatocellular injury that, if untreated, progresses to cirrhosis, liver failure, and death. 1

Core Pathophysiology

AIH develops when environmental triggers and genetic predisposition converge with failed immune tolerance mechanisms, initiating a T cell-mediated immune attack against liver antigens. 2 The disease involves:

• Autoreactive CD4+ and CD8+ T cells that break self-tolerance to hepatic autoantigens, with professional antigen-presenting cells presenting autoantigenic peptides to T cell receptors 2
• Autoreactive B cells producing autoantibodies in the absence of effective B regulatory cell inhibition 2
• Self-perpetuating inflammatory cycle with portal lymphocytic/lymphoplasmacytic infiltrates causing progressive hepatic necroinflammation and fibrosis 2

Diagnostic Hallmarks

The diagnosis requires a constellation of findings after excluding other liver diseases:

• Elevated serum aminotransferases with predominant transaminase pattern over alkaline phosphatase 1
• Hypergammaglobulinemia with elevated IgG or γ-globulin levels (≥1.5 times normal for definite diagnosis) 1
• Positive autoantibodies (ANA, SMA, or anti-LKM1) 1, 3
• Interface hepatitis on liver biopsy with lymphoplasmacytic infiltration 1, 3

Classification into Types

Two types of AIH have been proposed based on serological markers, though they do not represent distinct clinical entities with different etiologies or treatment responses, and the International Autoimmune Hepatitis Group has not endorsed them as valid separate diseases. 1

Type 1 AIH

Type 1 AIH constitutes 80% of all AIH cases and is characterized by: 1

• Serological markers: Positive ANA and/or SMA, present in 96% of North American adults 3
• Demographics: 70% female, peak incidence ages 16-30 years, though 50% are older than 30 and 23% are at least 60 years old 1
• Genetic associations: HLA DR3 (DRB10301) and DR4 (DRB10401) in Caucasian populations 1
• Clinical behavior: DRB10301 patients are younger with higher treatment failure rates and relapse frequency, while DRB10401 patients are older with better corticosteroid response 1
• Associated conditions: 15-34% have concurrent autoimmune diseases including thyroid disease, synovitis, celiac disease, and ulcerative colitis 1
• Cirrhosis at presentation: 25% of patients 1

Type 2 AIH

Type 2 AIH is characterized by: 1

• Serological markers: Positive anti-LKM1 and/or anti-LC1 antibodies, with anti-LC1 present in 30% of type 2 cases 3
• Geographic distribution: More common in Europe and South American countries than the United States 1
• Demographics: Most patients are children 1
• Genetic associations: Susceptibility may relate to DRB1*0701 1
• Immunoglobulin pattern: Elevated serum immunoglobulin levels except IgA, which may be reduced 1
• Clinical features: Concurrent immune diseases are common, acute severe presentation is possible, and progression to cirrhosis occurs 1
• Autoantibody distinction: pANCA (common in type 1 AIH) are not detectable in type 2 disease 1

Abandoned Type 3 Classification

A proposed type 3 AIH has been abandoned because its serologic marker (anti-SLA) is found in both type 1 and type 2 AIH, not defining a separate entity. 1 Anti-SLA has 99% specificity for AIH and is present in 7-22% of type 1 AIH patients. 3

Clinical Utility of Classification

The classification into types can be used to characterize the clinical syndrome or indicate serological homogeneity in clinical investigations, but does not alter treatment decisions. 1 Both types respond well to corticosteroids, and earlier perceptions that type 2 AIH had poorer outcomes have not been corroborated. 1

Critical Diagnostic Pitfall

Anti-LKM1 antibodies should be routinely investigated to avoid overlooking type 2 AIH, particularly in pediatric patients where simultaneous testing of ANA, SMA, and anti-LKM1 is recommended. 1, 3 Anti-LKM1 can be confused with antimitochondrial antibodies if rodent kidney is the sole substrate, and can occur in 5-10% of chronic hepatitis C patients, making viral hepatitis exclusion crucial. 3