What is autoimmune hepatitis?

What is Autoimmune Hepatitis?

Autoimmune hepatitis (AIH) is an immune-mediated inflammatory liver disease of uncertain cause that attacks the liver through autoreactive T and B cells, characterized by elevated aminotransferases, hypergammaglobulinemia, circulating autoantibodies, and interface hepatitis on liver biopsy—a disease that, if left untreated, progresses to cirrhosis and liver failure but responds favorably to immunosuppressive therapy. 1

Core Disease Characteristics

AIH represents a chronic inflammatory condition where the immune system loses tolerance to hepatocyte-specific autoantigens, creating a self-perpetuating cycle of liver inflammation. 2 The disease affects all ages, both genders (though predominantly women at 71-95% in adults), and all ethnic groups. 1

Pathophysiology

The disease develops through a convergence of three key factors: 2

• Environmental triggers (viral infections like hepatitis A or C, certain medications including TNF-alpha antagonists and immune checkpoint inhibitors, intestinal dysbiosis) initiate the process through molecular mimicry between viral epitopes and liver autoantigens 2
• Genetic predisposition (primarily HLA-DRB103:01, DRB104:01, and DRB1*13:01 alleles) determines which autoantigenic peptides can be presented to autoreactive T cells 2
• Failure of immune tolerance allows autoreactive CD4 and CD8 T cells to break self-tolerance, while regulatory T cells fail to prevent autoreactivity and B regulatory cells cannot inhibit autoantibody production 2

Diagnostic Features

AIH does not have a signature diagnostic feature and requires a constellation of typical findings: 1

Biochemical Hallmarks

• Elevated serum aminotransferases with a predominantly hepatitic pattern (transaminases ranging from just above normal to >50 times normal) 3
• Hypergammaglobulinemia with elevated IgG or γ-globulin levels ≥1.5 times normal for definite diagnosis 3
• ALP to AST (or ALT) ratio typically <1.5, distinguishing it from cholestatic liver diseases 3

Serological Markers

• Type 1 AIH (80% of cases): positive antinuclear antibodies (ANA) and/or smooth muscle antibodies (SMA), peak incidence in females aged 16-30 years 2, 3
• Type 2 AIH: positive anti-liver kidney microsomal type 1 (anti-LKM1) and/or anti-LC1 antibodies, more common in children and in European/South American populations 2, 3

Important caveat: The International Autoimmune Hepatitis Group does not endorse classification into types as distinct clinical entities with different etiologies or treatment responses, as both types respond similarly to corticosteroids. 2

Histological Features

Liver biopsy is essential and demonstrates: 3

• Interface hepatitis with portal lymphocytic/lymphoplasmacytic infiltrates extending into the lobule 1, 3
• Progressive hepatic necroinflammation and fibrosis if untreated 2

Clinical Presentation Spectrum

The clinical picture varies dramatically: 1

• Asymptomatic patients discovered incidentally
• Chronic illness with fatigue, jaundice, and progressive liver dysfunction
• Acute liver failure with INR ≥2 and hepatic encephalopathy within 26 weeks of illness onset 1
• Acute severe presentation mimicking acute hepatitis

Ethnic and Demographic Variations

Clinical manifestations vary significantly by race and ethnicity: 1, 2

• Alaskan Natives: high frequency of acute icteric disease 1, 2
• Hispanics: more commonly present with established cirrhosis 1
• African Americans: accelerated disease progression and higher recurrence rates after liver transplantation 1
• Middle Eastern patients: commonly exhibit cholestatic features 2
• Asian patients: typically present with late-onset, mild disease 2

Natural History and Prognosis

Untreated moderate to severe AIH progresses to cirrhosis in 82% of patients within 5 years, with 45% mortality. 3 Possible outcomes include advanced hepatic fibrosis, cirrhosis, death from liver failure, or need for liver transplantation. 1

With appropriate immunosuppressive treatment, approximately 80% of patients achieve remission, and the therapy has been life-saving. 3 Early diagnosis can result in near-normal life expectancy. 4

Associated Autoimmune Conditions

AIH frequently coexists with other autoimmune diseases: 5

• Autoimmune thyroiditis (most common, 10.2-14.1% of concomitant autoimmune diseases) 5
• Inflammatory bowel disease (particularly ulcerative colitis) 5
• Sjögren syndrome (2.8-7% of patients) 5
• Systemic lupus erythematosus (2.2-3% of patients) 5
• Rheumatoid arthritis (2-4% of patients) 5

First-degree relatives of AIH patients have increased occurrence of immune-mediated diseases, necessitating careful family history. 5

Epidemiology

The mean annual incidence among white Northern Europeans is 1.9 per 100,000, with a point prevalence of 16.9 per 100,000. 1 AIH accounts for 2.6% of liver transplantations in Europe and 5.9% in the United States. 1

Critical Diagnostic Pitfall

The exact triggering event often cannot be identified in individual patients. 2 What matters clinically is recognizing the syndrome early through its characteristic constellation of features—elevated aminotransferases, hypergammaglobulinemia, autoantibodies, and interface hepatitis on biopsy—rather than identifying the specific trigger. 2 Diagnosis requires exclusion of viral hepatitis, drug-induced liver injury, Wilson's disease, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. 3