What is autoimmune hepatitis in a 66-year-old female patient with elevated liver enzymes and abnormal laboratory results?

What is Autoimmune Hepatitis?

Autoimmune hepatitis (AIH) is a chronic immune-mediated inflammatory liver disease characterized by elevated liver enzymes (predominantly AST/ALT), hypergammaglobulinemia with elevated IgG levels, positive circulating autoantibodies (ANA, SMA, or anti-LKM1), and interface hepatitis on liver biopsy, occurring after exclusion of other causes of liver disease. 1

Core Pathophysiology

AIH develops when autoreactive CD4+ and CD8+ T cells break self-tolerance to hepatic autoantigens, creating a self-perpetuating cycle of inflammation with portal lymphocytic/lymphoplasmacytic infiltrates causing progressive hepatic necroinflammation and fibrosis. 2 This occurs due to:

• Environmental triggers (viral infections like hepatitis A, C, or EBV; certain medications including minocycline, nitrofurantoin, immune checkpoint inhibitors) 1, 2
• Genetic predisposition (HLA-DRB103:01, DRB104:01, and DRB1*13:01 alleles) 2
• Failure of immune tolerance mechanisms with inability of regulatory T cells to prevent autoreactivity 2

Clinical Presentation Spectrum

The clinical manifestations range dramatically from asymptomatic disease to fulminant hepatic failure: 1

• Asymptomatic (25%): Discovered incidentally with elevated liver enzymes, including some patients who already have cirrhosis at diagnosis 1
• Chronic insidious onset (40-50%): Fatigue (most common symptom), nonspecific body aches, joint pains (30-60%), nausea, anorexia, weight loss, amenorrhea 1, 3
• Acute hepatitis presentation (25-40%): Jaundice, influenza-like symptoms, AST/ALT levels exceeding 400 IU/mL or even several thousand 1, 3
• Acute liver failure (6%): Hepatic encephalopathy within 26 weeks of disease discovery, may be misdiagnosed as viral or toxic hepatitis 1

Critical pitfall: In acute presentations, 25-39% of patients have normal IgG levels and 29-39% have negative or weakly positive autoantibodies initially, making diagnosis challenging. 1, 3

Diagnostic Criteria

The diagnosis requires a constellation of findings after excluding competing diagnoses: 1

Laboratory Features (Definite AIH):

• AST/ALT elevation: Typically 5-20 times upper limit of normal, predominantly hepatitic pattern 1, 3
• **ALP/AST ratio <1.5** (ratio >3 argues against AIH) 3
• Hypergammaglobulinemia: γ-globulins or IgG >1.5 times upper normal limit in ~85% of patients 1
• Autoantibodies: ANA, SMA, or anti-LKM1 ≥1:80 in adults (≥1:40 for probable AIH) 1
• Negative viral markers: No active hepatitis A, B, C infection 1
• Alcohol <25 g/day 1
• No recent hepatotoxic drugs 1

Histological Features:

• Interface hepatitis (moderate to severe) with portal plasma cell infiltration 1
• No biliary lesions, granulomas, or prominent changes suggestive of another disease 1
• Hepatocyte rosettes and emperipolesis are characteristic but not required 3

Diagnostic Scoring:

The revised IAIHG scoring system assigns points for various features, with score ≥7 indicating definite AIH and ≥6 indicating probable AIH. 1, 3

Disease Subtypes

• Type 1 AIH (80% of cases): Positive ANA and/or SMA, peak incidence in females aged 16-30 years, though 50% are older than 30 and 23% are at least 60 years old 2
• Type 2 AIH: Positive anti-LKM1 and/or anti-LC1 antibodies, more common in children and in European/South American populations 2

Important note: The International Autoimmune Hepatitis Group does not endorse classification into types as distinct clinical entities since both respond similarly to corticosteroids and classification does not alter treatment decisions. 2

Critical Exclusions Required

Before diagnosing AIH, you must exclude: 3

• Viral hepatitis: Check HBsAg, anti-HBc, anti-HCV with reflex HCV RNA, HAV IgM, HEV serology 3
• Drug-induced liver injury: Approximately 9% of suspected AIH cases are actually DILI (common culprits: nitrofurantoin, minocycline, alpha-methyldopa, hydralazine, immune checkpoint inhibitors) 1, 3
• Wilson's disease: Especially in younger patients, check ceruloplasmin and 24-hour urinary copper 3
• Alcoholic liver disease: Detailed alcohol history 3
• EBV infection: Can mimic AIH with elevated liver enzymes, positive ANA, fever, and fatigue 3

Disease Severity and Prognosis

Untreated AIH has a high mortality rate and progresses rapidly. 1 Key severity indicators:

• Approximately 30-50% of patients have cirrhosis at presentation (1/3 of adults, 1/2 of children) 1
• Untreated disease leads to cirrhosis in at least 40% of survivors and esophageal varices in 54% within 2 years after cirrhosis 4
• With appropriate immunosuppressive treatment, 80% achieve remission and long-term survival approaches that of the general population 4, 5

Special Populations and Variations

Clinical phenotypes vary significantly by ethnicity: 1, 2

• African-American patients: More frequently present with cirrhosis 2
• Hispanic/South American patients: Aggressive presentation with very high prevalence of cirrhosis and cholestatic features 1
• Asian patients: Very poor outcomes, typically late-onset mild disease 1, 2
• Alaskan natives: Higher frequency of acute icteric disease 2

Female predominance is marked (3-4 times more common than males), suggesting hormonal influences on autoimmunity. 1, 2

Seronegative AIH

20% of AIH patients are seronegative for standard autoantibodies (ANA, SMA, anti-LKM1). 3, 4 In these cases:

• Consider testing for anti-SLA (disease-specific, present in 20-30% of AIH patients) 3
• Consider p-ANCA testing 3
• Diagnosis relies more heavily on histology, elevated IgG, and exclusion of other diseases 3
• Do not exclude AIH based solely on negative standard autoantibodies 3

Associated Conditions

AIH is associated with a broad variety of other autoimmune diseases in 30-50% of patients, including thyroid disease, celiac disease, inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus. 1 Recognition of these co-presentations is important because malabsorption of immunosuppressive medications may delay effective treatment. 1

Surveillance Requirements

For patients with established cirrhosis: 1

• Liver ultrasound every 6 months for hepatocellular carcinoma screening 1
• Esophagogastroduodenoscopy for variceal surveillance 4
• Dermatological monitoring for non-melanoma skin cancer after long-term immunosuppression 1