What is autoimmune hepatitis, including its epidemiology, clinical presentation, diagnostic criteria, and first‑line treatment?

Autoimmune Hepatitis Overview

Autoimmune hepatitis (AIH) is a chronic immune-mediated inflammatory liver disease characterized by elevated aminotransferases, hypergammaglobulinemia (particularly IgG), circulating autoantibodies, and interface hepatitis on liver biopsy, requiring prompt diagnosis and immunosuppressive treatment to prevent progression to cirrhosis and death. 1, 2

Epidemiology and Natural History

• AIH predominantly affects women across all age groups, with Type 1 AIH showing peak incidence in females aged 16-30 years, though 50% of patients are older than 30 and 23% are at least 60 years old 3

• Untreated moderate-to-severe AIH carries devastating prognosis: cirrhosis develops in 82% within 5 years and mortality reaches 45% 1, 2

• Approximately one-third of adults and half of children present with established cirrhosis at diagnosis, underscoring the need for early recognition 1

• Acute presentations occur in 40% of cases, and fulminant hepatic failure with encephalopathy within 8 weeks of onset is possible 1

Clinical Presentation

The clinical spectrum ranges from completely asymptomatic to fulminant hepatic failure, making AIH a diagnostic challenge 1, 4

Common Presentations:

• Insidious onset with fatigue, jaundice, and right upper quadrant discomfort in patients with gradual disease progression 1
• Acute hepatitis mimicking viral or drug-induced hepatitis in 40% of cases 1
• Incidental discovery during evaluation of elevated liver enzymes in asymptomatic patients 1
• Extrahepatic autoimmune manifestations including thyroiditis, inflammatory bowel disease, and rheumatoid arthritis are common associations 1

Diagnostic Criteria

Laboratory Features

The biochemical hallmark is a predominantly hepatitic pattern with aminotransferases (AST/ALT) elevated disproportionately to alkaline phosphatase, typically with an ALP:AST ratio <1.5 (ratios >3 argue against AIH) 1, 5, 2

• Hypergammaglobulinemia with IgG elevation ≥1.5 times upper normal limit is characteristic for definite diagnosis, though IgG is normal in approximately 10% of European patients and 25-39% of acute presentations 1, 5

• Elevated serum IgG is highly distinctive; elevated IgA suggests alcoholic steatohepatitis and elevated IgM suggests primary biliary cholangitis 1

Autoantibody Testing

Initial serological evaluation must include ANA, SMA, and anti-LKM1 as the conventional diagnostic battery 5

Type 1 AIH (80% of cases):

• ANA and/or SMA are present in 96% of North American adults, with ANA detected in 80% and SMA in 63% at presentation 5
• Diagnostic accuracy improves from 58% to 74% when two autoantibodies are detected concurrently 5

Type 2 AIH:

• Anti-LKM1 and/or anti-LC1 characterize Type 2 AIH, present in 3% of North American adults but more frequent in European patients 5
• These antibodies are typically detected in the absence of ANA and SMA 5

Additional Markers:

• Anti-SLA has 99% specificity for AIH and should be tested when conventional antibodies are negative, present in 7-22% of Type 1 AIH and can be the sole marker in 14-20% of cases 5, 2
• Atypical pANCA is present in 50-92% of Type 1 AIH patients and can be the only serological marker when conventional antibodies are negative 5, 2

Histological Requirements

Liver biopsy is mandatory for AIH diagnosis (except in highly typical acute presentations) and cannot be omitted 1, 5

• Interface hepatitis is the histologic hallmark, characterized by portal tract expansion with mononuclear infiltrate, disrupted limiting plate, and inflammatory extension into the acinus 1

• Portal plasma cell infiltration is typical but not required for diagnosis; plasma cells have eccentric clock-face nuclei and pale perinuclear cytoplasmic crescents 1, 5

• Hepatocyte rosettes and portal lymphocytic/lymphoplasmacytic infiltrates extending into lobules are characteristic features 5, 2

• Biopsy is essential to evaluate disease severity, determine treatment need, and exclude alternative diagnoses including biliary lesions, granulomas, steatosis, or iron overload 1

Mandatory Exclusions

Before confirming AIH, the following conditions must be ruled out 1, 5:

• Viral hepatitis (hepatitis A, B, C, and E) - no markers of current infection 1
• Wilson disease - normal ceruloplasmin level (mandatory in patients ≤30 years) 1, 5
• Hereditary hemochromatosis - normal iron, ferritin, and transferrin saturation 1, 5
• Alpha-1 antitrypsin deficiency - normal α1-antitrypsin phenotype 1, 5
• Drug-induced liver injury - no recent hepatotoxic drug use (minocycline, nitrofurantoin, isoniazid, propylthiouracil, methyldopa) 1, 5
• Alcoholic liver disease - daily alcohol <25 g/day for definite diagnosis 1
• Non-alcoholic fatty liver disease, primary biliary cholangitis, and primary sclerosing cholangitis 1, 5, 2

Diagnostic Scoring Systems

Two validated scoring systems aid diagnosis when features are atypical 1:

Revised IAIHG Score (1999):

• Incorporates female sex, ALP:AST ratio, IgG levels, autoantibody titers, absence of AMA, viral markers, drug/alcohol exposure, histology, and concurrent autoimmune diseases 1, 5, 2
• Definite diagnosis requires pretreatment score >15; probable diagnosis requires score 10-15 5

Simplified Scoring System (2008):

• Includes autoantibodies (ANA/SMA ≥1:40 = 1 point; ≥1:80 = 2 points; anti-LKM1 ≥1:40 or anti-SLA positive = 2 points), IgG levels (>ULN = 1 point; >1.1× ULN = 2 points), liver histology (compatible = 1 point; typical = 2 points), and absence of viral hepatitis (yes = 2 points) 1, 5, 2
• Score ≥6 indicates probable AIH; ≥7 indicates definite AIH 1

Special Diagnostic Considerations

In children with AIH, MR-cholangiography should be performed to exclude autoimmune sclerosing cholangitis, a variant syndrome 1

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, emphasizing the need to exclude viral hepatitis first 5

First-Line Treatment

Standard induction therapy consists of prednisone 15-20 mg/day combined with azathioprine 1-2 mg/kg/day for moderate-to-severe AIH 5, 2

• Treatment goals include normalization of aminotransferases and IgG levels, resolution of symptoms, and histological improvement with reduced inflammation 2

• Approximately 80% of patients achieve remission with first-line therapy, though 20-40% require second- or third-line therapies due to intolerance or insufficient response 2, 6, 7

• In acute presentations, high-dose prednisolone should be started promptly after exclusion of other causes, even if serology is atypical 5

Monitoring and Long-Term Management

Patients with cirrhosis require liver ultrasound every 6 months for hepatocellular carcinoma screening 1, 2

Regular monitoring should include liver function tests, IgG levels, and surveillance for esophageal varices in cirrhotic patients 2

Counseling for UV-protective measures and dermatological monitoring for non-melanoma skin cancer is recommended for patients on long-term immunosuppressants 1, 2

Most patients require lifelong maintenance immunosuppression, and treatment can reverse liver fibrosis, preventing progression to advanced cirrhosis 4