Autoimmune Hepatitis

Diagnosis

Indications for Testing

• Persistently elevated alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) in the absence of other liver disease, especially in presence of hypergammaglobulinemia (European Association for the Study of the Liver [EASL], 2015)
• Cirrhosis of undetermined etiology

Criteria for Diagnosis

• Diagnosis of exclusion – rule out other more common etiologies of liver disease, including toxins, infections, and hereditary diseases
• International clinical scoring system may be helpful in establishing diagnosis

  Simplified Scoring System of the International Autoimmune Hepatitis Group

  Autoantibodies	Test Results	Test Score
  ANA or SMA	≥1:40	+1
  ANA or SMA	≥1:80	+2
  Antibodies to LKM-1	≥1:40	+2
  Antibodies to SLA	Positive	+2
  Absent autoantibodies	None	0
  Immunoglobulin level
  Immunoglobulin G	>ULN	+1
  	>1.1 ULN	+2
  	Normal	0
  Histological findings
  Morphological features of AIH	Compatible	+1
  	Typical	+2
  	Incompatible	0
  Viral disease
  Absence of viral hepatitis	No viral markers	+2
  	Viral markers present	0
  Pretreatment aggregate score
  Definite diagnosis		≥7
  Probable diagnosis		6
  ANA, antinuclear antibodies; LKM-1, liver-kidney microsome-1; SLA, soluble liver antigen; SMA, smooth muscle antibodies; ULN, upper limit of normal range Source: Hennes, International Autoimmune Hepatitis Group, 2008

Laboratory Testing

• Liver function testing – transaminases (AST and ALT) usually elevated
  • Elevation in both bilirubin and alkaline phosphatase (cholestatic pattern) is unusual and warrants evaluation for other etiologies or overlap syndromes
• Hepatitis testing – important to rule out acute or chronic hepatitis (hepatitis A virus [HAV], hepatitis B virus [HBV], hepatitis C virus [HCV])
• Quantitative immunoglobulins – IgG usually elevated
• Antibody testing – consider the following
  • Antinuclear antibody (ANA)
  • Antineutrophil cytoplasmic antibody (ANCA)
  • Antismooth muscle antibody (anti-SMA)
  • Anti-F-actin (smooth muscle) antibody
  • Antimitochondrial antibody (AMA)
  • Antisoluble liver antigen antibody (anti-SLA)
  • Antiliver-kidney microsomal-1 antibody (anti-LKM-1; cytochrome P450 2D6)
  • Antiliver cytosol (anti-LC-1)
    • Serum titers of antibodies do not appear to correlate with disease activity
    • Titers may vary during course of disease without activity correlation

• Testing to rule out other conditions (see Differential Diagnosis)
• Histopathology
  • Tissue evaluation helps to exclude other disease processes, but features are not disease specific
  • Typically demonstrates interface hepatitis with plasma cell and lymphocytic infiltrates
    • Significantly progressed disease may only reveal cryptogenic cirrhosis

Prognosis

Differential Diagnosis

• Infection
  • Viral
    • Cytomegalovirus
    • Epstein-Barr virus
    • Herpes simplex virus
    • Varicella-zoster virus
    • Hepatitis A, B, C, D, or E
  • Bacterial
    • Leptospira spp
    • Coxiella burnetii
    • Rickettsia rickettsii
    • Treponema pallidum (secondary)
    • Sepsis
    • Rickettsia typhi
    • ​Mycobacterium tuberculosis
  • ​Parasitic
    • Liver trematodes
    • Echinococcus spp
    • Parasitic diarrhea
    • Toxocara spp
• Drug or toxin exposure
  • Acetaminophen
  • Antiseizure medications
  • Isoniazid (Nydrazid)
  • Oral contraceptives
  • Rifampin (Rifadin)
  • Sulfonamides
  • Alcohol abuse
  • Tetrachloride
• Nonalcoholic acute steatohepatitis (NASH)
• Other autoimmune diseases
  • Primary biliary cholangitis
  • Primary sclerosing cholangitis
  • Systemic lupus erythematosus
  • ​Autoimmune cholangitis
• Genetic diseases
  • Wilson disease
  • Hemochromatosis
  • Alpha-1-antitrypsin deficiency
• Granulomatous disease (eg, sarcoidosis)
• Hepatic ischemia

Monitoring

• Patients with cirrhosis – monitor for hepatocellular carcinoma
• Patients receiving glucocorticoids for treatment – monitor for adverse effects of long-term therapy

Background

Epidemiology

• Incidence – 0.85-1.9/100,000 per year for adults of White northern European ancestry (Czaja, 2015)
• Prevalence – 15-25/100,000; higher in some populations, eg, Alaskan natives (EASL, 2015)
• Sex – M<F, 1:4 (type 1), 1:10 (type 2) (Heneghan, 2013)

Classification

• AIH type 1 (AIH-1)
  • Most common
  • Characterized by ANA and/or SMA (EASL, 2015)
  • Age – bimodal peaks
    • 10-30 years
    • 40-50 years
  • Broad spectrum of disease from mild liver disease to cirrhosis
• AIH type 2 (AIH-2)
  • Rare – ~4% of patients with AIH in the U.S.
  • Characterized by anti-LKM-1, anti-LC-1, and, rarely, anti-LKM-3 (EASL, 2015)
  • Most common in children or young adults
  • Disease has a more rapid onset and progression than type 1
  • Associated with
    • IgA deficiency
    • Chronic hepatitis C infection
• AIH type 3 (AIH-3) (EASL, 2015)
  • Controversial subclassification
  • Characterized by presence of anti-SLA, also called antiliver-pancreas (anti-LP)
  • May predict more severe disease and need for lifelong immunosuppression

Genetics

• AIH-1 – DRB1*0301, DRB1*0401
• AIH-2 – DQB1*0201, DRB1*07, DRB1*03

Clinical Presentation

• ~25% of patients are asymptomatic when AIH is detected by liver function testing (Liberal, 2014)
• Nonspecific symptoms – fatigue, lethargy, anorexia, malaise
• Gastrointestinal – nausea, abdominal pain, jaundice, hepatomegaly, upper abdominal discomfort
• Musculoskeletal – arthralgias
• ​Extrahepatic associations
  • AIH-1 – thyroiditis, celiac disease, ulcertive colitis, rheumatoid arthritis, Sjögren, mixed connective tissue disease, CREST
  • AIH-2 – diabetes mellitus, thyroiditis, vitiligo
• Overlap syndromes
  • The two most common syndromes are AIH with either primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC)

• AIH antibody-negative disease
  • No other etiology found for cirrhosis – key to this diagnosis
  • Same clinical and histological presentation as antibody-positive disease
• AIH complications
  • Liver failure/cirrhosis
  • Increased risk of hepatocellular carcinoma