Autoimmune Hepatitis - Hepatitis, Autoimmune

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
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Indications for Testing

  • Persistently elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in the absence of other liver disease
  • Cirrhosis or chronic hepatitis 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

Laboratory Testing

  • Nonspecific testing
    • Liver function testing – transaminases (AST & ALT) usually elevated
      • Cholestatic pattern for enzymes is unusual and warrants evaluation for other etiologies or overlap syndromes
    • Hepatitis testing – important to rule out acute or chronic hepatitis (HAV, HBV, HCV)
    • Quantitative immunoglobulins – IgG usually elevated
    • Consider other testing based on clinical presentation – rule out other obvious causes of chronic liver disease
  • Antibody testing
    • May include any/all of the following
      • Anti-nuclear antibody (ANA)
      • Anti-neutrophil cytoplasmic antibody (ANCA)
      • Anti-smooth muscle antibody (SMA)
      • Anti-F-actin (smooth muscle) antibody
      • Anti-mitochondrial antibody (AMA)
      • Anti-soluble liver antigen antibody (SLA)
      • Anti-liver-kidney microsomal-1 antibody (LKM-1)
      • Anti-liver cytosol (LC-1)
    • Serum titers of antibodies do not appear to correlate with disease activity
      • Titers may vary during course of disease without activity correlation
  • Histology
    • Helps to exclude other disease processes, but features are not disease specific
    • Typically demonstrates interface hepatitis with plasma cell and lymphocytic infiltrates
      • Severely progressed disease may only reveal cryptogenic cirrhosis

Prognosis

Differential Diagnosis

Autoimmune hepatitis (AIH) is a chronic, progressive, inflammatory liver disease of unknown etiology. AIH is the most common form of autoimmune liver disease (ALD).

Epidemiology (Heneghan, 2013)

  • Incidence – 0.85-1.9/100,000 per year for adults of white northern European ancestry (Czaja, 2015)
  • Sex – M<F, 1:4 (type 1), 1:10 (type 2)

Classification

  • Two types – AIH types 1 and 2
  • AIH type 1
    • Most common
    • Age – bimodal peaks
      • 10-30 years
      • 40-50 years
    • Broad spectrum of disease from mild liver disease to cirrhosis
  • AIH type 2
    • Rare – ~4% of AIH patients in the U.S.
    • Age – childhood
    • Disease has a more rapid onset and progression than type 1
    • Associated with

Genetics

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

Clinical Presentation

  • ~25% of patients are asymptomatic when 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
  • Overlap syndromes
    • Two most common syndromes are AIH associated with either primary biliary cirrhosis (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

Pathophysiology

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Autoimmune Liver Disease Evaluation with Reflex to Smooth Muscle Antibody (SMA), IgG by IFA 2007210
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Recommended Use 

Recommended first-line panel for the evaluation of autoimmune liver disease (ALD)

Components include mitochondrial M2 antibody, IgG; liver-kidney microsome-1 antibody, IgG; F-actin (smooth muscle) antibody, IgG with reflex to smooth muscle antibody, IgG titer

Reflex pattern – if F-actin, IgG result is ≥20 units, then smooth muscle antibody, IgG titer will be added

Limitations 

Negative results do not rule out disease

All interpretation of antibody patterns must be done in conjunction with clinical presentation

There may be overlap between diseases and antibodies detected

No single test shows absolute specificity

Follow-up 

LC-1 and SLA testing should be considered if panel tests are negative

Obtain hepatitis serology to rule out acute or chronic viral hepatitis

Concurrent ANCA testing recommended

ANCA-Associated Vasculitis Profile (ANCA/MPO/PR-3) with Reflex to ANCA Titer 2006480
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay

Recommended Use 

Initial test in conjunction with autoimmune liver disease panel for evaluation of autoimmune liver disease

Panel detects ANCA, MPO, and PR-3 antibodies

Reflex pattern – if screen is positive, titer will be added

Limitations 

Negative antibody testing does not rule out autoimmune liver disease

All interpretation of antibody patterns must be done in conjunction with clinical presentation

There may be overlap between diseases and antibodies detected

No single test shows absolute specificity

Follow-up 

Concurrent autoimmune liver disease panel testing recommended

Liver Cytosolic Antigen Type 1 (LC-1) Antibody, IgG 2010711
Method: Qualitative Immunoblot

Recommended Use 

Use to evaluate for autoimmune hepatitis of unknown etiology, especially autoimmune hepatitis of childhood onset

Consider

  • If other serological tests in autoimmune liver disease panel are negative, or
  • In combination with specific tests
    • Anti-LKM-1
    • ANA
    • F-actin
    • SMA

Use in combination with Liver-Kidney Microsome-1 Antibody, IgG

Limitations 

Negative antibody testing does not rule out ALD

All interpretation of antibody patterns must be done in conjunction with clinical presentation – overlap may occur between diseases and antibodies

Neither LKM-1 nor LC-1 has absolute diagnostic sensitivity for AIH type 2

Guidelines

Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, Cooksley WG, Czaja AJ, Desmet VJ, Donaldson PT, Eddleston AL, Fainboim L, Heathcote J, Homberg JC, Hoofnagle JH, Kakumu S, Krawitt EL, Mackay IR, MacSween RN, Maddrey WC, Manns MP, McFarlane IG, Büschenfelde KH, Zeniya M. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999; 31(5): 929-38. PubMed

Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, Gores GJ, American Association for the Study of Liver Diseases. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010; 51(2): 660-78. PubMed

European Association For The Study Of The Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009; 51(2): 237-67. PubMed

Gleeson D, Heneghan MA, British society of Gastroenterology. British Society of Gastroenterology (BSG) guidelines for management of autoimmune hepatitis. Gut. 2011; 60(12): 1611-29. PubMed

Hennes EM, Zeniya M, Czaja AJ, Parés A, Dalekos GN, Krawitt EL, Bittencourt PL, Porta G, Boberg KM, Hofer H, Bianchi FB, Shibata M, Schramm C, de Torres BE, Galle PR, McFarlane I, Dienes H, Lohse AW, International Autoimmune Hepatitis Group. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008; 48(1): 169-76. PubMed

Manns M, Czaja A, Gorham J, Krawitt E, Mieli-Vergani G, Vergani D, Vierling J. AASLD Practice Guidelines: Diagnosis and management of autoimmune hepatitis. American Association for the Study of Liver Diseases. Alexandria, VA [Published Jun 2010; Accessed: Dec 2016]

Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, Vierling JM, American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis Hepatology. 2010; 51(6): 2193-213. PubMed

Morisco F, Pagliaro L, Caporaso N, Bianco E, Sagliocca L, Fargion S, Smedile A, Salvagnini M, Mele A, University of Naples Federico II, italy. Consensus recommendations for managing asymptomatic persistent non-virus non-alcohol related elevation of aminotransferase levels: suggestions for diagnostic procedures and monitoring. Dig Liver Dis. 2008; 40(7): 585-98. PubMed

General References

Bowlus CL, Gershwin E. The diagnosis of primary biliary cirrhosis. Autoimmun Rev. 2014; 13(4-5): 441-4. PubMed

Czaja AJ. Autoantibodies as prognostic markers in autoimmune liver disease. Dig Dis Sci. 2010; 55(8): 2144-61. PubMed

Czaja AJ. Autoantibody-negative autoimmune hepatitis. Dig Dis Sci. 2012; 57(3): 610-24. PubMed

Czaja AJ. Diagnosis and management of autoimmune hepatitis. Clin Liver Dis. 2015; 19(1): 57-79. PubMed

Czaja AJ. The overlap syndromes of autoimmune hepatitis. Dig Dis Sci. 2013; 58(2): 326-43. PubMed

Heneghan MA, Yeoman AD, Verma S, Smith AD, Longhi MS. Autoimmune hepatitis. Lancet. 2013; 382(9902): 1433-44. PubMed

Liberal R, Grant CR, Longhi MS, Mieli-Vergani G, Vergani D. Diagnostic criteria of autoimmune hepatitis. Autoimmun Rev. 2014; 13(4-5): 435-40. PubMed

Liberal R, Mieli-Vergani G, Vergani D. Clinical significance of autoantibodies in autoimmune hepatitis. J Autoimmun. 2013; 46: 17-24. PubMed

Mieli-Vergani G, Vergani D. Autoimmune paediatric liver disease. World J Gastroenterol. 2008; 14(21): 3360-7. PubMed

Yimam KK, Bowlus CL. Diagnosis and classification of primary sclerosing cholangitis. Autoimmun Rev. 2014; 13(4-5): 445-50. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Jaskowski TD, Konnick EQ, Ashwood ER, Litwin CM, Hill HR. Prevalence of IgG autoantibody against F-actin in patients suspected of having autoimmune or acute viral hepatitis. J Clin Lab Anal. 2007; 21(4): 249-53. PubMed

Layfield LJ, Cramer H. Primary sclerosing cholangitis as a cause of false positive bile duct brushing cytology: report of two cases. Diagn Cytopathol. 2005; 32(2): 119-24. PubMed

Medical Reviewers

Slev, Patricia R., PhD, Medical Director, Serological Hepatitis/Retrovirus, Immunology Core; Co-Medical Director, Microbial Immunology and Immunogenetics; Chief Medical Director, Immunology Division at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Tebo, Anne E., PhD, D(ABMLI), Medical Director, Immunology at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Last Update: July 2017