Autoimmune Hepatitis - Hepatitis, Autoimmune

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Content

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

Liver Disease or Hepatitis of Unknown Etiology Testing Algorithm

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

Indications for Laboratory Testing

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

Limitations

Negative antibody testing does not rule out ALD

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

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

Limitations

Negative antibody testing does not rule out ALD

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: Semi-Quantitative Immunoblot

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

Additional Tests Available

Hepatitis Panel, Acute with Reflex to HBsAg Confirmation 0020457
Method: Qualitative Chemiluminescent Immunoassay

Comments

Order to evaluate viral etiology in patients with acute hepatitis

Not recommended for screening asymptomatic patients

Panel includes HAV IgM, HBV core antibody IgM, HBV surface antigen, HCV antibody

Reflex pattern – if results for HBsAg are repeatedly reactive with index value between 1.00 and 50.00, HBsAg confirmation will be added

Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Comments

Initial screening for hepatobiliary disease

Panel includes albumin; alkaline phosphatase; aspartate aminotransferase; alanine aminotransferase; bilirubin, total; protein; bilirubin, direct

Immunoglobulins (IgA, IgG, IgM), Quantitative 0050630
Method: Quantitative Nephelometry

Comments

Initial test in the workup of immunoglobulin disorders

F-Actin and Mitochondrial M2 Antibodies, IgG by ELISA with Reflex to Smooth Muscle Antibody (SMA), IgG by IFA 2007209
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Comments

Reflex pattern – if F-actin, IgG by ELISA is ≥20 units, SMA IgG by IFA titer will be added

Anti-Nuclear Antibodies (ANA), IgG by ELISA with Reflex to ANA, IgG by IFA 0050080
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Comments

Aids in initial diagnosis of connective tissue disease

Reflex pattern – if ANA is detected, ANA by IFA titer will be added

Liver-Kidney Microsome - 1 Antibody, IgG 0055241
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments

Use in combination with Liver Cytosolic Antigen Type 1 (LC-1) Antibody, IgG

More likely to be positive than LC-1

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

Liver-Kidney Microsome Antibody, IgG 0099270
Method: Semi-Quantitative Indirect Fluorescent Antibody

Comments

Test does not differentiate among the four types of LKM antibodies (LKM-1, LKM-2, LKM-3, and a fourth type that recognizes CYP1A2 and CYP2A6 antigens)

Soluble Liver Antigen Antibody, IgG 0055235
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

F-Actin (Smooth Muscle) Antibody, IgG 0055248
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments

F-actin antibodies have greater sensitivity and specificity for autoimmune liver disease than anti-smooth muscle antibodies

Negative result does not rule out autoimmune liver disease or chronic active hepatitis; not all patients are F-actin antibody positive

F-Actin (Smooth Muscle) Antibody, IgG by ELISA with Reflex to Smooth Muscle Antibody, IgG Titer 0051174
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Comments

Reflex pattern – if F-actin ≥20 units, SMA IgG by IFA titer will be added

Mitochondrial M2 Antibody, IgG (ELISA) 0050065
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments

Differentiate AIH from PBC

Guidelines

Alvarez F, Berg P, Bianchi F, Bianchi L, Burroughs A, Cancado E, Chapman R, Cooksley W, Czaja A, Desmet V, Donaldson P, Eddleston A, Fainboim L, Heathcote J, Homberg J, Hoofnagle J, Kakumu S, Krawitt E, Mackay I, MacSween R, Maddrey W, Manns M, McFarlane I, Büschenfelde K, 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 D, Boberg K, Shneider B, Gores G, American Association for the Study of Liver Diseases. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010; 51(2): 660-78. PubMed

Diagnosis and management of autoimmune hepatitis. American Association for the Study of Liver Diseases - Nonprofit Research Organization. 2002 Aug (Revised 2010 Jun). NGC: 008005

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

Hennes E, Zeniya M, Czaja A, Parés A, Dalekos G, Krawitt E, Bittencourt P, Porta G, Boberg K, Hofer H, Bianchi F, Shibata M, Schramm C, de Torres B, Galle P, McFarlane I, Dienes H, Lohse A, 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 [Accessed: Jun 2015]

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

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

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

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

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

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

Liberal R, Grant C, Longhi M, 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 K, Bowlus C. 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 T, Konnick E, Ashwood E, Litwin C, Hill H. 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 L, 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

Last Update: February 2016