Autoimmune Hepatitis - Hepatitis, Autoimmune

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

Simplified scoring system of the International Autoimmune Hepatitis Group

Simplified Scoring System of the International Autoimmune Hepatitis Group (Hennes 2008)
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	Test Results	Test Score
Immunoglobulin G	>ULN	+1
	>1.1 ULN	+2
	Normal	0
Histological findings	Test Results	Test Score
Morphological features of AIH	Compatible	+1
	Typical	+2
	Incompatible	0
Viral disease	Test Results	Test Score
Absence of viral hepatitis	No viral markers	+2
Absence of viral hepatitis	Viral markers present	0
Pretreatment aggregate score
Definite diagnosis		≥7
Probable diagnosis		6
ANA = antinuclear antibodies; SMA = smooth muscle antibodies; ULN = upper limit of normal range; LKM-1 = liver-kidney microsme-1; SLA = soluble liver antigen

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

Antibody patterns

Antibody Patterns
Disease	ANA	pANCA	SMA	F-actin	AMA M2	LKM-1	LC-1	SLA
AIH-1	Homogenous pattern most common	Atypical staining	+	+	uncommon	-	-	+/- more common in children
AIH-2	-	Rare	-	-	-	+	+	+/- More common in children
PSC	+	Atypical staining	+/-	-	-	-	-	+/-
PBC	Multiple nuclear dot or rim-like membranous pattern on Hep-2 or HeLa cells	-	-	-	+	-	-	-
DISEASE KEY AIH – Autoimmune hepatitis type 1 or 2 PSC – Primary sclerosing cholangitis PBC – Primary biliary cirrhosis
TEST KEY AMA – Anti-mitochondrial antibody ANA – Anti-nuclear antibody LC-1 – Liver cytosolic antigen type 1 LKM-1 – Liver-kidney microsome-1 (cytochrome P450 2D6) M2 – Mitochondrial antigen 2 (PDH-E2) pANCA – Perinuclear antineutrophil cytoplasmic antibody SLA – Soluble liver antigen SMA – Smooth muscle antibody

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

Antibodies that may prognosticate

Antibodies That May Prognosticate (Czaja, 2010; Liberal, 2014)
Autoantibody	Associations
Anti-SLA	More severe histological changes Increased risk of relapse after drug withdrawal Increased risk for liver transplantation
Anti-actin	Younger age of onset Treatment dependence in children Increased risk for liver transplantation
Anti-LC-1	Severe liver inflammation Increased risk for rapid progression to cirrhosis Correlation of antibody titers with disease activity
Anti-ASGPR	Increased, more severe interface hepatitis Increased risk of relapse after treatment
Anti-LKM-1	Younger age at presentation Fulminant hepatic failure
ASGPR = asialoglycoprotein receptor

Differential Diagnosis

Infection
- Viral
  - Cytomegalovirus
  - Epstein-Barr virus
  - Herpes simplex virus
  - Varicella-zoster virus
  - Hepatitis A, B, C, D or E
- Bacterial infection
  - 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 cirrhosis
- Primary sclerosing cholangitis
- Systemic lupus erythematosus
- Autoimmune cholangitis tropathy
Genetic dis
Granulomatous disease (eg, Sarcoidosis)
Hepatic ischemia

Liver Disease or Hepatitis of Unknown Etiology Testing Algorithm

Read more about 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
  - IgA deficiency
  - Chronic hepatitis C infection

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
- AIH-1 – thyroiditis, celiac disease, ulcertive colitis, rheumatoid arthritis, Sjögren, mixed connective tissue disease, CREST
- AIH-2 – diabetes mellitus, thyroiditis, vitiligo

Overlap syndromes

Two most common syndromes are AIH associated with either primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC)

AIH Overlap syndromes

AIH Overlap Syndromes (Czaja 2013)
AIH Combined With	Criteria	Features
Autoimmune cholangitis (AC)	Predominant AIH phenotype AMA-negative Bile duct injury or loss Normal cholangiography	IAIHG score for AIH Likely mixed syndrome – AMA-negative PBC and small-duct PSC
AMA-negative PSC	Same as autoimmune cholangitis	IAIHG score for AIH
Autoimmune sclerosing cholangitis (ASC)	Same as AIH with PSC	Affects children Corticosteroid responsive
IgG4 cholangitis	>5 IgG4+ plasma cells per high-power field in liver tissue Abnormal biliary cholangiogram	Corticosteroid responsive Variable serum IgG4 level
Primary biliary cirrhosis (PBC)	Both AIH and PBC criteria AIH criteria (2 of 3) ALT ≥5 ULN IgG ≥2 ULN or SMA Interface hepatitis PBC criteria (2 of 3) Alk phos ≥2 ULN or GGT ≥5 ULN AMA Florid duct lesions	AIH predominant phenotype IAIHG score for AIH present Alk phos ≥2 ULN AMA positive frequently Bile duct destruction or loss
Primary sclerosing cholangitis (PSC)	AIH predominant AMA-negative phenotype Bile duct injury or loss Biliary sclerosis	IAIHG score for AIH present Concurrent inflammatory bowel disease possible Bile duct abnormalities

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
- Increased risk of hepatocellular carcinoma
- Liver failure/ cirrhosis

Pathophysiology

Autoantibody, molecular targets, AIH type, and overlap with other diseases

Autoantibody, Molecular Targets, AIH Type, Overlap Diseases
Autoantibody	Molecular Target(s)	AIH Association (% of patient antibody present)	Comments	Overlap with other diseases
ANA	Multiple nuclear targets including chromatin, histones, centromere	AIH-1 (70-80%)	n/a	Drug-, alcohol-induced hepatitis, rheumatoid disorders, PBC, PSC
pANCA	Unknown	AIH-1 (65-95%)	n/a	PSC, HCV
Anti-SMA	Variety of cytoskeletal components including vimentin, actin, and desmin	AIH-1 (80%)	Three patterns of staining – V, G, and T VG and VGT staining – specific for AIH Negative in up to 30% of patients	HCV, PBC
F-actin	Microfilaments (F-actin) of the cytoskeleton α-actinin	AIH-1 (100%)	n/a	HCV, PBC
Anti-LKM-1	CYP2D6	AIH-2 (100%)	More common in pediatric patients; rare in adults in U.S	HCV, HDV IgA deficiencies
Anti-SLA	UGA repressor tRNA associated protein	AIH-1 AIH-2 (pediatric)	Very high specificity for AIH	HCV, autoimmune cholangitis
Anti-LC-1	Formiminotransferase cyclodeaminase	AIH-2 (30-50%)	Commonly occurs in conjunction with anti-LKM-1	HCV

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 M2, IgG; LKM-1, IgG; F-actin, IgG; and SMA IgG antibodies

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 ALD

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 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

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 [Accessed: Jun 2015]

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, and Co-Medical Director of Immunogenetics at ARUP Laboratories; Assistant 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

Non-Invasive Assessment of Liver Fibrosis - Patricia R. Slev, PhD (FREE CME credit)

Spotlight on Testing: Non-Invasive Markers for Assessing Liver Fibrosis - Patricia R. Slev, PhD

Last Update: August 2016

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Autoimmune Hepatitis - Hepatitis, Autoimmune

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Prognosis

Differential Diagnosis

Liver Disease or Hepatitis of Unknown Etiology Testing Algorithm

Epidemiology (Heneghan, 2013)

Classification

Genetics

Clinical Presentation

Pathophysiology

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology®

Medical Reviewers

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