Autoimmune hepatitis (AIH) is a chronic, progressive, inflammatory liver disease of unknown etiology, and the most common form of autoimmune liver disease (ALD). Autoimmune hepatitis can co-occur with other autoimmune diseases; these conditions are labeled overlap syndromes (eg, primary biliary cholangitis [PBC]-AIH).
Quick Answers for Clinicians
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
Disease | ANA Pattern | ANCA Pattern | SMA | F-actin | AMA (M2) | LKM-1 | LC-1 | SLA |
---|---|---|---|---|---|---|---|---|
AIH-1 |
Homogenous pattern most common |
|
+ |
+ |
Uncommon |
- |
- |
+/- More common in children |
AIH-2 |
- |
Rare |
- |
- |
- |
+ |
+ |
+/- More common in children |
PSC |
+ |
Atypical p-ANCA |
+/- |
- |
- |
- |
- |
+/- |
PBC |
Nuclear dot or nuclear envelope pattern on HEp-2 cell substrate |
- |
- |
- |
+ |
- |
- |
- |
M2, mitochondrial antigen 2 (PDH-E2); p-ANCA, perinuclear antineutrophil cytoplasmic antibody; PSC, primary sclerosing cholangitis Sources: Liberal, 2013, 2014; Czaja, 2015 |
- 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
Autoantibody | Associations |
---|---|
Anti-SLA |
More severe histological changes Increased risk of relapse after drug withdrawal Increased risk for liver transplantation |
Anti-actin |
Younger age at 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 Sources: Czaja, 2010; Liberal, 2014 |
Differential Diagnosis
- Infection
- Viral
- Cytomegalovirus
- Epstein-Barr virus
- Herpes simplex virus
- Varicella-zoster virus
- Hepatitis A, B, C, D, or E
- Bacterial
- Parasitic
- Liver trematodes
- Echinococcus spp
- Parasitic diarrhea
- Toxocara spp
- Viral
- 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
- 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 Combined with | Criteria | Features |
---|---|---|
Autoimmune cholangitis |
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 |
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 |
PBC |
Both AIH and PBC criteria AIH criteria (2 of 3)
PBC criteria (2 of 3)
|
AIH predominant phenotype IAIHG score for AIH Alk phos ≥2 ULN AMA positive frequently Bile duct destruction or loss |
PSC |
AIH predominant AMA-negative phenotype Bile duct injury or loss Biliary sclerosis |
IAIHG score for AIH Concurrent inflammatory bowel disease possible Bile duct abnormalities |
Alk phos, alkaline phosphatase; GGT, gamma-glutamyl transpeptidase; IAIHG, International Autoimmune Hepatitis Group; PSC, primary sclerosing cholangitis Source: Czaja, 2013 |
- 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
ARUP Laboratory Tests
Recommended first-line panel for the evaluation of ALD
Negative results do not rule out disease
All interpretation of antibody patterns must be performed in conjunction with clinical presentation
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody
Initial test in conjunction with ALD panel for evaluation of ALD
Panel detects ANCA, myeloperox (MPO), and serine proteinase 3 (PR3) antibodies
Negative antibody testing does not rule out ALD
All interpretation of antibody patterns must be performed in conjunction with clinical presentation
There may be overlap between diseases and antibodies detected
No single test shows absolute specificity
Concurrent ALD panel testing recommended
Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay
Use to evaluate for AIH of unknown etiology
Use in combination with LKM-1 antibody, IgG
Consider if other serological tests in ALD panel are negative, or in combination with specific tests, such as ANA, F-actin, SMA
Negative antibody testing does not rule out ALD
All interpretation of antibody patterns must be performed in conjunction with clinical presentation – overlap may occur between diseases and antibodies detected
Neither LKM-1 nor LC-1 has absolute diagnostic sensitivity for AIH-2
Qualitative Immunoblot
Order to evaluate viral etiology in patients with acute hepatitis
Not recommended for screening asymptomatic patients
Qualitative Chemiluminescent Immunoassay
Panel includes HAV IgM, HBV core antibody IgM, HBV surface antigen (HBsAg), HCV antibody
Initial screening for hepatobiliary inflammation
Quantitative Enzymatic/Quantitative Spectrophotometry
Panel includes albumin; alkaline phosphatase; aspartate aminotransferase; alanine aminotransferase; bilirubin, total; protein, total; and bilirubin, direct
Initial test in the workup of immunoglobulin disorders
Quantitative Nephelometry
Aid in initial diagnosis of connective tissue disease
Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody
Differential evaluation of ALD of unknown etiology, especially AIH of childhood onset
Use in combination with LC-1 IgG testing when evaluating for AIH-2
More likely to be positive than LC-1
Negative antibody testing does not rule out ALD
All interpretation of antibody patterns must be performed in conjunction with clinical presentation – overlap may occur between diseases and antibodies detected
Neither LKM-1 nor LC-1 has absolute diagnostic sensitivity for AIH-2
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Differential evaluation of ALD of unknown etiology, especially AIH of childhood onset
Use in combination with LC-1 IgG testing when evaluating for AIH-2
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)
Semi-Quantitative Indirect Fluorescent Antibody
Recommended for the evaluation of ALD or hepatitis of unknown etiology
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
May be helpful in evaluating for ALD
For more comprehensive reflex panel, refer to ALD evaluation with reflex to SMA, IgG by IFA
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody
May be useful in confirming a diagnosis of PBC
Use to differentiate AIH from PBCv
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Medical Experts
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Components include mitochondrial M2 antibody, IgG; LKM-1 antibody, IgG; F-actin (smooth muscle) antibody, IgG with reflex to SMA, IgG titer; soluble liver antigen antibody, IgG; ANA with HEp-2 substrate, IgG