Autoimmune Hepatitis

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).

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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
Associated Autoantibody Profile
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

Antibodies That May Prognosticate
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

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
  • 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

Select AIH Overlap Syndromes with Common Features
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)

  • 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

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

ARUP Lab Tests

Primary 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

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

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

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

Related Tests

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 (HBsAg), HCV antibody

Initial screening for hepatobiliary inflammation

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

Initial test in the workup of immunoglobulin disorders

Aid in initial diagnosis of connective tissue disease

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

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)

Recommended for the evaluation of ALD or hepatitis of unknown etiology

May be helpful in evaluating for ALD

For more comprehensive reflex panel, refer to ALD evaluation with reflex to SMA, IgG by IFA

May be useful in confirming a diagnosis of PBC

Use to differentiate AIH from PBCv

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References

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Resources from the ARUP Institute for Clinical and Experimental Pathology®