Hepatitis, Autoimmune - AIH

Diagnosis

Indications for Testing

  • Persistently elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (5x normal) in the absence of any other cause of liver disease
  • Cirrhosis or chronic hepatitis without obvious etiology

Criteria for Diagnosis

  • Diagnosis of exclusion – need to rule out other 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 liver kidney microsome type 1

      ≥1:40

      +2

      Antibodies to soluble liver antigen

      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

      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

Laboratory Testing

  • Nonspecific testing
    • Liver function testing – usually elevated
    • Hepatitis testing – important to rule out acute or chronic hepatitis (HAV, HBV, HCV)
    • Quantitative immunoglobulins – IgG usually elevated
    • Consider testing (based on clinical presentation) to rule out other obvious causes of chronic liver disease
  • Antibody testing
    • Serum titers of any of the antibodies do not appear to correlate with disease activity
    • May include any/all of the following
      • Anti-nuclear antibody (ANA) – homogenous pattern most common
      • Anti-neutrophil cytoplasmic antibody (ANCA) –  pANCA pattern in most cases
      • 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 type 1 antibody (LKM-1)
      • Anti-liver cytosol (LC-1)
    • Antibody patterns may help determine autoimmune liver disease subtype

      Antibody Patterns

      Disease

      ANA

      pANCA*

      SMA

      F-actin

      M2

      LKM-1

      LC-1

      SLA

      AIH-1**

      +

      Usually +

      +

      +

      -

      -

      -

      +/-

      AIH-2

      -

      +/-

      -

      -

      -

      +

      +

      -

      PSC

      +

      Atypical

      +

      -

      -

      -

      -

      +/-

      PBC

      +/-

      -

      -

      -

      +

      -

      -

      -

      *May be an atypical pANCA staining pattern that disappears after formalin treatment

      **AIH-3 has been described as a variant of AIH-1. All patients with AIH are treated the same – may be unnecessary to make this distinction

      DISEASE KEY

      AIH – Autoimmune hepatitis type 1 or 2
      PSC – Primary sclerosing cholangitis
      PBC – Primary biliary cirrhosis

      TEST KEY

      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
    • Evaluation for fibrosis and inflammation
    • Helps to exclude other disease processes
    • Typically demonstrates interface hepatitis, but in severely progressed disease may only  reveal cryptogenic cirrhosis

Prognosis

  • Antibodies that may be useful in prognosis

    Antibodies That May Be Useful in Prognosis

    (Czaja 2010)

    Autoantibody

    Associations

    Anti-SLA

    • More severe histological changes
    • Increased relapse after drug withdrawal
    • Increased need for transplantation

    Anti-actin

    • Treatment dependence in children
    • Increased need for liver transplantation

    Anti-LC-1

    • Severe liver inflammation
    • Rapid progression to cirrhosis more common

    Anti-ASGPR

    • Increased hepatocytic apoptosis and interface hepatitis
    • Residual histological activity
    • Adequacy of treatment response
    • Relapse after treatment

    Anti-LKM-3

    • HCV
    • HDV

    ASGPR = asialoglycoprotein receptor

Differential Diagnosis

Clinical Background

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

  • Incidence – ~2/100,000 per year for white adults of northern European ancestry
  • Sex – M<F, 1:3

Classification

  • Two main types – AIH types 1 and 2
    • A variant of type 1, referred to as type 3, has been described
  • AIH type 1 – most common
    • Age – bimodal peaks 
      • 10-20 years
      • 45-70 years
    • Sex – M<F (usually young women)
  • AIH type 2
    • Rare – 4% of AIH patients in the U.S.
    • Usually presents in childhood
    • May be seen in association with chronic hepatitis C infection
    • Disease has a more rapid onset and progression than type 1
    • Often associated with IgA deficiency

Genetics

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

Clinical Presentation

  • Nonspecific symptoms – fatigue, lethargy, anorexia, malaise
  • Gastrointestinal – nausea, abdominal pain, jaundice, hepatomegaly, upper abdominal discomfort
  • Musculoskeletal – arthralgias
  • Overlap syndromes
    • Two most common syndromes are AIH associated with either primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC)
    • Overlap syndromes with AIH present

      Overlap Syndromes with AIH Present

      (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+ plasm 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
      • 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
  • 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

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

    Autoantibody

    Molecular Target

    Associated with AIH type

    Comments

    Overlap with other diseases

    ANA

    Multiple nuclear targets

    AIH-1 (70-80%)

    n/a

    Drug-, alcohol-induced hepatitis, rheumatoid disorders

    pANCA

    Unknown

    AIH-1 (65-95%)

    n/a

    PSC, HCV

    Anti-SMA

    Variety of cytoskeletal components

    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

    Anti-LKM-1

    CYP2D6

    AIH-2 (100%)

    More common in pediatric patients and rare in adults in US

    • Occur in only 4% of adults with AIH

    HCV

    Anti-SLA

    UGA repressor tRNA associated protein

    • AIH-1
    • AIH-2 (pediatric)
    • AIH-3

    ~99% specificity for AIH; however, only up to 30% of patients have these antibodies

    HCV, autoimmune cholangitis

    Anti-LC-1

    Formiminotransferase cyclodeaminase

    • AIH-2 (30-50%)
    • AIH-1

    Commonly occurs in conjunction with anti-LKM-1

    HCV

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
Test Name and Number Recommended Use Limitations Follow Up
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

Initial test in conjunction with ANCA-associated vasculitis profile for evaluation of autoimmune liver disease (ALD)

Components include M2, IgG; LKM-1, IgG; F-Actin, IgG; and SMA IgG antibodies

 

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

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

Panel detects ANCA, MPO, and PR-3 antibodies

If screen is positive, titer will be added

Cross reaction may occur with cationic protein 57 (CAP 57), cathepsin G, elastase, lactoferrin, and other lysosomal proteins

Concurrent autoimmune liver disease panel testing recommended

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

Use to rule out hepatitis B or C as etiology of liver disease

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

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Evaluate for liver injury

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

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

Evaluate for hypergammaglobulinemia

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
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

All ELISA results reported as Detected are further tested by IFA; ANA ELISA screen is designed to detect antibodies against dsDNA, histone, SS-A (Ro), SS-B (La), Smith, snRNP/Sm, Scl-70, Jo-1, centromere, and an extract of lysed HEp-2 cells

ANA ELISA assays have been reported to have lower sensitivities for antibodies associated with nucleolar and specked ANA-IFA patterns

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

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

LKM-1 does not have absolute diagnostic sensitivity for AIH type

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

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

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

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

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

Differentiate AIH from PBC