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 or damage

Criteria for Diagnosis

• Diagnosis of exclusion – need to rule out other etiologies of liver disease, including toxins, infections, and hereditary diseases
  • Serum IgG >2.5 g/dL
  • Autoantibodies may include the following
    • Antinuclear antibodies (ANA)
    • Anti-smooth muscle antibody (SMA)
    • Anti-liver/kidney microsomal type 1 (LKM-1) antibody
    • Antimitochondrial antibody (AMA)
    • Anti-soluble liver antigen (SLA) antibody
  • Autoantibodies may not be present in 10-30% of patients with clinical features of AIH
  • Histology to evaluate liver inflammation and fibrosis
• Clinical scoring system may be helpful in establishing diagnosis
  • Revised scoring system for autoimmune hepatitis  (International Autoimmune Hepatitis Group)

    Revised Scoring System for Autoimmune Hepatitis  (International Autoimmune Hepatitis Group)
    Parameters/Features	Score
    Female Sex	+2
    ALP-AST (or ALT) ratio
    <1.5	+2
    1.5-3.0	0
    >3.0	-2
    ANA, SMA, or LKM-1
    >1:80	+3
    1:80	+2
    1:40	-1
    <1:40	0
    AMA positive	-4
    Hepatitis viral markers
    Positive	-3
    Negative	+3
    Drug history
    Positive	-4
    Negative	+1
    Average alcohol intake
    <25 g/day	+2
    >60 g/day	-2
    Liver histology
    Interface hepatitis	+3
    Predominantly lymphoplasmacytic infiltrate	+1
    Rosetting of liver cells	+1
    None of the above	-5
    Biliary changes	-3
    Other changes	-3
    Other autoimmune disease	+2
    Optional additional parameters
    Seropositive for other defined autoantibodies       Perinuclear staining antineutrophil cytoplasmic antibody       Anti-liver-specific cytosolic antigen       Anti-soluble liver antigen       Anti-hepatic asialoglycoprotein receptor       Anti-liver-pancreas antigen       Anti-sulfatide	+2
    HLA-DR3 or -DR4	+1
    Complete response to therapy	+2
    Relapse	+3
    Interpretation of aggregate scores (pre-treatment)
    Definite AIH	>15
    Probable AIH	10-15
    Interpretation of aggregate scores (post-treatment)
    Definite AIH	>17
    Probably AIH	12-17

Laboratory Testing

• Liver function tests – usually elevated
• Hepatitis panel – rule out acute or chronic hepatitis
• Immunoglobulins (IgA, IgG) – elevated
• Nonspecific antibodies – positive ANA homogenous pattern, rheumatoid factor
• Specific antibodies
  • Anti-LKM-1 antibodies
    • React uniformly with cytochrome P450 2D6 – a 50kDA protein found in the cytoplasm of all hepatocytes and renal proximal tubular cells
    • In the U.S., LKM-1 antibodies are common in pediatric patients and rare in adults
    • More commonly associated with AIH type 2
    • LKM-1 antibodies occur in only 4% of adults with AIH
  • Anti-SMA (F-actin)
    • Presence of SMA antibodies – hallmark of AIH type 1
    • Also seen in chronic hepatitis
    • Testing anti-LKM-1 positive patients for ANA and SMA may be helpful in distinguishing between AIH types 1 and 2
  • Anti-SLA antibodies
    • Presence of SLA antibodies – almost 100% specificity for AIH; however, only 12-30% of patients have these antibodies
  • Antibody patterns

    Antibody Patterns
    AIH Type	ANA	SMA	pANCA*	LKM1	SLA	LC-1
    1	+	+	+/-	-	+/-	-
    2	-	-	+/-	+	-	+
    3	-	-	+/-	-	+	-
    *May be an atypical pANCA staining pattern that disappears after formalin treatment

Prognosis

• Anti-SLA – more severe histological changes; requires longer treatment duration
• Anti-liver crystal type I – severe liver inflammation with rapid progression to cirrhosis
• Anti-asialoglycoprotein receptor – greater frequency of relapse after treatment withdrawal

Differential Diagnosis

• Autoimmune disease
  • Primary biliary cirrhosis
  • Primary sclerosing cholangitis
  • Systemic lupus erythematosus
• Viral
  • Cytomegalovirus
  • Epstein-Barr virus
  • Herpes simplex virus
  • Varicella-zoster virus
  • Hepatitis A, B, C, D or E
• Toxin exposure
  • Alcohol abuse
  • Tetrachloride
• Nonalcoholic acute steatohepatitis (NASH)
• Drug-induced hepatitis
  • Acetaminophen
  • Antiseizure medications
  • Isoniazid (Nydrazid)
  • Oral contraceptives
  • Rifampin (Rifadin)
  • Sulfonamides
• Bacterial infection
  • Leptospira spp
  • Coxiella burnetii
  • Rickettsia rickettsii
  • Treponema pallidum (secondary)
  • Sepsis
  • Rickettsia typhi
• Granulomatous
  • Mycobacterium tuberculosis
  • Sarcoidosis
• Hereditary
  • Wilson disease
  • Hemochromatosis
  • Alpha-1-antitrypsin deficiency
• Ischemia
• Parasitic
  • Liver trematodes
  • Echinococcus spp
  • Parasitic diarrhea
  • Toxocara spp

Clinical Background

Autoimmune liver disease, or autoimmune hepatitis (AIH), is a chronic, progressive inflammatory liver disease of unknown etiology.

Epidemiology

• Incidence – 2/100,000
• Sex – M<F, 1:3

Classification

• Type 1 – most common form of AIH
  • Age – bimodal peaks 
    • 10-20 years
    • 45-70 years
  • Sex – M<F (usually young women)
• Type 2
  • Often seen in children and in persons from Mediterranean countries
  • May be seen in association with chronic hepatitis C infection
  • Disease has a more rapid onset and progression than types 1 or 3
  • Often associated with IGA deficiency
• Type 3
  • Least common form of AIH
  • Sex – M<F (usually young women)

Genetics

• Associated with HLA-DRB1*13

Clinical Presentation

• Nonspecific symptoms – fatigue, lethargy, anorexia, malaise
• Gastrointestinal – nausea, abdominal pain, jaundice, hepatomegaly, upper abdominal discomfort
• Musculoskeletal – arthralgias
• Overlap disease – AIH with concurrent primary biliary cirrhosis or primary sclerosing cholangitis
• Complications
  • Increased risk of hepatocellular carcinoma
  • Liver failure/cirrhosis

Treatment

• Therapeutic response to anti-inflammatory therapy may be the only indication of AIH in some patients
  • Immunosuppressive treatment is essential in AIH to prevent liver fibrosis and progression to cirrhosis
• AIH must be distinguished from viral hepatitis for treatment purposes
  • Immunosuppression is contraindicated for viral hepatitis
  • Interferon therapy may exacerbate AIH

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Immunoglobulins (IgA, IgG, IgM), Quantitative 0050630 Method: Quantitative Nephelometry	Evaluate for hypergammaglobulinemia
Autoimmune Hepatitis Panel with Reflex to ANA IFA Titer 0055356 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody	Antibodies tested: ANA, IgG; SMA, IgG; LKM-1, IgG; AMA, IgG
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
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

Diagnostic Algorithm

  Liver Disease or Hepatitis of Unknown Etiology Testing Algorithm