Hepatitis, Autoimmune - AIH

Dx
Background
Lab Tests
Algorithm

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

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
Granulomatous
- Mycobacterium tuberculosis
- Sarcoidosis
Hereditary
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

Test Name and Number	Recommended Use	Follow Up
Hepatic Function Panel 0020416 Method: Quantitative Enzymatic/Quantitative Spectrophotometry	Evaluate liver injury patterns Panel includes albumin; alkaline phosphatase; aspartate aminotransferase; alanine aminotransferase; bilirubin, total; protein; bilirubin, direct
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	Order for patient presenting with liver disease or hepatitis and negative viral serologies Determine autoimmune disease responsible for liver disease Components include Mitochondrial M2 Antibody, IgG; Liver-Kidney Microsome-1 Antibody, IgG; F-Actin (Smooth Muscle) Antibody, IgG; Smooth Muscle Antibody, IgG Titer	Obtain hepatitis serology to rule out acute or chronic viral hepatitis
Hepatitis Panel, Acute with Reflex to HBsAg Confirmation 0020457 Method: Qualitative Chemiluminescent Immunoassay	Order to evaluate viral etiology in patients with clinical acute hepatitis of unknown origin for less than 6 months; indications include Discrete onset of symptoms (eg, nausea, anorexia, fever, malaise, or abdominal pain) AND Jaundice or elevated serum alanine aminotransferase (ALT) level Panel includes HAV IgM, HBV core antibody IgM, HBV surface antigen, HCV antibody Positive HAV IgM shows current or recent infection with 98% sensitivity and specificity

Test Name and Number

Recommended Use

Limitations

Follow Up

Hepatic Function Panel 0020416

Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Evaluate liver injury patterns

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

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

Order for patient presenting with liver disease or hepatitis and negative viral serologies

Determine autoimmune disease responsible for liver disease

Components include Mitochondrial M2 Antibody, IgG; Liver-Kidney Microsome-1 Antibody, IgG; F-Actin (Smooth Muscle) Antibody, IgG; Smooth Muscle Antibody, IgG Titer

Obtain hepatitis serology to rule out acute or chronic viral hepatitis

Hepatitis Panel, Acute with Reflex to HBsAg Confirmation 0020457

Method: Qualitative Chemiluminescent Immunoassay

Order to evaluate viral etiology in patients with clinical acute hepatitis of unknown origin for less than 6 months; indications include

Discrete onset of symptoms (eg, nausea, anorexia, fever, malaise, or abdominal pain) AND
Jaundice or elevated serum alanine aminotransferase (ALT) level

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

Positive HAV IgM shows current or recent infection with 98% sensitivity and specificity

Additional Tests Available

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
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
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