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
• 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 (PBC) or primary sclerosing cholangitis (PSC)
• 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 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
• Gammaglobulins (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 is the 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
    • The presence of SLA antibodies has 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
  • PBC
  • PSC
  • 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
• Ischemic
• Parasitic
  • Liver trematodes
  • Echinococcus spp
  • Parasitic diarrhea
  • Toxocara spp

Tests generally appear in the order most useful for common clinical situations

Guidelines

• Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, Cooksley WG, Czaja AJ, Desmet VJ, Donaldson PT, Eddleston AL, Fainboim L, Heathcote J, Homberg JC, Hoofnagle JH, Kakumu S, Krawitt EL, Mackay IR, MacSween RN, Maddrey WC, Manns MP, McFarlane IG, Meyer zum Buschenfelde KH, Zeniya M, . International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999; 31 (5) :929-938.PubMed
• Manns MP, et al. Diagnosis and management of Autoimmune Hepatitis. [Accessed: 19 Oct 2011] 
• Morisco F, Pagliaro L, Caporaso N, Bianco E, Sagliocca L, Fargion S, Smedile A, Salvagnini M, Mele A. Consensus recommendations for managing asymptomatic persistent non-virus non-alcohol related elevation of aminotransferase levels: suggestions for diagnostic procedures and monitoring. Dig Liver Dis. 2008; 40 (7) :585-598.PubMed

General

• Bogdanos DP, Invernizzi P, Mackay IR, Vergani D. Autoimmune liver serology: current diagnostic and clinical challenges. World J Gastroenterol. 2008; 14 (21) :3374-3387.PubMed
• Czaja AJ, Manns MP. Advances in the diagnosis, pathogenesis, and management of autoimmune hepatitis. Gastroenterology. 2010; 139 (1) :58-72.PubMed
• Czaja AJ. Autoantibodies as prognostic markers in autoimmune liver disease. Dig Dis Sci. 2010; 55 (8) :2144-2161.PubMed
• Krawitt EL. Clinical features and management of autoimmune hepatitis. World J Gastroenterol. 2008; 14 (21) :3301-3305.PubMed
• Mieli-Vergani G, Vergani D. Autoimmune paediatric liver disease. World J Gastroenterol. 2008; 14 (21) :3360-3367.PubMed
• Muratori P, Granito A, Pappas G, Muratori L, Lenzi M, Bianchi FB. Autoimmune liver disease 2007. Mol Aspects Med. 2008; 29 (1-2) :96-102.PubMed
• Rust C, Beuers U. Overlap syndromes among autoimmune liver diseases. World J Gastroenterol. 2008; 14 (21) :3368-3373.PubMed
• Vergani D, Mieli-Vergani G. Autoimmune Hepatitis and PSC Connection. Clin Liver Dis. 2008; 12 (1) :187-202, x.PubMed

ARUP Institute for Clinical and Experimental Pathology®

• Jaskowski TD, Konnick EQ, Ashwood ER, Litwin CM, Hill HR. Prevalence of IgG autoantibody against F-actin in patients suspected of having autoimmune or acute viral hepatitis. J Clin Lab Anal. 2007; 21 (4) :249-253.PubMed
• Layfield LJ, Cramer H. Primary sclerosing cholangitis as a cause of false positive bile duct brushing cytology: report of two cases. Diagn Cytopathol. 2005; 32 (2) :119-124.PubMed

Alpha-1-Antitrypsin Deficiency
Cirrhosis
Cryoglobulinemia
Hemochromatosis
Hepatitis, Acute
Hepatitis A Virus
Hepatitis B Virus
Hepatitis C Virus
Hepatitis Delta Virus
Hepatocellular Carcinoma
Liver Disease Evaluation
Primary Biliary Cirrhosis
Wilson Disease