Epidemiology

• Less than 10% of all chronic hepatitis in the U.S.
• Female to male ratio: 5-10 to 1
• All ages affected, bimodal peaks: children up to age 30; 5th and 6th decades

Genetic Predisposition

• Familial clustering of cases
• Increased prevalence of autoantibodies in first-degree relatives

Triggering Factors

• Acute hepatitis A, B and C
• Epstein-Barr virus
• Herpes simplex virus
• Cytomegalovirus
• Measles virus
• Drugs

Histopathologic Factors

• Portal mononuclear and plasma cell infiltrate
• Spillage of infiltrate across limiting plate (interface hepatitis = piecemeal necrosis)
• Fibrous septae, bridging fibrosis, cirrhosis
• Relative sparing of bile ducts

Classification by Seriologic Marker

Type	ANA	ASMA	Anti-LKM1	Anti-LC1	Comments
I	+	+	--	--	Responds well to steroids
II	--	--	+	+	Does not respond well to steroids
Cryptogenic	--	--	--	--	Not sure what patient has

---

Features	Type I	Type II
Antibodies:	ANA, SMA, anti-actin	Anti-LKM-1
Autoantigens:	?	Cytochrome P450 2D6
Genetic Factors:	Yes	Yes
HLA haplotypes:	A1, B8, DR3, DR4	B14, DR3, C4A
Age:	Adult	Often girls and young women
Treatment:	Corticosteroids	Corticosteroids (less responsive)

Autoantibodies: Importance

ANA and ASMA titre at presentation:

• Non-predictive of disease severity
• Non-predictive of pronosis

ANA and ASMA disapperance:

• Associated with improved histology
• Associated with improved ALT, AST
• Non-predictive of disease outcome

Type 2 - Anti-LKM-1 Disease

• Rare in U.S.
• Children, young adults, female preponderance
• High globulin levels; other autoimmune disease may be present
• No ANA, AMA; anti-liver cytosol-1 antibody
• ?HLA B8/DR3
• Poor prognosis; less responsive to corticosteriods

Characteristics

• Sustained hepatocellular injury for ≥ 6 months
• Elevated aminotransferases ≥ 1.5 x ULN
• Seriopositivity for ANA, ASMA
• Hypergammaglobulinemia, IgG elevated

Accompanying Extrahepatic Syndromes

• Autoimmune thyroid disease
• Thrombocytopenic purpura
• Insulin-dependent diabetes
• Pernicious anemia
• Ulcerative colitis
• Glomerulonephritis
• Autoimmune hemolytic anemia
• Rheumatoid arthritis
• Fibrosing alveolitis
• Celiac disease
• Alopecia
• Vitiligo

Overlap Syndrome of AIH

• Histology of autoimmune hepatitis
• Antinuclear antibodies absent
• Antimitochondrial antibodies present
• Cholestasis present
• No intrahepatic bile duct damage
• Cholangiogram normal, no IBD
• Responds to prednisone like AIH

Biopsy looks like AIH

Autoimmune Cholangitis*

• ANA generally present
• Histology shows bile duct injury
• No AMA
• Cholestasis present
• Cholangiogram normal, no IBD
• Less responsive to prednisone than AIH

*?AMA-negative PBC

Diagnostic Criteria

Requisites	Definite	Probable
No genetic liver disease	Normal alpha-1-antitrypsin pheno-type Normal serum cerulopasmin, iron and ferritin levels	Partial alpha-1-antitrypsin deficiency Nonspecific serum copper, cerulopasmin, iron and/or ferritin abnormalities
No active viral hepatitis	No markers of current infection with HAV, HBV or HCV
No toxic or alcohol injury	Daily alcohol <25g	Daily alcohol <50g
	and no recent use of hepatotoxic drugs
Laboratory features	Predominant serum aminotransferase abnormality
	Globulin, gammaglobulinemia or IgG level >1.5 times ULN	Hypergammaglobulinemia of any degree
Autoantibodies	ANA, SMA or anti-LKM1 ≥ 1:80 in adults and ≥ 1:20 in children; no AMA	ANA, SMA or anti-LKM1 ≥ 1:40 in adults or other antibodies; e.g. pANCA
Histologic Finding	Interface hepatitis No biliary lesions, granulomas or prominent changes suggestive of another disease

Differential Diagnosis

• Chronic viral hepatitis(B, C, D, non-BCD)
• Drug-induced liver disease
• PBC or PSC
• Celiac disease
• Wilson's disease
• Non-alcoholic steatohepatitis
• Alcoholic hepatitis
• Alpha-1-antitrypsin deficiency
• Iron overload disorders

Drug-induced Hepatitis Resembling Autoimmune Hepatitis

Drug examples:

• Nitrofurantoin
• Minocycline
• Diclofenac
• Interferon alfa
• Atorvastatin
• Oxyphenisatin
• Methyldopa

Estimates of Survival - Severe Disease

	6 Months	5 Years	10 Years
Untreated:	60%	40%	10%
Treated:	--	95%	85%

Immunosuppressive Therapy

Corticosteroid action:

• Inhibit lymphocyte activation
• Suppress production of immunoglobulins and autoantibodies
• Block transcription of inflammatory proteins and induce expression of anti-inflammatory proteins

Azathioprine action:

• Slow suppression of K and NK cells

The Dilemma of Treatment of Mild Disease

• Survival unaffected by treatment
• Spontaneous recovery possible
• Risk of cirrhosis minimal

Treatment of Severe Disease

• Spontaneous recovery rare
• Improvement in survival rate
• Cirrhosis may improve or remain stable but it also may be linked with poor outcome

Treatment of Severe Disease

	Prednisone alone	Prednisone plus azathioprine
Initial:	20-50 mg	20-50 mg + 1 mg/kg
	Taper prednisone over 3-4 months
Maintenance:	5-15 mg	5-15 mg + 1 mg/kg
Duration:	>12-24 months	>12-24 months

Immunosuppressive Treatment

• Symptomatic improvement within weeks; reduction in ALT, AST and IgG levels within 1-3 months
• Histologic improvement lags by many months
• Treatment period: 12-36 months or longer to achieve remission in 80%
• No or minimal response: ~20%
• Relapse risk on discontinuing: as high as ~85% (most within 6 months)
• Sustained remission unlikely if >3 relapses

Factors Associated with Relapse

• Longer time to remission
• Failure to maintain consistently normal aminotransferase levels during remission
• High number of portal plasma cells

Experimental Therapy

• Cyclosporin, tacrolimus, mycophenolate
• 6-mercaptopurine
• Methotrexate
• Budenoside
• Intravenous immunoglobulin
• Rapamycin
• Thymus extracts
• Ursodeoxycholic acid

Liver Transplantation

Indications

• Unresponsive disease
• Presentation as acute liver failure
• Complications of cirrhosis

Results

• 90% 5-year survival; 75% 10-year survival
• Increased risk of rejection
• Recurrence in graft (15-20%) but easily controlled with corticosteroids