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Autoimmune Hepatitis Paul J. Pockros,MD Director of Clinical Research, Scripps Translational Science Institute Director, Liver Disease Center and Senior Consultant Scripps Clinic La Jolla, California
Thanks to John Vierling,MD for providing many of the slides in this presentation.
Response Question #1 Which of the following describe autoimmune hepatitis:
1. Hepatocellular necroinflammation 2. Autoantibodies: non-organ, non-species-specific 3. Hypergammaglobulinemia and/or serum IgG 4. Responsiveness to immunosuppressive medications 5. All of the above
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Autoimmune Hepatitis Definition: Syndrome of progressive hepatitis characterized by loss of tolerance to hepatic autoantigens that results in:
Hepatocellular necroinflammation Autoantibodies: non-organ, non-species-specific Hypergammaglobulinemia and/or IgG Non-pathognomic histopathology Responsiveness to immunosuppressive medications
Response Question #2 AIH occurs most commonly in females at an age of:
1. 10-20 yrs 2. 30-40 yrs 3. 45-75 yrs 4. 75-85 yrs 5. 1 and 3 6. 2 and 4
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Autoimmune Hepatitis Demographics and Epidemiology
Uncommon Afflicts 200,000 in U.S.A. Incidence 1.9 per 105 per year Prevalence 16.9 per 105 Female to male ratio= 4:1 Afflicts both children and adults Bimodal age distribution: 10-20 vs. 45-75 yrs 6% liver transplants in US 40% mortality in symptomatic patients ≤ 6 months if untreated
Autoimmune Hepatitis Female Predominant, Bimodal Age Distribution
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Autoimmune Hepatitis Clinical Spectrum
Acute Hepatitis
25-30% Usually younger Icteric acute viral hepatitis-like picture
Asymptomatic
15-20% Extrahepatic manifestations may be present
Fulminant Hepatic Failure
5% Potentially reversible without OLT Czaja AJ: Clin Liver Diseases 2002; 6: 317-334
Autoimmune Hepatitis
Classification Based on Autoantibodies Types:
1 (95-97%)
2 (3-5%)
AutoAbs:
ANA &/or SMA LKM1 SLA/LP pANCA**
3 (1-2%) SLA/LP* SLA/LP
Absence of unique autoAb in putative Type 3 Consensus: 2 types *SLA/LP=Anti-soluble liver antigen/liver-pancreas antibodies **pANCA=peri-nuclear (protoplasmicstaining) antineutrophil cytoplasmic antibodies
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Differential Diagnostic Dilemmas Autoantibodies Disease
ANA/SMA
LKM1
LKM2
LKM3
SLA/LP
Acute Hepatitis Chronic HCV HBV-HDV Alcoholic Hepatitis Wilson Disease
80% +
-
-
-
-
0-88%
-
-
-
75% +
-
-
13% -
-
Common*
-
-
-
-
20-25% +
*Acute phase reaction normalizes ceruloplasmin concentration!! Test Cu: 24 hour urine (>100 g) & hepatic (250 g/g dry wt)
Drug-Induced Autoimmune Hepatitis Drugs
Latency
Disease
Methyldopa
Weeks-Months
AIH type 1
Minocycline
Months-Years
AIH type 1
Nitrofurantoin
Months-Years
AIH type 1
Statins
Months
AIH type 1
Lie Z-X and Kaplowitz N. Clin Liver Dis. 2002; 6: 467-86 Alla V et al. J Clin Gastroenterol 2006; 40: 757-61.
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Immunology of Drug Metabolism Autoimmune Responses Against CYPs and UGTs
UGTs=UDP-glucuronosyltransferase enzymes ; P450s=Cytochrome P450 enzymes
AIH
Clinical Presentations Extrahepatic Autoimmune Manifestations AIH Type 2 (40%) > AIH Type 1 (10%) Spectrum Thyroid disease (Hashimoto’s, Graves) Rheumatoid arthritis Miscellaneous Diabetes mellitus type 1 Sjögren syndrome Vitiligo Addison disease Celiac sprue
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Response Question #3 Histological changes seen in AIH are:
1. Pathognomic 2. May be similar to those seen in viral or drug hepatitis
3. Exclude interface hepatitis 4. All of the above 5. None of the above
Autoimmune Hepatitis Requires a Biopsy Compatible, Not Pathognomic Histopathology
Interface hepatitis Lymphocytic infiltrates Variable % plasma cells Eosinophils Severe cases Lobular hepatitis Bridging necrosis Similar features: Viral & drug hepatitis Wilson disease PBC stage 3 PSC stage 3 Centrolobular inflammation without portal-interface infiltrates
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Autoimmune Hepatitis Characteristic Feature of Interface Hepatitis = Interface Hepatitis
Plasma Cells May or May Not Be Present
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Autoimmune Hepatitis Immunopathology of CD4 Th1 and CD8 CTL Hepatic Inflammatory Infiltrates Portal tracts CD4>>CD8 T cells Plasma cells Eosinophils
Interface Hepatitis CD8>CD4 T cells Indicative of CTL activity No Ig on hepatocytes
Autoimmune Hepatitis IgG Secreting B and Plasma Cells
IgG
IgM
Lee H, et al. Am J Clin Pathol 2010; 133: 430-7
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Autoimmune Hepatitis IgG4 Plasma Cell Subtype
Watanabe CH, et al Liver Int 2010; 30: 222-31 Umemura T, et al. J Gastroenterol 2011; 46 (Suppl): 48-55
AIH
HLA Associations Class HLA
II
I
III
C
DP,DO,DQ,DR
B
A
C’4, C’2, C4AQ0, HSP70,TNF
Class I: A1, B8 Class II:
Susceptibility DRB1*0301 DRB1*0401 DRB1*0404 DRB1*0405 DRB1*1301 Protective DRB1*1501 Immunologic
HLA DR
diseases: DRB4*0103
Class III: C4AQ0
Donaldson PT & Czaja AJ: Clin Liver Dis 2002; 6: 419-28
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Autoimmune Hepatitis
Class II HLA Associations DR3 44%
DR3-DR4 9%
DR4 32%
Others 15%
Czaja AJ et al: Hepatology 18:816, 1993 CP1020209-15
Autoimmune Hepatitis
Revised Scoring System of the International Autoimmune Hepatitis Group* Gender
Female
+2
HLA
DR3 or DR4
+1
>3 2.0 1.5-2.0 1.0-1.5 1:80 1:80 1:40 15 Probable diagnosis 10-15
60 g/day
+2 -2
Post-treatment aggregate score: Definite diagnosis >17 Probable diagnosis 12-17
*Adapted from Alvarez F, Berg PA, Bianchi FB, et al. J. Hepatology 1999;31:929-938.
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Response Question #4 The goals of treatment for AIH should be to:
1. Normalize ALT to