Autoimmune Hepatitis

7/24/2012 Autoimmune Hepatitis Paul J. Pockros,MD Director of Clinical Research, Scripps Translational Science Institute Director, Liver Disease Cent...
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7/24/2012

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

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