Autoimmune Hepatitis
Thomas W. Faust, M.D.,M.B.E.
Professor of Clinical Medicine
The University of Pennsylvania
Autoimmune Hepatitis
Overview
 Chronic hepatocellular injury
 Etiology unclear
 Lymphocytic or lymphoplasmacytic infiltrate with
interface hepatitis
 Lobular or panacinar necrosis
 Predominant aminotransferase elevation
 Autoantibodies and hypergammaglobulinemia
 Exclusion of other chronic diseases
Czaja et al. Hepatology 2002;36:479
Autoimmune Hepatitis
Overview
 Exclusion of other chronic diseases
– Viral hepatitis (HBV and HCV)
– Alcoholic liver disease and NAFLD
– Drug-induced hepatotoxicity
– Wilson disease
– Hereditary hemochromatosis
– Alpha-1-antitrypsin deficiency
– Primary biliary cirrhosis
– Primary sclerosing cholangitis
Autoimmune Hepatitis
Epidemiology
 Incidence: 1.9 cases per 100,000 persons per yr
 Prevalence: 16.9 cases per 100,000 persons per
yr
 Females account for 70% of cases, 50%  40
years
 Cause of chronic liver disease: 11-23%
 AIH accounts for 2.6% and 5.9% of liver
transplants in Europe and U.S. respectively
Czaja et al. Hepatology 2002;36:479
Autoimmune Hepatitis
Natural History
 Severe disease (untreated)
– 40% die within 6 months of diagnosis
– 40% of survivors develop cirrhosis
– 54% of cirrhotics develop varices within 2
years of diagnosis of cirrhosis
– 20% of patients with varices will bleed
Autoimmune Hepatitis
Poor Prognostic Factors Without Treatment
 Liver chemistry tests
– AST > 10 X ULN or > 5 X ULN + gamma
globulin > 2 X ULN
– Risk of cirrhosis and 90% mortality at 10 yr
 Bridging or multiacinar necrosis
– 82% of patients develop cirrhosis within 5
yr
– 45% mortality at 5 yr
Czaja et al. Hepatology 2002;36:479
Manns et al. Hepatology 2006;43:S132
Autoimmune Hepatitis
Genetics
 Type 1
– DRB1*0301, DRB1*0401, TNF*2A
 Type 2
– DRB1*0701, HLA B14, HLA DR3, C4A-QO
 First degree relatives
– Autoantibodies
– Hypergammaglobulinemia
Czaja et al. Hepatology 2002;36:479
Krawitt. N Engl J Med 2006;354:54
Manns et al. Hepatology 2006;43:S132
Autoimmune Hepatitis
Pathogenesis
 Genetic factors
– Antigen presentation/immunocyte activation
– DRB1 encodes for MHC II antigen binding grooves
(antigen presentation to T cells)
 Triggering factors
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Infections (HAV, HBV, HCV, HSV, EBV, measles)?
Medications (ABX, statins, NSAIDs etc.)?
Toxins?
Molecular mimicry?
Czaja et al. Hepatology 2002;36:479
Krawitt. N Engl J Med 2006;354:54
Manns et al. Hepatology 2006;14:S132
Autoimmune Hepatitis
Pathogenesis
 Autoantigenic peptide processed by APC
in context of MHC II
 Recognition of antigen-MHC II complex by
uncommitted CD4 cells
 Cytokine release from TH1 and TH2 CD4
cells
– IL-12 and IL-2: proliferation of CD8 cells
– IL-4 and IL-10: proliferation of B cells
Czaja et al. Hepatology 2002;36:479
Krawitt. N Engl J Med 2006;354:54
Autoimmune Hepatitis
Pathogenesis
 Antibody-dependent cellular cytotoxicity
– Antibodies directed against ASGPR
– Suppressor T cell defect
– Binding of NK cell to antigen-antibody complex
followed by hepatocyte destruction
 Cell-mediated cytotoxicity
– IL-12 and IL-2 released
– Aberrant display of MHC class II
– CD8 T cell destruction of hepatocyte
Czaja et al. Hepatology 2002;36:479
Krawitt. N Engl J Med 2006;354:54
Czaja. Am J Gastroenterol 2001;96:1224
Autoimmune Hepatitis
International Autoimmune Hepatitis Group
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Gender
AP/AST, ALT ratio
Serum globulins/IgG
ANA, ASMA, LKM-1
AMA positive
Viral serologies
Drug history
Alverez et al. J Hepatol 1999;31:929
 Alcohol intake
 Liver histology
 Other autoimmune
diseases
 HLA DR3/DR4
 Response to therapy
Autoimmune Hepatitis
Simplified Criteria
 Autoantibodies
– ANA, ASMA, LKM-1, SLA
 IgG
– Typically elevated in autoimmune hepatitis
 Histology
– Interface hepatitis, lymphocytic or
lymphoplasmacytic infiltrate, rosettes
 Exclusion of viral hepatitis
– Hepatotropic viruses and others
Hennes et al. Hepatology 2008;48:169
Autoimmune Hepatitis
Type 1
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Age: infants to elderly
Female: 78%
Autoantigen: asialoglycoprotein receptor?
Autoantibodies: ANA, ASMA
– Others: pANCA, actin, ASGPR, SLA/LP
 HLA: A1-B8-DR3 or HLA DR4 serotypes
 Extrahepatic autoimmune disease: 1540%
 -globulin elevation: marked
Czaja et al. Am J Gastroenterol 1995;90:1206
Krawitt. N Engl J Med 2006;354:54
Autoimmune Hepatitis
Type 1
 HLA A1-B8-DR3
– Young females
– Severe disease
– Relapse after
steroids
– Treatment failure
with steroids
– More likely to
require OLT
Donaldson. Semin Liver Dis 2002;22:353
Czaja et al. Hepatology 2002;36:479
 HLA DR4
– Older females
– Milder disease
– More steroid
responsive
– Higher frequency
of extrahepatic
autoimmune
diseases
Autoimmune Hepatitis
Type 2
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Age: 2-14 years
Female: 90%
Autoantigen: CYP450 IID6
Autoantibodies: LKM-1
– Others: LC-1, SLA/LP
 Extrahepatic autoimmune disease: 40%
 -globulin elevation: Mild
 Severity: more severe than type 1?
Krawitt. N Engl J Med 2006;354:54
Czaja et al. Am J Gastroenterol 1995;90:1206
Autoimmune Hepatitis
Type 3 (Variant Type 1) ?
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Age: 30-50 years
Female: 90%
Autoantigen: transfer ribonucleoprotein complex
Autoantibodies: SLA/LP
– Others: actin, ASMA, ANA
 Extrahepatic autoimmune disease: 58%
 -globulin elevation: Moderate
 Reclassification: type 1 AIH
Manns et al. Hepatology 2006;43:S132
Czaja et al. Am J Gastroenterol 1995;90:1206
Autoimmune Hepatitis
Clinical Manifestations
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Fatigue
Fever
Jaundice
RUQ pain
Myalgia/arthralgia
Anorexia
Hepatosplenomegaly
Spider angiomata
Cushingoid features
Desmet et al. Hepatology 1994;19:1513
 Hirsuitism
 Acne
 Portal hypertension
– Ascites
– Varices
– Encephalopathy
 FHF
 HCC
 Asymptomatic
Autoimmune Hepatitis
Complications of Cirrhosis
Netter’s Gastroenterology, 2nd ed., Elsevier Inc., 2010, all rights reserved
Autoimmune Hepatitis
Cirrhosis to Hepatocellular Carcinoma
HCC
Netter’s Gastroenterology,
2nd
ed., Elsevier Inc., 2010, all rights reserved
Autoimmune Hepatitis
Extrahepatic Autoimmune Diseases
 Autoimmune
thyroiditis
 Grave’s disease
 Connective tissue
diseases
 Inflammatory bowel
disease
 Celiac disease
 Adrenal insufficiency
Krawitt. N Engl J Med 2006;354:54
Czaja et al. Hepatology 2002;36:479
 Autoimmune
hematologic disorders
 Type 1 DM
 Sjogren’s syndrome
 Fibrosing alveolitis
 Vitiligo
 Vasculitis
 Nephritis
Autoimmune Hepatitis
Liver Chemistry Tests
 Aminotransferases
– Most commonly < 500 U/L
– Rarely over 1000 U/L
 Hyperbilirubinemia
– Severe acute decompensation
– End stage liver disease
 Alkaline phosphatase
– Usually < 2x ULN
Czaja et al. Hepatology 2002;36:479
Autoimmune Hepatitis
Serology
 Type 1
– ANA, ASMA, pANCA, actin, ASGPR
 Type 2
– LKM-1, LC-1
 Type 3 (variant type 1) ?
– SLA/LP
 Elevated gamma globulins and IgG
 Low IgA (type 2 AIH)
Czaja et al. Am J Gastroenterol 1995;90:1206
Autoimmune Hepatitis
Histology
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Piecemeal necrosis (interface hepatitis)
Panacinar inflammation or collapse
Lymphoplasmacytic infiltrates
Eosinophils
Rosette formation
Fibrosis or cirrhosis
Absence of portal lymphoid aggregates
and steatosis
Krawitt. N Engl J Med. 2006;354:54
Autoimmune Hepatitis
Histology
 Lymphoplasmacytic
infiltrate
 Interface hepatitis
Portal inflammation and invasion of
limiting plate
Autoimmune Hepatitis
Histology
 Prominent lobular
infiltrate composed of
mononuclear and
plasma cells
Lobular infiltrate
Autoimmune Hepatitis
Histology
 Prominent plasma
cells appreciated in
this specimen
Plasma cells
Autoimmune Hepatitis
Prognostic Indices
 Blood tests
– AST level
– Gamma globulin level
 Histology
– Interface hepatitis
– Bridging or multilobular necrosis
– Cirrhosis
Czaja et al. Hepatology 2002;36:479
Autoimmune Hepatitis
Severe Disease
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AST  10 x ULN
AST  5 x ULN + GG  2 x ULN
Bridging necrosis
Multilobular collapse
HLA B8, DR3
African American males
Mortality
– 50% at 3 years
– 90% at 10 years
Czaja et al. Hepatology 2002;36:479
Autoimmune Hepatitis
Mild to Moderate Disease
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AST < 10 x ULN
GG < 2 x ULN
Periportal hepatitis
HLA DR 4
Complications
– 49% risk of cirrhosis at 15 years
– 10% 10-year mortality
Czaja et al. Hepatology 2002;36:479
Autoimmune Hepatitis
Histology and Prognosis
 Interface hepatitis
– 17% risk of cirrhosis at 5 years
– Normal survival
 Bridging or multilobular necrosis
– 82% risk of cirrhosis at 5 years
– 45% 5-year mortality
 Cirrhosis
– 58% 5-year mortality
Czaja et al. Hepatology 2002;36:479
Autoimmune Hepatitis
Overall Goals of Treatment
 Induce remission
 Prevent disease progression
 Minimize relapse of disease
 Improve survival
 Minimize medication side effects
Czaja et al. Hepatology 2002;36:479
Krawitt. N Engl J Med 2006;354:54
Autoimmune Hepatitis
Absolute Treatment Indications
 Clinical
– Incapacitating symptoms
– Progression of disease
 Laboratory
– AST  10 x ULN
– AST  5 x ULN + GG  2 x ULN
 Histology
– Bridging necrosis
– Multilobular necrosis
Czaja et al. Hepatology 2002;36:479
Krawitt. N Engl J Med 2006;354:54
Autoimmune Hepatitis
Relative Treatment Indications
 Clinical
– Mild symptoms
 Laboratory
– AST 3-9 x ULN
– AST  5 x ULN + GG < 2 x ULN
 Histology
– Interface hepatitis
– Active cirrhosis
Czaja et al. Hepatology 2002;36:479
Krawitt. N Engl J Med 2006;354:54
Autoimmune Hepatitis
No Treatment
 Clinical
– Asymptomatic patient
– Intolerance to prednisone and azathioprine
 Laboratory
– AST < 3 x ULN
– Severe cytopenia
 Histology
– Portal hepatitis
– Inactive or decompensated cirrhosis
Czaja et al. Hepatology 2002;36:479
Krawitt. N Engl J Med 2006;354:54
Autoimmune Hepatitis
Immunosuppressive Therapy
 Prednisone
– 30 mg/d x 1 week
– 20 mg/d x 1 week
– 15 mg/d x 2 weeks
– 10 mg/d until
endpoint
 Azathioprine
– 50 mg/d until
endpoint
Czaja et al. Hepatology 2002;36:479
 Prednisone alone
– 60 mg/d x 1 week
– 40 mg/d x 1 week
– 30 mg/d x 2 weeks
– 20 mg/d until
endpoint
Autoimmune Hepatitis
Treatment Endpoints
 Disease remission
 Relapse after treatment
withdrawal
 Treatment failure
 Incomplete response
 Drug toxicity
Czaja et al. Hepatology 2002;36:479
Krawitt. N Engl J Med 2006;354:54
Autoimmune Hepatitis
Disease Remission
 Disappearance of symptoms
 Normalization or near normalization of
AST to < 2 x ULN
 GG and bilirubin: normal
 Minimal or no hepatic inflammation
 65% and 80% of patients within 18 months
and 3 yrs of initiation of Rx respectively
 10 year survival: 90%
Czaja et al. Hepatology 2002;36:479
Krawitt. N Engl J Med 2006;354:54
Autoimmune Hepatitis
Relapse after Drug Withdrawal
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Aminotransferases > 3 x ULN
GG > 2g/dL
Recurrent inflammation on liver biopsy
Risk of relapse
– 50% at 6 months and 70% at 3 years
 Prednisone or prednisone + AZA
– Same regimen as for naïve patients
– Long-term low dose prednisone or AZA (2 mg/kg/d)
for relapses (goal: AST  3x ULN)
– 47% of pts achieve sustained remission off
medications after 10 years
Czaja et al. Hepatology 2002;36:479
Krawitt. N Engl J Med 2006;354:54
Autoimmune Hepatitis
Treatment Failure
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Worsening symptoms (9% of patients)
Increase in AST/bilirubin by 67%
Progressive necroinflammatory activity
Signs of liver failure
– Jaundice
– Ascites
– Encephalopathy
 High dose immunosuppressive therapy
Czaja et al. Hepatology 2002;36:479
Autoimmune Hepatitis
Treatment Failure
 High dose immunosuppression
– Prednisone 60 mg daily
– Prednisone 30 mg + azathioprine 150 mg daily
– Above for at least 1 month/taper dose
 Clinical and biochemical improvement
– 70% of patients within 2 years
 Resolution of inflammatory activity
– 20% of patients
 Long-term therapy or OLT
Czaja et al. Hepatology 2002;36:479
Autoimmune Hepatitis
Incomplete Response
 Improvement in clinical, biochemical, and
histologic parameters
 Failure to satisfy remission criteria
 Remission unlikely if it cannot be obtained
within 3 years of initiation of drug therapy
 Low dose prednisone or azathioprine
– Control symptoms
– AST  5 x ULN
Czaja et al. Hepatology 2002;36:479
Autoimmune Hepatitis
Drug Toxicity
 Intolerable symptoms/obesity
 Osteoporosis and fractures
 Diabetes
 Cytopenia
 AZA-induced hepatotoxicity
 Reduction, withdrawal, or change of
immunosuppressive medications
Autoimmune Hepatitis
Alternative Medications
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Mycophenolate
Cyclosporine
Tacrolimus
Budesonide
Methotrexate
Cyclophosphamide
Autoimmune Hepatitis
Liver Transplantation
 End-stage liver disease
– Complications of portal
hypertension
– Hepatocellular carcinoma
 Fulminant liver disease
– Acute liver injury
– Acute decompensation
superimposed on chronic
liver injury
 Results
– 5 yr pt and graft survival:
80-90%
– Recurrence: 15-40%
– Higher rates of acute and
chronic rejection
Autoimmune Hepatitis
Take Home Points
 Chronic hepatocellular disease of
unknown etiology
 Clinical presentation is variable
 Diagnosis based upon LFTs, serology,
gamma globulins, and histology
 Immunosuppressive therapy is the
mainstay of treatment
 Tailor therapy based upon treatment
endpoints
Autoimmune Hepatitis
Question 1
 A previously healthy 40 yr. old woman presents
with fatigue and dark urine for 2 weeks. There is
no history of significant alcohol or drug use.
Physical exam is remarkable for jaundice and
tender hepatomegaly. Labs are notable for AST
1000 U/L, ALT 1500 U/L, and alkaline
phosphatase of 350 U/L. The total bilirubin is 10
mg/dl and the INR is 1.3. ASMA is positive to
1:320 and IgG is twice normal. Liver ultrasound
reveals hepatomegaly o/w normal. What findings
would be found on liver biopsy?
DDSEP 6, AGA Press, 2011.
Autoimmune Hepatitis
Question 1
 A. Perivenular neutrophil inflammation with
ballooned hepatocytes and Mallory bodies
 B. Infiltration of portal tracts with lymphocytes
and plasma cells, interface hepatitis, piecemeal
necrosis along limiting plate
 C. Infiltration of portal tracts with destruction of
interlobular bile ducts
 D. Periportal and lobular non-caseating
granulomas
 E. Ground glass hepatocytes and Councilman
bodies
DDSEP 6, AGA Press, 2011.
Autoimmune Hepatitis
Question 2
 Which one of the following statements about
prognostic factors and autoimmune hepatitis is true?
– A. Mild periportal hepatitis is associated with 90% mortality
at 10 years without treatment.
– B. 60% of patients die within 6 months of diagnosis.
– C. AST ≥ 10 times ULN or ≥ 5 times ULN + gamma
globulins ≥ 2 times ULN are associated with 90% mortality
at 10 yrs without treatment
– D. Bridging necrosis is associated with a favorable
prognosis
– E. Young pts are less likely to go to transplant when
compared to older patients
Autoimmune Hepatitis
Question 3
 A 12 yr. old female presents with malaise,
fatigue, and myalgias. She mentions that her
stools are lighter color than normal. Physical
examination is remarkable for jaundice and a
liver edge 2 finger breaths below the right costal
margin. Her laboratory evaluation reveals a total
bilirubin of 13.1 mg/dl, AST of 2300 U/L, an ALT
of 3124 U/L, and an INR of 1.4. Type 2
autoimmune hepatitis is suspected. Which
laboratory test is appropriate?
Autoimmune Hepatitis
Question 3
 A. Antinuclear (ANA) and antismooth muscle
antibodies (ASMA)
 B. Antimitochondrial antibodies (AMA) and total
lipid profile
 C. Antibodies to soluble liver antigen (SLA)
 D. Serum IgM
 E. Anti liver-kidney-microsomal (LKM-1)
antibodies
Autoimmune Hepatitis
Question 4
 Which one of the following is an absolute
indication for treatment with steroids and
azathioprine?
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A. Cirrhosis with minimal activity
B. Bridging and multilobular necrosis
C. AST < 3 times ULN
D. Periportal hepatitis
E. Mild symptoms
Autoimmune Hepatitis
Question 5
 A 28 yr. old female presents for evaluation of
abnormal liver-associated enzymes. Overall, she
feels well and the physical exam is
unremarkable. Labs reveal AST of 2124 U/L,
ALT of 2256 U/L, ANA and ASMA are positive.
Liver biopsy shows severe panlobular necrosis.
Which one of the following is the appropriate
next step?
Autoimmune Hepatitis
Question 5
 A. Begin azathioprine as monotherapy of 50 mg
daily until remission achieved.
 B. Begin cyclosporine 100 mg twice daily in
combination with mycophenolate 500 mg twice
daily.
 C. Refer patient for liver transplant evaluation
 D. Begin prednisone 30 mg daily in combination
with azathioprine 50 mg daily
 E. Repeat liver associated enzymes in 3-4
weeks prior to making treatment decisions
Autoimmune Hepatitis
Question 6
 Which treatment is most appropriate for patients that
have worsening liver enzymes despite standard
treatment with steroids and azathioprine?
– A. Increase prednisone to 60 mg daily or to 30 mg daily in
combination with azathioprine 150 mg daily for at least 1
month.
– B. Refer immediately for liver transplant evaluation
– C. Add tacrolimus 2 mg twice daily to prednisone 10 mg
daily and azathioprine 50 mg daily.
– D. Stop prednisone and start azathioprine 50 mg daily,
mycophenolate 500 mg daily, and tacrolimus 1 mg twice
daily
– E. Continue steroids and azathioprine at same dose and
repeat liver enzymes in 6 weeks.
Autoimmune Hepatitis
Answers to Questions
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1. B
2. C
3. E
4. B
5. D
6. A