1. Autoimmune Hepatitis Thomas W. Faust, M.D.,M.B.E.
Professor of Clinical Medicine
The University of Pennsylvania

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. Autoimmune Hepatitis Pathogenesis
Genetic factors
Antigen presentation/immunocyte activation
DRB1 encodes for MHC II antigen binding grooves (antigen presentation to T cells)
Triggering factors
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

9. 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

10. 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

11. Autoimmune Hepatitis International Autoimmune Hepatitis Group
Gender
AP/AST, ALT ratio
Serum globulins/IgG
ANA, ASMA, LKM-1
AMA positive
Viral serologies
Drug history
Alcohol intake
Liver histology
Other autoimmune diseases
HLA DR3/DR4
Response to therapy
Alverez et al. J Hepatol 1999;31:929

12. 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

13. Autoimmune Hepatitis Type 1
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: 15-40%
-globulin elevation: marked
Czaja et al. Am J Gastroenterol 1995;90:1206
Krawitt. N Engl J Med 2006;354:54

14. Autoimmune Hepatitis Type 1
HLA A1-B8-DR3
Young females
Severe disease
Relapse after steroids
Treatment failure with steroids
More likely to require OLT
HLA DR4
Older females
Milder disease
More steroid responsive
Higher frequency of extrahepatic autoimmune diseases
Donaldson. Semin Liver Dis 2002;22:353
Czaja et al. Hepatology 2002;36:479

15. Autoimmune Hepatitis Type 2
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

16. Autoimmune Hepatitis Type 3 (Variant Type 1) ?
Age: 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

17. Autoimmune Hepatitis Clinical Manifestations
Fatigue
Fever
Jaundice
RUQ pain
Myalgia/arthralgia
Anorexia
Hepatosplenomegaly
Spider angiomata
Cushingoid features
Hirsuitism
Acne
Portal hypertension
Ascites
Varices
Encephalopathy
FHF
HCC
Asymptomatic
Desmet et al. Hepatology 1994;19:1513

18. Autoimmune Hepatitis Complications of Cirrhosis
Netter’s Gastroenterology, 2nd ed., Elsevier Inc., 2010, all rights reserved

19. Autoimmune Hepatitis Cirrhosis to Hepatocellular Carcinoma
HCC
Netter’s Gastroenterology, 2nd ed., Elsevier Inc., 2010, all rights reserved

20. Autoimmune Hepatitis Extrahepatic Autoimmune Diseases
Autoimmune thyroiditis
Grave’s disease
Connective tissue diseases
Inflammatory bowel disease
Celiac disease
Adrenal insufficiency
Autoimmune hematologic disorders
Type 1 DM
Sjogren’s syndrome
Fibrosing alveolitis
Vitiligo
Vasculitis
Nephritis
Krawitt. N Engl J Med 2006;354:54
Czaja et al. Hepatology 2002;36:479

21. 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

22. 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

23. Autoimmune Hepatitis Histology
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

24. Autoimmune Hepatitis Histology
Lymphoplasmacytic infiltrate
Interface hepatitis
Portal inflammation and invasion of limiting plate

25. Autoimmune Hepatitis Histology
Prominent lobular infiltrate composed of mononuclear and plasma cells
Lobular infiltrate

26. Autoimmune Hepatitis Histology
Prominent plasma cells appreciated in this specimen
Plasma cells

27. 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

28. Autoimmune Hepatitis Severe Disease
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

29. Autoimmune Hepatitis Mild to Moderate Disease
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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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
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
Czaja et al. Hepatology 2002;36:479

36. 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

37. 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

38. Autoimmune Hepatitis Relapse after Drug Withdrawal
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

39. Autoimmune Hepatitis Treatment Failure
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

40. 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

41. 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

42. Autoimmune Hepatitis Drug Toxicity
Intolerable symptoms/obesity
Osteoporosis and fractures
Diabetes
Cytopenia
AZA-induced hepatotoxicity
Reduction, withdrawal, or change of immunosuppressive medications

43. Autoimmune Hepatitis Alternative Medications
Mycophenolate
Cyclosporine
Tacrolimus
Budesonide
Methotrexate
Cyclophosphamide

44. 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

45. 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

46. 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.

47. 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.

48. 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

49. 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?

50. 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

51. Autoimmune Hepatitis Question 4
Which one of the following is an absolute indication for treatment with steroids and azathioprine?
A. Cirrhosis with minimal activity
B. Bridging and multilobular necrosis
C. AST < 3 times ULN
D. Periportal hepatitis
E. Mild symptoms

52. 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?

53. 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

54. 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.

55. Autoimmune Hepatitis Answers to Questions
1. B
2. C
3. E
4. B
5. D
6. A