Autoimmune Hepatitis



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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
    • 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

  • 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

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

  • 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

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

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

Autoimmune Hepatitis Type 3 (Variant Type 1) ?

  • 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

  • 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

Autoimmune Hepatitis Complications of Cirrhosis

  • Netter’s Gastroenterology, 2nd ed., Elsevier Inc., 2010, all rights reserved

Autoimmune Hepatitis Cirrhosis to Hepatocellular Carcinoma

  • Netter’s Gastroenterology, 2nd ed., Elsevier Inc., 2010, all rights reserved
  • HCC

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

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

  • 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

  • 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

  • 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
  • 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

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

  • 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

  • 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

  • Mycophenolate
  • Cyclosporine
  • Tacrolimus
  • Budesonide
  • Methotrexate
  • Cyclophosphamide

Autoimmune Hepatitis Liver Transplantation

  • End-stage liver disease
  • 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?
    • 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

  • 1. B
  • 2. C
  • 3. E
  • 4. B
  • 5. D
  • 6. A

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