autoimmune hepatitis thomas w. faust, m.d.,m.b.e. professor of clinical medicine the university of...
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Autoimmune Hepatitis
Thomas W. Faust, M.D.,M.B.E.
Professor of Clinical Medicine
The University of Pennsylvania
Autoimmune HepatitisOverview
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 HepatitisOverview
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 HepatitisEpidemiology
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 HepatitisNatural 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 HepatitisPoor 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;36:479Manns et al. Hepatology 2006;43:S132
Autoimmune HepatitisGenetics
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;36:479Krawitt. N Engl J Med 2006;354:54Manns et al. Hepatology 2006;43:S132
Autoimmune HepatitisPathogenesis
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;36:479Krawitt. N Engl J Med 2006;354:54Manns et al. Hepatology 2006;14:S132
Autoimmune HepatitisPathogenesis
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;36:479Krawitt. N Engl J Med 2006;354:54
Autoimmune HepatitisPathogenesis
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;36:479Krawitt. N Engl J Med 2006;354:54Czaja. Am J Gastroenterol 2001;96:1224
Autoimmune HepatitisInternational 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 HepatitisSimplified 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 HepatitisType 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;90:1206Krawitt. N Engl J Med 2006;354:54
Autoimmune HepatitisType 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;22:353Czaja et al. Hepatology 2002;36:479
Autoimmune HepatitisType 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;354:54Czaja et al. Am J Gastroenterol 1995;90:1206
Autoimmune HepatitisType 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:S132Czaja et al. Am J Gastroenterol 1995;90:1206
Autoimmune HepatitisClinical 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 HepatitisComplications of Cirrhosis
Netter’s Gastroenterology, 2nd ed., Elsevier Inc., 2010, all rights reserved
Autoimmune HepatitisCirrhosis to Hepatocellular Carcinoma
Netter’s Gastroenterology, 2nd ed., Elsevier Inc., 2010, all rights reserved
HCC
Autoimmune HepatitisExtrahepatic 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;354:54Czaja et al. Hepatology 2002;36:479
Autoimmune HepatitisLiver 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 HepatitisSerology
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 HepatitisHistology
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 HepatitisHistology
Lymphoplasmacytic infiltrate
Interface hepatitis
Portal inflammation and invasion of limiting plate
Autoimmune HepatitisHistology
Prominent lobular infiltrate composed of mononuclear and plasma cells
Lobular infiltrate
Autoimmune HepatitisPrognostic Indices
Blood tests– AST level
– Gamma globulin level
Histology– Interface hepatitis
– Bridging or multilobular necrosis
– Cirrhosis
Czaja et al. Hepatology 2002;36:479
Autoimmune HepatitisSevere 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 HepatitisMild 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 HepatitisHistology 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 HepatitisOverall Goals of Treatment
Induce remission Prevent disease progression Minimize relapse of disease Improve survival Minimize medication side effects
Czaja et al. Hepatology 2002;36:479Krawitt. N Engl J Med 2006;354:54
Autoimmune HepatitisAbsolute 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;36:479Krawitt. N Engl J Med 2006;354:54
Autoimmune HepatitisRelative 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;36:479Krawitt. N Engl J Med 2006;354:54
Autoimmune HepatitisNo 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;36:479Krawitt. N Engl J Med 2006;354:54
Autoimmune HepatitisImmunosuppressive 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 HepatitisTreatment Endpoints
Disease remission Relapse after treatment
withdrawal Treatment failure Incomplete response Drug toxicity
Czaja et al. Hepatology 2002;36:479Krawitt. N Engl J Med 2006;354:54
Autoimmune HepatitisDisease 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;36:479Krawitt. N Engl J Med 2006;354:54
Autoimmune HepatitisRelapse 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 yearsCzaja et al. Hepatology 2002;36:479Krawitt. N Engl J Med 2006;354:54
Autoimmune HepatitisTreatment 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 HepatitisTreatment 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 HepatitisIncomplete 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 HepatitisDrug Toxicity
Intolerable symptoms/obesity Osteoporosis and fractures Diabetes Cytopenia AZA-induced hepatotoxicity Reduction, withdrawal, or change of
immunosuppressive medications
Autoimmune HepatitisAlternative Medications
Mycophenolate Cyclosporine Tacrolimus Budesonide Methotrexate Cyclophosphamide
Autoimmune HepatitisLiver 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 HepatitisTake 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 HepatitisQuestion 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 HepatitisQuestion 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 HepatitisQuestion 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 HepatitisQuestion 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 HepatitisQuestion 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 HepatitisQuestion 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 HepatitisQuestion 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 HepatitisQuestion 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.