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

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


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


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


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


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


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


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


Lymphoplasmacytic infiltrate

Interface hepatitis

Portal inflammation and invasion of limiting plate


Prominent lobular infiltrate composed of mononuclear and plasma cells

Lobular infiltrate


Prominent plasma cells appreciated in this specimen

Plasma cells

Autoimmune HepatitisPrognostic Indices

Blood tests– AST level

– Gamma globulin level

Histology– Interface hepatitis

– Bridging or multilobular necrosis

– Cirrhosis


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


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


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


Autoimmune HepatitisOverall Goals of Treatment

Induce remission Prevent disease progression Minimize relapse of disease Improve survival Minimize medication side effects


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


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


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


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


Autoimmune HepatitisTreatment Endpoints

Disease remission Relapse after treatment

withdrawal Treatment failure Incomplete response Drug toxicity


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%


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


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


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


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.


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


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?


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


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


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?


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


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 HepatitisAnswers to Questions

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

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

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