Autoimmune Hepatitis

1
Autoimmune Hepatitis

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

2
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 200236479
3
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

4
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 200236479
5
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

6
Autoimmune HepatitisPoor Prognostic Factors
Without Treatment

• Liver chemistry tests
• AST gt 10 X ULN or gt 5 X ULN gamma globulin gt 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 200236479 Manns et al.
Hepatology 200643S132
7
Autoimmune HepatitisGenetics

• Type 1
• DRB10301, DRB10401, TNF2A
• Type 2
• DRB10701, HLA B14, HLA DR3, C4A-QO
• First degree relatives
• Autoantibodies
• Hypergammaglobulinemia

Czaja et al. Hepatology 200236479 Krawitt. N
Engl J Med 200635454 Manns et al. Hepatology
200643S132
8
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 200236479 Krawitt. N
Engl J Med 200635454 Manns et al. Hepatology
200614S132
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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 200236479 Krawitt. N
Engl J Med 200635454
10
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 200236479 Krawitt. N
Engl J Med 200635454 Czaja. Am J Gastroenterol
2001961224
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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 199931929
12
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 200848169
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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
1995901206 Krawitt. N Engl J Med 200635454
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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 200222353 Czaja et
al. Hepatology 200236479
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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 200635454 Czaja et al. Am
J Gastroenterol 1995901206
16
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 200643S132 Czaja et al.
Am J Gastroenterol 1995901206
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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 1994191513
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Autoimmune HepatitisComplications of Cirrhosis
Netters Gastroenterology, 2nd ed., Elsevier
Inc., 2010, all rights reserved
19
Autoimmune HepatitisCirrhosis to Hepatocellular
Carcinoma
HCC
Netters Gastroenterology, 2nd ed., Elsevier
Inc., 2010, all rights reserved
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Autoimmune HepatitisExtrahepatic Autoimmune
Diseases

• Autoimmune thyroiditis
• Graves disease
• Connective tissue diseases
• Inflammatory bowel disease
• Celiac disease
• Adrenal insufficiency

• Autoimmune hematologic disorders
• Type 1 DM
• Sjogrens syndrome
• Fibrosing alveolitis
• Vitiligo
• Vasculitis
• Nephritis

Krawitt. N Engl J Med 200635454 Czaja et al.
Hepatology 200236479
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Autoimmune HepatitisLiver Chemistry Tests

• Aminotransferases
• Most commonly lt 500 U/L
• Rarely over 1000 U/L
• Hyperbilirubinemia
• Severe acute decompensation
• End stage liver disease
• Alkaline phosphatase
• Usually lt 2x ULN

Czaja et al. Hepatology 200236479
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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 1995901206
23
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. 200635454
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Autoimmune HepatitisHistology

• Lymphoplasmacytic infiltrate
• Interface hepatitis

Portal inflammation and invasion of limiting
plate

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Autoimmune HepatitisHistology

• Prominent lobular infiltrate composed of
  mononuclear and plasma cells

Lobular infiltrate

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Autoimmune HepatitisHistology

• Prominent plasma cells appreciated in this
  specimen

Plasma cells

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Autoimmune HepatitisPrognostic Indices

• Blood tests
• AST level
• Gamma globulin level
• Histology
• Interface hepatitis
• Bridging or multilobular necrosis
• Cirrhosis

Czaja et al. Hepatology 200236479
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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 200236479
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Autoimmune HepatitisMild to Moderate Disease

• AST lt 10 x ULN
• GG lt 2 x ULN
• Periportal hepatitis
• HLA DR 4
• Complications
• 49 risk of cirrhosis at 15 years
• 10 10-year mortality

Czaja et al. Hepatology 200236479
30
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 200236479
31
Autoimmune HepatitisOverall Goals of Treatment

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

Czaja et al. Hepatology 200236479 Krawitt. N
Engl J Med 200635454
32
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 200236479 Krawitt. N
Engl J Med 200635454
33
Autoimmune HepatitisRelative Treatment
Indications

• Clinical
• Mild symptoms
• Laboratory
• AST 3-9 x ULN
• AST ? 5 x ULN GG lt 2 x ULN
• Histology
• Interface hepatitis
• Active cirrhosis

Czaja et al. Hepatology 200236479 Krawitt. N
Engl J Med 200635454
34
Autoimmune HepatitisNo Treatment

• Clinical
• Asymptomatic patient
• Intolerance to prednisone and azathioprine
• Laboratory
• AST lt 3 x ULN
• Severe cytopenia
• Histology
• Portal hepatitis
• Inactive or decompensated cirrhosis

Czaja et al. Hepatology 200236479 Krawitt. N
Engl J Med 200635454
35
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 200236479
36
Autoimmune HepatitisTreatment Endpoints

• Disease remission
• Relapse after treatment withdrawal
• Treatment failure
• Incomplete response
• Drug toxicity

Czaja et al. Hepatology 200236479 Krawitt. N
Engl J Med 200635454
37
Autoimmune HepatitisDisease Remission

• Disappearance of symptoms
• Normalization or near normalization of AST to lt 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 200236479 Krawitt. N
Engl J Med 200635454
38
Autoimmune HepatitisRelapse after Drug Withdrawal

• Aminotransferases gt 3 x ULN
• GG gt 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 200236479 Krawitt. N
Engl J Med 200635454
39
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 200236479
40
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 200236479
41
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 200236479
42
Autoimmune HepatitisDrug Toxicity

• Intolerable symptoms/obesity
• Osteoporosis and fractures
• Diabetes
• Cytopenia
• AZA-induced hepatotoxicity
• Reduction, withdrawal, or change of
  immunosuppressive medications

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Autoimmune HepatitisAlternative Medications

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

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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

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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

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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 1320 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 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.
48
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

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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?

50
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

51
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 lt 3 times ULN
• D. Periportal hepatitis
• E. Mild symptoms

52
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?

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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

54
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.

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Autoimmune HepatitisAnswers to Questions

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