Is it autoimmune hepatitis or DILI? - AASLD

Is it autoimmune hepatitis or DILI? - AASLD

Autoimmune Hepatitis orDrug Induced Liver InjuryKeith D. Lindor, M.D.Arizona State UniversityTempe, AZ

AUTOIMMUNE HEPATITIS100,000 – 200,000 persons in USAFemale>Male, all ages, occurs worldwide

Etiology– Unknown – usually no trigger identified– Viruses, drugs (minocycline) and herbalpreparations can trigger– Disease can persist despite withdrawal oftrigger– ? Molecular mimicry between foreign and selfantigens– Associated with other AI diseases

AUTOIMMUNE HEPATITISDisease Spectrum• Classical chronic hepatitis + cirrhosis• “Burned-out” cirrhosis• Acute hepatitis• Fulminant hepatitis• Overlap syndrome with PSC or PBC

AUTOIMMUNE HEPATITISDiagnosis• International AIH scoring system• ComplicatedHistologic hallmark is interface hepatitis, but notspecificHypergammaglobulinemia and autoantibodiesNo cholestatic featuresNo drug or viral cause, alcohol limit 25 g/dAlvarez F, et al. J Hepatol 1999;31:929-38; Hennes EM, et al. Hepatology 2008;48:169-76

HISTOLOGYInterface Interface Hepatitis hepatitisLympho-PlasmacyticLympho-Plasmacyticinfiltrate infiltrate

AUTOIMMUNE HEPATITISClinical featuresClinical FeaturesPatients, %female 70< 40 yrs old 50acute onset 40fatigue 85jaundice 46myalgias 30hepatomegaly 78

AUTOIMMUNE HEPATITISGenetic Predispositions• HLA-DR3 and HLA-DR4 present in most CaucasianNorth American and Northern European patientswith type 1 autoimmune hepatitis• HLA-DR3 (DRB1*0301) associated with early-ageonset, more treatment failure and frequent need forliver transplantation• HLA-DR4 (DRB1*401) associated with a goodtreatment result, older patients, and frequentconcurrent immune diseases

NATURAL HISTORYCzaja A. Atlas Liver Disease 2005

INDICATIONS FOR THERAPYDefinedAST > 10 times ULNAST > 5 times ULN +IgG > 2 times ULNBridging or multilobularnecrosisRelative – symptoms,interface hepatitis, ASTlower than absolute criteriaMild diseaseNot well definedSevere fulminant diseaseSeronegative chronichepatitisAsymptomatic patients maynot required therapyFeld JJ, et al; Hepatology 2005;42:53-62

Drug Induced Liver Injury (DILI)Vs. Autoimmune Hepatitis (AIH)• AIH• DILI• Distinguishing features in histology

Clinical Manifestations• Minor liver abnormalities• Autoimmune hepatitis• Fulminant hepatitis

DILI or AIH• Can be impossible to differentiate byClinical presentationauto antibodies• Histology may help but not perfect

Histology of DILI vs. AIH• 35 DILI (19 hepatocellular 16 cholestasis)• 28 AIH• 4 pathologists– 65 % agreement in clinical diagnoses– 46% agreement in 4 pathologistTable 3. Agreement Between Clinical and HistologicalDiagnosis for AIH, DILI (HC), and DILI (CS)Histological DiagnosisClinicopathologicDiagnosis N AIH (%) DILI (%) Indeterminate (%)AIH 28 71.4 (20) 0.0 (0) 28.6 (8)DILI (HC) 19 15.8 (3) 57.9 (11) 26.3 (5)DILI (CS) 16 12.5 (2) 62.5 (10) 25.0 (4)DI-AIH* 7 57.1 (4) 28.6 (2) 14.3 (1)

AIH vs. DILI• More severe in AIH– Interface hepatitis– Focal necrosis– Portal inflammation• AIH proven by– Portal and intra-acinar plasma cells– Rosette formation– Emperiopolesis

Drug-induced Liver Injury(A) Plasma cell (B) Plasma cells with apoptotic body(C) Canalicular cholestasis (D) Rosettes (white arrow)

Autoimmune hepatitis(A) Interface hepatitis (B) An expanded portal tract (white arrows)(C) As above eosinophils (D) plasma cells

AIH vs. DILI• Model for hepatocellular vs AIHTable 5. Models to Predict DILI (HC) Versus AIH andDILI (CS) Versus AIHA. Model for DILI (HC) VersusAIHAUROC 0.90Estimates SE P ValueIntercept 1.304 1.510 0.388Portal inflammation* -0.939 1.080 0.384Prominent intra-acinar lymphocytes 1.832 1.116 0.101Prominent intra-acinar eosinophils -1.871 1.358 0.168Cholestasis canalicular 1.700 1.051 0.106Prominent portal-plasma cells -2.177 0.891 0.015Rosette formation -1.659 0.895 0.064

Model for cholestatic DILI orAIHB. Models for DILI (CS) Versus AIHAUROC 0.90Model 1 Estimates SE P ValueIntercept 2.193 1.510 0.147Portal inflammation* -1.773 1.112 0.111Fibrosis† -1.951 1.270 0.124Prominent portal-neutrophils 2.291 1.388 0.099CS-intracellular 2.709 1.490 0.069Focal necrosis‡ -1.738 1.233 0.159

Table 6. Histologic Features Favoring AIH Versus DILIFavoringHistologic Features AIH DILISevere portal inflammation (2:grade 2) *Prominent intra-acinar lymphocytes*hProminent intra-acinar eosinophils *Cholestasis canalicular *h, *cProminent portal plasma cells *Rosette formation *Any levels of fibrosis (2:grade 1)*Prominent port neutrophils*cHepatocellular cholestasis *cSeveral focal necrosis (2:grade 4) *

Conclusion• There is overlap histologically• Problems with inter-observer agreement• Patterns of injury can be useful

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