Pediatric DILI in the United States: Preliminary DILIN ... - AASLD

Pediatric DILI in the United States:Preliminary DILIN ExperienceNaga Chalasani, MD, FACGProfessor and DirectorDivision of Gastroenterology and HepatologyIndiana University School of MedicineFDA-AASLD-PHARMA DILI Conference: March 2010

Vignette # 1• One-year old baby referred for enrolling intothe DILIN Prospective Study• Born with complex congenital heart disease in2005 (TOF)• Blalock-Taussig procedure done on 2 nd day• One year later, she had a definitive procedureperformed to correct the TOF• Had pseudomonal UTI and receivedpiperacillin and gentamycin for 9 days

Vignette # 1• Trip to ER for fever and URI symptoms• Prescribed amoxicillin• Rash a day later with erythema and blisters onthe face and then to rest of her body• One week later, she developed jaundice• Bilirubin 8.3 mg/dl, AST 1355, ALT 907, Alk P 512U/L• Hep A/B/C, ANA/ASMA, liver us with doppler,blood cultures negative

Vignette # 1• Skin biopsy showed changes c/w toxicepidermal necrolysis• Liver failure ensued with multiple organ failureand subsequent death• Postmortem showed massive loss ofhepatocytes with negligible inflammation

Vignette # 2• 12-yr old girl was evaluated for acute hepatitis• One week before she developed nausea,diarrhea, and jaundice• She was restarted on atomoxetine (40 mg/d)three weeks prior to admission• Received atomoxetine for one year butinterrupted for 6-weeks due to prescriptionlapse

Vignette # 2• No history of liver disease, exposure tohepatitis or known hepatotoxins• AST 2999, ALT 3264, Alk P 231, TB 9.1 mg/dl• Hep A/B/C/EBV/CMV negative• ANA 1:160 but ASMA, LKM negative• Ceruloplasmin negative• Ultrasound showed mild fatty infiltration

LIVER BIOPSYLiver biopsy showed intact hepatic architecture withfocal thin bridging fibrosis. Portal areas showedmoderate mixed inflammatory infiltrates,predominantly lymphocytes, eosinophils.

Pediatric DILI• Rare cause of acute and chronic liver diseasein children• Can cause asymptomatic elevations in livertests, chronic liver disease, and ALF• Acetaminophen toxicity resulting in ALF is wellknown• Data are sparse in terms of clinicalcharacteristics and outcomes

Peds DILI: ALF• In a multicenter study of 348 children with ALFin the US, acetaminophen toxicity in 48children (14%)• Idiosyncratic DILI in 17 patients (5%)• Valproate (3), INH (2), mushroom (2), and oneeach of anesthetic, bactrim, cytoxan/dilantin,dilantin, Iron, minocycline, pravastatin, cylert,methotrexateSquires Jr RH et al. Journal of Pediatrics 2006;148:652-658

Peds DILI: Outcomes of ALFDead Alive TransplantedIdiosyncratic (n=17) 5 7 5Acetaminophen (n=48) 2 45 2Squires Jr RH et al. Journal of Pediatrics 2006;148:652-658

Peds DILI in the literature• Antibiotics, INH, Psychoactive drugs, andminocycline are the usual suspects in children• Children may be differentially susceptible toDILI caused by valproate, aspirin, and may beresistant to usual suspects such asamox/clavulanate

DILIN Prospective Study• Multicenter study at 8 academic centers• Children > 2 years are eligible• >25% likelihood of DILI• Detailed work-up at baseline• Standardized causality and severityadjudication• Follow-up duration of 6 – 24 monthsFontana RJ et al. Drug Safety 2009

DILIN Prospective Study: Initial 300• 93% adultspatients• Single prescription agent in 73% and CAM in9%• Antimicrobials (45.5%) and CNS agents (15%)• Chronic DILI in 14%• Death in 8%, but it was liver-related in 44%• Acute Hep C was an unsuspected culprit in 4casesChalasani N et al. Gastroenterology 2008

Peds DILI: DILIN Data• Data from 9/04 through 9/09• Out of 611 consecutively enrolled subjects, 30were children (>18 years of age)• AST or ALT > 5 ULN, two consecutive readingsor TB > 2.5 mg/dl or Alk P > 2 ULN or INR > 1.5along with elevated AST, ALT, Alk P• APAP toxicity is exclusionary• No obvious competing etiologies atenrollment

Peds DILI: DILIN Data• Mean and median ages were 12.3 and 13.7 yrs• 70% female• Prior drug allergy in 43%• Alcohol abuse was rare• One child with biliary atresia, but underlyingneuropsychiatric, pulmonary or cardiac comorbiditieswere common

Peds DILI: DILIN Data• Median latency for symptoms was 31 days andfor DILI identification was 46 days• Common symptoms: jaundice, abdominalpain, pruritus, nausea, rash, fever• S-J syndrome in 2 patients• 78% hepatocellular, 13% cholestatic and 9%mixed [Adults: HC -57%, CS – 23%, and Mixed20%]

DILIN Peds DILI DataClinical Presentation Median (25-75 th )Duration in daysDays from drug start to symptomsDays from drug start to DILIN startDays from onset to peak bilirubinDays from onset to peak ALTDays from onset to TB

Peds DILI: DILIN DataPeak Biochemical ValuesALT (U/L)AST(U/L)Alkaline Phosphatase(U/L)Total Bilirubin (mg/dL)INRANA PositiveAnti-SMA PositiveIgG Mean (Median) (mg/dl)Absolute Eosinophils (mm 3 )Mean values1032 ± 976915 ± 908383 ± 2719.4 ±111.7 ±1.4746%42%1873 ±1942196 ±194

DILIN Peds DILI: Implicated agentsAntimicrobials (n=15) CNS agents (n=13) Others (8)Minocycline (4)INH (N=3)Azithromycin (3)Amoxicillin (2)Oxacillin (1)Levofloxacin(1)TMP/SMX(1)Atoxometine (3)Lamotrigine (3)Valproate (2)Phenobarbital (1)Phenytoin(1)Fluoxetine (1)Amitriptyline (1)Methylphenidate (1)Hydroxycut (1)Nicotinamide (2)Daunorubicin (1)Vincristine (1)MethylDopa (1)Yasmin (1)Carbamazepine/perphenazine (1)

Causality ScoresDILIN ScoreDefiniteVery LikelyProbablePossiblyUnlikelyRUCAM ScoreHighly probableProbablePossibleUnlikelyExcluded39%35%13%9%4%12.5%46%29%8%4%

DILIN Severity ScoresCategory Proportion (%)MildModerateModerate / HospitalizedSevereFatal302222224

Liver Histology (n=10)Inflammation: Cells Plasma cells 1/10increasedEosinophils 5/10Neutrophils 2/10Inflammation: Pattern Interface hepatitis Grade 3 or 4 5/10Lobular hepatitis Grade 3 or 4 5/10Portal hepatitis Grade 3 or 4 1/10Bile duct injury Present 3/10Fibrosis Grade 3 or 4 (none 5, 6) 5/9Overall Pattern Acute hepatitis 1/10Chronic hepatitis 4/10Acute cholestasis 2/10Combined hepatitis/cholestasis 2/10

Peds DILI: OutcomesHospitalized 63%Death 4.5%Liver Transplant 0Chronic DILI 6.7%Received steroids 52%

Summary• Pediatric DILI accounts for 5-7% of the DILIcases in the DILIN Prospective Study• Antimicrobials and CNS agents are the mostcommon classes implicated• CAM DILI is rare• Autoimmune DILI is common• Fatality rate 5%

Acknowledgements• DILIN Co-investigators• NIDDK• Nursing staff• Research participants