title: Idiopathic acute liver injury in paediatric outpatients: incidence and signal detection in two European countries.
abstract: BACKGROUND
  Acute liver failure is idiopathic and drug-related in, respectively, around 50 and 15 % of children. Population-based, epidemiologic data about the pattern of disease manifestation and incidence of less severe acute liver injury, either idiopathic or potentially drug-attributed are limited in children and adolescents.
  
  
  OBJECTIVE
  (i) To assess the incidence of idiopathic acute liver injury (ALI) and its clinical features in children and adolescent outpatients; and (ii) to investigate the role of the drug as a potential cause of ALI which is considered idiopathic.
  
  
  METHODS
  A retrospective cohort study was performed during the years 2000-2008. Data were retrieved from three longitudinal electronic healthcare databases in two European countries: Pedianet and Health Search/CSD Longitudinal Patient Database from Italy and the Integrated Primary Care Information database from The Netherlands. Cases of idiopathic acute liver injury in population aged <18 years were identified by exclusion of all competing causes of liver injury (e.g. viral, autoimmune hepatitis), according to CIOMS criteria. The potential role of drug exposure as actual underlying cause of idiopathic ALI was detected through signal detection mining techniques. Both pooled and country-specific incidence rates [IR/100,000 person-years (PYs)] of idiopathic ALI and pooled adjusted rate ratios (RR) of drugs identified as a potential cause of idiopathic ALI, plus 95 % confidence intervals (CI) were estimated using the custom-built software Jerboa.
  
  
  RESULTS
  Among 785 definite cases of idiopathic ALI, the pooled IR was 62.4/100,000 PYs (95 % CI 58.1-66.8). The country-specific IR was higher in Italy (73.0/100,000 PYs, 95 % CI 67.8-78.4) than in The Netherlands (21.0/100,000 PYs, 95 % CI 16.0-27.2) and increased with age in both countries. Isolated elevations of liver enzymes were reported in around two-thirds of cases in Italy, while in The Netherlands the cases were more often identified by a combination of signs/symptoms. Among drugs detected as potential underlying cause of idiopathic ALI, clarithromycin (RR 25.9, 95 % CI 13.4-50), amoxicillin/clavulanic acid (RR 18.6, 95 % CI 11.3-30.6), and amoxicillin (RR 7.5, 95 % CI 3.4-16.8) were associated with the highest risk compared to non-use.
  
  
  CONCLUSIONS
  The incidence of idiopathic ALI in paediatrics is relatively low and comparable with adults. Clinical presentations differ between the two European countries. Signal detection in healthcare databases allowed identifying antibiotics as the drugs mostly associated with ALI with apparently unknown aetiology.
authors.affiliation: Campania Regional Center of Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine, Pharmacology Section, Second University of Naples, Via L. De Crecchio, 7, 80138, Naples, Italy, c.ferrajolo@erasmusmc.nl.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ferrajolo
authors.forename: Katia M C
authors.initials: KM
authors.lastname: Verhamme
authors.forename: Gianluca
authors.initials: G
authors.lastname: Trifirò
authors.forename: Geert W
authors.initials: GW
authors.lastname: 't Jong
authors.forename: Carlo
authors.initials: C
authors.lastname: Giaquinto
authors.forename: Gino
authors.initials: G
authors.lastname: Picelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Oteri
authors.forename: Sandra
authors.initials: S
authors.lastname: de Bie
authors.forename: Vera E
authors.initials: VE
authors.lastname: Valkhoff
authors.forename: Martijn J
authors.initials: MJ
authors.lastname: Schuemie
authors.forename: Giampiero
authors.initials: G
authors.lastname: Mazzaglia
authors.forename: Claudio
authors.initials: C
authors.lastname: Cricelli
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.forename: Annalisa
authors.initials: A
authors.lastname: Capuano
authors.forename: Miriam C J M
authors.initials: MC
authors.lastname: Sturkenboom
mesh_terms: D000293:Adolescent; D000553:Ambulatory Care; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016208:Databases, Factual; D057286:Electronic Health Records; D005260:Female; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D007558:Italy / Q000453:epidemiology; D017114:Liver Failure, Acute / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology; D008297:Male; D009426:Netherlands / Q000453:epidemiology; D012189:Retrospective Studies