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Idiopathic Acute Liver Injury in Paediatric Outpatients: Incidence and Signal Detection in Two European Countries

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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.

Objectives

(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.

Conclusion

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.

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Acknowledgments

We would like to thank Prof. John Van den Anker and Dr. Giuseppe Indolfi for their revision of the final version of the manuscript, and the Erasmus Trustfonds for research supporting.

Financial disclosure

Nothing to disclose.

Conflict of interest

Katia MC Verhamme has been involved as project leader in analyses contracted by various pharmaceutical companies and received unconditional research grants from Pfizer, Yamanouchi, and Boehringer Ingelheim, none of which are related to the subject of this study. Vera E Valkhoff has conducted research for AstraZeneca as an employee of the Erasmus Medical Center. Miriam CJM Sturkenboom is scientific coordinator of the IPCI group which is partially funded through unconditional research grants from the pharmaceutical industry, namely Pfizer, Merck, AstraZeneca, Eli Lilly, GSK and Altana. She has been consultant to Pfizer, Novartis Consumer Health, Servier, Celgene and Lundbeck. Carmen Ferrajolo, Gianluca Trifiró, Geert W ‘t Jong, Carlo Giaquinto, Gino Picelli, Alessandro Oteri, Sandra de Bie, Martijn J Schuemie, Giampiero Mazzaglia, Claudio Cricelli, Francesco Rossi, and Annalisa Capuano declare that they have no conflicts of interest.

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Authors and Affiliations

  1. 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

    Carmen Ferrajolo, Francesco Rossi & Annalisa Capuano

  2. Department of Medical Informatics, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands

    Carmen Ferrajolo, Katia M. C. Verhamme, Gianluca Trifirò, Geert W. ‘t Jong, Alessandro Oteri, Sandra de Bie, Vera E. Valkhoff, Martijn J. Schuemie & Miriam C. J. M. Sturkenboom

  3. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

    Gianluca Trifirò

  4. Department of Paediatrics, SickKids Hospital, Toronto, ON, Canada

    Geert W. ‘t Jong

  5. Department of Paediatrics, University Hospital of Padua, Padua, Italy

    Carlo Giaquinto

  6. Pedianet-Società Servizi Telematici SRL, Padua, Italy

    Gino Picelli

  7. Società Italiana di Medicina Generale, Florence, Italy

    Giampiero Mazzaglia & Claudio Cricelli

  8. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands

    Miriam C. J. M. Sturkenboom

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  1. Carmen Ferrajolo
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  2. Katia M. C. Verhamme
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  8. Sandra de Bie
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  9. Vera E. Valkhoff
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  10. Martijn J. Schuemie
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  11. Giampiero Mazzaglia
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  14. Annalisa Capuano
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  15. Miriam C. J. M. Sturkenboom
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Corresponding author

Correspondence to Carmen Ferrajolo.

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Ferrajolo, C., Verhamme, K.M.C., Trifirò, G. et al. Idiopathic Acute Liver Injury in Paediatric Outpatients: Incidence and Signal Detection in Two European Countries. Drug Saf 36, 1007–1016 (2013). https://doi.org/10.1007/s40264-013-0045-7

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  • DOI: https://doi.org/10.1007/s40264-013-0045-7

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