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Lamotrigine and the risk of fulminant hepatic failure

2008; Elsevier BV; Volume: 371; Issue: 9613 Linguagem: Inglês

10.1016/s0140-6736(08)60300-1

1474-547X

Debbie L. Shawcross, Georg Auzinger,

Drug-Induced Hepatotoxicity and Protection

We write in response to the letter by Ivan Iniesta (Dec 22, p 2101),1Iniesta I Lamotrigine and the risk of fulminant hepatic failure.Lancet. 2007; 370: 2101Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar written as a rebuttal to our letter2Shawcross D Knighton S Bernal W Sizer E Auzinger G Old versus new antiepileptic drugs: the SANAD study.Lancet. 2007; 370: 314-315Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar in which we cautioned physicians to be aware of the risks of severe hepatic dysfunction when prescribing lamotrigine, after publication of the SANAD study.3Marson AG Al Kharusi AM Alwaidh M et al.The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.Lancet. 2007; 369: 1000-1015Summary Full Text Full Text PDF PubMed Scopus (705) Google Scholar We were not given the chance to respond to Iniesta's letter, which suggested that we withheld relevant information on one of the cases we reported and detracted from the message we were trying to convey.Although the symptoms that developed 2 weeks after the patient started lamotrigine were typical of a mononucleosis syndrome, idiosyncratic adverse drug reactions to lamotrigine commonly present with hepatotoxicity, often as part of the DRESS (drug reaction with eosinophil and systemic symptoms) syndrome whereby patients typically develop fever, maculopapular rash, eosinophilia, atypical lymphocytosis, arthralgia, lymphadenopathy, and hepatosplenomegaly.4Zaccara G Franciotta D Perucca E Idiosyncratic adverse reactions to antiepileptic drugs.Epilepsia. 2007; 48: 1223-1244Crossref PubMed Scopus (275) Google ScholarWe acknowledge that the IgM was reactive to cytomegalovirus on presentation at the referral hospital, but repeat testing on three occasions at our institution (on admission, before transplantation, and after transplantation) were non-reactive for IgM, and cytomegalovirus DNA was not detectable in the blood, albeit after previous ganciclovir treatment. IgG for cytomegalovirus and Epstein-Barr virus were positive. Anticonvulsant-induced DRESS syndrome can also reactivate cytomegalovirus associated with IgM positivity.5Aihara M Sugita Y Takahashi S et al.Anticonvulsant hypersensitivity syndrome associated with reactivation of cytomegalovirus.Br J Dermatol. 2001; 144: 1231-1234Crossref PubMed Scopus (86) Google ScholarThere was continuous exposure to valproate before liver failure developed, but in our experience fulminant hepatic failure rarely develops in patients treated with anticonvulsants for many years without another precipitant.Lastly, the explant liver showed near-total hepatocyte loss with stromal loss and ductular reaction that were deemed most likely to be secondary to a drug and not cytomegalovirus, since inclusion bodies were not seen within the liver.We declare that we have no conflict of interest. We write in response to the letter by Ivan Iniesta (Dec 22, p 2101),1Iniesta I Lamotrigine and the risk of fulminant hepatic failure.Lancet. 2007; 370: 2101Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar written as a rebuttal to our letter2Shawcross D Knighton S Bernal W Sizer E Auzinger G Old versus new antiepileptic drugs: the SANAD study.Lancet. 2007; 370: 314-315Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar in which we cautioned physicians to be aware of the risks of severe hepatic dysfunction when prescribing lamotrigine, after publication of the SANAD study.3Marson AG Al Kharusi AM Alwaidh M et al.The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.Lancet. 2007; 369: 1000-1015Summary Full Text Full Text PDF PubMed Scopus (705) Google Scholar We were not given the chance to respond to Iniesta's letter, which suggested that we withheld relevant information on one of the cases we reported and detracted from the message we were trying to convey. Although the symptoms that developed 2 weeks after the patient started lamotrigine were typical of a mononucleosis syndrome, idiosyncratic adverse drug reactions to lamotrigine commonly present with hepatotoxicity, often as part of the DRESS (drug reaction with eosinophil and systemic symptoms) syndrome whereby patients typically develop fever, maculopapular rash, eosinophilia, atypical lymphocytosis, arthralgia, lymphadenopathy, and hepatosplenomegaly.4Zaccara G Franciotta D Perucca E Idiosyncratic adverse reactions to antiepileptic drugs.Epilepsia. 2007; 48: 1223-1244Crossref PubMed Scopus (275) Google Scholar We acknowledge that the IgM was reactive to cytomegalovirus on presentation at the referral hospital, but repeat testing on three occasions at our institution (on admission, before transplantation, and after transplantation) were non-reactive for IgM, and cytomegalovirus DNA was not detectable in the blood, albeit after previous ganciclovir treatment. IgG for cytomegalovirus and Epstein-Barr virus were positive. Anticonvulsant-induced DRESS syndrome can also reactivate cytomegalovirus associated with IgM positivity.5Aihara M Sugita Y Takahashi S et al.Anticonvulsant hypersensitivity syndrome associated with reactivation of cytomegalovirus.Br J Dermatol. 2001; 144: 1231-1234Crossref PubMed Scopus (86) Google Scholar There was continuous exposure to valproate before liver failure developed, but in our experience fulminant hepatic failure rarely develops in patients treated with anticonvulsants for many years without another precipitant. Lastly, the explant liver showed near-total hepatocyte loss with stromal loss and ductular reaction that were deemed most likely to be secondary to a drug and not cytomegalovirus, since inclusion bodies were not seen within the liver. We declare that we have no conflict of interest.