Acute liver failure associated with lamotrigine in children with epilepsy: A report of two cases and thoughts on pharmacogenomics

Jie Deng, Zheng-Ran Fu, Long Wang, Jun Liu, Chun-Hong Chen, Fang Fang, Xiao-Ling Wang, Jie Deng, Zheng-Ran Fu, Long Wang, Jun Liu, Chun-Hong Chen, Fang Fang, Xiao-Ling Wang

Abstract

Pediatric acute liver failure (PALF) is a rare and life-threatening clinical syndrome for which drug-induced liver injury is a cause. Lamotrigine (LTG) is generally a safe and effective antiseizure medication, and PALF related to LTG has rarely been reported. Here, we describe two cases of PALF associated with LTG in children with epilepsy. In both patients, LTG was used in combination with valproic acid at an initial dose exceeding the recommended dose, which increased the risk of adverse reactions. In addition, single nucleotide polymorphisms of genes associated with the pharmacokinetics and pharmacodynamics of LTG were selected for pharmacogenomic testing. However, the results revealed that genotypes of the patients had variable effects on the serum concentration and therapeutic responsiveness of LTG and therefore did not explain the clinical manifestations well. The findings of this case report caution clinicians to be aware of the risk of liver failure when using antiseizure medication in polytherapy, especially LTG in combination with valproic acid. When administered to children, the recommended dosage of LTG should be strictly followed. Further pharmacogenomic studies are needed to help improve the efficacy and safety of epilepsy treatment in the future.

Keywords: ASM, antiseizure medication; Antiseizure medication; DILI, drug-induced liver injury; Idiosyncratic drug-induced liver injury; LTG, lamotrigine; Lamotrigine; PALF, pediatric acute liver failure; Pediatric acute liver failure; Pharmacogenomics.

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

© 2022 The Authors.

Figures

Fig. 1
Fig. 1
Case 1. (A) Family pedigree of case 1. Solid black represents a family member with epilepsy. (B) Picture of abdomen showed skin jaundice with dark rashes. (C) Cranial CT showed a deepening of the cerebral sulci. (D) Abdomen CT indicated fullness of the liver and spleen.
Fig. 2
Fig. 2
Case 2. (A) Family pedigree of case 2. (B) Sanger sequencing confirmed a de novo heterozygous variant c.971A > C (p.His324Pro) of the SCN1A gene. (C) Axial, FLAIR brain MRI showed postoperative gliosis around the resected lesion in the left frontal lobe. (D) Electroencephalogram showed interictal epileptiform discharges predominantly in right temporal and frontal leads.

References

    1. Squires J.E., McKiernan P., Squires R.H. Acute liver failure: an update. Clin Liver Dis. 2018;22:773–805. doi: 10.1016/j.cld.2018.06.009.
    1. Bhatt H., Rao G.S. Management of acute liver failure: a pediatric perspective. Curr Pediatr Rep. 2018;6:246–257. doi: 10.1007/s40124-018-0174-7.
    1. Di Giorgio A., Bartolini E., Calvo P.L., Cananzi M., Cirillo F., Della Corte C., et al. Diagnostic approach to acute liver failure in children: a position paper by the SIGENP liver disease working group. Dig Liver Dis. 2021;53(5):545–557. doi: 10.1016/j.dld.2021.03.004.
    1. Makin A.J., Fitt S., Williams R., Duncan J.S. Fulminant hepatic failure induced by lamotrigine. BMJ. 1995;311:292. doi: 10.1136/bmj.311.7000.292b.
    1. Arnon R., DeVivo D., Defelice A.R., Kazlow P.G. Acute hepatic failure in a child treated with lamotrigine. Pediatr Neurol. 1998;18(3):251–252. doi: 10.1016/s0887-8994(97)00196-3.
    1. Ouellet G., Tremblay L., Marleau D. Fulminant hepatitis induced by Lamotrigine. South Med J. 2009;102:82–84. doi: 10.1097/SMJ.0b013e3181878b95.
    1. Andrade R.J., Chalasani N., Björnsson E.S., Suzuki A., Kullak-Ublick G.A., Watkins P.B., et al. Drug-induced liver injury. Nat Rev Dis Primers. 2019;5(1):58. doi: 10.1038/s41572-019-0105-0.
    1. Lamotrigine. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012.
    1. Taketomo C.K., Hodding J.H., Kraus D.M. 23rd edition. Lexi-Comp Inc; 2016. Pediatric & neonatal dosage handbook.
    1. Stephens C., Andrade R.J. Genetic predisposition to drug-induced liver injury. Clin Liver Dis. 2020;24:11–23. doi: 10.1016/j.cld.2019.08.003.
    1. Stephens C., Lucena M.I., Andrade R.J. Genetic risk factors in the development of idiosyncratic drug-induced liver injury. Expert Opin Drug Metab Toxicol. 2021;17:153–169. doi: 10.1080/17425255.2021.1854726.
    1. Balestrini S., Sisodiya S.M. Pharmacogenomics in epilepsy. Neurosci Lett. 2018;667:27–39. doi: 10.1016/j.neulet.2017.01.014.
    1. Mitra-Ghosh T., Callisto S.P., Lamba J.K., Remmel R.P., Birnbaum A.K., Barbarino J.M., et al. PharmGKB summary: lamotrigine pathway, pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2020;30(4):81–90.
    1. Li M., Zhong R., Lu Y., Zhao Q., Li G., Lin W. Association between SCN1A rs2298771, SCN1A rs10188577, SCN2A rs17183814, and SCN2A rs2304016 polymorphisms and responsiveness to antiepileptic drugs: a meta-analysis. Front Neurol. 2020;11 doi: 10.3389/fneur.2020.591828.
    1. Chang Y., Yang L., Zhang M., Liu S.-Y. Correlation of the UGT1A4 gene polymorphism with serum concentration and therapeutic efficacy of lamotrigine in Han Chinese of Northern China. Eur J Clin Pharmacol. 2014;70:941–946. doi: 10.1007/s00228-014-1690-1.
    1. Zhou Y., Wang X., Li H., Zhang J., Chen Z., Xie W., et al. Polymorphisms of ABCG2, ABCB1 and HNF4α are associated with Lamotrigine trough concentrations in epilepsy patients. Drug Metab Pharmacokinet. 2015;30(4):282–287.
    1. Shen C.-H., Zhang Y.-X., Lu R.-Y., Jin B., Wang S., Liu Z.-R., et al. Specific OCT1 and ABCG2 polymorphisms are associated with Lamotrigine concentrations in Chinese patients with epilepsy. Epilepsy Res. 2016;127:186–190. doi: 10.1016/j.eplepsyres.2016.09.004.
    1. Ortega-Vázquez A., Fricke-Galindo I., Dorado P., Jung-Cook H., Martínez-Juárez I.E., Monroy-Jaramillo N., et al. Influence of genetic variants and antiepileptic drug co-treatment on lamotrigine plasma concentration in Mexican Mestizo patients with epilepsy. Pharmacogenomics J. 2020;20(6):845–856. doi: 10.1038/s41397-020-0173-2.
    1. Kwan P., Poon W.S., Ng H.-K., Kang D.E., Wong V., Ng P.W., et al. Multidrug resistance in epilepsy and polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A: correlation among phenotype, genotype, and mRNA expression. Pharmacogenet Genomics. 2008;18(11):989–998. doi: 10.1097/FPC.0b013e3283117d67.
    1. Singkham N., Towanabut S., Lertkachatarn S., Punyawudho B. Influence of the UGT2B7 -161C>T polymorphism on the population pharmacokinetics of lamotrigine in Thai patients. Eur J Clin Pharmacol. 2013;69:1285–1291. doi: 10.1007/s00228-012-1449-5.
    1. Zhou Y., Wang X., Zhou L., Zhang J., Li H., Chen Z., et al. Interethnic differences in UGT1A4 genetic polymorphisms and its effect on lamotrigine trough concentrations. Chin J Clin Pharmacol. 2015;31:439–442. doi: 10.13699/j.cnki.1001-6821.2015.06.012.
    1. Mullan K.A., Anderson A., Illing P.T., Kwan P., Purcell A.W., Mifsud N.A. HLA-associated antiepileptic drug-induced cutaneous adverse reactions. HLA. 2019;93:417–435. doi: 10.1111/tan.13530.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe