García-Fariña Belén, Rink Lydia, Santarini Virginia, Westkemper Marco, Dohna-Schwake Christian, Möhlendick Birte
Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Department of Pediatrics I, Neonatology, Pediatric Intensive Care, Pediatric Neurology, University Hospital Essen, Essen, Germany.
Front Pharmacol. 2024 Oct 23;15:1477755. doi: 10.3389/fphar.2024.1477755. eCollection 2024.
A number of case reports have documented the occurrence of acute hepatic and renal toxicity during treatment with deferasirox (DFX). The precise mechanisms underlying these adverse events remain unclear, with the time to toxicity varying considerably between patients-some experiencing it within weeks of treatment initiation, while others after several years. Recent studies have underscored the association of pharmacogenetic variants in genes responsible for the metabolism and clearance of DFX (, , and ) in the development of toxicity. We present the case of an 8-year-old patient with beta thalassemia major who developed acute hepatic failure years after the initiation of DFX therapy. After ruling out the most likely causes, we performed a pharmacogenetic analysis, which suggested a possible link between the patient's genotype and the development of toxicity.
Sanger sequencing was performed for the most extensively studied single nucleotide polymorphisms (SNPs) studied associated with changes in transporter/enzyme function: rs717620 (c.-24C>T), rs2273697 (c.1249G>A), rs8187710 (c.4544G>A), rs369192412 (g.99781071delG); rs2231142 (c.421C>A); rs4148323 (c.211G>A), rs3064744 (g.233760235TA[8]), rs3064744 (g.233760235TA[6]) and rs3064744 (g.233760235TA[9]).
The patient is heterozygous for two variants, namely rs717620 (c.-24C>T) and rs2273697 (c.1249G>A). These variants have the potential to cause a reduction in transporter function, which could in turn result in decreased drug clearance and increased toxicity.
The precise mechanism by which toxicity developed in this case remains unclear and is likely multifactorial. However, it is probable that the presence of SNPs in the gene played a substantial role. Our findings align with those of previously published reports of remarkably similar cases, where patients also exhibited genetic variants in the gene .
多项病例报告记录了地拉罗司（DFX）治疗期间发生的急性肝毒性和肾毒性。这些不良事件的确切机制尚不清楚，患者出现毒性的时间差异很大——一些患者在开始治疗几周内就出现，而另一些患者则在几年后出现。最近的研究强调了负责DFX代谢和清除的基因（ 、 和 ）中的药物遗传学变异与毒性发生之间的关联。我们报告了1例8岁重型β地中海贫血患者，在开始DFX治疗数年之后发生急性肝衰竭。在排除了最可能的病因后，我们进行了药物遗传学分析，结果提示患者的基因型与毒性发生之间可能存在关联。
对研究最广泛的与转运蛋白/酶功能变化相关的单核苷酸多态性（SNP）进行桑格测序：rs717620（c.-24C>T）、rs2273697（c.1249G>A）、rs8187710（c.4544G>A）、rs369192412（g.99781071delG）；rs2231142（c.421C>A）；rs4148323（c.211G>A）、rs3064744（g.233760235TA[8]）、rs3064744（g.233760235TA[6]）和rs3064744（g.233760235TA[9]）。
该患者两个变异rs717620（c.-24C>T）和rs2273697（c.1249G>A）为杂合子。这些变异有可能导致转运蛋白功能降低，进而可能导致药物清除减少和毒性增加。
该病例中发生毒性的确切机制尚不清楚，可能是多因素的。然而，基因中存在SNP很可能起了重要作用。我们的发现与之前发表的非常相似病例的报告一致，这些病例中的患者在该基因中也表现出基因变异。
