PDF(Pubmed)
Abstract：
In the last 10 years, the care of patients with cystic fibrosis (CF) has been revolutionized with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs, with a major impact on symptoms and life expectancy, especially considering the newest and highly effective elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) therapy. Conversely, adverse effects are relatively frequent, with some being life-threatening, such as severe hepatitis. Clinical trials on children starting CFTR modulators have reported transaminase elevations >3× upper limit of the norm in 10%-20% of patients, whereas real-life studies have reported discontinuation rates three times higher than those observed in phase 3 trials. We report the case of a 10-year-old boy with CF who developed severe acute hepatitis 2 weeks after starting ELX/TEZ/IVA therapy. An extensive screening for potential causes led to the identification of heterozygous alpha1-antitrypsin (AAT) deficiency with genotype MZ. The Z allele of SERPINA1 gene, encoding AAT, is known as a risk factor for CF liver disease. We hypothesized that it may act as a risk factor for drug-induced liver injury from CFTR modulators, notably ELX/TEZ/IVA. Therefore, checking AAT before starting CFTR modulator therapy can be suggested, in particular for children with previous, even transient, liver disease.
摘要：
在过去的10年里,囊性纤维化（CF）患者的护理已随着囊性纤维化跨膜传导调节（CFTR）调节药物的引入而发生了革命性的变化，对症状和预期寿命有重大影响，特别是考虑到最新和高效的elexacaftor/tezacaftor/ivacaftor（ELX/TEZ/IVA）治疗。相反，不良反应相对频繁，有些人危及生命，比如严重的肝炎。开始使用CFTR调节剂的儿童的临床试验报告了转氨酶升高>10％-20％的患者的标准上限的3倍，而现实生活中的研究报告的停药率比3期试验中观察到的高3倍.我们报告了一名10岁的CF男孩在开始ELX/TEZ/IVA治疗2周后发展为严重的急性肝炎的情况。对潜在原因的广泛筛选导致鉴定出基因型MZ的杂合α1-抗胰蛋白酶（AAT）缺乏症。SERPINA1基因的Z等位基因,编码AAT，被称为CF肝病的危险因素。我们假设它可能是CFTR调节剂引起的药物性肝损伤的危险因素，特别是ELX/TEZ/IVA。因此,可以建议在开始CFTR调节剂治疗之前检查AAT，特别是对于以前的孩子，即使是短暂的，肝脏疾病。
