Clinical and Genetic Risk Factors for Drug-Induced Liver Injury Associated with Anti-Tuberculosis Treatment—A Study from Patients of Portuguese Health Centers

Journal of Personalized Medicine

Henriqueta Coimbra Silva¹  Carlos Robalo Cordeiro²  Celeste Alcobia²  Aurora Carvalho³  Luís Alcides Mesquita⁴  Fernando Regateiro⁴  Carolina Ribeiro⁴  João Mendes⁴  Bárbara Oliveiros⁵  Maria João Cavaco⁶  Fernando Matos⁷  José Miguel Carvalho⁸  Miguel Villar⁹  Raquel Duarte^1,10 

[1] Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal;Department of Pneumology, Coimbra Hospital and Universitary Centre, 3004-561 Coimbra, Portugal;Department of Pneumology, Vila Nova de Gaia Hospitalar Centre, 4434-502 Vila Nova de Gaia, Portugal;Institute of Medical Genetics/UC Genomics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal;Laboratory of Biostatistics and Medical Informatics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal;Oeste Hospital Center, 2560-295 Lisboa, Portugal;Pneumological Diagnostic Center of Aveiro, 3810-042 Aveiro, Portugal;Pneumological Diagnostic Center of Santarém, 2005-324 Santarém, Portugal;Pneumological Diagnostic Center of Venda Nova, 2700-220 Lisboa, Portugal;Pneumological Diagnostic Center of Vila Nova de Gaia, 4400-088 Vila Nova de Gaia, Portugal;

关键词: tuberculosis;    DILI;    NAT2;    ABCB11;    isoniazid;    RUCAM;   

DOI  :  10.3390/jpm12050790

来源: DOAJ

【 摘 要 】

Drug-induced liver injury (DILI) is an unpredictable and feared side effect of antituberculosis treatment (AT). The present study aimed to identify clinical and genetic variables associated with susceptibility to AT-associated hepatotoxicity in patients with pulmonary tuberculosis treated with a standard protocol. Of 233 patients enrolled, 90% prospectively, 103 developed liver injury: 37 with mild and 66 with severe phenotype (DILI). All patients with mild hepatitis had a RUCAM score ≥4 and all patients with DILI had a RUCAM score ≥ 6. Eight clinical variables and variants in six candidate genes were assessed. A logistic multivariate regression analysis identified four risk factors for AT-DILI: age ≥ 55 years (OR:3.67; 95% CI:1.82–7.41; p < 0.001), concomitant medication with other hepatotoxic drugs (OR:2.54; 95% CI:1.23–5.26; p = 0.012), NAT2 slow acetylator status (OR:2.46; 95% CI:1.25–4.84; p = 0.009), and carriers of p.Val444Ala variant for ABCB11 gene (OR:2.06; 95%CI:1.02–4.17; p = 0.044). The statistical model explains 24.9% of the susceptibility to AT-DILI, with an 8.9 times difference between patients in the highest and in the lowest quartiles of risk scores. This study sustains the complex architecture of AT-DILI. Prospective studies should evaluate the benefit of NAT2 and ABCB11 genotyping in AT personalization, particularly in patients over 55 years.

【 授权许可】

Unknown