{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T11:44:32Z","timestamp":1774352672358,"version":"3.50.1"},"reference-count":49,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,13]],"date-time":"2022-05-13T00:00:00Z","timestamp":1652400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cGenomePT\u2014National Laboratory for Genome Sequencing and Analysis\u201d","award":["POCI-01-0145-FEDER-022184"],"award-info":[{"award-number":["POCI-01-0145-FEDER-022184"]}]},{"name":"\u201cGenomePT\u2014National Laboratory for Genome Sequencing and Analysis\u201d","award":["CENTRO-08-5864-FSE-000039 (PEP IN1194)"],"award-info":[{"award-number":["CENTRO-08-5864-FSE-000039 (PEP IN1194)"]}]},{"name":"the program CENTRO2020","award":["POCI-01-0145-FEDER-022184"],"award-info":[{"award-number":["POCI-01-0145-FEDER-022184"]}]},{"name":"the program CENTRO2020","award":["CENTRO-08-5864-FSE-000039 (PEP IN1194)"],"award-info":[{"award-number":["CENTRO-08-5864-FSE-000039 (PEP IN1194)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>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 \u22654 and all patients with DILI had a RUCAM score \u2265 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 \u2265 55 years (OR:3.67; 95% CI:1.82\u20137.41; p &lt; 0.001), concomitant medication with other hepatotoxic drugs (OR:2.54; 95% CI:1.23\u20135.26; p = 0.012), NAT2 slow acetylator status (OR:2.46; 95% CI:1.25\u20134.84; p = 0.009), and carriers of p.Val444Ala variant for ABCB11 gene (OR:2.06; 95%CI:1.02\u20134.17; 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.<\/jats:p>","DOI":"10.3390\/jpm12050790","type":"journal-article","created":{"date-parts":[[2022,5,13]],"date-time":"2022-05-13T08:37:02Z","timestamp":1652431022000},"page":"790","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Clinical and Genetic Risk Factors for Drug-Induced Liver Injury Associated with Anti-Tuberculosis Treatment\u2014A Study from Patients of Portuguese Health Centers"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3505-6325","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Cavaco","sequence":"first","affiliation":[{"name":"Oeste Hospital Center, 2560-295 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0092-9376","authenticated-orcid":false,"given":"Celeste","family":"Alcobia","sequence":"additional","affiliation":[{"name":"Department of Pneumology, Coimbra Hospital and Universitary Centre, 3004-561 Coimbra, Portugal"},{"name":"Pneumological Diagnostic Center of the Centre, 3000-075 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7836-8161","authenticated-orcid":false,"given":"B\u00e1rbara","family":"Oliveiros","sequence":"additional","affiliation":[{"name":"Laboratory of Biostatistics and Medical Informatics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"given":"Lu\u00eds Alcides","family":"Mesquita","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics\/UC Genomics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"given":"Aurora","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Department of Pneumology, Vila Nova de Gaia Hospitalar Centre, 4434-502 Vila Nova de Gaia, Portugal"}]},{"given":"Fernando","family":"Matos","sequence":"additional","affiliation":[{"name":"Pneumological Diagnostic Center of Aveiro, 3810-042 Aveiro, Portugal"}]},{"given":"Jos\u00e9 Miguel","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Pneumological Diagnostic Center of Santar\u00e9m, 2005-324 Santar\u00e9m, Portugal"}]},{"given":"Miguel","family":"Villar","sequence":"additional","affiliation":[{"name":"Pneumological Diagnostic Center of Venda Nova, 2700-220 Lisboa, Portugal"}]},{"given":"Raquel","family":"Duarte","sequence":"additional","affiliation":[{"name":"Pneumological Diagnostic Center of Vila Nova de Gaia, 4400-088 Vila Nova de Gaia, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4697-0542","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Mendes","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics\/UC Genomics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3907-4544","authenticated-orcid":false,"given":"Carolina","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics\/UC Genomics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"given":"Carlos Robalo","family":"Cordeiro","sequence":"additional","affiliation":[{"name":"Department of Pneumology, Coimbra Hospital and Universitary Centre, 3004-561 Coimbra, Portugal"}]},{"given":"Fernando","family":"Regateiro","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics\/UC Genomics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"given":"Henriqueta Coimbra","family":"Silva","sequence":"additional","affiliation":[{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Institute of Medical Genetics\/UC Genomics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,13]]},"reference":[{"key":"ref_1","unstructured":"WHO (2020). Global Tubeculosis Report 2020, WHO."},{"key":"ref_2","unstructured":"WHO (2017). Guidelines for Treatment of Drug-Susceptible Tuberculosis and Patient Care, WHO."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1164\/rccm.200510-1666ST","article-title":"An official ATS statement: Hepatotoxicity of antituberculosis therapy","volume":"174","author":"Saukkonen","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1111\/bcp.12885","article-title":"Mechanism of isoniazid-induced hepatotoxicity: Then and now","volume":"81","author":"Metushi","year":"2016","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1378\/chest.99.2.465","article-title":"Toxic Hepatitis with Isoniazid and Rifampin","volume":"99","author":"Steele","year":"1991","journal-title":"Chest"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1002\/hep.1840210407","article-title":"Deleterious influence of pyrazinamide on the outcome of patients with fulminant or subfulminant liver failure during antituberculous treatment including isoniazid","volume":"21","author":"Durand","year":"1995","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1007\/s11095-016-2091-1","article-title":"Are Polymorphisms in Genes Relevant to Drug Disposition Predictors of Susceptibility to Drug-Induced Liver Injury?","volume":"34","author":"Daly","year":"2017","journal-title":"Pharm. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/j.cgh.2017.12.036","article-title":"Heavy Consumption of Alcohol is Not Associated With Worse Outcomes in Patients With Idiosyncratic Drug-induced Liver Injury Compared to Non-Drinkers","volume":"16","author":"Dakhoul","year":"2018","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_9","first-page":"339","article-title":"Functional effects of single nucleotide polymorphisms in the coding region of human N-acetyltransferase 1","volume":"8","author":"Zhu","year":"2008","journal-title":"Pharm. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1007\/s00204-013-1157-7","article-title":"Refinement of the prediction of N-acetyltransferase 2 (NAT2) phenotypes with respect to enzyme activity and urinary bladder cancer risk","volume":"87","author":"Selinski","year":"2013","journal-title":"Arch. Toxicol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1097\/FPC.0000000000000339","article-title":"NAT2 ultra-slow acetylator and risk of anti-tuberculosis drug-induced liver injury: A genotype-based meta-analysis","volume":"28","author":"Suvichapanich","year":"2018","journal-title":"Pharm. Genom."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1111\/bcp.13722","article-title":"The association between the NAT2 genetic polymorphisms and risk of DILI during anti-TB treatment: A systematic review and meta-analysis","volume":"84","author":"Zhang","year":"2018","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"293","DOI":"10.5588\/ijtld.18.0324","article-title":"NAT2 variants and toxicity related to anti-tuberculosis agents: A systematic review and meta-analysis","volume":"23","author":"Richardson","year":"2019","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"ref_14","first-page":"1733","article-title":"Should We Use N-Acetyltransferase Type 2 Genotyping To Personalize Isoniazid Doses?","volume":"49","author":"Jetter","year":"2005","journal-title":"Society"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1007\/s00228-007-0305-5","article-title":"The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid","volume":"63","author":"Donald","year":"2007","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1007\/s00228-012-1429-9","article-title":"NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: A randomized controlled trial for pharmacogenetics-based therapy","volume":"69","author":"Azuma","year":"2013","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.apsb.2016.07.014","article-title":"Isoniazid metabolism and hepatotoxicity","volume":"6","author":"Wang","year":"2016","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6518","DOI":"10.21037\/apm-21-1224","article-title":"The association between cytochrome P450 polymorphisms and anti-tuberculosis drug-induced liver injury: A systematic review and meta-analysis","volume":"10","author":"Liu","year":"2021","journal-title":"Ann. Palliat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1186\/s13643-018-0861-z","article-title":"CYP genetic variants and toxicity related to anti-tubercular agents: A systematic review and meta-analysis","volume":"7","author":"Richardson","year":"2018","journal-title":"Syst. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1111\/jcpt.13006","article-title":"Are genetic variations in glutathione S-transferases involved in anti-tuberculosis drug-induced liver injury? A meta-analysis","volume":"44","author":"Zhang","year":"2019","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e027940","DOI":"10.1136\/bmjopen-2018-027940","article-title":"Association of genetic polymorphisms of CYP2E1, NAT2, GST and SLCO1B1 with the risk of anti-tuberculosis drug-induced liver injury: A systematic review and meta-analysis","volume":"9","author":"Yang","year":"2019","journal-title":"BMJ Open"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"27750","DOI":"10.1038\/srep27750","article-title":"Role of polymorphic bile salt export pump (BSEP, ABCB11) transporters in anti-tuberculosis drug-induced liver injury in a Chinese cohort","volume":"6","author":"Chen","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"382","DOI":"10.3109\/15376516.2015.1033074","article-title":"The inhibition of hepatic bile acids transporters Ntcp and Bsep is involved in the pathogenesis of isoniazid\/rifampicin-induced hepatotoxicity","volume":"25","author":"Guo","year":"2015","journal-title":"Toxicol. Mech. Methods"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s12964-019-0356-0","article-title":"Response to IL-6 trans- A nd IL-6 classic signalling is determined by the ratio of the IL-6 receptor \u03b1 to gp130 expression: Fusing experimental insights and dynamic modelling","volume":"17","author":"Reeh","year":"2019","journal-title":"Cell Commun. Signal."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1002\/hep.21087","article-title":"Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair","volume":"43","author":"Jin","year":"2006","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"192","DOI":"10.3892\/ijmm.2016.2595","article-title":"Interleukin-6 and rs1800796 locus single nucleotide polymorphisms in response to hypoxia\/reoxygenation in hepatocytes","volume":"38","author":"Wang","year":"2016","journal-title":"Int. J. Mol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"154985","DOI":"10.1016\/j.cyto.2020.154985","article-title":"Promoter polymorphisms in IL-6 gene influence pro-inflammatory cytokines for the risk of osteoarthritis","volume":"127","author":"Singh","year":"2020","journal-title":"Cytokine"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e18408","DOI":"10.1097\/MD.0000000000018408","article-title":"Interleukin-6 gene polymorphisms and susceptibility to liver diseases: A meta-analysis","volume":"98","author":"Wang","year":"2019","journal-title":"Medicine"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.tube.2018.05.011","article-title":"rs1800796 of the IL6 gene is associated with increased risk for anti-tuberculosis drug-induced hepatotoxicity in Chinese Han children","volume":"111","author":"Li","year":"2018","journal-title":"Tuberculosis"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Danan, G., and Teschke, R. (2016). RUCAM in drug and herb induced liver injury: The update. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17010014"},{"key":"ref_31","unstructured":"WHO (2003). Treatment of Tuberculosis: Guidelines for National Programmes, WHO. [3rd ed.]."},{"key":"ref_32","unstructured":"World Health Organization (2010). Treatment of Tuberculosis: Guidelines, WHO. [4th ed.]."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/0168-8278(90)90124-A","article-title":"Criteria of drug-induced liver disorders: Report of an International Consensus Meeting","volume":"11","year":"1990","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1038\/clpt.2011.58","article-title":"Case Definition and Phenotype Standardization in Drug-Induced Liver Injury","volume":"89","author":"Aithal","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1161\/CIRCULATIONAHA.109.904235","article-title":"Glantz Health Effects of Light and Intermittent Smoking: A Review","volume":"121","author":"Schane","year":"2010","journal-title":"Circulation"},{"key":"ref_36","unstructured":"U.S. Department of Health and Human Services and U.S (2022, April 25). Department of Agriculture. 2015\u20132020 Dietary Guidelines for Americans, 8th ed., Available online: https:\/\/health.gov\/our-work\/food-nutrition\/previous-dietary-guidelines\/2015."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1016\/j.jhep.2019.02.014","article-title":"EASL Clinical Practice Guidelines: Drug-induced liver injury","volume":"70","author":"Andrade","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1158\/1055-9965.1543.13.9","article-title":"Impact of misclassification in genotype-exposure interaction studies: Example of N-acetyltransferase 2 (NAT2), smoking, and bladder cancer","volume":"13","author":"Deitz","year":"2004","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"31","DOI":"10.2217\/pgs.11.122","article-title":"Accuracy of various human NAT2 SNP genotyping panels to infer rapid, intermediate and slow acetylator phenotypes","volume":"13","author":"Hein","year":"2012","journal-title":"Pharmacogenomics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1007\/BF03346405","article-title":"Combined GSTM1 and GSTT1 null genotypes are associated with a lower risk of papillary thyroid cancer","volume":"31","author":"Lemos","year":"2008","journal-title":"J. Endocrinol. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1097\/00008571-199812000-00013","article-title":"N-acetyltransferase genotypes in the Portuguese population","volume":"8","author":"Lemos","year":"1998","journal-title":"Pharmacogenetics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1378\/chest.128.1.116","article-title":"Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection: A 7-year evaluation from a public health tuberculosis clinic","volume":"128","author":"Fountain","year":"2005","journal-title":"Chest"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1111\/j.1872-034X.2009.00492.x","article-title":"Clinical characteristics of drug-induced liver injury in the elderly","volume":"39","author":"Onji","year":"2009","journal-title":"Hepatol. Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ortega-Alonso, A., Stephens, C., Lucena, M.I., and Andrade, R.J. (2016). Case characterization, clinical features and risk factors in drug-induced liver injury. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17050714"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"95","DOI":"10.2174\/1872312813666190716155930","article-title":"Prominence of Oxidative Stress in the Management of Anti-tuberculosis Drugs Related Hepatotoxicity","volume":"13","author":"John","year":"2019","journal-title":"Drug Metab. Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1002\/cpt.2100","article-title":"Genetic Risk Factors in Drug-Induced Liver Injury Due to Isoniazid-Containing Antituberculosis Drug Regimens","volume":"109","author":"Nicoletti","year":"2021","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1007\/s00228-014-1703-0","article-title":"N-acetyltransferase 2 (NAT2) genotype as a risk factor for development of drug-induced liver injury relating to antituberculosis drug treatment in a mixed-ethnicity patient group","volume":"70","author":"Ng","year":"2014","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"735","DOI":"10.2217\/pgs.12.45","article-title":"Genetic basis of susceptibility to drug-induced liver injury: What have we learned and where do we go from here?","volume":"13","author":"Urban","year":"2012","journal-title":"Pharmacogenomics"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.jhep.2006.09.017","article-title":"A novel mechanism for drug-induced liver failure: Inhibition of histone acetylation by hydralazine derivatives","volume":"46","author":"Murata","year":"2007","journal-title":"J. Hepatol."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/12\/5\/790\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:10:28Z","timestamp":1760137828000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/12\/5\/790"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,13]]},"references-count":49,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["jpm12050790"],"URL":"https:\/\/doi.org\/10.3390\/jpm12050790","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,13]]}}}