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

Abstract

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.

Xiao-Yao-San protects against anti-tuberculosis drug-induced liver injury by regulating Grsf1 in the mitochondrial oxidative stress pathway

“…Isoniazid, rifampicin, pyrazinamide, and ethambutol cause liver damage, which leads to elevated liver transaminases and affects hepatocyte function ( Cavaco et al, 2022 ). The incidence of liver disease increases each year, and the development of drugs to treat drug-induced liver injury has become a hot topic of research worldwide.…”

“…A crucial first step in patients with suspected DILI receiving hepatotoxic drugs is to stop taking the medicine in question ( Andrade et al, 2019 ). Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is the most common adverse effect of anti-TB treatment, and it makes it difficult for patients to adhere to the entire course of anti-tuberculous chemotherapy (AC) ( Cavaco et al, 2022 ). Drugs available for the treatment of liver injury, such as silymarin, have limited clinical use due to their poor pharmacological effects ( Flora et al, 1998 ).…”

“…Both of these agents are anti-tuberculosis (AT) drugs. Isoniazid and rifampicin induce DILI in clinical practice, as assessed by the Roussel Uclaf Causality Assessment Method (RUCAM), which was updated in 2016 ( Cavaco et al, 2022 ). The current study constructed a mouse model of AT drug-induced liver injury using 100 mg/kg rifampicin combined with 50 mg/kg isoniazid ( Chowdhury et al, 2006 ).…”

Antibiotics enhancing drug-induced liver injury assessed for causality using Roussel Uclaf Causality Assessment Method: Emerging role of gut microbiota dysbiosis

“…DILI is considered the consequence of a combination of variable host or non-host risk factors (55,56), which may act by influencing the gut microbiota composition and metabolites (Table 1). Numerous studies have indicated that the reduced abundance of GM species and genes are the drivers of individual susceptibility to DILI (37,52,(57)(58)(59)(60).…”

Review article: clinical assessment of suspected drug‐induced liver injury and its management

“…In addition to the HLA, genes involved with immune signalling such as PTPN22 and ERAP2 have also been reported to be associated with an increased risk of DILI 7,20 . Finally, genetic variants in genes involved with drug disposition have been reported, but the strength of association and risk of DILI are typically not as high as those reported with HLA alleles 21–23 …”