The impact of heavy metal exposure on drug-induced liver injury in patients with drug-resistant tuberculosis

Abstract The aim of the study is to clarify the association between heavy metal exposure and drug-induced liver injury (DILI) in patients with drug-resistant tuberculosis (DR-TB), and to provide new epidemiological evidence for the prevention and treatment of DILI. In this study we utilized a 1:2 matched nested case–control study design based on a follow-up cohort of DR-TB patients at Hunan Provincial Chest Hospital from September 2021 to November 2024. Inductively coupled plasma mass spectrometry was used to detect plasma levels of Chromium (Cr), Manganese (Mn), Copper (Cu), Zinc (Zn), Arsenic (As), Selenium (Se), Molybdenum (Mo), Cadmium (Cd), Antimony (Sb), Thallium (Tl), and Lead (Pb)—a total of 11 heavy metals. Conditional logistic regression and restricted cubic spline (RCS) models were used to analyze the association between single heavy metal exposures and DILI. The weighted quantile sum (WQS), quantile g-computation (Qgcomp) and Bayesian kernel machine regression (BKMR) models to analyze the association between combined heavy metal exposure and the occurrence of DILI in DR-TB patients. A total of 974 DR-TB subjects have been enrolled in this study, of whom 930 have completed the follow-up, resulting in a loss-to-follow-up rate of 4.5%. A total of 88 DR-TB patients developed DILI, with an incidence rate of 9.5%. Using a 1:2 matching strategy, 158 DR-TB patients without DILI from the original cohort have been selected as the control group, resulting in a total of 237 cases and controls. Plasma concentrations of Cr, Mn, Cu, Zn, As, Cd, and Pb were significantly higher in the DILI group than in the control group ( p < 0.05). High concentrations of Cr (OR = 5.88, 95% CI 2.10–16.48), Mn (OR = 3.56, 95% CI 1.25–10.12), As (OR = 2.74, 95% CI 1.05–7.15), and Cd (OR = 5.31, 95% CI 1.81–15.59), and Pb (OR = 5.54, 95% CI 2.06–14.87) were significantly positively associated with the risk of DILI ( p < 0.05); RCS analysis showed that Cr and Mn exhibited a positive linear dose–response relationship with DILI, while Cd and Pb showed a nonlinear association. Analysis using the WQS regression model showed that combined exposure to the heavy metals Cr, Mn, As, Cd, and Pb was positively associated with the risk of DILI (OR = 2.01, 95% CI 1.12–3.59), with Mn having the highest weight. The Qgcomp model results showed a positive association between combined exposure to the heavy metals Cr, Mn, As, Cd, and Pb and the risk of DILI (OR = 1.78, 95% CI 1.44–2.20), with Cd having the highest weight. The BKMR model results indicated that Cd and Mn had higher posterior inclusion probabilities (PIPs); As the combined concentration of heavy metals increased, the risk of DILI also increased; when the concentrations of other heavy metals were fixed at the 25th, 50th, and 75th percentiles, Cd and Mn were positively associated with the risk of DILI; this study did not find any interactions among heavy metals in their association with DILI. Our findings revealed that there is a positive association between internal exposure to high concentrations of any single element—Cr, Mn, As, Cd, or Pb—and the risk of developing DILI. Combined exposure to the heavy metals Cr, Mn, As, Cd, and Pb increases the risk of DILI in DR-TB patients, with Cd and Mn contributing the most.