Table 1_Inflammatory and metabolic markers mediate the association between urinary metals and non-alcoholic fatty liver disease in U.S. adults: a cross-sectional study.docx

BackgroundNon-alcoholic fatty liver disease (NAFLD) is a global public health problem. Inflammation, oxidative stress, and insulin resistance are involved in the development and progression of NAFLD. Although the etiology of NAFLD remains unclear, environmental factors are increasingly recognized as non-negligible risk factors. This study was to evaluate the urine metal associated with the risk of NAFLD and inflammation and metabolic markers mediating role.
MethodsAccording to the national health and nutrition examination survey (NHANES), to detect the metal concentration in the urine of 3,948 U.S. adults, including barium (Ba), cadmium (Cd), cobalt (Co), and cesium (Cs), molybdenum (Mo), lead (Pb), antimony (Sb), thallium (Tl), and uranium (Tu). Multivariate logistic regression and weighted (WQS) and quantile regression were used to investigate the single and mixed metals associated with the risk of NAFLD. In addition, inflammatory and metabolic markers may mediate the relationship between metals and NAFLD. Inflammatory markers included neutrophil albumin ratio (NPAR) and neutrophil-to-lymphocyte ratio (NLR). The fatty liver index (FLI) was used as a liver metabolic marker. Mediation analysis aimed to investigate the mediating effects of inflammation and metabolism on the association between metals and NAFLD risk.
ResultsIn the single-exposure model, Ba, Cd, Cs, Mo, Tl, and Tu were identified to be positively associated with NAFLD risk, with odds ratios (OR) ranging from 1.29 to 1.48 (all P < 0.05). Mixed exposure analysis showed consistent associations (OR: 1.48, 95% CI: 1.06 to 2.06). In addition, Ba, Cd, Mo, Pb, and Tu and negatively correlated with inflammatory markers, but was positively correlated with hepatic metabolism markers. At the same time we have found that inflammatory markers and negative correlation with NAFLD, and hepatic metabolism markers are positively correlated with NAFLD risk relationship (P < 0.05). Further mediation analysis showed that the associations of single metals (mainly Mo, Ba, and Tu) and mixed metals with NAFLD risk were mediated in parallel by the above-mentioned inflammatory and metabolic markers, with the mediating proportions ranging from 16.89% to 69.39% (all P < 0.05). Show that metal concentration can reduce serum inflammatory markers in the urine and raise levels of metabolites markers and then induce NAFLD.
ConclusionThese findings suggest that exposure to the metal can increase the risk of NAFLD, this may be partly mediated by inflammation and metabolic markers. Clinically, this highlights the importance of monitoring environmental metal exposure and addressing inflammation and metabolic dysfunction as potential intervention targets to reduce NAFLD risk.

背景 非酒精性脂肪性肝病（Non-alcoholic fatty liver disease, NAFLD）是全球性公共卫生问题。炎症、氧化应激与胰岛素抵抗参与了NAFLD的发生与进展。尽管NAFLD的病因仍未明确，但环境因素正日益被视为不可忽视的危险因素。本研究旨在评估尿液金属与NAFLD发病风险的关联，以及炎症与代谢标志物在其中的介导作用。
方法 本研究基于美国国家健康与营养检查调查（National Health and Nutrition Examination Survey, NHANES）数据库，对3948名美国成年人的尿液金属浓度进行检测，所涵盖的金属包括钡（Ba）、镉（Cd）、钴（Co）、铯（Cs）、钼（Mo）、铅（Pb）、锑（Sb）、铊（Tl）以及铀（Tu）。本研究采用多因素logistic回归、加权分位数和（Weighted Quantile Sum, WQS）回归以及分位数回归，分别探究单一金属与混合金属暴露与NAFLD发病风险的关联。此外，炎症与代谢标志物可能介导金属暴露与NAFLD之间的关联：炎症标志物包括中性粒细胞白蛋白比值（Neutrophil Albumin Ratio, NPAR）与中性粒细胞与淋巴细胞比值（Neutrophil-to-Lymphocyte Ratio, NLR）；肝脏代谢标志物则采用脂肪肝指数（Fatty Liver Index, FLI）。本研究通过中介分析，探究炎症与代谢标志物在金属暴露与NAFLD发病风险关联中的中介效应。
结果 单一暴露模型分析显示，钡（Ba）、镉（Cd）、铯（Cs）、钼（Mo）、铊（Tl）以及铀（Tu）的尿液浓度与NAFLD发病风险呈显著正相关，其比值比（Odds Ratio, OR）范围为1.29~1.48（所有P<0.05）。混合暴露分析也得到了一致的关联结果（OR=1.48，95%置信区间：1.06~2.06）。此外，尿液中Ba、Cd、Mo、Pb及Tu的浓度与炎症标志物呈负相关，而与肝脏代谢标志物呈正相关。同时本研究发现，炎症标志物与NAFLD风险呈负相关，肝脏代谢标志物与NAFLD风险呈正相关（P<0.05）。进一步的中介分析表明，单一金属（主要为Mo、Ba及Tu）与混合金属暴露对NAFLD发病风险的关联，可通过上述炎症与代谢标志物并行介导，中介占比范围为16.89%~69.39%（所有P<0.05）。上述结果提示，尿液金属浓度升高可降低血清炎症标志物水平、升高代谢标志物水平，进而诱发NAFLD。
结论 本研究结果表明，金属暴露可升高NAFLD的发病风险，这一关联部分可通过炎症与代谢标志物介导。从临床角度而言，本研究凸显了监测环境金属暴露，并将炎症与代谢功能紊乱作为潜在干预靶点以降低NAFLD发病风险的重要性。