非酒精性脂肪性肝病患者的尿铅水平及其临床意义

Levels and clinical significance of urinary lead in patients with nonalcoholic fatty liver disease

摘要

目的 探讨尿铅与非酒精性脂肪性肝病（NAFLD）的关系。 方法 选取2017—2020年美国健康和营养检查调查数据（NHANES）中年龄≥18岁的注册参与者，并排除缺乏肝脏瞬时弹性成像数据、尿铅指标及患有乙型肝炎、丙型肝炎、饮酒量显著的人群。将纳入人群（n=2 492）分为NAFLD组852例，Non-NAFLD组1 640例。采用高效液相色谱-电喷雾电离-串联质谱和在线固相萃取联合同位素稀释等方法定量检测尿铅水平。计量资料两组间比较采用成组t检验或Wilcoxon秩和检验；计数资料两组间比较采用χ²检验或Fisher确切概率法。通过多因素Logistic回归分析、限制性立方样条函数、亚组分析、交互作用，探究尿铅与NAFLD的关联。 结果 NAFLD组尿铅水平高于Non-NAFLD组，差异有统计学意义（Z=-2.023，P=0.043）。调整年龄、性别、种族、婚姻、教育、家庭收入与贫困比比值、BMI、吸烟、饮酒、糖尿病、高血压、高脂血症协变量后，尿铅水平Q3组NAFLD的患病风险显著增加（比值比=1.360，95%CI：1.019～1.817，P=0.037）。尿铅与NAFLD的患病风险存在正向剂量-反应关系（P=0.047）且为非线性关系（P_non-linear=0.037）。尿铅与种族之间存在显著的交互作用，墨西哥裔美国人尿铅每上升1个四分位数，NAFLD的患病风险增加32.40%（比值比=1.324，95%CI：1.017～1.632，P<0.05）。 结论 尿铅水平与NAFLD患病风险显著相关。

Abstract

Objective To investigate the association between urinary lead and nonalcoholic fatty liver disease （NAFLD）. Methods The participants， aged ≥18 years， were selected from the 2017‍ ‍—‍ ‍2020 National Health and Nutrition Examination Survey （NHANES）， with the exclusion of the participants with a lack of liver transient elastography data and urinary lead markers and those with hepatitis B， hepatitis C， and significant alcohol consumption. A total of 2 492 participants were enrolled and divided into NAFLD group with 852 participants and non-NAFLD group with 1 640 participants. High-performance liquid chromatography-electrospray ionization-tandem mass spectrometry and online solid-phase extraction combined with isotope dilution were used to measure urinary lead level. The independent-samples t test or the Wilcoxon rank sum test was used for comparison of continuous data between two groups， and the chi-square test or the Fisher’s exact test was used for comparison of categorical data between two groups. Multivariate Logistic regression analysis， restricted cubic spline， subgroup analysis， and interaction analysis were used to investigate the association between urinary lead and NAFLD. Results The NAFLD group had a significantly higher urinary lead level than the non-NAFLD group （Z=-2.023， P=0.043）. After adjustment of the covariates of age， sex， race， marital status， education， family income-to-poverty ratio， body mass index， smoking， drinking， diabetes mellitus， hypertension， and hyperlipidemia， there was a significant increase in the risk of NAFLD in the Q3 urinary lead group （odds ratio ［OR］=1.360， 95% confidence interval ［CI］： 1.019‍ ‍—‍ ‍1.817， P=0.037）. There was a positive dose-response relationship between urinary lead and the risk of NAFLD （P=0.047）， which was a non-linear relationship （P_non-linear=0.037）. There was a significant interaction between urinary lead and race， and for every quartile increase in urinary lead， the risk of NAFLD in Mexican-Americans was increased by 32.40% （OR=1.324， 95%CI： 1.017‍ ‍—‍ ‍1.632， P<0.05）. Conclusion Urinary lead level is significantly associated with the risk of NAFLD.

Graphical abstract

关键词

非酒精性脂肪性肝病 / 铅 / 尿 / Logistic模型

Key words

Non-alcoholic Fatty Liver Disease / Lead / Urine / Logistic Models

非酒精性脂肪性肝病（NAFLD）是一种与胰岛素抵抗和遗传易感密切相关的代谢应激性肝损伤，其特征性病理表现是非酒精性因素引起的肝细胞内甘油三酯过量沉积^［1］。NAFLD全球患病率高达25.24%（95%CI： 22.10%～28.65%）^［2］。随着生活水平的提高，NAFLD患病率逐年升高且发病趋向年轻化，已成为我国第一大慢性肝病和健康体检肝脏生物学指标异常的首要原因^［3］。NAFLD作为一种进行性疾病，后期可进展为肝硬化、肝细胞癌，是肝衰竭和肝移植的重要原因。

铅是一种可干扰内分泌且具有累积效应和不可生物降解性质的强效环境毒素^［4］。铅暴露包括食物积累、直接吸入和皮肤接触等多种方式^［5］。无论暴露途径如何，吸收的铅都会在肝脏中结合，肝脏是铅毒性作用的靶器官^［6］。NAFLD的发病机制包括炎症、氧化应激、内质网应激、脂代谢异常等^［7］。铅毒性主要是由于铅离子（Pb²⁺）可取代其他二价阳离子（Ca²⁺、Mg²⁺）和单价阳离子（Na⁺），从而扰乱氧化-抗氧化平衡和炎症反应^［8］。铅还可影响脂质代谢导致肝细胞变性，进而促进NAFLD的发展^［9］。尿液和血清中的铅浓度可作为铅暴露的生物标志物^［10］。既往研究^［11］表明血清铅与NAFLD密切相关。然而尿铅与NAFLD的关系尚未可知。目前尚无针对NAFLD的特效药，改变不良生活方式（饮食及运动）、减少体质量和腰围是预防及治疗NAFLD的关键措施^［12］。

基于受控衰减参数（CAP）的瞬时弹性成像在量化NAFLD患者脂肪变性方面具有良好的准确性，该方法快速、可靠且可重复^［13］。多项关于NAFLD的研究选用CAP作为NAFLD脂肪变性的诊断标准^［14-15］。肝瞬时弹性成像已被广泛用于普通人群中检测NAFLD^［16］。故本研究选取CAP作为NAFLD脂肪变性的诊断依据来探讨尿铅与NAFLD疾病进展的风险相关性，旨在从不同角度探索NAFLD发展的生物标志物，以利于在个人和人群水平上制订预防策略。

1 资料与方法

1.1 研究对象

国家健康和营养检查调查（NHANES）是一项评估美国人口健康和营养状况的横断面调查^［17］。在本研究中，选取NHANES 2017—2020年数据，纳入NHANES数据库中2017—2020年≥18岁的注册参与者（n=9 693）。排除：（1）缺乏肝瞬时弹性成像数据的人群（n=1 376）；（2）患有乙型肝炎、丙型肝炎的人群（n=128）；（3）饮酒量显著的人群（男性>30 g/天、女性>20 g/天）（n=456）；（4）缺乏尿铅指标的人群（n=5 241）。最终共有2 492例受试者纳入分析。

1.2 NAFLD的评估

依据2023年美国肝病学会（AASLD）发布的NAFLD临床评估和管理实践指南^［18］，将CAP≥288 db/m同时排除患有乙型肝炎、丙型肝炎及饮酒量显著的人群（男性>30 g/天、女性>20 g/天）确诊为NAFLD。乙型肝炎定义为HBsAg阳性；丙型肝炎定义为HCV RNA阳性或丙型肝炎抗体阳性；饮酒量取饮食调查问卷第1天和第2天酒精摄入量的平均值^［19］。

1.3 尿铅水平

采用高效液相色谱-电喷雾电离-串联质谱和在线固相萃取联合同位素稀释等方法定量检测尿铅水平^［20］。本研究尿铅的检出限为0.03 μg/L，低于检测限的值被替换为检测限除以\sqrt[]{\mathrm{2}}^［21］。考虑到尿液样本中尿铅稀释度的变化，将尿铅除以肌酐以调整尿肌酐中铅的暴露量来进行标准化^［22］。

1.4 统计学方法

采用R 4.2.2软件进行数据分析。连续变量若符合正态分布以\overline{x}±s表示，两组间比较采用成组t检验；偏态分布以M（P₂₅～P₇₅）表示，两组间比较采用Wilcoxon秩和检验。分类资料采用χ²检验或Fisher确切概率法进行组间比较。采用多元Logistic回归模型探讨尿铅水平与NAFLD的关系，将尿铅分为连续变量和分类变量分别分析，并计算比值比（OR）和95%可信区间（95%CI）。使用限制性立方样条函数以检验尿铅与NAFLD是否存在非线性关联，并可视化二者之间的剂量-反应关系。此外，本研究根据年龄、性别、种族、教育、婚姻、家庭收入贫困比率（FMPIR）、BMI、吸烟、饮酒、糖尿病（DM）、高血压（HTN）、高脂血症（HL）将数据分为不同的亚组，构建包含上述变量的回归模型，然后加入乘法交互项以考量尿铅与各个亚组之间的交互作用，最后通过似然比检验来检测这些交互作用是否显著，从而明确尿铅在不同人群中对NAFLD影响的差异^［23］。P<0.05为差异有统计学意义。

2 结果

2.1 一般人口学特征

纳入的2 492例研究对象中NAFLD 852例，Non-NAFLD 1 640例，NAFLD组尿铅水平高于Non-NAFLD组，差异有统计学意义（Z=-2.023，P=0.043）。与Non-NAFLD组相比，NAFLD组的年龄、BMI较高，且主要集中在≥60岁年龄段，BMI≥30 kg/m²的肥胖人群（P值均<0.001）。此外，NAFLD组女性占比、非西班牙裔白人占比、已婚/与伴侣同居占比以及患有DM或HTN或HL的比例均高于Non-NAFLD人群，差异均有统计学意义（P值均<0.001）（表1）。

2.2 尿铅与NAFLD的Logistic回归分析

构建多元Logistic回归模型探究尿铅与NAFLD的关系。首先将尿铅作为连续性指标分析，在模型1、模型3中尿铅水平与NAFLD的患病风险无关；在模型2中尿铅每上升1个四分位数，NAFLD的患病风险增加17.70%（OR=1.117，P=0.026）。

其次，将尿铅水平按四分位数分类，Q1组（0～0.160 μg/L）592例、Q2组（0.161～0.291 μg/L）579例、Q3组（0.292～0.521 μg/L）644例、Q4组（≥0.522 μg/L）677例。在模型1中，与Q1组相比，Q3、Q4组NAFLD的患病风险增加34.70%（OR=1.347，P=0.014）、28.80%（OR=1.288，P=0.036）；在模型2中，与Q1组相比，Q3组NAFLD的患病风险增加31.00％（OR=1.310，P=0.031）；在模型3中，与Q1组相比，Q3组NAFLD的患病风险增加36.00％（OR=1.360，P=0.037）（表2）。

2.3 尿铅与NAFLD的剂量-反应关系

调整年龄、性别、种族、教育、婚姻、FMPIR、BMI、吸烟、饮酒、DM、HTN、HL后进一步使用限制性立方样条函数分析发现，尿铅与NAFLD的患病风险存在正向剂量-反应关系（P=0.047）且为非线性关系（P_non-linear=0.037）。以0.315 μg/L为参考值，当尿铅水平<0.315 μg/L时，NAFLD的患病风险较低；当尿铅水平>0.315 μg/L时，NAFLD的患病风险较高，随着尿铅的增加，NAFLD的患病风险逐渐增大（图1）。

2.4 尿铅与NAFLD患病风险相关变量的亚组分析及交互作用检验

以NAFLD为因变量，调整年龄、性别、种族、教育、婚姻、FMPIR、BMI、吸烟、饮酒、DM、HTN、HL多个协变量，结果显示尿铅与种族之间存在显著的交互作用，墨西哥裔美国人尿铅每上升1个四分位数，NAFLD的患病风险增加32.40%（OR=1.324，95%CI： 1.017～1.632），差异有统计学意义（P<0.05）（表3）。

3 讨论

基于NHANES 2017—2020年调查数据，本研究发现NAFLD组尿铅水平显著高于Non-NAFLD组（P=0.043）。构建多元Logistic回归模型，调整年龄、性别、种族、教育、婚姻、FMPIR、BMI、吸烟、饮酒、DM、HTN、HL后发现，尿铅水平与NAFLD的患病风险呈正相关（Q3 vs Q1：OR=1.360，95%CI：1.019～1.817，P=0.037）。在限制性立方样条函数分析中，尿铅与NAFLD的患病风险存在正向剂量-反应关系（P=0.047）且为非线性关系（P_non-linear=0.037）。以0.315 μg/L为参考值，当尿铅<0.315 μg/L时，NAFLD的患病风险较低；当尿铅>0.315 μg/L时，NAFLD的患病风险较高，随着尿铅的增加，NAFLD的患病风险率逐渐增大。尿铅与种族之间存在显著的交互作用，墨西哥裔美国人尿铅每上升1个四分位数，NAFLD的患病风险增加32.40%（OR=1.324，95%CI：1.017～1.632），差异具有统计学意义（P<0.05）。

一项基于韩国成年人群的横断面研究^［24］发现，血清铅与肝损伤标志物ALT、AST、ALP水平升高有关。在快速城市化背景下，中国长三角地区血清铅水平与NAFLD相关^［11］。血清铅与NAFLD脂肪变性和纤维化进展有关，且在不同性别中的相关性存在差异^［25］。血清铅与基于ALT升高的疑诊NAFLD的患病风险呈正相关^［26］。一项动物实验^［27］表明，长期铅暴露可加剧高脂饮食小鼠的肝糖脂代谢紊乱。长期接触铅会诱发与肠道菌群变化相关的脂肪肝疾病^［28］。铅暴露是增加肝功能障碍风险的重要因素^［29］。Pb²⁺通过破坏线粒体呼吸复合物可诱导严重的肝毒性^［30］。以上研究均表明血清铅与肝损伤、NAFLD密切相关。已有相关研究表明尿液硒^［31］、锰^［32］、砷^［33］、镉^［34］、钠^［35］与NAFLD患病风险有关，同样作为尿液金属铅，是否与NAFLD患病风险具有相关性值得探讨。基于血清铅与肝损伤、NAFLD的相关性研究，本研究首次探讨尿铅与NAFLD患病风险的关联性，发现尿液高水平的铅是NAFLD患病风险增高的危险因素。铅广泛存在于自然界和人们生活中，铅酸蓄电池行业、新兴的电子废品回收和金属冶炼是主要的铅污染源^［36］。高职业风险铅暴露的人群应警惕预防NAFLD。在NAFLD的预防和临床实践中，检测尿铅水平有利于NAFLD的早期预防和高危人群筛查。有研究^［37］表明饮食习惯偏爱海鲜、罐装食品、膨化食品的人群尿铅水平更高。但由于NHANES数据库的局限性，尚未采集人群的饮食偏爱数据，故本研究未能将膳食铅摄入纳入为协变量，未来如有条件，将进一步探索尿铅与NAFLD的关系，并将饮食偏好等其他混杂因素纳入为协变量进行分析。

参考文献

[1] TARGHER G, TILG H, BYRNE CD. Non-alcoholic fatty liver disease: A multisystem disease requiring a multidisciplinary and holistic approach[J]. Lancet Gastroenterol Hepatol, 2021, 6(7): 578-588. DOI: 10.1016/S2468-1253(21)00020-0 .

[2] YOUNOSSI ZM, KOENIG AB, ABDELATIF D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes[J]. Hepatology, 2016, 64(1): 73-84. DOI: 10.1002/hep.28431 .

[3] RIAZI K, AZHARI H, CHARETTE JH, et al. The prevalence and incidence of NAFLD worldwide: A systematic review and meta-analysis[J]. Lancet Gastroenterol Hepatol, 2022, 7(9): 851-861. DOI: 10.1016/S2468-1253(22)00165-0 .

[4] LIU X, JU YW, MANDZHIEVA S, et al. Sporadic Pb accumulation by plants: Influence of soil biogeochemistry, microbial community and physiological mechanisms[J]. J Hazard Mater, 2023, 444(Pt A): 130391. DOI: 10.1016/j.jhazmat.2022.130391 .

[5] LIU WY, FENG H, ZHENG SL, et al. Pb toxicity on gut physiology and microbiota[J]. Front Physiol, 2021, 12: 574913. DOI: 10.3389/fphys.2021.574913 .

[6] CUOMO D, FOSTER MJ, THREADGILL D. Systemic review of genetic and epigenetic factors underlying differential toxicity to environmental lead (Pb) exposure[J]. Environ Sci Pollut Res Int, 2022, 29(24): 35583-35598. DOI: 10.1007/s11356-022-19333-5 .

[7] GUO XY, YIN XZ, LIU ZJ, et al. Non-alcoholic fatty liver disease (NAFLD) pathogenesis and natural products for prevention and treatment[J]. Int J Mol Sci, 2022, 23(24): 15489. DOI: 10.3390/ijms232415489 .

[8] BOSKABADY M, MAREFATI N, FARKHONDEH T, et al. The effect of environmental lead exposure on human health and the contribution of inflammatory mechanisms, a review[J]. Environ Int, 2018, 120: 404-420. DOI: 10.1016/j.envint.2018.08.013 .

[9] TESCHKE R. Aluminum, arsenic, beryllium, cadmium, chromium, cobalt, copper, iron, lead, mercury, molybdenum, nickel, platinum, thallium, titanium, vanadium, and zinc: Molecular aspects in experimental liver injury[J]. Int J Mol Sci, 2022, 23(20): 12213. DOI: 10.3390/ijms232012213 .

[10] SOMMAR JN, HEDMER M, LUNDH T, et al. Investigation of lead concentrations in whole blood, plasma and urine as biomarkers for biological monitoring of lead exposure[J]. J Expo Sci Environ Epidemiol, 2014, 24(1): 51-57. DOI: 10.1038/jes.2013.4 .

[11] ZHAI HL, CHEN C, WANG NJ, et al. Blood lead level is associated with non-alcoholic fatty liver disease in the Yangtze River Delta Region of China in the context of rapid urbanization[J]. Environ Health, 2017, 16(1): 93. DOI: 10.1186/s12940-017-0304-7 .

[12] VUPPALANCHI R, NOUREDDIN M, ALKHOURI N, et al. Therapeutic pipeline in nonalcoholic steatohepatitis[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(6): 373-392. DOI: 10.1038/s41575-020-00408-y .

[13] MIKOLASEVIC I, ORLIC L, FRANJIC N, et al. Transient elastography (FibroScan^®) with controlled attenuation parameter in the assessment of liver steatosis and fibrosis in patients with nonalcoholic fatty liver disease-Where do we stand?[J]. World J Gastroenterol, 2016, 22(32): 7236-7251. DOI: 10.3748/wjg.v22.i32.7236 .

[14] PENG HY, PAN L, RAN SM, et al. Prediction of MAFLD and NAFLD using different screening indexes: A cross-sectional study in U.S. adults[J]. Front Endocrinol, 2023, 14: 1083032. DOI: 10.3389/fendo.2023.1083032 .

[15] ZHANG KW, NULALI J, ZHANG CX, et al. The association between serum vitamin A and NAFLD among US adults varied in different BMI groups: A cross-sectional study[J]. Food Funct, 2023, 14(2): 836-844. DOI: 10.1039/d2fo02204d .

[16] SELVARAJ EA, MÓZES FE, JAYASWAL ANA, et al. Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: A systematic review and meta-analysis[J]. J Hepatol, 2021, 75(4): 770-785. DOI: 10.1016/j.jhep.2021.04.044 .

[17] STANFIELD Z, SETZER RW, HULL V, et al. Bayesian inference of chemical exposures from NHANES urine biomonitoring data[J]. J Expo Sci Environ Epidemiol, 2022, 32(6): 833-846. DOI: 10.1038/s41370-022-00459-0 .

[18] RINELLA ME, NEUSCHWANDER-TETRI BA, SIDDIQUI MS, et al. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease[J]. Hepatology, 2023, 77(5): 1797-1835. DOI: 10.1097/HEP.0000000000000323 .

[19] WANG LL, YI JY, GUO XL, et al. Associations between life’s essential 8 and non-alcoholic fatty liver disease among US adults[J]. J Transl Med, 2022, 20(1): 616. DOI: 10.1186/s12967-022-03839-0 .

[20] SANDERS AP, MAZZELLA MJ, MALIN AJ, et al. Combined exposure to lead, cadmium, mercury, and arsenic and kidney health in adolescents age 12-19 in NHANES 2009-2014[J]. Environ Int, 2019, 131: 104993. DOI: 10.1016/j.envint.2019.104993 .

[21] CHEN L, SUN QZ, PENG SF, et al. Associations of blood and urinary heavy metals with rheumatoid arthritis risk among adults in NHANES, 1999-2018[J]. Chemosphere, 2022, 289: 133147. DOI: 10.1016/j.chemosphere.2021.133147 .

[22] BUSER MC, INGBER SZ, RAINES N, et al. Urinary and blood cadmium and lead and kidney function: NHANES 2007-2012[J]. Int J Hyg Environ Health, 2016, 219(3): 261-267. DOI: 10.1016/j.ijheh. 2016.01.005 .

[23] HINAI MA, JANSEN EC, SONG PX, et al. Iron deficiency and vitamin D deficiency are associated with sleep in females of reproductive age: An analysis of NHANES 2005-2018 data[J]. J Nutr, 2024, 154(2): 648-657. DOI: 10.1016/j.tjnut.2023.11.030 .

[24] KIM DW, OCK J, MOON KW, et al. Association between Pb, Cd, and Hg exposure and liver injury among Korean adults[J]. Int J Environ Res Public Health, 2021, 18(13): 6783. DOI: 10.3390/ijerph18136783 .

[25] CHUNG SM, MOON JS, YOON JS, et al. The sex-specific effects of blood lead, mercury, and cadmium levels on hepatic steatosis and fibrosis: Korean nationwide cross-sectional study[J]. J Trace Elem Med Biol, 2020, 62: 126601. DOI: 10.1016/j.jtemb.2020.126601 .

[26] CAVE M, APPANA S, PATEL M, et al. Polychlorinated biphenyls, lead, and mercury are associated with liver disease in American adults: NHANES 2003-2004[J]. Environ Health Perspect, 2010, 118(12): 1735-1742. DOI: 10.1289/ehp.1002720 .

[27] WANG NN, SHENG ZJ, ZHOU SM, et al. Chronic lead exposure exacerbates hepatic glucolipid metabolism disorder and gut microbiota dysbiosis in high-fat-diet mice[J]. Food Chem Toxicol, 2022, 170: 113451. DOI: 10.1016/j.fct.2022.113451 .

[28] WAN H, WANG YY, ZHANG HJ, et al. Chronic lead exposure induces fatty liver disease associated with the variations of gut microbiota[J]. Ecotoxicol Environ Saf, 2022, 232: 113257. DOI: 10.1016/j.ecoenv.2022.113257 .

[29] YANG ZR, LI XM, TIAN L, et al. Heavy metals exposure is associated with early liver dysfunction among rural residents aged 40-75 years in southwest China[J]. J Appl Toxicol, 2022, 42(6): 1044-1056. DOI: 10.1002/jat.4276 .

[30] MA L, LIU JY, DONG JX, et al. Toxicity of Pb²⁺ on rat liver mitochondria induced by oxidative stress and mitochondrial permeability transition[J]. Toxicol Res, 2017, 6(6): 822-830. DOI: 10.1039/c7tx00204a .

[31] URBANO T, FILIPPINI T, LASAGNI D, et al. Association of urinary and dietary selenium and of serum selenium species with serum alanine aminotransferase in a healthy Italian population[J]. Antioxidants, 2021, 10(10): 1516. DOI: 10.3390/antiox10101516 .

[32] LIU J, TAN L, LIU ZY, et al. Blood and urine manganese exposure in non-alcoholic fatty liver disease and advanced liver fibrosis: An observational study[J]. Environ Sci Pollut Res Int, 2023, 30(9): 22222-22231. DOI: 10.1007/s11356-022-23630-4 .

[33] FREDIANI JK, NAIOTI EA, VOS MB, et al. Arsenic exposure and risk of nonalcoholic fatty liver disease (NAFLD) among U.S. adolescents and adults: An association modified by race/ethnicity, NHANES 2005-2014[J]. Environ Health, 2018, 17(1): 6. DOI: 10.1186/s12940-017-0350-1 .

[34] HYDER O, CHUNG M, COSGROVE D, et al. Cadmium exposure and liver disease among US adults[J]. J Gastrointest Surg, 2013, 17(7): 1265-1273. DOI: 10.1007/s11605-013-2210-9 .

[35] HUH JH, LEE KJ, LIM JS, et al. High dietary sodium intake assessed by estimated 24-h urinary sodium excretion is associated with NAFLD and hepatic fibrosis[J]. PLoS One, 2015, 10(11): e0143222. DOI: 10.1371/journal.pone.0143222 .

[36] LUO J, XING WQ, IPPOLITO JA, et al. Bioaccessibility, source and human health risk of Pb, Cd, Cu and Zn in windowsill dusts from an area affected by long-term Pb smelting[J]. Sci Total Environ, 2022, 842: 156707. DOI: 10.1016/j.scitotenv.2022.156707 .

[37] MORADNIA M, MOVAHEDIAN ATTAR H, HEIDARI Z, et al. Monitoring of urinary arsenic (As) and lead (Pb) among a sample of pregnant Iranian women[J]. J Environ Health Sci Eng, 2021, 19(2): 1901-1909. DOI: 10.1007/s40201-021-00743-5 .

基金资助

国家自然科学基金(81673806)

中国医药教育协会科研课题(2020KTY001)