挥发性有机物暴露与代谢功能障碍相关脂肪性肝病患病风险存在正向关联

doi:10.12122/j.issn.1673-4254.2026.01.13

摘要/Abstract

摘要：

目的评估一般成年人群尿液挥发性有机化合物代谢物（mVOCs）暴露水平与代谢功能障碍相关脂肪性肝病（MASLD）患病风险之间的关联。方法基于2011~2018年美国国家健康与营养调查的四轮横断面调查，采用广义线性模型评估单一mVOC与MASLD患病风险之间的关联，进一步构建最小绝对收缩和选择算子—加权分位数（LASSO-WQS）两阶段回归模型探究mVOCs混合暴露与MASLD患病风险之间的联系，并量化各化合物的相对贡献。结果单一暴露分析结果表明，在调整混杂因素后，2-氨基噻唑啉-4-羧酸（ATCA）、N-乙酰-S-2-羧乙基-L-半胱氨酸（CEMA）和N-乙酰-S-3，4-二羟基丁基-L-半胱氨酸（DHBMA）与MASLD患病风险之间存在显著正向关联。混合暴露两阶段分析显示，第一阶段LASSO回归筛选出6种与MASLD患病风险更为相关的mVOCs，第二阶段WQS回归提示mVOCs混合暴露与 MASLD患病风险之间存在显著的正向关联关系（OR=1.306，95% CI：1.132~1.507，P<0.001），其中CEMA贡献权重最大（36%）。结论 VOCs对肝脏可能具有潜在健康风险，其中CEMA是VOCs混合暴露中贡献最大的独立风险因子，建议开展机制研究验证其肝毒性通路，并考虑将其纳入优先管控清单。

Abstract:

Objective To assess the association between urinary levels of volatile organic compound metabolites (mVOCs) and risks of metabolic dysfunction-associated steatotic liver disease (MASLD) in the general adult population. Methods Based on 4 cycles of cross-sectional surveys from the 2011-2018 National Health and Nutrition Examination Survey (NHANES), generalized linear models were employed to evaluate the associations between individual mVOC exposures and the risk of MASLD. A two-stage Least Absolute Shrinkage and Selection Operator-Weighted Quantile Sum (LASSO-WQS) regression model was constructed to investigate the relationship between mixed mVOCs exposures and MASLD risk, and the relative contributions of the individual compounds were quantitatively analyzed. Results The single-exposure analysis revealed significant positive associations of 2-aminothiazoline-4-carboxylic acid (ATCA), N-acetyl-S‑(2-carboxyethyl)‑L-cysteine (CEMA), and N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine (DHBMA) with MASLD risk after adjusting for confounders. In the two-stage mixed-exposure analysis, the first-stage LASSO regression identified 6 mVOCs with stronger association with MASLD risk. The second-stage WQS regression demonstrated a statistically significant positive association between mixed mVOCs exposures and MASLD risk (OR=1.306, 95% CI: 1.132-1.507; P<0.001), with CEMA contributing the highest weight (36%). Conclusion The study reveals a significant positive association between urinary levels of mVOCs mixtures and MASLD risk, suggesting potential hepatotoxic effects of VOC (especially CEMA) exposures, which urges future mechanistic studies of VOC mixture-related health impacts and listing of CEMA for health risk control.

Key words: metabolic dysfunction-associated steatotic liver disease, volatile organic compounds, mixed exposure, weighted quantile sum regression

李凯, 曾文倩, 张艳孜, 朱秀玲, 郭冰. 挥发性有机物暴露与代谢功能障碍相关脂肪性肝病患病风险存在正向关联[J]. 南方医科大学学报, 2026, 46(1): 122-130.

Kai LI, Wenqian ZENG, Yanzi ZHANG, Xiuling ZHU, Bing GUO. Exposures to volatile organic compounds are positively correlated with risks of metabolic dysfunction-associated steatotic liver disease[J]. Journal of Southern Medical University, 2026, 46(1): 122-130.

图/表 8

参考文献 39

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Biomarker code	Abbreviation	Detection rate	Chemical name
URX2MH	2-MHA	92.6%	2-Methylhippuric Acid
URX34M	3,4-MHA	99.5%	3,4-Dimethylhippuric Acid
URXAMC	AMCC	99.7%	N-Acetyl-S-(N-methylcarbamoyl)-L-cysteine
URXATC	ATCA	94.0%	2-Aminothiazoline-4-carboxylic Acid
URXBMA	BMA	99.4%	N-Acetyl-S-(benzyl)-L-cysteine
URXCEM	CEMA	99.1%	N-Acetyl-S-(2-carboxyethyl)-L-cysteine
URXCYM	CYMA	87.2%	N-Acetyl-S-(2-cyanoethyl)-L-cysteine
URXDHB	DHBMA	99.9%	N-Acetyl-S-(3,4-dihydroxybutyl)-L-cysteine
URXHP2	2HPMA	95.2%	N-Acetyl-S-(2-hydroxypropyl)-L-cysteine
URXHPM	3HPMA	99.8%	N-Acetyl-S-(3-hydroxypropyl)-L-cysteine
URXMAD	MA	98.8%	Benzoic Acid
URXPHG	PGA	99.4%	Phenylglyoxylic Acid
URXAAM	AAMA	99.9%	N-Acetyl-S-(2-carbamoylethyl)-L-cysteine
URXMB3	MHBMA3	97.2%	N-Acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine
URXPMM	HMPMA	99.9%	N-Acetyl-S-(1-methyl-3-hydroxypropyl)-L-cysteine

Biomarker code	Abbreviation	Detection rate	Chemical name
URX2MH	2-MHA	92.6%	2-Methylhippuric Acid
URX34M	3,4-MHA	99.5%	3,4-Dimethylhippuric Acid
URXAMC	AMCC	99.7%	N-Acetyl-S-(N-methylcarbamoyl)-L-cysteine
URXATC	ATCA	94.0%	2-Aminothiazoline-4-carboxylic Acid
URXBMA	BMA	99.4%	N-Acetyl-S-(benzyl)-L-cysteine
URXCEM	CEMA	99.1%	N-Acetyl-S-(2-carboxyethyl)-L-cysteine
URXCYM	CYMA	87.2%	N-Acetyl-S-(2-cyanoethyl)-L-cysteine
URXDHB	DHBMA	99.9%	N-Acetyl-S-(3,4-dihydroxybutyl)-L-cysteine
URXHP2	2HPMA	95.2%	N-Acetyl-S-(2-hydroxypropyl)-L-cysteine
URXHPM	3HPMA	99.8%	N-Acetyl-S-(3-hydroxypropyl)-L-cysteine
URXMAD	MA	98.8%	Benzoic Acid
URXPHG	PGA	99.4%	Phenylglyoxylic Acid
URXAAM	AAMA	99.9%	N-Acetyl-S-(2-carbamoylethyl)-L-cysteine
URXMB3	MHBMA3	97.2%	N-Acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine
URXPMM	HMPMA	99.9%	N-Acetyl-S-(1-methyl-3-hydroxypropyl)-L-cysteine

Variable	Overall (n=2122)	Non-MASLD (n=1149)	MASLD (n=973)	P
Age (year, Mean±SD)	45.30 (14.17)	43.43 (14.63)	47.52 (13.27)	<0.001
Gender [n (%)]				<0.001
Male	1168 (55%)	602 (52%)	566 (58%)
Female	954 (45%)	547 (48%)	407 (42%)
Education level [n (%)]				0.13
Less than high school	354 (17%)	181 (16%)	173 (18%)
High school or equivalent	413 (19%)	212 (18%)	201 (21%)
College or above	1355 (64%)	756 (66%)	599 (62%)
Income level [n (%)]				0.03
Low income	519 (24%)	283 (25%)	236 (24%)
Middle income	804 (38%)	408 (36%)	396 (41%)
High income	799 (38%)	458 (40%)	341 (35%)
Marital status [n (%)]				<0.001
Married	1400 (66%)	734 (64%)	666 (68%)
Divorced	329 (16%)	166 (14%)	163 (17%)
Single	393 (19%)	249 (22%)	144 (15%)
BMI (kg/m², Mean±SD)	29.19 (6.83)	24.88 (3.48)	34.27 (6.31)	<0.001
Diabetes [n (%)]	216 (10%)	63 (5.5%)	153 (16%)	<0.001
Hypertension [n (%)]	620 (29%)	219 (19%)	401 (41%)	<0.001
Total cholesterol level (mmol/L, Mean±SD)	4.94 (1.06)	4.80 (1.00)	5.11 (1.10)	<0.001
Urinary creatinine level (mg/100 mL, Mean±SD)	122.22 (79.13)	113.38 (76.69)	132.66 (80.72)	<0.001

Variable	Overall (n=2122)	Non-MASLD (n=1149)	MASLD (n=973)	P
Age (year, Mean±SD)	45.30 (14.17)	43.43 (14.63)	47.52 (13.27)	<0.001
Gender [n (%)]				<0.001
Male	1168 (55%)	602 (52%)	566 (58%)
Female	954 (45%)	547 (48%)	407 (42%)
Education level [n (%)]				0.13
Less than high school	354 (17%)	181 (16%)	173 (18%)
High school or equivalent	413 (19%)	212 (18%)	201 (21%)
College or above	1355 (64%)	756 (66%)	599 (62%)
Income level [n (%)]				0.03
Low income	519 (24%)	283 (25%)	236 (24%)
Middle income	804 (38%)	408 (36%)	396 (41%)
High income	799 (38%)	458 (40%)	341 (35%)
Marital status [n (%)]				<0.001
Married	1400 (66%)	734 (64%)	666 (68%)
Divorced	329 (16%)	166 (14%)	163 (17%)
Single	393 (19%)	249 (22%)	144 (15%)
BMI (kg/m², Mean±SD)	29.19 (6.83)	24.88 (3.48)	34.27 (6.31)	<0.001
Diabetes [n (%)]	216 (10%)	63 (5.5%)	153 (16%)	<0.001
Hypertension [n (%)]	620 (29%)	219 (19%)	401 (41%)	<0.001
Total cholesterol level (mmol/L, Mean±SD)	4.94 (1.06)	4.80 (1.00)	5.11 (1.10)	<0.001
Urinary creatinine level (mg/100 mL, Mean±SD)	122.22 (79.13)	113.38 (76.69)	132.66 (80.72)	<0.001

VOC	Model 1		Model 2
VOC	OR (95% CI)	P	OR (95% CI)	P
2-MHA	1.02 (0.77-1.36)	0.871	1.05 (0.93-1.18)	0.427
3,4-MHA	0.95 (0.78-1.15)	0.582	1.03 (0.94-1.13)	0.532
AMCC	0.85 (0.48-1.48)	0.558	0.98 (0.90-1.08)	0.743
ATCA	1.06 (0.95-1.18)	0.279	1.13 (1.03-1.25)	0.008
BMA	1.02 (0.94-1.12)	0.585	1.07 (0.94-1.22)	0.297
CEMA	1.98 (1.53-2.56)	<0.001	1.28 (1.11-1.46)	<0.001
CYMA	0.76 (0.55-1.04)	0.086	0.98 (0.89-1.08)	0.682
DHBMA	1.33 (1.14-1.56)	<0.001	1.29 (1.17-1.43)	<0.001
2HPMA	1.00 (0.91-1.09)	0.975	1.03 (0.94-1.12)	0.539
3HPMA	0.59 (0.46-0.76)	<0.001	1.02 (0.93-1.12)	0.697
MA	1.12 (0.60-2.09)	0.713	1.17 (0.94-1.46)	0.164
PGA	0.95 (0.54-1.66)	0.849	1.15 (0.94-1.42)	0.181
AAMA	0.81 (0.67-0.99)	0.036	1.00 (0.91-1.10)	0.963
MHBMA3	0.87 (0.64-1.18)	0.357	1.05 (0.95-1.15)	0.359
HMPMA	1.57 (1.11-2.21)	0.011	1.09 (0.99-1.21)	0.083