Abstract
Non-alcoholic fatty liver disease (NAFLD), the most common form of liver disease, affects over 30% of the US population. Our group and others have previously demonstrated that low-level environmental pollutant exposures were associated with increased odds ratios for unexplained alanine aminotransferase (ALT) elevation, a surrogate biomarker for NAFLD, in the adult National Health and Nutrition Examination Survey (NHANES). However, recently, more sensitive and lower ALT cutoffs have been proposed. The objective of this observational study is to utilize these ALT cutoffs to determine new associations between environmental chemicals and the surrogate NAFLD biomarker. Adult NHANES 2003–2004 participants without viral hepatitis, hemochromatosis, or alcoholic liver disease were analyzed in this cross-sectional study. ALT elevation was defined as > 30 IU/L in men and > 19 IU/L in women. Odds ratios adjusted for potential confounders for ALT elevation were determined across exposure quartiles for 17 pollutant subclasses comprised of 111 individual pollutants. The overall prevalence of ALT elevation was 37.6%. Heavy metal and organochlorine insecticide subclasses were associated with dose-dependent increased adjusted odds ratios for ALT elevation of 1.6 (95% CI 1.2–2.3) and 3.5 (95% CI 2.3–5.5) respectively, for the highest vs. lowest exposure quartiles (ptrend < 0.01). Within these subclasses, increasing whole blood levels of lead and mercury, and lipid-adjusted serum levels of dieldrin, and the chlordane metabolites, heptachlor epoxide, and trans-nonachlor, were associated with increased odds ratios for ALT elevation. In conclusion, organochlorine insecticide, lead, and mercury exposures were associated with ALT elevation and suspected NAFLD in adult NHANES 2003–2004.
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Abbreviations
- ALT:
-
Alanine aminotransferase
- BMI:
-
Body mass index
- CI:
-
Confidence intervals
- DDE:
-
Dichlorodiphenyldichloroethylene
- DDT:
-
Dichlorodiphenyltrichloroethane
- EGFR:
-
Epidermal growth factor receptor
- HOMA-IR:
-
Homeostasis model assessment of insulin resistance
- LLOD:
-
Lower limit of detection
- MeHg:
-
Methylmercury
- NAFLD:
-
Non-alcoholic fatty liver disease
- NASH:
-
Non-alcoholic steatohepatitis
- NCHS:
-
National Center for Health Statistics
- NHANES:
-
National Health and Nutrition Examination Survey
- OR:
-
Odds ratio
- PBDEs:
-
Polybrominated diphenyl ethers
- PCBs:
-
Polychlorinated biphenyls
- PCDDs:
-
Polychlorinated dibenzo-p-dioxins
- PCDFs:
-
Polychlorinated dibenzofurans
- PFCs:
-
Perfluorinated compounds
- PIR:
-
Poverty income ratio
- TASH:
-
Toxicant-associated steatohepatitis
References
Aguilera-Mendez A (2019) Nonalcoholic hepatic steatosis: a silent disease. Rev Med Inst Mex Seguro Soc 56:544–549
Al-Eryani L, Wahlang B, Falkner KC, Guardiola JJ, Clair HB, Prough RA, Cave M (2015) Identification of environmental chemicals associated with the development of toxicant-associated fatty liver disease in rodents. Toxicol Pathol 43:482–497. https://doi.org/10.1177/0192623314549960
Anonymous (2018) Fourth national report on human exposure to environmental chemicals. Updated Tables, Volume Two. Centers for Disease Control and Prevention (CDC). U.S. Department of Health and Human Services
Bassler J, Ducatman A, Elliott M, Wen S, Wahlang B, Barnett J, Cave MC (2019) Environmental perfluoroalkyl acid exposures are associated with liver disease characterized by apoptosis and altered serum adipocytokines. Environ Pollut 247:1055–1063. https://doi.org/10.1016/j.envpol.2019.01.064
Brautbar N, Williams J 2nd (2002) Industrial solvents and liver toxicity: risk assessment, risk factors and mechanisms. Int J Hyg Environ Health 205:479–491. https://doi.org/10.1078/1438-4639-00175
Carson R, Darling L (1962) Silent spring. Houghton Mifflin; Riverside Press, Boston; Cambridge, Mass
Cave M, Appana S, Patel M, Falkner KC, McClain CJ, Brock G (2010a) Polychlorinated biphenyls, lead, and mercury are associated with liver disease in American adults: NHANES 2003-2004. Environ Health Perspect 118:1735–1742. https://doi.org/10.1289/ehp.1002720
Cave M, Falkner KC, Ray M, Joshi-Barve S, Brock G, Khan R, Bon Homme M, McClain CJ (2010b) Toxicant-associated steatohepatitis in vinyl chloride workers. Hepatology 51:474–481. https://doi.org/10.1002/hep.23321
Cave M, Falkner KC, Henry L, Costello B, Gregory B, McClain CJ (2011) Serum cytokeratin 18 and cytokine elevations suggest a high prevalence of occupational liver disease in highly exposed elastomer/polymer workers. J Occup Environ Med 53:1128–1133. https://doi.org/10.1097/JOM.0b013e31822cfd68
Clair HB, Pinkston CM, Rai SN, Pavuk M, Dutton ND, Brock GN, Prough RA, Falkner KC, McClain CJ, Cave MC (2018) Liver disease in a residential cohort with elevated polychlorinated biphenyl exposures. Toxicol Sci 164:39–49. https://doi.org/10.1093/toxsci/kfy076
Clark JM (2006) The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol 40(Suppl 1):S5–S10. https://doi.org/10.1097/01.mcg.0000168638.84840.ff
Clark JM, Brancati FL, Diehl AM (2003) The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 98:960–967. https://doi.org/10.1111/j.1572-0241.2003.07486.x
De Coster S, van Larebeke N (2012) Endocrine-disrupting chemicals: associated disorders and mechanisms of action. J Environ Public Health 2012:713696. https://doi.org/10.1155/2012/713696
Dunn W, Xu R, Wingard DL, Rogers C, Angulo P, Younossi ZM, Schwimmer JB (2008) Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study. Am J Gastroenterol 103:2263–2271. https://doi.org/10.1111/j.1572-0241.2008.02034.x
Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ (2018) Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 67:123–133. https://doi.org/10.1002/hep.29466
Freire C, Koifman RJ, Koifman S (2015) Hematological and hepatic alterations in Brazilian population heavily exposed to organochlorine pesticides. J Toxicol Environ Health A 78:534–548. https://doi.org/10.1080/15287394.2014.999396
Guardiola JJ, Beier JI, Falkner KC, Wheeler B, McClain CJ, Cave M (2016) Occupational exposures at a polyvinyl chloride production facility are associated with significant changes to the plasma metabolome. Toxicol Appl Pharmacol 313:47–56. https://doi.org/10.1016/j.taap.2016.10.001
Guzelian PS, Vranian G, Boylan JJ, Cohn WJ, Blanke RV (1980) Liver structure and function in patients poisoned with chlordecone (Kepone). Gastroenterology 78:206–213
Hadizadeh F, Faghihimani E, Adibi P (2017) Nonalcoholic fatty liver disease: diagnostic biomarkers. World J Gastrointest Pathophysiol 8:11–26. https://doi.org/10.4291/wjgp.v8.i2.11
Hardesty JE, Al-Eryani L, Wahlang B, Falkner KC, Shi H, Jin J, Vivace BJ, Ceresa BP, Prough RA, Cave MC (2018) Epidermal growth factor receptor signaling disruption by endocrine and metabolic disrupting chemicals. Toxicol Sci 162:622–634. https://doi.org/10.1093/toxsci/kfy004
Hernaez R, McLean J, Lazo M, Brancati FL, Hirschhorn JN, Borecki IB, Harris TB, Genetics of Obesity-Related Liver Disease C, Nguyen T, Kamel IR, Bonekamp S, Eberhardt MS, Clark JM, Kao WH, Speliotes EK (2013) Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the third National Health and Nutrition Examination Survey. Clin Gastroenterol Hepatol 11:1183–1190 e2. https://doi.org/10.1016/j.cgh.2013.02.011
Ji G, Xu C, Sun H, Liu Q, Hu H, Gu A, Jiang ZY (2016) Organochloride pesticides induced hepatic ABCG5/G8 expression and lipogenesis in Chinese patients with gallstone disease. Oncotarget 7:33689–33702. https://doi.org/10.18632/oncotarget.9399
Kamel F, Engel LS, Gladen BC, Hoppin JA, Alavanja MC, Sandler DP (2007) Neurologic symptoms in licensed pesticide applicators in the Agricultural Health Study. Hum Exp Toxicol 26:243–250. https://doi.org/10.1177/0960327107070582
Kang MY, Cho SH, Lim YH, Seo JC, Hong YC (2013) Effects of environmental cadmium exposure on liver function in adults. Occup Environ Med 70:268–273. https://doi.org/10.1136/oemed-2012-101063
Kim KS, Lee YM, Kim SG, Lee IK, Lee HJ, Kim JH, Kim J, Moon HB, Jacobs DR Jr, Lee DH (2014) Associations of organochlorine pesticides and polychlorinated biphenyls in visceral vs. subcutaneous adipose tissue with type 2 diabetes and insulin resistance. Chemosphere 94:151–157. https://doi.org/10.1016/j.chemosphere.2013.09.066
Kiyosawa N, Kwekel JC, Burgoon LD, Dere E, Williams KJ, Tashiro C, Chittim B, Zacharewski TR (2008) Species-specific regulation of PXR/CAR/ER-target genes in the mouse and rat liver elicited by o, p'-DDT. BMC Genomics 9:487. https://doi.org/10.1186/1471-2164-9-487
Kwo PY, Cohen SM, Lim JK (2017) ACG clinical guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol 112:18–35. https://doi.org/10.1038/ajg.2016.517
Lazo M, Selvin E, Clark JM (2008) Brief communication: clinical implications of short-term variability in liver function test results. Ann Intern Med 148:348–352
Le MH, Devaki P, Ha NB, Jun DW, Te HS, Cheung RC, Nguyen MH (2017) Prevalence of non-alcoholic fatty liver disease and risk factors for advanced fibrosis and mortality in the United States. PLoS One 12:e0173499. https://doi.org/10.1371/journal.pone.0173499
Lee DH, Lee IK, Jin SH, Steffes M, Jacobs DR Jr (2007a) Association between serum concentrations of persistent organic pollutants and insulin resistance among nondiabetic adults: results from the National Health and Nutrition Examination Survey 1999-2002. Diabetes Care 30:622–628. https://doi.org/10.2337/dc06-2190
Lee DH, Lee IK, Porta M, Steffes M, Jacobs DR Jr (2007b) Relationship between serum concentrations of persistent organic pollutants and the prevalence of metabolic syndrome among non-diabetic adults: results from the National Health and Nutrition Examination Survey 1999-2002. Diabetologia 50:1841–1851. https://doi.org/10.1007/s00125-007-0755-4
Liangpunsakul S, Chalasani N (2004) Relationship between unexplained elevations in alanine aminotransferase and serum leptin in U.S. adults: results from the third National Health and Nutrition Examination Survey (NHANES III). J Clin Gastroenterol 38:891–897
Liangpunsakul S, Chalasani N (2005) Unexplained elevations in alanine aminotransferase in individuals with the metabolic syndrome: results from the third National Health and Nutrition Survey (NHANES III). Am J Med Sci 329:111–116
Lin YS, Ginsberg G, Caffrey JL, Xue J, Vulimiri SV, Nath RG, Sonawane B (2014) Association of body burden of mercury with liver function test status in the U.S. population. Environ Int 70:88–94. https://doi.org/10.1016/j.envint.2014.05.010
Liu Q, Shao W, Zhang C, Xu C, Wang Q, Liu H, Sun H, Jiang Z, Gu A (2017a) Organochloride pesticides modulated gut microbiota and influenced bile acid metabolism in mice. Environ Pollut 226:268–276. https://doi.org/10.1016/j.envpol.2017.03.068
Liu Q, Wang Q, Xu C, Shao W, Zhang C, Liu H, Jiang Z, Gu A (2017b) Organochloride pesticides impaired mitochondrial function in hepatocytes and aggravated disorders of fatty acid metabolism. Sci Rep 7:46339. https://doi.org/10.1038/srep46339
Martin-Rodriguez JL, Gonzalez-Cantero J, Gonzalez-Cantero A, Arrebola JP, Gonzalez-Calvin JL (2017) Diagnostic accuracy of serum alanine aminotransferase as biomarker for nonalcoholic fatty liver disease and insulin resistance in healthy subjects, using 3T MR spectroscopy. Medicine (Baltimore) 96:e6770. https://doi.org/10.1097/MD.0000000000006770
Ogata M, Izushi F (1991) Effects of chlordane on parameters of liver and muscle toxicity in man and experimental animals. Toxicol Lett 56:327–337
Pedro S, Boba C, Dietz R, Sonne C, Rosing-Asvid A, Hansen M, Provatas A, McKinney MA (2017) Blubber-depth distribution and bioaccumulation of PCBs and organochlorine pesticides in Arctic-invading killer whales. Sci Total Environ 601-602:237–246. https://doi.org/10.1016/j.scitotenv.2017.05.193
Perumpail BJ, Khan MA, Yoo ER, Cholankeril G, Kim D, Ahmed A (2017) Clinical epidemiology and disease burden of nonalcoholic fatty liver disease. World J Gastroenterol 23:8263–8276. https://doi.org/10.3748/wjg.v23.i47.8263
Porta M, Zumeta E (2002) Implementing the Stockholm treaty on persistent organic pollutants. Occup Environ Med 59:651–652
Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, Vianello L, Zanuso F, Mozzi F, Milani S, Conte D, Colombo M, Sirchia G (2002) Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 137:1–10
Reuber MD (1978a) Carcinomas and other lesions of the liver in mice ingesting organochlorine pesticides. Clin Toxicol 13:231–256. https://doi.org/10.3109/15563657808988235
Reuber MD (1978b) Carcinogenicity testing of chemicals with particular reference to organochlorine pesticides. Sci Total Environ 10:105–115
Rosenbaum PF, Weinstock RS, Silverstone AE, Sjodin A, Pavuk M (2017) Metabolic syndrome is associated with exposure to organochlorine pesticides in Anniston, AL, United States. Environ Int 108:11–21. https://doi.org/10.1016/j.envint.2017.07.017
Rotman Y, Koh C, Zmuda JM, Kleiner DE, Liang TJ, Nash CRN (2010) The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 52:894–903. https://doi.org/10.1002/hep.23759
Ruhl CE, Everhart JE (2015) Fatty liver indices in the multiethnic United States National Health and Nutrition Examination Survey. Aliment Pharmacol Ther 41:65–76. https://doi.org/10.1111/apt.13012
Schecter A, Colacino J, Haffner D, Patel K, Opel M, Papke O, Birnbaum L (2010) Perfluorinated compounds, polychlorinated biphenyls, and organochlorine pesticide contamination in composite food samples from Dallas, Texas, USA. Environ Health Perspect 118:796–802. https://doi.org/10.1289/ehp.0901347
Takyar V, Nath A, Beri A, Gharib AM, Rotman Y (2017) How healthy are the “healthy volunteers”? Penetrance of NAFLD in the biomedical research volunteer pool. Hepatology 66:825–833. https://doi.org/10.1002/hep.29247
Turusov V, Rakitsky V, Tomatis L (2002) Dichlorodiphenyltrichloroethane (DDT): ubiquity, persistence, and risks. Environ Health Perspect 110:125–128. https://doi.org/10.1289/ehp.02110125
Wahlang B (2018) Exposure to persistent organic pollutants: impact on women’s health. Rev Environ Health 33:331–348. https://doi.org/10.1515/reveh-2018-0018
Wahlang B, Beier JI, Clair HB, Bellis-Jones HJ, Falkner KC, McClain CJ, Cave MC (2013) Toxicant-associated steatohepatitis. Toxicol Pathol 41:343–360. https://doi.org/10.1177/0192623312468517
Wahlang B, Song M, Beier JI, Cameron Falkner K, Al-Eryani L, Clair HB, Prough RA, Osborne TS, Malarkey DE, Christopher States J, Cave MC (2014) Evaluation of Aroclor 1260 exposure in a mouse model of diet-induced obesity and non-alcoholic fatty liver disease. Toxicol Appl Pharmacol 279:380–390. https://doi.org/10.1016/j.taap.2014.06.019
Wahlang B, Prough RA, Falkner KC, Hardesty JE, Song M, Clair HB, Clark BJ, States JC, Arteel GE, Cave MC (2016) Polychlorinated biphenyl-xenobiotic nuclear receptor interactions regulate energy metabolism, behavior, and inflammation in non-alcoholic-steatohepatitis. Toxicol Sci 149:396–410. https://doi.org/10.1093/toxsci/kfv250
Wahlang B, Jin J, Beier JI, Hardesty JE, Daly EF, Schnegelberger RD, Falkner KC, Prough RA, Kirpich IA, Cave MC (2019) Mechanisms of environmental contributions to fatty liver disease. Curr Environ Health Rep 6:80–94. https://doi.org/10.1007/s40572-019-00232-w
Wang D, Wang X, Zhang P, Wang Y, Zhang R, Yan J, Zhou Z, Zhu W (2017) The fate of technical-grade chlordane in mice fed a high-fat diet and its roles as a candidate obesogen. Environ Pollut 222:532–542. https://doi.org/10.1016/j.envpol.2016.11.028
Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA (2011) Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140:124–131. https://doi.org/10.1053/j.gastro.2010.09.038
Wong VW, Wong GL, Tsang SW, Hui AY, Chan AW, Choi PC, Chim AM, Chu S, Chan FK, Sung JJ, Chan HL (2009) Metabolic and histological features of non-alcoholic fatty liver disease patients with different serum alanine aminotransferase levels. Aliment Pharmacol Ther 29:387–396. https://doi.org/10.1111/j.1365-2036.2008.03896.x
Yorita Christensen KL, Carrico CK, Sanyal AJ, Gennings C (2013) Multiple classes of environmental chemicals are associated with liver disease: NHANES 2003-2004. Int J Hyg Environ Health 216:703–709. https://doi.org/10.1016/j.ijheh.2013.01.005
Zhou JH, Cai JJ, She ZG, Li HL (2019) Noninvasive evaluation of nonalcoholic fatty liver disease: current evidence and practice. World J Gastroenterol 25:1307–1326. https://doi.org/10.3748/wjg.v25.i11.1307
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Wahlang, B., Appana, S., Falkner, K.C. et al. Insecticide and metal exposures are associated with a surrogate biomarker for non-alcoholic fatty liver disease in the National Health and Nutrition Examination Survey 2003–2004. Environ Sci Pollut Res 27, 6476–6487 (2020). https://doi.org/10.1007/s11356-019-07066-x
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DOI: https://doi.org/10.1007/s11356-019-07066-x