J Korean Med Sci.  2023 Dec;38(49):e412. 10.3346/jkms.2023.38.e412.

Blood Concentrations of Lead, Cadmium, and Mercury Are Associated With Alcohol-Related Liver Disease

• Kim JH
• Na JE
• Lee J
• Park YE
• Lee J
• Choi JH
• Heo NY
• Park J
• Kim TO
• Jang HJ
• Park HY
• Park SH

• KMID: 2549176
• DOI: http://doi.org/10.3346/jkms.2023.38.e412

Abstract

Background
An association between environmental pollutants and alcohol-related liver disease (ALD) has not been determined until now. The objectives of this study were to examine the association of the pollutants with ALD, and whether the pollutants together increased the risk of ALD.
Methods
Data were extracted from the Korea National Health and Nutrition Examination Survey (2010–2013 and 2016–2017; n = 11,993). Blood levels of lead, cadmium, and mercury were measured. ALD was defined by a combination of excessive alcohol consumption and ALD/non-alcoholic fatty liver disease index > 0. The aspartate aminotransferase-to-platelet ratio index and fibrosis (FIB)-4 score were used to evaluate ALD FIB.
Results
The odds ratios (ORs) of ALD for the highest versus the lowest quartiles of exposure were for lead, 7.39 (95% confidence interval [CI], 5.51–9.91); cadmium, 1.68 (95% CI, 1.32–2.14); and mercury, 5.03 (95% CI, 3.88–6.53). Adjusting for age, gender, smoking, occupation, education, and personal income attenuated the associations but indicated significant positive trends (all P trend < 0.001). A positive additive interaction between cadmium and lead was observed. The relative excess OR due to the interaction was 0.96 (95% CI, 0.41–1.51); synergy index = 2.92 (95% CI, 0.97–8.80). Among 951 subjects with ALD, advanced FIB was associated with lead and cadmium (OR, 3.46, 95% CI, 1.84–6.53; OR, 8.50, 95% CI, 2.54–28.42, respectively), but not with mercury. The effect estimates for lead and cadmium remained significant even after adjustment for daily alcohol intake.
Conclusion
Blood levels of lead, cadmium, and mercury were significantly associated not only with the risk of ALD but also with ALD FIB. Cadmium and lead have synergistic effects that increase the risk of ALD.

Keyword

Alcohol-Related Liver Disease; Cadmium; Lead; Mercury

Figure

• 

  Fig. 1 Differences in blood concentration of lead (A), cadmium (B), and mercury (C) by ALD. Data are expressed in terms of geometric means adjusted for age, sex, and smoking. All P < 0.001.ALD = alcohol-related liver disease.

• 

  Fig. 2 ORs of contributions of cadmium and lead to alcohol-related liver disease (adjusted for age, gender, smoking, occupation, education, and personal income).OR = odds ratio.

Reference

1. World Health Organization. Global Status Report on Alcohol and Health 2018. Geneva, Switzerland: World Health Organization;2018.

2. Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol. 2019; 70(1):151–171. PMID: 30266282.

3. Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines: management of alcoholic liver disease. Clin Mol Hepatol. 2013; 19(3):216–254. PMID: 24133661.

4. Järup L. Hazards of heavy metal contamination. Br Med Bull. 2003; 68(1):167–182. PMID: 14757716.

5. Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metal toxicity and the environment. Exp Suppl. 2012; 101:133–164. PMID: 22945569.

6. Grandjean P, Olsen NB, Hollnagel H. Influence of smoking and alcohol consumption on blood lead levels. Int Arch Occup Environ Health. 1981; 48(4):391–397. PMID: 7298208.

7. Rhainds M, Levallois P. Effects of maternal cigarette smoking and alcohol consumption on blood lead levels of newborns. Am J Epidemiol. 1997; 145(3):250–257. PMID: 9012598.

8. Shaper AG, Pocock SJ, Walker M, Wale CJ, Clayton B, Delves HT, et al. Effects of alcohol and smoking on blood lead in middle-aged British men. Br Med J (Clin Res Ed). 1982; 284(6312):299–302.

9. Park SH, Kim CH, Kim DJ, Park JH, Kim TO, Yang SY, et al. Prevalence of alcoholic liver disease among Korean adults: results from the fourth Korea National Health and Nutrition Examination Survey, 2009. Subst Use Misuse. 2011; 46(14):1755–1762. PMID: 21999409.

10. Habeebu SS, Liu J, Liu Y, Klaassen CD. Metallothionein-null mice are more sensitive than wild-type mice to liver injury induced by repeated exposure to cadmium. Toxicol Sci. 2000; 55(1):223–232. PMID: 10788577.

11. Lin TH, Huang YL, Huang SF. Lipid peroxidation in liver of rats administrated with methyl mercuric chloride. Biol Trace Elem Res. 1996; 54(1):33–41. PMID: 8862759.

12. Kweon S, Kim Y, Jang MJ, Kim Y, Kim K, Choi S, et al. Data resource profile: the Korea National Health and Nutrition Examination Survey (KNHANES). Int J Epidemiol. 2014; 43(1):69–77. PMID: 24585853.

13. Seo JW, Kim BG, Kim YM, Kim RB, Chung JY, Lee KM, et al. Trend of blood lead, mercury, and cadmium levels in Korean population: data analysis of the Korea National Health and Nutrition Examination Survey. Environ Monit Assess. 2015; 187(3):146. PMID: 25716526.

14. Dunn W, Angulo P, Sanderson S, Jamil LH, Stadheim L, Rosen C, et al. Utility of a new model to diagnose an alcohol basis for steatohepatitis. Gastroenterology. 2006; 131(4):1057–1063. PMID: 17030176.

15. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003; 38(2):518–526. PMID: 12883497.

16. Vallet-Pichard A, Mallet V, Nalpas B, Verkarre V, Nalpas A, Dhalluin-Venier V, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. Comparison with liver biopsy and fibrotest. Hepatology. 2007; 46(1):32–36. PMID: 17567829.

17. Park SH, Heo NY, Kim CH, Suk KT, Kim DJ, Lee HY. Upper reference limits for aminotransferase activities and the prevalence of elevated aminotransferase activities in a Korean population. J Clin Gastroenterol. 2013; 47(1):76–82. PMID: 22739218.

18. Moreno C, Mueller S, Szabo G. Non-invasive diagnosis and biomarkers in alcohol-related liver disease. J Hepatol. 2019; 70(2):273–283. PMID: 30658728.

19. Korea Disease Control and Prevention Agency. Korea Disease Control and Prevention Agency’s web page. Updated 2013. Accessed January 3, 2014. https://knhanes.cdc.go.kr/knhanes/sub03/sub03_06_02.do .

20. Andersson T, Alfredsson L, Källberg H, Zdravkovic S, Ahlbom A. Calculating measures of biological interaction. Eur J Epidemiol. 2005; 20(7):575–579. PMID: 16119429.

21. Hosmer DW, Lemeshow S. Confidence interval estimation of interaction. Epidemiology. 1992; 3(5):452–456. PMID: 1391139.

22. Wah Chu K, Chow KL. Synergistic toxicity of multiple heavy metals is revealed by a biological assay using a nematode and its transgenic derivative. Aquat Toxicol. 2002; 61(1-2):53–64. PMID: 12297370.

23. Zhai H, Chen C, Wang N, Chen Y, Nie X, Han B, 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. Environ Health. 2017; 16(1):93. PMID: 28859656.

24. Cave M, Appana S, Patel M, Falkner KC, McClain CJ, Brock G. Polychlorinated biphenyls, lead, and mercury are associated with liver disease in American adults: NHANES 2003-2004. Environ Health Perspect. 2010; 118(12):1735–1742. PMID: 21126940.

25. Magid E, Hilden M. Elevated levels of blood lead in alcoholic liver disease. Int Arch Occup Environ Health. 1975; 35(1):61–65. PMID: 1150327.

26. Castilla L, Castro M, Grilo A, Guerrero P, Lopez-Artiguez M, Soria ML, et al. Hepatic and blood lead levels in patients with chronic liver disease. Eur J Gastroenterol Hepatol. 1995; 7(3):243–249. PMID: 7743306.

27. Renugadevi J, Prabu SM. Cadmium-induced hepatotoxicity in rats and the protective effect of naringenin. Exp Toxicol Pathol. 2010; 62(2):171–181. PMID: 19409769.

28. Hazelhoff MH, Torres AM. Gender differences in mercury-induced hepatotoxicity: potential mechanisms. Chemosphere. 2018; 202:330–338. PMID: 29574386.

29. Pizent A, Jurasovie J, Telisman S. Blood pressure in relation to dietary calcium intake, alcohol consumption, blood lead, and blood cadmium in female nonsmokers. J Trace Elem Med Biol. 2001; 15(2-3):123–130. PMID: 11787977.

30. Sherlock JC, Pickford CJ, White GF. Lead in alcoholic beverages. Food Addit Contam. 1986; 3(4):347–354. PMID: 3803640.

31. Harrison-Findik DD. Is the iron regulatory hormone hepcidin a risk factor for alcoholic liver disease? World J Gastroenterol. 2009; 15(10):1186–1193. PMID: 19291818.

32. Gao B, Ahmad MF, Nagy LE, Tsukamoto H. Inflammatory pathways in alcoholic steatohepatitis. J Hepatol. 2019; 70(2):249–259. PMID: 30658726.

33. Flora SJ, Tandon SK. Effect of combined exposure to cadmium and ethanol on regional brain biogenic amine levels in the rat. Biochem Int. 1987; 15(4):863–871. PMID: 3435548.

34. Gupta V, Gill KD. Influence of ethanol on lead distribution and biochemical changes in rats exposed to lead. Alcohol. 2000; 20(1):9–17. PMID: 10680712.

35. Maia CS, Lucena GM, Corrêa PB, Serra RB, Matos RW, Menezes FC, et al. Interference of ethanol and methylmercury in the developing central nervous system. Neurotoxicology. 2009; 30(1):23–30. PMID: 19100288.

36. Singh N, Gupta VK, Kumar A, Sharma B. Synergistic effects of heavy metals and pesticides in living systems. Front Chem. 2017; 5:70. PMID: 29075624.

37. Kolachi NF, Kazi TG, Afridi HI, Kazi NG, Khan S. Investigation of essential trace and toxic elements in biological samples (blood, serum and scalp hair) of liver cirrhotic/cancer female patients before and after mineral supplementation. Clin Nutr. 2012; 31(6):967–973. PMID: 22607713.

38. Prystupa A, Błażewicz A, Kiciński P, Sak JJ, Niedziałek J, Załuska W. Serum concentrations of selected heavy metals in patients with alcoholic liver cirrhosis from the Lublin region in eastern Poland. Int J Environ Res Public Health. 2016; 13(6):582. PMID: 27304961.

39. Edenberg HJ. The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res Health. 2007; 30(1):5–13. PMID: 17718394.