Cumulative metabolic, behavioral, and early-life factors for MASLD in Chinese children with validation in U.S. adolescents

Abstract

Aim: This study aimed to explore the cumulative effects of metabolic, behavioral, and early-life risk factors on metabolic dysfunction-associated steatotic liver disease (MASLD).

Methods: Data were obtained from a school-based longitudinal survey conducted in Beijing in 2023. Logistic regression models were used to examine independent associations, construct a risk score, and assess the cumulative effects of risk factors on pediatric MASLD. The risk score was further validated using data from the National Health and Nutrition Examination Survey (NHANES) 2017-2020 cycles.

Results: The prevalence of MASLD among Chinese children was 4.4% at baseline and 7.6% at follow-up. Baseline MASLD was significantly associated with exposure to second-hand smoke (OR = 2.36) and sedentary behavior (SB, OR = 3.21). Each one-unit increase in the risk score was associated with a 73% higher risk of MASLD at baseline, with similar cumulative effects observed in the NHANES cohort. At follow-up, each unit increase in the score corresponded to a 263% higher risk of MASLD. Furthermore, the risk of incident MASLD and persistent MASLD increased by 150% and 111%, respectively, for each unit increase in the score.

Conclusion: Within a conceptual framework addressing multiple levels of risk, we found that metabolic, behavioral, and early-life factors exert cumulative effects on pediatric MASLD. These effects were evident despite the substantial differences between the Chinese and U.S. populations. Targeted intervention strategies informed by this framework - such as improving the early-life environment, promoting healthier lifestyle behaviors, and maintaining favorable metabolic profiles - are essential for the management of pediatric MASLD.

Keywords

Metabolic dysfunction-associated steatotic liver disease / pediatrics / metabolic / behavioral / and early-life risk factors / independent and cumulative effects

References

[1] Rinella ME, Lazarus JV, Ratziu V, et al; NAFLD Nomenclature consensus group. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023;79:1542-56.

[2] Younossi Z,Marietti M.Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.Nat Rev Gastroenterol Hepatol2018;15:11-20

[3] Inoue Y,Poti J,Gordon-Larsen P.Epidemiology of obesity in adults: latest trends.Curr Obes Rep2018;7:276-88 PMCID:PMC6215729

[4] Estes C,Arias-Loste MT.Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030.J Hepatol2018;69:896-904

[5] Nobili V,Newton KP.Comparison of the phenotype and approach to pediatric vs adult patients with nonalcoholic fatty liver disease.Gastroenterology2016;150:1798-810 PMCID:PMC4887388

[6] Chen Y,Kuppa A.Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease.Nat Genet2023;55:1640-50 PMCID:PMC10918428

[7] Yuan Q,Gao P.Prevalence and risk factors of metabolic-associated fatty liver disease among 73,566 individuals in Beijing, China.Int J Environ Res Public Health2022;19:2096 PMCID:PMC8871878

[8] Goldner D.Nonalcoholic fatty liver disease in children: unique considerations and challenges.Gastroenterology2020;158:1967-83.e1

[9] Zong X,Hong YM.Establishing international optimal cut-offs of waist-to-height ratio for predicting cardiometabolic risk in children and adolescents aged 6-18 years.BMC Med2023;21:442 PMCID:PMC10647138

[10] Chen YL,Li S.Prevalence of and risk factors for metabolic associated fatty liver disease in an urban population in China: a cross-sectional comparative study.BMC Gastroenterol2021;21:212 PMCID:PMC8111711

[11] Liu E,Pan T.Association between secondhand smoke exposure and nonalcoholic fatty liver disease in the general U.S. adult nonsmoker population.Nicotine Tob Res2024;26:663-8

[12] Romero-Gómez M,Trenell M.Treatment of NAFLD with diet, physical activity and exercise.J Hepatol2017;67:829-46

[13] Tsunoda K,Kai Y,Uchida K.Dose-response relationships of accelerometer-measured sedentary behaviour and physical activity with non-alcoholic fatty liver disease.Aliment Pharmacol Ther2021;54:1330-9

[14] Ebrahimi F,Hagström H.Birth weight, gestational age, and risk of pediatric-onset MASLD.JAMA Netw Open2024;7:e2432420 PMCID:PMC11388034

[15] Querter I,De Bruyne R.Maternal and perinatal risk factors for pediatric nonalcoholic fatty liver disease: a systematic review.Clin Gastroenterol Hepatol2022;20:740-55

[16] Wang X,Liu J.A cluster randomized trial of a comprehensive intervention nesting family and clinic into school centered implementation to reduce myopia and obesity among children and adolescents in Beijing, China: study protocol.BMC Public Health2023;23:1435 PMCID:PMC10373331

[17] Liu Y,Xing Y.Establish a noninvasive model to screen metabolic dysfunction-associated steatotic liver disease in children aged 6-14 years in China and its applications in high-obesity-risk countries and regions.Lancet Reg Health West Pac2024;49:101150 PMCID:PMC11338159

[18] Kojima S,Numata M,Matsuzaki S.Increase in the prevalence of fatty liver in Japan over the past 12 years: analysis of clinical background.J Gastroenterol2003;38:954-61

[19] Flynn JT, Kaelber DC, Baker-Smith CM, et al; SUBCOMMITTEE ON SCREENING AND MANAGEMENT OF HIGH BLOOD PRESSURE IN CHILDREN. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics. 2017; 140(3):e20171904. Pediatrics. 2017;140:e20173035.

[20] Chinese Society of Endocrinology CMA. Guideline for the diagnosis and management of hyperuricemia and gout in China (2019). Chin J Endocrinol Metab. 2020;36:1-13. (in Chinese).

[21] Committee on the Chinese Guidelines for Lipid Management. [Chinese guidelines for lipid management (2023)].Zhonghua Xin Xue Guan Bing Za Zhi2023;51:221-55

[22] Care of Preterm or Low Birthweight Infants Group. Electronic address: [e-mail]; Care of Preterm or Low Birthweight Infants Group. New WHO recommendations for the care of preterm or low birthweight infants have the potential to transform maternal and newborn health-care delivery.Lancet2022;400:1828-31

[23] Iasonos A,Raj GV.How to build and interpret a nomogram for cancer prognosis.J Clin Oncol2008;26:1364-70

[24] prevention UScfdca. National Health and Nutrition Examination Survey. Available from: https://www.cdc.gov/nchs/nhanes/index.html. [Last accessed on 3 Sep 2025].

[25] Zhou YJ,Nie YQ.Prevalence of fatty liver disease and its risk factors in the population of South China.World J Gastroenterol2007;13:6419-24

[26] Yang S,Ye M.Association between the non-HDL-cholesterol to HDL-cholesterol ratio and non-alcoholic fatty liver disease in Chinese children and adolescents: a large single-center cross-sectional study.Lipids Health Dis2020;19:242 PMCID:PMC7681973

[27] Li M,Zunong J.Predictors of non-alcoholic fatty liver disease in children.Pediatr Res2022;92:322-30

[28] Zhang X,Zhang S.Nonalcoholic fatty liver disease prevalence in urban school-aged children and adolescents from the Yangtze River delta region: a cross-sectional study.Asia Pac J Clin Nutr2015;24:281-8

[29] Luo D,Liu Y.Long-term trends and urban-rural disparities in the physical growth of children and adolescents in China: an analysis of five national school surveys over three decades.Lancet Child Adolesc Health2023;7:762-72

[30] Dong Y,Dong B.Trends in physical fitness, growth, and nutritional status of Chinese children and adolescents: a retrospective analysis of 1·5 million students from six successive national surveys between 1985 and 2014.Lancet Child Adolesc Health2019;3:871-80

[31] Obita G.Disparities in the prevalence of childhood obesity-related comorbidities: a systematic review.Front Public Health2022;10:923744 PMCID:PMC9298527

[32] She D,Yuan S.Association between serum cotinine and hepatic steatosis and liver fibrosis in adolescent: a population-based study in the United States.Sci Rep2024;14:11424 PMCID:PMC11102917

[33] Quek SXZ,Ren YP.Factors early in life associated with hepatic steatosis.World J Hepatol2022;14:1235-47 PMCID:PMC9258263

[34] Jiang X,Zhong H.Human milk-derived extracellular vesicles alleviate high fat diet-induced non-alcoholic fatty liver disease in mice.Mol Biol Rep2023;50:2257-68

[35] Kim D,Cholankeril G.Physical activity is associated with nonalcoholic fatty liver disease and significant fibrosis measured by fibroscan.Clin Gastroenterol Hepatol2022;20:e1438-55

[36] Sun Q,Manji L.Association between serum uric acid and non-alcoholic fatty liver disease: an updated systematic review and meta-analysis.Clin Epidemiol2023;15:683-93 PMCID:PMC10252946

[37] Lee E,Vidal-Puig A.An adipocentric perspective on the development and progression of non-alcoholic fatty liver disease.J Hepatol2023;78:1048-62

[38] Li Z,Chen S.Independent and cumulative effects of risk factors associated with stillbirths in 50 low- and middle-income countries: a multi-country cross-sectional study.EClinicalMedicine2022;54:101706 PMCID:PMC9637680

[39] Hernaez R,Bonekamp S.Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis.Hepatology2011;54:1082-90 PMCID:PMC4197002

[40] Balakrishnan M,Dunn-Valadez S.Women have a lower risk of nonalcoholic fatty liver disease but a higher risk of progression vs men: a systematic review and meta-analysis.Clin Gastroenterol Hepatol2021;19:61-71.e15 PMCID:PMC8796200

[41] Burra P,Schnabl B.Hepatic immune regulation and sex disparities.Nat Rev Gastroenterol Hepatol2024;21:869-84

[42] Burra P, Bizzaro D, Gonta A, et al; Special Interest Group Gender in Hepatology of the Italian Association for the Study of the Liver (AISF). Clinical impact of sexual dimorphism in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Liver Int. 2021;41:1713-33.

[43] Lonardo A.Sexual dimorphism of NAFLD in adults. Focus on clinical aspects and implications for practice and translational research.J Clin Med2020;9:1278 PMCID:PMC7288212

[44] Lonardo A,Ballestri S.Sex differences in nonalcoholic fatty liver disease: state of the art and identification of research gaps.Hepatology2019;70:1457-69 PMCID:PMC6766425

[45] Suzuki A, Abdelmalek MF, Schwimmer JB, et al; Nonalcoholic Steatohepatitis Clinical Research Network. Association between puberty and features of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2012;10:786-94. PMCID:PMC3382041

[46] Arnold AP,McCarthy MM.Male-female comparisons are powerful in biomedical research - don’t abandon them.Nature2024;629:37-40

[47] Sattar N,Preiss D.Non-alcoholic fatty liver disease.BMJ2014;349:g4596 PMCID:PMC4168663

[48] Lee J,Boursier J.Prognostic accuracy of FIB-4, NAFLD fibrosis score and APRI for NAFLD-related events: a systematic review.Liver Int2021;41:261-70 PMCID:PMC7898346