Modeling the progression of NAFLD: a multi-state Markov approach based on BMI classification in the Chinese population

Abstract

Aim: To investigate the natural history and progression of non-alcoholic fatty liver disease (NAFLD) in Chinese adults using a community-based longitudinal cohort. Methods: We analyzed data from 24,893 adults in the Beijing Health Management Cohort (2016–2021) with annual follow-up, including questionnaires, physical examinations, and laboratory tests. Participants were categorized into three states: healthy (S1, n = 17,906), NAFLD with body mass index (BMI) ＜ 24 kg/m² (S2, n = 1,139), and NAFLD with BMI ≥ 24 kg/m² (S3, n = 5,848). Transition probabilities, mean sojourn times, and determinants of progression were estimated using a multi-state Markov model, with analyses stratified by sex. Results: Most individuals remained in their baseline state. Females in S1 were more likely to stay healthy than males (93.76% vs. 83.52%), while males had a higher risk of progression to S3 (12.59% vs. 4.23%). Females in S3 had a greater chance of reverting to S1 (21.33% vs. 18.18%). Mean sojourn time in S1 was longer for females (18.58 vs. 6.97 years), whereas males spent more time in S3 (5.37 vs. 4.18 years). Age, hyperuricemia, abdominal obesity, high triglycerides, and low high-density lipoprotein cholesterol (HDL-C) significantly increased the risk of progression. Conclusions: Sex differences strongly affect NAFLD progression in Chinese adults. Males are more likely to deteriorate, while females show higher recovery. Metabolic factors and obesity are key targets for early prevention and intervention.

Keywords

non-alcoholic fatty liver disease / Markov model / disease progression / sex differences / Chinese population

References

[1] Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA. 2015; 313: 2263-73.

[2] Diehl AM, Day C. Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. N Engl J Med. 2017; 377: 2063-72.

[3] Cotter TG, Rinella M. Nonalcoholic Fatty Liver Disease 2020: The State of the Disease. Gastroenterology. 2020; 158: 1851-64.

[4] Li Z, Xue J, Chen P, Chen L, Yan S, Liu L. Prevalence of nonalcoholic fatty liver disease in mainland of China: a meta-analysis of published studies. J Gastroenterol Hepatol. 2014; 29: 42-51.

[5] Wang F, Fan J, Zhang Z, Gao B, Wang H. The global burden of liver disease: the major impact of China. Hepatology. 2014; 60: 2099-108.

[6] Fan J, Kim S, Wong VW. New trends on obesity and NAFLD in Asia. J Hepatol. 2017; 67: 862-73.

[7] Han E, Lee YH. Non-Alcoholic Fatty Liver Disease: The Emerging Burden in Cardiometabolic and Renal Diseases. Diabetes Metab J. 2017; 41: 430-7.

[8] Pisto P, Santaniemi M, Bloigu R, Ukkola O, Kesäniemi YA. Fatty liver predicts the risk for cardiovascular events in middle-aged population: a population-based cohort study. BMJ Open. 2014; 4: e004973.

[9] Patil R, Sood GK. Non-alcoholic fatty liver disease and cardiovascular risk. World J Gastrointest Pathophysiol. 2017; 8: 51-8.

[10] Park HE, Kwak M, Kim D, Kim M, Cha M, Choi S. Nonalcoholic Fatty Liver Disease Is Associated With Coronary Artery Calcification Development: A Longitudinal Study. J Clin Endocrinol Metab. 2016; 101: 3134-43.

[11] Nseir W, Shalata A, Marmor A, Assy N. Mechanisms linking nonalcoholic fatty liver disease with coronary artery disease. Dig Dis Sci. 2011; 56: 3439-49.

[12] Juanola O, Martínez-López S, Francés R, Gómez-Hurtado I. Non-Alcoholic Fatty Liver Disease: Metabolic, Genetic, Epigenetic and Environmental Risk Factors. Int J Environ Res Public Health. 2021; 18: 5227.

[13] Targher G, Corey KE, Byrne CD. NAFLD, and cardiovascular and cardiac diseases: Factors influencing risk, prediction and treatment. Diabetes Metab. 2021; 47: 101215.

[14] Zheng X, Xiong J, Zhang Y, Xu L, Zhou L, Zhao B, et al. Multistate Markov model application for blood pressure transition among the Chinese elderly population: a quantitative longitudinal study. BMJ Open. 2022; 12: e059805.

[15] Beyersmann J, Wolkewitz M, Allignol A, Grambauer N, Schumacher M. Application of multistate models in hospital epidemiology: advances and challenges. Biom J. 2011; 53: 332-50.

[16] Sun B, Li S, Wang Y, Xiao W, Zhao H, Liu X, et al. Sarcopenia Transitions and Influencing Factors Among Chinese Older Adults With Multistate Markov Model. Innov Aging. 2023; 7: igad105.

[17] Nuttall FQ. Body Mass Index: Obesity, BMI, and Health: A Critical Review. Nutr Today. 2015; 50: 117-28.

[18] Lin X. A report on the status of nutrition and chronic Diseases among Chinese residents. J Tradit Chin Med Manag. 2015; 23: 89.

[19] Polyzos SA, Kountouras J, Mantzoros CS. Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics. Metabolism. 2019; 92: 82-97.

[20] Quek J, Chan KE, Wong ZY, Tan C, Tan B, Lim WH, et al. Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2023; 8: 20-30.

[21] Kong L, Yang Y, Li H, Shan Y, Wang X, Shan X. Prevalence of nonalcoholic fatty liver disease and the related risk factors among healthy adults: A cross-sectional study in Chongqing, China. Front Public Health. 2023; 11: 1127489.

[22] Tu B, Li W, Xiao H, Xu X, Zhang Y. Optimizing lifestyle profiles is potential for preventing nonalcoholic fatty liver disease and enhancing its survival. Sci Rep. 2024; 14: 5516.

[23] Wong VW, Ekstedt M, Wong GL, Hagström H. Changing epidemiology, global trends and implications for outcomes of NAFLD. J Hepatol. 2023; 79: 842-52.

[24] Gu Y, Guo C, Liu Z, Zhang Y, Han X, Zhang X, et al. The trend in incidence of non-alcoholic fatty liver disease and its impact on cirrhosis and liver cancer: An analysis from Global Burden of Disease 2021. Public Health. 2025; 242: 79-86.

[25] Le MH, Le DM, Baez TC, Wu Y, Ito T, Lee EY, et al. Global incidence of non-alcoholic fatty liver disease: A systematic review and meta-analysis of 63 studies and 1,201,807 persons. J Hepatol. 2023; 79: 287-95.

[26] Koh JH, Wang M, Suzuki H, Muthiah M, Ng CH, Huang DQ. NAFLD and NAFLD-related HCC in Asia: Burden and Surveillance. J Clin Exp Hepatol. 2024; 14: 101213.

[27] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; 372: n71.

[28] National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology ; Chinese Medical Association Fatty Liver Expert Committee; Chinese Medical Doctor Association. Guidelines of prevention and treatment for nonalcoholic fatty liver disease: a 2018 update. Infect Dis Inf. 2018; 31: 393-402.

[29] Li Q, Li X, Kwong JS, Chen H, Sun X, Tian H, et al. Diagnosis and treatment for hyperuricaemia and gout: a protocol for a systematic review of clinical practice guidelines and consensus statements. BMJ Open. 2017; 7: e014928.

[30] Jackson C. Multi-State Models for Panel Data: The msm Package for R. J Stat Softw. 2011; 38: 1-28.

[31] Xiang M, Tian X, Wang H, Gan P, Zhang Q. Inappropriate Diet Exacerbates Metabolic Dysfunction-Associated Steatotic Liver Disease via Abdominal Obesity. Nutrients. 2024; 16: 4208.

[32] Yazıcı D, Demir S, Sezer H. Insulin Resistance, Obesity, and Lipotoxicity. Adv Exp Med Biol. 2024; 1460: 391-430.

[33] Tchernof A, Després J. Pathophysiology of human visceral obesity: an update. Physiol Rev. 2013; 93: 359-404.

[34] Kim E, Lee Y, Kwon Y, Lee J. Age at menopause and risk of metabolic dysfunction-associated fatty liver disease: A 14-year cohort study. Dig Liver Dis. 2024; 56: 1880-6.

[35] Sommerauer C, Gallardo-Dodd CJ, Savva C, Hases L, Birgersson M, Indukuri R, et al. Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis. Mol Syst Biol. 2024; 20: 374-402.

[36] Li L, Yao Y, Wang Y, Cao J, Jiang Z, Yang Y, et al. G protein-coupled estrogen receptor 1 ameliorates nonalcoholic steatohepatitis through targeting AMPK-dependent signaling. J Biol Chem. 2024; 300: 105661.

[37] Fu W, Zhao J, Cheng G, Xu L, Lyu L, Ding Y. Dietary Inflammatory index and its association with fatty liver disease: a study in obese and non-obese populations. BMC Gastroenterol. 2025; 25: 102.

[38] Bian L, Tang T, Yu Q, Tong X, Hu S, You Y, et al. Association between the triglyceride to high-density lipoprotein cholesterol ratio and type 2 diabetes mellitus in non-alcoholic fatty liver disease. Sci Rep. 2024; 14: 31048.

[39] Sheng G, Lu S, Xie Q, Peng N, Kuang M, Zou Y. The usefulness of obesity and lipid-related indices to predict the presence of Non-alcoholic fatty liver disease. Lipids Health Dis. 2021; 20: 134.

[40] Fallatah HI, Akbar HO, Fallatah AM. Fibroscan Compared to FIB-4, APRI, and AST/ALT Ratio for Assessment of Liver Fibrosis in Saudi Patients With Nonalcoholic Fatty Liver Disease. Hepat Mon. 2016; 16: e38346.

[41] Song R, Hu M, Qin X, Qiu L, Wang P, Zhang X, et al. The Roles of Lipid Metabolism in the Pathogenesis of Chronic Diseases in the Elderly. Nutrients. 2023; 15: 3433.

[42] Zhao D, Cui H, Shao Z, Cao L. Abdominal obesity, chronic inflammation and the risk of non-alcoholic fatty liver disease. Ann Hepatol. 2023; 28: 100726.

[43] Wong C, Lee MH, Yaow CYL, Chin YH, Goh XL, Ng CH, et al. Glucagon-Like Peptide-1 Receptor Agonists for Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: A Meta-Analysis. Front Endocrinol (Lausanne). 2021; 12: 609110.

[44] Lee HA, Kim HY. Therapeutic Mechanisms and Clinical Effects of Glucagon-like Peptide 1 Receptor Agonists in Nonalcoholic Fatty Liver Disease. Int J Mol Sci. 2023; 24: 9324.