Research Article| Volume 128, 154893, March 2022

The presence of NAFLD influences the transition of metabolically healthy to metabolically unhealthy obesity and the ten-year cardiovascular disease risk: A population-based cohort study

Published:September 30, 2021DOI:


      • MHO individuals had equal chances to have NAFLD compared with MUO subjects.
      • MHO participants with NAFLD had 2 times higher chance to become MUO in long-term.
      • This transition subsequently increased their cardiometabolic risk.
      • NAFLD inclusion in metabolic status definition of obese could be of added value.



      We evaluated the role of the presence of non-alcoholic fatty liver disease (NAFLD) at baseline in the transition from metabolically healthy to metabolically unhealthy obesity (MHO to MUO) ten years later.


      A prospective cohort study (ATTICA study, Greece) was performed between 2002 and 2012 studying a sample from the greater metropolitan Athens area. In total, 1514 (49·8%) men and 1528 (50.2%) women (aged >18 years old) free-of-CVD were included. Healthy metabolic status was defined as absence of all NCEP ATP III (2005) metabolic syndrome components. NAFLD was defined according to validated liver steatosis indices. Follow-up CVD assessment (2011–2012) was achieved in n = 2020 participants (n = 317 cases).


      NAFLD prevalence among MHO participants ranged from 29% to 39% according to the specific NAFLD score used. MHO participants who developed metabolically unhealthy status had about two times higher odds to have NAFLD at baseline compared with their metabolically healthy normal weight counterparts whereas stable MHO was not associated significantly with NAFLD. Moreover, MHO status accompanied by NAFLD was associated with increased CVD risk (Hazard Ratio = 2.90 95% Confidence Interval (1.35, 5.40)) in comparison to their non-NAFLD MHO counterparts. Further analysis revealed that in the obese, NAFLD indices and not simply visceral adiposity increased significantly the ability of metabolic status (using standard definition) to predict long-term CVD incidence.


      Considering NAFLD, even when assessed using validated indices only, in the clinical assessment of apparently healthy obese individuals predicts who is to develop MUO and contributes independently and more accurately to defining future cardiometabolic risk.


      ALT (Alanine transaminase), AST (Aspartate transaminase), BMI (Body mass index), CVD (Cardiovascular disease), GGT (Gamma-Glutamyl transferase), FLI (Fatty liver index), HR (Hazard ratio), HSI (Hepatic steatosis index), HOMA-IR (Homeostasis model assessment of insulin resistance), MHN (Metabolically healthy non-obese), MHO (Metabolically healthy obese), MetS (Metabolic syndrome), MUN (Metabolically unhealthy non-obese), MUO (Metabolically unhealthy obese), NAFLD (Non-alcoholic fatty liver disease), NAFLD-FLS (Non-alcoholic fatty liver disease fatty liver score), OR (Odds Ratio), 95% CI (95% Confidence Interval)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Metabolism - Clinical and Experimental
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Kivimäki M.
        • Kuosma E.
        • Ferrie J.E.
        • Luukkonen R.
        • Nyberg S.T.
        • Alfredsson L.
        • et al.
        Overweight, obesity, and risk of cardiometabolic multimorbidity: pooled analysis of individual-level data for 120,813 adults from 16 cohort studies from the USA and Europe.
        Lancet Public Health. 2017; 2: e277-e285
        • Mathew H.
        • Farr O.M.
        • Mantzoros C.S.
        Metabolic health and weight: understanding metabolically unhealthy normal weight or metabolically healthy obese patients.
        Metabolism. 2016; 65: 73-80
        • Tsatsoulis A.
        • Paschou S.A.
        Metabolically healthy obesity: criteria, epidemiology, controversies, and consequences.
        Curr Obes Rep. 2020; 9: 109-120
        • Eckel N.
        • Meidtner K.
        • Kalle-Uhlmann T.
        • Stefan N.
        • Schulze M.B.
        Metabolically healthy obesity and cardiovascular events: a systematic review and meta-analysis.
        Eur J Prev Cardiol. 2016; 23: 956-966
        • Fan J.
        • Song Y.
        • Chen Y.
        • Hui R.
        • Zhang W.
        Combined effect of obesity and cardio-metabolic abnormality on the risk of cardiovascular disease: a meta-analysis of prospective cohort studies.
        Int J Cardiol. 2013; 168: 4761-4768
        • Kramer C.K.
        • Zinman B.
        • Retnakaran R.
        Are metabolically healthy overweight and obesity benign conditions?: a systematic review and meta-analysis.
        Ann Intern Med. 2013; 159: 758-769
        • Zheng R.
        • Zhou D.
        • Zhu Y.
        The long-term prognosis of cardiovascular disease and all-cause mortality for metabolically healthy obesity: a systematic review and meta-analysis.
        J Epidemiol Community Health. 2016; 70: 1024-1031
        • Kouvari M.
        • Panagiotakos D.B.
        • Yannakoulia M.
        • Georgousopoulou E.
        • Critselis E.
        • Chrysohoou C.
        • et al.
        Transition from metabolically benign to metabolically unhealthy obesity and 10-year cardiovascular disease incidence: the ATTICA cohort study.
        Metabolism. 2019; 93: 18-24
        • Mongraw-Chaffin M.
        • Foster M.C.
        • Anderson C.A.M.
        • Burke G.L.
        • Haq N.
        • Kalyani R.R.
        • et al.
        Metabolically healthy obesity, transition to metabolic syndrome, and cardiovascular risk.
        J Am Coll Cardiol. 2018; 71: 1857-1865
        • Lin L.
        • Zhang J.
        • Jiang L.
        • Du R.
        • Hu C.
        • Lu J.
        • et al.
        Transition of metabolic phenotypes and risk of subclinical atherosclerosis according to BMI: a prospective study.
        Diabetologia. 2020; 63: 1312-1323
        • Lonardo A.
        • Ballestri S.
        • Marchesini G.
        • Angulo P.
        • Loria P.
        Nonalcoholic fatty liver disease: a precursor of the metabolic syndrome.
        Dig Liver Dis. 2015; 47: 181-190
        • Stefan N.
        • Häring H.-U.
        • Hu F.B.
        • Schulze M.B.
        Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications.
        Lancet Diabetes Endocrinol. 2013; 1: 152-162
        • Cariou B.
        • Byrne C.D.
        • Loomba R.
        • Sanyal A.J.
        Nonalcoholic fatty liver disease as a metabolic disease in humans: a literature review.
        Diabetes Obes Metab. 2021;
        • Chang Y.
        • Jung H.-S.
        • Cho J.
        • Zhang Y.
        • Yun K.E.
        • Lazo M.
        • et al.
        Metabolically healthy obesity and the development of nonalcoholic fatty liver disease.
        Am J Gastroenterol. 2016; 111: 1133-1140
        • Kim Y.
        • Chang Y.
        • Cho Y.K.
        • Ahn J.
        • Shin H.
        • Ryu S.
        Metabolically healthy versus unhealthy obesity and risk of fibrosis progression in non-alcoholic fatty liver disease.
        Liver Int. 2019; 39: 1884-1894
        • Gutiérrez-Grobe Y.
        • Juárez-Hernández E.
        • Sánchez-Jiménez B.A.
        • Uribe-Ramos M.H.
        • Ramos-Ostos M.H.
        • Uribe M.
        • et al.
        Less liver fibrosis in metabolically healthy compared with metabolically unhealthy obese patients with non-alcoholic fatty liver disease.
        Diabetes Metab. 2017; 43: 332-337
        • Sung K.-C.
        • Cha S.-C.
        • Sung J.-W.
        • So M.-S.
        • Byrne C.D.
        Metabolically healthy obese subjects are at risk of fatty liver but not of pre-clinical atherosclerosis.
        Nutr Metab Cardiovasc Dis. 2014; 24: 256-262
        • Pitsavos C.
        • Panagiotakos D.B.
        • Chrysohoou C.
        • Stefanadis C.
        Epidemiology of cardiovascular risk factors in Greece: aims, design and baseline characteristics of the ATTICA study.
        BMC Public Health. 2003; 3: 32
        • Ortega F.B.
        • Lavie C.J.
        • Blair S.N.
        Obesity and cardiovascular disease.
        Circ Res. 2016; 118: 1752-1770
        • Lavie C.J.
        • Laddu D.
        • Arena R.
        • Ortega F.B.
        • Alpert M.A.
        • Kushner R.F.
        Healthy weight and obesity prevention: JACC health promotion series.
        J Am Coll Cardiol. 2018; 72: 1506-1531
        • Castera L.
        • Friedrich-Rust M.
        • Loomba R.
        Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease.
        Gastroenterology. 2019; 156 (e4): 1264-1281
        • Yki-Järvinen H.
        Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome.
        Lancet Diabetes Endocrinol. 2014; 2: 901-910
        • Hamer M.
        • Bell J.A.
        • Sabia S.
        • Batty G.D.
        • Kivimäki M.
        Stability of metabolically healthy obesity over 8 years: the English Longitudinal Study of Ageing.
        Eur J Endocrinol. 2015; 173: 703-708
        • Kabat G.C.
        • Wu W.Y.-Y.
        • Bea J.W.
        • Chen C.
        • Qi L.
        • Stefanick M.L.
        • et al.
        Metabolic phenotypes of obesity: frequency, correlates and change over time in a cohort of postmenopausal women.
        Int J Obes (Lond). 2017; 41: 170-177
        • Eckel N.
        • Li Y.
        • Kuxhaus O.
        • Stefan N.
        • Hu F.B.
        • Schulze M.B.
        Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90,257 women (the Nurses’ Health Study): 30-year follow-up from a prospective cohort study.
        Lancet Diabetes Endocrinol. 2018; 6: 714-724
        • Hwang Y.-C.
        • Hayashi T.
        • Fujimoto W.Y.
        • Kahn S.E.
        • Leonetti D.L.
        • McNeely M.J.
        • et al.
        Visceral abdominal fat accumulation predicts the conversion of metabolically healthy obese subjects to an unhealthy phenotype.
        Int J Obes (Lond). 2015; 39: 1365-1370
        • Hwang Y.-C.
        • Ahn H.-Y.
        • Park C.-Y.
        Association between nonalcoholic fatty liver disease and future deterioration of metabolic health: a cohort study.
        Obesity (Silver Spring). 2019; 27: 1360-1366
        • Mantovani A.
        • Byrne C.D.
        • Bonora E.
        • Targher G.
        Nonalcoholic fatty liver disease and risk of incident type 2 diabetes: a meta-analysis.
        Diabetes Care. 2018; 41: 372-382
        • Lassale C.
        • Tzoulaki I.
        • Moons K.G.M.
        • Sweeting M.
        • Boer J.
        • Johnson L.
        • et al.
        Separate and combined associations of obesity and metabolic health with coronary heart disease: a pan-European case-cohort analysis.
        Eur Heart J. 2018; 39: 397-406
        • Hinnouho G.-M.
        • Czernichow S.
        • Dugravot A.
        • Nabi H.
        • Brunner E.J.
        • Kivimaki M.
        • et al.
        Metabolically healthy obesity and the risk of cardiovascular disease and type 2 diabetes: the Whitehall II cohort study.
        Eur Heart J. 2015; 36: 551-559
        • Gummesson A.
        • Strömberg U.
        • Schmidt C.
        • Kullberg J.
        • Angerås O.
        • Lindgren S.
        • et al.
        Non-alcoholic fatty liver disease is a strong predictor of coronary artery calcification in metabolically healthy subjects: a cross-sectional, population-based study in middle-aged subjects.
        PLoS One. 2018; 13e0202666
        • Yang S.
        • Kwak S.
        • Lee J.-H.
        • Kang S.
        • Lee S.-P.
        Nonalcoholic fatty liver disease is an early predictor of metabolic diseases in a metabolically healthy population.
        PLoS One. 2019; 14e0224626
        • Rana J.S.
        • Nieuwdorp M.
        • Jukema J.W.
        • Kastelein J.J.P.
        Cardiovascular metabolic syndrome - an interplay of, obesity, inflammation, diabetes and coronary heart disease.
        Diabetes Obes Metab. 2007; 9: 218-232