Commentary: Of women, liver, and heart

Abstract

This commentary is devoted to a recent study by Ren and Zheng (Nutr Metab Cardiovasc Dis. 2023;33:1349-1357). These authors analyzed sex-stratified long-term outcomes relevant to all-cause and cardiovascular field outcomes among 2,627 nonalcoholic fatty liver disease (NAFLD) adults enrolled in the 2000-2014 National Health and Nutrition Examination Surveys and identified with United States Fatty Liver Index (US FLI) score. Data have shown that, compared to women, men were exposed to a significantly higher all-cause mortality and the maximal risk was seen among those who had obesity and type 2 diabetes. However, women aged ≤ 60 years had a higher risk of death owing to cardiovascular disease (CVD). Conversely, no significantly increased risk of death from CVD was observed among women over 60 years compared to men of the same age group. The study by Ren and Zheng further fosters our understanding of cardiometabolic risk factors, illustrating sex differences present in NAFLD. The distinct impact of NAFLD on CVD by sex and age suggests that cardiometabolic comorbidities may be particularly underestimated among young and middle-aged women with NAFLD. The research by Ren and Zhang may stimulate future investigations exploring the molecular and cellular grounds underlying these findings, notably including the role of fibrosing NAFLD as a strong risk modifier of CVD. In conclusion, an improved understanding of sex-specific regulation of human metabolism in the liver and other key metabolic organs is a research priority finalized for implementing precision medicine approaches in NAFLD arena.

Keywords

Cardiovascular risk / nonalcoholic fatty liver disease / sex differences

References

[1] Lonardo A.Extra-hepatic cancers in metabolic fatty liver syndromes.Explor Dig Dis2023;2:11-7

[2] Petersen KF,Li F,Shulman GI.Ethnic and sex differences in hepatic lipid content and related cardiometabolic parameters in lean individuals.JCI Insight2022;7:e157906 PMCID:PMC9057590

[3] Lonardo A,Ricchi M,Loria P.Review article: hepatic steatosis and insulin resistance.Aliment Pharmacol Ther2005;22 Suppl 2:64-70

[4] Han SK,Kim MY.Correspondence on letter regarding "non-alcoholic fatty liver disease: definition and subtypes".Clin Mol Hepatol2023;29:817-9 PMCID:PMC10366801

[5] Lonardo A,Alswat KA.History of nonalcoholic fatty liver disease.Int J Mol Sci2020;21:5888 PMCID:PMC7460697

[6] Eckel RH,Grundy SM.The metabolic syndrome.Lancet2010;375:181-3

[7] Musso G,Bo S.Should nonalcoholic fatty liver disease be included in the definition of metabolic syndrome? a cross-sectional comparison with adult treatment panel III criteria in nonobese nondiabetic subjects.Diabetes Care2008;31:562-8

[8] Fu CE,Ng CH.The prognostic value of including non-alcoholic fatty liver disease in the definition of metabolic syndrome.Aliment Pharmacol Ther2023;57:979-87

[9] Wong VW,Wong GL.Changing epidemiology, global trends and implications for outcomes of NAFLD.J Hepatol2023;79:842-52

[10] Anstee QM,Day CP.Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis.Nat Rev Gastroenterol Hepatol2013;10:330-44

[11] Mantovani A,Petracca G.Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis.Lancet Gastroenterol Hepatol2021;6:903-13

[12] Lonardo A.Renaming NAFLD to MAFLD: could the lde system assist in this transition?.J Clin Med2021;10:492 PMCID:PMC7866816

[13] Rinella ME,Ratziu V.A multisociety Delphi consensus statement on new fatty liver disease nomenclature.J Hepatol2023;20:S0168-8278(23)00418

[14] Mauvais-Jarvis F,Barnes PJ.Sex and gender: modifiers of health, disease, and medicine.Lancet2020;396:565-82 PMCID:PMC7440877

[15] 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

[16] Regensteiner JG.Sex differences in cardiovascular consequences of hypertension, obesity, and diabetes: JACC focus seminar 4/7.J Am Coll Cardiol2022;79:1492-505 PMCID:PMC9503760

[17] Kautzky-Willer A,Harreiter J.Sex differences in type 2 diabetes.Diabetologia2023;66:986-1002 PMCID:PMC10163139

[18] Ren R.Sex differences in cardiovascular and all-cause mortality in nonalcoholic fatty liver disease in the US population.Nutr Metab Cardiovasc Dis2023;33:1349-57

[19] 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

[20] Ballestri S,Baldelli E,Romagnoli D.NAFLD as a sexual dimorphic disease: role of gender and reproductive status in the development and progression of nonalcoholic fatty liver disease and inherent cardiovascular risk.Adv Ther2017;34:1291-326 PMCID:PMC5487879

[21] Goossens GH,Blaak EE.Sexual dimorphism in cardiometabolic health: the role of adipose tissue, muscle and liver.Nat Rev Endocrinol2021;17:47-66

[22] 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

[23] Allen AM,Mara KC.Women with nonalcoholic fatty liver disease lose protection against cardiovascular disease: a longitudinal cohort study.Am J Gastroenterol2019;114:1764-71 PMCID:PMC6832850

[24] Khalid YS,Suga H,Reja D,McMahon D.Increased cardiovascular events and mortality in females with NAFLD: a meta-analysis.Am J Cardiovasc Dis2020;10:258-271. PMCID:PMC7486530

[25] Kim Y,Ryu S.Nonalcoholic fatty liver disease and risk of incident young-onset hypertension: effect modification by sex.Nutr Metab Cardiovasc Dis2023;33:1608-16

[26] Ciardullo S.Commentary on Kim et al. Silent threats: how NAFLD and hypertension team up in young adults, and the role of sex.Nutr Metab Cardiovasc Dis2023;33:1617-8

[27] Ruhl CE.Fatty liver indices in the multiethnic United States national health and nutrition examination survey.Aliment Pharmacol Ther2015;41:65-76

[28] Bedogni G,Miglioli L.The fatty liver index: a simple and accurate predictor of hepatic steatosis in the general population.BMC Gastroenterol2006;6:33 PMCID:PMC1636651

[29] Lonardo A,Bedogni G,Tiribelli C.The fatty liver index (FLI) 15 years later: a reappraisal.Metab Target Organ Damage2021;1:10

[30] Kasper P,Lang S.NAFLD and cardiovascular diseases: a clinical review.Clin Res Cardiol2021;110:921-37 PMCID:PMC8238775

[31] Ballestri S,Di Girolamo M,Capitelli M.Liver fibrosis in nonalcoholic fatty liver disease patients: noninvasive evaluation and correlation with cardiovascular disease and mortality.Metab Target Organ Damage2023;3:1.

[32] Lonardo A.Precision medicine in nonalcoholic fatty liver disease.J Gastroenterol Hepatol2022;37:1175-8