Metabolic (dysfunction)-associated fatty liver disease (MAFLD) affects up to a third of the global population; its burden has grown in parallel with rising rates of type 2 diabetes mellitus and obesity. MAFLD increases the risk of end-stage liver disease, hepatocellular carcinoma, death and liver transplantation and has extrahepatic consequences, including cardiometabolic disease and cancers. Although typically associated with obesity, there is accumulating evidence that not all people with overweight or obesity develop fatty liver disease. On the other hand, a considerable proportion of patients with MAFLD are of normal weight, indicating the importance of metabolic health in the pathogenesis of the disease regardless of body mass index. The clinical profile, natural history and pathophysiology of patients with so-called lean MAFLD are not well characterized. In this Review, we provide epidemiological data on this group of patients and consider overall metabolic health and metabolic adaptation as a framework to best explain the pathogenesis of MAFLD and its heterogeneity in individuals of normal weight and in those who are above normal weight. This framework provides a conceptual schema for interrogating the MAFLD phenotype in individuals of normal weight that can translate to novel approaches for diagnosis and patient care.
Lean metabolic (dysfunction)-associated fatty liver disease (MAFLD) is common, and these patients have a worse long-term outcome than patients without MAFLD.
MAFLD in patients of normal weight likely has a similar prognosis to that in patients with overweight or obesity.
Metabolic health is a major determinant of MAFLD pathogenesis in patients of normal weight.
Metabolic flexibility and adaptation have major roles in shaping the metabolic health of an individual and consequently the risk of MAFLD.
There are no specific guidelines for the management of patients of normal weight with MAFLD but lifestyle interventions remain a cornerstone of treatment.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
A comparison of NAFLD and MAFLD diagnostic criteria in contemporary urban healthy adults in China: a cross-sectional study
BMC Gastroenterology Open Access 19 November 2022
Subscribe to Nature+
Get immediate online access to Nature and 55 other Nature journal
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Eslam, M. & George, J. Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology. Nat. Rev. Gastroenterol. Hepatol. 17, 40–52 (2020).
Younossi, Z. et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 15, 11–20 (2018).
Eslam, M., Sanyal, A. J. & George, J. Toward more accurate nomenclature for fatty liver diseases. Gastroenterology 157, 590–593 (2019).
Sarin, S. K. et al. Liver diseases in the Asia-Pacific region: a Lancet Gastroenterology & Hepatology commission. Lancet Gastroenterol. Hepatol. 5, 167–228 (2020).
Paik, J. M. et al. Mortality related to nonalcoholic fatty liver disease is increasing in the United States. Hepatol. Commun. 3, 1459–1471 (2019).
Sayiner, M. et al. Assessment of health utilities and quality of life in patients with non-alcoholic fatty liver disease. BMJ Open Gastroenterol. 3, e000106 (2016).
Guthold, R., Stevens, G. A., Riley, L. M. & Bull, F. C. Worldwide trends in insufficient physical activity from 2001 to 2016: a pooled analysis of 358 population-based surveys with 1.9 million participants. Lancet Glob. Health 6, e1077–e1086 (2018).
Xie, X. et al. Healthy dietary patterns and metabolic dysfunction-associated fatty liver disease in less-developed ethnic minority regions: a large cross-sectional study. BMC Public Health 22, 118 (2022).
Eslam, M., Sanyal, A. J. & George, J., International Consensus Panel. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 158, 1999–2014.e1 (2020).
Eslam, M. et al. Defining paediatric metabolic (dysfunction)-associated fatty liver disease: an international expert consensus statement. Lancet Gastroenterol. Hepatol. 6, 864–873 (2021).
Chen, F. et al. Lean NAFLD: a distinct entity shaped by differential metabolic adaptation. Hepatology 71, 1213–1227 (2020).
Eslam, M. et al. The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol. Int. 14, 889–919 (2020).
Younes, R. et al. Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach? Gut 71, 382–390 (2022).
Eslam, M. et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J. Hepatol. 73, 202–209 (2020).
Chalasani, N. et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67, 328–357 (2018).
Targher, G. Concordance of MAFLD and NAFLD diagnostic criteria in “real-world” data. Liver Int. 40, 2879–2880 (2020).
Ayada, I. et al. Systematically comparing epidemiological and clinical features of MAFLD and NAFLD by meta‐analysis: focusing on the non‐overlap groups. Liver Int. 42, 277–287 (2021).
Fouad, Y. et al. The NAFLD-MAFLD debate: eminence vs evidence. Liver Int. 41, 255–260 (2021).
Eslam, M., Ratziu, V. & George, J. Yet more evidence that MAFLD is more than name change. J. Hepatol. 74, 977–979 (2021).
Shiha, G. et al. Redefining fatty liver disease: an international patient perspective. Lancet Gastroenterol. Hepatol. 6, 73–79 (2021).
Tsutsumi, T. et al. MAFLD better predicts the progression of atherosclerotic cardiovascular risk than NAFLD: generalized estimating equation approach. Hepatol. Res. 51, 1115–1128 (2021).
Yamamura, S. et al. MAFLD identifies patients with significant hepatic fibrosis better than NAFLD. Liver Int. 40, 3018–3030 (2020).
Zheng, K. I. et al. From NAFLD to MAFLD: a “redefining” moment for fatty liver disease. Chin. Med. J. 133, 2271–2273 (2020).
World Health Organization. Physical status: the use and interpretation of anthropometry (WHO, 1995).
WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 363, 157–163 (2004).
Kim, H. J. et al. Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch. Intern. Med. 164, 2169–2175 (2004).
Zeng, J. et al. Prevalence, clinical characteristics, risk factors, and indicators for lean Chinese adults with nonalcoholic fatty liver disease. World J. Gastroenterol. 26, 1792 (2020).
Wei, J. L. et al. Prevalence and severity of nonalcoholic fatty liver disease in non-obese patients: a population study using proton-magnetic resonance spectroscopy. Am. J. Gastroenterol. 110, 1306–1314 (2015).
Ye, Q. et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 5, 739–752 (2020).
Ito, T. et al. The epidemiology of NAFLD and lean NAFLD in Japan: a meta-analysis with individual and forecasting analysis, 1995–2040. Hepatol. Int. 15, 366–379 (2021).
Young, S. et al. Prevalence and profile of nonalcoholic fatty liver disease in lean adults: systematic review and meta‐analysis. Hepatol. Commun. 4, 953–972 (2020).
Lu, F. B. et al. Global epidemiology of lean non‐alcoholic fatty liver disease: a systematic review and meta‐analysis. J. Gastroenterol. Hepatol. 35, 2041–2050 (2020).
Browning, J. D. et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40, 1387–1395 (2004).
Foster, T., Anania, F. A., Li, D., Katz, R. & Budoff, M. The prevalence and clinical correlates of nonalcoholic fatty liver disease (NAFLD) in African Americans: the multiethnic study of atherosclerosis (MESA). Dig. Dis. Sci. 58, 2392–2398 (2013).
Weinberg, E. M. et al. Lean Americans with nonalcoholic fatty liver disease have lower rates of cirrhosis and comorbid diseases. Clin. Gastroenterol. Hepatol. 19, 996–1008.e6 (2021).
Rastogi, A. et al. Non‐alcoholic fatty liver disease–histological scoring systems: a large cohort single‐center, evaluation study. APMIS 125, 962–973 (2017).
Denkmayr, L. et al. Lean patients with non-alcoholic fatty liver disease have a severe histological phenotype similar to obese patients. J. Clin. Med. 7, 562 (2018).
Wang, Q. et al. Non-obese histologically confirmed NASH patients with abnormal liver biochemistry have more advanced fibrosis. Hepatol. Int. 13, 766–776 (2019).
Dela Cruz, A. C. et al. Characteristics and long-term prognosis of lean patients with nonalcoholic fatty liver disease. Gastroenterology 146, 726–735 (2014).
Hagstrom, H. et al. Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: a long-term follow-up study. Hepatol. Commun. 2, 48–57 (2018).
Leung, J. C. et al. Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients. Hepatology 65, 54–64 (2017).
Fracanzani, A. L. et al. Risk of nonalcoholic steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease and low visceral adiposity. J. Hepatol. 54, 1244–1249 (2011).
Wei, L. et al. Lean non-alcoholic fatty liver disease and risk of incident diabetes in a euglycaemic population undergoing health check-ups: a cohort study. Diabetes Metab. 47, 101200 (2021).
Zou, B. et al. Prevalence, characteristics and mortality outcomes of obese, nonobese and lean NAFLD in the United States, 1999–2016. J. Intern. Med. 288, 139–151 (2020).
Golabi, P. et al. Patients with lean nonalcoholic fatty liver disease are metabolically abnormal and have a higher risk for mortality. Clin. Diabetes 37, 65–72 (2019).
Corvellec, H. The practice of risk management: silence is not absence. Risk Manag. 11, 285–304 (2009).
Rothman, K. J. BMI-related errors in the measurement of obesity. Int. J. Obes. 32, S56–S59 (2008).
Banack, H. & Stokes, A. The ‘obesity paradox’ may not be a paradox at all. Int. J. Obes. 41, 1162–1163 (2017).
Bayoumi, A., Gronbaek, H., George, J. & Eslam, M. The epigenetic drug discovery landscape for metabolic-associated fatty liver disease. Trends Genet. 36, 429–441 (2020).
Eslam, M. & George, J. Genetic and epigenetic mechanisms of NASH. Hepatol. Int. 10, 394–406 (2016).
Loomba, R. et al. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology 149, 1784–1793 (2015).
Eslam, M., Valenti, L. & Romeo, S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J. Hepatol. 68, 268–279 (2018).
Yoshida, K. et al. Genome‐wide association study of lean nonalcoholic fatty liver disease suggests human leukocyte antigen as a novel candidate locus. Hepatol. Commun. 4, 1124–1135 (2020).
Bale, G. et al. Whole-exome sequencing identifies a variant in phosphatidylethanolamine N-methyltransferase gene to be associated with lean-nonalcoholic fatty liver disease. J. Clin. Exp. Hepatol. 9, 561–568 (2019).
Fracanzani, A. L. et al. Liver and cardiovascular damage in patients with lean nonalcoholic fatty liver disease, and association with visceral obesity. Clin. Gastroenterol. Hepatol. 15, 1604–1611.e1 (2017).
Eslam, M. et al. Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes. Hepatology 64, 34–46 (2016).
Liu, Y. L. et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat. Commun. 5, 4309 (2014).
Thabet, K. et al. MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C. Nat. Commun. 7, 12757 (2016).
Thabet, K. et al. The membrane-bound O-acyltransferase domain-containing 7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B. Hepatology 65, 1840–1850 (2017).
Eslam, M. et al. Interferon-lambda rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease. Nat. Commun. 6, 6422 (2015).
Petta, S. et al. Interferon lambda 4 rs368234815 TT>deltaG variant is associated with liver damage in patients with nonalcoholic fatty liver disease. Hepatology 66, 1885–1893 (2017).
Eslam, M. et al. FibroGENE: a gene-based model for staging liver fibrosis. J. Hepatol. 64, 390–398 (2016).
Nobili, V. et al. Intrauterine growth retardation, insulin resistance, and nonalcoholic fatty liver disease in children. Diabetes Care 30, 2638–2640 (2007).
Eslam, M., Fan, J.-G. & Mendez-Sanchez, N. Non-alcoholic fatty liver disease in non-obese individuals: the impact of metabolic health. Lancet Gastroenterol. Hepatol. 5, 713–715 (2020).
Rey‐Lopez, J., De Rezende, L., Pastor‐Valero, M. & Tess, B. The prevalence of metabolically healthy obesity: a systematic review and critical evaluation of the definitions used. Obes. Rev. 15, 781–790 (2014).
Stefan, N., Schick, F. & Haring, H. U. Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans. Cell Metab. 26, 292–300 (2017).
Araujo, J., Cai, J. & Stevens, J. Prevalence of optimal metabolic health in American adults: national health and nutrition examination survey 2009–2016. Metab. Syndr. Relat. Disord. 17, 46–52 (2019).
Smith, U. & Kahn, B. B. Adipose tissue regulates insulin sensitivity: role of adipogenesis, de novo lipogenesis and novel lipids. J. Intern. Med. 280, 465–475 (2016).
Bugianesi, E. et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 48, 634–642 (2005).
Despres, J. P. Body fat distribution and risk of cardiovascular disease an update. Circulation 126, 1301–1313 (2012).
Loos, R. J. F. & Kilpelainen, T. O. Genes that make you fat, but keep you healthy. J. Intern. Med. 284, 450–463 (2018).
Ampuero, J. et al. The effects of metabolic status on non-alcoholic fatty liver disease-related outcomes, beyond the presence of obesity. Aliment. Pharmacol. Ther. 48, 1260–1270 (2018).
Eckel, N. et al. 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. 6, 714–724 (2018).
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. 23, 956–966 (2016).
Gujral, U. P. et al. Cardiometabolic abnormalities among normal-weight persons from five racial/ethnic groups in the United States: a cross-sectional analysis of two cohort studies. Ann. Intern. Med. 166, 628–636 (2017).
Emerging Risk Factors Collaboration et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 375, 2215–2222 (2010).
Emerging Risk Factors Collaboration et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 302, 1993–2000 (2009).
Emerging Risk Factors Collaboration et al. Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies. Lancet 377, 1085–1095 (2011).
Eslam, M. & George, J. Refining the role of epicardial adipose tissue in non-alcoholic fatty liver disease. Hepatol. Int. 13, 662–664 (2019).
Pischon, T. et al. General and abdominal adiposity and risk of death in Europe. N. Engl. J. Med. 359, 2105–2120 (2008).
Abraham, T. M., Pedley, A., Massaro, J. M., Hoffmann, U. & Fox, C. S. Association between visceral and subcutaneous adipose depots and incident cardiovascular disease risk factors. Circulation 132, 1639–1647 (2015).
Schulze, M. B. Metabolic health in normal-weight and obese individuals. Diabetologia 62, 558–566 (2019).
McLaughlin, T., Lamendola, C., Liu, A. & Abbasi, F. Preferential fat deposition in subcutaneous versus visceral depots is associated with insulin sensitivity. J. Clin. Endocrinol. Metab. 96, E1756–E1760 (2011).
Gastaldelli, A. & Cusi, K. From NASH to diabetes and from diabetes to NASH: mechanisms and treatment options. JHEP Rep. 1, 312–328 (2019).
Kyle, U. G., Schutz, Y., Dupertuis, Y. M. & Pichard, C. Body composition interpretation: contributions of the fat-free mass index and the body fat mass index. Nutrition 19, 597–604 (2003).
Kim, J. A. & Choi, K. M. Sarcopenia and fatty liver disease. Hepatol. Int. 13, 674–687 (2019).
Nachit, M. et al. Muscle fat content is strongly associated with NASH: a longitudinal study in patients with morbid obesity. J. Hepatol. 75, 292–301 (2021).
Männistö, S. et al. Dietary and lifestyle characteristics associated with normal-weight obesity: the National FINRISK 2007 study. Br. J. Nutr. 111, 887–894 (2014).
Amani, R., Parohan, M., Jomehzadeh, N. & Haghighizadeh, M. H. Dietary and biochemical characteristics associated with normal-weight obesity. Int. J. Vitam. Nutr. Res. 89, 331–336 (2019).
Musso, G. et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 37, 909–916 (2003).
Yasutake, K. et al. Nutritional investigation of non-obese patients with non-alcoholic fatty liver disease: the significance of dietary cholesterol. Scand. J. Gastroenterol. 44, 471–477 (2009).
Enjoji, M., Yasutake, K., Kohjima, M. & Nakamuta, M. Nutrition and nonalcoholic fatty liver disease: the significance of cholesterol. Int. J. Hepatol. 2012, 925807 (2012).
Bellissimo, M. P. et al. Physical fitness but not diet quality distinguishes lean and normal weight obese adults. J. Acad. Nutr. Diet. 120, 1963–1973.e2 (2020).
Shivappa, N., Steck, S. E., Hurley, T. G., Hussey, J. R. & Hébert, J. R. Designing and developing a literature-derived, population-based dietary inflammatory index. Public Health Nutr. 17, 1689–1696 (2014).
Tabung, F. K. et al. Construct validation of the dietary inflammatory index among postmenopausal women. Ann. Epidemiol. 25, 398–405 (2015).
Carmody, R. N. Diet dominates host genotype in shaping the murine gut microbiota. Cell Host Microbe 17, 72–84 (2015).
Lotta, L. A. et al. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat. Genet. 49, 17–26 (2017).
Beals, J. W. et al. Increased adipose tissue fibrogenesis, not impaired expandability, is associated with nonalcoholic fatty liver disease. Hepatology 74, 1287–1299 (2021).
Shungin, D. et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature 518, 187–196 (2015).
Fehlert, E. et al. Genetic determination of body fat distribution and the attributive influence on metabolism. Obesity 25, 1277–1283 (2017).
Ji, Y. et al. Genome-wide and abdominal MRI-imaging data provides evidence that a genetically determined favourable adiposity phenotype is characterized by lower ectopic liver fat and lower risk of type 2 diabetes, heart disease and hypertension. Diabetes 68, 207–219 (2019).
Yaghootkar, H. et al. Genetic evidence for a link between favorable adiposity and lower risk of type 2 diabetes, hypertension, and heart disease. Diabetes 65, 2448–2460 (2016).
Harris, R. B. Role of set‐point theory in regulation of body weight. FASEB J. 6, 794 (1990).
Wilson, D. F. & Matschinsky, F. M. Metabolic homeostasis in life as we know it: its origin and thermodynamic basis. Front. Physiol. 12, 658997 (2021).
Leibel, R. L., Rosenbaum, M. & Hirsch, J. Changes in energy expenditure resulting from altered body weight. N. Engl. J. Med. 332, 621–628 (1995).
Goodpaster, B. H. & Sparks, L. M. Metabolic flexibility in health and disease. Cell Metab. 25, 1027–1036 (2017).
Chouchani, E. T. & Kajimura, S. Metabolic adaptation and maladaptation in adipose tissue. Nat. Metab. 1, 189–200 (2019).
Rachek, L. I. Free fatty acids and skeletal muscle insulin resistance. Prog. Mol. Biol. Transl. Sci. 121, 267–292 (2014).
Sangwung, P., Petersen, K. F., Shulman, G. I. & Knowles, J. W. Mitochondrial dysfunction, insulin resistance, and potential genetic implications: potential role of alterations in mitochondrial function in the pathogenesis of insulin resistance and type 2 diabetes. Endocrinology 161, bqaa017 (2021).
Galgani, J. E., Moro, C. & Ravussin, E. Metabolic flexibility and insulin resistance. Am. J. Physiol. Endocrinol. Metab. 295, E1009–E1017 (2008).
Ukropcova, B. et al. Family history of diabetes links impaired substrate switching and reduced mitochondrial content in skeletal muscle. Diabetes 56, 720–727 (2007).
Begaye, B. et al. Impaired metabolic flexibility to high-fat overfeeding predicts future weight gain in healthy adults. Diabetes 69, 181–192 (2020).
Gastaldelli, A. Insulin resistance and reduced metabolic flexibility: cause or consequence of NAFLD? Clin. Sci. 131, 2701–2704 (2017).
Malin, S. K. et al. Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes. Am. J. Physiol. Endocrinol. Metab. 305, E1292–E1298 (2013).
Huffman, K. M. et al. Caloric restriction alters the metabolic response to a mixed-meal: results from a randomized, controlled trial. PLoS ONE 7, e28190 (2012).
Malin, S. K. et al. A whole-grain diet reduces peripheral insulin resistance and improves glucose kinetics in obese adults: a randomized-controlled trial. Metabolism 82, 111–117 (2018).
Piaggi, P. Metabolic determinants of weight gain in humans. Obesity 27, 691–699 (2019).
Méndez-Sánchez, N. et al. Global multi-stakeholder endorsement of the MAFLD definition. Lancet Gastroenterol. Hepatol. 7, 388–390 (2022).
Mozaffarian, D., Angell, S. Y., Lang, T. & Rivera, J. A. Role of government policy in nutrition — barriers to and opportunities for healthier eating. BMJ 361, k2426 (2018).
Bonde, Y., Eggertsen, G. & Rudling, M. Mice abundant in muricholic bile acids show resistance to dietary induced steatosis, weight gain, and to impaired glucose metabolism. PLoS ONE 11, e0147772 (2016).
Joyce, S. A. et al. Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut. Proc. Natl Acad. Sci. USA 111, 7421–7426 (2014).
Wostmann, B. Intestinal bile acids and cholesterol absorption in the germfree rat. J. Nutr. 103, 982–990 (1973).
Keipert, S. et al. Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice. Nat. Commun. 11, 624 (2020).
Bayoumi, A. et al. Mistranslation drives alterations in protein levels and the effects of a synonymous variant at the fibroblast growth factor 21 locus. Adv. Sci. 8, 2004168 (2021).
Bulik, C. & Allison, D. The genetic epidemiology of thinness. Obes. Rev. 2, 107–115 (2001).
Riveros-McKay, F. et al. Genetic architecture of human thinness compared to severe obesity. PLoS Genet. 15, e1007603 (2019).
Orthofer, M. et al. Identification of ALK in thinness. Cell 181, 1246–1262.e22 (2020).
Tanaka, S. et al. Effect of adult weight gain on non-alcoholic fatty liver disease and its association with anthropometric parameters in the lean Japanese population. Diagnostics 10, 863 (2020).
Kim, M. N. et al. Weight gain during early adulthood, trajectory of body shape and the risk of nonalcoholic fatty liver disease: a prospective cohort study among women. Metabolism 113, 154398 (2020).
Jung, I. et al. Increased risk of nonalcoholic fatty liver disease in individuals with high weight variability. Endocrinol. Metab. 36, 845–854 (2021).
Eslam, M. & George, J. Genetic insights for drug development in NAFLD. Trends Pharmacol. Sci. 40, 506–516 (2019).
Sahebkar, A., Chew, G. T. & Watts, G. F. New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease. Expert Opin. Pharmacother. 15, 493–503 (2014).
Bourbeau, M. P. & Bartberger, M. D. Recent advances in the development of acetyl-CoA carboxylase (ACC) inhibitors for the treatment of metabolic disease. J. Med. Chem. 58, 525–536 (2015).
Goedeke, L. & Shulman, G. I. Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH. Mol. Metab. 46, 101178 (2021).
Alkhouri, N. Thyromimetics as emerging therapeutic agents for nonalcoholic steatohepatitis: rationale for the development of resmetirom (MGL-3196). Expert Opin. Investig. Drugs 29, 99–101 (2020).
Hardie, D. G. AMPK: a target for drugs and natural products with effects on both diabetes and cancer. Diabetes 62, 2164–2172 (2013).
Vilar-Gomez, E. et al. Type 2 diabetes and metformin use associate with outcomes of patients with nonalcoholic steatohepatitis–related, Child–Pugh A cirrhosis. Clin. Gastroenterol. Hepatol. 19, 136–145.e6 (2021).
Timmers, S. et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 14, 612–622 (2011).
de Ligt, M., Timmers, S. & Schrauwen, P. Resveratrol and obesity: can resveratrol relieve metabolic disturbances? Biochim. Biophys. Acta 1852, 1137–1144 (2015).
Coleman, N. J., Miernik, J., Philipson, L. & Fogelfeld, L. Lean versus obese diabetes mellitus patients in the United States minority population. J. Diabetes Complications 28, 500–505 (2014).
George, A. M., Jacob, A. G. & Fogelfeld, L. Lean diabetes mellitus: an emerging entity in the era of obesity. World J. Diabetes 6, 613 (2015).
Tobias, D. K. et al. Body-mass index and mortality among adults with incident type 2 diabetes. N. Engl. J. Med. 370, 233–244 (2014).
Carnethon, M. R. et al. Association of weight status with mortality in adults with incident diabetes. JAMA 308, 581–590 (2012).
Stamler, R., Ford, C. E. & Stamler, J. Why do lean hypertensives have higher mortality rates than other hypertensives? Findings of the hypertension detection and follow-up program. Hypertension 17, 553–564 (1991).
Arabshahi, S. et al. Adiposity has a greater impact on hypertension in lean than not-lean populations: a systematic review and meta-analysis. Eur. J. Epidemiol. 29, 311–324 (2014).
Eren, F., Kaya, E. & Yilmaz, Y. Accuracy of Fibrosis-4 index and non-alcoholic fatty liver disease fibrosis scores in metabolic (dysfunction) associated fatty liver disease according to body mass index: failure in the prediction of advanced fibrosis in lean and morbidly obese individuals. Eur. J. Gastroenterol. Hepatol. 34, 98–103 (2022).
Hamurcu Varol, P., Kaya, E., Alphan, E. & Yilmaz, Y. Role of intensive dietary and lifestyle interventions in the treatment of lean nonalcoholic fatty liver disease patients. Eur. J. Gastroenterol. Hepatol. 32, 1352–1357 (2020).
Sinn, D. H. et al. Weight change and resolution of fatty liver in normal weight individuals with nonalcoholic fatty liver disease. Eur. J. Gastroenterol. Hepatol. 33, e529–e534 (2021).
Wong, V. W.-S. et al. Beneficial effects of lifestyle intervention in non-obese patients with non-alcoholic fatty liver disease. J. Hepatol. 69, 1349–1356 (2018).
Osadnik, K. et al. Metabolically healthy obese and metabolic syndrome of the lean: the importance of diet quality. Analysis of MAGNETIC cohort. Nutr. J. 19, 19 (2020).
Kim, Y. et al. Cardiovascular risk is elevated in lean subjects with nonalcoholic fatty liver disease. Gut Liver 16, 290 (2022).
Pan, Z., Fan, J.-G. & Eslam, M. An update on drug development for the treatment of metabolic (dysfunction) associated fatty liver disease: progress and opportunities. Curr. Opin. Pharmacol. 60, 170–176 (2021).
Fouad, Y. et al. Redefinition of fatty liver disease from NAFLD to MAFLD through the lens of drug development and regulatory science. J. Clin. Transl. Hepatol. 10, 374–382 (2022).
Eslam, M. et al. Incorporating fatty liver disease in multidisciplinary care and novel clinical trial designs for patients with metabolic diseases. Lancet Gastroenterol. Hepatol. 6, 743–753 (2021).
Sarin, S. K., Prasad, M., Ramalingam, A. & Kapil, U. Integration of public health measures for NAFLD into India’s national programme for NCDs. Lancet Gastroenterol. Hepatol. 6, 777–778 (2021).
Fernández-Verdejo, R., Bajpeyi, S., Ravussin, E. & Galgani, J. E. Metabolic flexibility to lipid availability during exercise is enhanced in individuals with high insulin sensitivity. Am. J. Physiol. Endocrinol. Metab. 315, E715–E722 (2018).
M.E. and J.G. are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; National Health and Medical Research Council of Australia (NHMRC) Program and Investigator Grants (AAP2008983, APP1053206, APP1196492) and Project and Ideas grants (APP2001692, APP1107178, and APP1108422). H.B.E.-S. is supported by grants RP190641 and NIH P30DK056338.
The authors declare no competing interests.
Peer review information
Nature Reviews Gastroenterology & Hepatology thanks Jian Gao Fan, Herbert Tilg and the other, anonymous, reviewer for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Emerging Risk Factor Collaboration: https://www.phpc.cam.ac.uk/ceu/erfc/
Global Burden of Disease: https://www.healthdata.org/gbd/2019
Multi-Ethnic Study of Atherosclerosis: https://www.mesa-nhlbi.org/
About this article
Cite this article
Eslam, M., El-Serag, H.B., Francque, S. et al. Metabolic (dysfunction)-associated fatty liver disease in individuals of normal weight. Nat Rev Gastroenterol Hepatol 19, 638–651 (2022). https://doi.org/10.1038/s41575-022-00635-5
This article is cited by
A comparison of NAFLD and MAFLD diagnostic criteria in contemporary urban healthy adults in China: a cross-sectional study
BMC Gastroenterology (2022)
Nature Reviews Gastroenterology & Hepatology (2022)
Hepatology International (2022)