Download PDF
Semin Liver Dis 2019; 39(01): 086-095
DOI: 10.1055/s-0038-1677517
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

NASH in Lean Individuals

Ramy Younes
1   Department of Medical Sciences, Division of Gastroenterology, University of Torino, AOU Città della Salute e della Scienza, Torino, Italy
,
Elisabetta Bugianesi
1   Department of Medical Sciences, Division of Gastroenterology, University of Torino, AOU Città della Salute e della Scienza, Torino, Italy
› Author Affiliations Funding The study was supported by grants for EPoS (Elucidating Pathways of Steatohepatitis, Grant Agreement No: 634413) and for LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis, Grant Agreement No: 777377) projects, funded by the Horizon 2020 Framework Program of the European Union.
Further Information

Publication History

Publication Date:
17 January 2019 (online)

   Permissions and Reprints

Abstract

Nonalcoholic fatty liver disease (NAFLD) is generally associated with obesity and the related comorbidities but it can also develop in subjects with a body mass index (BMI) within the ethnic-specific cutoff of 25 kg/m2 BMI in Caucasian and 23 kg/m2 in Asian subjects, the so-called “lean” NAFLD. This sub-phenotype of NAFLD patients has been described across populations of different ethnicity, particularly in Asia, but it can be diagnosed in 10 to 20% of nonobese Americans and Caucasians. Pathophysiological mechanisms underpinning the “lean” phenotype are not completely understood, but they may include a more dysfunctional fat (visceral obesity, differences in adipocyte differentiation and altered lipid turnover), altered body composition (decreased muscle mass), a genetic background, not limited to patatin-like phospholipase domain-containing protein 3 (PNPLA3) C > G polymorphisms, epigenetic changes occurring early in life and a different pattern of gut microbiota. Lean subjects with NAFLD have milder features of the metabolic syndrome when compared with obese patients. Nonetheless they have a higher prevalence of metabolic alterations (e.g., dyslipidemia, arterial hypertension, insulin resistance, and diabetes) compared with healthy controls. Data on histological severity are controversial, but they can develop the full spectrum of liver disease associated with nonalcoholic steatohepatitis NASH. Since lean NAFLD usually present with less obesity-related comorbidities, it is commonly believed that this group would follow a relatively benign clinical course but recent data challenge this concept. Here, the authors describe the current knowledge about NAFLD in lean individuals and highlight the unanswered questions and gaps in the field.

Keywords

nonalcoholic fatty liver disease - body mass index - visceral adiposity - insulin resistance - genetic polymorphism - ethnicity
 

  • References

  • 1 Younossi Z, Anstee QM, Marietti M. , et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018; 15 (01) 11-20
    Google Scholar
  • 2 Ruderman NB, Schneider SH, Berchtold P. The “metabolically-obese,” normal-weight individual. Am J Clin Nutr 1981; 34 (08) 1617-1621
    CrossrefPubMedGoogle Scholar
  • 3 Leung JC, Loong TC, Wei JL. , et al. Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients. Hepatology 2017; 65 (01) 54-64
    CrossrefPubMedGoogle Scholar
  • 4 Consultation WHOE. ; WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004; 363 (9403): 157-163
    CrossrefPubMedGoogle Scholar
  • 5 Chen CH, Huang MH, Yang JC. , et al. Prevalence and risk factors of nonalcoholic fatty liver disease in an adult population of Taiwan: metabolic significance of nonalcoholic fatty liver disease in nonobese adults. J Clin Gastroenterol 2006; 40 (08) 745-752
    CrossrefPubMedGoogle Scholar
  • 6 Das K, Das K, Mukherjee PS. , et al. Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease. Hepatology 2010; 51 (05) 1593-1602
    CrossrefPubMedGoogle Scholar
  • 7 Xu C, Yu C, Ma H, Xu L, Miao M, Li Y. Prevalence and risk factors for the development of nonalcoholic fatty liver disease in a nonobese Chinese population: the Zhejiang Zhenhai Study. Am J Gastroenterol 2013; 108 (08) 1299-1304
    CrossrefPubMedGoogle Scholar
  • 8 Feng RN, Du SS, Wang C. , et al. Lean-non-alcoholic fatty liver disease increases risk for metabolic disorders in a normal weight Chinese population. World J Gastroenterol 2014; 20 (47) 17932-17940
    CrossrefPubMedGoogle Scholar
  • 9 Kwon YM, Oh SW, Hwang SS, Lee C, Kwon H, Chung GE. Association of nonalcoholic fatty liver disease with components of metabolic syndrome according to body mass index in Korean adults. Am J Gastroenterol 2012; 107 (12) 1852-1858
    CrossrefPubMedGoogle Scholar
  • 10 Kim NH, Kim JH, Kim YJ. , et al. Clinical and metabolic factors associated with development and regression of nonalcoholic fatty liver disease in nonobese subjects. Liver Int 2014; 34 (04) 604-611
    CrossrefPubMedGoogle Scholar
  • 11 Nishioji K, Sumida Y, Kamaguchi M. , et al. Prevalence of and risk factors for non-alcoholic fatty liver disease in a non-obese Japanese population, 2011-2012. J Gastroenterol 2015; 50 (01) 95-108
    CrossrefPubMedGoogle Scholar
  • 12 Wei JL, Leung JC, Loong TC. , 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 2015; 110 (09) 1306-1314 , quiz 1315
    CrossrefPubMedGoogle Scholar
  • 13 Bellentani S, Saccoccio G, Masutti F. , et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000; 132 (02) 112-117
    PubMedGoogle Scholar
  • 14 Kim LJ, Nalls MA, Eiriksdottir G. , et al; AGES-Reykjavik Study Investigators. Associations of visceral and liver fat with the metabolic syndrome across the spectrum of obesity: the AGES-Reykjavik study. Obesity (Silver Spring) 2011; 19 (06) 1265-1271
    CrossrefPubMedGoogle Scholar
  • 15 Browning JD, Szczepaniak LS, Dobbins R. , et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40 (06) 1387-1395
    CrossrefPubMedGoogle Scholar
  • 16 Younossi ZM, Stepanova M, Negro F. , et al. Nonalcoholic fatty liver disease in lean individuals in the United States. Medicine (Baltimore) 2012; 91 (06) 319-327
    PubMedGoogle Scholar
  • 17 Conjeevaram Selvakumar PK, Kabbany MN, Lopez R, Rayas MS, Lynch JL, Alkhouri N. Prevalence of suspected nonalcoholic fatty liver disease in lean adolescents in the United States. J Pediatr Gastroenterol Nutr 2018; 67 (01) 75-79
    CrossrefPubMedGoogle Scholar
  • 18 Bugianesi E, Gastaldelli A, Vanni E. , et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 2005; 48 (04) 634-642
    CrossrefPubMedGoogle Scholar
  • 19 Feng R, Luo C, Li C. , et al. Free fatty acids profile among lean, overweight and obese non-alcoholic fatty liver disease patients: a case–control study. Lipids Health Dis 2017; 16 (01) 165
    CrossrefPubMedGoogle Scholar
  • 20 Wattacheril J, Sanyal AJ. Lean NAFLD: an underrecognized outlier. Curr Hepatol Rep 2016; 15 (02) 134-139
    PubMedGoogle Scholar
  • 21 Conus F, Rabasa-Lhoret R, Péronnet F. Characteristics of metabolically obese normal-weight (MONW) subjects. Appl Physiol Nutr Metab 2007; 32 (01) 4-12
    PubMedGoogle Scholar
  • 22 Stefan N, Schick F, Häring HU. Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans. Cell Metab 2017; 26 (02) 292-300
    CrossrefPubMedGoogle Scholar
  • 23 Gujral UP, Vittinghoff E, Mongraw-Chaffin M. , 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 2017; 166 (09) 628-636
    CrossrefPubMedGoogle Scholar
  • 24 Hussain I, Garg A. Lipodystrophy syndromes. Endocrinol Metab Clin North Am 2016; 45 (04) 783-797
    CrossrefPubMedGoogle Scholar
  • 25 Bhanji RA, Narayanan P, Allen AM, Malhi H, Watt KD. Sarcopenia in hiding: the risk and consequence of underestimating muscle dysfunction in nonalcoholic steatohepatitis. Hepatology 2017; 66 (06) 2055-2065
    CrossrefPubMedGoogle Scholar
  • 26 Gaggini M, Carli F, Rosso C. , et al. Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance. Hepatology 2018; 67 (01) 145-158
    CrossrefPubMedGoogle Scholar
  • 27 Romeo S, Kozlitina J, Xing C. , et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40 (12) 1461-1465
    CrossrefPubMedGoogle Scholar
  • 28 Nishioji K, Mochizuki N, Kobayashi M. , et al. The impact of PNPLA3 rs738409 genetic polymorphism and weight gain ≥10 kg after age 20 on non-alcoholic fatty liver disease in non-obese Japanese individuals. PLoS One 2015; 10 (10) e0140427
    CrossrefPubMedGoogle Scholar
  • 29 Honda Y, Yoneda M, Kessoku T. , et al. Characteristics of non-obese non-alcoholic fatty liver disease: effect of genetic and environmental factors. Hepatol Res 2016; 46 (10) 1011-1018
    CrossrefPubMedGoogle Scholar
  • 30 Fracanzani AL, Petta S, Lombardi R. , et al. Liver and cardiovascular damage in patients with lean nonalcoholic fatty liver disease, and association with visceral obesity. Clin Gastroenterol Hepatol 2017; 15 (10) 1604-1611.e1
    CrossrefPubMedGoogle Scholar
  • 31 Wong VW, Wong GL, Yeung DK. , et al. Incidence of non-alcoholic fatty liver disease in Hong Kong: a population study with paired proton-magnetic resonance spectroscopy. J Hepatol 2015; 62 (01) 182-189
    CrossrefPubMedGoogle Scholar
  • 32 Watts GF, Riches FM, Humphries SE, Talmud PJ, van Bockxmeer FM. Genotypic associations of the hepatic secretion of VLDL apolipoprotein B-100 in obesity. J Lipid Res 2000; 41 (03) 481-488
    CrossrefPubMedGoogle Scholar
  • 33 Adams LA, Marsh JA, Ayonrinde OT. , et al. Cholesteryl ester transfer protein gene polymorphisms increase the risk of fatty liver in females independent of adiposity. J Gastroenterol Hepatol 2012; 27 (09) 1520-1527
    CrossrefPubMedGoogle Scholar
  • 34 Liu YL, Reeves HL, Burt AD. , et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun 2014; 5: 4309
    CrossrefPubMedGoogle Scholar
  • 35 Petta S, Valenti L, Tuttolomondo A. , et al. Interferon lambda 4 rs368234815 TT>δG variant is associated with liver damage in patients with nonalcoholic fatty liver disease. Hepatology 2017; 66 (06) 1885-1893
    CrossrefPubMedGoogle Scholar
  • 36 Nakatsuka A, Matsuyama M, Yamaguchi S. , et al. Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis. Sci Rep 2016; 6: 21721
    CrossrefPubMedGoogle Scholar
  • 37 Spalding KL, Arner E, Westermark PO. , et al. Dynamics of fat cell turnover in humans. Nature 2008; 453 (7196): 783-787
    PubMedGoogle Scholar
  • 38 Nobili V, Marcellini M, Marchesini G. , et al. Intrauterine growth retardation, insulin resistance, and nonalcoholic fatty liver disease in children. Diabetes Care 2007; 30 (10) 2638-2640
    CrossrefPubMedGoogle Scholar
  • 39 Das K, Chowdhury A. Lean NASH: distinctiveness and clinical implication. Hepatol Int 2013; 7 (Suppl. 02) 806-813
    CrossrefPubMedGoogle Scholar
  • 40 Abid A, Taha O, Nseir W, Farah R, Grosovski M, Assy N. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome. J Hepatol 2009; 51 (05) 918-924
    CrossrefPubMedGoogle Scholar
  • 41 Zhu L, Baker SS, Gill C. , et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 2013; 57 (02) 601-609
    CrossrefPubMedGoogle Scholar
  • 42 Soga T, Ohishi T, Matsui T. , et al. Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor. Biochem Biophys Res Commun 2005; 326 (04) 744-751
    CrossrefPubMedGoogle Scholar
  • 43 Duarte SMB, Stefano JT, Miele L. , et al. Gut microbiome composition in lean patients with NASH is associated with liver damage independent of caloric intake: A prospective pilot study. Nutr Metab Cardiovasc Dis 2018; 28 (04) 369-384
    CrossrefPubMedGoogle Scholar
  • 44 Hung ND, Kim MR, Sok DE. 2-Polyunsaturated acyl lysophosphatidylethanolamine attenuates inflammatory response in zymosan A-induced peritonitis in mice. Lipids 2011; 46 (10) 893-906
    CrossrefPubMedGoogle Scholar
  • 45 Heimerl S, Fischer M, Baessler A. , et al. Alterations of plasma lysophosphatidylcholine species in obesity and weight loss. PLoS One 2014; 9 (10) e111348
    CrossrefPubMedGoogle Scholar
  • 46 Feldman A, Eder SK, Felder TK. , et al. Clinical and metabolic characterization of lean Caucasian subjects with non-alcoholic fatty liver. Am J Gastroenterol 2017; 112 (01) 102-110
    CrossrefPubMedGoogle Scholar
  • 47 Yamakado M, Tanaka T, Nagao K. , et al. Plasma amino acid profile is associated with visceral fat accumulation in obese Japanese subjects. Clin Obes 2012; 2 (1-2): 29-40
    CrossrefPubMedGoogle Scholar
  • 48 Vos B, Moreno C, Nagy N. , et al. Lean non-alcoholic fatty liver disease (Lean-NAFLD): a major cause of cryptogenic liver disease. Acta Gastroenterol Belg 2011; 74 (03) 389-394
    PubMedGoogle Scholar
  • 49 Amato MC, Giordano C, Galia M. , et al; AlkaMeSy Study Group. Visceral Adiposity Index: a reliable indicator of visceral fat function associated with cardiometabolic risk. Diabetes Care 2010; 33 (04) 920-922
    CrossrefPubMedGoogle Scholar
  • 50 Marchesini G, Bugianesi E, Forlani G. , et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003; 37 (04) 917-923
    CrossrefPubMedGoogle Scholar
  • 51 Fracanzani AL, Valenti L, Bugianesi E. , et al. Risk of nonalcoholic steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease and low visceral adiposity. J Hepatol 2011; 54 (06) 1244-1249
    CrossrefPubMedGoogle Scholar
  • 52 Akyuz U, Yesil A, Yilmaz Y. Characterization of lean patients with nonalcoholic fatty liver disease: potential role of high hemoglobin levels. Scand J Gastroenterol 2015; 50 (03) 341-346
    CrossrefPubMedGoogle Scholar
  • 53 Kumar R, Rastogi A, Sharma MK. , et al. Clinicopathological characteristics and metabolic profiles of non-alcoholic fatty liver disease in Indian patients with normal body mass index: do they differ from obese or overweight non-alcoholic fatty liver disease?. Indian J Endocrinol Metab 2013; 17 (04) 665-671
    PubMedGoogle Scholar
  • 54 Younossi ZM, Otgonsuren M, Venkatesan C, Mishra A. In patients with non-alcoholic fatty liver disease, metabolically abnormal individuals are at a higher risk for mortality while metabolically normal individuals are not. Metabolism 2013; 62 (03) 352-360
    CrossrefPubMedGoogle Scholar
  • 55 Cruz ACD, Bugianesi E, George J. , et al. 379 Characteristics and long-term prognosis of lean patients with nonalcoholic fatty liver disease. Gastroenterology 2014; 146 (05) S-909
    PubMedGoogle Scholar
  • 56 Hagström H, Nasr P, Ekstedt M. , 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 2017; 2 (01) 48-57
    PubMedGoogle Scholar
  • 57 European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016; 64 (06) 1388-1402
    CrossrefPubMedGoogle Scholar
  • 58 Ohkawara K, Tanaka S, Miyachi M, Ishikawa-Takata K, Tabata I. A dose-response relation between aerobic exercise and visceral fat reduction: systematic review of clinical trials. Int J Obes 2007; 31 (12) 1786-1797
    CrossrefPubMedGoogle Scholar
  • 59 DeFronzo RA, Tripathy D, Schwenke DC. , et al; ACT NOW Study. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med 2011; 364 (12) 1104-1115
    CrossrefPubMedGoogle Scholar
  • 60 Armstrong MJ, Gaunt P, Aithal GP. , et al; LEAN trial team. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016; 387 (10019): 679-690
    CrossrefPubMedGoogle Scholar
  • 61 Marso SP, Daniels GH, Brown-Frandsen K. , et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375 (04) 311-322
    CrossrefPubMedGoogle Scholar