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Association between body size-metabolic phenotype and nonalcoholic steatohepatitis and significant fibrosis

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background and aims

Body size-metabolic phenotype may help predict whether or not individuals with nonalcoholic fatty liver disease (NAFLD) develop advanced liver disease. We studied the association of body size-metabolic phenotype with nonalcoholic steatohepatitis (NASH) and significant fibrosis.

Methods

Our cross-sectional study included 559 subjects (mean age of 53 years; women 51%) with biopsy-proven NAFLD. Clinical, genetic, and histological characteristic features of NAFLD were evaluated. The metabolically unhealthy phenotype was defined by the presence of two or more metabolic components, while body size was categorized based on body mass index: obese (≥ 25 kg/m2) or non-obese (< 25 kg/m2). Body size-metabolic phenotypes were divided into four study groups: (1) non-obese metabolic syndrome (MS)−, (2) non-obese MS+ , (3) obese MS−, and (4) obese MS+.

Results

Obese MS− and non-obese MS+ groups demonstrated comparable levels of insulin resistance, adipose tissue insulin resistance indexes, and visceral adipose tissue (VAT) areas. The VAT area was significantly higher in the obese MS+ group versus obese MS− group. However, the VAT to subcutaneous adipose tissue (SAT) ratio was highest in the non-obese MS+ group. There was no difference in histology between the non-obese MS+, obese MS−, and obese MS+ groups. Multivariate analyses adjusted for age, sex, smoking status, PNPLA3, TM6SF2, and VAT/SAT areas demonstrated an independent and dose-dependent relationship between the body size-metabolic phenotype and NASH or significant fibrosis.

Conclusion

The non-obese MS+ group displayed similar degree of hepatic histological severity compared to their obese MS− counterparts. Metabolic milieu beyond obesity may play a pathogenic role in non-obese MS+ individuals who develop NASH with significant hepatic fibrosis.

Clinical trial number

NCT 02206841.

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Abbreviations

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

MS:

Metabolic syndrome

ALT:

Alanine aminotransferase

HDL:

High-density lipoprotein

AST:

Aspartate aminotransferase

CT:

Computed tomography

PNPLA3 :

Patatin-like phospholipase domain-containing 3

TM6SF2 :

Transmembrane 6 superfamily member 2

SREBF :

Sterol regulatory element-binding factor

MBOAT7-TMC4 :

Membrane-bound O-acyltransferase domain containing 7-transmembrane channel-like 4

SD:

Standard deviation

VAT:

Visceral adipose tissue

SAT:

Subcutaneous adipose tissue

References

  1. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.

    Google Scholar 

  2. 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;15:11–20.

    PubMed  Google Scholar 

  3. Kim D, Kim WR, Kim HJ, et al. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology. 2013;57:1357–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Kim DD, Basu A. Estimating the medical care costs of obesity in the United States: systematic review, meta-analysis, and empirical analysis. Value Health. 2016;19:602–13.

    PubMed  Google Scholar 

  5. Badoud F, Perreault M, Zulyniak MA, et al. Molecular insights into the role of white adipose tissue in metabolically unhealthy normal weight and metabolically healthy obese individuals. FASEB J. 2015;29:748–58.

    CAS  PubMed  Google Scholar 

  6. Stefan N, Haring HU, Hu FB, et al. Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications. Lancet Diabetes Endocrinol. 2013;1:152–62.

    PubMed  Google Scholar 

  7. Stefan N, Schick F, Haring HU. Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans. Cell Metab. 2017;26:292–300.

    CAS  PubMed  Google Scholar 

  8. Wildman RP, Muntner P, Reynolds K, et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999–2004). Arch Intern Med. 2008;168:1617–24.

    PubMed  Google Scholar 

  9. Kramer CK, Zinman B, Retnakaran R. Are metabolically healthy overweight and obesity benign conditions?: a systematic review and meta-analysis. Ann Intern Med. 2013;159:758–69.

    PubMed  Google Scholar 

  10. Koo BK, Kim D, Joo SK, et al. Sarcopenia is an independent risk factor for non-alcoholic steatohepatitis and significant fibrosis. J Hepatol. 2017;66:123–31.

    PubMed  Google Scholar 

  11. Kim D, Kim W, Joo SK, et al. Subclinical hypothyroidism and low-normal thyroid function are associated with nonalcoholic steatohepatitis and fibrosis. Clin Gastroenterol Hepatol. 2018;16(123–31):e1.

    Google Scholar 

  12. Obesity: preventing and managing the global epidemic. In: Report of a WHO consultation. World Health Organ Tech Rep Ser. 2000;894:i-xii, 1–253.

  13. Mauss S, Berger F, Filmann N, et al. Effect of HBV polymerase inhibitors on renal function in patients with chronic hepatitis B. J Hepatol. 2011;55:1235–40.

    CAS  PubMed  Google Scholar 

  14. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640–5.

    CAS  PubMed  Google Scholar 

  15. 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;166:628–36.

    PubMed  PubMed Central  Google Scholar 

  16. Heianza Y, Arase Y, Tsuji H, et al. Metabolically healthy obesity, presence or absence of fatty liver, and risk of type 2 diabetes in Japanese individuals: Toranomon Hospital Health Management Center Study 20 (TOPICS 20). J Clin Endocrinol Metab. 2014;99:2952–60.

    CAS  PubMed  Google Scholar 

  17. Hashimoto Y, Hamaguchi M, Fukuda T, et al. Fatty liver as a risk factor for progression from metabolically healthy to metabolically abnormal in non-overweight individuals. Endocrine. 2017;57:89–97.

    CAS  PubMed  Google Scholar 

  18. Gasull M, Castell C, Pallares N, et al. Blood concentrations of persistent organic pollutants and unhealthy metabolic phenotypes in normal-weight, overweight, and obese individuals. Am J Epidemiol. 2018;187:494–506.

    PubMed  Google Scholar 

  19. Dobson R, Burgess MI, Sprung VS, et al. Metabolically healthy and unhealthy obesity: differential effects on myocardial function according to metabolic syndrome, rather than obesity. Int J Obes (Lond). 2016;40:153–61.

    CAS  Google Scholar 

  20. Brunt EM, Janney CG, Di Bisceglie AM, et al. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–74.

    CAS  PubMed  Google Scholar 

  21. Brunt EM, Kleiner DE, Wilson LA, et al. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology. 2011;53:810–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.

    PubMed  Google Scholar 

  23. Kim D, Choi SY, Park EH, et al. Nonalcoholic fatty liver disease is associated with coronary artery calcification. Hepatology. 2012;56:605–13.

    CAS  PubMed  Google Scholar 

  24. Yim JY, Kim D, Lim SH, et al. Sagittal abdominal diameter is a strong anthropometric measure of visceral adipose tissue in the Asian general population. Diabetes Care. 2010;33:2665–700.

    PubMed  PubMed Central  Google Scholar 

  25. Koo BK, Joo SK, Kim D, et al. Additive effects of PNPLA3 and TM6SF2 on the histological severity of non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2018;33:1277–85.

    CAS  PubMed  Google Scholar 

  26. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Kozlitina J, Smagris E, Stender S, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2014;46:352–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Musso G, Cassader M, Bo S, et al. Sterol regulatory element-binding factor 2 (SREBF-2) predicts 7-year NAFLD incidence and severity of liver disease and lipoprotein and glucose dysmetabolism. Diabetes. 2013;62:1109–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Mancina RM, Dongiovanni P, Petta S, et al. The MBOAT7-TMC4 Variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of european descent. Gastroenterology. 2016;150(1219–30):e6.

    Google Scholar 

  30. Karelis AD, St-Pierre DH, Conus F, et al. Metabolic and body composition factors in subgroups of obesity: what do we know? The Journal of clinical endocrinology and metabolism. 2004;89:2569–75.

    CAS  PubMed  Google Scholar 

  31. Kim D, Kim WR. Nonobese fatty liver disease. Clin Gastroenterol Hepatol. 2017;15:474–85.

    CAS  PubMed  Google Scholar 

  32. Hojland Ipsen D, Tveden-Nyborg P, Lykkesfeldt J. Normal weight dyslipidemia: is it all about the liver? Obesity (Silver Spring). 2016;24:556–67.

    Google Scholar 

  33. du Plessis J, van Pelt J, Korf H, et al. Association of adipose tissue inflammation with histologic severity of nonalcoholic fatty liver disease. Gastroenterology. 2015;149(635–48):e14.

    Google Scholar 

  34. Arner E, Westermark PO, Spalding KL, et al. Adipocyte turnover: relevance to human adipose tissue morphology. Diabetes. 2010;59:105–9.

    CAS  PubMed  Google Scholar 

  35. Munoz-Garach A, Cornejo-Pareja I, Tinahones FJ. Does metabolically healthy obesity exist? Nutrients. 2016;8:320.

    PubMed Central  Google Scholar 

  36. Mathew H, Farr OM, Mantzoros CS. Metabolic health and weight: understanding metabolically unhealthy normal weight or metabolically healthy obese patients. Metabolism. 2016;65(1):73–80. https://doi.org/10.1016/j.metabol.2015.10.019

    Article  CAS  PubMed  Google Scholar 

  37. Phillips CM. Metabolically healthy obesity across the life course: epidemiology, determinants, and implications. Ann N Y Acad Sci. 2017;1391:85–100.

    PubMed  Google Scholar 

  38. Leung JC, Loong TC, Wei JL, et al. Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients. Hepatology. 2017;65:54–64.

    CAS  PubMed  Google Scholar 

  39. Mongraw-Chaffin M, Foster MC, Anderson CAM, et al. Metabolically healthy obesity, transition to metabolic syndrome, and cardiovascular risk. J Am Coll Cardiol. 2018;71:1857–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Fan J, Song Y, Chen Y, et al. 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;168:4761–8.

    PubMed  Google Scholar 

  41. Alberti KG, Zimmet P, Shaw J, et al. The metabolic syndrome—a new worldwide definition. Lancet. 2005;366:1059–62.

    Google Scholar 

  42. Farrell GC, Chitturi S, Lau GK, et al. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary. J Gastroenterol Hepatol. 2007;22:775–7.

    PubMed  Google Scholar 

  43. Lomonaco R, Ortiz-Lopez C, Orsak B, et al. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology. 2012;55:1389–97.

    CAS  PubMed  Google Scholar 

  44. Stefan N, Haring HU, Schulze MB. Metabolically healthy obesity: the low-hanging fruit in obesity treatment? Lancet Diabetes Endocrinol. 2018;6(3):249–58.

    PubMed  Google Scholar 

  45. 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;112:102–10.

    PubMed  Google Scholar 

  46. Shen J, Wong GL, Chan HL, et al. PNPLA3 gene polymorphism accounts for fatty liver in community subjects without metabolic syndrome. Aliment Pharmacol Ther. 2014;39:532–9.

    CAS  PubMed  Google Scholar 

  47. 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;110:1306–14 (quiz 15).

    CAS  PubMed  Google Scholar 

  48. Pirola CJ, Sookoian S. The dual and opposite role of the TM6SF2-rs58542926 variant in protecting against cardiovascular disease and conferring risk for nonalcoholic fatty liver: a meta-analysis. Hepatology. 2015;62:1742–56.

    CAS  PubMed  Google Scholar 

  49. 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;46:1011–8.

    CAS  PubMed  Google Scholar 

  50. Schroder H, Ramos R, Baena-Diez JM, et al. Determinants of the transition from a cardiometabolic normal to abnormal overweight/obese phenotype in a Spanish population. Eur J Nutr. 2014;53:1345–53.

    PubMed  Google Scholar 

  51. Fan JG, Kim SU, Wong VW. New trends on obesity and NAFLD in Asia. J Hepatol. 2017;67:862–73.

    PubMed  Google Scholar 

  52. Consultation WHOE. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet. 2004;363:157–63.

    Google Scholar 

  53. Zheng W, McLerran DF, Rolland B, et al. Association between body-mass index and risk of death in more than 1 million Asians. N Engl J Med. 2011;364:719–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Seko Y, Yamaguchi K, Mizuno N, et al. Combination of PNPLA3 and TLL1 polymorphism can predict advanced fibrosis in Japanese patients with nonalcoholic fatty liver disease. J Gastroenterol. 2018;53:438–48.

    CAS  PubMed  Google Scholar 

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Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) (2016R1D1A1B04934590), and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (H I17C0912). The funding organization played no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript.

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Author notes

  1. Donghee Kim and Won Kim equally contributed to this work as the co-first authors and co-corresponding authors.

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA

    Donghee Kim & Aijaz Ahmed

  2. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, 20, Boramae-ro 5-gil, Dongjak-gu, Seoul, 07061, South Korea

    Won Kim, Sae Kyung Joo & Jimin Han

  3. Department of Pathology, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea

    Jung Ho Kim

  4. Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    Stephen A. Harrison

  5. Department of Medicine, Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA, USA

    Zobair M. Younossi

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  1. Donghee Kim
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  2. Won Kim
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Contributions

DK: study concept and design, analysis and interpretation of data, drafting the manuscript, and approval of the final draft manuscript. WK: study concept and design, obtained funding, acquisition of data, analysis and interpretation of data, drafting the manuscript, and approval of the final draft manuscript. SKJ, JH, and JHK: acquisition of data, interpretation of data, critical revision of the manuscript for important intellectual content, and approval of the final draft manuscript. SAH and ZMY: interpretation of data, critical revision of the manuscript for important intellectual content, and approval of the final draft manuscript. AA: study concept and design, interpretation of data, critical revision of the manuscript for important intellectual content, and approval of the final draft manuscript.

Corresponding authors

Correspondence to Donghee Kim or Won Kim.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Kim, D., Kim, W., Joo, S.K. et al. Association between body size-metabolic phenotype and nonalcoholic steatohepatitis and significant fibrosis. J Gastroenterol 55, 330–341 (2020). https://doi.org/10.1007/s00535-019-01628-z

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  • DOI: https://doi.org/10.1007/s00535-019-01628-z

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