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Endocrine

, Volume 57, Issue 1, pp 89–97 | Cite as

Fatty liver as a risk factor for progression from metabolically healthy to metabolically abnormal in non-overweight individuals

  • Yoshitaka Hashimoto
  • Masahide HamaguchiEmail author
  • Takuya Fukuda
  • Akihiro Ohbora
  • Takao Kojima
  • Michiaki Fukui
Original Article

Abstract

Purpose

Recent studies identified that metabolically abnormal non-obese phenotype is a risk factor for cardiovascular diseases. However, little is known about risk factor for progression from metabolically healthy non-overweight to metabolically abnormal phenotype. We hypothesized that fatty liver had a clinical impact on progression from metabolically healthy non-overweight to metabolically abnormal phenotype.

Methods

In this retrospective cohort study, 14,093 Japanese (7557 men and 6736 women), who received the health-checkup program from 2004 to 2012, were enrolled. Overweight and obesity were defined as body mass index 23.0–25.0 and ≥25.0 kg/m2. Four metabolic factors (impaired fasting glucose, hypertension, hypertriglyceridemia and low high density lipoprotein-cholesterol concentration) were used for definition of metabolically healthy (less than two factors) or metabolically abnormal (two or more). We divided the participants into three groups: metabolically healthy non-overweight (9755 individuals, men/women = 4290/5465), metabolically healthy overweight (2547 individuals, 1800/747) and metabolically healthy obesity (1791 individuals, 1267/524). Fatty liver was diagnosed by ultrasonography.

Results

Over the median follow-up period of 5.3 years, 873 metabolically healthy non-overweight, 512 metabolically healthy overweight and 536 metabolically healthy obesity individuals progressed to metabolically abnormal. The adjusted hazard risks of fatty liver on progression were 1.49 (95% confidence interval 1.20–1.83, p = 0.005) in metabolically healthy non-overweight, 1.37 (1.12–1.66, p = 0.002) in metabolically healthy overweight and 1.38 (1.15–1.66, p < 0.001) in metabolically healthy obesity, after adjusting for age, sex, alcohol, smoking, exercise, impaired fasting glucose, hypertension, hypertriglyceridemia, low high density lipoprotein-cholesterol concentration, and abdominal obesity.

Conclusions

Fatty liver is an independent risk factor for progression from metabolically healthy status to metabolically abnormal phenotype, even in non-overweight individuals.

Keywords

Non-alcoholic fatty liver disease Metabolic syndrome Insulin resistance Obesity Lean 

Notes

Acknowledgements

We thank all of the staff members in the medical health checkup center at Murakami Memorial Hospital.

Author contributions

Y.H. designed and conducted the study, researched, analyzed and interpreted the data, and wrote the manuscript; M.H. designed and conducted the study, researched and interpreted the data, and reviewed and edited the manuscript. T.F., A.O. and T.K. researched and interpreted the data, and reviewed the manuscript. M.F. designed and conducted the study, researched and interpreted the data, and reviewed the manuscript. All authors have approved the final draft submitted.

Compliance with ethical standards

Conflict of interest

M. Fukui has received grant and research support from AstraZeneca plc, Astellas Pharma Inc., Bristol-Myers Squibb K.K., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K., Kyowa Hakko Kirin Company Ltd., Kowa Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., MSD K.K., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Pharma Ltd., Nippon Chemiphar Company Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Sanofi K.K., Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Terumo Co. The sponsors were not involved in the study design; in the collection, analysis, interpretation of data; in the writing of this manuscript; or in the decision to submit the article for publication. M. Fukui, his immediate families, and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article. M. Fukui received no current funding for this study and this does not alter their adherence to all of the journal policies on sharing data and materials. The remaining authors declare that they have no competing interests.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki, and an independent ethics committee.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    M. Hamaguchi, T. Kojima, N. Takeda, T. Nakagawa, H. Taniguchi, K. Fujii, T. Omatsu, T. Nakajima, H. Sarui, M. Shimazaki, T. Kato, J. Okuda, K. Ida, The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann. Intern. Med. 143, 722–728 (2005)CrossRefGoogle Scholar
  2. 2.
    M. Blüher, Are metabolically healthy obese individuals really healthy? Eur. J. Endocrinol. 171,, R209–R219 (2014)CrossRefGoogle Scholar
  3. 3.
    Y. Hashimoto, M. Tanaka, H. Okada, T. Senmaru, M. Hamaguchi, M. Asano, M. Yamazaki, Y. Oda, G. Hasegawa, H. Toda, N. Nakamura, M. Fukui, Metabolically healthy obesity and risk of incident CKD. Clin. J. Am. Soc. Nephrol. 10, 578–583 (2015)CrossRefPubMedCentralGoogle Scholar
  4. 4.
    N. Eckel, K. Mühlenbruch, K. Meidtner, H. Boeing, N. Stefan, M.B. Schulze, Characterization of metabolically unhealthy normal-weight individuals: risk factors and their associations with type 2 diabetes. Metabolism 64, 862–871 (2015)CrossRefGoogle Scholar
  5. 5.
    Y. Heianza, Y. Arase, H. Tsuji, K. Fujihara, K. Saito, S.D. Hsieh, S. Tanaka, S. Kodama, S. Hara, H. Sone, 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. 99, 2952–2960 (2014)CrossRefGoogle Scholar
  6. 6.
    J. Zhang, H. Jiang, J. Chen, Combined effect of body mass index and metabolic status on the risk of prevalent and incident chronic kidney disease: a systematic review and meta-analysis. Oncotarget. in press. (2016). doi: 10.18632/oncotarget.10915
  7. 7.
    C.K. Kramer, B. Zinman, R. Retnakaran, Are metabolically healthy overweight and obesity benign conditions?: A systematic review and meta-analysis. Ann. Intern. Med. 159, 758–769 (2013)CrossRefGoogle Scholar
  8. 8.
    R. Dobson, M.I. Burgess, V.S. Sprung, A. Irwin, M. Hamer, J. Jones, C. Daousi, V. Adams, G.J. Kemp, F. Shojaee-Moradie, M. Umpleby, D.J. Cuthbertson, Metabolically healthy and unhealthy obesity: differential effects on myocardial function according to metabolic syndrome, rather than obesity. Int. J. Obes. 40, 153–161 (2016)CrossRefGoogle Scholar
  9. 9.
    N.J. Coleman, J. Miernik, L. Philipson, L. Fogelfeld, Lean versus obese diabetes mellitus patients in the United States minority population. J. Diabetes Complicat 28, 500–505 (2014)CrossRefGoogle Scholar
  10. 10.
    L. Di Renzo, E. Tyndall, P. Gualtieri, C. Carboni, R. Valente, A.S. Ciani, M.G. Tonini, A. De Lorenzo, Association of body composition and eating behavior in the normal weight obese syndrome. Eat. Weight. Disord. 21, 99–106 (2016)CrossRefPubMedCentralGoogle Scholar
  11. 11.
    A. De Lorenzo, V. Del Gobbo, M.G. Premrov, M. Bigioni, F. Galvano, L. Di Renzo, Normal-weight obese syndrome: early inflammation? Am. J. Clin. Nutr. 85, 40–45 (2007)CrossRefPubMedCentralGoogle Scholar
  12. 12.
    M. Masarone, A. Federico, L. Abenavoli, C. Loguercio, M. Persico, Non alcoholic fatty liver: epidemiology and natural history. Rev. Recent Clin. Trials 9, 126–133 (2014)CrossRefPubMedCentralGoogle Scholar
  13. 13.
    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. 64, 1388–1402 (2016)Google Scholar
  14. 14.
    T. Fukuda, M. Hamaguchi, T. Kojima, Y. Hashimoto, A. Ohbora, T. Kato, N. Nakamura, M. Fukui, The impact of nonalcoholic fatty liver disease on incident type 2 diabetes mellitus in non-overweight individuals. Liver Int. 36, 275–283 (2016)CrossRefPubMedCentralGoogle Scholar
  15. 15.
    J.M. Hazlehurst, C. Woods, T. Marjot, J.F. Cobbold, J.W. Tomlinson, Non-alcoholic fatty liver disease and diabetes. Metabolism 65, 1096–1108 (2016)CrossRefPubMedCentralGoogle Scholar
  16. 16.
    G. Musso, R. Gambino, J.H. Tabibian, M. Ekstedt, S. Kechagias, M. Hamaguchi, R. Hultcrantz, H. Hagström, S.K. Yoon, P. Charatcharoenwitthaya, J. George, F. Barrera, S. Hafliðadóttir, E.S. Björnsson, M.J. Armstrong, L.J. Hopkins, X. Gao, S. Francque, A. Verrijken, Y. Yilmaz, K.D. Lindor, M. Charlton, R. Haring, M.M. Lerch, R. Rettig, H. Völzke, S. Ryu, G. Li, L.L. Wong, M. Machado, H. Cortez-Pinto, K. Yasui, M. Cassader, Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med. 11, e1001680 (2014)CrossRefPubMedCentralGoogle Scholar
  17. 17.
    G. Musso, M. Cassader, S. Cohney, F. De Michieli, S. Pinach, F. Saba, R. Gambino, Fatty liver and chronic kidney disease: novel mechanistic insights and therapeutic opportunities. Diabetes Care 39, 1830–1845 (2016)CrossRefPubMedCentralGoogle Scholar
  18. 18.
    M. Hamaguchi, T. Kojima, N. Takeda, C. Nagata, J. Takeda, H. Sarui, Y. Kawahito, N. Yoshida, A. Suetsugu, T. Kato, J. Okuda, K. Ida, T. Yoshikawa, Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J. Gastroenterol. 13, 1579–1584 (2007)CrossRefPubMedCentralGoogle Scholar
  19. 19.
    A. Lonardo, S. Sookoian, C.J. Pirola, G. Targher, Non-alcoholic fatty liver disease and risk of cardiovascular disease. Metabolism 65, 1136–1150 (2016)CrossRefPubMedCentralGoogle Scholar
  20. 20.
    A. Federico, M. Dallio, M. Masarone, M. Persico, C. Loguercio, The epidemiology of non-alcoholic fatty liver disease and its connection with cardiovascular disease: role of endothelial dysfunction. Eur. Rev. Med. Pharmacol. Sci. 20, 4731–4741 (2016)PubMedPubMedCentralGoogle Scholar
  21. 21.
    L. Abenavoli, N. Milic, L. Di Renzo, T. Preveden, M. Medić-Stojanoska, A. De Lorenzo, Metabolic aspects of adult patients with nonalcoholic fatty liver disease. World J. Gastroenterol. 22, 7006–7016 (2016)CrossRefPubMedCentralGoogle Scholar
  22. 22.
    L. Abenavoli, N. Milic, V. Peta, F. Alfieri, A. De Lorenzo, S. Bellentani, Alimentary regimen in non-alcoholic fatty liver disease: mediterranean diet. World J. Gastroenterol. 20, 16831–16840 (2014)CrossRefPubMedCentralGoogle Scholar
  23. 23.
    M. Hamaguchi, N. Takeda, T. Kojima, A. Ohbora, T. Kato, H. Sarui, M. Fukui, C. Nagata, J. Takeda, Identification of individuals with non-alcoholic fatty liver disease by the diagnostic criteria for the metabolic syndrome. World J. Gastroenterol. 18, 1508–1516 (2012)CrossRefPubMedCentralGoogle Scholar
  24. 24.
    L. Abenavoli, L. DI Renzo, P.H. Guzzi, R. Pellicano, N. Milic, A. De Lorenzo, Non-alcoholic fatty liver disease severity, central fat mass and adinopectin: a close relationship. Clujul Med. 88, 489–493 (2015)PubMedPubMedCentralGoogle Scholar
  25. 25.
    A.J. McCullough, The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin. Liver Dis. 8, 521–533 (2004)CrossRefPubMedCentralGoogle Scholar
  26. 26.
    A. Suzuki, P. Angulo, J. St Sauver, A. Muto, T. Okada, K. Lindor, Light to moderate alcohol consumption is associated with lower frequency of hypertransaminasemia. Am. J. Gastroenterol. 102, 1912–1919 (2007)CrossRefPubMedCentralGoogle Scholar
  27. 27.
    Y. Hashimoto, M. Hamaguchi, T. Kojima, Y. Ohshima, A. Ohbora, T. Kato, N. Nakamura, M. Fukui, The modest alcohol consumption reduces the incidence of fatty liver in men; a population based large scale cohort study. J. Gastroenterol. Hepatol. 30, 546–552 (2015)CrossRefPubMedCentralGoogle Scholar
  28. 28.
    Y. Fukuda, Y. Hashimoto, M. Hamaguchi, T. Fukuda, N. Nakamura, A. Ohbora, T. Kato, T. Kojima, M. Fukui, Triglycerides to high-density lipoprotein cholesterol ratio is an independent predictor of incident fatty liver; a population-based cohort study. Liver Int. 36, 713–720 (2016)CrossRefPubMedCentralGoogle Scholar
  29. 29.
    D.J. Aaron, A.M. Kriska, S.R. Dearwater, J.A. Cauley, K.F. Metz, R.E. LaPorte, Reproducibility and validity of an epidemiologic questionnaire to assess past year physical activity in adolescents. Am. J. Epidemiol 142, 191–201 (1995)CrossRefPubMedCentralGoogle Scholar
  30. 30.
    S. Ryu, Y. Chang, D.I. Kim, W.S. Kim, B.S. Suh, gamma-Glutamyltransferase as a predictor of chronic kidney disease in nonhypertensive and nondiabetic Korean men. Clin. Chem. 53, 71–77 (2007)CrossRefGoogle Scholar
  31. 31.
    K.G. Alberti, P. Zimmet, J. Shaw, Metabolic syndrome—a new world-wide definition. A consensus statement from the international diabetes federation. Diabet. Med. 23, 469–480 (2006)CrossRefGoogle Scholar
  32. 32.
    M. Ashwell, S. Lejeune, K. McPherson, Ratio of waist circumference to height may be better indicator of need for weight management. BMJ 312, 377 (1996)CrossRefPubMedCentralGoogle Scholar
  33. 33.
    D. Gallagher, Overweight and obesity BMI cut-offs and their relation to metabolic disorders in Koreans/Asians. Obes. Res. 12, 440–441 (2004)CrossRefGoogle Scholar
  34. 34.
    Y. Hashimoto, M. Tanaka, T. Kimura, N. Kitagawa, M. Hamaguchi, M. Asano, M. Yamazaki, Y. Oda, H. Toda, N. Nakamura, M. Fukui, Hemoglobin concentration and incident metabolic syndrome: a population-based large-scale cohort study. Endocrine 50, 390–396 (2015)CrossRefGoogle Scholar
  35. 35.
    T. Kimura, Y. Hashimoto, M. Tanaka, M. Asano, M. Yamazaki, Y. Oda, H. Toda, Y. Marunaka, N. Nakamura, M. Fukui, Sodium-chloride difference and metabolic syndrome: a population-based large-scale cohort study. Intern. Med. 55, 3085–3090 (2016)CrossRefPubMedCentralGoogle Scholar
  36. 36.
    M. Hamaguchi, T. Kojima, Y. Itoh, Y. Harano, K. Fujii, T. Nakajima, T. Kato, N. Takeda, J. Okuda, K. Ida, Y. Kawahito, T. Yoshikawa, T. Okanoue, The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am. J. Gastroenterol. 102, 2708–2715 (2007)CrossRefGoogle Scholar
  37. 37.
    C.D. Byrne, G. Targher, Ectopic fat, insulin resistance, and nonalcoholic fatty liver disease: implications for cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 34, 1155–1161 (2014)CrossRefGoogle Scholar
  38. 38.
    N. Stefan, K. Kantartzis, H.U. Häring, Causes and metabolic consequences of Fatty liver. Endocr. Rev. 29, 939–960 (2008)CrossRefGoogle Scholar
  39. 39.
    Y. Hashimoto, M. Hamaguchi, T. Fukuda, N. Nakamura, A. Ohbora, T. Kojima, M. Fukui, BMI history and risk of incident fatty liver: a population-based large-scale cohort study. Eur. J. Gastroenterol. Hepatol. 28, 1188–1193 (2016)CrossRefGoogle Scholar
  40. 40.
    R. Taylor, R.R. Holman, Normal weight individuals who develop type 2 diabetes: the personal fat threshold. Clin. Sci. 128, 405–410 (2015)CrossRefGoogle Scholar
  41. 41.
    J.P. Després, Body fat distribution and risk of cardiovascular disease: an update. Circulation 126, 1301–1313 (2012)CrossRefGoogle Scholar
  42. 42.
    Y.C. Hwang, T. Hayashi, W.Y. Fujimoto, S.E. Kahn, D.L. Leonetti, M.J. McNeely, E.J. Boyko, Visceral abdominal fat accumulation predicts the conversion of metabolically healthy obese subjects to an unhealthy phenotype. Int. J. Obes. 39, 1365–1370 (2015)CrossRefGoogle Scholar
  43. 43.
    M.D. Fung, K.L. Canning, P. Mirdamadi, C.I. Ardern, J.L. Kuk, Lifestyle and weight predictors of a healthy overweight profile over a 20-year follow-up. Obesity 23, 1320–1325 (2015)CrossRefGoogle Scholar
  44. 44.
    Z. Cui, K.P. Truesdale, P.T. Bradshaw, J. Cai, J. Stevens, Three-year weight change and cardiometabolic risk factors in obese and normal weight adults who are metabolically healthy: the atherosclerosis risk in communities study. Int. J. Obes. 39, 1203–1208 (2015)CrossRefGoogle Scholar
  45. 45.
    Y.C. Klimentidis, Z. Chen, A. Arora, C.H. Hsu, Association of physical activity with lower type 2 diabetes incidence is weaker among individuals at high genetic risk. Diabetologia 57, 2530–2534 (2014)CrossRefPubMedCentralGoogle Scholar
  46. 46.
    T. Fukuda, M. Hamaguchi, T. Kojima, K. Mitsuhashi, Y. Hashimoto, A. Ohbora, T. Kato, N. Nakamura, M. Fukui, Transient remission of nonalcoholic fatty liver disease decreases the risk of incident type 2 diabetes mellitus in Japanese men. Eur. J. Gastroenterol. Hepatol. 28, 1443–1449 (2016)CrossRefGoogle Scholar
  47. 47.
    Y. Hashimoto, T. Fukuda, C. Oyabu, M. Tanaka, M. Asano, M. Yamazaki, M. Fukui, Impact of low-carbohydrate diet on body composition: meta-analysis of randomized controlled studies. Obes. Rev. 17, 499–509 (2016)CrossRefGoogle Scholar
  48. 48.
    N. Di Daniele, L. Petramala, L. Di Renzo, F. Sarlo, D.G. Della Rocca, M. Rizzo, V. Fondacaro, L. Iacopino, C.J. Pepine, A. De Lorenzo, Body composition changes and cardiometabolic benefits of a balanced Italian Mediterranean diet in obese patients with metabolic syndrome. Acta Diabetol. 50, 409–416 (2013)CrossRefGoogle Scholar
  49. 49.
    G. Merra, S. Gratteri, A. De Lorenzo, S. Barrucco, M.A. Perrone, E. Avolio, S. Bernardini, M. Marchetti, L. Di Renzo, Effects of very-low-calorie diet on body composition, metabolic state, and genes expression: a randomized double-blind placebo-controlled trial. Eur. Rev. Med. Pharmacol. Sci. 21, 329–345 (2017)PubMedGoogle Scholar
  50. 50.
    R. Hernaez, M. Lazo, S. Bonekamp, I. Kamel, F.L. Brancati, E. Guallar, J.M. Clark, Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology 54, 1082–1090 (2011)CrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Endocrinology and MetabolismKyoto Prefectural University of Medicine, Graduate School of Medical ScienceKyotoJapan
  2. 2.Department of DiabetologyKameoka Municipal HospitalKyotoJapan
  3. 3.Department of Gastroenterology, Murakami Memorial HospitalAsahi UniversityGifuJapan

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