Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Endocrine
Published in: Endocrine 1/2017

01-07-2017 | Original Article

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

Authors: Yoshitaka Hashimoto, Masahide Hamaguchi, Takuya Fukuda, Akihiro Ohbora, Takao Kojima, Michiaki Fukui

Published in: Endocrine | Issue 1/2017

Login to get access

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.
Literature
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)CrossRefPubMed
2.
M. Blüher, Are metabolically healthy obese individuals really healthy? Eur. J. Endocrinol. 171,, R209–R219 (2014)CrossRef
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMed
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)CrossRefPubMed
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.
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)CrossRefPubMed
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)CrossRef
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)CrossRef
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)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMed
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)
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)CrossRefPubMed
15.
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMed
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMed
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)PubMed
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMedCentralPubMed
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)PubMedPubMedCentral
25.
A.J. McCullough, The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin. Liver Dis. 8, 521–533 (2004)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMedCentralPubMed
33.
D. Gallagher, Overweight and obesity BMI cut-offs and their relation to metabolic disorders in Koreans/Asians. Obes. Res. 12, 440–441 (2004)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMed
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)CrossRefPubMed
38.
N. Stefan, K. Kantartzis, H.U. Häring, Causes and metabolic consequences of Fatty liver. Endocr. Rev. 29, 939–960 (2008)CrossRefPubMed
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)CrossRefPubMed
40.
R. Taylor, R.R. Holman, Normal weight individuals who develop type 2 diabetes: the personal fat threshold. Clin. Sci. 128, 405–410 (2015)CrossRef
41.
J.P. Després, Body fat distribution and risk of cardiovascular disease: an update. Circulation 126, 1301–1313 (2012)CrossRefPubMed
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)CrossRef
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)CrossRefPubMed
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)CrossRef
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMed
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)PubMed
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)CrossRefPubMed
Metadata
Title
Fatty liver as a risk factor for progression from metabolically healthy to metabolically abnormal in non-overweight individuals
Authors
Yoshitaka Hashimoto
Masahide Hamaguchi
Takuya Fukuda
Akihiro Ohbora
Takao Kojima
Michiaki Fukui
Publication date
01-07-2017
Publisher
Springer US
Published in
Endocrine / Issue 1/2017
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-017-1313-6

Other articles of this Issue 1/2017

Endocrine 1/2017 Go to the issue

Editorial

“Slow and steady wins the race”: the importance of perseverance in the management of oncogenic osteomalacia

Endocrine Imaging

“Pseudo-progression” in advanced thyroid cancer in response to kinase inhibitor therapy

Original Article

Resection of tumors of the third ventricle involving the hypothalamus: effects on body mass index using a dedicated surgical approach

Original Article

Long-term treatment of Cushing’s disease with pasireotide: 5-year results from an open-label extension study of a Phase III trial

Endocrine Methods and Techniques

Performance of low-dose cosyntropin stimulation test handled via plastic tube

Original Article

Circulating microRNA-1a is a biomarker of Graves’ disease patients with atrial fibrillation
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits