Clin Mol Hepatol > Volume 29(4); 2023 > Article
Han and Lee: Lean or Non-obese Nonalcoholic Fatty Liver Disease Patients: Are They Really Lean?
The prevalence of nonalcoholic fatty liver disease (NAFLD) has dramatically increased in recent decades, parallel with the expansion of the obese population [1]. However, a substantial number of individuals with NAFLD are lean. The proportion of lean or non-obese and obese NAFLD patients among those with NAFLD is 19.2% and 40.8%, respectively [2]. The definition of lean or non-obese is based on the body mass index (BMI) with ethnic-specific cut-off points. Given the lower prevalence of NAFLD in the Asian countries compared to that in Western countries and the comparable proportion of lean or non-obese proportion of NAFLD between those populations [2], the Asian population, with a relatively lower BMI, is more vulnerable to NAFLD. Moreover, Asians tend to have more visceral fat deposition with a similar BMI compared to other ethnicities [3]. Therefore, lean or non-obese NAFLD was considered a unique phenomenon among Asians in early studies, which is why most existing studies were conducted in Asian countries [2].
In this issue of Clinical and Molecular Hepatology, Kim et al. [4] demonstrated that visceral fat obesity had the strongest association with non-obese NAFLD, the impact of which is greater than that of diabetes or systemic inflammation. Although the pathophysiological mechanisms of non-obese or lean NAFLD are unclear, growing evidence supports that visceral obesity rather than BMI-based obesity plays a crucial role [5]. The association between sarcopenia, myosteatosis, and NAFLD is based on insulin resistance [6,7], and myosteatosis rather than sarcopenia determines the early stage of NAFLD progression [8]. Given that lipid oxidation capacity regulated by visceral adiposity controls lipid accumulation in muscle [9,10], visceral adiposity might be the main and early phenotype of lean or non-obese NAFLD individuals as well as obese NAFLD individuals. Therefore, the BMI-based obesity index does not accurately reflect visceral adiposity or obesity. Kim et al. [4] reported no statistical difference in the visceral to subcutaneous fat ratio between non-obese and obese NAFLD patients in the male population, although the values of those with NAFLD were higher than those without NAFLD. Another Korean population-based study reported that visceral adiposity was the main contributor to incident NAFLD [11] with a baseline mean BMI of 23.7 kg/m2, indicating that most individuals were non-obese; however, the mean waist circumference was 85.1 cm. Considering the sex ratio (40.2% female) and waist circumference cut-off value for central obesity in Asian women (85 cm) [12], a substantial number of individuals were centrally obese with a normal BMI.
NAFLD and nonalcoholic steatohepatitis are well-established risk factors for cardio-renal and metabolic diseases as well as advanced liver diseases, such as cirrhosis and cancers [13]. Although some data suggest that lean NAFLD individuals have less-severe disease and may have a more favorable outcome than their obese counterparts [14], lean NAFLD individuals also experienced both hepatic and extrahepatic complications [15-17]. The histological severity in non-obese NAFLD compared to obese counterparts seemed similar in terms of lobular inflammation and ballooning [14,15,18]. In longitudinal biopsy-proven NAFLD studies, the mortality risk of lean or non-obese NAFLD patients is similar to that of obese NAFLD patients [15,18]. A Chinese study demonstrated a better outcome in non-obese NAFLD patients compared to obese NAFLD patients, where the authors enrolled more individuals with liver fibrosis (55.1% vs. 80.1% for non-obese NAFLD vs. obese NAFLD, respectively) or those with metabolic syndrome (43.1% vs. 69.8% for non-obese NAFLD vs. obese NAFLD, respectively) in the obese group [14]. The follow-up duration was relatively short (median 49 months) for determining mortality. Nevertheless, the results indicated that risk factors such as hypertriglyceridemia and increased creatinine levels were associated with NAFLD progression in lean patients, suggesting that dysregulated metabolic profiles are key to disease prognosis. In this context, metabolic dysregulation, instead of BMI-based obesity, may better reflect the clinical outcomes of NAFLD. Lean NAFLD individuals with metabolically unhealthy profiles have a higher risk for cardiovascular disease than obese NAFLD individuals [19]. Likewise, the association between NAFLD and sarcopenia was strengthened in metabolic dysfunction [20]. In terms of sarcopenia as one of the predisposing phenotypes of NAFLD, the association between sarcopenia and NAFLD appears in both the obese and non-obese NAFLD populations [20], even though Kim et al. [4] did not report a statistically significant association between sarcopenic obesity and NAFLD, probably due to the small sample size of sarcopenic individuals with higher BMI. When NAFLD is combined with sarcopenia, the risk of cardiovascular disease increases regardless of obesity [21]. The above evidence suggests the need for a new index to predict cardiometabolic risk other than BMI.
In terms of NAFLD management, especially in lean populations, Kim et al. [4] provided clinical implications for body composition as a treatment goal. Reducing visceral fat and improving muscle quality and mass, instead of reducing body weight, were the main strategies for NAFLD treatment. In a Korean study with a median 4.4-year follow-up, NAFLD was resolved in 24.7% of individuals, whose visceral adipose tissue amounts were significantly reduced, indicating a close relationship between visceral adiposity and NAFLD risk [11]. Physical activity is recommended as it improves insulin resistance in adipose tissue, liver, and skeletal muscle, the triad in NAFLD development, and improved muscle function further ameliorates systemic insulin resistance, and hepatic inflammation can be resolved [22]. Exercise can ameliorate the risks of NAFLD [20] and liver fibrosis, even in individuals with sarcopenia [23]. Additionally, physical exercise improves cardiopulmonary fitness, which can decrease cardiovascular events and mortality. Although there are limited data on the type or duration of exercise on NAFLD regression, moderate to vigorous exercise might be helpful. A cross-sectional study showed that physical activity over 880 metabolic equivalent taskmin/week decreased the risk of fibrosis, sarcopenia, and cardiovascular disease [24].
In summary, the study by Kim et al. [4] supported the evidence that visceral obesity is a risk factor for sarcopenia and/ or myosteatosis in non-obese NAFLD individuals. This result was consistent with that of NAFLD as an ectopic fat deposit that manifested as visceral obesity, sarcopenia, and myosteatosis. Although the term “lean or non-obese” NAFLD individuals is widely accepted, the natural history or clinical prognosis of lean or non-obese NAFLD patients is comparable to that of obese NAFLD patients. Therefore, the BMIbased obesity index may need to be revised, and metabolic dysfunction should be considered to identify high-risk individuals with NAFLD. Moreover, NAFLD treatment strategies, besides reducing body weight, should be established to improve body composition, which includes the reduction of visceral adipose tissues and the increment of muscle mass/quality.

ACKNOWLEDGMENTS

National Research Foundation grant funded by the Korea Government (MSIP). Grant Numbers: 2021R1G1A1010975.

FOOTNOTES

Authors’ contribution
All authors were responsible for the conceptualization, interpretation of data, drafting, and critical revision of the manuscript.
Conflicts of Interest
The authors have no conflicts to disclose.

Abbreviations

NAFLD
nonalcoholic fatty liver disease
BMI
body mass index

REFERENCES

1. Han E, Han KD, Lee YH, Kim KS, Hong S, Park JH, et al. Fatty liver & diabetes statistics in Korea: Nationwide data 2009 to 2017. Diabetes Metab J 2023;47:347-355.
crossref pmid pmc pdf
2. Ye Q, Zou B, Yeo YH, Li J, Huang DQ, Wu Y, 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 2020;5:739-752.
crossref pmid
3. Fan JG, Kim SU, Wong VW. New trends on obesity and NAFLD in Asia. J Hepatol 2017;67:862-873.
crossref pmid
4. Kim HK, Bae SJ, Lee MJ, Kim EH, Park H, Kim HS, et al. Association of visceral fat obesity, sarcopenia, and myosteatosis with non-alcoholic fatty liver disease without obesity. Clin Mol Hepatol 2023 Jul 5. doi: 10.3350/cmh.2023.0035.
crossref pmid
5. Andreasson A, Carlsson AC, Önnerhag K, Hagström H. Waist/hip ratio better predicts development of severe liver disease within 20 years than body mass index: A population-based cohort study. Clin Gastroenterol Hepatol 2017;15:1294-1301.e2.
crossref pmid
6. Han E, Kim MK, Lee HW, Ryu S, Kim HS, Jang BK, et al. Muscle fat contents rather than muscle mass determines nonalcoholic steatohepatitis and liver fibrosis in patients with severe obesity. Obesity (Silver Spring) 2022;30:2440-2449.
pmid
7. Joo SK, Kim W. Interaction between sarcopenia and nonalcoholic fatty liver disease. Clin Mol Hepatol 2023;29(Suppl):S68-S78.
crossref pmid pmc pdf
8. Hsieh YC, Joo SK, Koo BK, Lin HC, Lee DH, Chang MS, et al. Myosteatosis, but not sarcopenia, predisposes NAFLD subjects to early steatohepatitis and fibrosis progression. Clin Gastroenterol Hepatol 2023;21:388-397.e10.
crossref pmid
9. Goodpaster BH, He J, Watkins S, Kelley DE. Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab 2001;86:5755-5761.
crossref pmid pdf
10. Kim JY, Choi J, Vella CA, Criqui MH, Allison MA, Kim NH. Associations between weight-adjusted waist index and abdominal fat and muscle mass: Multi-ethnic study of atherosclerosis. Diabetes Metab J 2022;46:747-755.
crossref pmid pmc pdf
11. Kim D, Chung GE, Kwak MS, Seo HB, Kang JH, Kim W, et al. Body fat distribution and risk of incident and regressed nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2016;14:132-138.e4.
crossref pmid
12. Yang YS, Han BD, Han K, Jung JH, Son JW; Taskforce Team of the Obesity Fact Sheet of the Korean Society for the Study of Obesity. Obesity fact sheet in Korea, 2021: Trends in obesity prevalence and obesity-related comorbidity incidence stratified by age from 2009 to 2019. J Obes Metab Syndr 2022;31:169-177.
crossref pmid pmc
13. Han E, Lee YH. Non-alcoholic fatty liver disease: The emerging burden in cardiometabolic and renal diseases. Diabetes Metab J 2017;41:430-437.
crossref pmid pmc pdf
14. Leung JC, Loong TC, Wei JL, Wong GL, Chan AW, Choi PC, et al. Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients. Hepatology 2017;65:54-64.
crossref pmid pdf
15. Younes R, Govaere O, Petta S, Miele L, Tiniakos D, Burt A, 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 2022;71:382-390.
crossref pmid
16. Chun HS, Lee M. Lean vs. obese phenotypes of nonalcoholic fatty liver disease: similar or different? Clin Mol Hepatol 2023;29:377-380.
crossref pmid pmc pdf
17. Chan WK. Comparison between obese and non-obese nonalcoholic fatty liver disease. Clin Mol Hepatol 2023;29(Suppl):S58-S67.
crossref pmid pmc pdf
18. Hagström H, Nasr P, Ekstedt M, Hammar U, Stål P, Hultcrantz R, et al. Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: A long-term followup study. Hepatol Commun 2017;2:48-57.
crossref pmid pmc pdf
19. Kim Y, Han E, Lee JS, Lee HW, Kim BK, Kim MK, et al. Cardiovascular risk is elevated in lean subjects with nonalcoholic fatty liver disease. Gut Liver 2022;16:290-299.
crossref pmid pmc
20. Lee YH, Jung KS, Kim SU, Yoon HJ, Yun YJ, Lee BW, et al. Sarcopaenia is associated with NAFLD independently of obesity and insulin resistance: Nationwide surveys (KNHANES 2008-2011). J Hepatol 2015;63:486-493.
crossref pmid
21. Han E, Lee YH, Kim YD, Kim BK, Park JY, Kim DY, et al. Nonalcoholic fatty liver disease and sarcopenia are independently associated with cardiovascular risk. Am J Gastroenterol 2020;115:584-595.
crossref pmid
22. Zhang XL, Wang TY, Targher G, Byrne CD, Zheng MH. Lifestyle interventions for non-obese patients both with, and at risk, of non-alcoholic fatty liver disease. Diabetes Metab J 2022;46:391-401.
crossref pmid pmc pdf
23. Han E, Lee YH, Kim BK, Park JY, Kim DY, Ahn SH, et al. Sarcopenia is associated with the risk of significant liver fibrosis in metabolically unhealthy subjects with chronic hepatitis B. Aliment Pharmacol Ther 2018;48:300-312.
crossref pmid pdf
24. Chun HS, Lee M, Lee HA, Oh SY, Baek HJ, Moon JW, et al. Association of physical activity with risk of liver fibrosis, sarcopenia, and cardiovascular disease in nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2023;21:358-369.e12.
crossref pmid

Editorial Office
The Korean Association for the Study of the Liver
Room A1210, 53 Mapo-daero(MapoTrapalace, Dowha-dong), Mapo-gu, Seoul, 04158, Korea
TEL: +82-2-703-0051   FAX: +82-2-703-0071    E-mail: kasl@kams.or.kr
Copyright © The Korean Association for the Study of the Liver.         
COUNTER
TODAY : 794
TOTAL : 1773569
Close layer