Dai et al. Nutr Metab (Lond) (2021) 18:21 https://doi.org/10.1186/s12986-021-00551-6 RESEARCH Open Access Fat mass to fat-free mass ratio and the risk of non-alcoholic fatty liver disease and fbrosis in non-obese and obese individuals Huajie Dai1,2†, Jiali Xiang1,2†, Yanan Hou1,2, Liping Xuan1,2, Tiange Wang1,2, Mian Li1,2, Zhiyun Zhao1,2, Yu Xu1,2, Jieli Lu1,2, Yuhong Chen1,2, Weiqing Wang1,2, Guang Ning1,2, Yufang Bi1,2 and Min Xu1,2* Abstract Context: Body composition may explain partially why non-obese individuals still at the risk of developing non- alcoholic fatty liver disease (NAFLD). The ratio of fat mass to fat-free mass (FM/FFM) has been proposed to assess the combined efect of diferent body compositions. Objective: We aimed to investigate the associations of FM/FFM ratio with the risk of developing NAFLD and fbrosis and to identify the potential mediators according to obesity status. Methods: This cohort study comprised 3419 adults age 40 years and free of NAFLD at baseline. Body composi- tion was measured by bioelectrical impedance analysis. NAFLD≥ was ascertained by ultrasonography and fbrosis was assessed by non-invasive score systems. Results: For each 1 standard deviation increment in FM/FFM ratio, the odds ratio for the risk of NAFLD was 1.55 (95% confdence interval [CI] 1.23–1.95) in non-obese men, 1.33 (95% CI 1.08–1.65) in obese men, 1.42 (95% CI 1.44–1.67) in non-obese women, and 1.29 (95% CI 1.12–1.50) in obese women. Similar associations were also found between FM/FFM ratio and NAFLD with fbrosis. Mediation analysis showed that insulin resistance, triglycerides, high-density lipoprotein cholesterol, white blood cells, and total cholesterol mediated the association of FM/FFM ratio with NAFLD risk in specifc sex and obesity subgroups. Conclusions: The FM/FFM ratio signifcantly associated with the NAFLD and fbrosis risk in both non-obese and obese individuals. Diferent factors may mediate the association between body composition and NAFLD risk accord- ing to diferent obesity status. Keywords: Fat-to-fat free mass ratio, Non-alcoholic fatty liver disease, Liver fbrosis, Mediation analysis, Prospective investigation Introduction Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver-lipid associated liver conditions rang- ing from excess fat deposits in the liver (steatosis) to the *Correspondence: [email protected] more aggressive nonalcoholic steatohepatitis (NASH), †Huajie Dai and Jiali Xiang have contributed equally to this work which is characterized by hepatic infammation (steato- 1 Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong hepatitis) that prompts fbrosis of liver tissue [1]. Com- University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, pelling data demonstrate that NAFLD is an established China risk factor for cardiovascular diseases, type 2 diabe- Full list of author information is available at the end of the article tes (T2D), and some kinds of cancers as well [2]. It has © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Dai et al. Nutr Metab (Lond) (2021) 18:21 Page 2 of 12 become the most common chronic liver disease in the predict the NAFLD risk in non-obese individuals has not world, with global prevalence was currently estimated to been estimated. be 25.2% [3]. Hence, more eforts are urgently needed on Te aim of this study was mainly to evaluate in non- the acquirement of knowledge about the prevention and obese and obese individuals separately: (1) the associa- management of NAFLD and ultimately help mitigate its tion between the FM/FFM ratio and the risk of incident global impact. NAFLD and fbrosis; (2) whether it is the same meta- Although NAFLD has been strongly associated with bolic or infammatory factors mediated the association obesity, a proportion of cases has a normal body mass between FM/FFM ratio and NAFLD. index (BMI) [4, 5]. Tis phenomenon is termed as “non- obese NAFLD” or “lean NAFLD”, and its worldwide prev- Methods alence is also growing substantially [5, 6]. Some studies Study population suggested that these patients had higher mortality and Participants were recruited from a community-based accelerated disease progression despite a less severe met- cohort study as reported previously [21]. In brief, abolic phenotype [6, 7]. However, there was little infor- between March to August 2010, 10,375 residents aged mation on pathogenesis, treatment, even screening of 40 years or older living in Jiading district, Shanghai, NAFLD in non-obese patients [8]. China, were invited and received a comprehensive health BMI is the most commonly used indicator to assess survey, which included a structured questionnaire and obesity. However, BMI has one major shortcoming, relevant clinical measurements. Of these participants, which is that BMI does not account for body composi- we excluded subjects who (a) did not complete abdomi- tion [9]. Individuals with the same BMI may vary in body nal ultrasound evaluation (n = 45); (b) diagnosed as hav- composition largely. Recent studies showed that diferent ing NAFLD by abdominal ultrasound (n = 2687); (c) with compositions including fat mass and fat-free mass might self-reported history of viral and autoimmune hepatitis, play diferent roles in health outcomes. Large prospec- cirrhosis, or hepatic malignancy (n = 378); (d) consumed tive cohort studies showed that increased fat mass could alcohol of ≥ 140 g/week for men and ≥ 70 g/week for signifcantly increase the risk of T2D, cardiovascular dis- women (n = 980); (e) with missing data on body compo- ease, even mortality [10–12]. In contrast, an increment sition (n = 1244). Finally, 5635 participants were eligible in fat-free mass reduced the risks of these conditions for this prospective investigation. From August 2014 to [12–14]. Terefore, BMI might not be a sufcient indi- May 2015, we invited the remaining 5635 participants to cator assessing obesity-related health risks. Worse body attend a follow-up visit. In the current analysis, we fur- composition in non-obese individuals classifed by BMI ther excluded participants who did not attend a follow- might have a hand in the occurrence and development up visit (n = 2039) or had missing data on abdominal of NAFLD. Te body composition in lean patients with ultrasonography (n = 177). Finally, 3419 participants NAFLD was deemed as a possible essential contributor were included in this study. to the development of the disease phenotype [15]. Te study protocol was approved by the Institutional Te ratio of fat mass to fat-free mass (FM/FFM) has Review Board of Ruijin Hospital afliated to the Shang- been proposed as a potential novel indicator to assess hai Jiaotong University School of Medicine and proce- the combined efect of diferent body compositions. dures were in accordance with the ethical standards of Prado CMM et al. proposed that FM/FFM ratio repre- the responsible committee on human experimentation sented metabolic load/capacity model, using fat mass as and with the Helsinki declaration of 1975, as revised in the agent of metabolic load, defned as the magnitude of 1983. Written informed consent was obtained from each an insult on a system, and fat-free mass as the agent of participant before data collection. metabolic capacity, defned as the ability of the system to counteract the insult [16]. Te higher FM/FFM ratio has Data collection also been proposed as an alternative defnition of sarco- Trained personnel performed data collection according penic obesity, which was characterized as a confuence of to a standard protocol at baseline and follow-up visits. A sarcopenia and obesity [17]. standard questionnaire was used to collect demographic Tere were several studies that investigated the asso- characteristics, as well as medical history and lifestyle ciations of FM/FFM with health outcomes and found that factors (including cigarette smoking and alcohol drink- the ratio was associated with insulin resistance, liver fat ing). Besides, we acquired physical activity at work and accumulation, glucose metabolic disorders, and meta- in leisure time using the short form of the International bolic syndrome [18–20]. However, the association of Physical Activity Questionnaire (IPAQ). the FM/FFM ratio with the risk of incident NAFLD and Body weight, height, waist circumference, and blood fbrosis remained unclear, especially whether it could pressure were measured according to a standard protocol Dai et al. Nutr Metab (Lond) (2021) 18:21 Page 3 of 12 and BMI was calculated as the weight in kilograms Outcome ascertainment divided by height in meters squared. NAFLD was diagnosed by ultrasonography with the All participants underwent an oral glucose tolerance presence of at least two of the following three fndings: test after an overnight fast of at least 10 h, blood sam- (a) difusely increased echogenicity of the liver relative ples were collected at 0 and 2 h during the test.