The non-alcoholic fatty liver disease (NAFLD) represents a spectrum of liver diseases not attributable to alcohol consumption, such as simple fatty infiltration, inflammation, and cirrhosis. Globally, the NAFLD is one of the most important causes of liver disease (1) and the previous studies have demonstrated that it is associated with metabolic syndrome (2), diabetes (3), and hypertension (4). As reported in a meta-analysis conducted in 2016, 25% of the global adult population were afflicted with NAFLD (5). Moreover, in China, the prevalence of NAFLD among adults in the general population is >20% and has paralleled the increase in obesity (6). In addition, the obesity prevalence rose from 3.1% (2.5–3.7) in 2004 to 8.1% (7.6–8.7) in 2018 (7). In parallel with increasing prevalence, the economic burden of NAFLD is enormous, especially at the time of diagnosis (8). Therefore, it is important to identify the modifiable risk factors and develop preventive strategies.

Insulin resistance is shown to be an important factor in NAFLD progression (9). A muscle is a target organ for insulin (10), and the previous studies suggested that the skeletal muscles secrete a variety of metabolically bioactive factors, such as myostatin, interleukin-6, and irisin (11, 12) that are subsequently involved in the regulation of insulin resistance and lipid metabolism. Thus, it is plausible that the muscles play an important role in the development of NAFLD. Indeed, several cross-sectional studies have shown that muscle strength is associated with NAFLD (13–18). For example, a cross-sectional study involving 5,132 adults in China showed that the low muscle strength was positively and independently associated with NAFLD [odds ratio (OR), 1.47; 95% CI, 1.21, 1.80] (13). Another nationwide population-based cross-sectional study demonstrated that the high hand grip strength (HGS) was negatively associated with the hepatic steatosis index (HSI) in 4,764 participants of Koreas (14). Because of the cross-sectional design of these studies, however, a causal relationship could not be identified.

To our knowledge, there has been no cohort study conducted to investigate the associations between muscle strength and the incidence of NAFLD. Thus, we conducted this prospective study to better understand the association between the HGS and NAFLD using data from a large population-based cohort study in adults in China.

Our large population-based cohort study in which we prospectively determined the association between HGS and NAFLD in the Chinese adults suggested that a higher HGS was associated with a lower risk of NAFLD. These associations were independent of the socio-demographic, behavioral, psychological, dietary, and health status factors. Furthermore, there were significant interaction effects between HGS and both BMI and waist size on the incidence of NAFLD. The results of our sensitivity analysis, which defined NAFLD using the HSI and FLI, were similar to those of the main analysis.

The muscles have been shown to play an important role in the development of NAFLD (35). The previous studies found that sarcopenia, which is a progressive and generalized skeletal muscle disorder that involves the accelerated loss of muscle mass and function (36), was shown to be associated with NAFLD (37, 38). Compared with measuring muscle mass, measuring muscle strength (an indicator of muscle function) is easy to do in both the clinical and community settings (39). Thus, muscle strength could be a valuable predictor of NAFLD. In recent years, several cross-sectional studies have determined the association between HGS and the prevalence of NAFLD (13–17). For example, a cross-sectional study of 20,957 Chinese adults reported that increased HGS was independently associated with a lower prevalence of NAFLD (17). Compared with the participants who had the lowest HGS, the OR (95% CI) for the highest HGS was 0.67 (0.57, 0.79) (17). Another cross-sectional study also suggested that the low muscle strength was positively associated with NAFLD (OR, 1.47; 95% CI, 1.21, 1.80) in 5,132 Chinese adults (13). The Korea National Health and Nutrition Examination Survey also found that the lower BMI-adjusted HGS was associated with NAFLD in the Korean adults (n = 8,001) (16) as well as in elderly participants (n = 4,764) (14). Moreover, another study revealed a linear decrease in the NAFLD index that was commensurate with the incremental HGS level changes among the 538 elderly Korean participants (15). No cohort study has investigated the associations between HGS and NAFLD prospectively; considering the cross-sectional designs of previous studies, it was not possible to draw conclusions with respect to causality.

Consistent with previous cross-sectional studies, the present cohort study suggested that HGS was negatively associated with the incidence of NAFLD after adjusting for the confounding factors. The mechanisms that have been proposed to explain this association are chiefly related to insulin resistance and inflammation. First, the skeletal muscle is a major site of insulin-stimulated whole-body glucose disposal, and muscle metabolism can influence whole-body glucose homeostasis and insulin sensitivity (40). Thus, low muscle mass may lead to insulin resistance and explain the propagation of NAFLD (35). In addition, the muscle secretes irisin, which is a hormone that reduces obesity and insulin resistance (12), and is shown to be inversely associated with hepatic steatosis (41). Second, sarcopenia is associated with inflammatory indicators, such as the C-reactive protein level (38) and the neutrophil-to-lymphocyte ratio (42). Inflammation is also well-documented as a central component of NAFLD pathogenesis (43). Moreover, a previous study suggested that interleukin-6, which is a myokine secreted by muscle, was shown to have a protective effect on the development of NAFLD in an inflammation-prone animal model (44).

The results of the subgroup analyses suggested that the strongest associations between HGS and NAFLD were found in the participants with normal BMI and waist circumference. Two reasons were possible to explain it. First, BMI (45) and waist circumference (46) are positively associated with NAFLD. Thus, the associations between the HGS and NAFLD could be covered by BMI and waist circumference in the participants with high BMI and waist circumference. Second, the small sample sizes of high BMI and waist circumference subgroups could result in wide CIs of the HRs for NAFLD. We further performed the sensitivity analyses by defining NAFLD using the HSI and FLI. The associations revealed using this method were similar to those found when NAFLD was detected using liver ultrasonography and alcohol consumption history, indicating the robustness of the results.

The main strengths of our study were the large sample size and prospective cohort design. The former strength allowed for sufficient statistical power to detect the associations between HGS and NAFLD, while the latter strength helped ensure that the reverse causation would be minimized as much as possible. Moreover, the previous studies did not include dietary confounding factors in the adjustment models, even though the factors are strongly associated with muscle strength (47) and NAFLD (48). In the present study, we adjusted for sociodemographic, behavioral, psychological, dietary, and health status factors as much as possible to ascertain the independence from the association between HGS and NAFLD.

Some limitations are notable in our study. First, owing to its observational study design, the mechanism underlying the associations could not be determined. Second, even though we adjusted for the potential confounding factors, we could not rule out the possibility that other unmeasured factors might contribute to the associations observed. Third, we used hepatic ultrasonography scanning instead of the liver biopsies to detect fatty liver given that liver biopsy was not available during the health examinations of the target population. Even though a previous study found that ultrasonography had a sensitivity of 89% and a specificity of 93% for NAFLD and was widely used in population-based studies because of its non-invasiveness and accessibility (49), ultrasound has limited sensitivity and does not reliably detect steatosis when the amount of fat was low or in individuals with an elevated BMI. Thus, the patients from the NAFLD group (future NAFLD patients) may have NAFLD at the baseline but are diagnosed without NAFLD when using liver ultrasound. Future studies which use more accurate methods, such as liver biopsy and controlled attenuation parameter, are needed to confirm the observed associations in the present study. Fourth, we excluded participants with choric hepatitis B or C, autoimmune liver disease, and those who have previous liver surgery. Nevertheless, the participants with other causes of NAFLD (such as a drug), celiac disease, or thyroid disease were not excluded. Therefore, the observed associations may be affected. Finally, the mechanisms that underline the associations between HGS and NAFLD may be explained by the metabolic factors (e.g., insulin resistance). Otherwise, various factors play important roles in the development of NAFLD. For example, lean NAFLD was developed without obesity (50), and there is also a substantial proportion of patients with normal BMI NAFLD without insulin resistance. Moreover, the susceptible polygenic host background also contributes to the development of NAFLD (51). Therefore, despite metabolic factors, further studies should also focus on the effect of aforenoted factors on the development of NAFLD.

Despite the aforementioned limitations, ours is the first cohort study to demonstrate that HGS is inversely associated with the incidence of NAFLD. The data suggested that a high HGS predicts a lower risk of NAFLD; hence, measuring HGS may serve as a possible strategy for detecting NAFLD at an early stage.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved the protocol of this study was approved by the Institutional Review Board of the Tianjin Medical University; the subjects provided written informed consent to participate in the study. The study protocol conformed to the Ethical guidelines of the 1975 Declaration of Helsinki. The patients/participants provided their written informed consent to participate in this study.

YX and KN contributed to the study conception and design. YX, LC, YL, XuW, SZ, GM, QZ, LL, HW, YG, YW, TZ, XiW, SS, MZ, QJ, and KS contributed to data collection, assembly, analysis, and interpretation of the data. YX, YZ, and KN contributed to the revising of the manuscript. YX, LC, and YZ contributed to the manuscript drafting and approval of the final version of the manuscript. All authors contributed to the article and approved the submitted version.

This study was supported by grants from the National Natural Science Foundation of China (Nos. 81903302, 91746205, and 81673166) and 345 Talent Project of Shengjing Hospital of China Medical University (No. M0294).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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