This population-based longitudinal study suggested that high baseline fat mass rather than muscle mass may be a better predictor for incident NAFLD across BMI categories in participants without NAFLD at baseline. Moreover, reciprocal changes in fat and muscle masses during the first year of follow-up also predicted incident NAFLD in the non-obese population. Both findings were significantly associated with NAFLD development after adjustment for metabolic parameters.
The incidence rate of NAFLD in the present study (59.4 per 1000 person-years) was comparable to the pooled incidence rates in Asia (50.9 per 1000 person-years) in a recent systematic review11. The incremental incidence rates in subgroups with higher BMI categories reaffirmed the role of obesity in the development of NAFLD12. However, because BMI is an imperfect marker of adiposity or body fat distribution13, decreased or excess components of body composition at a given time and their changes with time were investigated to understand their roles in NAFLD development in various BMI categories. Low skeletal muscle mass has been suggested as a risk factor for NAFLD, considering the important role of skeletal muscles in insulin-mediated glucose disposal and secretion of myokines14,15.
Several recent studies have reported the relevance of sarcopenia as a risk factor for NAFLD, mostly in cross-sectional settings. According to a study based on a Korean nationwide survey, sarcopenia was independently associated with an increased prevalence of NAFLD defined by hepatic steatosis index score after adjusting for obesity or insulin resistance16. Other studies have also reported an association between low muscle mass and NAFLD prevalence in cross-sectional settings17,18. Recently, a longitudinal retrospective cohort study from Korea demonstrated that relative skeletal muscle mass at baseline was inversely associated with NAFLD development and positively associated with the resolution of NAFLD9. Because NAFLD incidence differed significantly among different BMI subgroups in the present study, we explored risk factors for incident NAFLD among the four different BMI subgroups. Consistent with former studies, the results of the present study for 9967 participants with at least two health examinations suggested associations between reduced relative muscle mass at baseline and incident NAFLD risk in the normal-weight group in a dose-dependent manner, after adjustment for multiple confounders.
Additionally, our results indicated that high baseline fat mass was a better predictor for incident NAFLD than low muscle mass in the normal-weight, overweight, and obese groups. From the Rotterdam study of a large population-based cohort, cross-sectional analysis showed that both high fat mass and low muscle mass were associated with NAFLD in normal-weight women (BMI < 25), whereas fat mass was a better predictor for NAFLD prevalence in both sexes19. Likewise, our results suggested that relative excess of fat mass predicted incident NAFLD better in all study populations except in participants with BMI < 18.5, whereas low muscle mass was only significant in the normal-weight subgroup. In addition, changes between the first and second health examinations were investigated to identify their relationship with the development of NAFLD in participants who underwent three or more health checkups during the study period (n = 5033). Even in the case of relatively small changes in body weight, muscle mass, and fat mass between the first and second examinations, differences among the four BMI subgroups were significant concerning the direction of changes (Table 3). Table 4 shows that changes in weight were correlated with changes in body composition and metabolic abnormalities, that is, even a small amount of weight gain was associated with blood pressure elevation, serum glucose and triglyceride increases, and HDL cholesterol decrease in addition to reduced muscle mass and increased fat mass. These findings suggest an evolving process toward metabolic abnormalities in NAFLD development as in previous studies, which reported insulin resistance or low adiponectin in non-obese participants with NAFLD20,21.
Considering the small, but significant, reciprocal changes in muscle and fat mass accompanying weight changes in our study participants, we further explored the relationship between changes in body composition parameters and incident NAFLD risk. A significant increase in incident NAFLD risk was noted per percent increase in fat mass after adjustment for baseline values and other confounders in all BMI categories between the first and second examinations with a median interval of 1.2 years (Table 5). However, the degree of increase in incident NAFLD risk per percent decrease in muscle mass showed less robustness overall, as well as a nonsignificant association in the obese group. A recent single-center retrospective study from Korea reported that a progressive increase in fat mass and loss of muscle mass with aging was significantly associated with incident NAFLD, particularly in non-obese participants, between baseline and follow-up health examinations at 10 years22. However, loss of muscle mass over a longer time period is an aging process23. Instead of evaluating the effect of aging on NAFLD development, we focused on the effect of early changes in body composition from the perspective of NAFLD prevention. Studies have demonstrated the efficacy of lifestyle intervention in preventing progression to diabetes in individuals with prediabetes, even compared with metformin24,25. Similarly, our results show that if participants with unfavorable body composition at baseline achieve an increase in muscle mass and more importantly decrease in fat mass over a 1- or 2-year period, even small amounts of such changes can reduce the risk of future NAFLD.
Generally, Asians have proportionately higher body fat for a given BMI than people of other races26,27. Non-obese Asian participants with NAFLD have a higher body fat content compared with those with comparable BMI without NAFLD28. Therefore, more robustness of fat mass compared with muscle mass in terms of NAFLD risk in the present study must be validated in other populations, including those in the West. Although there have been several Western studies on the relationship between body composition and NAFLD, which included advanced nonalcoholic steatohepatitis29,30, similar studies in a presumably healthy population are scarce, except for the Rotterdam study19. Despite its cross-sectional design, the results of the Rotterdam study at least underscore the relative importance of fat mass in NAFLD risk. Additionally, a recent randomized controlled trial from Hong Kong concluded that NAFLD remission was achieved with lesser weight reduction through lifestyle interventions in non-obese patients compared with obese patients31. The effect of fat mass and its changes on NAFLD development, particularly in the non-obese participants of the present study, suggest common pathophysiologic processes to those in the Hong Kong study in which non-obese patients achieved NAFLD remission with a modest degree of weight reduction31.
Recently, an international expert consensus statement recommended an updated definition of MAFLD instead of NAFLD32. MAFLD may more accurately reflects current knowledge of fatty liver diseases associated with metabolic dysfunction than NAFLD. When we applied MAFLD as the outcome, the change in muscle mass was not significantly associated with the development of MAFLD in the low bodyweight group and the effect was smaller in the normal-weight group. These results may have been affected by the smaller number of subjects in the lean group and normal-weight groups. However, the associations between MAFLD development and low muscle mass/high FP at baseline were consistent with the NAFLD results.
The present study had several limitations. First, NAFLD diagnosis was based on ultrasonography, instead of liver biopsy, which is the gold standard for the diagnosis of and severity assessment for NAFLD. Additionally, the use of ultrasonography for diagnosis raises concerns about possible misclassification bias of incident NAFLD diagnosis, which may weaken the associations found. However, recommending or performing liver biopsy in presumably healthy individuals could raise an ethical concern, considering that this study exclusively enrolled health checkup examinees. Second, the bioelectrical impedance analyzer used in this study was unable to determine the distribution (android or gynoid) of the fat mass, which is known to be related to metabolic abnormalities and NAFLD19,33. In addition, assessment of visceral adiposity, such as abdominal fat computed tomography, was unavailable. Third, the database lacked information on muscle function, such as grip strength, which is one of the various aspects in the assessment of sarcopenia34. Fourth, noninvasive techniques for NAFLD severity assessment, such as transient elastography, was not included in the health examination programs. Fifth, the present study included health checkup examinees from Korea, which may limit generalization of the results to other settings or ethnic groups with different cut-off values of BMI for obesity and different body composition patterns27,35. Lastly, we were unable to assess the effect of genetic variants due to the study design (lack of study samples). Recent genetic studies suggest a possible link between altered body composition and the development of NAFLD, for example, higher prevalence of patatin-like phospholipase domain-containing protein 3 (PNPLA3) [G] allele among non-obese individuals, an association between transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 genotype and NAFLD that was independent of obesity, and interferon lambda 4 variant in non-obese nonalcoholic steatohepatitis20,36,37. More detailed studies are required to confirm the mechanistic link among genetic factors, body composition, and the risk of NAFLD.
In summary, although low muscle mass at baseline was a significant predictor for incident NAFLD in individuals with normal weight, high baseline fat mass predicted incident NAFLD in overweight and obese participants, as well as in those with normal weight, in this large-scale population-based study. In addition, reciprocal changes in fat and muscle masses during the first year of follow-up predicted incident NAFLD in participants with BMI < 25 kg/m2. The results of the present study add to the rationale of lifestyle interventions to prevent NAFLD development in individuals with high relative fat mass regardless of body habitus. Prospective validation is warranted for a bidirectional relationship between NAFLD and fat mass, that is, the effect of changes in body composition on incident NAFLD development, as well as resolution/progression of preexisting NAFLD with lifestyle intervention.