The prevalence of nonalcoholic fatty liver disease (NAFLD) is 30% to 40% worldwide and approximately 30% in Korea.^1-4 In young Korean adults, the prevalence of NAFLD was estimated to be 16% by 2021.⁵

A recent study using a Swedish nationwide cohort demonstrated that patients with NAFLD and fibrosis have a 5.88-fold higher mortality rate than do patients without NAFLD or fibrosis.^6,7 These findings highlight the importance of identifying patients with liver fibrosis, particularly young patients.

Sarcopenia, which is associated with increased risk of NAFLD and fibrosis, has been extensively studied over the last decade.^8-10 Although it is widely accepted that sarcopenia is a key factor in the management of NAFLD, it is unclear whether sarcopenia causes NAFLD, or vice versa.

Since the relationship between NAFLD and sarcopenia has not been studied in younger populations, this study sought to elucidate the correlation between liver fibrosis and muscle mass in young adults with NAFLD. The correlation was evaluated using total muscle mass adjusted for body weight (muscle mass percentage [MMP]) and muscle-to-fat ratio (MFR).

Study population

This study was approved by the Institutional Review Board of the Korean Armed Forces Medical Command (AFMC-202212-HR-061-01) and was performed in accordance with the Declaration of Helsinki. We retrospectively reviewed the medical records of patients diagnosed with NAFLD by abdominal ultrasonography between July 2022 and September 2022. Patients between 18 and 35 years of age were included. Patients with transaminase level >300 U/L were excluded because of the possibility of transient elastography (TE) overestimation. Informed consent was not required because this research was retrospective.

Measurements

Liver stiffness was measured by vibration-controlled TE using the FibroScan 502 (Echosens). Muscle mass, fat mass, body mass index (BMI), and waist-to-hip ratio (WHR) were measured using a bioelectrical impedance analyzer (T-Scan Plus; Jawon Medical). Additionally, we used the controlled attenuation parameter scores, measured by FibroScan 502, to identify hepatic steatosis.

Definitions

Significant fibrosis (F2 or higher in the META-analysis of histological data in VIRal hepatitis [METAVIR] scoring system) was determined using the FibroScan-aspartate aminotransferase (FAST) score and was considered absent with a score <0.35.¹¹ To reduce bias, the following two additional cut-offs were adopted to define significant fibrosis and reveal its associated factors: FAST score ≥0.67 and TE ≥7.0 kPa.¹² We applied the cut-off value proposed by Karlas et al.¹³ to classify the degree of steatosis. Severe obesity was defined as BMI ≥30 kg/m², while nonsevere obesity was defined as BMI <30 kg/m².

Statistical analysis

All statistical analyses were performed using R statistical software version 4.0.3 (R Foundation Inc.). Detailed statistical methods are described in the Supplementary Methods.

Baseline characteristics

The total number of participants was 88, among whom 38 had a FAST score >0.35, which was classified as significant fibrosis (Table 1). Differences in the MMP, WHR, BMI, and MFR between the two groups were significant (P<0.001). Supplementary Fig. 1 demonstrates the MMP stratified by the presence of fibrosis and degree of steatosis.

Factors associated with significant fibrosis

In the univariate analysis, MMP, MFR, WHR, BMI, impaired fasting glucose (IFG)/diabetes mellitus (DM), and alanine transaminase (ALT) level were all associated with significant fibrosis (Table 2). Two models were established in the multivariate analysis. Age and height were adjusted as covariates for model 1, whereas ALT level was added as an adjustment for model 2. All included variables in model 1 were associated with significant fibrosis. In contrast, only MMP, WHR, and IFG/DM were associated with significant fibrosis in model 2 (MMP: odds ratio [OR] 0.685, P=0.050; MFR: OR 0.105, P=0.086; WHR: OR 1.525, P=0.049; IFG/DM: OR 499.2, P=0.032). When the threshold for significant fibrosis was set as FAST score ≥0.67 and TE ≥7.0 kPa, the MFR and MMP were again associated with significant fibrosis (Supplementary Tables 1 and 2).

Nonsevere obese NAFLD subgroup analysis

Subgroup analyses were performed for non-severely obese and severely obese patients with NAFLD (Supplementary Table 3). After adjusting for height and age as covariates, MMP, MFR, WHR, IFG/DM, and ALT were significantly associated with fibrosis in the obese NAFLD subgroup (MMP: OR 0.705, P=0.014; MFR: OR 0.090, P=0.040; WHR: OR 1.271, P=0.048; IFG/DM: OR 18.710, P=0.001; and ALT: OR 1.164, P=0.039). In the nonsevere obese subgroup, MMP, MFR, WHR, and IFG/DM were significantly associated with fibrosis (MMP: OR 0.758, P=0.013; MFR: OR 0.208, P=0.019; WHR: OR 1.292, P=0.033; and IFG/DM: OR 11.629, P=0.011).

In this study, the MMP and MFR were significantly correlated with fibrosis, as were WHR and BMI. Both MMP and MFR were associated with significant fibrosis in nonsevere obese patients with NAFLD.

Another study similarly found that NAFLD seems to share diverse mechanisms with sarcopenic obesity, and the correlation between them is widely accepted.⁹ The prevalence of NAFLD and the proportion of cirrhosis caused by NAFLD are both increasing.¹⁴ Considering that NAFLD at younger ages is related to increased mortality,⁷ the modifiable factors of NAFLD, such as the MFR, need to be identified.

To the best of our knowledge, this is the first study revealing the relationship between muscle mass and liver fibrosis in young adults. Due to the lack of consideration for sarcopenia in younger groups, BMI has been considered the only correctable factor for young patients with NAFLD. In this study, we suggest that not only fat mass, but also muscle mass needs to be corrected to ameliorate fibrotic changes in NAFLD. In addition, the relationship between liver fibrosis, MFR, and MMP was validated in the nonsevere obese group, emphasizing a role of these possible correctable factors in NAFLD in young patients.

This study has several limitations, such as the small number of patients enrolled. Also, technical limitations of the bioelectrical impedance analyzer prevented us from calculating the skeletal muscle mass.

In conclusion, our findings indicate that MMP and MFR are correlated with liver fibrosis in (both obese and non-obese) young patients with NAFLD. Further analysis, including biopsy-proven data and skeletal muscle mass, will better explain this correlation.

Supplementary materials can be found online at https://doi.org/10.7570/jomes23035.

The authors declare no conflict of interest.

This study was supported by the Korean Military Medical Research Project, which is funded by the Ministry of National Defense (grant number 2023-KMMRP-004).

Study concept and design: JL and SN; acquisition of data: all authors; analysis and interpretation of data: JL; drafting of the manuscript: JL and SN; critical revision of the manuscript: all authors; statistical analysis: JL and SN; obtained funding: JL; administrative, technical, or material support: JL and SN; and study supervision: JL and SHB.