Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
J Cachexia Sarcopenia Muscle. 2023 Feb;14(1):260-269. doi: 10.1002/jcsm.13125. Epub 2022 Nov 20.
Non-alcoholic fatty liver disease (NAFLD) and sarcopenia share insulin resistance as a common pathophysiology and have overlapping clinical manifestation of metabolic derangement; hence, it is difficult to differentiate the independent effect of sarcopenia on the development of NAFLD from concomitant metabolic disorders. Using a community-based prospective cohort study, the contributions of low muscle mass and genetic risk factors to the development of NAFLD and NAFLD-related hepatic fibrosis were investigated in the Korean population.
This prospective community-based cohort study included 40-70-year-old adults, followed up biennially from 2001-2002 to 2017-2018. NAFLD was defined as a hepatic steatosis index of ≥36, and hepatic fibrosis was defined based on the fibrosis-4 index. Sex-specific quartiles of body mass index (BMI)-adjusted muscle mass were calculated (muscle mass/BMI), and low muscle mass was defined as the lowest quartile (Q1). Cox proportional hazard models for incident NAFLD or hepatic fibrosis incorporating age, sex, BMI of ≥25 kg/m , metabolic syndrome and PNPLA3 and TM6SF2 risk alleles were used to assess the independent determinants for incident NAFLD and hepatic fibrosis among individuals with NAFLD at baseline.
Among the 4038 participants without NAFLD at baseline (mean age, 51.5 ± 8.8 years), 920 (22.8%) developed NAFLD during the 12-year follow-up period. As muscle mass decreased, the risk of NAFLD increased even after adjustment for age, sex, obesity, metabolic syndrome and PNPLA3 and TM6SF2 risk alleles [hazard ratio (HR) per quartile, 1.18, 95% confidence interval (CI), 1.11-1.27, P < 0.001]. TM6SF2 also affected the risk of NAFLD development [HR 1.19, (95% CI, 1.00-1.40), P = 0.044]. Of the 1176 patients with NAFLD but without hepatic fibrosis at baseline, the incident of hepatic fibrosis was found in 51.8%, 44.7%, 42.6% and 41.0% in Q1, Q2, Q3 and Q4 of BMI-adjusted muscle mass, respectively, during the follow-up period (P for trend = 0.006). However, this trend lost its statistical significance when adjusted for confounders. The PNPLA3 risk variant, but not the TM6SF2 genotype, was an independent risk factor for developing hepatic fibrosis among patients with NAFLD (HR 1.17, 95% CI 1.04-1.32, P = 0.010).
Both lower muscle mass index and genetic risk variants are important contributors to the development of NAFLD. In patients already diagnosed with NAFLD, however, PNPLA3 confers a greater risk for hepatic fibrosis progression than lower muscle mass.
非酒精性脂肪性肝病 (NAFLD) 和肌肉减少症具有胰岛素抵抗这一共有的病理生理学特征，且临床表现有代谢紊乱的重叠，因此，很难区分肌肉减少症对 NAFLD 发展的独立影响与并存的代谢紊乱。本研究利用基于社区的前瞻性队列研究，在韩国人群中调查了低肌肉量和遗传风险因素对 NAFLD 和 NAFLD 相关肝纤维化发展的作用。
本前瞻性社区队列研究纳入了 40-70 岁的成年人，从 2001-2002 年至 2017-2018 年每两年进行一次随访。NAFLD 的定义为肝脏脂肪指数≥36，肝纤维化则基于纤维化-4 指数进行定义。计算了身体质量指数 (BMI) 调整后的肌肉量的性别特异性四分位数（肌肉量/BMI），并将最低四分位数（Q1）定义为低肌肉量。使用 Cox 比例风险模型对纳入基线时患有 NAFLD 的个体的新发 NAFLD 或肝纤维化进行分析，模型中纳入了年龄、性别、BMI≥25 kg/m2、代谢综合征以及 PNPLA3 和 TM6SF2 风险等位基因。该模型用于评估年龄、性别、BMI≥25 kg/m2、代谢综合征以及 PNPLA3 和 TM6SF2 风险等位基因调整后，个体发生 NAFLD 和肝纤维化的独立决定因素。
在基线时无 NAFLD 的 4038 名参与者（平均年龄 51.5±8.8 岁）中，12 年的随访期间有 920 名（22.8%）发生了 NAFLD。随着肌肉量减少，即使在调整了年龄、性别、肥胖、代谢综合征以及 PNPLA3 和 TM6SF2 风险等位基因后，NAFLD 的发病风险仍会增加[四分位距（Q），1.18；95%置信区间（CI），1.11-1.27；P<0.001]。TM6SF2 也影响 NAFLD 发病风险[HR 1.19；95%CI，1.00-1.40；P=0.044]。在基线时患有 NAFLD 但无肝纤维化的 1176 名患者中，在随访期间，BMI 调整后的肌肉量 Q1、Q2、Q3 和 Q4 组中分别有 51.8%、44.7%、42.6%和 41.0%的患者发生了肝纤维化（趋势检验 P=0.006）。然而，在调整混杂因素后，该趋势失去了统计学意义。PNPLA3 风险变异体，而不是 TM6SF2 基因型，是 NAFLD 患者发生肝纤维化的独立危险因素（HR 1.17；95%CI，1.04-1.32；P=0.010）。
较低的肌肉量指数和遗传风险变异体都是 NAFLD 发病的重要因素。然而，在已经诊断为 NAFLD 的患者中，PNPLA3 导致肝纤维化进展的风险大于低肌肉量。
