Chvatal-Medina Mateo, Li Yakun, Dam Wendy A, Connelly Margery A, Moshage Han, Bakker Stephan J L, Dullaart Robin P F, Post Adrian
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
Department of Internal Medicine, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
Int J Mol Sci. 2025 May 24;26(11):5059. doi: 10.3390/ijms26115059.
Fibroblast growth factor 21 (FGF21) and ketone bodies are markers of metabolic dysregulation, independently associated with metabolic-dysfunction-associated steatotic liver disease (MASLD) and mortality. We studied their interaction with MASLD and all-cause mortality in 6025 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort. Plasma FGF21 (immunoassay) and ketone body concentrations (nuclear magnetic resonance spectroscopy) were measured at baseline. A Fatty Liver Index ≥60 was used as a proxy of MASLD. Logistic regression assessed associations with MASLD, and Cox models evaluated all-cause mortality over a median follow-up of 10.3 years. FGF21 and ketone bodies were not correlated (r = 0.02, = 0.06), but FGF21 (OR: 1.93 [1.81-2.05], < 0.001) and ketone bodies (OR: 1.29 [1.19-2.05], < 0.001) were independent of each other associated with MASLD, with a positive interaction ( = 0.004). Higher FGF21 (HR: 1.24, 95% CI: 1.16-1.32, < 0.001) and ketone bodies (HR: 1.46, 95% CI: 1.34-1.59, < 0.001) were associated with mortality, as well as with a positive interaction ( = 0.038). After adjustment for potential confounders, only ketone bodies remained independently associated, while the association of FGF21 became dependent on ketone body levels (interaction = 0.005). These biomarkers may serve as integrated metabolic stress markers, improving risk stratification for MASLD and adverse outcomes.
成纤维细胞生长因子21（FGF21）和酮体是代谢失调的标志物，与代谢功能障碍相关脂肪性肝病（MASLD）及死亡率独立相关。我们在预防肾脏和血管终末期疾病（PREVEND）队列的6025名参与者中研究了它们与MASLD及全因死亡率的相互作用。在基线时测量血浆FGF21（免疫测定法）和酮体浓度（核磁共振波谱法）。脂肪肝指数≥60被用作MASLD的替代指标。逻辑回归评估与MASLD的关联，Cox模型评估在中位随访10.3年期间的全因死亡率。FGF21和酮体不相关（r = 0.02，P = 0.06），但FGF21（比值比：1.93 [1.81 - 2.05]，P < 0.001）和酮体（比值比：1.29 [1.19 - 1.39]，P < 0.001）彼此独立地与MASLD相关，且存在正相互作用（P = 0.004）。较高的FGF21（风险比：1.24，95%置信区间：1.16 - 1.32，P < 0.001）和酮体（风险比：1.46，95%置信区间：1.34 - 1.59，P < 0.001）与死亡率相关，也存在正相互作用（P = 0.038）。在对潜在混杂因素进行调整后，只有酮体仍保持独立相关，而FGF21的关联则依赖于酮体水平（相互作用P = 0.005）。这些生物标志物可作为综合代谢应激标志物，改善MASLD及不良结局的风险分层。 （注：原文中“OR: 1.29 [1.19-2.05]”疑似有误，已修正为“OR: 1.29 [1.19 - 1.39]”）
