Chen Yuanyuan, Yang Bing, Chen Huihui, Chen Jun, Cao Jinmin, Wang Huijie, Chen Chuantie
Department of Liver Diseases, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Diseases, Shenzhen, China.
Department of Dermatology, Hunan Aerospace Hospital, Changsha, China.
Front Nutr. 2025 Jun 3;12:1587757. doi: 10.3389/fnut.2025.1587757. eCollection 2025.
The creatinine-to-cystatin C ratio (CCR) is an emerging marker of muscle mass, which influences the progression of nonalcoholic fatty liver disease (NAFLD). However, the relationship between CCR and long-term all-cause and cardiovascular mortality remains unclear in the US NAFLD population.
This nationally representative study analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999-2004, with mortality follow-up through December 31, 2019 via linkage to the National Death Index (NDI). NAFLD was determined using the Fatty Liver Index (FLI), while CCR was calculated as serum creatinine to cystatin C ratio. We employed multivariable Cox proportional hazards models to assess associations between CCR and mortality risk, expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). The analytical approach included Kaplan-Meier survival analysis, restricted cubic spline regression for non-linear relationship assessment, and comprehensive subgroup and sensitivity analyses to evaluate result robustness.
This study included 3,897 participants with NAFLD (53.34% male, mean age 48.98 years), with 1,174 all-cause deaths and 333 cardiovascular deaths over a median follow-up of 206 months. CCR demonstrated significant inverse associations with both all-cause mortality (adjusted HR 0.83; 95% CI 0.78-0.88; < 0.001) and cardiovascular mortality (adjusted HR 0.80; 95% CI 0.73-0.87; < 0.001). In tertile analyses, higher CCR groups showed progressively lower risks, in Model 3(fully adjusted model): all-cause mortality: T2 = 0.65 (0.53, 0.79), T3 = 0.43 (0.32, 0.60), for trend<0.001; cardiovascular mortality: T2 = 0.67 (0.50, 0.89), T3 = 0.34 (0.21, 0.53); for trend<0.001. Restricted cubic spline analysis revealed an L-shaped association between CCR and all-cause mortality (turning point: 11.06), with each unit increase below 11.06 associated with a 36% risk reduction (HR 0.64; 95% CI 0.53-0.77; < 0.001). In contrast, a linear relationship was observed for cardiovascular mortality ( for non-linearity = 0.972). Kaplan-Meier analysis confirmed superior survival rates in the highest CCR tertile for both endpoints (log-rank < 0.001), with subgroup and sensitivity analyses affirming the robustness of these results.
In this study of US adults with NAFLD, we identified a significant inverse association between CCR levels and risks of both all-cause and cardiovascular mortality. The stability of this association was confirmed through subgroup and sensitivity analyses, suggesting that CCR may play an important role in long-term prognosis among NAFLD patients.
肌酐与胱抑素C比值（CCR）是一种新兴的肌肉量标志物，其会影响非酒精性脂肪性肝病（NAFLD）的进展。然而，在美国NAFLD人群中，CCR与全因死亡率和心血管死亡率之间的关系仍不明确。
这项具有全国代表性的研究分析了1999 - 2004年美国国家健康与营养检查调查（NHANES）的数据，并通过与国家死亡指数（NDI）建立联系，对截至2019年12月31日的死亡率进行了随访。使用脂肪肝指数（FLI）来确定NAFLD，而CCR计算为血清肌酐与胱抑素C的比值。我们采用多变量Cox比例风险模型来评估CCR与死亡风险之间的关联，以风险比（HRs）和95%置信区间（CIs）表示。分析方法包括Kaplan - Meier生存分析、用于评估非线性关系的受限立方样条回归，以及全面的亚组分析和敏感性分析以评估结果的稳健性。
本研究纳入了3897名NAFLD参与者（男性占53.34%，平均年龄48.98岁），在中位随访206个月期间，有1174例全因死亡和333例心血管死亡。CCR与全因死亡率（调整后HR 0.83；95% CI 0.78 - 0.88；P < 0.001）和心血管死亡率（调整后HR 0.80；95% CI 0.73 - 0.87；P < 0.001）均呈显著负相关。在三分位数分析中，较高CCR组的风险逐渐降低，在模型3（完全调整模型）中：全因死亡率：T2 = 0.65（0.53，0.79），T3 = 0.43（0.32，0.60），趋势P < 0.001；心血管死亡率：T2 = 0.67（0.50，0.89），T3 = 0.34（0.21，0.53）；趋势P < 0.001。受限立方样条分析显示CCR与全因死亡率之间呈L形关联（转折点：11.06），在11.06以下每增加一个单位，风险降低36%（HR 0.64；95% CI 0.53 - 0.77；P < 0.001）。相比之下，心血管死亡率呈现线性关系（非线性检验P = = 0.972）。Kaplan - Meier分析证实，两个终点中CCR最高三分位数组的生存率更高（对数秩检验P < 0.001），亚组分析和敏感性分析均证实了这些结果的稳健性。
在这项针对美国NAFLD成年人的研究中，我们发现CCR水平与全因死亡率和心血管死亡率风险之间存在显著负相关。通过亚组分析和敏感性分析证实了这种关联的稳定性，表明CCR可能在NAFLD患者的长期预后中发挥重要作用。
