TO THE EDITOR
Wang et al[1] recently published a study in the World Journal of Gastroenterology, which provided a retrospective analysis of the association between serum uric acid to high-density lipoprotein cholesterol (UHR) and cardiovascular disease (CVD) risk among 3901 individuals suffering from metabolic dysfunction-associated steatotic liver disease (MASLD). The research determined that UHR was an independent predictor of 10-year CVD risk in Asian patients with MASLD. The relationship between UHR and the Framingham risk score (FRS) was linear, with higher UHR linked to increased CVD risk, especially in younger individuals, males, and those with central obesity. UHR outperformed traditional biomarkers in predicting CVD risk, making it a valuable and cost-effective tool for routine clinical assessment in MASLD patients. The authors addressed a crucial topic, particularly given the increasing global impact of MASLD and its link to cardiovascular issues. While these findings possess clinical significance, several additional factors, beyond the limitations discussed in the text, may constrain their broader applicability and affect the accuracy and precision of their interpretation across diverse populations.
Firstly, regarding participant inclusion and disease definition, the study by Wang et al[1] adhered to the 2019 ACC/AHA guidelines for CVD prevention[2] by including only participants aged 40 and above, thereby excluding 4103 individuals under the age of 40 years. This approach may limit the applicability of study to the Chinese population, where CVD prevention guidelines commence at age 18 years[2]. Additionally, the focus of study on MASLD did not clarify whether alcohol intake was assessed, which could potentially affect the accuracy of study. Future research should conform to national age guidelines and provide a clear definition of MASLD criteria. Moreover, MASLD diagnosis was based on abdominal ultrasonography and the presence of at least one cardiometabolic risk factor. Although ultrasonography is a common diagnostic tool, it has limitations in detecting mild steatosis and cannot distinguish between simple fatty liver disease and metabolic dysfunction-associated steatohepatitis, thereby impacting cardiovascular risk assessment. Future studies should broaden age criteria to align with Chinese guidelines and explicitly report alcohol consumption. Incorporating non-invasive fibrosis markers, including the fibrosis-4 (FIB-4) index or liver stiffness measurement, could improve the stratification of liver disease severity and the evaluation of cardiovascular risk.
Secondly, this study was potentially affected by biases and limitations related to the representativeness of the sample[1]. The cohort was derived from a single medical center, which may introduce selection bias. Furthermore, males constituted 76.9% of the cohort, while the female sample size was relatively small, possibly compromising the reliability of gender-specific findings. The sex-specific variations in the relationship between UHR and CVD risk[3,4] are noteworthy and warrant further investigation in prospective, sex-balanced cohorts. Future research should include multicenter, cross-regional samples, particularly by incorporating patients from primary care hospitals and rural areas, to enhance the representativeness and generalizability of the findings. In pursuing multicenter collaborations, efforts should be made to include a more balanced sex distribution.
Thirdly, the possibility of residual confounding due to unmeasured variables, particularly the use of medications affecting uric acid or high-density lipoprotein cholesterol (HDL-C) levels, cannot be dismissed. Medications, including uric acid-lowering agents, diuretics, and lipid-lowering drugs, are frequently administered within this patient cohort and may significantly alter the component values of the UHR. An uneven distribution of these pharmacological treatments across risk groups could introduce considerable confounding bias, potentially distorting the true relationship between UHR and CVD risk. To improve the accuracy and reliability of future research findings, it is imperative that studies meticulously document medication histories, conduct stratified analyses and multivariate adjustments, and explicitly address the potential impact of these factors in the discussion section.
In conclusion, despite comprehensive adjustments for confounding factors through the application of multivariable logistic regression models, a significant limitation persists due to the inclusion of multiple metabolically related variables in models 3 and 4, including body mass index, central obesity, diabetes, hypertension, hyperlipidemia, and metabolic syndrome. These variables exhibit substantial multicollinearity, which may lead to unstable estimates and obscure the true independent associations of predictors, including UHR. This multicollinearity may account for the non-significant link between UHR and cardiovascular risk observed in adjusted models for females and older adults (≥ 50 years), as the predictive value of UHR might be attenuated by other correlated metabolic indicators.
The research conducted by Wang et al[1] highlighted the UHR’s potential as a clinical predictor, whereas its biological mechanisms need further study. Uric acid, a metabolic byproduct of purine catabolism, promotes hepatic lipid accumulation and impairs vascular function by inducing oxidative stress and inflammation when its levels are elevated, serving as a crucial independent risk factor in the development of MASLD and CVD[5-7]. While HDL-C typically protects against CVDs due to its anti-inflammatory and antioxidant effects, it can become dysfunctional in dysmetabolic conditions, reducing its protective effects[8-10]. The UHR reflects a balance between 'pro-CVD drivers' (high uric acid) and 'compromised anti-CVD defenses' (dysfunctional HDL-C), indicating a systemic metabolic-inflammatory imbalance[11]. Future research should validate the mechanisms, and focus on the role of UHR in cardiovascular pathways.
In summary, there was a clinical consensus that MASLD should be considered an independent contributor to cardiovascular risk[12-14]. The study by Wang et al[1] underscored the potential of UHR as a promising and cost-effective biomarker for assessing CVD risk in Asian patients with MASLD. This indicator addressed the limitations of existing traditional risk prediction tools, including the FRS, Prediction for Atherosclerotic Cardiovascular Disease Risk in China, Pooled Cohort Equations, or Atherosclerotic Cardiovascular Disease risk score, which do not consider liver-specific markers (e.g., FIB-4, triglyceride-glucose index) and therefore demonstrate reduced discriminative ability in the MASLD population, and significantly underestimate their actual cardiovascular risk[15-17]. Future research should aim to validate these findings across diverse populations and explore the interrelationships between UHR, liver steatosis, and cardiovascular outcomes. We commend the authors for their contributions and anticipate their further insights on these pertinent topics.
