Letter to the Editor: Precise phenotyping clarifies uric acid-to-high-density lipoprotein cholesterol ratio for cardiovascular risk in metabolic dysfunction-associated steatotic liver disease

Abstract

This letter concerns the study by Wang et al titled “Serum uric acid-to-high-density lipoprotein cholesterol ratio and cardiovascular risk in Asian patients with metabolic dysfunction-associated steatotic liver disease”, published in World Journal of Gastroenterology. The study demonstrated a linear dose-response association between the uric acid-to-high-density lipoprotein cholesterol ratio and 10-year cardiovascular disease risk in Asian populations with metabolic dysfunction-associated steatotic liver disease. However, reliance on ultrasonography to assess hepatic steatosis under the metabolic dysfunction-associated steatotic liver disease criteria can introduce phenotypic heterogeneity, as this modality cannot reliably distinguish simple steatosis from metabolic dysfunction-associated steatohepatitis or assess the fibrosis stage. We suggest that future studies incorporate more precise phenotyping strategies, such as quantifying steatosis and staging fibrosis, to clarify whether the association between uric acid-to-high-density lipoprotein cholesterol ratio and cardiovascular disease risk is independent of, or modified by, underlying liver disease severity.

Key Words: Metabolic dysfunction-associated steatotic liver disease; Cardiovascular risk; Uric acid-to-high-density lipoprotein cholesterol ratio; Phenotypic heterogeneity; Risk stratification; Noninvasive assessment

Core Tip: The diagnosis of ultrasonography-based metabolic dysfunction-associated steatotic liver disease overlooks hepatic phenotypic heterogeneity and the shared inflammatory metabolic mechanisms of the cardiohepatic axis, potentially confounding the association between uric acid-to-high-density lipoprotein cholesterol ratio (UHR) and cardiovascular disease risk. We argue that precise phenotyping, namely quantification of steatosis using the controlled attenuation parameter or magnetic resonance imaging proton-density fat fraction and staging fibrosis using vibration-controlled transient elastography, is essential to determine whether UHR is an independent predictor of cardiovascular disease risk, thereby clarifying whether UHR is a general biomarker or an indicator of high-risk patients requiring integrated cardiometabolic–hepatic management.

TO THE EDITOR

We read with great interest the recent article by Wang et al[1] titled “Serum uric acid-to-high-density lipoprotein cholesterol ratio and cardiovascular risk in Asian patients with metabolic dysfunction-associated steatotic liver disease”, published in World Journal of Gastroenterology. This study is the first to reveal a linear dose–response association between the uric acid-to-high-density lipoprotein cholesterol ratio (UHR) and 10-year cardiovascular disease (CVD) risk in Asian populations with metabolic dysfunction-associated steatotic liver disease (MASLD). This finding provides a simple, cost-effective biomarker for cardiovascular risk stratification in this population, particularly noting its higher predictive value in younger, male, and centrally obese patients. However, we raise a potential issue that might have affected the observed association and suggest a solution for future research.

PHENOTYPIC HETEROGENEITY AND THE CARDIOHEPATIC AXIS

The authors used ultrasound to assess hepatic steatosis. We acknowledge that Wang et al[1] recognized both the operator-dependency of ultrasonography and the retrospective design as study limitations. However, ultrasound has limited sensitivity for detecting mild steatosis, and it cannot reliably distinguish simple steatosis from metabolic dysfunction-associated steatohepatitis (MASH) and remains insensitive to liver fibrosis staging[2]. Therefore, the MASLD cohort defined by ultrasound likely exhibits substantial phenotypic heterogeneity, potentially including patients with simple steatosis, MASH with mild fibrosis, and MASH with significant fibrosis (≥ F2). Existing evidence indicates that patients with MASH and advanced fibrosis have a significantly higher CVD risk than those with simple steatosis, with this risk increasing alongside fibrosis severity[3]. Mechanistically, this risk gradient is driven by bidirectional liver–heart crosstalk via the cardiohepatic axis, in which hepatokines (e.g., fibroblast growth factor-21, proprotein convertase subtilisin/kexin type-9), cytokine spillover, and bone marrow alterations, including reprogramming and clonal hematopoiesis of indeterminate potential, create a shared systemic inflammatory and metabolic environment that simultaneously promotes hepatic fibrosis and cardiovascular remodeling[4]. If an elevated UHR is associated with these higher-risk phenotypes, then the observed UHR-CVD association might partly reflect unmeasured liver injury severity rather than an independent effect of UHR itself.

PRECISE HEPATIC PHENOTYPING AND RISK STRATIFICATION

To examine this possibility, we recommend adopting more precise phenotyping strategies in future studies. First, controlled attenuation parameter (CAP) or magnetic resonance imaging proton-density fat fraction (MRI-PDFF) should be used to quantify hepatic steatosis (using CAP ≥ 248 dB/m or magnetic resonance imaging proton-density fat fraction ≥ 5% as the steatosis threshold). Second, vibration-controlled transient elastography (VCTE) should be applied to assess liver fibrosis (using liver stiffness measurement ≥ 8 kPa as the threshold for significant fibrosis)[2]. Although we recognize that CAP and VCTE might not be universally available in large-scale retrospective health examination cohorts, their incorporation in prospective studies or available subgroups would significantly strengthen risk stratification. Based on these criteria, patients could be stratified into simple steatosis, active MASH, or significant fibrosis (≥ F2) subgroups. Multivariable regression analyses (with CVD risk as the endpoint) could then be repeated within each stratum, and researchers could introduce an interaction term between UHR and fibrosis stage to examine whether UHR’s predictive performance strengthens with liver disease progression.

If confirmed, the clinical relevance of UHR would extend beyond a general risk marker, becoming a practical stratification tool for identifying patients with high-risk MASLD, especially those with significant fibrosis, who should be prioritized for combined hepatic and cardiovascular evaluation and intensive cardiometabolic monitoring. Conversely, if the performance of UHR is independent of the fibrosis stage, then it could serve as a robust universal biomarker applicable across all MASLD phenotypes without necessitating additional hepatic staging, thereby streamlining cardiovascular risk assessment. This differential diagnostic utility dictates whether integrated cardiohepatic management or simplified universal screening is warranted. If the original retrospective cohort lacks CAP or liver stiffness measurement data, then this framework could first be tested in available subgroups with such data. Prospective studies incorporating systematic hepatic phenotyping could then follow for validation.

CONCLUSION

The findings by Wang et al[1] are significant but require confirmation through prospective cohorts employing precise phenotyping strategies, such as VCTE. Future research must go beyond simple association by utilizing quantitative steatosis assessment and fibrosis staging to assess potential effect modification by liver disease severity and determine the incremental prognostic value of UHR over standard risk scores. Clarifying this relationship is critical to distinguish whether UHR serves as a universal screening tool or a specific signal for cardiohepatic comorbidity. Ultimately, refining this role will inform evidence-based guidelines for cardiovascular risk stratification in MASLD patients.