Do biomarkers matter? Cardiovascular risk stratification in Asian patients with metabolic dysfunction-associated steatotic liver disease in the era of fibrosis-centric assessment

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a multisystem disorder with significant cardiovascular implications, particularly in Asian populations characterized by a high prevalence of lean phenotypes and early metabolic dysregulation. Identifying reliable biomarkers for cardiovascular risk stratification in this group remains a clinical priority. This review critically appraises the current evidence on metabolic, inflammatory, cardiac, and fibrosis-related biomarkers in Asian patients with MASLD. Metabolic indices such as the uric acid-to-high-density lipoprotein ratio and triglyceride-glucose index capture underlying insulin resistance and oxidative stress and show consistent associations with steatotic liver disease. However, direct validation for cardiovascular outcomes remains limited. Inflammatory markers, including high-sensitivity C-reactive protein and homeostasis model assessment of insulin resistance, are mechanistically important but are confounded by their inclusion within MASLD diagnostic criteria, limiting their incremental predictive value. Cardiac biomarkers such as high-sensitivity troponins and natriuretic peptides demonstrate strong associations with adverse outcomes but lack sufficient validation in Asian MASLD cohorts for routine screening. In contrast, fibrosis-based indices, particularly the fibrosis-4 score, consistently associate with cardiovascular events, coronary artery calcification, and mortality across multiple Asian studies. These markers likely reflect cumulative metabolic and inflammatory injury linking hepatic and vascular pathology. An integrated, multivariable approach incorporating fibrosis markers alongside metabolic and cardiac indices may provide the most clinically meaningful framework for cardiovascular risk assessment in Asian patients with MASLD.

Key Words: Cardiovascular diseases; Metabolic dysfunction-associated steatotic liver disease; Obesity; Uric acid; Endothelial dysfunction; High-density lipoprotein cholesterol; Framingham risk score

Core Tip: Cardiovascular risk in Asian patients with metabolic dysfunction-associated steatotic liver disease is multifactorial and not adequately captured by single biomarkers. While metabolic indices reflect upstream metabolic stress, their prognostic value for cardiovascular events remains limited. Inflammatory markers are mechanistically relevant but confounded by their inclusion in disease definitions. In contrast, fibrosis-based scores, consistently associate with cardiovascular outcomes across Asian cohorts, likely reflecting cumulative metabolic injury. An integrated, multivariable approach combining metabolic, inflammatory, and fibrosis markers is more appropriate for cardiovascular risk stratification in this population.

INTRODUCTION

The shift in change from terminology for fatty liver diseases to metabolic dysfunction-associated steatotic liver disease (MASLD) was an attempt to diagnose steatotic liver disease positively through metabolic dysfunction rather than negatively through alcohol exclusion, and that shift has particular relevance in Asia, where lean steatosis, mixed etiologies, and high cardiometabolic risk at a relatively low body mass index are especially common[1-4]. The core MASLD framework endorsed by the Asian Pacific Association for the Study of the Liver requires evidence of hepatic steatosis plus overweight/obesity, type 2 diabetes, or, in lean/normal-weight individuals, at least two metabolic abnormalities[5]. In Asian practice, the lean phenotype is commonly operationalized at a body mass index < 23 kg/m², with central adiposity and metabolic dysregulation thresholds lower than those used in many Western cohorts[5-8].

The high cardiovascular risk in Asian ethnicities raises concerns about the need for a biomarker that can identify Asian patients who truly carry excess cardiovascular risk beyond standard metabolic profiling. Fibrosis-linked markers in Asian cohorts are the closest to clinically actionable. Composite metabolic markers such as uric acid/high-density lipoprotein (HDL) cholesterol ratio (UHR), uric acid alone, and the triglyceride-glucose (TyG) index are promising, especially in lean or non-obese Asian populations, but they still function more as risk enrichers than as stand-alone cardiovascular predictors. Cardiac injury markers such as troponins and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are arguably the most pathophysiologically proximate to cardiovascular events, yet they remain under-studied specifically within Asian MASLD populations[9-13].

DEFINING MASLD AND THE CARDIOVASCULAR PHENOTYPE IN ASIAN POPULATIONS

MASLD in Asian populations is epidemiologically substantial and phenotypically distinctive. A major meta-analysis of MASLD in Asia estimated a pooled prevalence of 29.62%, rising from 25.28% in 1999-2005 to 33.90% in 2012-2017[14-16]. A meta-analysis of Asian clinical profiles showed that about one-third of Asian MASLD patients were non-obese and that aminotransferases were often normal or only minimally elevated, reinforcing the point that classical “obese fatty liver” heuristics perform poorly in Asia[17]. More recently, a population-based study from Delhi reported an MASLD prevalence of 56.4%, with lean MASLD accounting for 11.3% of cases, underscoring how cardiometabolic exposure can accumulate in South Asian settings even without overt obesity[18].

Studies from Asia have reported incident cardiovascular disease rates of 6.2, 8.5, 8.5, and 9.6 per 1000 person-years in individuals with no steatotic liver disease, MASLD, metabolic and alcohol-associated liver disease, and alcohol-related liver disease, respectively[19,20]; MASLD carried an adjusted sub-distribution hazard ratio of 1.19 for incident myocardial infarction or stroke (Table 1)[21-28]. A 2022 meta-analysis further estimated a pooled relative risk of 1.95 for cardiovascular event incidence or cardiovascular mortality in MASLD patients vs controls, although that analysis was not Asia-specific and should therefore be interpreted as supportive rather than definitive for Asian populations.

Table 1 Selected Asian cohort studies linking metabolic dysfunction-associated steatotic liver disease or metabolic dysfunction-associated steatotic liver disease to cardiovascular outcomes.

Ref.	Study population	Sample size	Outcome	Key finding	Effect size
[21]	Korea	9584399	Composite CVD event	MASLD identified a larger, more cardiometabolically complex population than MASLD	HR 1.43 for MASLD-only; HR 1.56 for both-FLD vs neither
[22]	Korea	351068	Incident MI or stroke	MASLD independently increased CVD risk	SHR 1.19 vs no SLD
[23]	Korea	104399	Incident CVD	Excess risk in MASLD concentrated in FIB-4-defined fibrosis	HR 2.27 for MASLD with FIB-4 ≥ 1.3
[24]	Taiwan	26676	Incident HF	MASLD associated with HF, especially HFpEF	SHR 2.59 for HF; SHR 1.91 for HFpEF
[25]	Korea	2773	Coronary artery calcification	Both labels associated with CAC, but MASLD tracked severe CAC more consistently	aOR 1.21 for CAC and 1.38 for severe CAC
[26]	China	203	Obstructive CAD and high-risk plaque	MASLD predicted adverse plaque anatomy and physiology	aOR 2.44 for obstructive CAD; 2.52 for HRP; 3.53 for FFRCT ≤ 0.8
[27]	Taiwan	6058	Coronary artery calcification	FIB-4 provided incremental referral value within MASLD	OR 1.217 per FIB-4 unit for CAC presence
[28]	Korea	8622	Any plaque and obstructive CAD	SAFE score and MASLD both stratified subclinical coronary atherosclerosis	MASLD OR 3.64 for obstructive CAD; higher SAFE strongly associated with plaque and obstruction

CVD: Cardiovascular disease; MASLD: Metabolic dysfunction-associated steatotic liver disease; HR: Hazard ratio; FLD: Fatty liver disease; MI: Myocardial infarction; SHR: Subdistribution hazard ratio; SLD: Steatotic liver disease; FIB-4: Fibrosis-4 index 4; HF: Heart failure; HFpEF: Heart failure with preserved ejection fraction; CAC: Coronary artery calcium; aOR: Adjusted odds ratio; CAD: Coronary artery disease; HRP: Hazard ratio point; FFRCT: Fractional flow reserve derived from computed tomography; OR: Odds ratio; SAFE: Steatosis-activity-fibrosis evaluation index.

BIOMARKER LANDSCAPE FOR CARDIOVASCULAR RISK IN ASIAN MASLD POPULATIONS

The literature is widest for UHR, uric acid, HDL, and insulin-resistance ratios, but this is also where interpretive caution is most needed. UHR is attractive because it compresses two biologically opposing signals into one index: Uric acid as a marker of oxidative stress, xanthine oxidase activity, endothelial dysfunction, and inflammasome activation, and HDL as a marker of reverse cholesterol transport and anti-inflammatory capacity. It has been shown to be independently associated with MASLD, even in non-obese MASLD phenotype[2,29].

Furthermore, insulin-resistance markers have stronger direct cardiovascular linkage in Asian fatty liver cohorts. In Chinese patients with MASLD and chest pain undergoing coronary angiography, the TyG index was independently associated with coronary heart disease (CHD), with an odds ratio of 2.519 after adjustment; each one-unit increase in TyG was associated with approximately a twofold increase in CHD risk, and each 0.1-unit increase was related to a 2.44-point increase in Gensini score[30,31].

Moreover, high-sensitivity C-reactive protein (hs-CRP) and homeostatic model assessment of insulin resistance (HOMA-IR) occupy an analytically challenging yet clinically relevant space, as they are both definitional and mechanistic. Within the MASLD framework, HOMA-IR ≥ 2.5 and hs-CRP > 2 mg/L contribute to defining metabolic dysregulation, particularly in lean individuals. Supporting this, a North Indian study demonstrated significantly higher hs-CRP levels in MASLD (3.12 mg/L vs 1.05 mg/L), with an independent association [adjusted odds ratio (OR): 1.311][32,33]. However, their lack of hepatic specificity limits interpretability. Emerging perspectives suggest that these markers function less as static disease identifiers and more as intermediate mediators linking MASLD to atherosclerotic cardiovascular disease[34]. When a biomarker lies on the causal pathway and simultaneously contributes to disease definition, its incremental predictive value becomes inherently constrained. Clinically, hs-CRP and HOMA-IR remain informative but are unlikely to serve as stand-alone cardiovascular risk stratifiers without integration into multivariable models[35].

Cardiac biomarkers represent a biologically intuitive yet underdeveloped domain in Asian MASLD research. In Chinese biopsy-proven MASLD, lower NT-proBNP levels were paradoxically associated with a higher odds of NASH (OR: Approximately 0.5 across higher tertiles), likely reflecting natriuretic peptide deficiency in insulin resistance rather than cardioprotection[36]. Troponins, by contrast, may better capture downstream myocardial injury. In MASLD cohorts, elevated high-sensitivity cardiac troponin T and high-sensitivity cardiac troponin I were independently associated with increased all-cause (adjusted hazard ratio: Approximately 1.9-2.0) and cardiovascular mortality (adjusted hazard ratio: Approximately 2.4-3.0)[37,38]. Nonetheless, the absence of robust Asian validation limits their application as screening tools. At present, these markers are best viewed as contextual cardiovascular indicators, relevant in high-risk or symptomatic patients rather than for routine population-level stratification.

Fibrosis indices offer the most consistent and clinically actionable signal. Across Asian cohorts, the fibrosis-4 index (FIB-4) and related markers demonstrate reproducible associations with cardiovascular risk. In a Japanese study (n = 3512), advanced fibrosis conferred a markedly elevated odds of high Framingham risk (OR: 5.9-35.6)[39]. Similarly, FIB-4 predicted major adverse cardiovascular events in biopsy-proven MASLD, incident cardiovascular disease in Korean MASLD patients (hazard ratio: 2.27), and coronary artery calcification in Taiwanese cohorts (OR: 1.217)[27,40]. Longitudinal Korean data further show that time-updated FIB-4 predicts coronary artery calcium progression, particularly in older men[41]. Collectively, these findings suggest that fibrosis markers outperform other biomarkers not through cardiac specificity, but by integrating cumulative metabolic-inflammatory injury, which underpins both hepatic and vascular pathology.

Moreover, recent advances have led to the emergence of novel biomarkers, but they remain exploratory. Wisteria floribunda agglutinin-positive Mac-2 binding protein is particularly interesting in East Asian practice because it may capture fibrogenic remodeling not fully represented by transaminase-based scores, and Japanese data tie it to higher Framingham risk when elevated[42]. Table 2 provides a snapshot of the most studied biomarkers of cardiovascular risk[39,40,43-50].

Table 2 Biomarker-centred studies relevant to cardiovascular risk stratification in Asian patients with metabolic dysfunction-associated steatotic liver disease or closely overlapping fatty liver phenotypes.

Biomarker	Study population	Sample size	Key finding	Effect size or performance
UHR[43]	Lean Chinese adults with MASLD by ultrasound	6285	UHR independently associated with MASLD; marked gradient across quintiles	OR 1.105 per unit; prevalence 191% to 24.54% across quintiles
UHR[44]	Non-obese Chinese adults with normal lipids, 5-year follow-up	9837	UHR predicted incident MASLD better than uric acid or HDL alone	HR 1.76 in highest quintile; AUC: 0.690; sensitivity: 71%
UHR[45]	Chinese case-control MASLD study	1390	Strong positive dose-response relation between UHR and MASLD	OR: 3.888, highest vs lowest quartile
UHR[46]	Lean Chinese patients with type 2 diabetes	343	UHR useful for MASLD discrimination in non-overweight diabetes	AUC: 0.697; sensitivity: 0.761; specificity: 0.553
hs-CRP[47]	North Indian MASLD case-control study	200	hs-CRP rose with MASLD and severity	Adjusted OR: 1.311; mean: 3.12 mg/L vs 1.05 mg/L
TyG[48]	Chinese MASLD patients with chest pain undergoing angiography	424	TyG associated with prevalent CHD and angiographic severity	OR 2.519 for CHD; per 1-unit OR 2.06; β 2.44 in Gensini per 0.1-unit
TyG[49]	Chinese MASLD cohort with carotid follow-up	739	TyG predicted incident carotid atherosclerosis	HR 3.11 in Q2 and 4.51 in Q3 vs Q1
FIB-4, NFS, WFA+-M2BP[39]	Japanese prospective screening cohort	3512	Advanced fibrosis markers independently linked to high CV risk	Fatty liver plus advanced fibrosis OR 5.90-35.6 for high Framingham risk
FIB-4[50]	Korean MASLD prospective cohort	104399	Fibrosis enriched incident CVD risk in MASLD	HR 2.27 for CVD when FIB-4 ≥ 1.3
FIB-4[40]	Taiwanese MASLD-CAC referral study	6058	FIB-4 associated with CAC beyond MASLD status	OR 1.217 for CAC presence

UHR: Uric acid/high-density lipoprotein cholesterol ratio; MASLD: Metabolic dysfunction-associated steatotic liver disease; OR: Odds ratio; HDL: High-density lipoprotein; HR: Hazard ratio; AUC: Area under the curve; hs-CRP: High-sensitivity C-reactive protein; TyG: Triglyceride-glucose; CHD: Coronary heart disease; FIB-4: Fibrosis-4 index 4; NFS: Non-alcoholic fatty liver disease fibrosis score; WFA+-M2BP: Wisteria floribunda agglutinin-positive Mac-2 binding protein; CV: Cardiovascular; CVD: Cardiovascular disease; CAC: Coronary artery calcium.

The pathophysiology that best explains these patterns is not a single pathway but a network (Figure 1). Hepatic steatosis in MASLD sits at the intersection of visceral adiposity, lipotoxicity, insulin resistance, chronic low-grade inflammation, oxidative stress, endothelial dysfunction, prothrombotic signalling, and in advanced disease, fibrotic remodelling and hepatokine dysregulation. UHR and TyG capture the metabolic front end of this continuum; hs-CRP, Wisteria floribunda agglutinin-positive Mac-2 binding protein, steatosis-activity-fibrosis evaluation index, and FIB-4 capture inflammatory or fibrotic propagation; troponins and natriuretic peptides capture the downstream cardiac footprint[49-51].

Figure 1 Conceptual framework linking biomarker domains to cardiovascular risk in metabolic dysfunction-associated steatotic liver disease. Metabolic indices (uric acid/high-density lipoprotein ratio, triglyceride-glucose, and triglyceride/high-density lipoprotein-cholesterol) reflect upstream insulin resistance and visceral adiposity, driving hepatic steatosis and lipotoxicity. Inflammatory markers (high-sensitivity C-reactive protein and homeostatic model assessment of insulin resistance) contribute to hepatokine dysregulation and endothelial dysfunction, promoting atherogenesis. Fibrosis-related markers (fibrosis-4 index, steatosis-activity-fibrosis evaluation index, and Wisteria floribunda agglutinin-positive Mac-2 binding protein) capture cumulative metabolic-inflammatory injury and progressive liver fibrosis, which closely associates with vascular pathology. Cardiac biomarkers (N-terminal pro-B-type natriuretic peptide and troponins) reflect downstream myocardial stress and injury. These interconnected pathways culminate in coronary artery disease, carotid atherosclerosis, and heart failure susceptibility. UHR: Uric acid/high-density lipoprotein cholesterol ratio; TyG: Triglyceride-glucose; HDL-C: High-density lipoprotein-cholesterol; hs-CRP: High-sensitivity C-reactive protein; HOMA-IR: Homeostatic model assessment of insulin resistance; FIB-4: Fibrosis-4 index; SAFF: Steatosis-activity-fibrosis evaluation index; WFA+-M2BP: Wisteria floribunda agglutinin-positive Mac-2 binding protein; NT-proBNP: N-terminal pro-B-type natriuretic peptide.

CLINICAL UTILITY AND RESEARCH PRIORITIES

For day-to-day practice in Asian MASLD patients, the authors currently recommend prioritizing biomarkers in three tiers. First-line are fibrosis-oriented scores, especially FIB-4, because they already influence hepatology pathways and have now demonstrated repeated cardiovascular linkage in Asia. A threshold of 1.3 consistently identifies a higher-risk group in Asian MASLD cohorts, whereas 2.67 retains value as a more specific indicator of advanced fibrosis[39,52]. Second-line are metabolic enrichment markers such as UHR, TyG, and possibly triglyceride/HDL-C. These are particularly appealing in younger, non-obese, or “metabolically ambiguous” Asian patients. However, no universal event-validated threshold exists for Asian MASLD patients; therefore, study-specific cut-offs should not be over-literalised[53,54]. Third-line are myocardial stress or injury markers such as NT-proBNP and high-sensitivity troponins, which are likely most useful when symptoms, imaging abnormalities, diabetes, chronic kidney disease, or known cardiovascular disease already heighten pre-test probability[39,55].

The principal limitation of almost every candidate biomarker is confounding by the very metabolic dysfunction that defines MASLD. Low HDL, high triglycerides, insulin resistance, central obesity, hypertension, and inflammation are not external exposures; they are mechanistically intertwined with the disease label itself[56,57]. This means that statistically significant associations can overstate clinical increment. Very few Asian studies tested whether a biomarker materially improves discrimination beyond conventional risk engines, diabetes status, renal function, smoking, and imaging. Moreover, hard endpoints remain less frequent than subclinical ones: Calcium scores, carotid disease, Framingham risk, and angiographic burden dominate the literature more than adjudicated myocardial infarction, stroke, cardiovascular death, or heart-failure outcomes.

There are also notable geographical gaps. East Asian cohorts dominate, especially from Korea, China, and Japan. South Asian evidence remains much thinner and is often cross-sectional, while Southeast Asian cardiovascular biomarker studies in MASLD are remarkably sparse. That matters because body composition, diet, genetic susceptibility, and diabetes burden differ substantially across Asian subregions. An event-predictive UHR or TyG threshold in one Chinese health-screening cohort should not be assumed to transport directly to South Asian or Southeast Asian populations[58-60]. The same caution applies to “lean MASLD”, a phenotype likely overrepresented in parts of Asia but still insufficiently characterised with adjudicated cardiovascular outcomes[7,18].

The current research agenda is to evaluate cardiovascular biomarkers among Asian hepatology and cardiometabolic groups using harmonised MASLD definitions, adjudicated major adverse cardiovascular events, sex-specific and lean-phenotype analyses, and direct testing of biomarker add-on value over standard scores and simple imaging. Serial biomarker trajectories may be more informative than single baseline values. A particularly attractive model would combine one fibrosis marker, one metabolic ratio, and one myocardial injury marker in a stepwise algorithm, and then test whether that triad outperforms conventional clinical profiling in Asian MASLD populations. Until such data emerge, the most defensible opinion is that fibrosis scores should anchor cardiovascular risk enrichment, while UHR and TyG-class markers remain promising adjuncts rather than definitive stand-alone predictors.

CONCLUSION

In Asian MASLD populations, cardiovascular risk is real, common, and too often underestimated, especially in lean or mildly overweight patients. The present evidence does not support a single “magic” biomarker. Rather, it supports a hierarchy: Fibrosis-linked scores are the most clinically mature and best connected to cardiovascular phenotypes in Asian cohorts; UHR and TyG-class indices are promising metabolic enrichers; hs-CRP and HOMA-IR are mechanistically important but insufficiently specific; troponins and NT-proBNP are clinically meaningful but not yet validated for routine MASLD screening. Our recommendation is that clinical care for Asian patients with MASLD should move towards integrated cardiovascular triage, with FIB-4-rich algorithms as the immediate, practical starting point.