Cardiovascular Mortality in MASLD: A Matter of Fat. Caution in Interpreting Liver Fat Quantification in Populations With High Fibrosis Variability

Abstract

We read with great interest the recent article by Kim and Vutien, et al., which reports that substantial liver fat, measured via Vibration-controlled Transient Elastography (VCTE), is associated with a reduced risk of decompensation (aHR: 0.54, 95% CI: 0.32–0.90) and mortality (aHR: 0.52, 95% CI: 0.37–0.73) in metabolic dysfunction-associated steatotic liver disease (MASLD) patients [1]. This study brings valuable insights by examining liver fat's unique prognostic value independent of fibrosis, which has often been overshadowed by an isolated focus on fibrosis. Their findings align with previous meta-analyses showing that lower liver fat content in MASLD individuals with significant/advanced fibrosis is associated with an increased risk of composite adverse outcomes, including decompensation, hepatocellular carcinoma, and death (aHR: 42.2, 95% CI: 7.5–235.5) [2].

While commending the authors for this significant contribution, we suggest caution in interpreting steatosis quantification in populations with high variability in fibrosis levels [as indicated by interquartile range (IQR) of 6.4–17.9 (median 10.6 kPa)] in this study [1]. A large cohort study involving 9.8 million individuals, deemed to be at low risk of advanced fibrosis, illustrated that high Liver fat content, as measured by the surrogate Fatty Liver Index (FLI) was associated with a higher risk of cardiovascular events in MASLD (aHR: 1.39, 95% CI: 1.38–1.40 for FLI ≥ 30 and aHR: 1.52, 95% CI: 1.51–1.54 in FLI ≥ 60) [3]. Similarly, in a recent meta-analysis of 19 studies involving 147 411 participants, primarily from population-based studies, we found that higher liver fat levels in MASLD were associated with an increased risk of subclinical atherosclerosis (pooled OR: 1.27, 95% CI: 1.13–1.41 for mild steatosis and 1.68, 95% CI: 1.41–2.00 for moderate to severe steatosis) [4]. However, this association reversed in populations with a high prevalence of significant/advanced fibrosis, in parallel with increasing fibrosis levels [4].

This paradox may be explained by the ‘burnout’ NASH phenomenon. As liver disease progresses, alterations in portal circulation—such as reduced blood flow, portosystemic shunting, and loss of sinusoidal fenestrations—diminish hepatocyte interactions with insulin and lipoproteins, leading to decreased hepatic fat accumulation [5]. Additionally, while low levels of the insulin-sensitising and anti-steatotic adipocytokine adiponectin are linked with hepatic steatosis and inflammation, elevated adiponectin levels in later disease stages may contribute to reduced hepatic fat storage in advanced (burnt-out) MASH with liver dysfunction [6]. Consequently, individuals with significant/advanced fibrosis may exhibit lower liver fat levels, which could distort associations between steatosis and clinical outcomes, suggesting that fibrosis severity biases liver fat assessment and should be considered when evaluating cardiovascular risk in relation to liver fat.

Based on these observations, we propose a sequential approach for cardiovascular risk assessment (Figure 1) [7]. This approach begins by excluding advanced fibrosis using liver stiffness measurement (LSM < 8 kPa) or FIB-4 < 1.3—thresholds that are well established in MASLD guidelines and have been extensively validated for ruling out advanced fibrosis in diverse populations [8]. By stratifying patients based on fibrosis status, this framework accounts for the differing prognostic significance of liver fat in early versus advanced disease. Applying this algorithm/procedure/protocol in clinical practice could potentially enhance cardiovascular risk assessment by refining patient selection, improving risk stratification and facilitating timely referral for more comprehensive cardiovascular evaluation.

Although Kim and Vutien, et al. adjusted their analyses for liver fibrosis and performed sensitivity analyses in patients with advanced fibrosis (LSM ≥ 10 KPa) and without cirrhosis (LSM < 15 KPa), it remains unclear whether patients at lower fibrosis risk exhibit a similar risk pattern [1]. Specifically, in their LSM < 15 KPa analysis, MASLD individuals with LSM values of 10–15 KPa represent approximately 20% of the patient population, while around 25% have LSM values below 6.4 KPa [1]. Combined together, these groups might obscure distinct cardiovascular risk patterns associated with intrahepatic content/steatosis extent in these patient subpopulations.

Furthermore, individuals with higher steatosis extent, particularly those without advanced fibrosis, may experience substantially increased risk of major adverse cardiovascular events over the medium and long term [3]. This is likely driven by the strong association between steatosis and insulin resistance, dyslipidemia, and systemic inflammation, which contribute to endothelial dysfunction and atherosclerosis [4]. Excess liver fat also promotes pro-atherogenic lipoprotein production and atherogenic dyslipidemia, creating a pro-inflammatory and pro-thrombotic systemic milieu that elevates the risk of major cardiovascular events [4]. The short-term outcomes in this study [1] may primarily capture risks in advanced cases (where steatosis often fades as fibrosis progresses), potentially overlooking broader and ominous cardiovascular implications for those with higher steatosis levels. As a matter of fact, cardiovascular mortality remains the leading cause of death among MASLD subjects.

Another important consideration, also pinpointed by the authors, is the predominance of males among participating Veterans [1]. Sex-based differences in MASLD are well established, influencing liver fat content, fibrosis progression, liver-related complications, and extrahepatic outcomes, including cardiovascular disease [9]. For instance, oestrogen regulates lipid metabolism, reduces inflammation, and enhances insulin sensitivity, contributing to lower liver fat accumulation in premenopausal women [9]. However, this protection diminishes after menopause [9]. Thus, the prognostic significance of liver fat appears to be strongly age- and sex-specific. Given these differences, the finding of Kim and Vutien et al. [1] may not be fully generalisable to females with MASLD, and future studies should specifically investigate whether these associations hold true in women with MASLD.

Both M.J. and A.L. conceptualised, wrote and accepted the manuscript.

Mohamad Jamalinia, MD is the guarantor of the article. The authors declare no conflicts of interest.