Metabolic dysfunction–associated steatotic liver disease (MASLD) contributes to rising incidences of liver-related mortality and MASLD-related hepatocellular carcinoma on a global scale.1,2 It poses a significant public health challenge with a global prevalence of 30-40%, and its incidence is expected to rise further.3,4 The reclassification from “non-alcoholic fatty liver disease” to MASLD aims to highlight the role of metabolic dysfunction in the central pathogenesis of the disease, with the inclusion of at least one of the five cardiometabolic risk factors (CMRFs), including (i) overweight or obesity or central obesity, (ii) dysglycaemia or type 2 diabetes mellitus (T2D), (iii) plasma triglycerides ≥1.7 mmol/L or currently on lipid-lowering treatment, (iv) high-density lipoprotein (HDL)-cholesterol ≤1.0 mmol/in men and ≤1.3 mmol/L in women or currently on lipid-lowering treatment, and (v) blood pressure ≥130/85 mmHg or treatment for hypertension.5
Shekhar et al. conducted a retrospective study on the long-term effects of CMRFs and their combinations on clinical outcomes in patients with MASLD. This study included 1043 patients with a median follow-up of 5.3 years. Liver-related events (LREs) were classified as ascites, hepatic encephalopathy, variceal bleeding, hepatocellular carcinoma, and liver-related mortality. Extrahepatic events included coronary artery disease, cerebrovascular accidents, and chronic kidney disease.
This study demonstrated that T2D was associated with the highest risk of mortality (4.1%), LREs (7.0%), and extrahepatic events (4.5%), when compared to other components of CMRFs. Notably, patients with all five CMRFs had the highest incidence rate of clinical events compared to patients with lower numbers of CMRFs, although there was no statistical difference, likely owing to limited sample size in each subgroup. Patients were stratified into two distinct groups based on their liver stiffness measurement (LSM): LSM >/ = 10 kPa and LSM <10 kPa. This value was chosen as it was established as the threshold for ruling out compensated advanced chronic liver disease with reference to Baveno VII criteria.6 An LSM >/ = 10 kPa was shown to be an independent predictor of LREs and all-cause mortality in this study.
Patients with MASLD exhibit significant variability in their cardiometabolic burden, leading to different prognoses. Prognostication for MASLD is therefore being extensively researched due to the high prevalence of MASLD and its heterogeneity in clinic outcomes. This paper offers timely insights into the impact of CMRFs on long-term clinical outcomes in a substantial cohort of MASLD patients. The findings are consistent with recent compelling evidence, reinforcing T2D as a risk factor for cardiovascular, malignancy, and liver-related outcomes in patients with MASLD.7 Shekhar et al. provided a novel and comprehensive evaluation of the impact of CMRFs on MASLD outcomes in patients residing in a South-East Asian country: they not only demonstrated the positive association between T2D and clinical outcomes but also compared the various components of CMRFs and their different combinations alongside their clinical outcomes. In addition, this study highlighted an LSM>/ = 10 kPa as the key predictor of clinical outcomes, which was consistent with current existing evidence.8
The association of T2D with higher rates of LREs and mortality is likely attributable to its role as an independent risk factor of advanced fibrosis in MASLD.9 At the molecular level, the pathogenesis of MASLD is characterized by excessive hepatic de novo lipogenesis. Prior studies illustrated a positive correlation between 24-h plasma glucose and insulin concentrations with hepatic de novo lipogenesis.10 A high glucose level causes subclinical inflammation and insulin resistance in the liver. This complex process increases signaling through fatty acids, diacylglycerols, and ceramides. Consequently, the resulting insulin resistance, hyperinsulinemia, and hyperglycemia amplify hepatic de novo lipogenesis, leading to MASLD.11
Having established the relationship between T2D and MASLD, the pivotal next question is the application of this finding in daily clinical practice. At the present, we adopt the two-step non-invasive assessment algorithm for fibrosis assessment: the Fibrosis-4 index followed by vibration-controlled transient elastography or other imaging.12 In light of the high prevalence (65%) of MASLD in patients with T2D,13 some experts advocate universal screening for MASLD in this subgroup of patients.14 Similarly, MASLD patients should be regularly followed up for the new onset of T2D. A critical question remains: Should MASLD patients with T2D undergo more frequent screening than those without? Given the retrospective nature of this study, future longitudinal studies with extended follow-up across multiple centers is essential to evaluate the effects of various CMRFs on mortality and liver-related outcomes in MASLD. This study, however, could not address the impact of anti-diabetic treatment, in particular glucagon-like peptide 1 receptor agonist, on the risk of LREs and mortality in patients with MASLD and diabetes. Moreover, it would be of interest to explore the degree of glycemic control on the effect size of the adverse clinical outcomes in MASLD, similar to what has been demonstrated in chronic hepatitis B infection.15
The specific type of CMRF holds a greater significance than the number of CMRFs in the prognostication of MASLD. T2D and liver stiffness have a profound impact on long-term clinical outcomes in patients with MASLD and therefore should be prioritized in MASLD evaluation and management strategies.
Credit authorship contribution statement
KCY Ho was involved in drafting of the editorial. LY Mak was involved in the critical revision of manuscript and overall study supervision. The authors declare that they have participated in the preparation of the manuscript and have seen and approved the final version.
Funding
None declared.
DECLARATION OF COMPETING INTEREST
LY Mak received research grant support from Roche Diagnostics.
Acknowledgements
None declared.
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