Dear Editor,
We thank Zerehpoosh et al. for their insightful comments on our recent territory-wide cohort study, which demonstrated that time-varying hypothyroidism is associated with increased risk of liver-related events (LREs) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) [
1,
2].
Zerehpoosh et al. [
2] highlighted the importance of liver in metabolic health. We agree that the liver plays an integral role in systemic metabolic regulation and endocrine balance through its interactions with multiple organ systems. The transition of nomenclature from non-alcoholic fatty liver disease to MASLD underscores this conceptual shift, recognizing that hepatic steatosis represents a hepatic manifestation of a broader metabolic dysfunction, rather than simply fat accumulation in the liver [
3,
4]. Specifically, a series of longitudinal cohort studies have shown that MASLD is closely linked to a spectrum of cardiometabolic risk factors, each independently associated with liver disease progression. Hypertension has been shown to be associated with accelerated liver fibrosis progression and adverse clinical outcomes in MASLD [
5], and poor long-term glycemic control significantly increases the risk of liver stiffness progression and LREs [
6]. In parallel, weight gain is associated with worse liver-related prognosis [
7]. Moreover, the impact of metabolic dysfunction appears to be cumulative, as longer duration of type 2 diabetes has been independently associated with a higher risk of LREs [
8].
This complex interplay highlights the need for an integrated clinical framework that accounts for the interdependence of metabolic organs. The recent conceptualization of cardiovascular-kidney-metabolic (CKM) syndrome represents an important step toward such a holistic approach [
9]. However, the liver, despite its key role in metabolic regulation, has not been incorporated into this model. This warrants further consideration, given the well-established bidirectional associations between hepatic and extrahepatic metabolic dysfunction. For example, hepatic insulin resistance is associated with atherogenic dyslipidemia and impaired glycemic control, while systemic inflammation arising from steatohepatitis may contribute to vascular dysfunction and progressive renal injury. Consistent with this concept, emerging data further support the relevance of the CKM framework to liver disease progression in MASLD. A recent study found that higher CKM stages were independently associated with liver fibrosis severity, and the risk of progression and LRE, with advanced CKM stages conferring nearly a two-fold increased risk of LREs compared with early stages [
10].
Taken together, across both liver-specific and systemic metabolic frameworks, these findings imply that metabolic health plays a pivotal role in determining disease trajectories across organ systems. Accordingly, a multidisciplinary approach to patient care is warranted, with lifestyle modification remaining a cornerstone for managing shared metabolic risk factors and improving long-term outcomes.
FOOTNOTES
-
Authors’ contributions
All authors contributed to the conception. Xinrui Jin prepared the first draft, and Terry Yip and Vincent Wong revised and edited the manuscript. All authors reviewed the manuscript.
-
Conflicts of Interest
Vincent Wong served as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, and Visirna; and a speaker for Abbott, AbbVie, Gilead Sciences, Novo Nordisk, and Unilab. He has received a research grant from Gilead Sciences, and is a co-founder of Illuminatio Medical Technology. Terry Yip has served as an advisory committee member for Gilead Sciences and GSK, and a speaker for Gilead Sciences. He has received a research grant from Gilead Sciences.
Abbreviations
cardiovascular-kidney-metabolic
metabolic dysfunction-associated steatotic liver disease
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Citations
Citations to this article as recorded by
- Reply to correspondence on “Hypothyroidism and the risk of liver-related events in patients with metabolic dysfunction-associated steatotic liver disease”
Shadi Zerehpoosh, Ziyan Pan, Mohammed Eslam
Clinical and Molecular Hepatology.2026; 32(3): e450. CrossRef
