Dear Editor,
We thank Jin et al. for their insightful response to our correspondence, “ A call for more efforts to incorporate liver in the metabolic health framework.” [
1-
3] We noted with great interest their echo of our views on the critical importance of recognizing individual metabolic risk factors and the necessity of a holistic approach to metabolic health, particularly by acknowledging the liver’s integral role in systemic metabolic regulation.
The transition from non-alcoholic fatty liver disease to metabolic dysfunction-associated fatty liver disease (MAFLD) was a pioneering conceptual shift, recognizing that metabolic dysfunction is a key driver of the disease in these patients [
4,
5]. Evidence consistently shows that MAFLD (also known as metabolic dysfunction-associated steatotic liver disease or MASLD) is closely linked to a range of cardiometabolic adverse outcomes. These outcomes extend beyond liver-related issues to include increased risks of cardiovascular disease, diabetes, chronic kidney disease, and various types of extrahepatic cancers [
5,
6]. This connection arises partly due to hepatic insulin resistance, which initiates hyperinsulinemia and systemic glucose dysregulation, accelerating atherosclerosis and contributing to renal microvascular injury. Additionally, hepatocyte-derived proinflammatory cytokines and pro-atherogenic lipoproteins exacerbate endothelial dysfunction, creating a damaging “hepato-cardio–renal axis.” [
7]
The Cardiovascular-Kidney-Metabolic (CKM) syndrome framework represents a significant advancement in providing a unified perspective on metabolic health [
8]. However, as emphasized in our correspondence, the ongoing omission of the liver highlights a critical gap, given its documented connections to systemic metabolic disruptions [
8]. A recent cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) identified MAFLD/MASLD as an independent risk factor for the severity of CKM syndrome [
9]. This connection is evident not only in outcomes such as increased fibrosis, but also through higher disease severity, as indicated by elevated values in multiple non-invasive scoring systems such as FIB-4 [
10]. This finding aligns with growing evidence that the progression of CKM syndrome is positively associated with severe liver disease and liver-specific mortality. This association is due to overlapping pathophysiological mechanisms, such as lipid toxicity, oxidative stress, and inflammation [
11]. In fact, dysfunctional adipose tissue, commonly observed in CKM syndrome, secretes pro-inflammatory products that interfere with hepatic lipid metabolism, driving steatosis and cirrhosis.
Collectively, this data reinforces our view of the need to incorporate liver health into metabolic frameworks, including expanding the CKM syndrome into a Cardiovascular-Renal-Hepatic-Metabolic syndrome to acknowledge the liver’s central role. It is imperative to ensure accurate assessment of liver disease within these frameworks.
In conclusion, the emerging evidence on the pivotal role of liver in metabolic health and determining disease trajectories across various systemic metabolic dysfunctions reaffirms the necessity for a multidisciplinary approach to patient care and the implementation of integrated care models for developing comprehensive healthcare policies, advancing research, and facilitating drug development, with the ultimate aim of delivering the best care for patients by addressing all active diseases and improving underlying metabolic dysfunctions [
12].
FOOTNOTES
-
Authors’ contributions
Shadi Zerehpoosh: Investigation, Writing - Original Draft, Writing - Review and Editing. Ziyan Pan: Writing - Review and Editing. Mohammed Eslam: Investigation, Writing - Review and Editing.
-
Acknowledgements
ME is supported by a National Health and Medical Research Council of Australia (NHMRC) investigator and ideas grants (AAP2008983 and APP2001692).
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
Cardiovascular-Kidney-Metabolic
metabolic dysfunction-associated fatty liver disease
metabolic dysfunction-associated steatotic liver disease
National Health and Nutrition Examination Survey
REFERENCES
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