The validity of serum ferritin levels in predicting cardiovascular events of metabolic dysfunction-associated steatotic liver disease patients may need more consideration

We read with great interest the informative study by Armandi et al., which shed light on the potential role of serum ferritin in predicting the long-term prognosis of patients with metabolic dysfunction-associated steatotic liver disease (1). However, there remain certain facets requiring in-depth investigation and interpretation.

First of all, the study found that integrating stepwise increased ferritin thresholds (215.5 and 272 µg/L) into predictive models can improve the performance of fibrosis-4 (FIB-4) and Non-Alcoholic Fatty Liver Disease Fibrosis Score (NFS) in the longitudinal risk assessment of liver-related events and overall mortality. However, it has been suggested that metabolic hyperferritinaemia (MHF) appears to exhibit a male predominance (2,3). Since the study primarily comprised male participants (65%), it raises the query of whether the ferritin threshold based on the entire population can accurately predict risks within female patients. Therefore, a sex-specific analysis is warranted to ensure a more precise evaluation.

Furthermore, we find the exclusion criteria did not address advanced cancer, active infection, or active inflammatory disease. These conditions can significantly impact the baseline serum ferritin levels, potentially compromising the accuracy of mortality prediction.

Currently, there are several different methods to determine ferritin levels, including labelled radiometric (immunoradiometric assay and radioimmune assay), labelled nonradiometric (fluorimetric, enzyme linked immunosorbent assay, chemiluminescent, microparticle enzyme immunoassay and radial partition immunoassay), agglutination (turbidimetric, nephelometric and latex photometric immunoassay), and others (4). It is also reported that the enzyme linked immunosorbent assay has poor agreement with microparticle enzyme immunoassay or chemiluminescent assay (5). Considering the maximum follow-up period of up to 540 months in this multi-center study, it is critical to clarify the precise measurement of ferritin across different centers. Consequently, the following concerns were raised: Firstly, were the assays utilized consistent across different centers, or sufficiently aligned for horizontal comparison? Secondly, did the results demonstrate continuity over the past 45 years for longitudinal comparison, taking the developments in assays, testing reagents, and measuring accuracy into consideration?

This study demonstrated that serum ferritin levels cannot accurately predict cardiovascular events. On the contrary, several studies have implicated significant associations between ferritin and risk factors pertinent to cardiovascular events, such as dyslipidemia, atheromatous plaque formation, hypertension and insulin resistance (6-8). The latest consensus has also highlighted the relationship between hyperferritinaemia and cardiovascular events (9). Notably, numerous medications have been developed and applied to manage abnormal low-density lipoprotein, hypertension, and vascular plaque over the course of the study. For instance, it has been proven that widely prescribed statins were capable of reducing serum ferritin levels (10). Therefore, it is pivotal to take into account the potential impact of medication on the predictive performance of baseline serum ferritin levels in relation to cardiovascular events.

Acknowledgments

Funding: This work was supported by the grant from Beijing iGandan Foundation (iGandanF-1082024-LG013).

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-217/coif). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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