Letter: Iron Metabolism in SLD—A Complex Puzzle Yet to be Explored. Authors' Reply

Abstract

We appreciate the thoughtful comments on our letter discussing the role of iron metabolism in steatotic liver disease (SLD) [1]. We acknowledge their concerns regarding ferritin's role as an acute-phase reactant and the potential confounding effect of inflammation. While serum ferritin is influenced by systemic inflammation, it also reflects hepatic iron stores and metabolic stress, both of which may contribute to liver disease progression [2]. To further clarify this issue, we conducted an additional analysis incorporating C-reactive protein (CRP), an inflammatory marker that was available for 16,966 individuals in our cohort. When CRP was included as a covariate in our fully adjusted Cox proportional hazards model, the association between high ferritin and liver-related events (LREs) remained significant (HR 3.53, 95% CI: 2.10–5.91, p < 0.001). These findings suggest that ferritin is not merely an inflammatory marker but may independently reflect hepatic metabolic dysfunction or subclinical iron overload, contributing to an increased risk of LRE.

Regarding the use of gender-specific ferritin thresholds, we acknowledge the potential influence of racial and genetic differences in ferritin levels [3]. The cut-offs we applied (≥ 300 μg/L for men and ≥ 200 μg/L for women) are widely used in clinical practice and prior research evaluating hyperferritinemia in metabolic-associated liver disease [4, 5]. However, we recognise that dietary habits, genetic predispositions, and ethnic variability could significantly influence ferritin levels and their association with liver-related outcomes [6]. Future research should aim to refine ethnicity-specific thresholds and investigate the role of dietary patterns and genetic variations in modifying ferritin's impact on liver disease progression.

Shen and Xu also raised concerns about the exclusion of patients with iron deficiency. In our sensitivity analysis, we excluded individuals with a diagnosis of iron deficiency anaemia (IDA) and those who had received iron supplementation, as their ferritin levels could be influenced by factors unrelated to hepatic iron stores [7]. In our primary analysis, we did not exclude these individuals, but in our sensitivity analysis, we specifically excluded those diagnosed with IDA and those who had received iron supplementation to assess the independent impact of hyperferritinemia. A separate investigation into the impact of iron deficiency on LREs, particularly in patients with SLD, could be an important area for future research, as exploring the potential risks in this subgroup may provide further insights into iron metabolism and liver disease progression.

Lastly, we appreciate the suggestion to consider the impact of antidiabetic medications on iron metabolism. While metformin and other agents may influence hepcidin regulation [8], our study adjusted for diabetes status as a key confounder. Conducting a stratified analysis based on specific diabetes medications would be of interest in future work to determine whether pharmacologic interventions modulate the ferritin-LRE association.

We thank the authors for their thoughtful comments, which have allowed us to refine our interpretation and highlight the robustness of our findings. Further research integrating a broader spectrum of iron metabolism markers and metabolic parameters will continue to enhance our understanding of the interplay between ferritin, hepatic injury, and long-term liver outcomes.

Byeong Geun Song: conceptualization, methodology, data curation, investigation, validation, formal analysis, visualization, writing – original draft, writing – review and editing. Dong Hyun Sinn: conceptualization, methodology, supervision, project administration, writing – original draft, writing – review and editing.

This article is linked to Song et al papers. To view these articles, visit https://doi.org/10.1111/apt.18402 and https://doi.org/10.1111/apt.70037.