Iron metabolism and sepsis-associated liver injury: Methodological considerations and clinical perspectives

Abstract

This letter offered commentary on the recently published article by Wang et al that investigated the relationship between iron metabolism disorders and sepsis-associated liver injury (SALI). The original study identified serum iron and total iron-binding capacity as potential predictive markers of SALI, contributing important insights to critical care hepatology. In this correspondence several methodological considerations that may influence the interpretation and generalizability of the findings were discussed. These include the limitations of a single-center design, the lack of serial biomarker measurements, the omission of hepcidin (a central iron regulatory hormone) as a measured variable, and the exclusive reliance on biochemical criteria for diagnosing liver injury. The potential value of incorporating imaging modalities and additional iron-related markers such as ferritin and transferrin saturation were also highlighted. The aim was to reinforce the importance of a comprehensive approach to iron metabolism in sepsis and to suggest future directions for clinical research that may enhance the diagnostic and prognostic utility of iron-related biomarkers in SALI.

Key Words: Sepsis-associated liver injury; Iron metabolism; Hepcidin; Serum iron; Total iron-binding capacity; Prognostic markers; Biomarkers in critical illness; Liver imaging; Ferritin; Transferrin saturation

Core Tip: This letter to the editor provided commentary on a recent study addressing the relationship between iron metabolism and sepsis-associated liver injury. Key methodological considerations, including the absence of hepcidin (a central iron-regulating hormone) in the biomarker panel, and the reliance solely on biochemical criteria for sepsis-associated liver injury diagnosis were highlighted. The importance of serial measurements and imaging-based confirmation was emphasized. The discussion aimed to enhance clinical interpretation and guide future studies on the prognostic role of iron-related markers in critical care settings.

TO THE EDITOR

I read with great interest the article by Wang et al[1] titled “Study of the relationship between iron metabolism disorders and sepsis-associated liver injury: A prospective observational study” published in the World Journal of Gastroenterology. The authors are to be congratulated for conducting a well-designed prospective study that highlighted the potential predictive roles of serum iron (SI) and total iron-binding capacity (TIBC) in sepsis-associated liver injury (SALI)[1].

While the valuable contributions of this work is acknowledged, I would like to offer several comments to help contextualize and further strengthen its implications: (1) The study enrolled 139 patients in a single center, limiting the generalizability of the results. A multicenter cohort would improve the external validity and ensure applicability across diverse populations. For instance the study by Cui et al[2] that included a substantially larger cohort to develop a predictive model for 90-day mortality in SALI provided a more robust basis for generalizable clinical inferences; (2) Iron-related parameters were measured only upon admission. Serial measurements of SI, TIBC, and related biomarkers over time (e.g., days 3, 7, and 14) would be informative for capturing the dynamics of disease progression[3]. Although the authors highlighted the importance of hepcidin in the discussion and cite supporting literature, hepcidin was not measured in the cohort. Given its central regulatory role in iron metabolism, inclusion of hepcidin would have enhanced the mechanistic understanding of SALI[4]; (3) The diagnosis of liver injury relied solely on biochemical criteria. Integration of hepatic imaging (e.g., elastography, Doppler ultrasound) or histopathological assessment when feasible could have provided a more definitive evaluation[5,6]; and (4) While the study focused on SI and TIBC, other iron-related markers such as serum ferritin and transferrin saturation, both of which are altered in critical illness, could have also contributed prognostic insights[7].

Beyond their methodological relevance, each of the above limitations carries important mechanistic implications. For instance the exclusion of hepcidin, a central regulator of iron flux, limits our understanding of the inflammatory-hepatic axis in sepsis as hepcidin overexpression under interleukin-6 stimulation leads to intracellular iron retention, hypoferremia, and ferroptosis-mediated liver injury[4]. Similarly, the reliance on single-time-point biomarkers overlooks the dynamic nature of iron metabolism during critical illness in which sequential changes in ferritin, transferrin saturation, or hepcidin may reflect different immune-metabolic phases[3].

To advance this field future studies should incorporate time-series assessments of iron parameters, apply liver-specific imaging modalities, and explore mechanistic models using iron chelators or ferroptosis inhibitors to clarify causality and therapeutic targets. Despite these limitations this study added meaningful knowledge to the field and opened new avenues for biomarker-driven management in patients who are critically ill with sepsis. I encourage future studies to expand upon these findings.