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Abstract

In this letter, we present a brief overview of recent studies on the hepcidin-to-ferritin ratio, emphasizing its emerging role as a crucial biomarker in understanding the interplay between iron metabolism and immune responses, particularly in inflammatory diseases. We discuss the dynamics of hepcidin and ferritin in various clinical settings, including their responses in conditions like septic shock and COVID-19. The letter highlights the ratio's predictive capacity for disease severity and patient outcomes. It calls for further research to explore its potential in personalized medicine, thereby contributing to precision diagnostics and improved patient care strategies.
Journal of Medicine, Surgery, and Public Health 2 (2024) 100056
Available online 18 January 2024
2949-916X/© 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
From immunity to iron homeostasis: Understanding the predictive power of
hepcidin-to-ferritin ratio
ARTICLE INFO
Keywords
Hepcidin-to-Ferritin ratio
Iron homeostasis
Inammatory diseases
Biomarkers in immunity
Septic shock
ABSTRACT
In this letter, we present a brief overview of recent studies on the hepcidin-to-ferritin ratio, emphasizing its
emerging role as a crucial biomarker in understanding the interplay between iron metabolism and immune
responses, particularly in inammatory diseases. We discuss the dynamics of hepcidin and ferritin in various
clinical settings, including their responses in conditions like septic shock and COVID-19. The letter highlights the
ratios predictive capacity for disease severity and patient outcomes. It calls for further research to explore its
potential in personalized medicine, thereby contributing to precision diagnostics and improved patient care
strategies.
Dear Editor,
The hepcidin-to-ferritin ratio is an emerging biomarker in medicine,
offering signicant insights into iron metabolism and immune system
functioning. Hepcidin, a peptide hormone produced in the liver, is
crucial in regulating iron absorption and distribution in the body [1]. It
controls the release of iron into the bloodstream by regulating the iron
exporter, ferroportin. Ferritin, on the other hand, is a cellular protein
that stores iron and releases it in a controlled fashion [2]. The balance
between hepcidin and ferritin is vital for maintaining iron homeostasis,
which is crucial for various physiological processes, including erythro-
poiesis, immune function, and cellular respiration [3].
The hepcidin-to-ferritin ratio becomes particularly relevant in in-
ammatory diseases and immune responses [4]. Research has shown
that this ratio can provide valuable information about the bodys iron
status and the activity of the immune system under various patho-
physiological conditions, including septic shock, severe COVID-19, and
iron depletion scenarios like those experienced by frequent blood donors
[57].
The signicance of the hepcidin-to-ferritin ratio in understanding
immune responses and inammatory diseases has become increasingly
evident. Hepcidin expression is intricately linked to the bodys iron
levels but can also be inuenced by inammatory conditions [8]. In-
ammatory stimuli lead to an elevation of hepcidin levels, reducing iron
availability to pathogens and thereby impacting the immune response
and inammation [3]. This mechanism is crucial in conditions like
septic shock and COVID-19, where hepcidin levels are signicantly
elevated [6].
Ferritin, the iron storage protein, is also pivotal in iron homeostasis
[9,10]. During inammation, ferritin binds free iron to prevent the
formation of harmful free radicals [11]. Its blood levels are boosted
independently of iron status during infection and inammation. It is an
acute phase reactant that eliminates available iron, depriving pathogens
of this essential nutrient [12]. This response is mainly observed in
conditions such as septic shock and COVID-19, where elevated ferritin
levels are expected [6].
The hepcidin-to-ferritin ratio, therefore, offers a window into the
complex interplay between iron metabolism and immune response in
inammatory diseases. For instance, in a study involving patients with
septic shock, an altered hepcidin-to-ferritin ratio was indicative of the
overall prognosis, identifying patients who required more intensive
medical supervision. A signicantly lower ratio was observed in mor-
tality groups compared to survivors. This contrasted with COVID-19
cases, where the ratio did not show a signicant trend between survi-
vors and non-survivors [6].
The predictive potential of the hepcidin-to-ferritin ratio has been
particularly highlighted in the context of septic shock. In the same study,
this ratio demonstrated signicant predictive potential with an area
under the receiver operating characteristic (ROC) curve of 0.79, indi-
cating its efcacy in predicting overall mortality in septic shock patients
[6].
Furthermore, research on β-thalassemia major (β-TM) patients with
iron overload investigated the role of the hepcidin-to-ferritin ratio in
iron metabolism [13]. The study found that the median
hepcidin-to-ferritin ratio was signicantly lower in β-TM patients with
iron overload than in controls [13]. This ratio, with an accuracy of
99.2%, was proposed as an excellent diagnostic index for iron overload
in β-TM patients, helping to differentiate them from non-thalassemic
individuals [13].
The role of iron homeostasis in the progression of diseases like
COVID-19 has also been studied, revealing a strong association between
decreased iron levels and disease progression [12,14,15]. It is under-
stood that dysregulated iron and hepcidin levels may be linked to
disease-associated dysfunction of neutrophils, a critical immune cell
subset in the dysregulated immune response observed in severe
COVID-19 and septic shock.
The hepcidin-to-ferritin ratio is a crucial biomarker in understanding
the relationship between iron metabolism and immune responses in
inammatory diseases. Its ability to predict disease severity and out-
comes, particularly in conditions like septic shock, positions it as a
valuable tool in clinical practice. Furthermore, the ratios varying
Contents lists available at ScienceDirect
Journal of Medicine, Surgery, and Public Health
journal homepage: www.sciencedirect.com/journal/journal-of-medicine-surgery-and-public-health
https://doi.org/10.1016/j.glmedi.2024.100056
Received 16 January 2024; Accepted 17 January 2024
Journal of Medicine, Surgery, and Public Health 2 (2024) 100056
2
signicance in different conditions like COVID-19 underscores the need
for more personalized approaches in using this biomarker.
Ethics approval and consent to participate
Not applicable.
CRediT authorship contribution statement
Abdulqadir J. Nashwan, Mohamed A. Yassin, Md Ariful Haque:
Manuscript Preparation (draft and nal editing). All authors have read
and approved the nal manuscript.
Declaration of Competing Interest
The authors declare that they have no known competing nancial
interests or personal relationships that could have appeared to inuence
the work reported in this paper.
Acknowledgments
None.
Consent for publication
Not applicable.
References
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to hepatitis C virus, Cells 8 (6) (2019) 603.
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Abdulqadir J. Nashwan
a
,
b
,
*
,
1
a
Nursing Department, Hamad Medical Corporation, Doha, Qatar
b
Department of Public Health, College of Health Sciences, QU Health, Qatar
University, Doha, Qatar
Mohamed A. Yassin
2
Hematology and Oncology, National Center for Cancer Care & Research,
Hamad Medical Corporation, Doha, Qatar
E-mail address: yassin@hamad.qa.
Md Ariful Haque
3
Department of Orthopaedic Surgery, Yanan Hospital Afliated to Kunming
Medical University, Kunming, Yunnan, China
Department of Public Health, Atish Dipankar University of Science and
Technology, Dhaka, Bangladesh
Voice of Doctors Research School, Dhaka, Bangladesh
E-mail address: arifulhaque58@gmail.com.
*
Correspondence to: PO Box 3050, Doha, Qatar.
E-mail address: anashwan@hamad.qa (A.J. Nashwan).
1
ORCID: https://orcid.org/00000003-48454119
2
ORCID: 00000002-11448076
3
ORCID: 00000003-46325153
A.J. Nashwan et al.
... The clinicians can employ this alternative approach, as the hepcidin-to-ferritin ratio provides a more detailed understanding of iron metabolism and immune responses in inflammatory diseases like sepsis. 9 This emphasizes the need for further investigation to confirm the role of elevated serum iron levels in ICU mortality and to assess the contribution of the hepcidin-to-ferritin ratio alongside iron, which can ultimately improve sepsis management. ...
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Objectives: We aimed to determine a threshold cutoff for hepcidin, ferritin, and the hepcidin-to-ferritin ratio in the diagnosis of liver fibrosis in chronic hepatitis C virus (HCV)-free ß-thalassemia major patients with iron overload. Methods: This 1:1-matched case-control study included 102 individuals (3–30 yr.); 51 patients with iron overload anemia, and 51 apparently healthy individuals. Results: The highest areas under the ROC (receiver operating characteristic) curves (AUC-ROCs) for the diagnosis of patients vs. controls had overlapping 95% confidence intervals (CIs): serum hepcidin (0.758; 0.64–0.87; P ˂ 0.001), serum ferritin (1.000; 1.00–1.00; P ˂ 0.001), and the hepcidin/ferritin ratio (1.000; 1.00–1.00; P ˂ 0.001). For differentiation of patients with liver fibrosis stages of F0–F1 vs. F2–F4 and F0–F1 vs. F3–F4, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) with P-values ˂ 0.001 were the only statistically significant parameters, while the AUC-ROCs of the hepcidin/ferritin ratio (0.631, P = 0.188 and 0.684, P = 0.098) exhibited 90% and 89.5% sensitivity, respectively, in staging liver fibrosis. Conclusion: The hepcidin/ferritin ratio is suggested as an aspartate aminotransferase (AST)-to-platelet ratio index (APRI) to differentiate liver fibrosis patients. This ratio may have excellent sensitivity in the prediction of liver fibrosis.