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Year : 2021  |  Volume : 8  |  Issue : 1  |  Page : 5-6

Hyperferritinemia: An important maker in sepsis

Department of Pediatric Intensive Care, NMC Royal Hospital, Abu Dhabi, UAE

Date of Submission06-Nov-2020
Date of Acceptance18-Nov-2020
Date of Web Publication08-Jan-2021

Correspondence Address:
Dr. Govind Benakatti
Department of Pediatric Intensive Care, NMC Royal Hospital, Abu Dhabi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpcc.jpcc_180_20

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How to cite this article:
Benakatti G, Ismail J. Hyperferritinemia: An important maker in sepsis. J Pediatr Crit Care 2021;8:5-6

How to cite this URL:
Benakatti G, Ismail J. Hyperferritinemia: An important maker in sepsis. J Pediatr Crit Care [serial online] 2021 [cited 2021 Sep 23];8:5-6. Available from: http://www.jpcc.org.in/text.asp?2021/8/1/5/306487

Ferritin, an iron-binding protein, is primarily known as a storage form of iron. Traditionally, low ferritin levels indicate iron deficiency and high levels indicate hemochromatosis. Intracellular free iron levels are regulated by binding with ferritin which prevents iron-mediated oxidative damage. Recently, there has been a growing body of evidence on its role as an acute phase reactant in inflammation. Elevated serum ferritin levels have been demonstrated in various inflammatory states such as sepsis, immune dysregulation like hemophagocytic syndromes, macrophage-activation syndrome, neurodegenerative diseases, and malignancies.[1] During sepsis and other bacterial infections, ferritin binds free iron in order to deprive bacteria thriving on it and thereby aids to contain infection. This helps to prevent oxidative damage to host cells as well. Ferritin acts as a local cytokine amplifying the inflammatory response by increasing expression of several pro-inflammatory cytokines such as inducible nitric oxide synthase, interleukin-1β, and RANTES.[2] In addition, complex feedback mechanisms exist between ferritin and the cytokines. On the one hand, cytokines can induce ferritin expression, whereas on the other hand, ferritin can induce the expression of both pro- and anti-inflammatory cytokines. Hence, a dysregulated response or a sustained activation could lead to a feed-forward loop resulting in persistent activation of macrophages presenting with various manifestations of hyperferritinemic syndrome. This feed-forward loop mechanism resulting in sustained macrophage activation has been shown in response to viruses, bacterial components, and free hemoglobin. Hyperferritinemic sepsis due to various etiologies such as dengue, COVID-19, and bacterial infections has been correlated with severe form of disease and poor outcomes.[3],[4] Hyperferritinemic syndromes encompass various etiologies such as severe sepsis and inflammatory and rheumatological diseases which present with hyperferritinemia and shared clinical and laboratory features. These features include at least five of the following eight criteria: fever, splenomegaly, cytopenia, elevated triglyceride, hypofibrinogenemia, low or absent NK cell activity, hemophagocytosis, and increased soluble CD25.

Levels of ferritin have been found to correlate with severity of inflammation and high levels are associated with mortality.[5],[6] Apart from diagnostic importance, ferritin as a prognostic marker is getting wider recognition. Various cutoff levels of serum ferritin have been used to predict clinical outcomes. Ferritin levels above 3000 ng/mL were predictive of intensive care needs and mortality.[5],[7] In the current issue of the Journal of Pediatric Critical Care, Sarkar et al.[8] in their study peak ferritin levels on day 1–3 postintensive care unit admission were found to have had high predictive value for mortality (sensitivity: 96.7% and specificity: 88%). With high prevalence of iron deficiency anemia in India, the cut-off value of ferritin with regard to disease severity and poor outcome in intensive care conditions could be lower than that seen developed countries.[7],[9] Hence, there seems to be a considerable variation in the threshold levels of ferritin, and therefore, the cutoff value needs to be further explored in the context of various sepsis subcohorts. Identification of patients using such cutoff values could help in prognostication and early initiation of disease-modifying therapies like immunomodulators.

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  References Top

Sackett K, Cunderlik M, Sahni N, Killeen AA, Olson AP. Extreme hyperferritinemia: Causes and impact on diagnostic reasoning. Am J Clin Pathol 2016;145:646-50.  Back to cited text no. 1
Kernan KF, Carcillo JA. Hyperferritinemia and inflammation. Int Immunol 2017;29:401-9.  Back to cited text no. 2
Pastora GJ, Weigand M, Kim J, Wu X, Strayer J, Palmer AF, et al. Hyperferritinemia in critically ill COVID-19 patients-Is ferritin the product of inflammation or a pathogenic mediator? Clin Chim Acta 2020;509:249-51.  Back to cited text no. 3
Ahmed F, Raj YA. Serum ferritin as an early predictor of the severity of dengue infection in children. J Infect Dis Ther 2020;8:424.  Back to cited text no. 4
Bennett TD, Hayward KN, Farris RW, Ringold S, Wallace CA, Brogan TV. Very high serum ferritin levels are associated with increased mortality and critical care in pediatric patients. Pediatr Crit Care Med 2011;12:e233-6.  Back to cited text no. 5
Carcillo JA, Sward K, Halstead ES, Telford R, Bacardi JA, Shakoory B, et al. A systemic inflammation mortality risk assessment contingency table for severe sepsis: Pediatr Crit Care Med 2017;18:143-50.  Back to cited text no. 6
Tonial CT, Costa CA, Andrades GR, Crestani F, Einloft PR, Bruno F, et al. Prediction of poor outcomes for septic children according to ferritin levels in a middle-income setting: Pediatr Crit Care Med 2020;21:e259-66.  Back to cited text no. 7
Sarkar M, Roychowdhury S, Zaman MA, Raut S, Bhakta S, Nandy M. Can serum ferritin be employed as prognostic marker of pediatric septic shock and severe sepsis? J Pediatr Crit Care 2021;8:20-6.  Back to cited text no. 8
  [Full text]  
Ghosh S, Baranwal AK, Bhatia P, Nallasamy K. Suspecting hyperferritinemic sepsis in iron-deficient population: do we need a lower plasma ferritin threshold?. Pediatr Crit Care Med 2018;19:e367-73.  Back to cited text no. 9


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