Volume 8, Issue 4, July 2020, Page: 153-158
Controversial Impact of Hepcidin Metabolism in the Pathogenesis of Anemia in Myelofibrosis
Stela Dimitrova, Clinic of Hematology, UMHAT “Sveta Marina”, Medical University, Varna, Bulgaria
Liana Gercheva, Clinic of Hematology, UMHAT “Sveta Marina”, Medical University, Varna, Bulgaria
Daniela Gerova, Laboratory of Immunology, UMHAT “Sveta Marina”, Medical University, Varna, Bulgaria
Ilina Micheva, Clinic of Hematology, UMHAT “Sveta Marina”, Medical University, Varna, Bulgaria
Received: May 22, 2020;       Accepted: Jun. 18, 2020;       Published: Jul. 6, 2020
DOI: 10.11648/j.ajim.20200804.13      View  50      Downloads  30
Abstract
Anemia in myelofibrosis (MF) is a result of a multifactorial process, which is incompletely understood. The central pathogenetic mechanism is a replacement of normal hemopoietic tissue by fibrotic stroma. However, ineffective erythropoiesis, inflammation and iron overload have an additional impact on anemia development, suggesting the role of dysregulated iron homeostasis and hepcidin. The aim of the study was to analyze parameters of iron metabolism and inflammation in patients with different forms and stages of myelofibrosis. Thirty-six patients with primary MF, post-polycythemia vera and post-essential thrombocythemia MF and fourteen healthy controls were included in the study. In the patient group, serum ferritin, Fe, TIBC and parameters of CBC were measured as a part of routine clinical assessment. Plasma total hepcidin levels and concentrations of Interleukin-6 (IL6) and Interleukin-8 (IL8) were measured in duplicate by ELISA (My BioSource, San Diego, USA) in patients and healthy controls. The hepcidin level in the patient group was found statistically lower compared to healthy controls (27,64±41,56 ng/ml; 111,13±49,56 ng/ml; F=2,81, p<0,001). Patients with newly diagnosed MF had significantly higher levels of hepcidin compared to those with prolonged evolution: between 1 and 5 years (p=0,005) and >5 years (p=0,038). Transfusion dependent patients presented with lower hepcidin compared to transfusions independent (10,10±6,67 ng/ml; 31,15±44,37 ng/ml; p=0,026). In patients receiving cytoreductive or target treatment hepcidin level was significantly lower compared to patients on best supportive care (17,74±21,99 ng/ml; 43,05±58,46 ng/ml; p=0,037). No difference was found in hepcidin level within the risk groups according to DIPSS, neither between the subtypes of disease (primary MF and secondary MF). Higher hepcidin positively correlated with leukocytosis (R=0,665, p=0,009) and age (R=0,392, p=0,0081). By multivariate analysis, a significant highly positive correlation was found between hepcidin and IL-6 (R=0,535, p=0,002) and weaker between hepcidin and IL-8 (R=0,413, p=0,21) A significant straight correlation was demonstrated between IL-6 and IL-8 (R=0,464, p=0,009) and a negative between serum iron and IL-6 (R=-0,367, p=0,42) and IL-8 (R=-0,438, p=0,14), respectively. The hepcidin regulation is complex and multifactorial. Its role in pathogenesis of anemia in myelofibrosis is controversary. Probably it has a higher impact in early stages of the disease and depends on treatment and transfusions.
Keywords
Myelofibrosis, Hepcidin, Anemia, Inflammatory Cytokines
To cite this article
Stela Dimitrova, Liana Gercheva, Daniela Gerova, Ilina Micheva, Controversial Impact of Hepcidin Metabolism in the Pathogenesis of Anemia in Myelofibrosis, American Journal of Internal Medicine. Vol. 8, No. 4, 2020, pp. 153-158. doi: 10.11648/j.ajim.20200804.13
Copyright
Copyright © 2020 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Reference
[1]
Tefferi A, Lasho TL, Jimma T, et al. One thousand patients with primary myelofibrosis: the mayo clinic experience. Mayo Clin Proc. 2012; 87 (1): 25-33.
[2]
Naymagon, Leonard; Mascarenhas, John Myelofibrosis-Related Anemia: Current and Emerging Therapeutic Strategies. HemaSphere: December 2017 - Volume 1 - Issue 1 - p e1.
[3]
Nemeth, E., Tuttle, M. S., Powelson, J., Vaughn, M. B., Donovan, A., Ward, D. M., Ganz, T. & Kaplan, J. (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science, 306, 2090–2093.
[4]
Asher Winder, Rafi Lefkowitz, Hussam Ghoti et al. Urinary hepcidin excretion in patients with myelodysplastic syndrome and myelofibrosis. British Journal of Haematology. 2008; 142, 668–680.
[5]
David H. Manz, Nicole L. Blanchette, Bibbin T. Paul, Frank M. Torti and Suzy V. Torti. Iron and cancer: recent insights Ann N Y Acad Sci. 2016 March; 1368 (1): 149-161.
[6]
Alessia Pagani1, Antonella Nai1,2, Laura Silvestri1,2 and Clara Camaschella1, Hepcidin and Anemia: A Tight Relationship, MINI REVIEW ARTICLE Front. Physiol., 09 October 2019.
[7]
Teasfay L., et al. Hepcidin regulation in prostate and its disruption in prostate cancer. Cancer research. 2015; 75: 2254-2263. [PubMed: 25858146].
[8]
Zhang S. et al. Disordered hepcidin-ferroportin signaling promotes breast cancer growth. Cellular signaling. 2014; 26: 2539-2550. [PubMed: 25093806].
[9]
Goh JB, et al. Endofin, a novel BMP-SMAD regulator of the iron-regulatory hormone, hepcidin. Sci Rep. 2015; 5: 13986. [PubMed: 26358513].
[10]
Guada C, Altamura S, Klein FA, at al. A novel inflammatory pathway mediating rapid hepcidin-independent hypoferremia. Blood 2015; 125: 2265-2275.
[11]
Deaschemin JC, Vaulont S. Role of hepcidin in the setting of hypoferremia during acute inflammation. PLos One 2013; 8:e61050.
[12]
Nairz M, Haschka D, Demetz E, Weiss G. Iron at the interface of immunity and infection. Front Pharmacol 2014; 5: 152.
[13]
Weiss G. Anemia of chronic disorders: new diagnostic tools and new treatment strategies. Semin Hematol 2015; 52: 313-320.
[14]
Pardanani A, Finke C, Abdelrahman RA, Lasho TL, Tefferi A. Associations and prognostic interactions between circulating levels of hepcidin, ferritin and inflammatory cytokines in primary myelofibrosis. Am J Hematol. 2013; 88 (4): 312-316. [PubMed].
[15]
Barbui T, Thiele J, Gisslinger H, Finazzi G, Vannucchi AM, Tefferi A The 2016 revision of WHO classification of myeloproliferative neoplasms: Clinical and molecular advances. Blood Rev. 2016 Nov; 30 (6): 453-459. doi: 10.1016/j.blre.2016.06.001. Epub 2016 Jun 11.
[16]
Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood 2010; 115 (9): 1703-1708.
[17]
Chia-Yu Wang and Jodie L. Babitt. Hepcidin regulation in anemia of inflammation Curr Opin Hematol 2016, 23: 189-197.
[18]
McCranor BJ, Langdon JM, Prince OD, at al. Investigation of the role of interleukin-6 and hepcidin antimicrobial peptide in the development of anemia with age. Haematologica 2013; 98: 1633-1640.
[19]
Kim A, Rivera S, Shprung D, at al. Mouse models of anemia of cancer. PLoS One 2014; 9: e93283.
[20]
Santini V, Girelli D, Sanna A, Martinelli N, Duca L, et al. (2011) Hepcidin Levels and Their Determinants in Different Types of Myelodysplastic Syndromes. PLoS ONE 6 (8): e23109. doi: 10.1371/journal.pone.0023109.
[21]
Animesh D. Pardanani, Terra L Lasho, Christy Finke, Ramy A. Abdelrahman, Curtis A. Hanson and Ayalew Tefferi Serum Ferritin Level At Referral Provides Independent Prognostic Information For Overall Survival In Primary Myelofibrosis. Blood 2013 122: 2824.
[22]
Maccio A, Madeddu C, Gramignano G, et al. The role of inflammation, iron, and nutritional status in cancer-related anemia: results of a large, prospective, observational study. Haematologica 2014; 100: 124-132.
[23]
Ganz T: Hepcidin and iron regulation, 10 years later. Blood 2011, 117: 4425–4433.
[24]
Maha F. Yacoub et al. Effect of Interleukin and Hepcidin in Anemia of Chronic Diseases, Hindawi Anemia Volume 2020, Article ID 3041738, 5 pages.
[25]
Liana Gercheva, Stela Dimitrova, Ilina Micheva Impact of the impaired iron homeostasis on the pathogenesis of anemia in primary myelofibrosis. Journal of IMAB – 2016, vol. 22, issue 1.
[26]
Tomas Ganz Hepcidin and iron regulation, 10 years later CA Blood (2011) 117 (17): 4425–4433.
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