THE ROLE OF HEPCIDIN IN PATIENTS WITH HEART FAILURE AND RHEUMATOID ARTHRITIS
Abstract
Hepcidin is the central peptide hormone regulating systemic iron homeostasis and has increasing clinical relevance in chronic inflammatory diseases, particularly heart failure and rheumatoid arthritis. In both conditions, inflammation, impaired iron trafficking, reduced iron bioavailability and anemia contribute to fatigue, exercise intolerance, reduced quality of life and worse prognosis. Hepcidin is mainly produced by hepatocytes and is upregulated by interleukin-6, inflammation and iron loading, while it is suppressed by iron deficiency, hypoxia and increased erythropoietic demand. By binding to ferroportin, hepcidin prevents intestinal iron absorption and macrophage iron export, producing functional iron deficiency despite normal or elevated ferritin. In heart failure, hepcidin biology is complex because absolute iron deficiency, chronic inflammation, renal dysfunction and myocardial iron handling may coexist. In rheumatoid arthritis, IL-6-driven hepcidin elevation is a major mechanism of anemia of chronic disease and correlates with inflammatory activity in several studies. Therapeutically, intravenous iron improves outcomes in selected heart failure patients, whereas IL-6 inhibition in rheumatoid arthritis can reduce hepcidin and improve hemoglobin. This review summarizes hepcidin biology, its diagnostic significance, disease-specific mechanisms and therapeutic implications in heart failure and rheumatoid arthritis.
References
Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B. K., & Ganz, T. (2004). IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. Journal of Clinical Investigation, 113(9), 1271–1276.
Ganz, T. (2013). Systemic iron homeostasis. Physiological Reviews, 93(4), 1721–1741.
Ganz, T., & Nemeth, E. (2012). Hepcidin and iron homeostasis. Biochimica et Biophysica Acta, 1823(9), 1434–1443.
Weiss, G., & Goodnough, L. T. (2005). Anemia of chronic disease. New England Journal of Medicine, 352(10), 1011–1023.
Muckenthaler, M. U., Rivella, S., Hentze, M. W., & Galy, B. (2017). A red carpet for iron metabolism. Cell, 168(3), 344–361.
van der Meer, P., van Veldhuisen, D. J., & Ponikowski, P. (2018). Anemia and iron deficiency in heart failure. Circulation, 138(1), 80–98.
Klip, I. T., Comin-Colet, J., Voors, A. A., Ponikowski, P., Enjuanes, C., Banasiak, W., Lok, D. J. A., Rosentryt, P., Torrens, A., Polonski, L., van Veldhuisen, D. J., & Jankowska, E. A. (2013). Iron deficiency in chronic heart failure: An international pooled analysis. American Heart Journal, 165(4), 575–582.e3.
Jankowska, E. A., Rozentryt, P., Witkowska, A., Nowak, J., Hartmann, O., Ponikowska, B., Borodulin-Nadzieja, L., von Haehling, S., Doehner, W., Banasiak, W., Poole-Wilson, P. A., Anker, S. D., & Ponikowski, P. (2010). Iron deficiency: An ominous sign in patients with systolic chronic heart failure. European Heart Journal, 31(15), 1872–1880.
Okonko, D. O., Mandal, A. K. J., Missouris, C. G., & Poole-Wilson, P. A. (2011). Disordered iron homeostasis in chronic heart failure: Prevalence, predictors, and relation to anemia, exercise capacity, and survival. Journal of the American College of Cardiology, 58(12), 1241–1251.
Anker, S. D., Comin Colet, J., Filippatos, G., Willenheimer, R., Dickstein, K., Drexler, H., Lüscher, T. F., Bart, B., Banasiak, W., Niegowska, J., Kirwan, B. A., Mori, C., von Eisenhart Rothe, B., Pocock, S. J., Poole-Wilson, P. A., & Ponikowski, P. (2009). Ferric carboxymaltose in patients with heart failure and iron deficiency. New England Journal of Medicine, 361(25), 2436–2448.
Ponikowski, P., van Veldhuisen, D. J., Comin-Colet, J., Ertl, G., Komajda, M., Mareev, V., McDonagh, T., Parkhomenko, A., Tavazzi, L., Levesque, V., Mori, C., Roubert, B., Filippatos, G., Ruschitzka, F., Anker, S. D., & CONFIRM-HF Investigators. (2015). Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. European Heart Journal, 36(11), 657–668.
Ponikowski, P., Kirwan, B. A., Anker, S. D., McDonagh, T., Dorobantu, M., Drozdz, J., Fabien, V., Filippatos, G., Haboubi, T., Keren, A., Khintibidze, I., Kragten, H., Martinez, F. A., Metra, M., Milicic, D., Nicolau, J. C., Ohlsson, M., Parkhomenko, A., Pascual-Figal, D. A., … AFFIRM-AHF Investigators. (2020). Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: A multicentre, double-blind, randomised, controlled trial. The Lancet, 396(10266), 1895–1904.
Kalra, P. R., Cleland, J. G. F., Petrie, M. C., Thomson, E. A., Kalra, P. A., Squire, I. B., Ahmed, F. Z., Al-Mohammad, A., Cowburn, P. J., Foley, P. W. X., Ghosh, J., Kaye, G. C., Ludman, A. J., Macdougall, I. C., McMurray, J. J. V., Ray, R., Shaboodien, G., Sibbring, G. C., Witte, K. K., … IRONMAN Study Group. (2022). Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK: A randomized, controlled trial. The Lancet, 400(10369), 2199–2209.
Mentz, R. J., Garg, J., Rockhold, F. W., Butler, J., De Pasquale, C. G., Ezekowitz, J. A., Fonarow, G. C., Lewis, G. D., Metra, M., Ponikowski, P., Voors, A. A., & Hernandez, A. F. (2023). Ferric carboxymaltose in heart failure with iron deficiency. New England Journal of Medicine, 389(11), 975–986.
Lewis, G. D., Malhotra, R., Hernandez, A. F., McNulty, S. E., Smith, A., Felker, G. M., Tang, W. H. W., LaRue, S. J., Redfield, M. M., Semigran, M. J., Givertz, M. M., Van Buren, P., Whellan, D., Anstrom, K. J., Shah, M. R., & NHLBI Heart Failure Clinical Research Network. (2017). Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency: The IRONOUT HF randomized clinical trial. JAMA, 317(19), 1958–1966.
McDonagh, T. A., Metra, M., Adamo, M., Gardner, R. S., Baumbach, A., Böhm, M., Burri, H., Butler, J., Čelutkienė, J., Chioncel, O., Cleland, J. G. F., Coats, A. J. S., Crespo-Leiro, M. G., Farmakis, D., Gilard, M., Heymans, S., Hoes, A. W., Jaarsma, T., Jankowska, E. A., … ESC Scientific Document Group. (2021). 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal, 42(36), 3599–3726.
Ezekowitz, J. A., McAlister, F. A., & Armstrong, P. W. (2003). Anemia is common in heart failure and is associated with poor outcomes: Insights from a cohort of 12,065 patients with new-onset heart failure. Circulation, 107(2), 223–225.
Anand, I. S. (2008). Anemia and chronic heart failure: Implications and treatment options. Journal of the American College of Cardiology, 52(7), 501–511.
Masson, C. (2011). Rheumatoid anemia. Joint Bone Spine, 78(2), 131–137.
Song, S. N. J., Tomosugi, N., Kawabata, H., Ishikawa, T., Nishikawa, T., Yoshizaki, K., & Yamamura, T. (2013). Comparative evaluation of the effects of treatment with tocilizumab and TNF-α inhibitors on serum hepcidin, anemia response and disease activity in rheumatoid arthritis patients. Arthritis Research & Therapy, 15(5), R141.
Isaacs, J. D., Harari, O., Kobold, U., Lee, J. S., & Bernasconi, C. (2013). Effect of tocilizumab on haematological markers implicates interleukin-6 signalling in the anaemia of rheumatoid arthritis. Arthritis Research & Therapy, 15(6), R204.
Kim, H. R., Kim, K. W., Yoon, S. Y., Kim, S. H., Lee, S. H., & Kim, H. Y. (2010). Serum pro-hepcidin could reflect disease activity in patients with rheumatoid arthritis. Journal of Korean Medical Science, 25(3), 348–352.
Sahebari, M., Rezaieyazdi, Z., Saadati, N., & Hatef, M. R. (2018). Serum hepcidin level and rheumatoid arthritis disease activity. European Journal of Rheumatology, 5(2), 76–80.
Khalaf, W., Al-Rubaie, H. A., & Shihab, S. (2019). Studying anemia of chronic disease and iron deficiency in patients with rheumatoid arthritis by iron status and circulating hepcidin. Hematology Reports, 11(1), 7708.
Nita, E., Grigorescu, E. D., Giușcă, S. E., Caruntu, I. D., & Amalinei, C. (2021). Role of hepcidin in anemia of chronic disease in rheumatoid arthritis. Journal of Medicine and Life, 14(6), 772–779.
Ganz, T., & Nemeth, E. (2009). Iron sequestration and anemia of inflammation. Seminars in Hematology, 46(4), 387–393.
Raj, D. S. C. (2009). Role of interleukin-6 in the anemia of chronic disease. Seminars in Arthritis and Rheumatism, 38(5), 382–388.
Ohsugi, Y. (2007). Recent advances in immunopathophysiology of interleukin-6: An innovative therapeutic drug, tocilizumab. Biological and Pharmaceutical Bulletin, 30(11), 2001–2006.
Smolen, J. S., Landewé, R. B. M., Bijlsma, J. W. J., Burmester, G. R., Dougados, M., Kerschbaumer, A., McInnes, I. B., Sepriano, A., van Vollenhoven, R. F., de Wit, M., Aletaha, D., Aringer, M., Askling, J., Balsa, A., Boers, M., den Broeder, A. A., Buch, M. H., Buttgereit, F., Caporali, R., … van der Heijde, D. (2020). EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Annals of the Rheumatic Diseases, 79(6), 685–699.
Aletaha, D., & Smolen, J. S. (2018). Diagnosis and management of rheumatoid arthritis: A review. JAMA, 320(13), 1360–1372.
McInnes, I. B., & Schett, G. (2011). The pathogenesis of rheumatoid arthritis. New England Journal of Medicine, 365(23), 2205–2219.
Weiss, G., Ganz, T., & Goodnough, L. T. (2019). Anemia of inflammation. Blood, 133(1), 40–50.
Camaschella, C. (2015). Iron-deficiency anemia. New England Journal of Medicine, 372(19), 1832–1843.
