Role of hepcidin in the development of anemia in patients with rheumatoid arthritis

Chronic disease anemia (CDA) diagnosed in many patients with rheumatoid arthritis (RA) was described in the early 1970s. As earlier noted, iron metabolic disturbances in CDA are its diagnostic feature and the discovery of hepcidin, an iron-regulatory acute-phase protein, could largely clarify an association between the immune mechanism of impaired iron homeostasis and the development of CDA. Objective: to define the role of hepcidin in the differential diagnosis of CDA and true iron deficiency in patients with RA. Subjects and methods. The investigation enrolled 76 patients with RA (1987 ACR criteria) admitted to the Research Institute of Rheumatology, Russian Academy of Medical Sciences, to be treated. The patients were divided into two groups. A study group comprised anemic patients (n = 47). The WHO criteria for anemia were considered to be hemoglobin (Hb) levels of below 120 g/l for women and below 130 g/l for men. A control group consisted of non-anemic patients (n = 29). The anemic and non-anemic patients were matched for age (45.5±14.3 and 49.8±14.3 years, respectively) and disease duration (2 months to 20 years) (p > 0.05). Iron metabolic parameters, such as serum iron, total serum iron-binding capacity (TSIBC), iron transferrin saturation (ITS), transferrin receptors, and serum ferritin (SF), were studied and the level of hepcidin prohormone was estimated by direct enzyme immunoassay (Hepcidin Prohormone Enzyme Immunoassay Kit, IBL, Germany) in all the patients to be analyzed. Cytokines, such as interleukin 6, tumor necrosis factor-а) were determined by enzyme immunoassay (Bender MedSystems, Austria). The Institute’s differential diagnostic algorithm involving SF, TSIBC, and ITS was used to diagnose iron deficiency. The diagnosis was based on two stages of estimating iron values: isolated iron-deficiency anemia (IDA) was diagnosed if SF was below the normal value (< 40 μg/l). If the patient had SF of μ40 μg/l with a simultaneous rise of TSIBC above the normal level (> 70 μg/l) and a drop of ITS (> 20%), he/she might be suspected as having the mixed genesis of anemia, in which both iron deficiency and CDA are detectable. The other patients could be diagnosed as having isolated CDA. Results. The study has established that irrespective of the hemoglobin level, the content of serum hepcidin prohormone in the examined patients with RA averaged 89.2±65.1 pg/ml and was much higher than that in donors (64.9+21.6 pg/ml; р < 0.05). An analysis of the blood biochemical parameters characterizing iron metabolism showed that, whether they were anemic or non-anemic, the patients with RA, as compared with donors, were found to have an elevated level of SF that is an acute-phase indicator and reflects the high activity of an inflammatory process. To rule out IDA, the anemic patients with RA were subdivided into 3 subgroups according to the differential diagnostic algorithm. Subgroup 1 included patients with isolated CDA (n = 13 patients (28% of those in the study group)); Subgroup 2 consisted of 17 (32%) patients with anemia of mixed genesis (CDA ± IDA), and Subgroup 3 comprised 17 patients with IDA. An analysis of the clinical and laboratory parameters in RA independent of the nature of anemia demonstrated that only the patients with isolated CDA had significantly higher mean values of hepcidin prohormone (120.3±56.1 pg/ml) as compared to the control group (90.3±37.9 pg/ml) and RA patients with iron deficiency (both isolated IDA and that of mixed genesis). The same subgroup had a higher inflammatory RA activity characterized by the highest values of DAS 28, C-reactive protein, and SF. Conclusion. Hepcidin is a negative regulator of iron metabolism and may be used for the differential diagnosis of CDA and true iron deficiency in patients with RA.

chronic disease anemia, iron-deficiency anemia, hepcidin

1. <div><p>Weiss G., Goodnough L.T. Anemia of chronic disease. New Eng J Med 2005;352(10):1011-23.</p><p>Nikolaisen C., Figenschau Y., Nossent J.C. Anemia in early rheumatoid arthritis is associated with interleukin 6-mediated bone marrow suppression, but has no effect on disease course or mortality. J Rheumatol 2008;35(3):380-6.</p><p>Jaworski J., Maslinski W., Pazdur J. et al. Decreased expression of integrins by hematopoietic cells in patients with rheumatoid arthritis and anemia: relationship with bone marrow cytokine levels. J Investig Allergol Clin Immunol 2008;18(1):17-21.</p><p>Nissenson A.R., Goodnough L.T., Dubois R.W. Anemia: not just an innocent bystander? Arch Intern Med 2003;163:1400-4.</p><p>Левина А.А., Казюкова Т.В., Цветаева Н.В. и др. Гепсидин как регулятор гомеостаза железа. Педиатрия 2008;8(1):67-75.</p><p>Andrews N.C. Anemia of inflammation: the cytokine-hepcidin link. J Clin Invest 2004;113:1251-3.</p><p>Ganz T. Hepcidin in iron metabolism. Curr Opin Hematol 2004;11(4):251-4.</p><p>Pigeon C., Ilyin G., Courselaud B. et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 2001;7811 -9.</p><p>Nicolas G., Chauvet C., Viatte L. et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002;(110):1037-44.</p><p>Nemeth E., Valore E.V., Territo M. et al. Hepcidin, a putative mediator of anemia of inflammation, is a type II acutephase protein. Blood 2003;101:2461-3.</p><p>Nemeth E., Rivera S., Gabayan V. et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004;113:1271-6.</p><p>Галушко Е.А. Анемия хронического заболевания. Науч-практич ревматол 2009;3(Прил.):70-8.</p><p>Галушко Е.А., Левина А.А., Муравьев Ю.В. Дифференциальная диагностика характера анемии у больных ревматоидным артритом. Науч-практич ревматол 2003;3:23-6.</p><p>Demirjian S.G., Nurko S. Anemia of chronic kidney disease: when normalcy becomes undesirable. Cleve Clin J Med 2008;75(5):353-6.</p><p>Masson C. Rheumatoid anemia. Joint Bone Spine 2011;78(2):131-7.</p><p>Kim H.R., Kim K.W., Yoon S.Y. et al. Serum pro-hepcidin could reflect disease activity in patients with rheumatoid arthritis. J Korean Med Sci 2010;25(3):348-52.</p><p>Demirag M., Haznedaroglu S.R., Banu S.K. et al. Circulating hepcidin in the crossroads of anemia and inflammation associated with rheumatoid arthritis. Inter Med 2009;48:421-6.</p><p>Jayaranee S., Sthaneshwar P., Sokkalingam S. Serum prohepcidin concentrations in rheumatoid arthritis. Pathology 2009;41(2):178-82.</p><p>Genovese M.C., McKay J.D., Nasonov E.L. et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthr Rheum 2008;58(10):2968-80.</p><p>Насонов Е.Л., Панасюк Е.Ю., Булдаков С.Г. и др. Эффективность и безопасность тоцилизумаба при ревматоидном артрите (промежуточные результаты российского многоцентрового исследования). Науч-практич ревматол 2010;2:21-30.</p></div><br />