Pathobiochemical Mechanisms Relating Iron Homeostasis with Parameters of Inflammatory Activity and Autoimmune Disorders in Rheumatoid Arthritis

Open access


Aim: To find the correlations between the parameters of iron homeostasis, inflammatory activity and autoimmune disorders in rheumatoid arthritis (RA).

Materials and methods: The present study included 114 patients with RA and 42 healthy controls. We determined the parameters of iron homeostasis: serum iron, total iron binding capacity (TIBC), ferritin and soluble transferrin receptor (sTfR), the parameters of inflammatory activity: C-reactive protein (CRP), interleukin-6 (IL-6) and prohepcidin, and the parameters of autoimmune disorders: rheumatoid factor (RF), anti-cyclic citrullinated peptide (antiCCP) antibodies and DAS 28.

Results: The levels of sTfR, CRP, IL-6 and prohepcidin were significantly higher in RA patients than those in the controls and the level of serum iron was significantly lower in RA than that in the control group. Unlike the controls, in RA, there was a significant positive correlation of sTfR with the parameters of inflammatory activity (IL-6, prohepcidin, ESR) and with the parameters of autoimmune disorders (DAS 28, RF, antiCCP). A negative correlation of serum iron with sTfR was found only in RA patients. Prohepcidin positively correlated with the parameters of inflammation (CRP, ESR) and with the parameters for evaluation of autoimmune disorders (DAS 28 and RF) in the RA group.

Conclusion: Our study shows that the simultaneous determination of the two parameters sTfR and prohepcidin is most informative for evaluation of the changes in iron homeostasis in RA. The increase of both parameters provides information for tissue iron deficiency (assessed by the level of sTfR), caused by the inflammation when prohepcidin is expressed.

1. Weiss G. Anemia of chronic disease. N Engl J Med 2005;352(10):1011-23.

2. Weiss G. Iron metabolism in the anemia of chronic disease. Biochim Biophys Acta 2009;1790(7):682-93.

3. Raj DS. Role of interleukin-6 in the anemia of chronic disease. Semin Arthritis Rheum 2009;38(5):382-8.

4. Demirag MD, Haznedaroglu S, Sancak B, et al. Circulating hepcidin in the crossroads of anemia and inflammation associated with rheumatoid arthritis. Intern Med 2009;48(6):421-6.

5. Ganz T. Hepcidin - a regulator of intestinal iron absorption and iron recycling by macrophages. Best Pract Res Cl Ha 2005;18(2):171-82.

6. Benito-Garcia E, Feskanich D, Hu FB, et al. Protein, iron and meat consumption and risk for rheumatoid arthritis: a prospective cohort study. Arthritis Res Ther 2007;9:R16.

7. Telfer JF, Brock JH. Proinflammatory cytokines increase iron uptake into human monocytes and synovial fibroblasts from patients with rheumatoid arthritis. Med Sci Monit 2004;10(4):91-5.

8. Thomas C, Thomas L. Anemia of chronic disease: pathophysiology and laboratory diagnosis. Lab Hematol 2005;11(1):14-23.

9. Wahle M. Anemia in patients with rheumatoid arthritis. Z Rheumatol 2012;71(10):864-8.

10. R’zik S, Beguin Y. Serum soluble transferrin receptor concentration is an accurate estimate of the mass of tissue receptors. Exp Hematol 2001;29(6):677-85.

11. Feelders RA, Kuiper-Kramer EP, van Eijk HG. Structure, function and clinical significance of transferrin receptors. Clin Chem Lab Med 1999;37(1):1-10.

12. Siebert S, Williams BD, Henley R, et al. Single value of serum transferrin receptor is not diagnostic for the absence of iron stores in anaemic patients with rheumatoid arthritis. Clin Lab Haematol 2003;25(3):155-60.

13. Hanif E, Ayyub M, Anwar M, et al. Evaluation of serum transferrin receptor concentration in diagnosing and differentiating iron deficiency anaemia from anaemia of chronic disorders. J Pak Med Assoc 2005;55(1):13-6.

14. Moore C Jr, Ormseth M, Fuchs H. Causes and significance of markedly elevated serum ferritin levels in an academic medical center. J Clin Rheumatol 2013;19(6):324-8.

15. Ichida H, Kawaguchi Y, Sugiura T, et al. Clinical manifestations of adult-onset Still’s disease presenting with erosive arthritis: Association with low levels of ferritin and interleukin-18. Arthritis Care Res (Hoboken) 2014;66(4):642-6.

16. Bari MA, Sutradhar SR, Sarker CN, et al. Assessment of anaemia in patients with rheumatoid arthritis. Mymensingh Med J 2013;22(2):248-54.

17. Pavai S, Jayaranee S, Sargunan S. Soluble transferrin receptor, ferritin and soluble transferrin receptor - ferritin index in assessment of anaemia in rheumatoid arthritis. Med J Malaysia 2007;62(4):303-7.

18. Ravindran V, Jain S, Mathur DS. The differentiation of anaemia in rheumatoid arthritis: parameters of iron-deficiency in an Indian rheumatoid arthritis population. Rheumatol Int 2008;28(6):507-11.

19. Aletaha D, Neogi T, Silman AJ. 2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010;69(9):1580-8.

20. Fransen J, van Riel PLCM. The disease activity score and the EULAR response criteria. Clin Exp Rheumatol 2005;23(39):93-9.

21. Masson C. Rheumatoid anemia. Joint Bone Spine 2011;78(2):131-7.

22. Calisto Pérez C, León R, León F, et al. Rheumatoid arthritis and anemia: the impact of different anti-inflammatory therapies on hemoglobin levels. An observational study. Bol Asoc Med P R 2012;104(2):34-41.

23. Braga F, Infusino I, Dolci A, et al. Soluble transferrin receptor in complicated anemia. Clin Chim Acta 2014;20(431):143-7.

24. Beguin Y. Soluble transferrin receptor for the evaluation of erythropoiesis and iron status. Clin Chim Acta 2003;329(1-2):9-22.

25. Lv F, Song LJ, Li XF. Combined measurement of multiple acute phase reactants to predict relapse of rheumatoid arthritis. Int J Rheum Dis 2015;18(7):725-30.

26. Yildirim K, Karatay S, Melikoglu MA, et al. Associations between acute phase reactant levels and disease activity score (DAS28) in patients with rheumatoid arthritis. Ann Clin Lab Sci 2004;34:423-6.

27. Önder B, Kurtaran A, Kimyon S, et al. Association of anti-CCP positivity with serum ferritin and DAS-28. Rheumatol Int 2009;30(2):223-7.

28. Schmidt PJ, Toran PT, Giannett AM, et al. Transferrin receptor modulates Hfe-dependent regulation of hepsidin expression. Cell Metab 2008;7(3):205-14.

29. Pasricha SR. Is it time for hepcidin to join the diagnostic toolkit for iron deficiency? Expert Rev Hematol 2012;5(2):153-5.

30. Lemos Ados R, Ismael LA, Boato CC, et al. Hepcidin as a biochemical parameter for the assessment of iron deficiency anemia. Rev Assoc Med Bras 2010;56(5):596-9.

31. Kim H, Kim K, Yoon S, et al. Serum pro-hepcidin could reflect disease activity in patients with rheumatoid arthritis. J Korean Med Sci 2010;25:348-52.

32. Koca SS, Isik A, Ustundag B, et al. Serum pro-hepcidin levels in rheumatoid arthritis and systemic lupus erythematosus. Inflammation 2008;31(3):146-53.

33. Jayaranee S, Sthaneshwar P, Sokkalingam S. Serum prohepcidin concentrations in rheumatoid arthritis. Pathology 2009;41(2):178-82.

34. Hashizume M, Mihara M. The roles of interleukin-6 in the pathogenesis of rheumatoid arthritis. Arthritis 2011;2011:765624.

Folia Medica

The Journal of Medical University-Plovdiv

Journal Information

CiteScore 2017: 0.54

SCImago Journal Rank (SJR) 2017: 0.206


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 217 217 11
PDF Downloads 131 131 12