Anemia of Chronic Disease: Key Mechanisms of Pathogenesis in Patients with Malignancies and Feasible Classification Approaches

VT Sakhin1, ER Madzhanova1, EV Kryukov3, AV Sotnikov2, AV Gordienko2, OA Rukavitsyn3

1 1586 Military Clinical Hospital, 4 Mashtakova str., Moscow Region, Podolsk, Russian Federation, 142110

2 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

3 NN Burdenko Central Military Clinical Hospital, 3 Gospital’naya sq., Moscow, Russian Federation, 105229

For correspondence: Valerii Timofeevich Sakhin, MD, PhD, 4 Mashtakova str., Moscow Region, Podolsk, Russian Federation, 142110; Tel.: +7(916)314-31-11; e-mail:

For citation: Sakhin VT, Madzhanova ER, Kryukov EV, et al. Anemia of Chronic Disease: Key Mechanisms of Pathogenesis in Patients with Malignancies and Feasible Classification Approaches. Clinical oncohematology. 2019;12(3):344–9 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-344-349


Aim. To study the effect of hepcidin, soluble transferrin receptor (sTfR), and cytokines on iron metabolism and occurrence of anemia in patients with malignancies and to propose, on this basis, a draft classification of anemia of chronic disease (ACD) based on the major pathogenic factor.

Materials & Methods. The trial included 63 patients with malignancies of stage II/IV: 41 patients with anemia (34 men, 7 women, mean age 67.1 ± 9.9 years), 22 patients without anemia (17 men, 5 women, mean age 60.2 ± 14.9 years). Comparative analysis was based on the values of iron metabolism, C-reactive protein (CRP), hepcidin, sTfR, as well as pro-inflammatory (interleukin-6 [IL-6], tumour necrosis factor α [TNF-α]) and anti-inflammatory (IL-10) cytokines in solid malignancy patients with and without anemia. The correlation analysis between IL-6, IL-10, TNF-α, hepcidin, sTfR, and blood count was performed.

Results. Compared with the control group patients with anemia show lower levels of iron concentration, total iron-binding capacity (TIBC), and percent transferrin saturation (TSAT), as well as higher level of CRP, hepcidin, sTfR, IL-6, IL-10, and TNF-α (< 0.05). IL-6 (r = –0.58), TNF-α (r = –0.32), and hepcidin (r = –0.57) proved to negatively affect erythrocyte level. A negative correlation was established between hemoglobin concentration and IL-6 (r = –0.57), IL-10 (r = –0.64), TNF-α (r = –0.65), hepcidin (r = –0.3), and sTfR (r = –0.57). A correlation was identified between concentrations of hepcidin and IL-6 (r = 0.58), IL-10 (r = 0.33), TNF-α (r = –0.4), as well as between concentrations of sTfR and IL-10 (r = 0.58), TNF-α (r = –0.53). A relationship was identified between IL-6 concentration and iron status (r = –0.38), TIBC (r = –0.56), TSAT (r = –0.31), ferritin (r = 0.56), transferrin (r = –0.72), CRP (r = 0.86) as well as between concentrations of IL-10 and iron (r = –0.63), TSAT (r = –0.67), transferrin (r = –0.7), ferritin (r = 0.55), CRP (r = 0.65), TIBC (r = –0.71). A correlation between the levels of TNF-α and TIBC (r = –0.36), transferrin (r = –0.5) was confirmed.

Conclusion. The paper deals with multi-factorial pathogenesis of anemia in patients with malignancies. Most important factors are iron deficiency and erythropoietic disorder. A draft ACD classification based on the major pathogenic factor of anemia (ACD with dominating iron deficiency, ACD with impaired regulatory mechanism of erythropoiesis, and ACD with insufficient erythropoietin production) is proposed.

Keywords: cancer, anemia, iron metabolism, interleukin-6, interleukin-10, tumor necrosis factor alpha, hepcidin, soluble transferrin receptor.

Received: January 21, 2019

Accepted: June 18, 2019

Read in PDF 


  1. Weiss G. Pathogenesis and treatment of anaemia of chronic disease. Blood Rev. 2002;16(2):87–96. doi: 10.1054/blre.2002.0193.

  2. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352(10):1011–23. doi: 10.1056/nejmra041809.

  3. Means RT. Recent developments in the anemia of chronic disease. Curr Hematol Rep. 2003;2(2):116–21.

  4. Poggiali E, De Amicis MM, Motta I, et al. Anemia of chronic disease: a unique defect of iron recycling for many different chronic diseases. Eur J Int Med. 2014;25(1):12–17. doi: 10.1016/j.ejim.2013.07.011.

  5. Weiss G. Iron metabolism in the anemia of chronic disease. Biochim Biophys Acta. 2009;1790(7):682–93. doi: 10.1016/j.bbagen.2008.08.006.

  6. Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta. 2012;1823(9):1434–43. doi: 10.1016/j.bbamcr.2012.01.014.

  7. McCranor BJ, Kim MJ, Cruz NM, et al. Interleukin-6 directly impairs the erythroid development of human TF-1 erythroleukemic cells. Blood Cells Mol Dis. 2014;52(2–3):126–33. doi: 10.1016/j.bcmd.2013.09.004.

  8. Анемии. Под ред. О.А. Рукавицына. 2-е изд., перераб. и доп. М.: ГЭОТАР-Медиа, 2016. 256 c.

    [Rukavitsyn OA, ed. (Anemias.) 2nd revised edition. Moscow: GEOTAR-Media Publ.; 2016. 256 p. (In Russ)]

  9. Сахин В.Т., Маджанова Е.Р., Крюков Е.В. и др. Анемия хронических заболеваний: особенности патогенеза и возможности терапевтической коррекции (обзор литературы и результаты собственных исследований). Онкогематология. 2018;13(1):45–53. doi: 10.17650/1818-8346-2018-13-1-45-53.

    [Sakhin VТ, Madzhanova ЕR, Kryukov EV, et al. Anemia of chronic disease: features of pathogenesis and possible therapeutic correction (literature review and results of own research). Oncohematology. 2018;13(1):45–53. doi: 10.17650/1818-8346-2018-13-1-45-53. (In Russ)]

  10. Steinmetz T, Totzke U, Schweigert M, et al. A prospective observational study of anaemia management in cancer patients–results from the German Cancer Anaemia Registry. Eur J Cancer Care. 2011;20(4):493–502. doi: 10.1111/j.1365-2354.2010.01230.x.

  11. Waters JS, O’Brien MER, Ashley S. Management of anemia in patients receiving chemotherapy. J Clin Oncol. 2002;20(2):601–3. doi: 10.1200/JCO.2002.20.2.601.

  12. Grotto HZ. Anaemia of cancer: an overview of mechanisms involved in its pathogenesis. Med Oncol. 2008;25(1):12–21. doi: 1007/s12032-007-9000-8.

  13. Гематология: национальное руководство. Под ред. О.А. Рукавицына. М.: ГЭОТАР-Медиа, 2015. С. 143–9.

    [Rukavitsyn OA, ed. Gematologiya: natsional’noe rukovodstvo. (Hematology: national guidelines.) Moscow: GEOTAR-Media Publ.; 2015. pp. 143–9. (In Russ)]

  14. Steinmetz HT, Tsamaloukas A, Schmitz S, et al. A new concept for the differential diagnosis and therapy of anaemia in cancer patients. Support Care Cancer. 2010;19(2):261–9. doi: 10.1007/s00520-010-0812-2.

  15. Maccio A, Madeddu C, Massa D, et al. Hemoglobin levels correlate with interleukin-6 levels in patients with advanced untreated epithelial ovarian cancer: role of inflammation in cancer-related anemia. 2005;106(1):362–7. doi: 10.1182/blood-2005-01-0160.

  16. Сахин В.Т., Маджанова Е.Р., Крюков Е.В. и др. Патогенетические особенности анемии у больных с солидными опухолями. Клиническая онкогематология. 2017;10(4):514–8. doi: 10.21320/2500-2139-2017-10-4-514-518.

    [Sakhin VT, Madzhanova ER, Kryukov EV, et al. Pathogenetic Characteristics of Anemia in Patients with Solid Tumors. Clinical oncohematology. 2017;10(4):514–8. doi: 10.21320/2500-2139-2017-10-4-514-518. (In Russ)]

  17. Park S, Jung CW, Kim K, et al. Iron deficient erythropoiesis might play key role in development of anemia in cancer patients. Oncotarget. 2015;6(40):42803–12. doi: 10.18632/oncotarget.5658.

  18. Speeckaert MM, Speeckaert R, Delanghe JR. Biological and clinical aspects of soluble transferrin receptor. Crit Rev Clin Lab Sci. 2010;47(5–6):213–28. doi: 10.3109/10408363.2010.550461.

  19. Moldawer LL, Marano MA, Wei H, et al. Cachectin/tumor necrosis factor-alpha alters red blood cell kinetics and induces anemia in vivo. FASEB J. 1989;3(5):1637–43.

  20. Raj DSC. Role of interleukin-6 in the anemia of chronic disease. Sem Arthritis Rheum. 2009;38(5):382–8. doi: 10.1016/j.semarthrit.2008.01.006.

  21. Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood. 2006;108(9):3204–9. doi: 10.1182/blood-2006-06-027631.

  22. Huang P, Wang J, Lin X, et al. Effects of IL-10 on iron metabolism in LPS-induced inflammatory mice via modulating hepcidin expression. Eur Rev MedPharmacol Sci. 2017;21(15):3469–75.

  23. Shanmugam NKN, Ellenbogen S, Trebicka E, et al. Tumor necrosis factor α inhibits expression of the iron regulating hormone hepcidin in murine models of innate colitis. PLoS One. 2012;7(5):e38136. doi: 10.1371/journal.pone.0038136.

  24. De Lurdes Cabrita AA, Pinho A, Malho A, et al. Risk factors for high erythropoiesis stimulating agent resistance index in pre-dialysis chronic kidney disease patients, stages 4 and 5. Int Urol Nephrol. 2011;43(3):835–40. doi: 10.1007/s11255-010-9805-9.

  25. Nazemian F, Karimi G, Moatamedi M, et al. Effect of silymarin administration on TNFalpha serum concentration in peritoneal dialysis patients. Phytother Res. 2010;24(11):1654–7. doi: 10.1002/ptr.3175.