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: SahinVT@yandex.ru

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


ABSTRACT

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

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Pathogenetic Characteristics of Anemia in Patients with Solid Tumors

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

11586 Military Clinical Hospital, 4 Mashtakova str., Podolsk, Russian Federation, 142110

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

3NN Burdenko Main Military Clinical Hospital, 3 Gospitalnaya sq., Moscow, Russian Federation, 105229

For correspondence: Valery Timofeevich Sakhin, PhD, 4 Mashtakova str., Podolsk, Russia, 142110; Tel.: +7(916)314-31-11; e-mail: SahinVT@yandex.ru

For citation: Sakhin VT, Madzhanova ER, Kryukov EV, et al. Pathogenetic Characteristics of Anemia in Patients with Solid Tumors. Clinical oncohematology. 2017;10(4):514–8 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-514-518


ABSTRACT

Aim. To study the impact iron metabolism disturbances and cytokine levels on the development of anemia in patients with solid tumors.

Materials & Methods. The research included 42 patients with malignant neoplasms, including 24 patients with anemia (19 men and 5 women, median age 67.7 ± 10 years) and 18 patients without anemia (15 men, 3 women, median age 65.7 ± 14 years). Anemia was diagnosed according to the WHO criteria (in men: erythrocytes < 4.0 × 1012/L, hemoglobin < 130 g/L, hematocrit < 39 %; in women: erythrocytes < 3.8 × 1012/L, hemoglobin < 120 g/L, hematocrit < 36 %).

Results. A comparative analysis of iron metabolism in patients with and without anemia was performed. The lower values of serum iron and transferrin saturation in patients with anemia were shown (< 0.05). The total iron-binding capacity, the levels of ferritin, transferrin, C-reactive protein, indirect bilirubin were similar between groups (> 0,05). Higher levels of interleukins 6 and 10 (IL-6 and IL-10) were observed in patients with anemia (< 0.05). For IL-6, correlations were observed with levels of erythrocytes (r = –0,58), hemoglobin (r = –0,57), hematocrit (r = –0,52), and leukocytes (r = 0,42). The levels of IL-10 slightly correlated with the levels of erythrocytes, leukocytes, platelets, MCV, and MCH (r < 0.3). For IL-10, correlations were established with levels of MCHC (r = –0,71), hemoglobin (r = –0,64) and hematocrit (r = –0,32). Correlations between the levels IL-6, IL-6 and hemoglobin, erythrocytes and several color indices may indicate their influence on the development of anemia in patients with malignant neoplasms.

Conclusion. A functional iron deficiency in patients with anemia was found. Several causes of anemia development and significant role of interleukins in anemia pathogenesis were also discovered.

Keywords: cancer, anemia, iron metabolism, interleukin-6, interleukin-10.

Received: March 21, 2017

Accepted: June 22, 2017

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  4. 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.
  5. Grotto HZ. Anaemia of cancer: an overview of mechanisms involved in its pathogenesis. Med Oncol. 2008;25(1):12–21. doi: 10.1007/s12032-007-9000-8.
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  12. 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. Blood. 2005;106(1):362–7. doi: 10.1182/blood-2005-01-0160.
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Iron Metabolism in Normal and Pathological Conditions

E.A. Lukina, A.V. Dezhenkova

Hematology Research Center under the Ministry of Health of the Russian Federation, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Elena Alekseevna Lukina, DSci, Professor, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-09-23; e-mail: elenalukina02@gmail.com

For citation: Lukina EA, Dezhenkova AV. Iron Metabolism in Normal and Pathological Conditions. Clinical oncohematology. 2015;8(4):355–361 (In Russ).

DOI: 10.21320/2500-2139-2015-8-4-362-367


ABSTRACT

This review describes modern conceptions of the physiological and pathological roles of iron, as well as the main mechanisms of iron metabolism regulation. In recent years, it has been shown that both deficiency and excess of iron can have damaging effects on the body, and the existence of homeostatic mechanisms controlling the total iron content of the body has been proved. The body of an average healthy adult human contains 3 to 5 g iron, most of which is contained in blood cells, bone marrow and liver; it is bound to proteins and this is important for prevention of cytotoxic effects of free iron ions. This review summarizes data on the main proteins involved in iron metabolism and their role in iron homeostasis. The processes of iron recirculation and the functional role of hepcidin, the key protein regulating extracellular iron concentration, are emphasized. The review provides brief data on pathogenic mechanisms of functional iron deficiency development and its role in anemia of chronic disease, as well as the pathogenesis, diagnostics and management of secondary iron overload.


Keywords: iron metabolism, ferritin, hepcidin, iron recirculation, anemia of chronic disease, iron overload.

Received: July 1, 2015

Accepted: November 9, 2015

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  42. Gerhard G, Still Ch, Wood C, et al. Primary hepatic iron overload in extreme obesity is common and not associated with metabolic abnormalities. The abstract book of 5th Congress of the International Bioiron Society; 2013. Podium #58.
  43. Miyanishi K, Tanaka Sh, Kobune M, et al. Increased hepatic oxidative DNA damage in patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. The abstract book of 5th Congress of the International Bioiron Society; 2013. Poster #227.
  44. Kobune M, Kikuchi S, Iyama S, et al. Iron chelation therapy improves oxidative DNA damage in hematopoietic cells derived from transfusion-dependent myelodysplastic syndrome. The abstract book of 5th Congress of the International Bioiron Society; 2013. Poster #93.
  45. Jones E, Allen A, Evans P, et al. Differences in hepcidin regulation distinguish mild and severe phenotypes of e-beta thalassaemia. The abstract book of 5th Congress of the International Bioiron Society; 2013. Podium #27.