Acasa > Reviste de specialitate > Oncolog-Hematolog.ro > Deficitul de fier şi cancerul – implicaţii clinice
REVIEW

Deficitul de fier şi cancerul – implicaţii clinice

 Iron deficiency and cancer – clinical implications

Andreea-Daniela Gheorghe, Andra-Iulia Suceveanu, Adrian-Paul Suceveanu, Doina Tofolean, Prof. Dr. Laura Mazilu

First published: 27 martie 2019

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/OnHe.46.1.2019.2307

Abstract

Anemia is a frequent complication in oncologic patients, being encountered both at the moment of cancer diagnosis and during different oncologic therapies. The presence of anemia, regardless of the cause or mechanism, in oncologic patients adversely affects the quality of life, the outcome of the neoplastic disease and the adherence to treatment. The mechanisms involved in the appearance of anemia in oncologic patients are intricated. Iron deficiency is a frequent cause of anemia in oncologic patients. This de­fi­cien­cy is noticed in approximately 50% of patients with solid and hematological tumors. In oncologic patients, the pre­va­lent mechanism for iron deficiency is the functional mechanism. In this case, the iron stores are reduced due to the underlying oncologic condition or due to inflammatory processes associated to cancer treatments. Iron deficiency in cancer patients is often underestimated, mainly due to the difficulty of defining iron deficiency on the basis of usual laboratory markers. The current therapeutic options of cancer anemia include blood transfusions, iron substitution and erythropoietin-stimulating agents. 

Keywords
cancer anemia, iron deficiency, anemia treatment

Rezumat

Anemia este o complicaţie frecventă la pacienţii oncologici, fiind întâlnită atât la momentul diagnosticului, cât şi în cursul terapiilor oncologice. Prezenţa anemiei, indiferent de cau­ză, la pacienţii oncologici are un impact negativ asupra ca­li­tă­ţii vieţii, a prognosticului bolii şi a aderenţei la tratament. Me­ca­nis­mele de producere a anemiei la pacienţii oncologici sunt multiple, putând fi determinată de malabsorbţie şi mal­nu­tri­ţie, sângerare acută sau cronică, inflamaţie sistemică, in­fil­tra­re metastatică a măduvei osoase şi de mielosupresie se­cun­da­ră tratamentului. Deficitul de fier la pacienţii cu can­cer este una dintre cele mai frecvente cauze de anemie. Este în­tâl­nit la aproape jumătate din pacienţii cu tumori solide şi he­ma­to­lo­gice. La pacienţii cu boală oncologică, mecanismul pre­do­mi­nant al deficitului de fier este cel funcţional, disponibilitatea fie­ru­lui fiind redusă din cauza bolii sau a proceselor inflamatorii le­ga­te de terapie. Deficitul de fier la pacienţii cu cancer ră­mâ­ne adesea subevaluat, în mare parte din cauza dificultăţii de­fi­ni­rii acestuia pe baza markerilor de laborator uzuali. Op­ţiu­ni­le terapeutice actuale ale anemiei din cancer includ trans­fu­zii­le de sânge, substituţia cu fier şi agenţii de stimulare a eri­tro­po­ie­ti­nei.

Cuvinte cheie
anemia în cancer deficit de fier terapia anemiei

Introduction

Anemia is a frequent complication in cancer patients, both with solid and haematological tumors, and negatively influences the quality of life, the performance status and the prognosis of these patients. It is important to recognise this condition rapidly and to manage and treat it, and consequently to improve the quality of life, the tolerability and adherence to cito­toxic treatment and the response to oncologic treat­ments.

The data available show that the frequency of anemia in cancer patients is very high. A study in Europe in the early 2000’s, with a total of 15,000 patients diagnosed with solid and haematological malignancies, showed an anemia prevalence at the study entry of 39%, and in the follow-up period of the study anemia was found in 67% of the assessed patients(1). The increased incidence of anemia in oncologic patients is associated with the type of oncologic disease, the advanced stage of the disease and previous treatments. As for the type of disease, anemia is more common in haematological diseases compared to solid tumors. In solid neoplasia, anemia is commonly associated with bronchopulmonary, breast, gastrointestinal and gyne­cological cancers(2,3).

1. Mechanisms involved in anemia and iron deficiency in oncologic patients

The mechanisms involved in the occurrence of anemia in cancer patients are multiple and complicated, with several mechanisms responsible for anemia occurring at the same time or at different times(4).

By reviewing the most important mechanisms of anemia, these may be acute or chronic bleeding, commonly found in gynecological tumors and digestive tract. The nutritional deficiencies of iron, vitamin B12 and folate, determined by malnutrition or malabsorption, are other common causes of anemia in these patients. Bone marrow infiltration by metastatic disease is frequently found in patients with anemia and breast or prostate cancer. Other causes in patients with neoplastic disease is the decline in the production of endogenous erythropoietin, seen in patients with cancer and associated chronic renal disease, or due to decreased response to bone marrow erythropoietin(2,5,6).

In terms of iron deficiency, it is classified into two types – absolute and functional. Absolute deficiency appears when the iron storage are low and depleted. Functional deficiency is present when iron reserve is normal or increased, but the disponibility of iron for erythropoiesis is low due to inflammatory processes that cause iron blocking in macrophages and enterocytes.

In oncologic patients, the predominant deficiency is the functional type, and data from literature show that functional iron deficiency is present in aproximately 50% of cancer patients(7).

The mechanism of functional iron deficiency in cancer patients is well known. Iron is taken by the transferrin from duodenal enterocytes or macro­phages that recycle the iron from aging erythrocytes and it is transported to the bone marrow(8). These mechanisms are controlled by hepcidin, which is an amino acid produced in the liver by peptic hepcidin anti-microbial genes at chromosome 19, in the pre­sence of cancer or chemotherapy-induced inflam­mation. Hepicidin has the role of maintaining iron homeostasis(9). Hepcidin block the release of iron from the macrophages in the bone marrow by blocking ferroportin, which has the role to transfer the iron from the gastric mucosa to the transferrin. The functional deficiency of iron occurs following the release of cytokines, especially inter­leukin-6, in the presence of inflammation, which results in hepcidin production increased in the liver. High levels of hepcidin are found in many types of hematological and solid cancers. Low levels of hepcidin have been observed in patients with hepatic metastases(10-13).

2. Evaluation of patients with anemia and iron deficiency

Iron deficiency in cancer patients is a common state. But it is very difficult to recognize it. As shown in trials, the incidence of iron deficiency in cancer patients is about 42%(1). Evaluating the profile of patients with iron deficiency, data available from studies show that patients with tumors of the colon, rectum, pancreas and pulmonary syndrome have a very frequent iron deficiency. Also, patients with advanced disease and chemotherapeutic treatment have iron deficiency. It may be present even in the absence of anemia, it can influence the performance status of patients and may cause fatigue, an important and frequent sign(1,2).

In healthy people, ferritin values show the status of iron stores. Other parameters, such as transferrin saturation, the percentage of hypochromic erythrocytes, the soluble transferrin receptor and the reticulocyte hemoglobin content, show the amount of iron that is biologically available. All these markers are modified in cancer patients. Particularly ferritin, which is an acute phase protein, may not properly reflect iron deposits in cancer patients who have an inflammatory status. Transferrin saturation assessment is recommended, but it has also limitations in cancer patients, because of the presence of inflammation or malnutrition that causes transferrin levels to be reduced, so normal or elevated false values may occur(14,15).

The measurement of circulating hepcidin levels appears to be a useful tool in the diagnosis of iron deficiency in these patients, but is still under evaluation(16).

Conclusion

Iron deficiency in cancer patients is an important issue, with an impact on the patients’ quality of life, on adherence to oncologic therapies and ultimately on the prognosis of these patients. Moreover, the functional iron deficiency is difficult to diagnose and often remains unnoticed and consequently untreated. It is therefore important to evaluate in details the iron profile of the patients, in order to highlight the presence of iron deficiency. Additional studies are also needed to evaluate more precisely the biomarkers that can be used in the diagnosis of iron deficiency, especially the functional deficiency.  

Conflict of interests: The authors declare no conflict of interests.

Bibliografie

  1. Ludwig H, Van Belle S, Barrett-Lee P, Birgegard G, Bokemeyer C, Gascon P, Kosmidis P, Krzakowski M, Nortier J, Olmi P, et al. The European cancer anaemia survey (ECAS): A large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur. J. Cancer. 2004; 40:2293–2306. 
  2. Busti F, Marchi G, Ugolini S, Castagna A, Girelli D. Anemia and Iron Deficiency in Cancer Patients: Role of Iron Replacement Therapy. Pharmaceuticals (Basel, Switzerland). 2018; 11(4), 94. 
  3. Grotto HZ. Anaemia of cancer: An overview of mechanisms involved in its pathogenesis. Med. Oncol. 2008; 25:12–21. 
  4. Gaspar BL, Sharma P, Das R. Anemia in malignancies: Pathogenetic and diagnostic considerations. Hematology. 2015; 20:18–25. 
  5. Gilreath JA, Stenehjem DD, Rodgers GM. Diagnosis and treatment of cancer-related anemia. Am. J. Hematol. 2014; 89: 203–212. 
  6. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005; 352(10): 1011–1023.
  7. Ludwig H, Evstatiev R, Kornek G, Aapro M, Bauernhofer T, Buxhofer-Ausch V. Iron metabolism and iron supplementation in cancer patients. Wien Klin Wochenschr. 2015; 127(23/24):907–919.
  8. Girelli D, Nemeth E, Swinkels DW. Hepcidin in the diagnosis of iron disorders. Blood. 2016; 127: 2809-2813.
  9. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003; 102: 783-788. 
  10. Kali A, Charles MV, Seetharam RS. Hepcidin – a novel biomarker with changing trends. Pharmacogn Rev. 2015; 9: 35-40.
  11. Orlandi R, De Bortoli M, Ciniselli CM, et al. Hepcidin and ferritin blood level as noninvasive tools for predicting breast cancer. Ann Oncol. 2014; 25: 352-357. 
  12. Tanno T, Rabel A, Alleyne M, et al. Hepcidin, anaemia, and prostate cancer. BJU Int. 2011; 107: 678-679.
  13. Wang J, Pantopoulos K. Regulation of cellular iron metabolism. Biochem J. 2011; 434(3):365–381.
  14. National Comprehensive Cancer Network (accessed on 27 August 2018). Available online: http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf.
  15. Aapro M, Beguin Y, Bokemeyer C, Dicato M, Gascon P, Glaspy J, Hofmann A, Link H, Littlewood T, Ludwig H, et al. Management of anaemia and iron deficiency in patients with cancer: Esmo clinical practice guidelines. Ann. Oncol. 2018 Oct 1; 29(Supplement_4):iv96-iv110.
  16. Shu T, Jing C, Lv Z, Xie Y, Xu J, Wu J. Hepcidin in tumor-related iron deficiency anemia and tumor-related anemia of chronic disease: Pathogenic mechanisms and diagnosis. Eur. J. Haematol. 2015; 94:67–73.

Articole din ediţiile anterioare

HEMATOLOGY | Ediţia 3 60 / 2022

Iron deficiency anemia – clinical onset of an occult celiac disease

Alexandra Maria Baciu, Adrian Roşca, Cristina-Stela Căpuşă, Iuliana Iordan, Ana Maria Prof. Dr. Vlădăreanu

Anemia este o problemă comună în practica clinică de zi cu zi. Anemia poate fi singura expresie a unei boli celiace subclinice. Deficitul de fier e...

21 octombrie 2022