You are on page 1of 4

Journal of Medicine, Radiology, Pathology & Surgery (2015), 1, 13–16

REVIEW ARTICLE

Anemia of chronic disease: A comprehensive review
H. N. Santosh1, Tejavathi Nagaraj1, Arun Sasidaran2
Department of Oral Medicine and Radiology, Sri Rajiv Gandhi Dental College & Hospital, Bengaluru, Karnataka, India, 2Department of General Medicine,
Sri Rajiv Gandhi College of Dental Sciences, Bengaluru, Karnataka, India
1

Keywords
Anemia of chronic disease, chronic
inflammation, hepcidin
Correspondence: 
Dr. H. N. Santosh, Department of Oral
Medicine and Radiology, Sri Rajiv Gandhi
Dental College and Hospital, Cholanagar,
Bengaluru - 560 032, Karnataka, India.
Phone: +91-9448721428,
Email: drhnsantosh29@yahoo.co.in

Abstract
Iron has varied importance in the biological activity of cells. Supraphysiologic levels of
iron are deleterious for cellular survival. Besides, iron also plays a significant role in the
immunologic surveillance. Anemia of chronic disease (ACD) is the anemia that is caused
not due to marrow deficiency of iron, but due to an underlying chronic inflammatory
disease. ACD is caused due to factors, which impede the availability of iron stores in the
body. Identification of the condition requires meticulous hematologic work up. Therapy
for ACD involves manipulating the inflammatory process and the resultant inflammatory
cytokines, which are a major source for inhibition of iron availability.

Received 16 November 2014;
Accepted 20 December 2014
doi: 10.15713/ins.jmrps.4

Introduction

Iron Homeostasis

Anemia of chronic disease (ACD) is defined as anemia
present in chronic infectious and inflammatory conditions or
neoplastic disorders, which is not due to marrow deficiencies
and occurs even though the presence of iron stores and
vitamins is adequate. It is the most common form of anemia
observed next to iron deficiency anemia.[1] The common
conditions associated with ACDs are acute and chronic
infections, cancer, autoimmune disorders, chronic kidney
diseases (CKDs), and chronic inflammatory conditions.
The estimated prevalence of ACD caused due to chronic
inflammation accounts to 23-50%. The condition has thus
been termed “anemia of inflammation.”[2] A number of
different pathways have been presumed to cause ACD like
aversion of iron traffic, reduced erythropoiesis, decreased
response to erythropoietin, erythrophagocytosis and invasion
of bone marrow by tumor cells and pathogens.
ACD is a commonly present, poorly understood condition
that affects patients with a variety of diseases, including chronic
infections, malignancies and rheumatological diseases.[3] It is
characterized by impaired erythropoietin response, diminished
red blood cell (RBC) survival and an impairment in iron
absorption and macrophage iron retention, which hinders iron
delivery to erythroid precursor cells.

Iron is an essential compound for all living beings. It is a co
factor for enzymes in mitochondrial respiration chain, citric
acid cycle and is a binding moiety for oxygen transport by
hemoglobin (Hb) and myoglobin.[4] However on the other
hand, cellular accumulation of iron in supraphhysiologic limits
may be detrimental to survival of cells since iron is also able to
catalyze the formation of highly toxic hydroxyl radicals by Haber
Weiss reaction.[5] Hence, a stable regulation of iron homeostasis
is essential for maintaining cellular functions. Maintenance
of iron homeostasis is exerted at post transcriptional level by
cytoplasmic proteins i.e. iron regulatory proteins (IRP) with iron
responsive elements (IRES). Iron deficiency in cells stimulates
binding affinity of IRP to IRES thus resulting in blockage of
ferritin.[6]
On the contrary, when cells harbor sufficient amounts of
metabolically active iron, the target binding affinity of IRP to
IRES is reduced.
Iron and Immunity
IRP binding affinity to IRES is not only controlled by the need
of iron, but also by labile radicals produced by activated immune
cells.[7] An adequate supply of iron is of prime importance for

Journal of Medicine, Radiology, Pathology & Surgery  ●  Vol. 1:1  ●  Jan-Feb 201513

[18] Until recently there was no indication that hepcidin has additional role in iron metabolism until 2001. Peripheral blood picture shows ACD as normochromic.[11] The etiology of ACD are many and is categorized by an activation of immune cell and response of inflammatory cytokine that blunts erythropoietin production.[12] Inflammatory cytokines induce changes in the pattern of iron distribution.[13] The primary feature of ACD is an accumulation of iron in the reticuloendothelial macrophages despite decreased circulating iron levels. 8 g/dl). Diagnostic parameters to detect ACD Detection of the type of anemia is important to execute a correct treatment plan.[17] ACD and Hepcidin Hepcidin is produced in the liver and detectable in the serum and urine. Apart from being an acute phase protein.[18] The molecular mechanism by which inflammation regulates hepcidin is the Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway. decreases erythropoiesis. and anemia in chronic CKDs.[19] Ligand binding to the IL-6 receptor activates JAK2. The expression of hepcidin increases in response to inflammatory stimuli. 1:1  ●  Jan-Feb 2015 . ferritin also plays a crucial role in iron storage and recycling.[15] Recent research has indicated possible role of hepcidin in functional iron deficiency present in ACD. Patients with ACD usually have a decreased reticulocyte count. The upregulation of hepcidin gene expression is brought about by translocation of phosphorylated STAT3 into the nucleus and binding to the canonical STAT3 binding site in the proximal hepcidin promoter. But on the contrary transferrin levels may remain normal or are decreased in ACD.[24] In iron deficiency anemia.[21] Hepcidin has the ability to reduce the function of ferroportin on duodenal enterocytes and macrophages. thus allowing an influx of bioavailable iron from the duodenal enterocyte cells and tissue iron stores. IL-6/JAK2-STAT3 pathway controls the production of hepcidin.10] Pathophysiology of ACD ACD is a clinical entity. anemia associated with rheumatoid arthritis. low or normal total iron binding capacity.[9. T-cells and B-cells. Pathology & Surgery  ●  Vol.[8] Besides. impaired red cell life span.[22. which is usually characterized by microcytic and hypochromic.[16] Overexpression of hepcidin in mice causes classic features of ACD like hypoferremia and iron retention in macrophages. limited circulating iron levels downregulate the hepcidin synthesis. which is commonly observed in patients with various underlying diseases that includes anemia of chronic infection. Radiology. anemia of cancer. The depleted levels serum transferring in ACD a reflection of the same. duodenal enterocytes and macrophages makes it an important transporter of cellular iron. chronic infection and chronic liver diseases. normocytic anemia that is characteristically mild (Hb level.[3] Thus. many of which require iron for growth and survival. autoimmune disorders. Patients with ACD have low serum iron concentration. Anemia of chronic disease  immune surveillance because of its growth-promoting function of immune cells and its intrusion with cell-mediated effector pathways and cytokine activities. This is done to protect the body against excess total body iron built up and increased distribution of iron into the circulation. Hepcidin is a negative regulator of intestinal iron absorption and macrophage associated iron release. which leads to impaired iron absorption from the gut and exaggerated iron retention. In contrast. and low transferrin saturation and low reticulocyte counts. It has intrinsic antimicrobial activity. a depletion of ferroprotein will stop the transfer of cellular iron into the plasma.[14] It was hypothesized that humans evolved this mechanism to sequester iron as an act of defense against certain invading pathogens. Cellular iron availability controls the differentiation and proliferation of T helper cells. This in turn phosphorylates the transcription factor STAT3. Thus. Hematologic differences between iron deficiency anemia and ACD The levels of transferrin are an indicator of serum iron stores.[20] Presence of ferroportin on the cell surface of hepatocytes. and dysregulated iron homeostasis. Interleukin (IL) 6 acts on the hepatocytes and promotes the release of hepcidin. the transferrin saturation may be even reduced because of the relevant increase in serum concentrations of transferring. Regulation of hepcidin Inflammation due to infection. 9. such as interferon. autoimmune disease and oral cancers stimulates the synthesis of many pro inflammatory cytokines. long-term release of hepcidin causes ACD. a reduced circulating iron is available for Hb synthesis in spite of the presence of adequate or high body iron stores. which is a hallmark of ACD. 14 High serum hepcidin levels decreases the intestinal iron absorption and inhibits iron export from tissue stores into the bloodstream.Santosh. IL-1. monocytes and macrophages. which indicates under production of RBCs. iron deficiency and iron overload can exert certain effects on immune status by varying the proliferation and activation of NK cells. and IL-6 and proinflammatory cytokines which have been shown to induce excess hepcidin production. Hepcidin acts by compounding and initiating the degradation of the only known iron exporter like ferroportin.23] Evaluation of ACD includes determination of whole body iron store status in order to rule out iron-deficiency anemia.5 g/dl) to moderate (Hb level. when mouse studies were published showing that hepatic hepcidin mRNA synthesis was induced by iron loading. It is imperative to differentiate between ACD and iron deficiency anemia keeping in view their pathogenesis and treatment approach.[19] Hepcidin is the key regulatory protein that regulates the iron absorption in intestine and distribution of iron from various body stores including reticuloendothelial macrophage cells.[25] Ferritin is an acute-phase reactant which is commonly increased in chronic inflammation.[26] Journal of Medicine. Thus. et al.

Research should also be directed at finding new hematologic and serologic markers to distinguish ACD from iron deficiency status. The evaluation of the levels of soluble transferrin receptors is helpful to differentiate between patients with only ACD and patients with ACD accompanied by iron deficiency. anti-tumor necrosis factor. along with increased ferritin levels due to immune activation. Administration of anti-IL-6R antibody therapy has shown to substantially lower hepcidin levels. An ideal treatment for ACD is to reduce the underlying chronic disease. and rheumatoid arthritis after correction of anemia.[24] The ratio of concentration of soluble transferrin receptors to the log of the ferritin level may also be helpful in differentiating iron deficiency anemia with ACD. because the inflammatory cytokines negatively affect the transferring receptor expression.[31] Another approach to treat ACD is RNA interference and gene silencing antisense oligonucleotides that target transcription or translation of hepcidin. membrane bound enzymes for redox reactions like hephaestein and new circulating IRPs like hepcidin. A better positive predictive value of iron deficiency is reflected with ferritin level of 30  ng/ml. Hepcidin has emerged as one such molecule which has caught Journal of Medicine. iron chelators and stem cell factors.[28] There is a marked improvement in the quality of life and energy levels in patients of ACD associated with hemodialysis. supraphysiologic levels of iron can be deleterious as it is believed that certain Anemia of chronic disease organisms require iron for their growth and survival. Hence. A hyper immune response compliments the migration of ferritin from the plasma to within the cells. The future of research on this field should strengthen our knowledge about the transmembrane iron transporters like ferroprotein. over supplementation of iron can be detrimental in such cases. the levels of soluble transferrin receptors in ACD are not significantly different from normal. Treatment of ACD Anemia often complicates the underlying chronic diseases. intravenous iron therapy is more effective.[32] Research should be directed toward elucidating how these factors induce the disturbance in iron metabolism under inflammatory conditions. 1:1  ●  Jan-Feb 201515 . but their effectiveness is diminished due to hepcidin mediated iron block in the intestine. Future Course There has been an active research in the field of hematology pertaining to ACDs in the past few decades. It is considered a predictor of poor prognosis of the disease.[34] Conclusion ACD is quite distinct due to the fact that it is caused not due to deficiency.[30] A number of new strategies like direct hepcidin antagonists.[29] Present therapeutic management of ACD involves increasing Hb levels by blood transfusions or iron administration. natural resistance-associated macrophage protein 1. without causing the adverse risks from supraphysiologic iron supplementation. Hence.  Besides its function as an iron storage protein. Recent Advances in Treatment of ACD The recent advances in treatment of ACD targets the hepcidin – ferroprotein axis.[1] In contrast. the treatment changes according to the underlying systemic disease. Although oral iron tablets are easily available and are of low cost. ferritin plays an important role in macrophages where it recycles iron from old RBCs and transfers it to apoferritin. whereas a ratio of more than 2 suggests absolute iron deficiency coexisting with ACD. The levels of soluble transferrin receptor are increased in iron deficiency. this is not possible for many ACD patients. It is a known fact that IL6 promote the production of hepcidin. research should also be targeted at therapeutic options to interfere with hematological and immunological network in ACD. Anti-hepcidin monoclonal antibodies are direct hepcidin antagonists. However. however. It has to be supported with appropriate therapy. et al. Pharmacologic agents that reduce hepcidin production and increase ferroportin activity would improve iron bioavailability from the diet and would mobilize existing body iron stores for erythropoiesis. Such agents are cytokine inhibitors. but due to factors impeding the availability of iron. Ferritin is considered as a marker of iron storage.[29] However. when the availability of iron for erythropoiesis is low. zinc protoporphyrin IX and possibly hepcidin. there is increased storage and retention of iron within the reticulo endothelial system. This happens in order to counter the binding of the infective agent that attempts to combine with iron from the host tissue.[30] Due to the functional iron deficiency in ACD. Inflammation is one such impeding factor causing ACD. ACD with CKD involves improving the erythropoietin levels by administration of epoetin alpha. so that iron is not available to the infective agent.Santosh. decrease C-reactive protein levels within 1  week and improve other hematological parameters over a treatment period of 4 weeks. A level of 15  ng/ml is generally indicative of absent iron stores. IL6 inhibitors have known to inhibit hepcidin production. The iron in transferrin is transported to immature RBCs in the bone marrow in order to complete the cycle. divalent metal transporter 1. Hence. Pathology & Surgery  ●  Vol. hormones like testosterone. cancer.[27] Ferritin plays a crucial role in host immune response. Radiology.[33] Parameters that are under investigation are soluble transferrin receptor. Mere removal or reduction of inflammation may not correct the anemic status. iron supplementation is frequently administered either alone or in combination with erythropoietin stimulating agents. hepcidin production inhibitor or ferroportin agonists/stabilizers are currently under investigation. A ratio of <1 suggests ACD. In patients with ACD. This is evident from increased concentration of ferritin during chronic infectious diseases. Concomitant to these.

306:183-98. Zarychanski R. J  Biol Chem 2001. A  specific mRNA binding factor regulates the iron-dependent stability of cytoplasmic transferrin receptor mRNA. et al.16:87-96. 14. Beutler E. 33. Int J Hematol 1999. Szczech L.37:1768‑73. 18. Barnhart H. 26. Weiss G. et al. inflammation and neoplasia. Correction of anemia with epoetin alfa in chronic kidney disease. Journal of Medicine. Iron in infection. 5.139:138‑47. Goldberg MA. Petrak J.36:3-6. How to cite this article: Santosh HN. et al. 17. Am J Clin Pathol 2001. Hepcidin and the anemia of chronic disease. Galy B. Fabian TC. Nemeth E. 12. Two to tango: Regulation of Mammalian iron metabolism. 6. Mohan C. J Clin Invest 2004. J  Nutr 2004. Jurado RL. Nagaraj T. Philadelphia: WB Saunders Co. In: Iron Metabolism in Health and Disease.334:619-23. Locke A. Kushner I. Sasidaran A. 25.18:2569-78. Different regulatory elements are required for response of hepcidin to interleukin-6 and bone morphogenetic proteins 4 and 9. free radicals. Trends in anemia treatment with erythropoietin usage and patient outcomes. The acute phase response and the hematopoietic system: The role of cytokines.70:7-12. 29. Vaughn MB.50:49-56. 10. Afzali B. 13. Schneider TJ. Medappa N. Cell 2010. 7. et al. Int J Biochem Cell Biol 2005. Tang KL. Rosbash DO. Means RT Jr. 34.16:495‑500. Hepcidin – A peptide hormone at the interface of innate immunity and iron metabolism.306:2090-3. 28. Ann Clin Lab Sci 2006. Pathogenesis and treatment of anaemia of chronic disease. N Engl J Med 2007. Hepcidin: A  direct link between iron metabolism and immunity. Anemia of inflammation: The cytokine-hepcidin link. 22.11:527-42. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.2:116-21. a key regulator of iron metabolism and mediator of anemia of inflammation. De Domenico I. Arthritis Res Ther 2012. 16 Santosh. Anemia of chronic disease: A harmful disorder or an adaptive. Recombinant erythropoietin for the treatment of anemia in inflammatory bowel disease. 32. Muckenthaler MU. et al. Hepcidin.. beneficial response? CMAJ 2008. Iron. N Engl J Med 2006. Blood 1992. Ganz T. Radiology. Hentze MW. May A. et al. References 1. Anemia of chronic disease: A comprehensive review. 30. Collins AJ. The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Urban JE. 15.113:1251-3. Waring AJ. yet intriguing disease called ACD. Hepcidin. 23.102:783-8.30:1-7.13:151-62. Means RT Jr. Valberg LS. Weiss G. Ma JZ. Tuttle MS. Goldsmith DJ. Finch CA. Crit Rev Oncol Hematol 1995. N Engl J Med 1982. Müllner EW. Houston DS. Heard S. 8. Am J Kidney Dis 1998. and anemia of inflammation. Immunol Today 1995. Ltd. Iron absorption and its implications on strategies to control iron deficiency anaemia. immunity. Linkage of cell-mediated immunity to iron metabolism. Gettinger A. Plasma ferritin concentrations: Their clinical significance and relevance to patient care. Xia A. Main ER.306:1520-8. Corwin HL. Haurani FI. Curr Hematol Rep 2003. Sundquist WI.Anemia of chronic disease  the attention of researchers. Sapp S. Brock JH. Strategies for the laboratory diagnosis of some common causes of anaemia in elderly patients. 19.355:2085-98. 27. Kühn LC. Truksa J. 1994. Can Med Assoc J 1980. Efficacy and safety of epoetin alfa in critically ill patients. Ganz T. Vyoral D.357:965-76.115:112-8. Keffer JH. Han J. Cell 1989.134:3171S-2S. Kroft SH. Blood Rev 2002. 21. Xie C. and oxidative injury. Park CH. Effect of inflammatory cytokines on hypoxia-induced erythropoietin production. Inflammation associated anemia and ferritin as disease markers in SLE.142:24-38. Lee P. Joosten E. Bauditz J. Blood 2003. Ganz T. Powelson J. Schnoor M. Br J Haematol 2007. Recent developments in the anemia of chronic disease. The anaemia of infection. Science 2004. Vaughn MB. Discriminating between iron deficiency anemia and anemia of chronic disease using traditional indices of iron status vs transferrin receptor concentration. a urinary antimicrobial peptide synthesized in the liver. Curr Top Microbiol Immunol 2006. Neupert B. 3. Schreiber S. Pathology & Surgery  ●  Vol. Wachter H. 1:1  ●  Jan-Feb 2015 . Andrews NC. Valore EV. Ward DM.276:7806-10. Gasché C. Singh AK. Howaldt S. Pearl RG. infections. Langelier C. Baillieres Best Pract Res Clin Haematol 2000. 31. 11. Wu T. 20. Mol Biol Cell 2007. 16. Clin Infect Dis 1997.14:R182. Huebers H. N Engl J Med 1996.179:333-7. Peng H. 9. Trey JE.25:888-95.79:1987-94. McCord JM. Intravenous iron therapy in renal failure: Friend and foe? J Nephrol 2004. Perspectives in iron metabolism. 2. Wolfson M. Donovan A. Nemeth E.32:S133-41. J Med Radiol Pathol Surg 2015.21:1-18. Ebben J. Fuchs D. Indian Councs Med Res Bull 2000. 353-89. Faquin WC. J Clin Invest 1932.1:13-16. Nikolaus S. The copper and nonhemoglobinous iron contents of the blood serum in disease. Means RT Jr. 24. Wians FH Jr.122:1240-8. 4. Vanarsa K. Further evaluation of this acute phase protein along with other hematologic parameters will throw light on this common. p. Ye Y.17:487-95. Gerontology 2004. Ward DM.58:373-82. Advances in the anemia of chronic disease. Iron. Camaschella C.