Iron deficiency or anemia of inflammation? : Differential diagnosis and mechanisms of anemia of inflammation

Abstract

Iron deficiency and immune activation are the two most frequent causes of anemia, both of which are based on disturbances of iron homeostasis. Iron deficiency anemia results from a reduction of the body's iron content due to blood loss, inadequate dietary iron intake, its malabsorption, or increased iron demand. Immune activation drives a diversion of iron fluxes from the erythropoietic bone marrow, where hemoglobinization takes place, to storage sites, particularly the mononuclear phagocytes system in liver and spleen. This results in iron-limited erythropoiesis and anemia. This review summarizes current diagnostic and pathophysiological concepts of iron deficiency anemia and anemia of inflammation, as well as combined conditions, and provides a brief outlook on novel therapeutic options.

Keywords: Anemia of chronic disease; Anemia of inflammation; Hepcidin; Iron; Macrophage.

Conflict of interest statement

Conflict of interestM. Nairz, I. Theurl, D. Wolf, and G. Weiss declare that they have no competing interests.

Figures

Fig. 1

a Under homeostatic conditions, the absorption of 1–2 mg of iron per day compensates for its loss via desquamation of epithelial cells from skin and mucosal membranes and during menstrual bleeding. The majority of the 20–25 mg of iron required for daily erythropoiesis is provided by the degradation of effete RBC and the iron contained within their Hb (Hemoglobin). Both duodenal iron absorption and iron recycling in spleen and liver are negatively regulated by HAMP (Hepcidin antimicrobial peptide). HAMP is mainly generated by hepatocytes in response to an increase in serum iron or storage iron while erythropoietic activity inhibits HAMP expression via soluble mediators including GDF15 and ERFE. b Following immune activation by pathogen- or damage-associated molecular patterns, the interaction of myeloid cells with T and B lymphocytes results in the generation of pro- and anti-inflammatory cytokines. These divert iron fluxes from the circulation to storage sites by controlling the expression of HAMP, of iron transporters, and of the iron-storage protein FT. Therefore, duodenal iron absorption and macrophage iron recycling are reduced, the serum becomes iron-starved and the erythron lacks sufficient iron for proliferation and hemoglobin synthesis. Therefore, zinc may replace iron as the central heme-cation. Zinc protoporphyrin-IX (not depicted) can be measured to confirm the presence of this mechanism of iron sequestration. In addition to cytokines, other mediators such as auto-antibodies and reactive intermediates can tag mature RBC for degradation or damage them or their precursors, contributing to the hyporegenerative nature of AI. In parallel, renal EPO production is reduced and the responsiveness of the erythron to EPO is dampened. In the end, a mild to moderate normocytic anemia with evidence of iron-restricted erythropoiesis (low TSAT, high FT, low reticulocytes, high ZnPP-IX in reticulocytes, low to normal EPO) occurs. Key pathways for the pathogenesis are in boldface. Putative additional pathways are in lightface. BMP6 bone morphogenetic protein-6, ERFE erythroferrone, EPO erythropoietin, FPN1 ferroportin-1, FT ferritin, GDF15 growth differentiation factor-15, HAMP hepcidin anti-microbial peptide, IL interleukin, KC Kupffer cell, MPS mononuclear phagocyte system, PDGF-BB platelet-derived growth factor isoform BB, RBC red blood cell, RPM red pulp macrophage, Tf-Fe transferrin-bound iron, TNF tumor necrosis factor, ZnPP-IX zinc protoporphyrin-IX

Fig. 2

For the differential diagnosis of IDA vs. AI vs. a combination of both forms or other causes of anemia, a stepwise approach is proposed. A CBC enables the differentiation of isolated anemias from bi- and pancytopenias [161]. The latter may require a more extensive work-up. Also, the RPI can be estimated from the CBC. An RPI of 3 is observed in regenerative forms such as the hemolytic anemias. Two out of three erythrocyte indices are relevant, i. e., the MCV and the MCH, as they allow for the classification of microcytic hypochromic, normocytic normochromic, and makrocytic hyperchromic anemias. In IDA, both serum FT and TSAT are reduced. In contrast, an increased FT is typical of AI. In combined conditions, the FTI, as calculated from the serum TFR divided by the logarithmic serum FT, continues to be helpful for the differential diagnosis. In the future, novel parameters such as HAMP may be incorporated into diagnostic algorithms. Note: Reference ranges may vary between countries, laboratories, and assays. Hb cutoffs correspond to WHO definitions. AI anemia of inflammation, BM bone marrow, CBC complete blood count, DD differential diagnosis, EPO erythropoietin, GFR glomerular filtration rate, FACS fluorescence activated cell sorting, FT ferritin, FTI ferritin index, Hb hemoglobin, Hx history, IDA iron-deficiency anemia, LDH lactate dehydrogenase, MCH mean corpuscular hemoglobin, MCV mean corpuscular volume, MDS myelodysplastic syndrome, PNH paroxysmal nocturnal hemoglobinuria, RPI reticulocyte production index, sTFR soluble transferrin receptor, TSAT transferrin saturation