P. Brent Ferrell, MD, and Mark J. Koury, MD
Dr. Ferrell indicated no relevant conflicts of interest. Dr. Koury is a consultant with Keryx Biopharmaceuticals, Inc. and the Pharmaceutical Division of Japan Tobacco, Inc.
1. Clinical Fellow, Division of Hematology/Oncology, Vanderbilt University
2. Professor of Medicine, Division of Hematology/Oncology, Vanderbilt University and Veterans Affairs Tennessee Valley Healthcare System
A 64-year-old man had a history of two years of weight loss and mild normocytic anemia, but over the preceding two months, worsening polyarthritis, fatigue, and anemia (Hgb 8.6 g/dL, Hct 25%, MCV 91 fL) were noted. The reticulocyte count was 1.4 percent with a normal WBC and normal platelet count. He had normal serum cobalamin, methylmalonate, LDH, RBC folate, and negative hepatitis serologies. Laboratory tests were consistent with normal renal, thyroid, and liver function. Abnormal laboratory tests included an erythrocyte sedimentation rate of 87 mm/h, serum C-reactive protein (CRP) of 145 mg/L, haptoglobin of 447 mg/dL, and serum albumin of 2.5 g/dL. Iron studies showed a serum iron of 23 ug/dL, TIBC of 209 ug/dL, transferrin saturation of 11 percent, and serum ferritin of 299 ng/mL. He was transfused with two units of packed erythrocytes, begun on low-dose prednisone, and referred for evaluation of anemia.
What is your approach to the diagnosis and management of the anemia of chronic inflammation (ACI)?
The traditional disease categories associated with ACI are malignancy, infection, and connective tissue disorders. When excess cytokine production is a pathologic manifestation, ACI may be associated with such processes as severe heart failure and poorly controlled diabetes that fall outside of the customary listing of chronic inflammatory diseases. ACI is often subtle and insidious in onset, presenting as a mild, persistent anemia that may worsen over time. Causes of the underlying inflammation such as rheumatoid arthritis may be obvious, or the basis of the inflammation may not be immediately apparent as in cases of occult malignancy or chronic infection.
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Multiple mechanisms are responsible for the development of ACI.1-3 Although erythrocytes in ACI have slightly shortened survivals, the following three mechanisms, mediated by inflammatory cytokines, exert major effects in sequential periods of erythropoiesis (Figure): 1) inhibited survival and differentiation of erythroid progenitor cells; 2) suppressed erythropoietin (EPO) production; and 3) hepcidinmediated sequestration of reticuloendothelial iron. Chronic inflammatory states increase production of cytokines such as IL-1, TNF-α, and interferon-γ that directly inhibit the survival and differentiation of erythroid progenitor cells.1,2 Inflammatory cytokines suppress EPO production, decreasing plasma EPO concentration and increasing apoptosis of erythroid cells in the EPO-dependent stages of differentiation (Figure).4 Finally, the inflammatory cytokines IL-6 and members of the bone morphogenetic protein (BMP) family diminish serum iron concentration by inducing transcription of hepcidin, the master regulator of iron homeostasis.3 Hepcidin exerts its effects primarily through interaction with the cellular iron exporter, ferroportin, expressed on the basolateral surface of enterocytes and on reticuloendothelial cells. Binding to hepcidin induces endocytosis and degradation of ferroportin thereby restricting gastrointestinal iron absorption and impairing macrophage export and recycling of iron from phagocytosed senescent erythrocytes. The trapping of iron in reticuloendothelial cells accounts for the characteristic ironladen macrophages observed in ACI bone marrow aspirates stained with Prussian blue. Because iron absorption and iron recycling are impaired, plasma iron concentration is low, and transferrin saturation is often subnormal (as in our case), resulting in a functional iron deficiency state with consequent suboptimal delivery of iron to maturing erythroblasts. Interpretation of transferrin saturation must also take into account the fact that transferrin is a negative acute phase reactant, and as such, the serum concentration is often subnormal or at the lower end of the normal range in patients with ACI (as illustrated in our case).
In most instances, ACI is normocytic, normochromic, but approximately one-third of cases fall into the microcytic, hypochromic morphological classification. In the latter cases, functional iron deficiency as a consequence of excess hepcidin production dominates the pathophysiology, and review of the peripheral blood film reveals features similar to other processes, such as iron deficiency or thalassemia, that affect production of heme or globin. ACI is typically a mild-to-moderate hypoproliferative process manifested as grade I or grade II anemia. If more severe, (grade III or worse, hemoglobin < 8.0 gm/dL), the anemia is likely multifactorial with other processes, such as concurrent gastrointestinal bleeding contributing to the etiology. Blood loss and inflammation may coexist, especially in patients with renal failure on hemodialysis, in patients with gastrointestinal malignancy or inflammation, or in patients with arthritis treated with corticosteroids or non-steroidal antiinflammation drugs. In those cases, determining the relative contributions of absolute iron deficiency and functional iron deficiency can be challenging without performing a bone marrow analysis.
Serum ferritin concentration is less than 20 ng/mL in uncomplicated iron deficiency anemia. Although as an acutephase protein, the ferritin concentration can be driven into the normal range by the underlying inflammatory process, a ferritin concentration greater than 150 ng/mL is rare in ACI patients who have concomitant absolute iron deficiency. As noted above, low serum iron is characteristic of ACI, and low serum transferrin concentration and low transferrin saturation are also observed routinely in ACI.
Transferrin receptor (TfR) expression is regulated post-transcriptionally by intracellular iron concentration through the iron regulatory element (IRE)/IRE binding protein (IREBP) system. When intracellular iron concentration is low, the IRE/IREBP system stabilizes TfR mRNA, thereby increasing translation and protein expression. The effect of intracellular iron concentration on TfR production led to development of a clinical test of iron status. In this case, the concentration of TfR in plasma (soluble TfR or sTfR) serves as a surrogate marker of iron status (i.e., the concentration of sTfR is elevated in absolute iron deficiency). Subsequent studies suggested that the sensitivity of the assay in distinguishing absolute iron deficient states from inflammatory processes that affect iron metabolism can be improved by calculating the sTfR index by dividing the sTfR concentration by the log of the serum ferritin concentration. Another proposed method for identifying iron deficiency is to measure reticulocyte hemoglobin concentration (CHr) by flow cytometry. As the most recently produced 1 percent of erythrocytes in the blood, the reticulocytes are the subpopulation most affected by iron deficiency at the time the blood sample is obtained, and decreased CHr is a sensitive indicator of iron-restricted erythropoiesis.5 Combining CHr with sTfR index has been used to improve the identification of absolute iron deficiency in patients with inflammation.5 While these studies may have value is some particularly problematic cases, their clinical utility is relatively modest. This interpretation is based on the fact that functional iron deficiency plays an important role in the pathophysiology of ACI, and patients with functional iron deficiency, without absolute iron deficiency, may benefit from supplemental iron. Therefore, the practical value of distinguishing functional iron deficiency from absolute iron deficiency is arguable because iron supplementation can be therapeutic in either case.
Although many patients have mild anemia that does not require treatment, establishing a diagnosis of ACI is important as doing so implies an ongoing inflammatory process, the etiology of which should be investigated. Furthermore, effective treatment of the underlying disease results in improvement or resolution of the anemia. In some instances, however, the underlying disease may be resistant to therapy (e.g., poorly responsive malignancy or refractory connective tissue disease). In such cases, red cell transfusion support and therapy that targets the pathophysiologic mechanisms that underlie ACI (Figure) are the mainstays of management. ACI may respond to recombinant human EPO (rhEPO),6 but the response may be blunted by concomitant functional iron deficiency. Iron supplementation, with a goal transferrin saturation of > 20 percent, may increase the effectiveness of rhEPO, and some patients respond to iron supplementation in the absence of rhEPO support. Infused iron rather than oral iron supplementation is often needed as hepcidin restricts gastrointestinal iron absorption. The desired response (increase in transferrin saturation) to iron supplementation, however, is relatively short lived, and repeated iron infusion puts patients at risk for iatrogenic hemochromatosis1,2 because the high hepcidin prevents the recycling of this iron. Anti-TNF-α agents have been shown to increase hemoglobin concentration in patients with ACI independent of an effect on EPO concentration.7 Looking forward, suppression of hepcidin activity has been examined in animal models. In a mouse model of ACI, antibodies to hepcidin also required the concurrent administration of EPO to reverse the anemia,8 whereas inhibition of hepcidin transcription, by blocking BMP receptor activation or downstream signaling, prevented and reversed ACI without the need for exogenous EPO administration.9,10 As more therapeutic options become available, well-designed clinical studies will be needed to determine the optimal pharmacologic approach to the management of ACI.
The patient described in the introduction was diagnosed with seronegative rheumatoid arthritis, and two months after beginning therapy with prednisone and methotrexate, his arthritis symptoms had improved and his Hgb was 12.5 g/dL.
1. Weiss G, Schett G. Anaemia in inflammatory rheumatic diseases. Nat Rev Rheumatol. 2012. Epub ahead of print.
2. Davis SL, Littlewood TJ. The investigation and treatment of secondary anaemia. Blood Rev. 2012;26:65-71.
3. Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta. 2012;1823:1434-1443.
4. Miller CB, Jones RJ, Piantadosi S, et al. Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med. 1990;322:1689-1692.
5. Thomas C, Thomas L. Biochemical markers and hematologic indices in the diagnosis of functional iron deficiency. Clin Chem. 2002;48:1066-1076.
6. Pincus T, Olsen NJ, Russell IJ, et al. Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis. Am J Med.1990;89:161-168.
7. Papadaki HA, Kritikos HD, Valatas V, et al. Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-α antibody therapy. Blood. 2002;100:474-482.
8. Sasu BJ, Cooke KS, Arvedson TL et al. Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia. Blood. 2010;115:3616-3624.
9. Steinbicker AU, Sachidanandan C, Vonner AJ, et al. Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation. Blood. 2011;117:4915-4923.
10. Theurl I, Schroll A, Sonnweber T, et al. Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats. Blood. 2011;118:4977-4984.
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