Functional Iron Deficiency - Anemia

Differentiate between absolute and functional iron deficiency in the context of ACD and IDA. Absolute iron deficiency is when the stores of iron are depleted and bone marrow iron is absent, resulting in low serum ferritin and low transferrin saturation. Simple absolute iron deficiency usually results in iron deficiency anemia and can be resolved with iron supplementation. Functional iron deficiency results in anemia of chronic disease/inflammation, where infections, connective tissue disorders, or other diseases can cause inflammatory cytokines to be released.

These inflammatory cytokines inhibit survival of erythroid progenitor cells, reduce EPO production, and cause excess hepcidin production, which decreases the amount of iron absorbed by enterocytes and blocks the release of iron stored in macrophages. In this case, the iron stores in the body are adequate, but are not being released for use, resulting in hypoferremia and creating a pathological basis for ACD.

Explain why transferrin levels in the blood are not increased in ACD patients, unlike in IDA patients.

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Transferrin is a transport protein that is responsible for mediating the exchange of iron between tissues. Most of the iron transferred is derived from the iron stored in the macrophages and not from iron absorbed via the digestive tract. This affects transferrin levels in the blood in ACD because transferrin is a negative acute phase reactant. This means that during an infection or inflammation, the levels of transferrin in the blood decrease as the body tries to minimize the amount of iron accessible to pathogens and sequesters iron within macrophages.

Also, most iron-bound transferrin is delivered to the bone marrow for erythropoiesis or tissues for storage, leaving the bloodstream. On the contrary in IDA, transferrin levels in the blood increase because the body is trying to accumulate iron by increasing the level of transferrin. These transferrin proteins aren’t bound to any iron, due to the deficiency, and circulate the bloodstream.

Describe the alternative method of assessing or identifying iron deficiency, which we have not discussed in class. The alternative method of assessing or identifying iron deficiency mentioned in the paper was the use of flow cytometry to measure reticulocyte hemoglobin concentration (CHr). Reticulocytes are immature red blood cells that are only present for 1-2 days and are the most recently produced 1% of the erythrocytes. As such any sort of iron deficiency that affects proper erythropoiesis will be present upon analysis of reticulocyte hemoglobin concentration. Use of CHr as well as serum transferrin receptor levels to form diagnostic plots has been useful in identifying iron-restricted erythropoiesis (functional iron deficiency), regardless of whether or not an infection, an acute phase response, or ACD is concurrent. Thomas C, Thomas L. Biochemical markers and hematologic indices in the diagnosis of functional iron deficiency. Clin Chem. 2002;48:1066-1076.

How can iron supplementation work in ACD patients? How is it administered? Any drawbacks? In certain cases of ACD, iron supplementation can be therapeutic. Usually, since ACD is not a true iron deficiency, the anemia is resolved when the underlying condition of disease or inflammation is resolved. However, in some cases where the pathophysiological condition cannot be resolved, hematologists must instead target the issues that cause ACD, namely suppressed EPO production and increased iron sequestration as a result of excess hepcidin production. In the case of suppressed EPO production, iron supplements as well as rhEPO therapy can relieve the symptoms of anemia by inducing erythropoiesis. However, hematologists must also take into account that since excess hepcidin is being produced, the iron is unable to be absorbed via enterocytes, and must be administered intravenously. Because of the intravenous iron infusion, patients with ACD are at a high risk of being overloaded with iron and developing hemochromatosis. Drueke, T. B. "Intravenous Iron: How Much Is Too Much?" Journal of the American Society of Nephrology 16.10 (2005): 2833-835.

How have mouse models of ACD helped in the search for better management of ACD? Mouse models of ACD have helped in the search for better management of ACD by providing two different methods of curbing excessive hepcidin production in those with ACD. Firstly, an ACD mouse was created by infection with Brucella. This mouse was then treated with a short-hairpin RNA sequence that would bind to the mRNA transcript products of the hepcidin gene. The mouse was found to have significantly less hepcidin concurrent with pre-inflammation levels, alleviating anemic symptoms. Secondly, the scientists were able to develop an anti-hepcidin antibody that would inhibit hepcidin production. They first created a knock-in mouse with a human hepcidin gene and then used the anti-hepcidin antibody as an effective treatment for anemia when used with ESA (similar to EPO in humans). Another mouse study was also able to inhibit a bone morphogenetic protein that is elevated (along with IL-6) in ACD patients and responsible for increase in hepcidin production making inhibiting of BMP a possible anemia treatment.

1. 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.
2. Steinbicker AU, Sachidanandan C, Vonner AJ, et al. Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation. Blood. 2011;117:4915-4923.