Making the Case for INFeD

Laboratory Assessment of Iron Deficiency

Diagnosis of iron deficiency in most patients can be made based on the measurement of a low serum iron and low serum ferritin with an elevated total iron binding capacity (TIBC).3 Serum ferritin and stainable iron in tissue stores decrease even in the early stages of iron deficiency, as iron stores become depleted.7 Other parameters such as transferrin saturation (TSAT) and free erythrocyte protoporphyrin do not reach abnormal levels until tissue iron stores are completely depleted.7 Only when iron stores are insufficient for heme synthesis (ie, iron deficiency anemia) do hemoglobin levels and red cell indices begin to decrease (Figure 1).7

Serum ferritin

A low serum ferritin (<12 ng/mL) is virtually diagnostic of iron deficiency;9 however, an elevated serum ferritin level does not necessarily imply that iron stores are adequate. Serum ferritin can serve as a surrogate marker for iron stores, but it is also an acute-phase reactant and its levels may be elevated under conditions of chronic inflammation, liver disease, or malignancy, independent of iron status.28 Infection and systemic inflammation can induce secretion of hepcidin by the liver, which leads to sequestration of iron within storage sites and reduced intestinal absorption of iron.29 Thus, iron stores may be sufficient but may not be available for erythropoiesis. Under these conditions, serum iron is low, iron-binding capacity is low to normal, but serum ferritin may be normal to high.29 Therefore, in patients with inflammation, infection, or malignancy, serum ferritin may not be a reliable indicator of iron status.

Stainable tissue iron

The absence of stainable iron on a bone marrow aspirate that contains spicules is diagnostic of iron deficiency.3 However, bone marrow aspiration is an invasive and costly procedure and has been largely replaced by performance of serum iron, TIBC, and serum ferritin measurements on blood samples.3

Serum iron and TIBC measurements

Iron is carried to the bone marrow by transferrin, which is an iron-transport protein that is found in plasma. Serum iron levels measure transferrin-bound iron. TIBC, or total iron binding capacity, measures the amount of circulating transferrin that is available to bind iron.28

TSAT

Transferrin is a protein whose primary function is to transport iron from iron storage sites in the reticuloendothelial system to the bone marrow for use in erythropoiesis. Transferrin saturation (TSAT) is defined as the ratio of serum iron to the total iron-binding capacity (TIBC, a measure of circulating transferrin) x 100.28

Serum iron  x 100
     TIBC

TSAT indicates the percentage of binding sites on transferrin that are occupied by iron and is therefore a measure of circulating iron that is immediately available for erythropoiesis. A reduction in TSAT suggests an inadequate supply of iron to the developing erythrocyte. However, a reduced TSAT does not always indicate iron deficiency since other disorders can cause iron deficient erythropoiesis.28

Hemoglobin

Hemoglobin is the iron-containing protein that carries oxygen to the various tissues of the body. Hemoglobin values represent the total amount of hemoglobin in grams per 100 mL of blood. Measurement of hemoglobin is convenient, simple, and inexpensive to obtain.28 The hemoglobin level provides a quantitative measure of the severity of iron deficiency, but only after anemia has developed.28 Hemoglobin levels decrease to below-normal only after iron stores have been depleted and heme synthesis is impaired. As an index of iron deficiency, hemoglobin has low specificity since various other conditions, such as malnutrition, hemoglobinopathies, and chronic infections can also cause a decrease in erythropoiesis.28 It also has a low sensitivity due to overlap of values between patients with and without iron deficiency.28

Soluble serum transferrin receptor (sTfR)

With iron deficiency, eythroblasts in the bone marrow will increase the presentation of membrane transferrin receptor. If a patient is not receiving sufficient iron and erythropoiesis is being stimulated by an erythropoiesis-stimulating agent, then increased transferrin receptors will become expressed on the erythroblasts, some of which come off and will be detectable in the circulation. The sTfR correlates with this membrane expression of the transferrin receptor and also tends to be elevated in the presence of increased erythroid activity.30 Some studies indicate that soluble transferrin receptor level may not be affected by inflammation of liver disease and so can be used to identify iron deficiency anemia under conditions of inflammation or liver disease.10 However, measurement of sTfr is not routinely performed in most centers.8,30

 NormalIron DepletionPrelatent Iron DeficiencyLatent Iron DeficiencyIron Deficient ErythropoiesisEarly Iron Deficiency AnemiaLate Iron Deficiency Anemia
Serum Ferritin (μg/l)6020<12<12<12<12<12
Stainable Tissue Iron (0-4+)2+1+00000
Transferrin Saturation (%)35353520<16<16<16
Free Erythrocyte Protoporphyrin (μg/dl)30303075>100>100>100
Hemoglobin (ug/dl)1414141413<12<12
Mean Corpuscular Volume (μ3)909090908886<82
Mean Corpuscular Hemoglobin Concentration (0/0)333333333331<28
Figure 1: Laboratory measurements during gradual progression of iron deficiency7
Adapted from Conrad ME. Am J Hematol. 1981;10:199-225.

INFeD is indicated in the treatment of patients with documented iron deficiency in whom oral administration is unsatisfactory or impossible.

Important Safety Information

Anaphylactic-type reactions, including fatalities, have followed the parenteral administration of iron dextran injection. A test dose should be administered prior to the first therapeutic dose, followed by the full therapeutic dose if no signs or symptoms of anaphylactic-type reactions are seen. Resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions must be readily available during all INFeD administrations. Patients should be observed for signs or symptoms of anaphylactic-type reactions during all INFeD administrations. Fatal reactions have followed the test dose and have also occurred in situations where the test dose was tolerated. Use INFeD only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy. Patients with a history of drug allergy or multiple drug allergies may be at increased risk of anaphylactic-type reactions. INFeD should be used with caution in individuals with histories of significant allergies and/or asthma, and is contraindicated in patients with hypersensitivity to the product and patients with all anemias not associated with iron deficiency. INFeD should be used with extreme care in patients with serious impairment of liver function, and should not be used during the acute phase of infectious kidney disease. Unwarranted therapy with parenteral iron will cause excess storage of iron with the consequent possibility of exogenous hemosiderosis, which is particularly apt to occur in patients with hemoglobinopathies and other refractory anemias.