DDx
Diagnostic Considerations
Other conditions to be considered include the following:
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Anemia of chronic disorders
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Hemoglobin CC disease
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Hemoglobin DD disease
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Lead poisoning
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Microcytic anemias
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Autoimmune hemolytic anemia
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Hemoglobin S-beta thalassemia
Go to Anemia, Sideroblastic Anemias, and Chronic Anemia for complete information on these topics.
In a meta-analysis of indices for discriminating between iron deficiency anemia and thalassemia trait in subjects with microcytic red blood cells (RBCs), the ratio of microcytic to hypochromic RBCs (M/H ratio) showed the best performance. An M/H ratio >6.4 was strongly indicative of thalassemia. The authors concluded that the sensitivity and specificity of the M/H ratio are not high enough for making a definitive diagnosis, but the ratio can be valuable for identifying patients with microcytic RBC who should undergo diagnostic tests for confirming thalassemia. [17]
Differential Diagnoses
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Sideroblastic Anemias
Media Gallery
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The sequence of events (left to right) that occur with gradual depletion of body stores of iron. Serum ferritin and stainable iron in tissue stores are the most sensitive laboratory indicators of mild iron deficiency and are particularly useful in differentiating iron deficiency from the anemia of chronic disorders. The percentage saturation of transferrin with iron and free erythrocyte protoporphyrin values do not become abnormal until tissue stores are depleted of iron. Subsequently, a decrease in the hemoglobin concentration occurs because iron is unavailable for heme synthesis. Red blood cell indices do not become abnormal for several months after tissue stores are depleted of iron.
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Sequential changes in laboratory values following blood loss are depicted. A healthy human was bled 5 L in 500-mL increments over 45 days. A moderate anemia ensued, initially with normal cellular indices and serum iron. Subsequently, the mean corpuscular volume (MCV) increased as iron was mobilized from body stores and reticulocytosis occurred. The serum iron decreased, followed by an increase in the total iron-binding capacity. Gradual decreases in the red blood cell indices occurred, with maximal microcytosis and hypochromia present 120 days after bleeding. Values returned to normal approximately 250 days after blood loss. At the end of the experiment, iron was absent from body stores (marrow) because hemoglobin has a first priority for iron. Iron-59 absorption was increased after all values returned to normal in order to replenish the body store with iron. This suggests that the serum iron, total iron-binding capacity, hemoglobin concentration, and indices were not the primary regulators of iron absorption.
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The total body iron in a 70-kg man is about 4 g. This is maintained by a balance between absorption and body losses. Although the body only absorbs 1 mg daily to maintain equilibrium, the internal requirement for iron is greater (20-25 mg). An erythrocyte has a lifespan of 120 days so that 0.8% of red blood cells are destroyed and replaced each day. A man with 5 L of blood volume has 2.5 g of iron incorporated into the hemoglobin, with a daily turnover of 20 mg for hemoglobin synthesis and degradation and another 5 mg for other requirements. Most of this iron passes through the plasma for reutilization. Iron in excess of these requirements is deposited in body stores as ferritin or hemosiderin.
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Dietary iron contains both heme and nonheme iron. Both chemical forms are absorbed noncompetitively into duodenal and jejunal mucosal cells. Many of the factors that alter the absorption of nonheme iron have little effect upon the absorption of heme iron because of the differences in their chemical structures. Iron is released from heme within the intestinal absorptive cell by heme oxygenase and then transferred into the body as nonheme iron. Factors affecting various stages of iron absorption are shown in this diagram. The simplest model of iron absorption must consider intraluminal, mucosal, and corporeal factors.
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Ultrastructural studies of the rat duodenum from iron-deficient (top), healthy (middle), and iron-loaded (bottom) animals are shown. They were stained with acid ferrocyanide for iron, which is seen as black dots in the specimens. No staining was seen with acid ferricyanide. This indicates that iron was in the ferric redox state. Respectively, the specimens showed no iron, moderate deposits, and increased deposits with ferritin (arrow).Incubation of the specimens with iron-nitrilotriacetic acid to satiate iron-binding proteins with iron provided specimens with equal iron staining, except that the iron-loaded specimens contained ferritin. The quantity of iron in the cell is derived from both the diet and body stores. It probably is important in the regulation of the quantity of iron accepted by the absorptive cell from the gut lumen. The authors postulate that the iron either satiates iron-binding proteins with iron, up-regulates iron regulatory protein, or does both to diminish iron uptake by the absorptive cell. The consequences of these findings are depicted in the flow charts.
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Mucosal cells in the proximal small intestine mediate iron absorption. Intestinal cells are born in the crypts of Lieberkuhn and migrate to the tips of the villi. The cells are sloughed into the intestinal lumen at the end of their 2- to 3-day lifespan. Absorptive cells remain attuned to the body requirement for iron by incorporating proportionate quantities of body iron into the absorptive cells. This iron and recently absorbed iron decrease uptake of iron from the gut lumen by satiation of iron-binding proteins with iron, by stimulating an iron regulatory element, or both. The incorporation of iron into these cells in quantities proportional to body stores of iron also provides a limited method of increasing iron excretion in individuals replete in iron.
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Both nonheme iron and heme iron have 6 coordinating bonds; however, 4 of the bonds in heme bind pyrroles, making them unavailable for chelation by other compounds. Therefore, ascorbic acid chelates nonheme iron to enhance absorption but has no effect upon heme iron. Many dietary components, such as phytates, phosphates, oxalates, and tannates, bind nonheme iron to decrease nonheme iron absorption. They do not affect heme. This explains why heme is so effectively absorbed with foods containing these chelators. Iron hemoglobin structure.
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Three pathways exist in enterocytes for uptake of food iron. In the United States and Europe, most absorbed iron is derived from heme. Heme is digested enzymatically free of globin and enters the enterocyte as a metalloporphyrin. Within the cell iron is released from heme by heme oxygenase to pass into the body as inorganic iron. Most dietary inorganic iron is ferric iron. This can enter the absorptive cell via the integrin-mobilferrin pathway (IMP).Some dietary iron is reduced in the gut lumen and enters the absorptive cell via the divalent metal transporter-1 (DMT-1/DCT-1/Nramp-2). The proteins of both pathways interact within the enterocyte with paraferritin, a large protein complex capable of ferrireduction. Excess iron is stored as ferritin to protect the cell from oxidative damage. Iron leaves the cell to enter plasma facilitated by ferroportin and hephaestin, which associate with an apotransferrin receptor. The enterocyte is informed of body requirements for iron by transporting iron from plasma into the cell using a holotransferrin receptor.
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A 70-year-old man who is 4 years post-Whipple surgery for pancreatic adenocarcinoma had been in good health with no evidence of recurrence until he had a maroon-colored stool that was heme positive. Physical examination was unrevealing. Laboratory study values showed a WBC of 9000 cells/µL, a hemoglobin of 11.5 g/dL, a mean corpuscular volume (MCV) of 95 fL, a mean corpuscular hemoglobin concentration (MCHC) of 34 g/dL, a platelet count of 250,000 cells/µL, a creatinine level of 0.9 mg/dL, a BUN level of 27 mg/dL, a total bilirubin level of 0.4 mg/dL, a serum iron level of 160 µg/dL, a total iron-binding capacity (TIBC) of 280 µg/dL, and a ferritin level of 85 ng/mL. A peripheral smear is shown.
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A 26-year-old white man was referred with a microcytic anemia that failed to respond to treatment with ferrous sulfate over 6 months. Physical examination showed only mild pallor of mucous membranes. His stool was dark but heme negative. The CBC count showed a WBC of 6000 cells/µL, a hemoglobin level of 11 g/dL, a mean corpuscular volume (MCV) of 70 fL, a mean corpuscular hemoglobin concentration (MCHC) of 33 g/dL, a platelet count of 234,000 cells/µL, a hemoglobin electrophoresis AA, a hemoglobin A2 value of 3.8%, and a fetal hemoglobin value of 2.0%.
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