As shown in Table 3.2, the appearance of iron deficiency requires a progressive sequence of stages before there is frank anemia. The first stage is negative iron balance during which there is more iron leaving the body than is coming in. If this state persists, there is a gradual loss of iron stores and that will be reflected in a fall in the serum ferritin. Throughout this period, iron is being mobilized to support hemoglobin synthesis and there are no changes in the serum iron and the percent transferrin saturation until iron stores have been exhausted. At that point, iron-deficient erythropoiesis appears, and that is manifested by the release of iron deficient (hypochromic) reticulocytes into the circulation. If iron-deficient erythropoiesis persists, the hemoglobin begins to fall (anemia) and the MCV will also begin to fall.
How Does Iron Deficiency Come About?
There are really only two major mechanisms by which iron deficiency occurs. The first is inadequate intake or absorption of iron. This may be due to an inadequate diet, but classically is seen during pregnancy, infancy, the rapid growth spurt during puberty, or in women who have increased
Table 3.2. Stages in the development of iron deficiency
1. Negative iron balance
2. Fall in iron stores (serum ferritin falls to <12-15 ng/mL)
3. Serum iron and transferrin saturation fall
4. Hypochromic reticulocytes appear in circulation
6. MCV falls menstrual blood loss. The second major category, and partly overlapping with the first, is blood loss in excess of the individual's ability to absorb sufficient iron from the diet to keep up with ongoing losses. Table 3.3 (modified from (2)) shows a detailed list of conditions that can result in iron deficiency, either because of decreased intake or absorption or because of increased loss.
Table 3.3. Causes of iron deficiency (adapted from 2). Adapted with permission. Copyright © 1999 Massachusetts Medical Society. All rights reserved
Inadequate absorption Poor bioavailability Antacid therapy or high gastric pH Excess dietary bran, tannin, phytates or starch Competition from other metals (e.g., copper or lead) Loss or dysfunction of absorptive enterocytes Bowel resection Celiac disease Inflammatory bowel disease Intrinsic enterocyte defects
Increased loss Gastrointestinal blood loss Epistaxis Varices Gastritis Ulcer Tumor
Meckel's diverticulum Parasitosis
Chronic infection Pulmonary blood loss Pulmonary hemosiderosis Infection Other blood loss Trauma
Excessive phlebotomy Large vascular malformations
What are the Diagnostic Criteria that Define IDA?
First, iron-deficient erythropoiesis occurs when the percent transferrin saturation falls into the range of 15-20%. However, it is important to realize that no transferrin saturation, by itself, is absolutely diagnostic of IDA. As discussed in the chapter on the anemia of chronic inflammation (ACI), there can be very rapid changes in the serum iron as a result of the effect of hepcidin to reduce iron absorption and, particularly, hepcidin's effect on blocking the release of iron from reticuloendothelial cells.
In contrast, a low serum ferritin level is absolutely diagnostic of iron deficiency (or at least absent marrow iron stores). Absent marrow iron stores are associated with serum ferritin levels of <12-15 ng/mL. Because ferritin is an acute phase reactant and will rise with inflammation, possible iron deficiency may exist with serum ferritin levels between 15 and 200 ng/mL and any ferritin level must be interpreted in the context of all of the clinical circumstances (4).
As a result, ACI and IDA share a number of overlapping features (Table 3.4). Evidence of iron-deficient erythropoiesis with a serum ferritin >200 ng/mL suggests ACI, while a serum ferritin <12-15 ng/mL is diagnostic of (at least) depleted iron stores. However, if there is doubt, one can obtain a bone marrow specimen and stain the specimen for iron.
An underutilized approach to distinguish IDA from ACI combines the serum ferritin level with the sTfR protein level. As reported by Punnonen et al. (7),
Table 3.4. The anemia of chronic disease and iron deficiency: similarities and differences
Iron deficiency anemia ACD
Low serum iron Low serum iron
High TIBC Normal to low TIBC
Low % Tf saturation Low % Tf saturation
Elevated red cell protoporphyin Elevated red cell protoporphyrin
Red cell microcytosis Normocytic to microcytic red cells
Absent marrow iron stores; no sideroblasts Marrow iron stores normal to increased; reduced sideroblasts sTrR/log ferritin < 1 sTrR/log ferritin < 2
the serum ferritin level will be elevated in patients with ACI and depressed in patients with iron deficiency. The sTfR protein level will be elevated in iron deficiency and normal or depressed in patients with ACI. Neither of these tests, alone, distinguished patients with IDA from those with ACI or a small subset of patients who had both. However, when these investigators divided the sTfR protein value by the log of the serum ferritin, a result of <2 denoted ACI and values >2 captured patients with uncomplicated IDA or those with a combination of IDA and ACI (Fig. 3.3). However, this approach has not been validated for elderly patients who may have a chronic low level of inflammation.
Finally, if there is uncertainty, one can give a trial of iron replacement therapy. A clinical response to iron therapy (defined as an increase in hemoglobin of 1 gm/dL or more) is the ultimate definition of IDA.
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