Pathology Thread

Microcytic/hypochromic erythrocytes indicate some inadequacy of structural matter, usually, not enough hemoglobin.

This is most commonly due to an inadequate dietary supply of iron (Fe deficiency). In fact, iron deficiency anemia is the most common of all anemias.

Determining the cause of the Fe deficiency is of pivotal importance in selecting appropriate therapy.

Remember, microcytic/hypochromic erythrocytes may also be seen in anemia of chronic disease, in thalassemia and in the sideroblastic anemias.

Blood loss is the most common cause of iron deficiency. Menstruation is the most likely reason in women ages 15 to 45 years. Iron deficiency anemia in adult men and postmenopausal women is most likely due to chronic gastrointestinal blood loss. Such losses are usually secondary to ulcerating lesions [peptic ulcer disease, mucosal trauma (hiatal hernias), drug ingestion (aspirin, nonsteroidal anti-inflammatory drugs, steroids, potassium), parasitic infections, inflammatory bowel disease and malignancy.

Lack of dietary iron may cause anemia in infancy when the daily need for iron is not met by milk alone. This is why iron supplements are given to infants. Iron deficiency is a major cause of anemia in pregnancy.

Malabsorption of iron is a rare cause of iron deficiency but is seen in patients who have had a partial gastrectomy or who have a malabsorption disorder.

Ferritin is in essence an "iron buffer", taking up excess iron or releasing iron as needed. Small amounts of ferritin, derived from iron stores, circulate in the plasma.

The amount of serum ferritin closely reflects iron stores, thus providing a readily measured assessment of body iron stores.

Remember:

1) ferritin increases in chronic inflammation;
2) ferritin is increased in hepatocellular disease; and
3) ferritin may be increased in malignancy.

Transferrin, the major iron transport protein, is synthesized by the liver and macrophages.

Each molecule of transferrin can bind two atoms of iron. Usually about one-third (25 - 45%) of the total transferrin is bound to iron (referred to as % saturation).

Transferrin carries iron via plasma to cells throughtout the body, though the most important site of delivery is to the marrow erythroblast. Transferrin (diferric) binds to transferrin receptors (CD71) on the erythroblast surface membrane.

The CD71 receptor-transferrin-iron complex is incorporated into the cell by endocytosis. The endocytotic vacuole fuses with a lysozyme, where at an acid pH, iron is released from transferrin as Fe++ and transported to mitochondria where it is complexed with protoporphyrin IX forming heme.

Non-heme iron (mainly Fe+++) is stabilized by gastric HCl; bound to mucin and then transferred to a mucosal cell surface receptor.

Most heme iron is catabolized to Fe++ and tetrapyrrole in the mucosal cell.

In the mucosal cell the iron is bound to mobilferrin, transported through the cell to the submucosal capillary network where the iron is oxidized to Fe+++, bound to transferrin and delivered via the blood to the marrow and other tissues.

Note that some iron is stored or "trapped" as ferritin in the mucosal cell. This "trapped" iron plays only a minor role in regulation of iron intake/loss as it is readily overwhelmed by ingestion of inorganic iron.

Total Iron Binding Capacity approximates a measure of transferrin.

Serum iron is a measure of Fe bound to transferrin.

Normally 25 - 45% of transferrin is bound to iron, ie. the % saturation of transferrin.

In inflammatory and malignant conditions transferrin is decreased possibly due to macrophage degradation.

Iron is decreased due to decreased release of Fe from macrophages into the plasma.

Iron deficiency is best screened for with serum ferritin levels (serum ferritin levels correspond to marrow stores).

A serum ferritin of <30 mg/L in men or <10 mg/L in women indicates iron deficiency.

Ferritin, an acute phase reactant, may be elevated in inflammatory conditions. Still, if the serum ferritin is not greater than 50 mg/L, iron deficiency is likely.

The definitive test for iron deficiency is a Prussian blue stained bone marrow.

The upper image demonstrates an absence of iron in the bone marrow macrophages of an individual with iron deficiency.

Compare the upper image with the lower image of a normal bone marrow stained with Prussian blue and demonstrating coarse granular storage iron in macrophages.

Iron deficiency develops gradually. Storage iron in the bone marrow is the first to become depleted. Serum ferritin levels decrease (corresponding to the marrow stores), while the Hct, Hgb and MCV remain normal, thus a latent state.

In time, serum iron decreases and iron-binding capacity increases, but there may be little or no evidence of anemia (small D in the Hct, Hgb, and MCV).

Later, synthesis of hemoglobin becomes impaired by the lack of iron and readily recognizable anemia results.

Eventually iron is lost from tissues other than blood including the liver, skin and skeletal muscle.

Erythropoiesis in iron deficiency is severely disrupted resulting in anisocytosis (high RDW). With iron deficiency each developing erythrocyte grabs whatever Fe is available, some get more, most get less! As a result the RBCs tend to vary in size.

Patients with thalassemia trait (mild anemia), usually have a normal RDW. In thalassemia, each erythrocyte has the same genetic defect, each makes the same reduced amount of hemoglobin and so each RBC is about the same size.

Caution! RDWs in Fe deficiency and thalassemia overlap and cannot be used to definitively distinguish between the two.

Summary of laboratory findings in Fe deficiency anemia:

1. Decreased hematocrit and hemoglobin
2. Hypochromic microcytic RBCs on peripheral smear
3. Decreased serum iron and increased total iron binding capacity (TIBC)
4. Decreased bone marrow iron stores or decreased serum ferritin

The microcytic/hypochromic anemia of Fe deficiency must be distinguished from anemia of chronic disease, from thalassemia and from sideroblastic anemia.

Blood loss the most common cause of iron deficiency (menstruation and GI blood loss), but lack of dietary iron may be the cause in infancy and pregnancy.

The oral administration of ferrous sulfate is the usual therapy for Fe deficiency. The starting dose is 300 mg/day, increasing to 900 mg/day if tolerated, usually for 2 - 3 months.

Complications include nausea, abdominal cramps, constipation and diarrhea.

Iron medications should be stored away from children in "child proof" containers.