Iron Deficiency Anemia

Iron deficiency anemia is a condition where there is anemia and a clear evidence of iron deficiency. It is categorized under ‘Hypoproliferative Anemias’.

Stages:
Stage of negative iron balance – The demand (or loss) for Iron exceeds that of the body’s capacity to absorb from the diet. Most common causes of the above condition are pregnancy, blood loss from bleeding, growth spurts in adolescence. Blood loss of 25-30 micrograms/dL can exceed the total body’s capacity to absorb iron from diet. The iron from reticulo-endothelial system and other iron stores is utilized.
In this condition, iron in stores like ferritin or stainable iron in bone marrow decrease. As long as iron stores are present and mobilized, serum iron, total iron binding capacity (TIBC) red cell protoporphyrin levels remain normal. At this stage, RBC morphology and indices are normal.

Stage of Iron deficient erythopoiesis – When the iron stores are depleted, TIBC and red cell protoporphyrin levels increase. Marrow iron stores are absent when serum ferritin levels fall to 15 micrograms/dL. Once the transferrin saturation falls to 15 – 20%, hemoglobin synthesis is impaired.

Stage of Iron deficiency anemia – In this stage, microcytic, hypochromic RBC are visible in the peripheral smear. Hemoglobin and hematocrit begin to fall. Transferrin saturation at this point is 10-15%.
At moderate anemia (Hb -10 to 13 g/dL), the bone marrow is hypoproliferative. At severe anemia (Hb – 7 to 8 g/dL), misshapen red cells called poikilocytes, cigar shaped cells, target cells, are seen. Marrow becomes ineffective. Microcytes and hypochromatic cells become more prominent. With severe prolonged anemia, the erythroid hyperplasia is seen in the marrow rather than hypoproliferation.

Clinical features:
Pallor, decreased exercise capacity, fatigue, Cheilosis (fissures at the corners of mouth), Koilonychia (spooning of fingernails) are the few signs and symptoms of iron deficiency anemia.
As a cardinal rule, Iron deficiency anemia in an adult male is due to gastrointestinal bleeding, until proved otherwise.

Laboratory investigations:
Serum Iron and Total Iron binding capacity (TIBC)-
Normal serum iron range = 50-150 migs/dL
Normal serum Total iron binding capacity = 300-350 migs/dL
Normal transferrin saturation = 25-50 %
Transferrin saturation = Total serum iron x 100 ÷ TIBC

Iron deficiency states are associated with transferrin saturation <> 50% indicates that disproportionate transferrin bound iron is being delivered to non erythroid tissues. If this condition persists for a long time, tissue iron overload may occur.
There is diurnal variation in serum iron level.

Serum Ferritin-
Serum ferritin indicates the total iron stores of the body. Thus serum ferritin estimation is the most appropriate laboratory test for estimating iron stores.Normal serum transferrin levels in adult male – 100 migs/L, levels in female – 30 migs/L.Serum ferritin levels of

Evaluation of Bone Marrow Iron Stores-
Reticulo endothelial stores of iron can be estimated by
1. Iron staining of bone marrow aspirate
2. Serum ferritin levels.
Measurement of Serum ferritin levels has largely replaced iron staining of bone marrow and is a better indicator of iron overload. But iron staining of bone marrow provides information about iron delivery to developing erythroblasts. 20-40% of sideroblasts (developing erythroblasts) have visible iron granules in them.
In myelodysplastic syndrome, mitochondrial dysfunction occurs and accumulation of iron in the mitochondria around the nucleus in a necklace fashion. Such cells are termed as ringed sideroblasts.

Red cell Protoporphyrin levels:
Protoporphyrin is a metabolite used in the production of heme molecule. Heme production is impaired in iron deficiency states causing in increase in protoporphyrin levels in RBC. Most common causes are Iron deficiency and Lead poisoning. Normal value (of red cell protoporphyrin) – 30 migs. In iron deficiency, its value may go up to 100 migs.

Serum levels of Transferrin Receptor Protein:
Erythroblasts have the highest number of transferrin receptors on their surface. Erythroblast receptor protein is released by cells into circulation. Therefore estimation of Transferrin receptor proteins gives an indication about erythroid marrow mass. Normal value = 4-9 migs/L.

Differential Diagnosis:
Conditions which show microcytic, hypochromic anemia which need to be distinguished from Iron Deficiency Anemia –
1. Thalassemias – Inherited defects in globin chain synthesis. Serum iron levels are normal in this case, which help in differentiating it from iron deficiency anemia.
2. Chronic inflammatory diseases – Here the serum iron levels are normal but iron is not efficiently supplied to erythroid cells.
3. Myelodysplastic syndromes – Most rare condition of the three. Here hemoglobin synthesis is impaired due to defective mitochondria resulting in defective mitochondrial incorporation into the heme molecule. Serum iron levels are normal here and more than adequate iron is delivered to the marrow.

Diets rich in Iron:
Red meat is the easiest source of Iron that is easily absorbed by the body.
Few Foods rich in heme Iron –
• Clams
• Oysters
• Chicken Liver
• Mussels
• Beef Liver
• Turkey

Foods rich in non heme Iron –
• Enriched breakfast cereals
• Cooked beans and lentils
• Pumpkin seeds
• Blackstrap Molasses

Phytates (found in legumes) and tannins (found in tea) decrease Iron absorption. Iron absorption is increase when the serum iron level is less and decreased when the serum iron is normal to increased.

Further reading about Iron containing foods - http://dietary-supplements.info.nih.gov/factsheets/iron.asp#h2,
www.bloodbook.com, http://www.healthcastle.com/iron.shtml

Treatment:
Parenteral Iron Therapy :
Intravenous Iron is given to patients who can not tolerate oral iron, or who need Iron on an ongoing basis and who have persistent gastrointestinal blood loss. Serious adverse reaction rate to intravenous Iron dextran is 0.7%.Other Iron complexes available are Sodium ferric gluconate (ferrlecit) and iron sucrose (venofer).

The amount of Iron needed for an individual patient is calculated by the formula – Body weight (in Kgs) x 2.3 x (15-patient’s hemoglobin in g/dL) + 500 or 1000 mg (for stores).

Parenteral iron is used for
1. To correct the Hemoglobin deficiency
2. Provide the patient with at least 500 mg of iron stores.
3. To give small doses of parenteral iron over a protracted period – This is usually done in dialysis centers to augment the response to recombinant erythropoietin therapy.100 mg of elemental iron is given weekly for 10 weeks.

Anaphylaxis is the major concern while administering iron dextran.It is never seen in newer preparations.Patients who are sensitive to iron dextran are treated with iron gluconate.Factors associated with serious anaphylactic like reaction are previous history of allergies or prior allergic reaction to dextran.Generalised symptoms like arthralgias, skin rash, low grade fever appearing several days after infusion of large amounts of iron can be noted. If large amounts of iron (>100 mg) is to be administered, the iron preparation should be diluted in 5% dextrose in water or 0.9% NaCl solution.The preparation is infused over a period of 60 to 90 mins.A test dose of 25 mg of parenteral iron is recommended. If early in infusion of iron, systemic symptoms like chest pain, wheezing or a fall in blood pressure is noted, the infusion must be stopped immediately.

Oral Iron Therapy:
It is treatment of choice in patients with established, asymptomatic iron deficiency anemia. Daily dose of 300 mg of elemental iron is given in 3 or 4 divided doses. It causes absorption of 50 mg of elemental iron per day. This supports a erythrocyte production of two to three times that of normal. Oral iron tablets should be taken empty stomach because some foods interfere with the obsorption of iron in the intestines (phytates and phosphates reduce its absorption by 50%). Iron stores of 500 to 1000 mg should be achieved along with correction of the deficiency. To achieve this, sustained treatment for 6 to 12 months is needed. Ascorbic acid helps in the absorption of iron.

Gastrointestinal distress is the most common adverse effect of oral iron therapy. Abdominal pain, nausea, vomiting and constipation are usually seen

Generic Name	Tablet (iron content) in mg
Ferrous Sulfate Extended release	325 (65) 525 (105)
Ferrous fumarate	325 (107)
Ferrous gluconate	325 (39)
Polysaccharide iron	150 (150)

Response – Typically reticulocyte count should begin to increase within 4 to 7 days and peaks at 1.5 weeks. In absence of good response due to incompliance or poor absorption, parenteral therapy should be considered.

Transfusion Therapy:
This is considered in patients with symptoms of anemia, cardiovascular instability and excessive bleeding. Transfusion not only corrects anemia, but also the transfused RBC provide with iron for reutilization.