Investigations
Investigations that are required to establish the diagnosis of IDA and to determine its underlying cause are:
Screening Tests:
Red cell count, hemoglobin, and Hematocrit are all decreased in IDA. MCV, MCH, and MCHC are also decreased. The peripheral blood film shows hypochromic, microcytic red cells. If anemia is severe, other morphological abnormalities such as poikilocytosis and target cells may be seen. When iron deficiency is associated with deficiency of other hematinics like it. B12 or Folate, there may be a dimorphic picture with Hypochromic, microcytic red cells along with macrocytosis. These routine investigations may not be useful to diagnose early iron deficiency state. The reticulocyte count is normal unless the patient has had a recent acute blood loss or the patient has received hematinics, in which case it may be increased. In severe IDA, reticulocyte count may be decreased (Table 2).
Red cell osmotic fragility is decreased, and this along with low MCV may cause some confusion with beta-thalassemia trait, which causes a similar blood picture and is common in India. NESTROFT (Naked Eye Single Tube Osmotic Fragility Test), a useful screening test for thalassemia trait is positive in adults 15% of cases of I.D.A. However if nestroft is negative, it is unlikely to be thalassemia trait.
Leucocyte count is usually normal. Hypersegmented neutrophils may be seen due to concomitant B12 or folate deficiency or due to iron deficiency-induced interference with folate utilization, or due to IDA - induced impairment of jejunal function leading to poor absorption of B12 or folate. In a majority of such cases, the abnormality is corrected by iron therapy without B12 or folate.
Thrombocytosis may occur in patients with IDA, as a result of iron deficiency per se or due to underlying conditions such as malignancy or bleeding.
Red cell indices:
With the availability of electronic particle counters estimation of PVC, MCV, MCH, RBC count has become accurate, reproducible, and practical laboratory test for screening anemic patients. The manual determination of these red cell indices is time-consuming and poorly reproducible. Low MCV and MCH with anemia favor the diagnosis of IDA. However, a specific reference standard must be used for comparison. Klee G in his study showed that more than half of the 62 patients with IDA had an MCH value clearly within a normal range and nearly 70% of cases exhibited distinct microcytosis, suggesting that MCV is much more sensitive than MCH in determining changes of iron deficiency. However, 30% of cases of IDA will be misdiagnosed if a physician relies only on these indices. Red cell indices in IDA are generally low i.e. MCV <80 cu mm, MCH <27 pg and MCHC <33%. Microcytosis also may be seen in other conditions like abnormal hemoglobinopathies, anemia of chronic infection and inflammation, lead poisoning and in rare conditions like sideroblastic anemia, chronic renal diseases, etc. Red blood cell survival is reduced in iron deficiency due to reduced cellular deformability resulting from a reduced red cell glutathione peroxidase activity.
Red cell size Distribution Width (RDW):
An estimation on electronic counter reveals the elevated value of red cell distribution width (RDW) in iron deficiency anemia as compared to normal levels in anemia of chronic diseases or beta - Thalassemia trait. RDW gives objective evidence of the degree of anisocytosis.
Confirmatory Tests for IDA:
As shown in Table 6, Serum iron is reduced (Normal- 50 - 180 mcg/dl), TIBC is increased (Normal- 250 - 450 mcg/dl), Transferrin saturation is low (less than 16% suggestive and less than 7% diagnostic of severe iron deficiency anemia), Serum Ferritin is less than 10 - 12 ng/ml. However, when infectious or inflammatory diseases like rheumatoid arthritis, collagen disorders, liver disorders, chronic renal disease, or malignancy are also present, the serum ferritin level is usually higher but less than 50-60ng/ml. The test still lacks sensitivity and normal value does not reliably exclude iron deficiency.
TABLE 6: CONFIRMATORY TESTS FOR IDA
| Age in years | Serum Ferritin (ng/dl) | Transferrin Saturation% | RBC FEP mcg/dl |
| 0.5-4 | < 10 | < 12 | < 80 |
| 5-10 | < 10 | < 14 | > 70 |
| 11-14 | < 10 | < 16 | > 70 |
| > 15 | < 12 | < 16 | > 70 |
Free Erythrocyte Protoporphyrin (FEP):
Protoporphyrin accumulates in the red blood cells when it does not have sufficient iron to combine with, to form Hb. The FEP can be measured rapidly by a simple fluorescence assay performed directly on the thin film of the blood. FEP value in the normal person is 15.5 + 8.3 mcg/dl of RBC. More than 80 mcg/dl of RBC below the age of 4 years, and more than 70 mcg/dl of RBC above that age, are significant values to detect IDA. FEP/Hb ratio is a useful index of iron deficiency. FEB/Hb ratio increases when the iron reserve is exhausted, even before anemia becomes apparent. The ratio is normal in thalassemia trait and renal anemia. FEB/Hb ratio remains elevated during iron therapy and returns to normal only after the majority of the cells containing FEP formed during iron deficiency are replaced. FEP/Hb ratio is not subject to daily fluctuation and sudden changes as is transferrin saturation. The highest value of FEP is seen in lead intoxication - a level of FEP greater than, 160 mcg/dl of RBC is taken as a cut-off value for the detection of lead intoxication. In IDA, FEP/Hb ratio is moderately elevated and never exceeds 17.5 mcg/gm of Hb (equivalent to 500 mcg/dl of RBC). An FEP/Hb ratio in the range of 5.5 -17.5 mcg of Hb may be attributed to either IDA or lead intoxication whereas the FEP/Hb ratio greater than 17.5 mcg/gm of Hb indicates lead intoxication with or without associated iron deficiency and requires immediate medical attention. Higher values may also be associated with rare genetic disorders like erythropoietic protoporphyria.
Bone marrow examination:
Bone marrow aspiration is not routinely indicated in the diagnosis of IDA. The degree of cellularity and the proportion of myeloid to the erythroid cells on bone marrow examination vary depending on the severity as well as the duration of IDA. The bone marrow aspirate shows an erythroid normoblasts hyperplasia. Erythroblasts may be smaller than the normal with a narrow ragged rim of cytoplasm containing little Hb. However, morphological changes are not distinctive enough to be of diagnostic values. Prussian blue staining of iron particles revealing little or no stainable iron in reticulum cells and normoblast is diagnostic (iron granules are normally found in the cytoplasm of 10% or more erythroblasts). High iron may be seen in the above marrow of the patient who has been recently transfused or received parenteral iron.
Prevention Of Iron Deficiency Anemia
The basic approaches for prevention of IDA include:
- Supplementation with medicinal iron
- Increase the dietary iron intake.
- Control of infection and treatment of helminthiasis.
- Fortification of staple food with iron.
Supplementation with medicinal iron:
These programs do best when concentrated on high-risk groups such as pregnant women, infants, and preschool children and captive audiences such as school children or plantation workers who can receive their supplements at school or workplace. In infants, promoting breastfeeding for as long as possible and encouraging the timely introduction of appropriate weaning food is the best method of prevention. Major constraints against the effectiveness of supplementation are:
- Side-effects of oral iron medication
- Continuing iron medication for 2 - 3 months by those who do not perceive themselves as ill.
Iron supplementation should be started in full-term infants by 4 months and in pre-term infants by 2 months of age in a dose of 1 mg/kg/day in full-term and 2 mg/kg/day in preterm infants.
Dietary Modification:
Increase total intake to fulfill energy requirements. The total iron consumption has been shown to increase by 25 -30%. Include heme iron and vitamin C containing food and reduce inhibitory factors in diet i.e. Tannin and Phytates, etc.
Control of Viral, Bacterial and Parasitic Infections:
Feeding and breastfeeding must be continued during illness. Immunization and other preventive public health measures such as safe water, proper sanitation, etc. should be ensured. Giardiasis, hookworm, and other worm infestations and schistosomiasis should be treated promptly.
Food Fortification:
Fortification staple food which will reach the masses at large will virtually eliminate iron deficiency in the world. In India, salt fortification has been successfully tried, but with fortification, the cost increased by 20%. Salt contains 3500 ppm of ferric orthophosphate and 5000 ppm of acid sulfate. At this level of fortification, each gm of salt will provide 1 mg of elemental iron. However, this was done only in field trials in a few places and has to be implemented further. EDTA (NaFeEDTA) increased the bioavailability of iron in sugar and condiments and the cost increased by 2%. This has been tried in Guatemala and should be explored in India too.
Two major sources of fortification iron in infancy are infant formulas and infant cereals using ferric pyrophosphate and ferric orthophosphate, ferrous fumarate, and succinate or dried bovine Hemoglobin. Fortification of wheat flour has been done by adding ferrous sulfate and elemental iron powder, ferric pyrophosphate, ferric orthophosphate. NaFeEDTA also has been used for the fortification of fish sauce, masala (condiments). Dried bovine hemoglobin has been used for the fortification of cereals.
Cost and benefits of prevention:
Levin from the world bank has prepared a cost-benefit analysis of the impact of fortification and supplementation on iron deficiency anemia. The conclusions drawn are that when it comes to benefit, anemia control produces an immediate increase in physical work output and long term leads to reduced morbidity and mortality, higher productivity, improved quality of leisure time, increased capacity, and a greater sense of well being. Apart from many of the benefits, which cannot be measured in material terms, an impressive improvement in the earnings occurs out of increased labor productivity. He concludes that both iron fortification and supplementation programs represent highly productive investments for developing countries.
Management
Management of iron deficiency anemia can be considered in two parts:
- Treatment of individual patient
- Treatment of IDA-public health problem
Treatment of individual patient:
Management of individual patient consists of:
- Replenishment of reduced body iron
- Correction of underlying factors responsible for the deficiency.
In 80-85% of patients, it is possible to determine the causes of deficiency.
Successful management requires:
- Confirmation of diagnosis
- Through investigation of the underlying cause
- Supplementation of iron
It is important to find out the cause of the iron deficiency. In children, it is often due to poor intake rather than blood loss. Therefore the key to success in the management of IDA is proper nutritional counseling. Parents should be made to understand the need for a well-balanced diet, particularly in growing children. Continuation of breast milk should be encouraged beyond 6 months, as the bioavailability of iron in breast milk is high. Restriction of milk to one pint a day, and introduction of iron-rich weaning foods like a mechanic, jaggery, cereals, spinach, beans, meat, fruits, etc. and iron-fortified food should be advocated.
Oral iron therapy: This is the treatment of choice, as it is cheap, safe, effective, and well-tolerated. Parenteral administration is reserved for patients who are completely intolerant to oral iron or when compliance is poor. Various preparations available are shown in Table 5.
Table 5: PERCENTAGE & AMOUNT OF IRON IN SOME COMMONLY USED IRON TABLETS
| Preparation |
Iron compound (mg) per tab |
Elemental iron (mg) per tab |
% of iron given |
| Ferrous fumarate |
200 |
66 |
33 |
| Ferrous gluconate |
300 |
36 |
12 |
| Ferrous sulphate(7H2O) |
300 |
60 |
20 |
| Ferrous sulphate(anhydrous) |
200 |
74 |
37 |
Ferrous salts are absorbed better than ferric salts. Of the ferrous salts, ferrous sulfate is most preferred because of its low cost. Various types of preparation available are as follows:
- Uncoated tablets and sugar-coated tablets: Least expensive but less effective as they get oxidized
- Enteric-coated tablets: More expensive, disintegrate only partially in gastric acidity. Side-effects are minimal, therefore better compliance. However, if the disintegration of the tablet does not take place, then it may not be effective.
- Liquid preparations: They include syrups and drops. Useful for children and infants but are expensive and deteriorate on storage.
- Combination of other nutrients: Ascorbic acid in the dose of 100 mg/15 mg elemental iron enhances absorption of 30%. But it is expensive and increases side-effects.
Dose/duration: 4-6 mg/kg/day of elemental iron is started and continued for three months after Hb returns to the normal so as to also replenish the deficiency of storage. For children effective dosage is 1.5-2.0 mg of elemental iron/kg/body weight 3 times per day.
Difficulty encountered with oral iron: Sub-optimal response may be due to:
- Poor compliance
- Preparation with poor content and absorption of iron
- Malabsorption
- Loss greater than intake as seen in telangiectasia, portal hypertension, piles, etc.
- Discontinuation of treatment after initial 3 - 4 weeks because of a feeling of well - being or due to gastrointestinal adverse side effects.
- Concurrent protein, folic acid, B12 or other nutrients deficiencies
- Incorrect diagnosis
Response to Treatment: A positive response to treatment can be defined as a daily increase in Hemoglobin concentration of 0.1 - 0.3 g/dl or 1% rise in Hematocrit daily from the fourth day onwards. Reticulocytes increase within 3 to 5 days of initiation of treatment, reaching a peak at 7 - 10 days. Hemoglobin is virtually normalized after two months of therapy. With the onset of treatment, the patient shows rapid subjective improvement with the disappearance of fatigability, lassitude, pica, and other non-specific symptoms even before there is an increase in hemoglobin level.
Side-effects: Side-effects are probably related to dose and amount of elemental iron. They include gastrointestinal symptoms - heartburn, nausea, abdominal cramps, diarrhea, constipation, Blackish discoloration of tongue and teeth, etc.
Parenteral Iron Therapy:
This mode of administration should be resorted to only in cases where anemia persists due to the factors causing failure of oral iron therapy like:
- Intolerance to oral iron therapy
- Non-compliance
- Loss of iron at a rate too rapid for the oral intake to compensate for the loss (eg. hereditary hemorrhagic telangiectasia)
- Disorders of GI tract like ulcerative colitis, malabsorption, unable to maintain iron balance on treatment or hemodialysis.
- Donating large amounts of blood for autotransfusion programme.
It includes both intramuscular and intravenous iron therapy. The preparation most popularly used is iron dextran, which contains 50 mg/ml of elemental iron.
Intramuscular iron administration:
It is very painful and may cause serious allergic reactions. Hence, it is not used in children. IM injections are best given deep into the upper outer quadrant of the gluteal region and skin should be laterally displaced before injection (Z tract technique) to prevent iron staining of the skin. A dose of 0.25 cc should be given as a test dose IM, and if there are no reactions after 1 hour, then a full dose can be given.
Intravenous iron therapy: There are two methods employed -
- Infusion of iron dextran (diluted in ratio of 5 ml iron dextran complex in 100 ml of saline solution). Initially flow rate should be kept at 20 drops per minute for 5 minutes, if there are no side-effects, then the rate may be increased to 40-60 drops per minute.
- Bolus iron dextran (diluted in a small volume).
Both are however given only after a prior sensitivity testing with intravenous test dose injection. Infusion therapy is associated with a higher incidence of adverse effects as compared to bolus treatment. Nevertheless, both forms of treatment are not spared from anaphylactic reactions. This must be taken as a word of caution against the use of intravenous iron therapy.
Side Effects: Reactions to both IM and IV therapy are either immediate or delayed.
Immediate: This includes pain in vein injected, flushing, metallic taste. Such reactions are brief in duration and often are relieved immediately by slowing the rate of injection. Other immediate side-effects include hypotension, anaphylaxis with cardiac arrest, headache, malaise, vomiting, nausea, etc.
Delayed reactions: They include regional lymphadenitis which may be tender for several weeks, myalgia, arthralgia, fever, etc. Most of the reactions though are mild and transient, the anaphylactic reactions may be life-threatening. Hence one should keep ready Inj adrenaline, Inj Hydrocortisone, and measures of resuscitation handy before injection is started. The reported incidence of reaction varies from 13 - 26%.
Total dose of iron to be given intravenously is calculated by follows:
Dose of iron (mg) = Wt (kg) x Desired increment of Hb (gm/dl) x 3.
We tried this modality of treatment in 100 of our patients. The results were as follows:
- Certainty of the dose was established.
- Administration was assured - i.e. compliance by patient eliminated.
- Hematological response was achieved more rapidly though there was no statistical difference as compared to oral iron therapy.
- Adverse reactions commonly encountered in our series were as follows:
* Fever in 50% of patients
* Arthralgia in 19%
* Vomiting 5%
* Allergic reactions causing skin rash, flushing with sweating 3%
* Local pain along with the vein 2%
* 3 patients had anaphylaxis or vasogenic shock, needing resuscitation and hence we do not recommend total dose iron therapy parenterally in children routinely.
Conclusion
In conclusion, iron deficiency anemia is the commonest type of anemia seen in as high as 70 - 80% of children in India. The commonest causes of this are faulty dietary habits with recurrent infections and infestations. It is easily preventable and treatable by simple, safe, and cheap oral iron therapy.
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