Iron Deficiency Anemia

M R Lokeshwar*, Nitin Shah**
*Visiting Pediatrician - P.D.Hinduja National Hospital, Mumbai
Pediatrician and Hematologist-Oncologist,Lilavati Hospital, Bandra, Mumbai.
**Division of Pediatric Hematology-Oncology, Dept of Pediatrics, LTMG Hospital & LTM Medical College, Sion, Mumbai - 400 022.

First Created: 02/08/2001 

Introduction

Anemia is defined as a reduction in the oxygen-carrying capacity of the blood, as observed by reduced levels of hemoglobin concentration and red cell mass (Hematocrit) leading to tissue hypoxia. It reflects the disturbance of the dynamic balance between production and destruction of erythrocytes and hemoglobin. In normal subjects, the average life span of red cell i.e. time between the release of the red cell from bone marrow and its disappearance from circulation is between 100 to 120 days. The cells destroyed each day are replaced by new cells released from marrow, with the result the red cell population in the blood consists of cells ranging in the age from 1 to 120 days. Thus approximately 1% or slightly less of the body's red cells are destroyed and replaced each day. Any disruption of this balance - such as reduced production or increased destruction leads to anemia. The aged cells are removed from circulation by the reticuloendothelial system, where the flow of blood is slow, particularly in the splenic pulp. A child is said to be anemic when the hemoglobin and or Hematocrit are two standard deviations below the mean for that particular age and sex.

Table 1 gives the normal values (normal mean and lower limit of normal) of various hematological parameters at different age groups.

Table 1: AVERAGE NORMAL BLOOD VALUES AT DIFFERENT AGE GROUPS

AGE Hb (gm%) RBC (m/L) HCT% MCV (cu. mm) MCH (pg) MCHC% Reticulocyte%
1 day 18.0 5.14 61 119 36.0 31.6 32
4 weeks 14.2 4.0 43 106 35.5 33.5 0.6
1 year11.64.6357725.033.00.9
10-12 years13.04.8398027.033.01.0
Adult- Men16.05.4478729.034.01.0
Adult- women14.04.8428729.034.01.0

The lower limit of hemoglobin at the newborn period is 16 gm%, at 3 months - 9 gm%, 6 months to 6 years- 10 gm%, 7 to 12 years - 12 gm%. Thus 9 gm% - 11 gm% Hb is normal for a child around the age of 3 months needing no treatment and the same will represent severe anemia needing blood transfusion in the newborn period.

Classification and Etiology of Anemia:

There are four basic causes of anemia - loss, destruction, sequestration, and hypoproduction.

Anemia can be further classified by

  • RBC size: micro, normo, and macrocytic anemia.
  • RBC shape: e.g. Sickle cell.
  • Etiology

Etiological Classification of Anemia:

Nutritional Anemia: Anemia is a major nutritional global problem of immense public health significance, affecting persons of all ages, sex, and economic group. It is ranked as the commonest chronic malady of mankind affecting approximately 30% i.e. 1500 million people all over the world. It is a pathologic condition where hemoglobin or Hematocrit level becomes abnormally low because of low essential nutrients regardless of the causes of these deficiencies. In developing countries like ours, besides deficiencies of food-specific nutrients like iron, folic acid, B12 protein, vitamin C, vitamin E, trace elements, etc, poor health facilities, poor socioeconomic status, faulty dietary patterns, the degree of urbanization, ethnic background, prevalence of hookworm and other worm infestations, repeated bacterial infections, etc also influence the incidence of anemia particularly in children. The nutritional anemia has major consequences not only on the morbidity and mortality in children but also on affects the growth and intellectual development of these children.

In India, anemia is the most common nutritional problem affecting more than ½ of the total population, particularly in children and pregnant women where the incidence is 50 to 97%. It has been suggested that the prevalence of anemia in pre-school children, and pregnant women are a sensitive index of the situation in the community. Iron deficiency anemia in children occurs most frequently between the age of 6 months to 3 years and 11 to 17 years.

Stages of Iron Deficiency

Iron deficiency anemia is the end stage of a relatively long-drawn process of deterioration in the iron status of the individual. It is the only the tip of the iceberg of the iron deficiency state.

  • Storage iron depletion (Pre-latent iron deficiency):

    Iron reserve is decreased or absent in this stage. At this stage, the only abnormalities are decreased iron stores and increased iron absorption from the gastrointestinal tract. It is characterized by reduced serum ferritin, reduced iron concentration in the marrow and liver tissue. Hemoglobin, serum iron, total iron-binding capacity, and transferrin saturation are within normal limits.
  • Iron limited erythropoiesis (Latent iron deficiency):

    As the iron stores get exhausted, latent iron deficiency state develops. At this stage, in addition to already reduced iron stores (decreased serum ferritin), serum iron and transferrin saturation also are low with increased total iron-binding capacity and increased free erythrocyte protoporphyrin. However, hemoglobin levels are still normal.
  • Iron deficiency anemia:

    As the negative iron balance continues, now the production of erythroid cells in the marrow is impaired leading to reduction in hemoglobin concentration with development of progressive microcytic, hypochromic anemia. Thus, Hb, MCV, MCH & MCHC are reduced in addition to already decreased serum iron, increased TIBC, and decreased transferrin saturation. Transferrin saturation below 12 - 16% is diagnostic of iron deficiency state.

Etiology of Iron Deficiency Anemia (IDA)

Iron deficiency results when an insufficient amount of iron is available to meet the body's requirements. This can occur because of:

  • Decreased supply of iron due to:

    * Inadequate intake of iron

    * Reduced bioavailability of dietary iron

  • Decreased absorption of iron:

    Cause of iron malabsorption includes chronic diarrhea, malabsorption syndromes, milk allergy, sprue, partial or total gastrectomy, and rarely genetically determined absorptive defect specific for iron. Pica through may be a manifestation of iron deficiency, is also considered to be a predisposing factor for poor iron absorption.

  • Increased requirement of iron:

    as seen in premature babies during the first few months (as they have a rapid growth) and during the periods of growth as in infancy and adolescence, lactation, pregnancy.
  • Chronic blood loss:

    * Gastrointestinal bleeding: The chronic loss of few milliliters of blood daily is sufficient to deplete iron stores and lead to iron deficiency. Often these bleeds are occult and unsuspected. In the western world, milk induced enteropathy is the commonest cause of occult GI bleeding seen in approximately more than 50% of infants with IDA. Hookworm infestation is the other important cause of intestinal blood loss, particularly in developing countries. 450 million people all over the world harbor this parasite and about 0.2 cc of blood/worm of ankylostoma per day may be lost and with necator - infestation each worm accounts for the loss of about 0.1 - 0.5 ml/day. Female subjects harboring more than 100 worms (5 ml/day blood loss) and male subjects harboring more than 250 worms (12.5 ml/day blood loss) tend to become anemic. The daily blood loss may be as great as 250 cc/day.

    * Feto-maternal bleed: It is one of the important causes of anemia in newborn. In about 50% of all pregnancies, there is some degree of feto-maternal hemorrhage of which 8% is significant (0.5 - 40 cc fetal blood loss) and 1% severe (>100 cc fetal blood loss).

    * Repeated venepunctures for investigations, hemodialysis, regular blood donations are important iatrogenic causes of iron deficiency due to chronic blood loss.

Decreased Supply of Iron

Breast milk, the primary source of infant nutrition is poor in iron, containing 0.28 - 0.73 mg/lit as compared. However, the iron in breast milk has a very high bioavailability (20 - 80%) and hence iron deficiency rarely occurs in exclusively breastfed infants till the age of 4 - 6 months. Breastfeeding does not protect against iron deficiency after the age of 6 months unless iron-containing weaning foods are introduced. During adolescence, false concern about the body figure, food fads, ignorance, particularly in girls lead to iron deficiency.

Table 2 : ETIOLGICAL FACTORS IN IRON DEFICIENCY ANEMIA :

Decreased iron assimilationBlood lossIncreased physiologic requirement
  • Iron poor diet & poor bioavailability of Fe in the food
  • * GI bleeding Hookworm infestation,Peptic ulcer,Diverticulitis,
  • Prematurity
  • Iron malabsorption
    • Chronic diarrhea & Malabsorption Syndrome
    • Sprue
    • G. I. Surgery
Milk induced enteropathy
  • Aspirin & other drugs
  • Feto- maternal transfusion
  • Early clamping of cord
  • Bleeding disorders
  • Period of growth
  • Infancy
  • Adolescence
  • Pica
  

Table 4: FACTORS AFFECTING THE BIOAVAILABILITY OF THE DIETARY NON-HEME IRON

Enhance Ascorbic acid, meat, fish, poultry
InhibitTannates (tea, coffee), Bran, Egg Yolk, Calcium Phosphate, EDTA, Antacids, phytates, cholestyramine, clay, starch.

Iron Metabolism

An average adult has about 3 -5 grams of iron and children have 55 mg/kg/bodyweight of iron in the body. It is more in males as compared to females. 70% of the iron in the body is in the form of Hb, 26% constitutes the stores and 3.9% is incorporated in myoglobin and various other iron-containing enzymes. Plasma iron forms only 0.1% of the body iron.

Iron balance in the body is achieved mainly by control of the absorption of iron rather than its excretion. Body iron remains fixed within relatively narrow limits. Most of the iron is recirculated in the body. Only 1-1.5 mg of iron is excreted daily. Thus daily requirement is minimum. Absorption of iron mainly depends upon the dietary content of iron. Various foodstuffs with their iron content are listed in Table 3.

Table 3 : IRON CONTENT OF FOOD ARTICLES

Class of Food Iron content
mg/100 g
Articles rich in iron 
> 10 mg/100 g
Cereals 2.5-14.0 Bajra, Wild Barley, Kang Ragi, Rice flakes, whole wheat Flour, Kodra (Harik)
Pulses & Legumes2.7-11.0Bengal gram, Cow gram, Soya bean
Leafy Vegetables0.9-40.0Amaranth, Beet, Greens,Bengal gram leaves, Coriander, Alu leaves, Pudina, Neem, Radish top, Rajgira leaves, Turnip greens, all types of green bhajis. (Spinach, methi, lettuce, etc.)
Roots & tubers0.4-13.9 
Other Vegetables0.2-22.2Amaranth seeds,Daincha seeds
Nuts & oil seeds2.5-10.0Garden cress, Gingelly, mustard, Pistachio
Fruits
0.1-10.0Dates, Karwanda, Raisins
Sea food1.0-11.5Most Indian fish, crab
Meat2.0-18.8Beef
Milk0.2-0.8 
Miscellaneous Jaggery, Yeast

  • Non-vegetarian diet is the richest source of iron-containing 10-18 mg of iron per 100 grams.

  • Bioavailability of iron:

    Ultimate absorption of iron into mucosal cells mainly depends upon bioavailability of iron in the various foodstuffs. The non-vegetarian foods have iron (haem) with very high bioavailability and the absorption of this is not affected by any other factor in the lumen including various food ingredients. Absorption of iron from vegetarian sources is affected by various factors as shown in Table no. 4.

  • Mucosal cell control:

    Appropriate iron balance in the body is achieved by mucosal cell control through transferrin and apoferritin receptors. When the serum iron is normal and adequate, the iron gets incorporated into apoferritin in the mucosal cell and this is ultimately excreted after 3 - 4 days when the lifespan of mucosal cells is over. However, if iron deficiency state exists in the body, transferrin is utilized to combine with iron and is transported and stored at the storage site.

  • Iron transport and storage:

    Transferrin helps in the transport of iron from the intestine to the site of its utilization. Iron is stored in the body in the form of ferritin and hemosiderin.

  • Transport of iron across the placenta:

    The transport of iron across placenta occurs against a gradient, thereby protecting fetus against iron deficiency. However, this effective fetal parasitism is limited in cases of severe maternal iron deficiency. Thus babies with low iron stores may be born to mothers who are severely iron deficient during pregnancy. It is important to remember that most of the placental transfer of the iron occurs during the 3rd trimester of pregnancy. As a consequence of this, all preterm babies invariably develop anemia unless supplemented by iron and conversely iron deficiency in the mother may cause preterm labor.

Clinical Features

The effects of iron deficiency anemia are well known since ages and it is well established that iron deficiency is a systemic disorder involving multiple systems, rather than a purely hematological condition associated with anemia.

Age incidence:

IDA is most common in the 6 months to 3 years and 11 years to 17 years age groups. In all age groups, the development of anemia is almost always insidious and it may go unnoticed till Hb concentration drops to as low as 3 - 4 gm%.

Features due to anemia:

In mild anemia, there may be no signs and symptoms but a definite sense of well being and better exercise tolerance is observed following treatment. In severe deficiency, all the symptoms of anemia like fatigue, breathlessness, irritability, anorexia, etc. may be seen. Spleen is often enlarged slightly but is of normal consistency.

Other features:

Deletion of non-haem iron contained in tissue proteins is responsible for various other manifestations like:

  • Pica: It is a well-documented symptom but unexplainable. Pica is the habitual ingestion of unusual substances, the most common of which is eating mud or clay (Geophagia), laundry starch (amylophagia), and ice (pagophagia). Pica usually is the manifestation of iron deficiency and is relieved when the condition is treated. Clay can behave in the gut as an exchange resin and can interfere with iron absorption.

  • Changes in Epithelial cells: These include koilonychia, paronychia, angular stomatitis, atrophic glossitis, and mucosal changes in the stomach and small bowel leading to the mucosal web as seen in Plummer Wilson syndrome, Patterson Kelly syndrome which are rare in children.

  • Growth retardation: There is a marked reduction in weight in iron deficient children, thought height seems to be unaffected.

  • Exercise intolerance: Maximum work capacity, work output and endurance are impaired in iron deficiency state. This is due to a reduction in the mitochondrial enzyme - alpha pyrophosphatase dehydrogenase besides anemia. A study in Indonesia demonstrated a correlation between the work output of latex tapper and hemoglobin concentration. Work output was significantly less (19%) from tappers with iron deficiency anemia than from non-anemic tappers. Similarly, another study found a significant decrease in the area of the ground cleared of weeds by anemic laborers as compared with their non-anemic counterparts.

    The study done in Sri Lanka demonstrated a significantly smaller work output by anemic tea-pickers. In some of the studies, work output increased significantly following the correction of anemia by the administration of iron.

  • Behavioral changes: Theses changes occur due to diminished activity of aldehyde oxidase, required for serotonin catabolism, thus leading to increased levels of serotonin and 6 - hydroxy indole compounds. MAO which is also required for catabolism of catecholamine is also reduced. Reduced attention span, irritability, decreased scholastic performance, poor academic achievement, and conduct disorders occur in these iron-deficient children.

    In Egypt and Java, deficiency in the mental performance of school children was reversible with the treatment. They have shown in their study that intravenous iron administration reverses low scores of cognitive function even before hemoglobin rises. Behavior studies in Young iron-deficient rats, before and after iron replacement, have shown that rats are less responsive to environmental stimuli when iron deficient.

    In a study of iron deficiency in the rat, depletion of total non-haem iron and ferritin iron in the brain established shortly after the time of weaning, could not be reversed in spite of continuous supply of iron from that time until adult life. A study done by Dallmann et al have shown lower mental and psychomotor development index score significantly lower than control infants. Anemic infants failed specifically in language capabilities, body balance, co-ordination skills when compared with control. Iron deficiency affects attention span and memory control rather than information processing and retrieval. Webb and Oski also have found poor scholastic performance in anemic students. Gopaldas & associates noted a substantial improvement in cognitive function in anemic children after treatment with iron.

    Lokeshwar et al in their study of 36 children between the age group of 6 months to 18 months, demonstrated impairment of cognitive function in iron-deficient children and there was a significant improvement in MDI (Mental Development Index) and PDI (Psychomotor Development Index) after iron therapy.

  • Altered host response: Iron deficiency affects both cell-mediated as well as humoral immunity, though phagocytic activity may be normal. The killing of E.coli and Staph. Aureus is reduced. In contrast, some studies state that immunity is enhanced in an iron-deficient state. This is due to increased unsaturated transferrin which inhibits bacterial growth and hence high dose IV iron therapy could be harmful in such cases. However oral iron therapy only minimally changes the saturation of transferrin and hence practically it does not have any adverse effect on the incidence of infection. In several studies, results show that infants who receive iron supplementary formulae have fewer episodes of respiratory and gastrointestinal infections than those who receive unsupplemented formula.


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