Iron Deficiency and Health Consequences?

K N Agarwal

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K N Agarwal.

Department of Pediatrics, University College Medical Sciences and GTBH, New Delhi, India.

ADDRESS FOR CORRESPONDENCE
Dr K. N. Agarwal, Professor Pediatrics, University College Medical Sciences & GTBH, Delhi-110095. Email: kna_noida@hotmail.com

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Historically (1500 B C) in Ayurvedic literature Charak Samhita described fatigue and pallor due to bloodlessness, which can be cured by Lauha bhasma (Calcified iron). During the same period, Egyptian manual of therapeutics 'Ebers Papyrus' described the disease characterized by pallor, dyspnoea and edema. In Greek literature (1554 - 1700) "Chlorosis/Demeorbo Virgineo or green sickness were described as curable by drinking iron rust dissolved in water or wine.

Anemia is the late manifestation of deficiency of nutrient(s) needed for hemoglobin synthesis. Most of the anemias are due to inadequate supply of nutrients like iron, folic acid and vitamin B12, Proteins, amino acids, vitamins A, C and other vitamins of B-complex group i.e. niacin and pantothenic acid are also involved in the maintenance of hemoglobin level. (1)

In India, anemia affects an estimated 50 percent of the population (2). In women, anemia may become the underlying cause of maternal mortality and perinatal mortality (3). Anemia also results in an increased risk of premature delivery and low birth weights. Iron deficiency in late pregnancy results in poor fetal iron stores (4,5). Latent iron deficiency is known to alter brain iron content and neurotransmitters irreversibly in fetal life and postnatal babies (6). These aspects have been reviewed. (7)

Current knowledge in the development of iron deficiency: (1,2)
Iron deficiency is an end result of a long period of negative iron balance mainly due to poor dietary availability, rapid growth and blood loss. The pathological stages are :

Prelatent deficiency:
hepatic (Hepatocytes and macrophages), spleen and bone marrow show reduced iron stores (Reduced bone marrow iron and serum ferritin).

Latent deficiency:
As the bone marrow iron stores become absent, plasma iron decreases and bone marrow receives little iron for hemoglobin regeneration (Bone marrow iron absent, serum ferritin < 12ug/l, transferrin saturation < 16% and free erythrocyte porphyrin is increased), however, hemoglobin concentration remains normal.

Iron deficiency anemia:
This is a very late stage of iron deficiency with progressive fall in hemoglobin and mean corpuscular volume (Table 1).

Table 1. Stages in the development of iron deficiency and available confirmatory tests

	Normal	Prelatent	Latent	Iron deficiency anemia
Bone marrow iron	Normal	Reduced	Absent	Absent
Serum ferritin (SF)	Normal	Reduced	<12	<12
Transferrin saturation (TF)	Normal	Normal	<16 %	<16 %
Free erythrocyte porphyrin (EP)	Normal	Normal	Increased	Markedly increased
Hemoglobin	Normal	Normal	Normal	Progressive reduction
Mean corpuscular volume	Normal	Normal	Normal	Reduced

Table 2: Cut off levels for iron deficiency tests

Age (years)	Serum ferritin (ug/l)	Transferrin saturation (%)	Free erythrocyte porphyrin (ug/dl RBC)
0.5 - 4	< 10	< 12	> 80
5-10	< 10	< 14	> 70
11-14	< 10	< 16	> 70
> 15	< 12	< 16	> 70

Health Consequences
Pregnancy outcome in anemia: (3,4)
In the case of moderate to severe anemia - breathlessness, edema, congestive heart failure and even cerebral anoxia have been observed. 200 anemic pregnant women observed in the University Hospital, Varanasi, showed reduced gestation, higher incidence of premature labor, preterm , low birth weight and still birth deliveries. In the newborns the Apgar score was low and there were increased number of neonatal deaths. Maternal mortality was 13 out of 200 anemic as compared to 1 in 50 control. Similar findings were reported in other Indian studies. Anemic mothers do not tolerate blood loss ,as little as 150 ml can be fatal. Normally a healthy mother during child birth may tolerate a blood loss of up to 1000 ml.

Magnitude of pregnancy anemia in India: (5,6)
As per ICMR studies (1985-86), 11 states data in 4775 women showed that 87.6% had hemoglobin < 10.9 g/dl. In 1987-89, 6 states data in 1968 women showed hemoglobin < 11.0g/dl in 62.3%, however hematinic response was found in 80%.Even District Nutrition survey data of 1999-2000 by the ICMR showed prevalence of hemoglobin < 11.0g/dl in 61, 79, 84, 91and 97% in the districts of HP, UP, Bihar, Assam and Kashmir respectively. These national data suggest high prevalence of nutritional anemia in pregnancy. The iron- folate supplementation as recommended in the national anemia control programme improved maternal hemoglobin, birth weight and reduced low birth weight deliveries (7).

Effects of iron deficiency on feto placental unit:
Studies by Vahlquist (8), Sturgeon (9) and Rios (10) demonstrated that inspite of maternal hypoferriemia and anemia, the cord blood hemoglobin, iron and ferritin levels do not differ in babies born of anemic and non-anemic mothers. This may be true for women with good iron stores and nutrition in developed countries. Recent studies in UK (11) have also shown that higher hemoglobin gain with iron supplementation could be a risk for increased preterm and low birth weight deliveries. In contrast studies in India have shown that fetus suffers in maternal hypoferriemia. The findings are summarized below:

- Cord serum iron and hemoglobin were reduced in preterm as well as full term. There is an increased gradient in presence of maternal iron deficiency for transport of iron from mother to fetus but the transport remains proportionate to the degree of maternal hypoferriemia (12-14).
- Placenta plays an important role in maintaining iron transport to fetus. This process of iron transport is purely a placental function over which mother and fetus have no control, as placenta continues to trap iron even when fetus is removed in animals (15). Inspite of this efficient protective mechanism the placental iron content reduces significantly in maternal hypoferriemia. The placenta showed qualitative decrease in villous surface area, volume of villi and length of blood vessel, while surface area and volume of intervillous space was increased. These placental changes in anemia did not normalize on rehabilitation- suggesting "Maturational arrest" (16-18).
- Bigger the infant and more advanced the gestational age higher was the amount of iron in fetal liver, spleen and kidney. The tissue iron content increased steeply in last 8 weeks of gestation. Infant born before 36 weeks had half the iron content in hepatic reserve (19).
- Placental iron content reduces significantly in maternal hypoferriemia.
- Breast milk iron content is increased in maternal hypoferriemia (20,21).

Iron deficiency and the fetal brain :
Iron deficiency anemia in rat mothers results in low fetal brain content which did not improve inspite of rehabilitation in mid-gestation (22).There were changes in the dopamine, serotonin and gamma aminobutyric acid (GABA) systems in such fetal brains. Further the binding receptors of dopamine D2 decreased and GABA increased (23).

Latent iron deficiency-(No anemia but hepatic iron content reduced): The fetal as well as weanling rat brain iron content decreased irreversibly in maternal hypoferreimia. In the post weaning group iron content decreased in corpus striatum 32%, mid brain 21%, hypothalamus 19%, cerebellum 18%,hippocampus15%, but no change in medulla oblongata. In latent iron deficiency neurotransmitter changes were: a) marked reduction in levels of brain GABA and L-glutamic acid. Enzymes for biosynthesis of GABA and L-glutamate like glutamate decarboxylase and glutamate transaminase were also reduced. b) Binding of GABA receptor increased by 143%, glutamate receptor binding decreased by 63%. These findings indicate that iron plays an important functional role in the both excitatory and inhibitory neurotransmitter receptors and c) Whole brain and corpus striatum showed reduction in catecholamine, dopamine norepinepherine, tyrosine and monoamino oxidase, while tyrosine aminotransferase increased in corpus striatum, inspite of reduction in whole brain suggesting that latent iron deficiency induced irreversible neurotransmitter alterations (24-30). These changes were specific to iron deficiency as neurotransmitter alterations in fetal brain due to malnutrition get normalized partially of completely on rehabilitation (31-32).

Iron deficiency in fetal brain induces permanent neurotransmitter changes. This is an important observation as in pregnancy, anemia particularly the iron deficiency remains a public health problem in our country.

Iron deficiency in infancy and childhood: (3,4)
Iron deficiency without anemia (impaired hemoglobin production), includes children whose hemoglobin has fallen but not below the cut off to meet the definition of anemia: Their growth, physical activity and mental functions could be affected. On administration of iron rise in hemoglobin, confirms the diagnosis of iron deficiency (Responders). Further, in childhood to meet the needs of growth iron stores may be low or absent (Low/ no bone marrow iron), with reduced serum Ferritin (But not below the cut off level of < 10 ug/l). These were not iron deficient but vulnerable to develop. Once anemia sets in clinical manifestations appear as described below.

The prevalence of iron deficiency anemia is around 50-70% in rural as well as urban studies. In an ICDS block of northeast Delhi in the proximity of a medical school operative since 1979, in 523 children of 9-36 months of age, found 63.5% with <11.0g/dl of hemoglobin (7.8% had hemoglobin < 7.0g/dl) and 87.1% had serum ferritin < 10ug/l. This shows apathy in recognizing and controlling the most common nutritional anemia which is manageable.

Clinical manifestations in iron deficiency (anemia): (1, 2)
- Impairs growth in infancy
- Fatigue, irritability, palpitation, dizziness, breathlessness and headache
- Impairs muscular performance (Reduced levels of glycerophosphate oxidase in muscle produces lactic acidosis).
- Impairs psychomotor development and cognitive functions (See above neurotransmitter alterations). Develop 'Pica' for mud, clay fibre etc.
- Poor body temperature maintenance - due to reduced conversion of thyroxine (T4) to triiodothyronine.
- Rarely increased intracranial pressure
- Epithelial changes(in order of frequency): gastritis and achlorhydria; tongue- papillary atrophy, nails - softness, flattening, koilonychias (rare below 5 years of age-iron is supplied for tissue growth by breakdown of hemoglobin) and dysphagia (common in females- Plummer-Vinson syndrome) for solid foods, with discomfort in neck near the cricoid cartilage. The condition is reversible on iron therapy before formation of web/stricture.
- Spleen is palpable in 10%
- Skeletal changes like those in chronic hemolytic anemia (33).

Iron requirements: (1,2)
In pregnancy: the red cell mass increases by 17-25% with an overall increase in blood volume by 43% (maximum by 24 wk) and to maintain PCV levels of 40-50% as much as 450 mg of iron is needed. The additional needs were fetus 280 mg, placenta and umbilical cord 90 mg, maternal blood loss 150 mg obligatory blood loss from gut, etc - 230 mg (Total 1200 mg). It is estimated that 2/3 of the fetal iron is utilized in the formation of hemoglobin, while 1/3 is stored in the liver as ferritin to serve as iron deposit for first year of life.
In growing children: A newborn baby has 0.25 to 0.30 g of iron (80-90 mg/kg) as compared to adult male 3.5 g (50 mg/kg) and female 2.1 g (35 mg/kg). To make up this, atleast 0.8 mg must be absorbed daily for over 15 years of age. During 4-12 months of age 0.8 mg of iron daily provides 0.6 mg for growth and 0.2 mg to balance losses. Breast and cow milk contain around 1.5 mg of iron per 1000 calories (0.5-1.0 mg/l), the high bioavailability (49% absorption) from the former provides sufficient iron till the infant doubles birth weight. Iron supplementation is required in cow milk fed babies (10-12% absorption of available iron). An adult meets iron requirements by 95% recycled iron, in contrast an infant of 1 year needs 30% iron from the dietary sources as available recycled iron is 70% only. Thus, iron rich diet during weaning and in growing years of life is very important. The iron requirements at different age and stage of growth were summarized in table 3

Age	Iron needs in mg/kg	Start at age	Note
Birth weight gm< 1000	4	1 Month	Vitamin E deficiency
Birth weight gm1000-1500	3	1 Month	Vitamin E deficiency
Low birth weight	2	2 Months	Nil
Full term	1	4 Months	Nil
Upto 10 years	10 mg/ day
> 11 years (Girls)	15 mg/day
> 11years (Boys)	12 mg/day
Pregnant	30 mg/day

Lactation needs are met by saving of 20-25 mg of iron in amenorrhea every month. Fortunately, in India cow's milk is always boiled before feed, this removes heat labile milk component causing sub-clinical bleeding in gut. In addition, boiling in cast iron utensils provides easily absorbable dietary iron.

Measures to control iron deficiency
Available iron in food: Food has primarily non-heme iron (From cereals, legumes, etc) as ferric complexes, which partly convert to readily absorbable ferrous form during digestion (Hydrochloric acid in stomach).The absorption of iron from non-heme containing food is 1-6%. In contrast heme iron from flesh and sea foods has absorption of 20-30%. Iron absorption is enhanced from diets having ascorbic acid/vitamin C (Fruit juices, green leafy vegetables) and other organic acids e.g. citric, malic and tartaric acid. The process of fermentation/germination and malting increases vitamin C, lowers phytic acid and tannin contents. The dietary iron absorption inhibitors were cereal bran, phytates, fibre, oxalic acid, polyphenols (Tannin), soya protein, calcium and zinc. While planning supplementation of iron/fortification of food items, the above dietary aspects should be kept in mind.

Promotion of regular consumption of foods rich in iron:
- Baby should be breast fed colostrum and mature milk. Both have 49% absorbable iron. This is sufficient with available stores till baby doubles the birth weight.
- Weaning foods from 4 months onwards should have one iron rich dietary item and iron supplementation be given as recommended. If cows milk is used as complementary and weaning food boil it in cast iron pot to get enriched with absorbable iron.
- Green leafy vegetable rich in iron-mustard leaves (Sarson saag), amaranth (Chaulai saag), colocasia leaves (Arvi saag), Bengal gram greens (Channa saag), shepu of sow, turnip greens (Shalgum saag), radish green (Mooli saag), spinach (Palak saag). Include one or more of these items in family meal.
- Cereals and sprouted pulses
- Vitamin C rich - lime, lemon, orange, amla, green mango etc.
- Jaggery (gur)
- Meat ,fish, liver etc.

Availability of dietary iron by cooking in cast iron utensils: WHO 1992 (34) prevalence of pregnancy anemia report, records that lowest rates of anemia of all the sub-regions of the developing world were observed in southern Africa, due to wide spread use of iron cooking pots by indigenous people. Lal et al (35) had demonstrated that cooking in cast iron utensils, which were traditionally used in Indian families until 4 decades back for boiling milk, cooking vegetables etc, provided extra dietary iron. Cutting by cast iron knife and cooking without washing the potato doubled the iron content. This available dietary iron is well absorbed.

Anemia control by food fortification:Studies conducted since 1970 on fortifying a broad range of foods and condiments have led to the successful use of two forms of iron for food fortification: iron EDTA and hemoglobin. Iron EDTA has been highly effective in fortification trials with Egyptian flat breads, curry powder in South Africa, fish sauce in Thailand, and sugar in Guatemala, to name only a few examples. In Grenada, flour used in commercial baking is enriched with iron and B vitamins. Indian researchers have field tested with success iron fortified salt. In India, the cost of fortification increases the price of salt by about 20%, while adding iron to sugar in Guatemala raised its cost by only 2%. It should be noted, however, that the price of salt is low and the amount consumed every day is small, so that a 20% increase is still acceptable. It is estimated that the cost per person per year in a large scale programme of fortification with iron is about $ 0.20-0.30. The cost would probably be double if ascorbic acid was added as well.

Regular weekly/ bi-weekly/ iron supplementation: In rats, iron administered (weekly/biweekly) was equally effective as compared to daily dosing, relating it to mucosal renewal time (36,37). The available studies (38,39) and our data (In press) tentatively conclude : a) In pregnancy daily iron dosing is needed to provide iron stores. b) In growing children with mild to moderate severity of iron deficiency - biweekly or weekly therapy is effective. However in moderate to severe iron deficiency areas, to meet growth needs, daily iron is required. c) Adolescent girls do well on weekly iron supplementation. Thus weekly iron supplement was effective in all the groups' a-c , as it reduced the risk of developing anemia.

Compliance with Ethical Standards

Funding None

Conflict of Interest None

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