Iron Deficiency: Beyond Anemia-Juniper Publishers
Juniper Publishers-Journal of Pediatrics
Abstract
Iron deficiency is most common nutritional disorder
affecting at least one third of world population. Iron is crucial to
biologic functions, including respiration, energy production, DNA
synthesis, and cell proliferation. Impaired brain development and
cognitive, behavioral and psychomotor impairment are worrisome
manifestation of iron deficiency. Studies have demonstrated that some of
the changes occurring during period of brain growth spurt (<2 years
age) may be irreversible. Association of iron deficiency with febrile
convulsion, pica, breath holding spells, restless leg syndrome and
thrombosis is increasingly being recognized. Impaired cell-mediated
immunity and bactericidal function are generally noted in iron
deficiency however, the findings are inconsistent
Keywords: Iron deficiency anemia; impaired Cognition; Breath holding spells; Pica Febrile convulsion; Thrombosis; Infections
Introduction
It is estimated that more than 1.5 billion people
affected globally. One third of the world population suffers from Iron
deficiency anemia of which 90% live in developing third world. Iron is
the most important component of hemoglobin. Iron deficiency is the most
common cause of nutritional anemia and commonly occurs during period of
increased requirement e.g. in infancy, adolescence pregnancy and during
lactation especially among the people with poor socioeconomic status due
to inadequate intake of dietary iron, infestation, infections, and
malabsorption Anemia is just one manifestation of iron deficiency.
Pallor is seen over the face, palm, nail and tongue. The child may like
to eat inedible objects such as clay and mud (pica). The child may not
be playful and active because of easy fatigability Anemic children are
susceptible to develop frequent infection. Iron deficiency during early
life has been seen shown to slow neurodevelopment, cause attention
deficit hyperactivity disorders, reduce learning capacity, and
predispose to development of febrile convulsion. Iron deficiency result
in to conduct disorders, significantly lower scholastics performance,
reduces cognitive performance, breath holding spells and papilledema.
Pathophysiology
Iron plays an essential role in the synthesis of
hemoglobin. It is unique in that it takes up and releases oxygen with no
energy expenditure. Large amounts of the iron are recycled daily from
the breakdown from the destroyed red cells. Dietary iron occurs in two
forms. Heme iron from animal proteins is better absorbed than non heme
iron. Non heme iron is obtained from plant foods and vegetables and is
absorbed in the ferrous form mostly in the duodenum and to a lesser
extent in the jejunum and proximal ileum. Absorbed iron from the
intestinal lumen is transported with a divalent metal protein (DMT)
across the mucosal border. From the enterocyte the iron reaches the
plasma by the specific transporter proteins called ferroprotein. The
primary mechanism of iron homeostasis is regulated by hepcidin.
Hepcidin level decreases in iron deficiency and
increases in inflammation and iron excess. The elevated hepcidin blocks
the ferroprotein and limits the mobilization of iron in to the plasma.
Iron circulates the blood bound to the transferring. Bone marrow
erythroblasts have receptors for the iron transferrin complex and the
iron complex enters the cells by the endocytosis for the hemoglobin
synthesis. The absorption of iron is regulated by iron deficiency
(absorption increases), inflammation and iron repletion (absorption
decreases), mediated by hepcidin.
Over 90% of the dietary iron for infants and young
children are non heme iron. Only 10% of dietary non heme iron is
absorbed. The absorption of non heme iron is highly altered by the
dietary factors. Food rich in Vitamin C like orange juice, meat and fish
enhance iron absorption; calcium, phosphate, tannin in tae and bran
decreases the absorption. Breast milk iron, present in low concentration
is well absorbed; cow milk contains high level calcium and phosphorus
that interfere with iron absorption [1-5].
Stages of iron deficiency
First stage: A decrease in concentration of serum ferritin.
Second stage: Hb concentration is normal or
the normal range, low serum iron concentration and transferring
saturation, increase in total iron binding capacity.
Third stage: Decrease Haemoglobin associated with low MCV & MCH and high RDW (Figure 1).
Iron and Brain
Behavioral and cognitive dysfunction are must
worrisome manifestation of iron deficiency. Recent research has revealed
that anemia is late manifestation of iron deficiency, brain deficiency
occurs even with normal level of hemoglobin, as iron is most important
to red blood cells over all other organs including brain. The biological
basis of the behavioral and cognitive development delays due to
abnormalities in neurotransmitter metabolism, decreased myelin formation
and alterations in brain energy metabolism [6].
IDA and Infants < 2 years age
In Infants adverse effects of iron deficiency on
behavior are special concern because the latter part of brain spurt
coincides with the period in which iron deficiency anemia is most
prevalent (6-24 month). Observational studies have suggested that iron
deficient children have lower IQ scores, decreased attentiveness and
lower scores on tests of academic performance compare with non anemic
controls. These studies indicates that iron deficiency anemia in
infancy, perhaps of particular severity and chronicity, has irreversible
cognitive impairment [7].
IDA in Children > 2 years Age
Observational studies in children over 2 years have
reported poorer cognition and school achievement in iron deficient
children. Adolescent girls are prone to develop iron deficiency because
of poor dietary intake along with increased iron requirement related to
rapid growth and menstrual blood loss and are at greater risk of
cognitive impairment [8].
Preventive Trails
Two recent trials reported beneficial effects of iron
therapy in infancy. Developmental and behavioral benefits from iron
supplementation in infancy.
IDA and Pica
The word Pica is derived from latin root meaning
magpie, a bird capable of eating a variety of things. Lanzkowsky define
Pica as "a perversion of appetite with persistent and purposeful
ingestion of non nutritive substances like Pica includes geophagia (dirt
or clay ingestion) tricophagia (hair ingestion), amylophagia (starch
ingestion) and pagophagia (ice ingestion). It is a well documented
feature of iron deficiency anemia in children.
IDA and Breath Holding Spells (BHS)
The low hemoglobin cause rapid cerebral anoxia due to
decreased oxygen carrying capacity of blood that in turn lead to Breath
holding spells. Anemic children being irritable may be more predisposed
to breath holding spells. Iron therapy should more remarkable
therapeutic beneficial in controlling the spells in children with
evidence of iron deficiency. Iron has role as a cofactor in
catecholamine metabolism in central nervous system. Clinical profile and
hematological associations of BHS as result of interaction of cerebral
erythropoietin, nitric oxide and interleukin 1 [10-13].
IDA and Febrile Seizure
Febrile seizures are the most common type of
seizures, occurring in 2-5% of all children. Kebrinsky et al studied the
role of iron in febrile seizures and they reported significantly
increased incidence of iron deficiency in non seizures compared to
seizure group. Iron deficiency may increase frequency of febrile
convulsion. Exact etiology of febrile seizures is not known however
depend on metabolism of several neurotransmitters, enzyme activities and
cerebral erythropoietin has been postulated as causative factor for
seizures [14].
IDA and Stroke
Iron deficiency anemia is significant risk factor for
stroke in otherwise healthy young children. This increased incidence of
thrombotic complications in IDA due to various factors. Increased level
of erythropoietin in IDA has been incriminated to have a possible role
in stimulating megskaryopoesis, resulting in thrombocytosis. Recently,
Bilic & Bilic [5]
have reported that amino acid sequences homology of thrombopoietin and
erythropoietin may explain the thrombocytosis in children with iron
deficiency anemia. In addition to the increased thrombotic risk
associated with high platelet count, other possible mechanism suggested
is decreased in antioxidant defense in iron deficiency anemia result in
to increased oxidative stress, prone to develop platelet aggregation.
Reduced deformability and increased viscosity of microcytic red blood
cells in iron deficiency may contributory by affecting blood flow
patterns within the vessels. Furthermore, anemic hypoxia secondary to
iron deficiency could precipitate situations of increased metabolic
stress ( i.e. infection ) at risk area of brain supplied by end
arteries, such as the basal ganglia, thalamus and hypothalamus resulting
in stroke [15,16].
IDA and Restless Leg Syndrome (RLS)
Restless leg syndrome is characterized by repeated
aphasic involuntary muscles contractions. It is mostly reported in adult
patient and largely under reported from pediatric population. Although
most of the cases with RLS are idiopathic or hereditary; decreased brain
iron content and metabolism can lead to RLA. Iron deficiency state may
precipitate RLS in as much as 25-30% of people. MRI studies have
demonstrated decreased iron content in substantia nigra and red nucleus.
Fatigue decrease productivity and decrease learning capacity with iron
deficiency [17-20].
Iron and Infection
Iron is required for normal immune function, cell
differentiation and growth. Iron is also required for peroxide
generating mechanism, cytokine production and myeloperoxidase function
in neutrophil. Impaired cell-mediated immunity and bactericidal function
are generally noted in iron deficient children; however, the findings
are inconsistent. Impaired immunity result into repeated infection [21-25].
Iron and Temperature Regulation
Iron deficiency anemia more readily become hypothermic and have depress thyroid function.
Iron and Growth
Iron deficiency anemia result into impaired growth [26].
Celiac Disease
Malabsorption of iron and result into iron deficiency anemia [27].
Prematurity
Preterm baby due to low iron store and more to growth result into iron deficiency anemia.
Vitamin A and iron deficiency anemia
Deficiency of Vitamin A Limit Mobilization of Iron from Its Stored Site hence Causing Iron Deficiency Anemia [25].
Hook worn infestation
Having hook worn infestation in children decrease level of blood hence increasing iron demand.
Conclusion
Being most common nutritional disorder, it is
imperative to recognize effects and long term consequences of iron
deficiency Though anemia is common, iron deficiency state without anemia
is largely under-recognized. Studies have reported lower cognitive
scores even in children with iron deficiency without anemia.
Irreversible cognitive impairment has been reported in children who
experienced iron deficiency during period of critical brain growth
(<2 years of age). Iron deficiency anemia is highly prevalent in
India (reported 55.7% to 85.1% in different states in NFHS-3) and much
larger population having iron deficiency without anemia; hence it is
critical to recognize the cognitive impairment and treat early [28,29].
Point to be Remember
• Iron Deficiency is most common preventable nutritional deficiency in the world, especially among infants and young children.
• Prevalence of iron deficiency anemia among children under 5 year of age has been estimated to be 75% in India.
• Iron deficiency has adverse effect on physical, mental, emotional, cognitive performance.
• The role of iron deficiency in precipitating febrile convulsion breath holding spell, hyper cyanotic blue spell and infection.
• Iron deficiency has been frequent association
oftendency of pica. Pica is common symptoms which predisposes to
consumption of lead resulting in plumbism.
• Long term consequences of iron deficiency are poor growth & development, depressed immune function and behavioral changes.
• Serum ferritin along with C-reactive protein serves as best indicator of body iron store.
• The committee of nutrition of the American Academy
of Pediatrics recommends the hemoglobin <11 gm/dl and serum ferritin
<10 mcg/L as diagnostic of iron deficiency anemia in presence of
normal CRP.
• The absorption of iron is regulated by iron
deficiency (absorption increases), inflammation and iron repletion
(absorption decreases), mediated by hepcidin.
Acknowledgement
The authors wish to thank B.J Medical College Civil Hospital Ahmadabad for support this work.
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