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As early as 5th century B.C., the relation between fever and convulsions in children has been documented by Hippocrates.31 Febrile seizures was recognized as a distinct clinical entity, separate from other types of convulsions in early childhood, only by 1980.32
The International League Against Epilepsy (2009) defines Febrile Seizure (FS) as 'a seizure occurring in childhood between 6 months and 6 years of age, associated with a fever more than 38ï‚°C (rectal temperature) not caused by an infection of the central nervous system, without previous neonatal seizures or a previous unprovoked seizure and not meeting criteria for other acute symptomatic seizures.33
3.1.3 TYPES OF FEBRILE SEIZURES
Febrile seizures are of two types: simple or typical FS and complex or atypical FS.
Simple febrile seizure is one in which seizures occur within 24 hrs of onset of fever, are of generalized tonic clonic in nature, lasting for not more than 15 minutes, is followed by a brief period of post ictal drowsiness and occurs only once in 24 hrs. 1,2
Complex or atypical febrile seizure is one in which the duration is >15 minutes or when a focal seizure activity is present or recur more than once in 24 hours or when focal findings are present in post ictal period. 1,2,34
GEFS+ (Generalized Epilepsy with Febrile Seizure plus) is an autosomal dominant syndrome. It is characterized by multiple FS and several types of afebrile generalized seizures.1Four gene mutations have been identified to date, these are the SCN1A, SCN2A, SCN1B genes and the GABARG2 gene 1,35
Dravet syndrome is considered to be the most severe of the phenotypic spectrum of febrile seizures plus. Its onset is in the 1st yr of life, characterized by febrile and afebrile unilateral clonic seizures. They are more prolonged, are more frequent, and come in clusters. This syndrome is usually caused by a new mutation located on 2q24-31 and encodes for SCN1A, the same gene mutated in GEFS+ spectrum.1,35,36
Incidence - Febrile seizures occur in 3-4% of children.1. Studies conducted worldwide, indicate that the cumulative incidence of FS vary from country to country 2-5% in Western Europe and USA, 8.8% in Japan and 14% Guam.36
Earlier studies done in our country showed that 10% of our Indian children experience at least one episode of FS37 but recent studies show that the rate is only 4-5%, 38which is similar to that of the western world.1,6
Age - Though FS could occur anytime between 6 months and 6 years of age, 1,33 the median age of onset is 18 months,1,6 and half of children present between 12 and 30 months. 39
Sex- Boys are consistently reported to have a higher incidence of FS than girls, although this is statistically not significant. (M:F :: 1.7:1) 39,40
Seasonal variation - The incidence of FSs may show seasonal variation, but the patterns are complex and probably quite local, reflecting the epidemiology of childhood infectious diseases 25
The pathophysiology of FS remains unclear even after decades of studies on it. Several factors have been proposed.
126.96.36.199 Febrile Seizures and Immature Brain
It is believed that febrile seizure is the response of an immature brain to fever. 40
This postulation is supported by the fact that most of the FS, about 80-85%, occur between 6 months and 3 years of age.36 During this period of brain maturation, important changes are occurring in the neurotransmitter systems (GABA & other neuromodulatoy peptides) and in voltage-gated ion channels. It is suggested that these changes confer upon the infants' brain an enhanced excitability and vulnerability to FS. 40
A positive family history for FS can be elicited in 25-40% 1,2,6, of children with FS, and the reported frequency in their siblings ranges from 9-22%.39 indicating that there is a definite genetic influence.
Also, familial clustering studies indicate a doubling of risk in children when both parents, rather than one parent, had FS34 Similarly, studies have shown a higher concordance rate in monozygotic as compared to dizygotic twins.34,35,36,39
Although there is clear evidence for a genetic basis, the precise mode of inheritance is unclear. Linkage studies mapped the FS susceptibility genes to several loci, FEB 1, 2, 3, 4, 5, 6, and 7 genes on chromosomes 8q13-q21, 19p13.3, 2q24, 5q14-q15, 6q22-24, 18p11.2, and 21q22 indicating an autosomal dominant pattern with reduced penetrance.1,42,43
188.8.131.52 Fever-Related Mechanisms
Although the essential precursor of a FS is necessarily a fever, no definition provides at what specific temperature FS occurs.6 Over the years, an axillary temperature of >38Â°C as a cut off level has been proposed, but there is still no consensus.40 It has been suggested that the height of the fever and the rapidity of the elevation of temperature are both involved in triggering a seizure.36 Variations in temperature have effects on almost all cellular events. Hyperthermia can provoke several neurological disorders, including febrile seizures.44
Hyperthermia and Alkalosis- In human infants withÂ FS,Â the increase in the rate of breathing lead to hyperventilation (defined as a loss ofÂ CO2) and respiratory alkalosis.45 A rise in pH leads not only to an increase in neuronal excitability but often also to epileptiform activity.41,45
Inflammation - In some of the animal studies, some pro- inflammatory markers (Tumor Necrosis Factor-alpha, Interleukin-1alpha, Interleukin-1beta and Interleukin 1R) have been shown to be of significance in the etiopathogenesis of FS. This is supported by another recent observation in which, children with FS had higher concentrations of the same markers in their CSF. 34,35,41,46
Common childhood infections of viral and bacterial etiology have been comprehensively reviewed and are now shown to be important causative factors of FS. 1,41,47
The following viruses have been implicated in the occurrence of FS - influenza A and B, respiratory syncytial virus, 45 enterovirus, rotavirus and human herpes virus infection.47
Studies to date have implicated Shigella dysenteriae, Salmonella enteritidis, Streptococcus pneumoniae, and Escherichia coli in relation to FS.47
For over 50 years, concerns have been raised about the risk of vaccine-induced FS and epilepsy. Many studies have been done. A significantly elevated risk of FS on the day of receipt of DTP vaccine and 8 to 14 days after the receipt of MMR vaccine was proposed which corresponds to the time at which these vaccines induce fever. 1,41.48
184.108.40.206 Structural Brain Defects and Perinatal Events
Currently there is conflicting evidence linking cerebral disgenesis, neonatal brain injuries, low APGAR scores, premature birth, delayed discharge from the neonatal intensive care unit to the occurrence of FS.36,41
220.127.116.11 Trace Elements
Evidences indicate that the deficiency of some trace elements can play a role in the occurrence of FS.49,50,51
Zinc regulates the activity of glutamic acid decarboxylase which plays a role in producing GABA receptors.49
Magnesium is needed for enzymes that play role in cell membrane stability and nerve conduction.49
Copper inhibits Mg++-adenosine triphosphatase (ATPase) and Na+-K+-ATPase enzymes and disturbs the sodium and potassium homeostasis, which results in genesis of epileptiform discharges.49
Selenium is essential for Glutathione peroxidase and thioredoxin reductase, antioxidant enzymes. Reduced activity of antioxidative defense mechanisms can cause some forms of seizures and in addition, increases the risk of seizure recurrence.50
18.104.22.168 Role of iron
Iron deficiency has been postulated as a risk factor for febrile seizures. Its association with FS was first observed and published in mid 90's in an Italian study done by Pisacane, et al., 18 in which 293 controls and 146 patients aged between 6 to 24 months were studied. Iron status was measured by hemoglobin, MCV and serum iron and the study showed a significantly higher rate of iron deficiency anemia in patient with FS as compared to controls. This was followed by few more international studies.19-27 In 2001, in a study by Naveed-ur-Rehman, 21 5 parameters i.e. hemoglobin, hematocrit, MCV, MCH, and serum ferritin were studied all of which were found to be low in cases with FS.
Daoud et al.19 in 2002 concluded that only a low plasma ferritin level correlated with FS, but there was no significant difference in hemoglobin and MCV.
In 2009, Hartfield and colleagues,20 from University of Alberta, Canada reported in a retrospective study that children with FS were twice as likely to have iron deficiency as those with febrile illness alone.
In 2010, Momen et al.21 along with hemoglobin and serum ferritin levels studied 2 other parameters - serum Iron and total iron binding capacity (TIBC) levels. There was no significant difference in Hb, Iron and TIBC but ferritin level in the case group was significantly lower than the control group. Similar study was done by Khalid et al.23 in Iraq but in this study all the parameters were significantly low in children with FS.
In India, Vaswani et al. 22 studied fifty children between 6 months and 6 years with the first episode of FS (cases) and 50 children with febrile illnesses but without convulsions (controls). Iron deficiency was determined by measuring hemoglobin, red blood cell indices and serum ferritin. Serum ferritin level was significantly low in children with the first episode of FS (12). In yet another case-control study done in the Indian population in 2012, 25 it was reported that iron deficiency is a modifiable risk factor for simple FS in age group 6 months to 3 years.
Some international studies denied any role of iron insufficiency in FS. 26,27 In 1995, Kobrinsky et al 26suggested that iron deficiency anemia raised the seizure threshold. In 2006, Bidabadi et al27 suggested that iron deficiency anemia was less frequent in cases with febrile convulsions compared to the controls. This may be explained by the fact that the study population was small (25 children with febrile seizures against 25 febrile children without seizures) and their criteria for assessing anemia were only based on blood hemoglobin level and blood indices, without measuring serum ferritin level. These parameters do not reveal the real bone marrow iron storage status.
Risk Factors for First Febrile Seizure
A study done in the Iranian population showed that gender, family history of FS, breast-feeding duration, and body temperature are among the risk factors associated with first FS. 52 Presence of upper respiratory infections, prematurity, labor difficulties and prenatal exposure to cigarettes, coffee and alcohol as risk factors for FS was shown in yet another study.54
In a case control population-based study, four factors were associated with an increased risk of FS: 1,33,51,53
(1) First or second degree relative with a history of febrile seizures
(2) Neonatal nursery stay of 30 days
(3) Developmental delay
(4) Attendance at day care.
There is a 28% chance of experiencing at least one FS for children with two of these factors
What are risk factors for recurrence?
The most consistent risk factors reported are a family history of FS and first FS at 18 months of age. 1, 2, 3, 34, 36, 51, 53
In one study, those with peak temperatures of 101Â°F (38.3Â°C) had a 42% recurrence risk at one year. The recurrence risk at one year was 46% for those with a FS within an hour of recognized onset of fever.6,
In a study in Riyadh, four major risk factors for recurrent FS were identified: early age at onset (< 12 months), first-degree consanguinity of parents, epilepsy in a first-degree relative, and complex initial FS.55
Are febrile seizures benign?
Risk of developing epilepsy
Accumulating evidence indicates that children with FS have a slightly higher incidence of epilepsy compared with the general population (2% versus 1%).1,3,51,56
And the proposed risk factors for epilepsy later in life include:1,56
Family history of febrile seizure or epilepsy
Complex febrile seizure
Neurologic abnormality prior to first FS
Most population based studies have shown no obvious association between FS and the later development of neurological deficits. 1,17,57
Febrile Seizures and Mesial Temporal Sclerosis
Mesial temporal sclerosis and FS has long been a debatable issue. Epidemiological data do not suggest that mesial temporal sclerosis is a cause of FS; it is more likely to be an association. 1,58
Approximately 5% of FS meet the usual definition of status epilepticus and about a quarter of all episodes of convulsive status epilepticus in children are febrile.35,59
Most population studies have shown no increased risk or incidence of mortality in children with FS, including febrile status epilepticus. 32,59
A detailed history is mandatory. 1,2 The history should elucidate the details of the seizure activity, symptoms of CNS infection if any and should also explore the illness triggering the febrile seizure, looking in particular for any clues to the likely source of the infection. 2,6 The examination should include a thorough search for the source of the fever along with looking for evidence of any signs suggestive of a intracranial pathology.1,2,6
Laboratory investigation is not always required. 1,2,6,60,61
Lumbar Puncture (LP) 1,60,61
In 2011, the AAP has recommended in a child with fever and seizures the following conditions in which lumbar puncture can be considered:61
In any child who has meningeal signs and symptoms or in whom history or examination suggests the presence of intracranial infection.
In any infant <12 months of age who is considered deficient inÂ Haemophilus influenzaeÂ type b (Hib) orÂ Streptococcus pneumoniaeÂ immunizations or when immunization status cannot be determined.
Any child with FS who is pretreated with antibiotics
Electroencephalogram - If the child is presenting with first FS and is otherwise neurologically healthy, an EEG need not normally be performed as part of the evaluation. 1,60,61
According to the AAP practice parameter, a CT or MRI is not recommended in evaluating the child after a first simple FS. 1,60,61
Blood studies (serum electrolytes, calcium, phosphorus, magnesium, and complete blood count [CBC]) are not routinely recommended in the work-up of a child with a first simple FS. 1,6,60,61
Control the seizure
Most often the FS has already ended spontaneously by the time a child is brought to a physician.62 Intravenous Benzodiazepines or rectal diazepam should be given, 1 alternatively, buccal or intranasal midazolam may be used.63 Intravenous lorazepam has also been found to be effective in stopping FS, with the added advantage of it being a safer drug with slow distribution and lack of accumulation after single bolus. 64
Long term management of febrile seizures
The AAP in 2008 concludes that, neither continuous nor intermittent anticonvulsant therapy is recommended for children with 1 or more simple FS.65
In situations where parental anxieties remain high or when the child is at risk for recurrence, oral benzodiazepine (diazepam or clobazam) at the onset of febrile illness is an effective measure in reducing the risk of recurrence.1,65
A potential drawback is that seizure could occur before fever is noticed. The sedation associated can mask the evolving signs of meningitis and this therapy does not decrease the incidence epilepsy later. 65
Phenobarbital is effective in preventing the recurrence of simple FS. 65 The adverse effects include hyperactivity, irritability, lethargy, sleep disturbances, and hypersensitivity reactions. 65
Control of fever
AAP guideline on long term management of FS 2008,65 has concluded that no studies have demonstrated that antipyretics, in the absence of anticonvulsants, reduce the recurrence risk of simple febrile seizures.
In comparison with other diseases, febrile convulsion, despite its excellent prognosis, is a cause of high anxiety among mothers.1,6,7 After an initial FS, parents can develop persistent fear of fever, of their recurrence and of future epilepsy - all of which negatively affect their family life.120, 121 Therefore, reassuring and counselling parents is one of the most important aspects of management of febrile seizures. 7
Iron is the sixth most abundant elementÂ in the Universe.28 It is essential to most life forms and to normal human physiology.10
In the human body, iron is present in all cells and has several vital functions. 10 It is an essential element for the growth and development and is important for many physiological processes in the body.10.66
Functions of Iron in the Body
1. Oxygen Transport and Cellular Respiration:
Iron is an important component of several respiratory proteins and respiratory enzymes. 66 Several mitochondrial proteins within the cells including cytochromes contain iron and these are both haem proteins and non haem iron-sulphur complexes.Â Several of the citric acid cycle enzymes like aconitase, succinate dehydrogenase, isocitrate dehydrogenase require iron as the essential cofactor for the enzyme activity.Â Hence deficiencies of iron in these molecules can affect cellular respiration. 10
2. Bactericidal activity and oxidant damage:
Several enzymes which are involved in the production and break down of hydrogen peroxide are iron containing enzymes. Iron plays a role in specific and non specific immune function by involving in T cell activation and neutrophil myeloperoxidase activity in microbial killing. 67
3. Porphyrin metabolism:
Certain porphyrin metabolizing enzymes like Haem synthase, Uroporphyrinogen decarboxylase are under the feed back control of iron. In the absence of iron, cellular respiration is affected and the cells are metabolically compromised causing; (i) cells may not be in a position to carry out their assigned function. (ii) cells may not be able to reproduce or divide, as these need energy and the energy is derived from cellular respiration and oxidative phosphorylation (iii) finally cells may die by apoptosis. 10
4. Pigment metabolism:
Iron is intimately concerned with melanin metabolism as the enzyme phenylalanine hydroxylase, homogentisic oxidase requires iron for formation of homogentisic acid and melanin quinones. 10
5. DNA and RNA metabolism:
The enzyme ribonucleotide reductase responsible for converting ribonucleotides to deoxyribonucleotides, requires iron for its optimum action. Xanthine oxidase, which is involved in oxidation of purines also requires iron as one of the cofactors. 10
6. Cytochrome P-450 and drug metabolizing enzyme:
Cytochrome P-450 and a large number of drug metabolizing enzymes contain heme iron as an essential component. 10
IRON AND BRAIN
Brain contains higher concentration of iron than any other metal.14
Studies have revealed that brain iron content is maximum at birth, decreases during early infancy and again increases during weaning.11 This high iron content is essential for neuronal differentiation, myelin lipid and receptor formation.13,14
Iron in brain has heterogenous distribution with basal ganglia, substantia nigra and deep cerebellar nuclei being richer in iron content.11
Brain iron is required for normal oligodendrocytic functioning and myelination.11,69 Iron is required for synthesis of neurotransmitters like dopamine, serotonin, nor-epinephrine and epinephrine by tryptophan hydroxylase and tyrosine hydroxylase enzymes and for normal brain metabolim.30,68,70,71 It is an important component of enzymes required for DNA synthesis, respiratory chain and lipid metabolism.10,14
Iron has also been found to be an important component of neuronal monoamino oxidase. 11,13,70,71 Dopamine receptors are downregulated during iron deficiency72Â and there is an altered GABA metabolism in this condition.73
To summarize, the biochemical functions of iron are so basic for survival that iron deficiency is likely to interfere with function of every organ system in the body.Â 10,11,13,14,28,66-73
Iron deficiency has been recognized since medieval times.74
Iron deficiency (ID) is a state in which there is insufficient iron to maintain the normal physiological function of tissues such as the blood, brain and muscles.75
In clinical terms anemia is an insufficient mass of RBCs circulating in the blood;75 in public health terms anemia is defined as a hemoglobin concentration below the thresholds for the age and sex.76 Iron-deficiency anemia (IDA) occurs when the hemoglobin concentration is below two standard deviations (-2SD) of the distribution mean for hemoglobin in an otherwise normal population of the same sex and age.77
Epidemiology of Iron deficiency Anemia
Anemia is one of the most common and intractable nutritional problems of the world today. 30 Globally, anemia affects 1.62 billion people which correspond to 24.8 % of the population.29
The recent NFHS III (National Family Health Survey) survey conducted in India revealed that 70% of the under-five children were anemic.78 Inspite of measures being taken, the prevalence of anemia in children in age group 6-35 months has increased from 74% in NFHS II to 79% in NFHS III.78
Risk factors for Iron Deficiency and Iron deficiency Anemia:
Although the cause of IDA among young children can be multifactorial, the consumption of foods with low bioavailable iron is likely the primary contributing factor.76,77 Before 24 months of age, rapid growth coincident with frequently inadequate intake of dietary iron places children at the highest risk of any age group for ID.76
Etiology of Iron Deficiency Anemia
Poor intake of iron rich foods is one of the most common cause of IDA which may be due to low socioeconomic status, ignorance or food fads.76,77,79
Poor maternal iron stores is another important cause of ID, which might get manifested even in the first few months, in exclusively breast fed children. 77,79
Periods of increased demand in early childhood (6 months-2years), if not adequately compensated, leads to iron deficiency. 76,77,79
Poor absorption of dietary iron like in celiac disease and tropical sprue are some of the rare causes of IDA.77,79
The chronic blood loss, often occult, due to worm infestation, cow's milk protein induced inflammatory colitis, peptic ulcer, meckels diverticulum, polyp and inflammatory bowel disease is sufficient to deplete iron stores and lead to iron deficiency. 77,79
Repeated venepunctures in diseased young infants are an important iatrogenic cause. 77,79
Clinical Features of Iron Deficiency Anemia
The clinical features vary depending upon the severity of anemia.
The overt physical manifestationsÂ ofÂ ID include the generic symptomsÂ ofÂ anemia, which are tiredness, lassitude, feelingÂ ofÂ lack ofÂ energy, breathless on exertion, dizziness, dimness of vision, headache and anorexia.74-77,79
Clinical manifestationsÂ ofÂ ID are pallor of the bulbar conjunctiva, mucous membrane of the tongue and palmar creases, koilonychia (spoon shaped nails), glossitis and angular stomatitis.74-77
When the anemia is severe (<7 gms %), the child could present with hyperdynamic circulation with resultant palpitations, easy fatigability, decreased exercise intolerance. With even more low levels of Hb, congestive heart failure with tachycardia, systolic murmur and cardiac dilatation can occur.75
Dyspepsia can occur in Iron deficiency due to associated stomatitis and atrophic gastritis.79
Behavioral disturbances such as pica, which is characterized by abnormal consumptionÂ of non-nutritive items such as dirt (geophagia) and ice (pagophagia), areÂ often present in ironÂ deficiency but clear biological explanations for these abnormalities are lacking. 66,77
The exact role of iron in Breath holding spells (BHS) is uknown; abnormalities in catecholamine metabolism and various neurotransmitters are some of the proposed mechanisms.66
The increased incidence of thrombotic complications in IDA has been linked to various factors:66
- Increased erythropoietin level stimulating megakaryopoiesis, resulting in thrombocytosis.
- Increased oxidant stress, which in turn may result in a tendency toward platelet aggregation.
- Reduced deformability and increased viscosity affects the vascular blood flow.
Iron deficiency states may precipitate Rest Less leg Syndrome (repeated aphasic involuntary muscle contractions) in as much as 25-30% of people. In these children, MRI studies showed decreased iron content in substantia nigra and red nucleus.11,66
Iron deficiency in infancy produces alteration in cognitive performance.11 The biological basis is not completely understood but possibilities include: a) abnormalities in neurotransmitter metabolism b) decreased myelin formation, and c) alterations in brain energy metabolism. In the study by Lozoff et al 12 the reversal of the iron deficiency state did not produce an improvement in the test scores, suggesting that iron deficiency at a critical period of brain growth and differentiation may produce irreversible abnormalities.
Diagnosis of iron deficiency and iron deficiency anemia
There are many laboratory tests available for the detection of iron deficiency anaemia. These are as follows:
Hemoglobin (Hb): It is the most common test to identify the presence of anemia.77 Hemoglobin estimation by cyanmethemoglobin method is considered sensitive, rapid and inexpensive investigation for routine practice and at field level.77,79,82 The Hb concentration gives an estimation of degree of anemia, but, it does not distinguish between iron deficiency anemia and anemia due to other causes.76
WHO cut off values for diagnosis of anemia at different ages.79
Hb gm %
6 months - 6 years
6 years - 14 years
Adult females (non pregnant)
Adult females (pregnant)
Measuring serum ferritin level is a specific, sensitive and a reliable test for detecting iron depletion in the early stages of the disease and the best standard for determining the total body iron storage (WHO).82 Its values do not undergo diurnal variation and are not influenced by recent iron therapy; so it truly reflects iron stores. 80,81 Serum ferritin was given more importance in the diagnosis of pre clinical iron deficiency anaemia as other parameters compared to ferritin either lacked specificity or altered only in the later stages of IDA. 83,84 Techniques employed to assess serum ferritin are ELISA, Immuno-radiometric assay and radio-immuno assay.28,80
Serum ferritin is an acute-phase reactant protein and is therefore elevated in response to any infectious or inflammatory process. 79,81,83
Iron stores in bone marrow are also one of the tests for assessing preclinical iron deficiency. It is an invasive test and not freely available, hence it is not routinely applicable.79,81
Serum iron: It is one of the confirmatory tests for detection of iron deficiency anemia. It has diurnal variation with a peak in morning and fall in evening, which makes the normal serum iron level vary accordingly. Further, it may also be affected by chronic infection which limits the sensitivity of the test.
Soluble Transferin ferritin receptor (STfR) to log plasma ferritin concentration: It is the most sensitive method available to distinguish iron deficiency anemia from anemia of chronic diseases.79 If it is > 4 it indicates IDA and if < 1 indicates chronic disease.28,79-81
Free Erythrocyte Protoporphyrin: Erythrocyte protoporphyrin, is a precursor of heme and accumulates in red blood cells when it has insufficient iron to combine with and to form heme; so, in Iron deficiency anemia, its level in the blood gets elevated 79-81
Red blood cell indicies: It consists of Mean corpuscular volume (MCV), Mean corpuscular haemoglobin (MCH), Mean corpuscular haemoglobin concentration (MCHC) which all get decreased in iron deficiency anemia. MCV is more sensitive than MCH.
Red cell distribution width (RDW):
The red cell distribution width which is derived from the red cell histogram is an index of variation in the size of red cell and can be used to detect subtle degrees of anisocytosis. Normally the RDW ranges from 11.5 to 14.5 percent. An elevated red cell distribution width appears to be the earliest hematologic manifestation of iron deficiency.
Peripheral smear: Red cells in the blood film are hypochromic (there is increased central pallor) and microcytic (smaller than usual). There is anisocytosis and poikilocytosis. Target cells are often present. Red blood cell count is below normal. When iron deficiency is associated with vitamin B12 def or folate deficiency, a dimorphic blood picture appears i.e macrocytic as well as microcytic hypochromic blood picture.79-81
STAGES OF IRON DEFICIENCY77,79
There are three stages in iron deficiency, which occur sequentially:
I stage: Storage iron depletion (Pre-latent iron deficiency): if iron is not supplied to the body for some time, the available iron stores compensate and so get decreased or might become absent. At this stage the only abnormalities are decreased iron stores and increased iron absorption from the gastrointestinal tract without functional changes.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.
II stage: Iron limited erythropoiesis (Latent iron deficiency): If the negative balance persists, the second stage begins - iron-deficient erythropoiesis occurs. In this stage, work capacity may be reduced. At this stage, 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.
III stage: Iron deficiency anemia: As the negative iron balance continues, 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 and ferritn, increased TIBC and decreased transferrin saturation.