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IRON METABOLISM AND IRON DEFICIENCY ANAEMIA
DR. ABOLARIN A.T
DEPARTMENT OF
HAEMATOLOGY
BUTH , OGBOMOSO
2nd most abundant metal in earth’s crust
Most common nutritional deficiency in the world
Low solubility requires complex system of absorption & utilization for living organisms from bacteria to humans
Still only 10% ingested Fe is absorbed by humans
Iron is essential for many metabolic processes. It shares with other transition metals two properties of particular importance in biology –
the ability to exist in more than one relatively stable oxidation state, Its ability to exist in both ferric and ferrous
the ability to form many complexes.
DISTRIBUTION OF BODY IRON
The concentration of iron in the adult human body is normally about 50 mg/kg in males and 40 mg/kg in females.
450mls of whole blood contains 200mg of iron
Iron is found in the following proteins
Haemoglobin (65%)
Ferritin and haemosiderin (30%)
Myoglobin (3.5%)
Haem enzymes (Cytochromes b, a and c as well as in the cytochrome P450 enzymes) 0.5%
Transferrin bound iron (0.1%)
Ferritin is the primary iron storage protein
It provides a reserve of iron.
It consists of an approximately spherical apoprotein shell (mol. wt = 480 000)
Human ferritin is made up Of 24 subunits (mol. wt c. 20 000) of two immunologically distinct types: H and L.
These are coded by genes on xsome 11 and 19 respectively
Haemosiderin is a water-insoluble crystalline, protein–iron complex, visible by light microscopy when stained by the Prussian blue (Perls’) reaction.
In normal subjects, the majority of storage iron is present as ferritin, and haemosiderin is predominantly found in macrophages rather than hepatocytes.
TRANSFERRIN AND TRANSFERRIN RECEPTORS
Transferrin is a single chain polypeptide (mol. wt = 79 500) present in plasma (1.8–2.6 g/L) and extravascular fluid .
The protein is synthesized predominantly by the liver, synthesis being inversely related to iron stores.
Two atoms of ferric iron bind to each molecule.
IRON ABSORPTION
Iron absorption depends not only on the amount of iron in the diet, but also on the bioavailability of that iron.
A normal Western diet provides approximately 15 mg of iron daily.
Only about 1mg of this amount is usually absorbed per day
in iron deficiency, the maximum iron absorption from a mixed Western diet is not more than 3–4 mg daily.
IRON ABSORPTION CTD.
2 pathways of iron absorption
Mainly occurs in the epithelial cells lining the villi close to the gastroduodenal junction
Inorganic [ non haem ]Fe3+ is reduced toFe2+ by Duodenal cytochrome b [ Dcytb] \ ferroreductase at the brush border of the duodenum
Enters the labile Iron pool in the enterocyte via the divalent metal transporter [DMT-1]
Haem iron is released from apoprotein by the gastric acid
About one quarter of haem is absorbed directly , after cellular uptake , it is broken down and iron is released, enters the labile pool and some may be incorporated into ferritin and lost when cells are exfoliated
Iron for retention by the body is transported into the plasma via ferroportin1 in the basolateral serosal membrane
It is first converted from Fe2+ to Fe3+ by hephaestin [ a cu containing ferroxidase ] which is expressed predominantly in villous cells of the small intestine
REGULATION OF IRON ABSORPTION
May be regulated at
---1] stage of mucosal uptake
---2]stage of transfer to the blood
. Regulation is by Hepcidin
. is a small peptide of 20-25 amino acids
. It is predominantly expres sed in the liver
. Down regulated in reduced iron store
.Upregulated in increased Fe stores or inflammation
HEPCIDIN CTD.
It is a negative regulator of iron absorption from the small intestine ,transport across the placenta , release from the macrophage by binding to ferroportin and accelerating it’s destruction
It is decreased in Fe def , hypoxia and ineffective erythropoiesis
HFE ,TfR2 HJV ,have an indirect role in control of iron absorption via regulation of hepcidin synthesis
TfR2 senses degree of saturation of transferrin with diferric iron
At high saturation ,it stimulates hepcidin synth and vice versa
TfR2 IS restricted to erythroid , duodenal crypts and liver cells
It binds to cell-surface ferroportin, triggering tyrosine phosphorylation and ubiquitin-mediated degradation in lysosomes; iron transport to circulating transferrin is reduced
Its synthesis is induced independently by increasing storage iron, and inflammation (IL-6)
Its synthesis is suppressed by iron deficiency ,anemia, hypoxemia and accelerated ineffective erythropoeisis
Only mechanism to regulate stores is
through absorption
Occurs in duodenum & upper jejunum
Heme form better absorbed than free iron
Meat forms better absorbed than plant
IRON EXCRETION
Not regulated
1-2 mg per day sloughed from skin & GI tract
Increases by 1 mg/day in menstruating women
IRON DEFICIENCY ANEMIA
Iron deficiency is the most common cause of anemia in every part of the world
It is also the most important cause of microcytic hypochromic anemia in which the two red cell indices MCV and MCH are reduced
When the body is in a state of negative iron balance, the first event is depletion of body stores, which are mobilized for haemoglobin production.
Iron absorption is increased when stores are reduced, before anaemia develops
With further iron depletion, the serum transferrin saturation falls to less than 15% due to a rise in transferrin concentration and a fall in serum iron.
If the negative balance continues, frank iron deficiency anaemia develops. The red cells become obviously microcytic and hypochromic and
Poikilocytosis becomes more marked.
The reticulocyte count is low for the degree of anaemia
The number of erythroblasts containing cytoplasmic iron (sideroblasts) is reduced at an early stage in the development of anemia.
As iron deficiency progresses , siderotic granules are entirely absent from these erythroblasts
STAGES OF DEVELOPMENT OF IRON DEFICIENCY ANEMIA
Prelatent reduction in iron stores without reduced serum iron levels
Hb (N), MCV (N), iron absorption (), transferin saturation (N), serum ferritin (), marrow iron ()
Latent iron stores are exhausted, but the blood haemoglobin level remains normal Hb (N), MCV (N), TIBC (), serum ferritin (), transferin saturation (), marrow iron (absent)
Iron deficiency anemiablood haemoglobin concentration falls below the lower limit of normal Hb (), MCV (), TIBC (), serum ferritin (), transferin saturation (), marrow iron (absent)
INCREASED PHYSIOLOGIC DEMANDS
Infants are at high risk because milk diets contain small amounts of iron
Human breast milk contains about 0.3mg/l of iron . Cow milk contains about twice as much of iron.
Children during early years of life have increased dietary iron needs to accommodate for growth and development.
CAUSES OF IRON DEFICIENCY ANEMIA
DIET
This is a rare cause of iron deficiency anemia in industrialized countries having an abundant food supply
In developing countries food is less abundant and diets are predominantly vegetables and cereals which contains poorly absorbable inorganic iron
Premenopausal particularly pregnant women have a much greater requirement for iron than do non-menstruating females
Although iron absorption increases throughout pregnancy ,
This may not be sufficient to meet the resultant net maternal outlay of over 600 mg iron.
IMPAIRED ABSORPTION
Inhibitors—calcium , tea, antacids within 2hrs of iron ingestion
Intestinal mucosal disorder – coeliac dx inflammatory bowel dx
Impaired gastric acid secretion
Helicobacter pylori colonisation
Slow release iron formulation
CHRONIC BLOOD LOSS
It is the most common cause of iron deficiency in the western world
If the bleeding occurs into tissues or body cavities, heme iron can be totally recovered and recycled
Menorrhagia is an important cause of iron deficiency anemia in premenopausal women
Blood loss from the gastrointestinal tract is a major cause of iron deficiency. This could be due to
oPeptic ulcer disease
oHemorrhagic gastritis
oGastric carcinoma
oColonic carcinomas
oHemorrhoids
oHookworm or pinworm disease
Cow’s milk intolerance in infants may lead to gastrointestinal haemorrhage.
Self-induced haemorrhage
Chronic intravascular haemolysis, such as that in paroxysmal nocturnal haemoglobinuria or mechanical haemolytic anaemia, may be a serious source of urinary iron loss.
GENETIC CAUSES
Mutations in the gene encoding DMT1
Mutations in the gene encoding glutaredoxin 5
Hypotransferrinaemia or atransferrinaemia
Deficiency of ceruloplasmin
IRIDA (Iron- Refractory, Iron-Deficiency Anaemia)
When all potential causes of iron deficiency are taken into consideration,deficiency in adult men and postmenopausal women must be attributed to GIT blood loss until proven otherwise
CLINICAL FEATURES
Koilonychias (ridged nails,breaking easily),
Angular stomatitis
Painless Glossitis
Pharyngeal webs and dysphagia (Paterson- Kelly syndrome)
Hair loss
Partial villous atrophy, with minor degrees of malabsorption of xylose and fat, reversible by iron therapy
Blue sclera
infants with iron deficiency anaemia may have impaired mental development and function
Premature labour is more frequent in mothers with iron deficiency.
Iron deficiency anaemia could also be a cause of pruritus
Pica(unusual dietary cravings)
LAB. FINDINGS IN IRON DEFICIENCY ANEMIA
There is a fall in mean corpuscular volume even before anemia occurs
Blood film shows
Hypochromic and microcytic cells.
Target cells occasionally
Pencil shaped poikilocytes
A dimorphic picture can also be seen.
Reticulocyte count is low for the degree of the anemia.
There is complete absence of iron from stores and from developing erythroblasts
The erythroblasts are small and have a ragged cytoplasm
BONE MARROW
high cellularity
mild to moderate erythroid hyperplasia
Micronormoblastic erythropoiesis— polychromatic pyknotic with ragged cytoplasm
absence of stainable iron from stores [macrophages] , and from developing erythroblasts
SERUM IRON AND TOTAL IRON BINDING CAPACITY(TIBC)
Serum iron is reduced
TIBC is increased and could even be less than 10% saturated.
SERUM TRANSFERRIN RECEPTOR AND SERUM FERRITIN
Serum transferrin receptor is increased in iron deficiency anemia
Serum ferritin level is very low in iron deficiency anemia
Serum ferritin is the most commonly employed indicator of the size of iron stores
Serum ferritin level <15g/L IS DIAGNOSTIC OF IDA
Serum ferritin level of15-30g/L IS Suggestive of IDA
Ferritin ---an acute phase protein is also raised in ---Liver disease
----Malignancy
-Inflammation
--Infection
MANAGEMENT OF IRON DEFICIENCY ANEMIA
Correction of the iron deficiency
orally
intramuscularly
intravenously
Treatment of the underlying disease
ORAL IRON THERAPY
Recommended daily dose in adult is 100-200mg of elemental Iron in 2-3 divided doses
Types of Iron preparation Ferrous
Gluconate
Fumarate
Sulphate ---best preparation ,contain 67mg Iron /200mg tablet
iron is absorbed more completely when the stomach is empty
it is necessary to continue treatment for 3 - 6 months after the anemia is relieved
iron absorption
is enhanced: vitC, meat, orange juice, fish
is inhibited: cereals, tea, milk
side effects heartburn, nausea, abdominal cramps, diarrhoea
FAILURE OF RESPONSE TO ORAL IRON THERAPY
Incorrect diagnosis
Underlying malignancy or inflammation
Poor compliance
Combined deficiency states
inadequate prescription (dose or form)
Continuing iron loss in excess of intake
Malabsorption of iron
PARENTERAL IRON THERAPY
Is indicated when the patient
demonstrated intolerance to oral iron
loses iron (blood) at a rate too rapid for
the oral intake
has a disorder of gastrointestinal tract
is unable to absorb iron from
gastrointestinal tract
Preparations and administration
iron - dextran complex (50mg iron /ml)
By slow I.V inj or infusion as a small single dose or a total dose infusion given in one day
Others are 1] Iron sucrose –given to px with
Chronic renal dx who have ery-
thropoietin stimulating agent.
2] Iron carboxymaltose
3] Iron gluconate
4] Ferumoxytol.
SIDE EFFECTS OF PARENTERAL IRON
I.m therapy ---pain
---permanent skin staining
I.v therapy---- anaphylatic reaction
DIFFERENTIAL DIAGNOSIS
CONCLUSION
Iron deficiency anemia is a disease with an estimated 500 million people affected and represents a major public health problem worldwide.
Recent advances in iron metabolism led to the recognition of new entities of iron deficiency anemia in non-bleeding and “high cost diet”nourished individuals
Apparently rare, these genetic forms of iron deficiency anemia should be recognized by hematologists, as they are refractory to classical oral or intravenous iron administration
THANK YOU FOR YOUR ATTENTION