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