The Role of Iron
Ahmad Sh. Silmi
Msc Haematology, FIBMS
Iron containing compounds
1. Iron compounds involved in cellular
metabolism:• A – Haem. Iron compounds:
1-Haemoglobin : O2 carrying pigment in RBCs.
2-Myoglobin : O2 carrying pigment in muscles.
3-Cytochroms: electron transport enzyme for oxidation
metabolism.
Iron containing compounds
• B – non-haem members:
1- NADH Enzyme .
2- Succinic dehydrogenase enzyme.
2 – Those compounds required for iron storage:Transferrin.
Hemosidrin.
Ferritin.
Body iron storage
• Total iron body contents ≈ 4 gm. ¾ total
iron body is found in O2 carriers;
Hb & myoglobin ; and ¼ body iron is in
stores.
Approximate distribution of
body iron is:•
•
•
•
•
•
Circulating Hb
Bodystores
Myoglobin
B.M
Enzymes
Plasma iron
60%
25%
10%
4%
1%
<0.1%
RBC
2500mg
Daily Fe++ Turnover
Daily RBC Turnover of
Old Cells 1%
R.E 20mg
Fe
Released
Daily
ABSORPTIONِِ
1-2mg ONLY
Daily RBC in B.M Production to
Replace Old Cells 1%
20mg Fe
Returned to
Immature
RBC in Bone
Marrow
Plasma Fe Transferrin Carries
4mg
Transferri
n Carrier
Body Stores
1000mg (male)
300-500mg (Female)
Transferri
n Carrier
Myoglobin
Respspiratory
Enzyme
300mg
Loss Cells Fromِِ
G.I Tract
1-2mg ONLY
Daily iron losses and requirements
(WHO 2001)
Daily iron requirements
1.
Iron is a one way element
2- absorption is increased in iron deficiency and decreased
when body iron stores are deleted.
3- daily iron requirement = amount lost + amount required
4- Increased requirement is found :
•
A- menstruating female / 30-60 ml of blood in each
cycle .This contains between 15-30 mg iron/cycle
B- pregnancy
(1) Foetal/placental growth requirement.
(2) Expansion in maternal mother blood volume.
(3) Haemorrhage in delivery involve highly significant loss of
iron.
Iron Absorption
• The average western diet contain 10-15 mg of iron daily.
Only 5-10% is absorbed.
• The main dietary sources are liver, red meat, green
vegetables, spinach, supplemented cereals and fish.
Dietary iron falls into one of two categories
• Inorganic iron, which mainly is present in cereals and
vegetables and Haem iron, which is found in haemoglobin and
myoglobin of meat products.
Iron Absorption
• Inorganic compounds absorption is enhanced by
the presence of reducing substances, which
increase its solubility, such as ascorbic acid and
other chelating agents such as Fructose,
glucose, succinate which forms soluble
complexes with iron. Conversely, inorganic iron
absorption is retarted in the presence of
substances, which decrease its solubility such
as phosphates and phytates, which are present
in cereals and also by alkaline pancreatic
secretions.
Control of iron absorption
mucosal block theory
Iron Transport & Storage
• Iron is transferred by specific carrier protein
called Transferrin.
• Transferrin is b-globulin with molecular weight of
74,000, which can carry up to two ferric ions
(Fe3+) per molecule.
• Iron is transported to bone marrow to developing
erythroblast, which carry specific receptor to
transferrin.
• The receptor-transferrin complex is internalized
by the erythroblast, the iron is removed for
utilization in haem synthesis and the receptor
and apotransferrin return to the cell surface.
Iron Transport & Storage
Iron Storage Forms
• ferritin : MW 45000, consist of 24 polypeptide
sub-unit cluster together to form hollow sphere
of 5 nm in diameter & the stored iron form the
central core of the sphere. Typically, ferritin
contains about 25% of iron by weight. About 2/3
of body iron stores are present as ferritin.
• If the capacity for storage of iron in ferritin is
exceeded, a complex of iron with phosphate and
hydroxide forms. This is called hemosiderin; it
is physiologically available.
Ferritin Storage Molecule
Ferritin molecules store thousands
of iron atoms within their mineral
core. When excess dietary iron is
absorbed, the body responds by
producing more ferritin to facilitate
iron storage
Iron Storage Forms
• haemosiderin : it's not a single substance but a
variety of different, amorphous, iron- protein
complexes. Typically it contains about 37% of
iron by weight. Haemosiderin may represent
ferritin in various form of degradation.
• As the body burden of iron increases beyond
normal levels, excess hemosiderin is deposited
in the liver and heart. This can reach the point
that the function of these organs is impaired, and
death
Differential diagnosis of hypochromic
anaemia.
Serum Transferrin receptor
• It reflects both the number of erythroid
precursors & iron supply to the bone
marrow.
• Serum Transferin receptor only increase in
ACD in the absence of storage iron; so
ferritin-transferin receptor ratio is used to
diagnose ACD in general hospital practice.
Disorders of iron metabolism
• The state of iron deficiency is defined as a
reduction below normal limits of the total
body iron content.
• Iron deficiency anaemia is the most sever
manifestation of iron deficiency, develops
slowly through a series of successive
stages, although progression from one
stage to the next is not inevitable.
Stages of iron deficiency
anaemia
1- Negative iron balance:
when the rate of absorption of iron from
the diet is insufficient to meet the daily
requirement, iron is mobilized from the
body stores to meet the shortfall.
2- Latent iron deficiency:
A stage progress when the negative iron
balance persists and the body iron
stores become depleted. In this stage
the body is deficient in iron but
erythropoiesis is still normal and no
adverse physiological effects are
present. Many people exist for prolonged
period and never develop anaemia.
3- Iron deficient erythropoiesis:
this progresses when the iron body stores
are exhausted as a result of persistence of
negative iron balance.
4- Iron deficiency anaemia:
this is the final stage of this sequence of
events, which develop after the BM is
affected.
Causes of iron deficiency
anaemia
1- Decreased supply of iron.
2- Increased requirement for iron
1- Decreased supply of iron
• 1st : Inadequate diet: This is considered as a seldom
factor since the normal adult mixed diet contain 18 mg of
iron/day, although it’s considered as a contributing factor
to the more rapid onset of iron deficiency due to another
primary cause.
• 2nd : Malabsorption of dietary iron: This relatively a
common complication of diseases of the upper
alimentary tract such as coelic disease. Partial
gastrectomy or chronic anti-acid ingestion are major
causes for the absence of stomach acid and
subsequently impairs the absorption of dietary iron.
2- Increased requirement for
iron
There are three main causes of an
increased in daily iron requirement:
A. loss of blood
B. growth & pregnancy
C. loss of iron
1st : blood loss
The most common causes of blood loss are:
• Menestruation.
• parasitic infection (Ancylostoma & necator
americanus).
• Carcinoma,
• duodenal ulcer.
• hiatus hernia.
• haemoroids and menorrhgia.
2nd : growth & pregnancy
Adolescence & pregnancy are known as periods of
accelerated growth. This makes iron deficiency very
common. For example:
• In normal, uncomplicated pregnancy, maternal total red
cell volume increases 20%-40%. This imposes an extra
requirement for iron of up to 500mg.
• The developing feotus, requires about 300mg.
• Blood loss at delivery is compounded the iron balance.
• The excess requirement for iron in pregnancy is offset
partially by amenorrhea which saves about 200mg of
iron.
3rd : loss of iron
• chronic intravascular haemolysis can
result in the loss of considerable amounts
of iron as haemosidein in the urine.
Pathophysiology
Sever iron deficiency anaemia is accompanied by
a wide range of clinical manifestation, this can
be considered under two main headings:
• Effects on the blood & blood-forming tissue
• Effects on other tissue
1st : effects on blood & bloodforming tissue
Decreased iron incorporation into the haemoglobin in the developing
erythroblast leads to:
• Decreased Hb concentration denoted by decreased MCHC
• Increased free protoporphyrin concentration within the cell
• Mature microcytic red blood cell due to extra mitotic division before
the nucleus die.
• Thus, the anaemia which accompain iron deficiency anaemia
typically is hypochromic and microcytic.
• Reticulocytopenia is present.
• The bone marrow represents erythroid hypoplasia, decreased
macrophage iron and normoblast have ragged cytoplasm.
• One of the whole mark in the iron deficiency anaemia is the
combination of raised TIBC with reduced % saturation of transferrin
and decreased iron concentration. Ferritin levels are also reduced.
Laboratory Studies in Iron Deficiency
2nd : General effects of iron deficiency
anaemia
• Koilonychia- Flattening or spoon of the nail.
• Angular stomatitis- atrophic lessions at the
corner of the mouth.
• Glossitis- smoothed, inflamed tongue.
• Atrophic gastritis- inflammation of the lining of
the stomach
• Achlorhydria- decrease in gastric secretion
• Pica: Soil-geophagia & Ice- pagophagia
Koilonychia
Anaemia of Chronic
Disorder
Anaemia of Chronic Disorder
• Chronic inflammatory or malignant
disorders frequently are accompanied by a
normocytic, normochromic anaemia, which
is refractory to all treatment except that
which causes regression of the primary
condition. This form of anaemia is known
as anaemia of chronic disorders (ACD).
Pathophysiology
• Chronic inflammation causes activation to macrophages and
upregulation of surface apotransferrin receptors. Binding of
significant quantities of apotransferrin to macrophage reduces
TIBC.
• Inflammation also stimulates neutrophils to synthesis and release
large quantities of apolactoferrin, which acts as iron binding protein.
The apolactoferrin is bound to specific receptors on the activated
macrophages and acts like a magnet for the circulating iron. Any
iron that is bound to the apolactoferrin:receptor complex is
internalized by the macrophage and stored as ferritin. Thus
increasing tissue iron stores.
• Erythropoietic activity of the BM is suppressed in ACD. This most
likely to be caused by the release of growth inhibitors such as IL-1,
γ-interferon and tumor necrosis factor in response to the primary
condition. RBC life span is also reduced.
Diagnosis of ACD
• Anemia (mainly normo-, event. microcytic)
• Inflammatory disease, cancer
• Low serum iron concentration
• This could be true also for iron deficiency
anemia
• FERRITIN – increased
• TRANSFERRIN – decreases
• IRON STORES – sufficient
H E P CIDIN
(not available in clinical
practice)
Sideroblastic Anaemia
Sideroblastic Anaemia
• The sideroblastic anaemias are heterogeneous group of
disorders, which are characterized by disordered
incorporation of iron within the haem in developing
erythroblasts.
• The resulting toxic accumulation of iron in the mitochondria of
erythroblast leads to the formation of iron encircling the nuclei
(ringed sideroblast) and ineffective erythropoiesis ensues.
However, ringed sideroblasts are not specific indicators of
sideroblastic anaemia: they are frequently found in leukaemia,
megaloblastic anaemia and alcoholism.
• The sideroblastic anaemias are classified according to their
aetiology as:
• Hereditary
• Secondary or idiopathic
Sideroblastic anaemia. Erythroblasts showing
perinuclear rings of iron (Perls’ stain).
Siderocytes and sideroblasts.
•
Siderocyte Mature red cell containing one or more siderotic granules
(Pappenheimer bodies)
•
Normal sideroblast Nucleated red cell containing one or more siderotic
granules, granules few, difficult to see, randomly distributed in the
cytoplasm, reduced proportion of sideroblasts in iron deficiency and
anaemia of chronic disorders
•
Abnormal sideroblasts Cytoplasmic iron deposits (ferritin aggregates):
increased granulation, granules larger and more numerous than normal,
easily visible and randomly distributed, proportion of sideroblasts usually
parallels the percentage saturation of transferrin (e.g. haemolytic anaemia,
megaloblastic anaemia, iron overload, thalassaemia disorders)
Mitochondrial iron deposits (non-ferritin iron): ring sideroblasts in inherited
and acquired sideroblastic anaemias
Hereditary Sideroblastic
Anaemia
• They are X-linked inherited diseases,
which are mostly characterized by
functional deficiencies of enzymes of the
haem synthetic pathway, most commonly
δ-aminolaevulinic acid (δ-ALA) synthetase
or ferrochelatase.
• Affected male have hypochromic,
dimorphic anaemia with mild ineffective
erythropoiesis and erythroid hyperplasia.
Lead Poisoning
• Chronic lead poisoning was a relatively common
condition when most drinking water was supplied via
lead pipes.
• Lead is absorbed by inhalation or ingestion.
• Most absorbed lead accumulates in bone & bone
marrow.
• In bone marrow, lead is associated with red cell
precursors and more specifically with mitochondrial
membranes and disrupts haem synthesis.
• This leads to sever sideroblastic changes.
• Lead also cause damages to red cell membrane and
inhibits glycolytic activity.
• These two activities result in mild haemolysis which
contributes to anaemia of chronic lead poisoning.
Investigation of lead poisoning
• Blood lead levels.
• The free erythrocyte protoporphyrin.
(Lead particularly affects the enzymes involved in haem
synthesis; thus a screening test for early lead poisoning
is the measurement of haem precursors).
• An abdominal radiograph may show radio-opaque lead
fragments in the gastrointestinal tract.
•
Also lead lines may be seen on examination of a
radiograph of bony structures because lead interferes
with the growing ends of bones.
Secondary Sideroblastic
Anaemia
1- Drug-induced Siderblastic A naemia:
• The most common cause of this condition is
the administration of drugs such as
Chloramphenicol and alcohol. These drugs
inhibit the synthesis of δ A L A
synthetase and ferrochelatase.
• The blood picture is the same as in
hereditary sideroblastic anaemia.
Other investigations include
• urinary coproporphyrin
• microcytic hypochromic anaemia
• The blood film shows basophilic stippling
in the red cells and reticulocytosis. The
basophilic stippling result of the
acculmulation of pyrimidine nucleotides in
the cytoplasm and is only present in the
youngest red cells.
3- Idiopathic Sideroblastic
Anaemia
• It's the disease of eldery and most common one.
It's identical to the mylodyplastic syndrome
refractory anaemia with sideroblast (RAS).
• Characteristic dyserythropoietic changes
include macrocytosis, poikilocytosis, basophilic
stippling and ringed sideroblast affecting all
stages of erythroblast development.
• In the early stages of the disease platelets and
leucocytes appear normal.
Iron overload
There three commonly encountered forms
of chronic overload:
1- Hereditary haemochromatosis
2- Transfusion-associated haemochromatosis
3- Dietary causes
1- Hereditary haemochromatosis
Hereditary haemochromatosis is:
• a multi-organ disease
• inherited in an autosomal recessive manner
• the most common genetic disease in Northern Europe
• The disease results from the excessive absorption of iron
which is subsequently deposited in tissues such as the
pancreas, heart and liver.
• The normal body content of iron is 2-6 g; patients with
haemochromatosis may have 50-60 g.
Pathophysiology
• One of the major sign of this condition is greatly
increased % saturation with transferrin.
• Thus, when iron is absorbed inappropriately and
released in circulation some may be unable to bind to
transferrin because it's already fully saturated.
• About 30% of the circulating iron exists as ferric or
ferrous and waiting for binding sites to be available.
• These ionic iron acts as a catalyst for formation of toxic
oxygen radicals in the presence of NADPH.
• Oxygen radical compound are short-lived and extremely
reactive causing extensive localized tissue damage.
• The most common one is hydroxyl radical (OH.).
• Accumulated organ damage can result in hepatic
cirrhosis, skin pigmentation, diabetes and congestive
heart failure.
Laboratory Findings
• raised serum ferritin
• reduced total iron binding capacity - TIBC
• raised iron binding saturation:
– >60% transferrin saturation in males
– >50% transferrin saturation in females
• liver biopsy for parenchymal iron deposition
• exclusion of secondary causes by examination of a
blood film, and if necessary, the bone marrow.
(The patient's siblings should be screened by measurement
of iron, TIBC and genetic Screening tests.)
Radiograph of hand –
patient with
haemochromatosis
showing loss of joint
space and erosion of
cartilage at the
metacarpophalangeal
joints.
Liver biopsy for a patient with type 1 haemochromatosis,
showing staining predominantly in parenchymal cells.
Liver biopsy for a patient with type 4 haemochromatosis,
showing iron staining predominantly in Kupffer cells.
Symptoms
Treatment
• Early diagnosis and treatment with venesection permits
the avoidance of all the complications of
haemochromatosis.
• At first venesection should be performed weekly, and
each time the patient attends a full blood count should
be done, as well as checking the liver function. Iron,
TIBC and ferritin should be checked monthly.
• Venesection stops when haemoglobin reaches 10 g per
dl, and follow up is by checking bloods and venesection
every three months.
• Chelation with desferrioxamine may be tried in rare
patients who cannot tolerate venesection because of
cardiac failure or anaemia.
Prognosis
• The arthropathy, hypogonadism and
hepatic cirrhosis rarely resolve with
treatment.
• Intensively treated patients show an 11%
five year mortality rare compared to 67%
in those not treated.
• Hepatocellular carcinoma, cardiac disease
and liver failure are the main causes of
death.
2- Transfusion-associated Haemochromatosis
• Patients who are completely dependent on
a program of regular blood transfusion as
in thalassemia are exposed to extensive
iron intake, which can't be excreted.
• Each transfusion of 400ml carries with it
200ml of iron.
• Steady accumulation of iron can lead to
haemochromatosis. This can be removed
by administration of chelating agent.
3- Dietary causes
• Iron overload due to dietary causes was
reported to be a serious problem among people
who are exclusively cooking in iron pots.
• Acute iron poisoning due to ingestion of large
number of iron tablets for therapeutic use is one
of the most common causes of fatal poisoning in
young children.
• Chronic use of iron supplements in the absence
of iron deficiency can lead to iron overload,
because iron is absorbed by passive diffusion
across the gut in this condition regardless of the
state of the body iron stores.