This document discusses iron metabolism, including:
- Iron's role in hemoglobin and its distribution in the body.
- Proteins involved in iron transport, including transferrin, ferritin, and ferroportin.
- Iron absorption in the small intestine, transport in plasma via transferrin, and storage in tissues.
- Regulation of iron levels by hepcidin and mechanisms for increasing or decreasing absorption.
- Clinical significance of iron deficiency, overload, and methods for assessing body iron levels.
2. LEARNING OBJECTIVES
• Define iron and general characteristics of iron
• Define iron metabolism participating proteins
• Discuss the balanced distribution and physiology of iron in the
body
• Explain intake, absorption and excretion of iron
• Explain transport, utilization and storage of iron
• Describe the regulation of Iron metabolism
• Describe the assessment of body iron
• Describe the clinical significance of iron levels
3. IRON
• Iron metabolism refers to the processes involved in the absorption,
transport, storage, and utilization of iron in the body.
• is a component of a metalloprotein found on haemoglobin which
serves to bind Oxygen for transport to cells.
• Classified as a trace element in the body.
• Iron ions readily form complexes with certain ligands and are able
to participate in redox chemistry between the ferrous (Fe(II)) and
ferric (Fe(III)) states, allowing iron to fill many biochemical roles as a
carrier of other biochemically active substances (e.g., oxygen)
4. IRON METABOLISM PARTICIPATING PROTEINS
• HAPTOGLOBULIN – a transport molecule which binds free
hemoglobin and serves to facilitate disposal of Hgb Iron.
• Haemoglobin (MW 64 500) has 4 heme groups
• Myoglobin (MW 17 000) accounts for 4 – 5% of body iron, has a
single haem group and has higher affinity for oxygen than
haemoglobin and behaves as an oxygen reserve in muscles
• HEMOPEXIN – attaches to heme to aid in its removal from the
circulation.
5. CONTI…..
• DIVALENT METAL TRANSPORTER 1
DMT 1 is an electrogenic pump that requires proton cotransport in order
to transfer Fe 2+ across cell membranes.
• FERROPORTIN (SLC40A1)
This transmembrane domain protein is the basolateral transporter of iron,
essential for iron release from the:
macrophages
intestinal absorptive enterocyte
placental syncytiotrophoblasts
6. TRANSFERRIN
Transports iron from the enterocytes transferrin receptors to the marrow
normoblasts via the blood stream
It can exist as:
a) a single-chain glycoprotein with no iron attached is called apotransferrin)
b) a monoferric transferrin
c) diferric form transferrin
Transferrin synthesis is inversely related to iron stores and it has a plasma half -
life of 8 – 11 days
TRANSFERRIN RECEPTORS
• It is a glycoprotein dimer found on all cells except mature RBCs and provides
access for transferring to bind and deliver iron into the cell
• It provides transferrin-bound iron access into the normoblast
• Control of transferrin receptor biosynthesis is a major mechanism for regulation
of iron metabolism
• Transferrin receptor synthesis is induced by iron deficiency.
7. HAEMOSIDERIN
An aggregate of several ferritin molecules, concerned with iron storage;
It is a water - insoluble, crystalline, protein – iron complex that is visible
by light microscopy when stained by the Prussian blue (Perls’) reaction
It has an amorphous structure, with a higher iron/protein ratio than
ferritin,
haemosiderin is predominantly found in macrophages rather than
hepatocytes.
Haemosiderin increases greatly, in iron overload
FERRITIN
a) The primary and major storage form of iron it provides a
reserve of iron for the body.
b) Normally, the majority of storage iron is present as ferritin
c) Ferritin stores are found in the liver, bone marrow, and
spleen
d) When released into circulation, it can be measured to
assess IRON DEFICIENCY
8. NORMAL IRON BALANCE
• Blood volume and haemoglobin concentration are dependent
on body iron stores
• Normally, the new born contains 80 mg/kg which are utilized
for growth
• From 6 months to 2 years virtually, there no iron stores but
they gradually accumulate to 5 mg/kg in childhood.
• From 15 to 30 years, about 10 – 12 mg/kg (up to 1 g). Iron
stores average 300 mg in pre-menapausal females.
9. DISTRIBUTION AND PHYSIOLOGY OF IRON
• Iron is also stored as: ferritin and hemosiderin, primarily in the:
Bone marrow
Spleen
Liver.
• The storage pool of iron is CRITICAL and may be the first to become
diminished in iron deficiency states.
• Only 3 to 5 mg of iron is found in plasma, almost all of it associated with
transferrin, albumin, and free hemoglobin
• approximately 2 to 2.5 g of iron is in:
a) haemoglobin, mostly in RBCs b) red cell precursors.
10. CONTI…..
• A small (8 mg), but extremely important, pool is in tissue
where iron is bound to several enzymes that require iron
for full activity of:
peroxidases
cytochromes
many of the Krebs cycle enzymes
11. The major compartments of iron in a 70 - kg man. Iron supply for
erythropoiesis and release of iron from senescent red cells
dominate internal iron exchange. RE, reticuloendothelial.
12. SOURCES OF IRON
Iron sources include:
• 1. Diet : meat (liver), beans, soya beans & products, other vegetables such
as spinach
• 2. Hemoglobin and myoglobin breakdown by the enzyme heme
oxygenase to produce ferrous iron, carbon monoxide, and bilirubin-Ixa
13. IRON ABSORPTION AND PHYSIOLOGY
• Absorption of iron from the intestine is the primary means of
regulating the amount of iron within the body.
• About 10% of the 1 g/day of dietary iron is absorbed. To be
absorbed by intestinal cells, iron must be in the Fe(II) (ferrous)
oxidation state and bound to protein.
• Because Fe(III) is the predominant form of iron in foods, it must
first be reduced to Fe(II) by vitamin C before it can be absorbed.
• In the intestinal mucosal cell, Fe(II) is bound by apoferritin, then
oxidized by ceruloplasmin to Fe(III) bound to ferritin.
• From there, iron is absorbed into the blood by apotransferrin,
which becomes diferrotransferrin as it binds two Fe(III) ions
14. IRON ABSORPTION
Iron is obtained from diet in the ferric state (Fe3+) and 3 – 4 mg of iron are
normally absorbed daily by the enterocytes of mostly the duodenum and
some in the jejunum
Iron is reduced by enzyme vitamin C ferri reductase on the surface of the
duodenal enterocyte from F3+ to F2+, in order to be absorbed
Non-heme iron is converted from F3+ to the soluble F2+ form by a duodenum
specific cytochrome b–like protein, DCYTB.
IRON METABOLISM
Ferrous iron is transported across the duodenal epithelium bound to the apical
divalent metal transporter 1 (DMT1).
The ferrous iron is carried to the basolateral membrane (base and sides of the
enterocyte membrane)
Iron exported to the portal circulation, a process mediated by ferroportin, a
basolateral transport protein facilitated by a copper-containing iron oxidase, called
hephaestin
15. IRON METABOLISM
• Hephaestin may facilitate iron regression by
reoxidation of ferrous to ferric iron
• The trivalent (ferric) iron must be bound to
transferrin to be transported through the blood
circulation.
• Some iron remains in the enterocytes as ferritin
and is released to the circulation over a few hours.
• Enterocyte stored ferritin iron is excreted when the
cells are exfoliated in the stool.
16. IRON ABSORPTION, TRANSPORT, AND EXCRETION
• In plasma, transferrin carries and releases Fe to the bone marrow,
where it is incorporated into haemoglobin of RBCs.
• After about 4 months in circulation, red cells are degraded by the:
spleen , liver and macrophages, which return Fe to the circulation,
to be bound and carried by transferrin for reuse .
• Ferroportin controls the release of iron from cells.
• The peptide hormone hepcidin, largely controls iron metabolism
by its ability to modulate the release of iron from cells by inhibiting
ferroportin.
17. REGULATION OF IRON
Iron regulation is primarily through modified absorption from the upper
gastrointestinal tract. Absorption and transport capacity can be increased
in:
a) iron deficiency
b) anemia
c) hypoxia.
Iron is lost primarily by:
a) desquamation
b) red cell loss to urine and feces
c) During menstruation, women lose 20 to 40 mg of iron.
18. REGULATION OF IRON CONTI…..
Hepcidin, an antimicrobial peptide produced in the liver, acts as a
negative regulator of intestinal iron absorption.
It suppresses release of iron from macrophages.
Hepcidin binds to the ferroportin receptor, causing degradation of
ferroportin and trapping iron in the intestinal cells.
High plasma iron and inflammation stimulate hepcidin synthesis.
Increased hepsidin, prevents iron absorption by the enterocytes.
Hepsidin levels diminishes when iron saturation is low (7-9) thereby
allowing more absorption by the enterocytes
19. IRON LOSS
The average daily requirement is 1 mg but MUST always be higher for pregnant
and menstruating females.
a. Iron loss occurs through epithelial cell breakdown in the intestines and skin
(about 1mg loss / day)
b. During menstruation a further 1mg is lost in addition to the normal loss.
c. During internal bleeding problems, additional iron is lost.
IRON DEFICIENCY
Iron deficiency affects about 15% of the worldwide population.
High risk of iron deficiency anemia populations:
a) pregnant women b) young children
b) c) adolescents d) women of reproductive age.
Increased blood loss, decreased dietary iron intake, or decreased release from
ferritin may result in iron deficiency.
Reduction in iron stores usually precedes both a reduction in circulating iron and
anemia, as demonstrated by a decreased red blood cell count, mean corpuscular
hemoglobin concentration, and microcytic RBCs.
20. IRON TOXICITY
Iron overload states are collectively referred to as hemochromatosis,
whether or not tissue damage is present.
Primary Fe overload is most frequently associated with hereditary
hemochromatosis (HH). HH is a single-gene homozygous recessive disorder
leading to abnormally high Fe absorption, culminating in Fe overload.
Secondary Fe overload may result from excessive dietary, medicinal, or
transfusional Fe intake or be due to metabolic dysfunction.
Hemosiderosis - iron overload characterised by:
a) an increased serum iron
b) increased total iron binding capacity (TIBC)
c) increased transferrin transferrin
d) No demonstrable tissue damage.
21. ASSESMENT OF BODY IRON
Measurement of FERRITIN levels is very important in
assessing the depletion of IRON STORES.
Methods employed are IRMA and ELISA.
Reference range;
a) serum iron 65 – 180 uG / dL – the diurnal pattern shows
10% higher in the morning b) TIBC 250 – 450
uG/dL
c) Ferritin (male) 20 – 300 uG/dL
d) Ferritin (Female) 10 – 120 uG/dL
22. CLINICAL SIGNIFICANCE
IRON OVERLOAD:- excessive iron intake. Normally, the body has no way
to excrete iron. Accumulation occurs mainly in the LIVER. Progressive
hepatic damage culminating in cirrhosis and hepatic failure takes place.
HEMOCHROMATOSIS – hereditary disease in which intestinal mucosal
uptake of iron increases; frequent blood transfusions or iron injections
leading to iron accumulation.
Excessive dietary intake.
In iron overload, ferritin rises first, followed by serum iron but TIBC may
not be affected.
TREATMENT:- phlebotomy, one 500ml blood contains 250mg of iron
administration of iron chelating agents to allow chelated iron to be
passed out in urine.
23. REFERENCES
Hoff brand's essential
haematology
Review of clinical chemistry
Whitby’s lecture notes in clinical
chemistry
Adaptation from lecture notes by
H. Lekgetho