Iron Metabolism
Dr mukhtiar baig
Objectives
• Iron metabolism
• Iron distribution & transport
• Dietary iron
• Iron absorption
• Iron requirements
• Disorders of iron metabolism
The most common nutritional
disorder in the world.
Iron
• Molecular weight 56
• Abundance (4th abundant element)
• 2nd abundant metal (after aluminum)
• May be 2+ or 3+
– Ferric (3+) “oxidised” - lost an electron
- Ferrous (2+) “reduced” - gained an
electron
Fe+++ + e- Fe++
• Redox states allows activity passing
electrons around body
• Redox change required for iron
metabolism
• Daily intake 10-20mg
• Only 10% is absorbed
• Absorption increased 20-30% in iron
deficiency and pregnancy
• Non haem iron derived from cereals
(fortified with iron)
• Haem iron derived from haemoglobin
and myoglobin in red or organ meats.
Iron (Fe)
• RDA: for men: 10 mg/day
for women: 20 mg/day
• UL: 40 mg/day
• Serum iron level
men= 120 ug/dl
women= 100 ug/dl
**RDA value for vegetarians is 1.8 times for non-
vegetarians
Iron sources
The best sources of iron include:
• Dried beans
• Dried fruits
• Eggs (especially egg yolks)
• Iron-fortified cereals
• Liver
• Lean red meat (especially beef)
• Oysters
• Poultry, dark red meat
• Salmon
• Whole grains
Reasonable amounts of iron
• Lamb, pork, and shellfish.
• Fruits (apple, bannana, pomegranate
etc), Dates
• Green leafy vegetables
Dietary iron
• Ferric hydroxides
• Ferric-protein complexs
• Heme-protein complexes
Types of Iron
Functional Storage
Heme proteins Ferritin
Enzymes Haemosiderin
Heme proteins
• Haemoglobin & Myoglobin
• Catalase
• Peroxidase (glutathion peroxidase)
• Cytochromes, heme containing
enzymes (organo iron compound)
Iron containing enzymes
• Xanthine oxidase, Cytochrome oxidase,
Acyl CoA dehydrogenase, NADH-
reductase, Succinate dehydrogenase,
Aconitase, etc
Iron Distribution
• 35 – 45 mg / kg in adult male body
• Total approx 4 g
– Red cell mass as haemoglobin - 60%
– Muscles as myoglobin – 5-10%
– Storage as ferritin - 30%
• Bone marrow
• Reticulo-endothelial cells
• Liver
– Other Haem proteins – 1-2%
• Cytochromes, others
– In Serum - 0.1%
Iron distribution in healthy young adults (mg)
Pool Men Women
Total 3450 2450
Functional
Hemoglobin 2100 1750
Myoglobin 300 250
Enzymes 50 50
Storage
Ferritin, 1000 400
Hemosiderin
Iron Functions
• Oxygen carriers
– haemoglobin
• Oxygen storage
– Myoglobin
• Energy Production
– Cytochromes (oxidative phosphorylation)
– Krebs cycle enzymes
• Other
– Liver detoxification (cytochrome p450)
• An essential element
Iron Absorption
• 1 – 2 mg iron are absorbed each day (in
iron balance 1 – 2 mg iron leaves the
body each day)
• Occurs in the duodenum
• Taken up as ionic iron or haem iron
• Only 10% of dietary iron absorbed
• Dietary iron usually in excess
– either not absorbed, or kept in
enterocytes and shed into the gut
Tf-Fe3+
Tf
Enterocyte
Hb,Mb Heme
Stomach
Duodenum
Tf-Fe3+
Tf
Enterocyte
Fe3+ Fe3+
Chelates
Stomach
Duodenum
Haem iron absorption
• Haem split from globin in intestine
• Absorbed into enterocyte as haem
• Iron freed into enterocyte pool or
absorbed intact.
Heme Fe
h- transporter
Ferroportin 1
Fe3+
Fe2+
Non
h Fe Fe3+
Fe2+ Hephaestin
DMT1 transferrin
Lost by shedding
of epithelial cells
Fe2+
Fe3+ DMT1
Ferric
reductase
Ferritin
Ferroportin 1 Hephaestin
Fe3+
Fe2+
Basolateral surface Plasma transferrin
Iron Absorption
• DcytB
– Reduction Fe+++ to Fe++
• DMT1
– Transport into cell
• Ferritin
– Storage in cell
• Hephaestin
– Oxidises Fe++ to Fe+++
• Ferroportin
– Transport out
Factors Affecting Iron Absorption
• Haem iron is absorbed better
• Fe+2 is absorbed better
• Gastric acidity helps to keep iron in the
ferrous state and soluble in the upper gut
• Phytate and phosphates decreases
absorption
• Increased with low iron stores and
increased erythropoietic activity, eg
bleeding, hemolysis, high altitude.
• Decreased in iron overload except in
hereditary haeochromatosis
• Enhanced with vit C, citric acid, amino
acids, and sugars in diet.
• Inhibited by cereals (phytates) , tea
(tannates), milk (phosphates), oxalates
(spinach, chocolates), carbonates.
Iron absorption regulation
• Increased
– Low dietary iron
– Low body iron stores
– Increased red cell production
– Low haemoglobin
– Low blood oxygen content
Decreased
– Systemic inflammation
leads to increased hepcidin production.
Increased Iron Uptake
• Low dietary iron
Leads to increased activity of:
– DCytB and DMT1
• Caused by local factors in gut
• Signal from body to gut in response to
increased needs
• Hepcidin
– Increased levels decrease absorption
– Low levels increase absorption
Hepcidin
• 25 aa peptide
• Identified 2000
• Antimicrobial activity
• Hepatic bacteriocidal protein
• Master iron regulatory hormone
• Inactivates ferroportin
– Stops iron getting out of gut cells
– Iron lost in stool when gut cells shed
• Leads to decreased gut iron absorption.
Iron Release from cells
• Ferroportin present on cell surface to
release iron
• Found on gut cells, liver cells and
macrophages
• Requires cofactor to oxidize iron to allow
for binding to transferrin
– Hephaestin in gut
– Caeruloplasmin in other cells
• Hepcidin blocks iron release from all cells
Iron Transport in Blood
• Red cells
– As haemoglobin
– Cannot be exchanged
• Plasma
– Bound to Transferrin
– Carries iron between body locations
eg between gut, liver, bone marrow,
macrophages
– Iron taken up into cells by transferrin receptors
Transferrin
• Glycoprotein MW 77,000
• Synthesized in the liver.
• Major function: deliver iron to cells,
including erythroid precursors.
• Each molecule can bind two Fe3+
molecules (oxidised)
• Contains 95% of serum Fe.
• Usually about 33% saturated with Fe.
• Production decreased in iron overload.
• Production increased in iron
deficiency.
• Measured in blood as a marker of iron
status.
Transferrin Testing
• A routine blood test used for iron status
• Also known as TIBC (total iron binding
capacity)
• High levels:
– Low body iron stores.
• Low levels:
– High body iron stores.
Transferrin Saturation
NORMAL IRON STATUS
Normal iron Normal transferrin Saturation 33%
IRON OVERLOAD
High iron Low transferrin Saturation 80%
Transferrin Iron
Iron Storage - Ferritin
• Iron store in the liver and nearly all
other cells.
• MW 460,000.
• Outer shell: apoferritin, consists of 22
protein subunits
• 20% iron by weight, binding up 4,500
atoms of iron per molecule.
• Small fraction found in circulation
(contains less than 1% of serum
iron).
• Stores iron and releases it in a
controlled fashion.
Ferritin - Measurement
• A routine blood test – reflects iron stores
• Low serum levels
– Indicate Iron deficiency (high specificity)
• High serum levels
– Iron overload
• Other - Ferritin may be increased in
serum by:
– Tissue release (hepatitis, leukaemia,
lymphoma)
– Acute phase response (tissue
damage, infection, cancer)
• Interpretation
– Low levels always indicate Fe
deficiency.
Iron re-use
• Old cells broken down in macrophages in
spleen and other organs
• Iron transported to liver and other
storage sites
• Red cell iron recovered from old red cells
• Very little iron lost in routine metabolism
Internal iron cycle
Circulating
erythrocytes
Marrow RE
erythroid Liver Stores
precursors
Plasma tf
iron
Intestinal
absorption
Diseases of iron deficiency
1. Iron-deficiency anemia (IDA)
2. Anemia of chronic disease (ACD)
Diseases of iron overload
What is iron-deficiency anemia ?
It is the lack of iron in the blood, which is ne
cessary to make hemoglobin.
Iron Deficiency
Can result from
• A) dietary lack (eg in infants, children, old
age etc)
• B) impaired absorption (eg in sprue, chronic
diarrhea, gastrectomy etc)
• C) increased requirement (growing infants,
children, premenopausal females
(particularly pregnant)
• D) chronic blood loss (from GIT eg peptic
ulcer, hemorrhagic gastritis, gastric
carcinoma, hemorroids, or hookworm or pin
worm disease), urinary tract tumors, genital
tract (menorrhagia, uterine cancer)
Iron Loss
• Physiological
– Cell loss: gut, desquamation
– Menstruation
• Pathological
– Bleeding
– Gut, menorrhagia, surgery, gross
haematuria
Iron Deficiency
• Laboratory changes:
– Low iron (poor specificity)
– Low ferritin (excellent specificity)
– Elevated Transferrin (TIBC)
– Low transferrin saturation
– Hypochromia, microcytosis
– Anaemia
Symptoms of anemia
• Fatigue
• Dizziness
• Headache
• Palpitation
• Dyspnea
• Lethargy
• Disturbances in menstruation
• Impaired growth in infancy
Symptoms of iron deficiency
• Irritability
• Poor attention span
• Lack of interest in surroundings
• Poor work performance
• Behavioural disturbances
• Pica
• Defective structure and function of epithelial tissue
– especially affected are the hair, the skin, the
nails, the tongue, the mouth, the hypopharynx
and the stomach
• Increased frequency of infection
Pica
• The habitual ingestion of unusual
substances
– earth, clay (geophagia)
– laundry starch (amylophagia)
– ice (pagophagia)
• Usually is a manifestation of iron
deficiency and is relieved when the
deficiency is treated
Management of iron deficiency anemia
• Correction of the iron deficiency
– orally
– intramuscularly
– intravenously
• Treatment of the underlying disease
Oral iron therapy
• The optimal daily dose - 200 mg of
elemental iron
–Ferrous
•Gluconate , Fumarate, sulphate.
•Continue treatment for 3 - 6 months
after the anemia is relived
• Side effects
•Heartburn, nausea, abdominal cramps,
diarrhoea.
Genetic haemochromatosis
• Iron overload disease
• Caused by increased iron absorption
• May affect liver, pancreas, skin, heart,
joints, endocrine organs.
• Gradual accumulation of iron over the
life of the person (positive iron balance)
– Iron overload detectable in teens and 20s
– Organ overload in 30s
– Organ damage in 40s and 50s
• Cirrhosis and liver disease main cause
of increased mortality
Genetic Haemochromatosis
• >95% defect in HFE gene (C282Y)
• Associated with low hepcidin
• Leads to overactivity of ferroportin
– Increased gut absorption of iron
• Also other mechanisms
– Increased DMT1 and DcytB activity
IRON OVERLOAD
May be due to
• Excessive absorption
• Parental iron therapy
• Repeated transfusions
• 1) Hemosiderosis (Iron overload without
cell injury)
• 2) Hemochromatosis (Iron overload with
cell injury)
Iron Toxicity
• Iron can damage tissues
• Catalyzes the conversion of hydrogen
peroxide to free-radical ions
• Free-radicals can attack:
– cellular membranes
– Proteins
– DNA
• Iron excess possibly related to cancers,
cardiac toxicity and other factors
The impact of iron overload
