Iron Metabolism and Iron Disorders Flashcards
Write about iron
(3)
A component of haemoglobin
A rate limiting step in erythropoiesis
Haem iron/ferrous iron and non haem iron/ferric iron
What is haem iron derived from?
Derived from haemoglobin, particularly myoglobin from food of animal origin
It is ferrous and in the form Fe++
What is Non-haem iron?
(3)
Ferric iron in the Fe+++ form
It is converted to the ferrous form before absorption
It is reduced in the stomach because of its acid environment
How many mg of iron do we need a day
1-2mg
Give some sources of iron
(3)
Red meat, liver, green vegetables, poultry and dried form
Organic iron already in the haem form Fe2+ derived from red meat and liver is more rapidly absorbed
Inorganic iron found in vegetables which is in the Fe3+ form is less easily absorbed
What can increase iron absorption and how?
(2)
Foods containing ascorbic acid and muscle protein increase iron absorption
They do so by reducing ferric iron to ferrous iron
What can inhibit iron absorption?
Caffeine
How much iron does the human body contain
3-5grams
Why do we need iron?
(3)
Synthesis of haem, myoglobin, cytochromes
Co-factor in DNA synthesis
Connective tissue production
Why do we not want excess iron
Excess iron is toxic to the body
Where is iron primarily found?
In RBCs, macrophages, hepatocytes, enterocytes
How much iron do we lose everyday
1-2mg lost per day through blood loss, urine, faeces, or sloughed mucosal epithelial cells
This must be replaced through the day
What are the three types of iron found in the body and what % of total iron are they
Functional iron (80%)
Transport iron (0.1%)
Storage iron (20%)
What is included in functional iron?
Haemoglobin
Myoglobin
Enzymes
What is meant by transport iron
Transferrin
What is meant by storage iron
Ferritin
Haemosiderin
Briefly describe the life cycle of iron in the body
(4)
Transit of iron from the bone marrow to RBCs
To the spleen for removal by macrophages
With iron recycled to the bone marrow via transferrin
The intestine absorbs iron to balance the iron that is lost daily
How is iron excreted?
There is no physiological mechanism for excretion of iron
Where is iron balance controled
Controlled at the level of iron absorption in the duodenum and jejunum
How do we modify the absorption of iron by the intestine?
(5)
Modified by:
- availability of iron in the body
- blood oxygen content/hypoxia
- Blood haemoglobin concentration
- EPO activity in bone marrow/rate of erythropoiesis
- Inflammation can minimise iron availability
What might cause iron excess?
(4)
Dietary excess (over supplementation)
Inherited protein defect (haemochromatosis)
Anaemia (ineffective erythropoiesis)
Iatrogenic (red cell transfusions)
Write about the steps in iron absorption
(7)
Iron released from protein complexes by acid/proteolytic enzymes in stomach
Free iron is absorbed by interstitial epithelial cells (enterocytes) via a specific cell membrane molecule called divalent metal transporter-1 (DMT-1)
Ferric iron Fe3+ is converted to Fe2+ by ferroreductase enzymes on surface of enterocytes
Haem iron is released from haem by enzyme Haemoxygenase-1
Iron moves from enterocyte into the circulation through a membrane protein called Ferroportin
The movement of iron into plasma by Ferroportin is regulated by a liver derived enzyme called Hepcidin
Hephaestin oxidises iron to Fe3+ the form required for binding to apotransferin
What is the first step in iron absorption - food has just reached the stomach
Iron released from protein complexes by acid/proteolytic enzymes in stomach
What is the second step in the absorption of iron, iron has just been released from protein complexes?
Free iron is absorbed by interstitial epithelial cells (enterocytes) via a specific cell membrane molecule called divalent metal transporter-1 (DMT-1)
How does iron get absorbed into the enterocytes?
Via a specific cell membrane molecule called divalent Metal Transporter-1 (DMT)
What is the third step in iron absorption, iron has just been absorbed by enterocytes?
Ferric iron Fe3+ is converted to Fe2+ by ferroreductase enzymes on surface of enterocytes
What does ferroreductase do?
Converts ferric iron (Fe3+) to ferrous iron (Fe2+)
What is the fourth step of iron absorption, Ferrous iron (Fe2+) has been formed?
Haem iron/ferrous iron is released from haem by enzyme Haemoxygenase-1
What does haemoxygenase-1 do?
it releases haem iron/ferrous iron from haem
What is the fifth step in iron absorption, haem iron has just been released from haem?
Iron moves from enterocyte into the circulation through a membrane protein called ferroportin (port for iron)
What is ferroportin?
A membrane protein that iron can move through
What is the sixth step of iron absorption, iron has just moved into circulation
At this step hepcidin, a liver derived enzyme, regulates the movement of iron into plasma
What is hepcidin and what does it do?
a liver derived enzyme
Regulates the movement of iron into plasma
What is the seventh step of iron absorption
Hephaestin oxidises iron to Fe3+ (ferric) form required for binding to apotransferrin
What does hephaestin do
Oxidises iron to Fe3+ form required for binding to apotransferrin
List 9 factors favouring iron absorption
Haem iron
Ferrous iron
Acids (HCl, vitamin C)
Solubilizing agents e.g. sugars, amino acids
Reduced serum hepcidin e.g. iron deficiency
Ineffective erythropoiesis
Pregnancy
Hereditary haemochromatosis
Increased expression of DMT-1 in duodenal enterocytes
List 8 factors decreasing absorption
Inorganic iron
Ferric form
Alkalis -> antacids, pancreatic secretions
Precipitating agents - phytates, phosphates, tea
Increased serum hepcidin, e.g. iron excess
Decreased erythropoiesis
Inflammation
Decreased expression of DMT-1 in duodenal enterocytes
What is hepcidin
(4)
The master regulator
25 amino acid length peptide
Coded by the HAMP gene on Ch19
Produced in the liver
What are some of the functions of Hepcidin
(5)
Has antibacterial and antifungal activity
Circulating hepcidin regulates iron export by binding to ferroportin and inducing its degradation in lysosomes
Blocks intestinal Fe absorption
Inhibits release of Fe from macrophages
Decreases export of Fe from liver cells
What are the three main iron transporters in the body?
Transferrin, lactoferrin and albumin
List the seven steps in iron transport
Plasma iron taken up by iron transporters synthesised in the liver (transferrin, lactoferrin, albumin)
Iron is best transported as ferric iron (Fe3+) which is converted from ferrous iron by ceruloplasmin and ferroconvertase
Apotransferrin bound to iron is termed transferrin
Transferrin delivers iron to the bone marrow
Transferrin is also termed the total iron binding capacity (TIBC)
The amount of iron being transported as transferrin can be used as an indication of body iron status
Aprroximately 85% of iron from degraded Hb is promptly recycled from the macrophage to the plasma and delivered by transferrin to the bone marrow
What is the best form of iron for transport
Ferric iron (Fe3+)
What converts ferrous iron to ferric iron
Ceruloplasmin and ferroconvertase
What does ceruloplasmin and ferroconvertase do?
Converts ferrous iron to ferric iron
What is transferrin and what does it do
(4)
Apotransferrin bound to iron
It delivers iron to the bone marrow
It is also termed the total iron binding capacity (TIBC)
This amount of iron being transported as transferrin can be used as an indication of body iron status
What percentage of iron from degraded Hb is recycled and how?
85%
Recycled from the macrophage to the plasma and delivered by transferrin back to the bone marrow
Explain how iron is incorporated into the developing red blood cell in the bone marrow
(5)
In BM the iron-transferrin complex enters the developing RC by receptor mediated endocytosis by attaching to TfR on the RC membrane
Iron is incorporated into haem molecule in the mitochondria
80-90% of iron taken up is converted to haem within 1 hour
Any excess iron taken up is stored as ferritin
Apotransferrin returns back to plasma to collect more iron from intestines
TfR expression responds to changes in iron i.e. down-regulated by high iron conditions
What receptor is needed for the uptake of iron by developing erythroblasts?
TfR
Transferrin receptor
How long does it take for 80-90% of iron to be converted to haem
1 hour
What happens to excess iron taken up by rbcs
Stored as ferritin
What does apotransferrin do after giving it’s iron to rbcs
Goes back into plasma to travel to intestine for more iron
What does TfR expression depend on?
(4)
Responds to change in iron status
Down-regulated by high iron condition
Up-regulated by low iron conditions
Soluble TFR (sTfR) are receptors shed from red cells and can be used as an indication of increased erythropoiesis
Where is iron stored in the body
Bone marrow
Liver
Pancreas
Spleen
What are the storage forms of iron
Ferritin
Haemosiderin
What is haemosiderin
Formed from aggregates of ferritin
Ferritin vs Haemosiderin
(4)
Release of iron from Haemosiderin is slow and considered long term storage of iron
Ferritin is the primary iron storage protein
Plasma ferritin used as an indicator of iron status
Ferritin is an acute phase protein
What stain do we use for iron stores?
Perls Prussian Blue
Why is it important to remember that ferritin is an acute phase protein?
(3)
Ferritin levels may increase in inflammation
Ferritin is used to determine iron levels
Storage form of iron may be inadequate but may appear normal
Write about iron deficiency anaemia
(5)
Most common cause of anaemia
Affects 500 million people worldwide
Microcytic, hypochromic anaemia
MCV and MCH are reduced
Small and pale red cells due to defect in Hb synthesis
What are some signs of Iron deficiency anaemia
Tachypnea
Koilonychia
Angular cheilitis
Atrophic glossitis
Angular Stomatitis
What would we test for to determine iron status on a FBC
Haemoglobin - would be low
MCV = low
MCH = low
Blood film - hypochromic, microcytic rbcs
How do we carry out iron studies in the lab
Serum iron
Transferrin measured as total iron binding capacity (TIBC)
% transferrin saturation
Serum ferritin
What can serum iron by influenced by?
(4)
Iron absorption from meals
Infection
Inflammation
Diurnal variation
What is TIBC
The amount of transferrin that is available to bind to and transport is reflected in measurements of the total iron binding capacity (TIBC)
How do you determine % transferrin saturation
Serum iron/ TIBC x100
What is considered normal % transferrin saturation
30%
What is considered iron deficient % transferrin saturation
Less than 15%
What is considered iron overload % transferrin saturation
Greater than 55%
What are the laboratory findings of IDA
Decreased:
- Hb
- MCV and MCH
- Reticulocytes
- Ferritin
- Serum iron
- % Transferrin saturation
Increased
- TIBC
What are the two ways of managing iron deficiency anaemia?
Identification and treatment of the underlying cause
Correction of the deficiency by therapy with inorganic iron - oral iron therapy
What is failure to respond to iron therapy often caused by
(3)
Not taking the oral therapy
Or taking it incorrectly i.e. with coffee not orange juice etc (most common)
Continued haemorrhage
Malabsorption
What should you do if a patient has microcytic anaemia but isn’t responding to iron deficiency?
Reassess the diagnosis to exclude other cause of the anaemia
What might cause a microcytic anaemia
(4)
A poor response to infection
Renal or hepatic failure
Underlying malignant disease
Anaemia of inflammation due to high hepcidin levels
What would be the clinical findings of anaemia of chronic disorders
Decreased
- Hb
- Serum iron
- (or normal) Transferrin saturation
- (or normal) TIBC
Increased
- ferritin (or normal)
- CRP
What would indicate iron overload?
High transferrin saturation
High non-transferrin bound iron in plasma
What are the two main affects of non-transferrin bound iron in plasma as seen in iron overload?
(2)
Excess iron promotes the generation of free hydroxyl radicals, which cause damage to oxygen related tissues
Insoluble iron complexes are deposited in the tissues and initiates toxicity to organ
What are the symptoms of iron overload
(5)
Hydroxyl radicals cause
- cardiac failure
- liver cirrhosis/fibrosis/cancer
- diabetes mellitus
Iron deposition causes
- diabetes mellitus
- infertility
- growth failure
What is Hereditary Haemochromatosis
(6)
Increased absorption of iron from the GIT
High Fe protein is involved in Hepcidin production
HFE is encoded on chromosome 6
Arises due to a single point mutation (G>A at nucleotide position 845) which results in a substitution of Cyt with Tyr at position 282 in HFE protein
Causes decreased hepcidin production
Mutation is called C282Y, less common is H63D
What causes Hereditary Haemochromatosis?
Mutation in HFE gene on chromosome 6
Arises due to a single point mutation (G>A at nucleotide position 845) which results in a substitution of Cyt with Tyr at position 282 in HFE protein
What are the two most common HH mutations?
282Y (most common) (on HFE)
H63D (on HFE)
Mutations have also been found on TfR2, HJV and ferroportin that are known to cause HH
Comment on HH in Irish population
Approximately 10% of Europeans are heterozygous
1 in 83 carry the mutation
What happens in HH
(3)
Hepcidin is released from the liver but in low amounts
This causes the uncontrolled release of iron from macrophages and duodenal enterocytes
Low levels of hepcidin causes too much iron to be absorbed from the GIT
How does HH progress?
(5)
Asymptomatic
Non-specific symptoms
Signs of organ damage
Bronze diabetes
Early death
What are the clinical findings of HH
(7)
Haemoglobin increased
Normochromic, normocytic cells
Serum ferritin very high
Serum iron increased
% Transferrin saturation >45%
Haemosiderin staining of bone marrow and liver positive
Demonstration of mutations by PCR
How is HH treated?
(4)
Phlebotomy -> this is donated to IBTS
Done weekly for 6 months
When iron stores are exhausted the frequency of phlebotomy should be reduced to two to four units each year to continue indefinitely
Early diagnosis to prevent cirrhosis, hepatocellular carcinoma etc
