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2.2 Haematology > Iron Metabolism and Iron Disorders > Flashcards

Iron Metabolism and Iron Disorders Flashcards

1
Q

Write about iron
(3)

A

A component of haemoglobin

A rate limiting step in erythropoiesis

Haem iron/ferrous iron and non haem iron/ferric iron

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2
Q

What is haem iron derived from?

A

Derived from haemoglobin, particularly myoglobin from food of animal origin

It is ferrous and in the form Fe++

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3
Q

What is Non-haem iron?
(3)

A

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

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4
Q

How many mg of iron do we need a day

A

1-2mg

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5
Q

Give some sources of iron
(3)

A

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

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6
Q

What can increase iron absorption and how?
(2)

A

Foods containing ascorbic acid and muscle protein increase iron absorption

They do so by reducing ferric iron to ferrous iron

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7
Q

What can inhibit iron absorption?

A

Caffeine

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8
Q

How much iron does the human body contain

A

3-5grams

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9
Q

Why do we need iron?
(3)

A

Synthesis of haem, myoglobin, cytochromes
Co-factor in DNA synthesis
Connective tissue production

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10
Q

Why do we not want excess iron

A

Excess iron is toxic to the body

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11
Q

Where is iron primarily found?

A

In RBCs, macrophages, hepatocytes, enterocytes

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12
Q

How much iron do we lose everyday

A

1-2mg lost per day through blood loss, urine, faeces, or sloughed mucosal epithelial cells

This must be replaced through the day

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13
Q

What are the three types of iron found in the body and what % of total iron are they

A

Functional iron (80%)
Transport iron (0.1%)
Storage iron (20%)

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14
Q

What is included in functional iron?

A

Haemoglobin
Myoglobin
Enzymes

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15
Q

What is meant by transport iron

A

Transferrin

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16
Q

What is meant by storage iron

A

Ferritin
Haemosiderin

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17
Q

Briefly describe the life cycle of iron in the body
(4)

A

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

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18
Q

How is iron excreted?

A

There is no physiological mechanism for excretion of iron

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19
Q

Where is iron balance controled

A

Controlled at the level of iron absorption in the duodenum and jejunum

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20
Q

How do we modify the absorption of iron by the intestine?
(5)

A

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

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21
Q

What might cause iron excess?
(4)

A

Dietary excess (over supplementation)
Inherited protein defect (haemochromatosis)
Anaemia (ineffective erythropoiesis)
Iatrogenic (red cell transfusions)

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22
Q

Write about the steps in iron absorption
(7)

A

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

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23
Q

What is the first step in iron absorption - food has just reached the stomach

A

Iron released from protein complexes by acid/proteolytic enzymes in stomach

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24
Q

What is the second step in the absorption of iron, iron has just been released from protein complexes?

A

Free iron is absorbed by interstitial epithelial cells (enterocytes) via a specific cell membrane molecule called divalent metal transporter-1 (DMT-1)

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25
Q

How does iron get absorbed into the enterocytes?

A

Via a specific cell membrane molecule called divalent Metal Transporter-1 (DMT)

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26
Q

What is the third step in iron absorption, iron has just been absorbed by enterocytes?

A

Ferric iron Fe3+ is converted to Fe2+ by ferroreductase enzymes on surface of enterocytes

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27
Q

What does ferroreductase do?

A

Converts ferric iron (Fe3+) to ferrous iron (Fe2+)

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28
Q

What is the fourth step of iron absorption, Ferrous iron (Fe2+) has been formed?

A

Haem iron/ferrous iron is released from haem by enzyme Haemoxygenase-1

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29
Q

What does haemoxygenase-1 do?

A

it releases haem iron/ferrous iron from haem

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30
Q

What is the fifth step in iron absorption, haem iron has just been released from haem?

A

Iron moves from enterocyte into the circulation through a membrane protein called ferroportin (port for iron)

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31
Q

What is ferroportin?

A

A membrane protein that iron can move through

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32
Q

What is the sixth step of iron absorption, iron has just moved into circulation

A

At this step hepcidin, a liver derived enzyme, regulates the movement of iron into plasma

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33
Q

What is hepcidin and what does it do?

A

a liver derived enzyme

Regulates the movement of iron into plasma

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34
Q

What is the seventh step of iron absorption

A

Hephaestin oxidises iron to Fe3+ (ferric) form required for binding to apotransferrin

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35
Q

What does hephaestin do

A

Oxidises iron to Fe3+ form required for binding to apotransferrin

36
Q

List 9 factors favouring iron absorption

A

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

37
Q

List 8 factors decreasing absorption

A

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

38
Q

What is hepcidin
(4)

A

The master regulator

25 amino acid length peptide

Coded by the HAMP gene on Ch19

Produced in the liver

39
Q

What are some of the functions of Hepcidin
(5)

A

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

40
Q

What are the three main iron transporters in the body?

A

Transferrin, lactoferrin and albumin

41
Q

List the seven steps in iron transport

A

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

42
Q

What is the best form of iron for transport

A

Ferric iron (Fe3+)

43
Q

What converts ferrous iron to ferric iron

A

Ceruloplasmin and ferroconvertase

44
Q

What does ceruloplasmin and ferroconvertase do?

A

Converts ferrous iron to ferric iron

45
Q

What is transferrin and what does it do
(4)

A

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

46
Q

What percentage of iron from degraded Hb is recycled and how?

A

85%

Recycled from the macrophage to the plasma and delivered by transferrin back to the bone marrow

47
Q

Explain how iron is incorporated into the developing red blood cell in the bone marrow
(5)

A

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

48
Q

What receptor is needed for the uptake of iron by developing erythroblasts?

A

TfR
Transferrin receptor

49
Q

How long does it take for 80-90% of iron to be converted to haem

A

1 hour

50
Q

What happens to excess iron taken up by rbcs

A

Stored as ferritin

51
Q

What does apotransferrin do after giving it’s iron to rbcs

A

Goes back into plasma to travel to intestine for more iron

52
Q

What does TfR expression depend on?
(4)

A

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

53
Q

Where is iron stored in the body

A

Bone marrow
Liver
Pancreas
Spleen

54
Q

What are the storage forms of iron

A

Ferritin
Haemosiderin

55
Q

What is haemosiderin

A

Formed from aggregates of ferritin

56
Q

Ferritin vs Haemosiderin
(4)

A

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

57
Q

What stain do we use for iron stores?

A

Perls Prussian Blue

58
Q

Why is it important to remember that ferritin is an acute phase protein?
(3)

A

Ferritin levels may increase in inflammation

Ferritin is used to determine iron levels

Storage form of iron may be inadequate but may appear normal

59
Q

Write about iron deficiency anaemia
(5)

A

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

60
Q

What are some signs of Iron deficiency anaemia

A

Tachypnea
Koilonychia
Angular cheilitis
Atrophic glossitis
Angular Stomatitis

61
Q

What would we test for to determine iron status on a FBC

A

Haemoglobin - would be low
MCV = low
MCH = low
Blood film - hypochromic, microcytic rbcs

62
Q

How do we carry out iron studies in the lab

A

Serum iron
Transferrin measured as total iron binding capacity (TIBC)
% transferrin saturation
Serum ferritin

63
Q

What can serum iron by influenced by?
(4)

A

Iron absorption from meals
Infection
Inflammation
Diurnal variation

64
Q

What is TIBC

A

The amount of transferrin that is available to bind to and transport is reflected in measurements of the total iron binding capacity (TIBC)

65
Q

How do you determine % transferrin saturation

A

Serum iron/ TIBC x100

66
Q

What is considered normal % transferrin saturation

A

30%

67
Q

What is considered iron deficient % transferrin saturation

A

Less than 15%

68
Q

What is considered iron overload % transferrin saturation

A

Greater than 55%

69
Q

What are the laboratory findings of IDA

A

Decreased:
- Hb
- MCV and MCH
- Reticulocytes
- Ferritin
- Serum iron
- % Transferrin saturation

Increased
- TIBC

70
Q

What are the two ways of managing iron deficiency anaemia?

A

Identification and treatment of the underlying cause

Correction of the deficiency by therapy with inorganic iron - oral iron therapy

71
Q

What is failure to respond to iron therapy often caused by
(3)

A

Not taking the oral therapy
Or taking it incorrectly i.e. with coffee not orange juice etc (most common)

Continued haemorrhage

Malabsorption

72
Q

What should you do if a patient has microcytic anaemia but isn’t responding to iron deficiency?

A

Reassess the diagnosis to exclude other cause of the anaemia

73
Q

What might cause a microcytic anaemia
(4)

A

A poor response to infection

Renal or hepatic failure

Underlying malignant disease

Anaemia of inflammation due to high hepcidin levels

74
Q

What would be the clinical findings of anaemia of chronic disorders

A

Decreased
- Hb
- Serum iron
- (or normal) Transferrin saturation
- (or normal) TIBC

Increased
- ferritin (or normal)
- CRP

75
Q

What would indicate iron overload?

A

High transferrin saturation

High non-transferrin bound iron in plasma

76
Q

What are the two main affects of non-transferrin bound iron in plasma as seen in iron overload?
(2)

A

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

77
Q

What are the symptoms of iron overload
(5)

A

Hydroxyl radicals cause
- cardiac failure
- liver cirrhosis/fibrosis/cancer
- diabetes mellitus

Iron deposition causes
- diabetes mellitus
- infertility
- growth failure

78
Q

What is Hereditary Haemochromatosis
(6)

A

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

79
Q

What causes Hereditary Haemochromatosis?

A

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

80
Q

What are the two most common HH mutations?

A

282Y (most common) (on HFE)

H63D (on HFE)

Mutations have also been found on TfR2, HJV and ferroportin that are known to cause HH

81
Q

Comment on HH in Irish population

A

Approximately 10% of Europeans are heterozygous

1 in 83 carry the mutation

82
Q

What happens in HH
(3)

A

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

83
Q

How does HH progress?
(5)

A

Asymptomatic
Non-specific symptoms
Signs of organ damage
Bronze diabetes
Early death

84
Q

What are the clinical findings of HH
(7)

A

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

85
Q

How is HH treated?
(4)

A

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

2.2 Haematology (38 decks)

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