Iron in Disease Flashcards
1
Q
What 2 things is iron essential for?
A
- Iron transport
* Electron transport
2
Q
In iron, there is reversible/irreversible O2 binding from Hb
A
Reversible
3
Q
Ferric
A
Fe3+
4
Q
Ferrous
A
Fe2+
5
Q
What 3 things is iron present in?
A
- Haemoglobin.
- Myoglobin.
- Enzymes e.g. cytochromes.
6
Q
Why is iron dangerous?
A
Due to its chemical reactivity - oxidative stress
7
Q
Because iron can be toxic to the body, what does the body do to prevent this?
A
- Safe transport.
- Safe storage.
- Regulation of iron absorption.
8
Q
Iron does NOT have a ….
A
Mechanism of excretion
9
Q
Iron does NOT have a mechanism of excretion
A
T
10
Q
What is there in each globin chain?
A
1 haem group
11
Q
What ion is found in each haem group of every globin chain?
A
Fe2+
12
Q
Where does the Fe2+ ion in the haem group sit?
A
In the porphyrin ring
13
Q
Where is the majority of body iron found?
A
In haem
14
Q
How is haem formed?
A
Protoporphyrin is formed from porphobilinogen
This combines with Fe3+ to form haem.
15
Q
Porphyrin ring + Fe2+ =
A
Haem
16
Q
How much iron does the body absorb per day?
A
1mg / day
17
Q
How much iron exists in:
i) plasma
ii) parenchymal tissues
iii) erythroid marrow
iv) red cell haemoglobin
v) macrophage stores?
A
i) 4mg
ii) 500mg
iii) 150mg
iv) 2500mg
v) 500mg
18
Q
How much iron is lost per day?
A
1mg
19
Q
Where does iron absorption occur?
A
In the duodenum
20
Q
Iron absorption occurs in the _________
A
Duodenum
21
Q
What is responsible for the transport of IRON INTO the DUODENAL ENTEROCYTE?
A
DMT (Divalent metal transporter) -1
22
Q
What is the role of FERROPORTIN?
A
Facilitates iron EXPORT from the enterocyte
23
Q
What happens to iron once it has been exported from he enterocyte?
A
It is passed on to transferrin for transport elsewhere
24
Q
What is responsible for the down-regulation of ferroportin?
A
Hepcidin
25
What does hepcidin do?
Down-regulates ferroportin to decrease exportation of iron from the enterocyte
26
The regulation of iron absorption can be grouped into 3 factors, what are these?
1. Intra-luminal factors.
2. Mucosal factors.
3. Systemic factors.
27
What does intraluminal factors for regulation of iron absorption take into account?
* Solubility of inorganic iron.
* Haem iron is easier to absorb.
* The reduction of (Fe3+) to ferrous (Fe2+)
28
What does mucosal factors refer to?
The expression of iron transporters
29
Give examples of 2 iron transporters (used in the regulation of iron absorption).
* DMT-1 (divalent metal transporter) - at mucosal surface.
| * Ferroportin - at serosal surface.
30
Where is ferroportin found?
At serosal surface
31
Where is DMT-1 found?
At mucosal surface
32
What is the major systemic factor which regulates iron absorption?
HEPCIDIN
33
What is hepcidin?
The major NEGATIVE REGULATOR of iron uptake.
34
_________ is the major NEGATIVE REGULATOR of iron uptake.
Hepcidin !!!
35
Where is hepcidin produced?
In the liver
36
What is hepcidin produced in response to?
* Iron overload
| * Inflammation
37
What does hepcidin do?
Down-regulates ferroportin
38
What is the result of hepcidin (down-regulating ferroportin)?
Iron is ‘trapped’ in duodenal cells and macrophages.
39
How many compartments are there in the assessment of iron status?
3
40
What are the 3 compartments in the assessment of iron status?
1. Functional iron - haemoglobin concentration.
2. Transport iron/iron supply to tissues - % saturation of transferrin with iron.
3. Storage iron - serum ferritin / tissue biopsy (rarely needed).
41
Describe the structure of transferrin.
A protein with 2 binding sites for iron atoms
42
What does transferrin do?
Transports iron FROM donor tissues (macrophages, intestinal cells and hepatocytes) TO tissues expressing transferrin receptors.
43
What area of the body is rich in transferrin receptors?
Erythroid marrow
44
What measures iron supply?
Transferrin saturation
45
Transferrin saturation measures _____ ______
Iron supply
46
How is transferrin saturation calculated?
Serum iron/total iron binding capacity (to transferrin) x 100%
47
What does transferrin saturation reflect?
Reflects proportion of diferric transferrin (high affinity for cellular transferrin receptors
48
What is unbound transferrin called?
Apotransferrin
49
What is iron bound to transferrin called?
Holotransferrin
| think it is (w)hole when bound to transferrin
50
What is a normal transferrin saturation?
20-50%
51
In iron overload, transferrin saturation increases/decreases
Increases
52
In iron deficiency, transferrin saturation increases/decreases
Decreases
53
Describe the structure of ferritin.
* Spherical intracellular protein (450kDa).
| * Stores up to 4000 ferric ions (Fe3+)
54
Why can serum ferritin be used to measure storage iron?
A tiny amount of serum ferritin reflects intracellular ferritin synthesis.
It is an INDIRECT MEASURE OF STORAGE IRON
55
What is ferritin involved in?
Iron storage
56
In what 2 situations is iron increased?
* Iron overload
| * Inflammation
57
Ferritin is ____ in iron deficiency
LOW
58
Ferritin is _____ in iron overload
HIGH
59
State 3 broad groups of disorders of iron metabolism.
* Iron deficiency.
* Iron malutilisation – ‘anaemia of chronic disease.’
* Iron overload.
60
Outline the consequences of negative iron balance, in order as they progress over time.
1. Exhaustion of iron stores
2. Iron deficient erythropoiesis - falling red cell MCV
3. Microcytic anaemia
4. Nail changes - skin, angular stomatitis, koilonychia
61
What do Hypochromic Microcytic Anaemias occur due to?
Deficient haemoglobin synthesis
62
Outline the 2 main groups of causes of deficiency haemoglobin synthesis.
1. Haem deficiency
| 2. Globin deficiency
63
What are the 3 main groups of causes of haem deficiency?
* Iron deficiency
* Anaemia of chronic disease
* Congenital sideroblastic anaemia
64
A combination of what CONFIRMS iron deficiency?
A combination of anaemia (decreased HAEMOGLOBIN IRON) and reduced storage iron (low SERUM FERRITIN).
65
Anaemia + low ferritin =
Anaemia
66
Outline the main causes of iron deficiency.
* Insufficient intake
* Loosing too much e.g bleeding
* Not absorbing enough
67
Who, is more susceptible to insufficient intake of iron?
* Women
| * Children
68
Suggest the main causes of chronic blood loss.
* Menorrhagia
* GI
* Haematuria
69
What GI conditions can cause chronic blood loss?
* Tumour
* Ulcer
* NSAID
* Parasitic infection
70
What is occult blood loss?
Small amounts of blood can be lost (usually from the GI tract), without the patient experiencing any symptoms
71
What volume of GI blood loss can occur per day without any signs or sx of bleeding?
8-10mls i.e 4-5mg of iron
72
What is the max dietary absorption of iron?
Around 4-5mg per day.
73
What essentially is iron malutilisation?
Anaemia of chronic disease.’
74
Outline the process of normal haemoglobin recycling?
Haemoglobin is broken down into its haem and globin components.
Globin: broken down into amino acids
Haem: broken down into porphyrin and iron
The porphyrin is then further broken down to bilirubin. The iron is either stored as ferritin, or transported as transferrin to marrow erythroblasts.
75
'Inflammatory macrophage iron block' is seen in what condition?
Anaemia of chronic disease
76
Outline the inflammatory macrophage iron block which occurs in anaemia of chronic disease.
1. Increased transcription of ferritin mRNA stimulated by inflammatory cytokines so ferritin synthesis is increased.
2. Increased plasma hepcidin blocks ferroportin-mediated release of iron.
3. Results in impaired iron supply to marrow erythroblasts and eventually hypochromic red cells.
77
Causes of iron overload can be _________ or __________
1. Primary
| 2. Secondary
78
Name a primary cause of iron overload.
Hereditary haemochromatosis
79
Name a secondary cause of iron overload.
Transfusional; iron loading anaemias
80
What is primary iron overload?
Long-term excess iron absorption with parenchymal rather than macrophage iron loading
81
What is the commonest gene to cause hereditary haemochromatosis?
Mutations in HFE gene
82
What do mutations of the HFE gene result in?
Decreased synthesis of hepcidin
83
What does decreased synthesis of hepcidin result in?
Increased iron absorption
84
What is the effect of chronic increased absorption of iron?
Gradual iron accumulation with risk of end organ damage
85
What are the clinical features of hereditary haemochromatosis?
* Weakness/fatigue.
* Joint pains.
* Impotence.
* Arthritis.
* Cirrhosis.
* Diabetes.
* Cardiomyopathy.
86
When does hereditary haemochromatosis usually present?
In middle age, or later
87
What is classified as 'iron overload'?
>5mg
88
How is molecular diagnosis of hereditary haemochromatosis achieved?
By identifying mutations of HFE gene
89
HFE gene mutations account for ___% of HH
95%
90
HFE gene mutations show ___________ penetrance
INCOMPLETE
91
When would you be concerned about risks of iron overloading?
If transferrin saturation is >50%
| sustained on repeat fasting sample
92
What qualifies as increased iron stores?
Serum ferritin:
>300 mg/l in men.
or
>200 mg/l in pre-menopausal women.
93
When, in HH, should you do a liver biopsy?
Only if uncertain about iron loading or to assess tissue damage
94
What is the treatment of HH?
Weekly venesection
95
How much blood should be venosected during the weekly venesection of someone with HH?
450-500ml
i.e 200-250mg of iron
96
How is HH diagnosed?
```
* Transferrin saturation >50%
+
Serum ferritin:
>300 mg/l in men.
or
>200 mg/l in pre-menopausal women.
```
97
What is the aim of weekly venesection in HH patients?
* Initially - aim to exhaust iron stores (ferritin <20 µg/l)
* Thereafter – keep ferritin below 50 µg/l
98
What do people with HH die of?
Hepatoma
99
If someone is diagnosed with HH, who in their family is offered screening?
First degree relatives, especially siblings – risk is 1 in 4.
100
Should children be screened for HH if a relative is diagnosed?
No – wait until they are adults and able to give informed consent.
101
How is screening for HH carried out?
HFE genotype and iron status.
* Ferritin and transferrin saturation.
102
Why is familiar screening so important in HH?
Haemochromatosis may be asymptomatic until irreversible organ damage has occurred
Better to screen, catch early, and treat quick
103
What are the potential sources of iron-loading anaemias?
* Repeated red cell transfusions.
| * Excessive iron absorption, related to over-active erythropoiesis.
104
What 2 groups of disorder may result in iron overloading anaemia?
1. Massive ineffective erythropoiesis.
| 2. Refractory hypoplastic anaemia
105
Give examples of conditions that cause massive ineffective erythropoiesis.
* Thalassaemia syndromes.
| * Sideroblastic anaemias.
106
Name 2 conditions under the heading of 'refractory hypo plastic anaemia'
* Red cell aplasia.
| * Myelodysplasia (MDS).
107
How much iron does each unit of blood contain?
250 mg
108
How often may patients with thalassaemia require transfusion?
Every 2-3 weeks. lifelong
109
What is transfusion need in myelodysplasia like?
Highly variable
110
What qualifies as ‘iron overload’ in terms of
i) total
ii) liver dry weight?
i) >5g.
| ii) >15mg/g dry weight.
111
What can iron overload result in damage to?
Liver, heart and endocrine glands.
112
Iron overload is inevitable and predictable with regular red cell transfusions, but risk of excess intestinal iron absorption may be hidden until tissue damage becomes symptomatic.
T
113
What tx is NOT an option in secondary iron overload?
Venesection – not ok if pt is already anaemic
114
What is the treatment for secondary iron overload?
Iron chelating agents
115
Given examples of iron chelating agents.
* Desferrioxamine (subcut or IV infusion).
OR newer oral agents:
* Deferiprone.
* Deferasirox.
