Iron in Health and Disease

Question 1

What are the different forms of iron?

Answer 1

Ferric (Fe3+)

Ferrous (Fe 2+)

Question 2

Where is iron present in the body?

Answer 2

Haemaglobin
Myoglobin
Cytochromes

Question 3

Why can iron be dangerous?

Answer 3

Chemical reactivity; oxidative stress and free radical production
Adaptive requirements for safe transport, storage and absorption required
We have no mechanism to excrete iron

Question 4

What is the fenton reaction?

Answer 4

Formation of free radicals from iron

Ferrous + Water = Ferric + free radical + hydroxyl group

Question 5

Where is haem synthesised?

Answer 5

Cytoplasm of cell

Some of it occurs in the mitochondrion

Question 6

How much iron is absorbed a day?

Answer 6

1mg/ day

Question 7

How much iron is present in the plasma?

Answer 7

4mg

Question 8

How much iron is found in the erythroid marrow?

Answer 8

150mg

Question 9

How much iron is found in the haemaglobin of red cells?

Answer 9

2500 mg

Question 10

How much iron is found in the macrophages?

Answer 10

500mg

Question 11

How much iron is found in parenchymal tissues (liver)?

Answer 11

500mg

Question 12

How much iron is lost a day?

Answer 12

1mg / day

Question 13

Where does iron absorption occur?

Answer 13

Duodenum

Question 14

What will enhance iron absorption?

Answer 14

Haem vs non-haem iron (dedicated haem iron transporter)
Ascorbic acid (reduces iron to Fe2+ form)
Alcohol

Question 15

What will inhibit iron absorption?

Answer 15

Tannins e.g. tea
Phytates e.g. cereals, bran, nuts, seeds
Calcium e.g. dairy produce

Question 16

What is the function of duodenal cytochrome B?

Answer 16

Found on luminal surface of duodenum

Reduces ferric iron (3+) to ferrous form (2+)

Question 17

What is the function of DMT?

Answer 17

Transports ferrous iron into the duodenal enterocyte

Question 18

What is the function of ferroportin?

Answer 18

Facilitates iron export from enterocyte

Passed onto transferrin for transport elsewhere

Question 19

How is iron absorption regulated?

Answer 19

Hepcidin:
Major negative regulator or iron uptake
Produced in liver in response to increased iron load and inflammation
Will bind to ferroportin to result in degradation and therefor iron is “trapped” in the duodenum cells and macrophages

Question 20

How is iron transported within transferrin?

Answer 20

Fe3+

This occurs via hephaestin present on the duodenal enterocyte

Question 21

How is functional iron assessed?

Answer 21

Hb conc

Question 22

How is transport iron/ supply to tissues assessed?

Answer 22

% saturation of transferrin with iron

Question 23

How is storage iron assessed?

Answer 23

Serum ferritin
Tissue biopsy (rarely needed)

Question 24

How many ion of iron can transferrin carry?

Answer 24

2 binding sites

Question 25

What is the function of transferrin?

Answer 25

Transports iron from donor tissues (macrophages, interstitial cells and hepatocytes) to tissues expressing transferrin receptors

Question 26

What is a structure especially rich in transferrin receptors?

Answer 26

Erythroid marrow

Question 27

What measures iron supply?

Answer 27

Transferrin saturation Serum iron/ total binding capacity x 100% Reflects proportion of diferric transferrin

Question 28

What is a normal transferrin saturation?

Answer 28

20-50%

Question 29

What is holotransferrin?

Answer 29

Iron bound to transferrin

Question 30

What is apotransferrin?

Answer 30

Unbound transferrin

Question 31

What will happen to transferrin saturation in iron overload?

Answer 31

Increased (and vice versa)

Question 32

How many ferric ions can ferritin store?

Answer 32

4000

Question 33

What can cause high levels of ferritin outwith iron stores?

Answer 33

Acts as an acute phase protein so increased in infection, malignancy etc

Question 34

What are disorders of iron metabolism?

Answer 34

Iron deficiency Iron malutilisation - anaemia of chronic disease Iron overload

Question 35

What are the consequences of a negative iron balance?

Answer 35

Exhaustion of iron stores Iron deficiency erythropoiesis; falling red cell MCV Microcytic anaemia Epithelial changes; dry skin, koilonychia, angular stomatitis

Question 36

What does hypochromic microcytic anaemia suggest?

Answer 36

Deficiency haemaglobin synthesis

Question 37

What can cause a haem deficiency?

Answer 37

Lack of iron for erythropoiesis - iron deficiency, anaemia of chronic disease Congenital sideroblastic anaemia

Question 38

What can cause a globin deficiency?

Answer 38

Thalassaemia

Question 39

What can cause an iron deficiency?

Answer 39

Insufficient intake to meet physiological needs Bleeding Malabsorption; coeliac

Question 40

What can cause chronic blood loss?

Answer 40

Menorrhagia GI; tumours, ulcers, NSAIDs, parasitic infection Haematuria

Question 41

What can cause occult blood loss?

Answer 41

GI blood loss of 8-10 ml a day (4-5mg of iron) without any symptoms or signs Max dietary iron absorption is 4-5mg a day

Question 42

How pathologically, will chronic disease lead to iron deficiency anaemia?

Answer 42

AOCD; inflammatory macrophage iron block Increased transcription of ferritin mRNA by inflam cytokines so ferritin synthesis increased Increased plasma hepcidin blocks ferroportin mediated release of iron This results in an impaired iron supply to marrow erythroblasts and eventually hypochromic red cells

Question 43

Why does inflammatory macrophage iron block occur?

Answer 43

Protective mechanism to reduce supply of iron to pathogens

Question 44

What are the primary and secondary causes of iron overload?

Answer 44

Primary; hereditary haemochromatosis | Secondary: transfusional, iron loading anaemia

Question 45

What is primary iron overload?

Answer 45

Long term excess iron absorption with parenchymal rather than macrophage iron loading

Question 46

Describe hereditary haemochromatosis

Answer 46

Commonest form due to mutations in HFE gene Decreases synthesis of hepcidin Increased iron absorption Results in gradual iron accumulation with risk of end-organ damage

Question 47

What are the clinical features of hereditary haemochromatosis?

Answer 47

``` Weakness/ fatigue Joint pains Impotence Arthritis Cirrhosis Diabetes Cardiomyopathy ```

Question 48

What is defined as iron overload?

Answer 48

>5g

Question 49

How is haemochromatosis diagnosed molecularly?

Answer 49

Mutations of HFE gene | Mutations of other iron regulatory proteins e.g. transferrin receptor, hepcidin, ferroportin

Question 50

What is the phenotype of haemochromatosis?

Answer 50

Transferrin saturation >50% Serum ferritin >300 microgram/l in men or >200 microgram/l in pre-menopausal women Liver biopsy; rarely needed as fibroscan available now to assess cirrhosis

Question 51

How is haemochromatosis treated?

Answer 51

Weekly venesection; 450-500ml (200-250 mg iron) Initial aim to exhaust iron stores (ferritin <20 microgram/l) Maintenance <50 microgram/l

Question 52

What causes the most deaths in haemochromatosis?

Answer 52

Hepatic failure | Hepatoma

Question 53

Is family screening indicated in haemochromatosis?

Answer 53

First degree relatives esp siblings Children; wait until adults for informed consent HFE genotype and iron status

Question 54

Why are family studies so important in haemochromatosis?

Answer 54

May be asymptomatic until irreversible organ damage has occured

Question 55

What can cause iron loading anaemia?

Answer 55

Repeated red cell transfusions Excessive iron absorption related to over active erythropoiesis Thalassaemia Sideroblastic anaemia Refractory hypoplastic anaemia; red cell aplasia, myelodysplasia

Question 56

How much iron does each unit of blood contain?

Answer 56

250 mg | Beta thal maj - transfusion every 2-3 weeks

Question 57

How is secondary iron overload treated?

Answer 57

Venesection not an option in already anaemic patients | Iron chelating agents; desferrioxamine, deferiprone, deferaasirox

Question 58

What is sideroblastic anaemia?

Answer 58

Failure to incorporate iron into haem | Can be hereditary or acquired (MDS, lead poisoning, alcohol excess)