Iron in Health and Disease

Question 1

What are some of the functions of iron?

Answer 1

Oxygen transport = reversible oxygen binding by Hb

Electron transport

Question 2

What are some molecules that contain iron?

Answer 2

Haemoglobin, myoglobin and enzymes

Question 3

What are some of the issues with iron?

Answer 3

Can produce free radicals and cause oxidative stress

No mechanism for its excretion

Question 4

Where is the majority of body iron found?

Answer 4

In haem = Fe2+sits in porphyrin ring

Question 5

Where does iron absorption mainly occur?

Answer 5

In the duodenum = uptake into duodenal mucosal cells

Question 6

What influences iron absorption?

Answer 6

Dietary factors

Question 7

What are some dietary chemicals that influence iron absorption?

Answer 7

Enhanced by ascorbic acid (reduces iron to Fe2+) and alcohol

Inhibited by tannins, phylates and calcium

Question 8

What are the different mechanisms of iron absorption?

Answer 8

Duodenal cytochrome B, DMT-1 and ferroportin

Question 9

How does duodenal cytochrome B absorb iron?

Answer 9

Found in lumenal surface = reduces ferric iron (Fe3+) to ferrous form (Fe2+)

Question 10

How does DMT-1 absorb iron?

Answer 10

Transports ferrous iron into duodenal enterocytes

Question 11

How does ferroportin absorb iron?

Answer 11

Facilitates iron export from enterocyte where it is passed on to transferrin for transport elsewhere

Question 12

What is hepcidin?

Answer 12

Major negative regulator of iron uptake = levels decrease in iron deficiency

Question 13

Where is hepcidin produced?

Answer 13

Produced in liver in response to increased iron load and inflammation

Question 14

What is the action of hepcidin?

Answer 14

Binds to ferroportin and causes its degradation = iron trapped in duodenal cells and macrophages

Question 15

How is iron status assessed?

Answer 15

Functional iron = Hb concentration
Transport iron = % saturation of transferrin
Storage iron = serum ferritin, tissue biopsy (rarely used)

Question 16

What is transferrin?

Answer 16

Protein with two binding sites for iron = transports iron from donor tissues to those expressing transferrin receptors

Question 17

What area of the body is especially rich in transferrin receptors?

Answer 17

Erythroid marrow

Question 18

What does saturation of transferrin measure?

Answer 18

Iron supply = serum iron/total iron binding capacity x 100

Question 19

What does % saturation of transferrin reflect?

Answer 19

Proportion of diferric transferrin = has high affinity for cellular transferrin receptors

Question 20

What do the different types of transferrin represent?

Answer 20

Holotransferrin represents bound

Apotransferrin represents unbound

Question 21

How do transferrin saturation vary in different iron states?

Answer 21

In normal levels, saturation is 20-50%

Elevated saturation in iron overload

Question 22

What is ferritin?

Answer 22

Spherical intracellular protein = stores up to 4000 ferric ions

Question 23

What does serum ferritin reflect?

Answer 23

Tiny amount of serum ferritin reflects intracellular ferritin synthesis = indirect measure of storage iron

Question 24

What is the additional function of ferritin?

Answer 24

Acts as an acute phase protein

Question 25

What causes ferritin levels to rise?

Answer 25

Iron overload, sepsis, inflammation, malignancy

Question 26

What are examples of disorders of iron metabolism?

Answer 26

Iron deficiency, iron malutilisation (anaemia of chronic disease), iron overload

Question 27

What are the consequences of negative iron balance?

Answer 27

Exhaustion of iron stores Iron deficient erythropoiesis = falling rec cell MCV Microcytic anaemia Epithelial changes = skin, koilonychia, angular stomatitis

Question 28

Is iron deficiency anaemia a diagnosis?

Answer 28

No = symptom not a diagnosis, iron replacement therapy will mask symptoms but won't treat underlying problem

Question 29

What causes increased ferritin synthesis in anaemia of chronic disease?

Answer 29

Increased transcription of ferritin in mRNA stimulated by inflammatory cytokines

Question 30

What effect does anaemia of chronic disease have on iron release?

Answer 30

Increased plasma hepcidin blocks ferroportin-mediated release of iron

Question 31

What is the end result of anaemia of chronic disease?

Answer 31

Results in impaired iron supply to marrow erythroblasts and eventually hypochromatic red cells

Question 32

Why does inflammatory macrophage iron block occur in anaemia of chronic disease?

Answer 32

Protective mechanism = reduces iron supply to pathogens

Question 33

What are some causes of iron overload?

Answer 33

``` Primary = hereditary haemochromatosis Secondary = transfusional, iron loading anaemias ```

Question 34

What occurs in primary iron overload?

Answer 34

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

Question 35

What causes the most common form of hereditary haemochromatosis?

Answer 35

Mutation in HFE gene

Question 36

What occurs in hereditary haemochromatosis?

Answer 36

Decreases synthesis of hepcidin = increased iron absorption resulting in gradual iron accumulation with risk of end organ damage

Question 37

When does hereditary haemochromatosis present?

Answer 37

In middle age or older when iron overload >5g = may be asymptomatic until end-organ damage has occurred

Question 38

What are the features of hereditary haemochromatosis?

Answer 38

Weakness/fatigue, arthritis, cirrhosis, joint pains, impotence, diabetes, cardiomyopathy

Question 39

What are some features of mutations in HFE causing hereditary haemochromatosis?

Answer 39

Accounts for 95% of cases H63D mutation most common followed by C282Y Patients usually C282Y homozygotes Shows incomplete penetrance

Question 40

How is hereditary haemochromatosis diagnosed?

Answer 40

Transferrin saturation >50% on repeated fasted test Serum ferritin >300ug/l in men or >200ug/l in women Liver biopsy = rarely needed, non-invasive techniques like Fibroscan can assess cirrhosis

Question 41

How is hereditary haemochromatosis treated?

Answer 41

Weekly venesection = 400-500ml, 200-250mg iron Initial aim to exhaust iron stores = ferritin <20ug/l Thereafter keep ferritin <50ug/l

Question 42

What patients are screened for hereditary haemochromatosis?

Answer 42

All first degree relatives of patients (esp siblings) | Wait until children are adults

Question 43

How is hereditary haemochromatosis screened for?

Answer 43

HFE genotype and iron status = ferritin and transferrin status

Question 44

What are the causes of iron loading anaemias?

Answer 44

Repeated red cell transfusions, excessive iron absorption related to overactive erythropoiesis

Question 45

What are some disorders that cause iron loading anaemias?

Answer 45

Massive ineffective erythropoiesis = thalassaemias, sideroblastic anaemias Refractory hypoplastic anaemias = red cell aplasia, myelodysplasia

Question 46

How much iron does each unit of blood given in a transfusion contain?

Answer 46

About 250mg of iron

Question 47

How often do patients with thalassaemia require transfusion?

Answer 47

Every 2-3 weeks lifelong

Question 48

What organs can be damaged by iron loading?

Answer 48

Liver, heart and endocrine glands

Question 49

What is the definition of iron loading?

Answer 49

Iron >5g or liver >15mg/g dry weight

Question 50

How are iron loading anaemias treated?

Answer 50

Venesection = not option in already anaemic patients | Iron chelating agents = desferrioxamine (SC or IV), oral deferiprone or deferasirax