Iron in Health and Disease

Question 1

What does transferrin do?

Answer 1

Transports iron from donor tissues (macrophages, intestinal cells and hepatocytes) to tissues expressing transferrin receptors (especially erythroid marrow)

Question 2

What is transferrin?

Answer 2

Protein with two binding sites for iron atoms

Question 3

What does transferrin saturation measure?

Answer 3

Iron supply

Question 4

What is holo- and apotransferrin?

Answer 4

Holo- iron bound to transferrin

Apo- unbound

Question 5

What is ferritin?

Answer 5

Large intracellular protein

Stores up to 4000 ferric ions in Fe3+ form

Question 6

What does a tiny amount of serum ferritin reflect?

Answer 6

Intracellular ferritin synthesis in response to iron- indirect measure of storage of iron

Question 7

What does serum ferritin levels rise in?

Answer 7

Infection, malignancy etc

Acts as an acute phase protein

Question 8

What intraluminal factors regulate iron absorption?

Answer 8

Solubility of inorganic iron
Haem iron easier to absorb
Reduction of ferric (Fe3+) to ferrous (Fe2+)

Question 9

What mucosal factors (expression of iron transporters) regulate iron absorption?

Answer 9

DMT-1 (divalent metal transporter) at mucosal surface

Ferroportin at serosal surface

Question 10

What systemic factors regulate iron absorption?

Answer 10

Hepcidin:
The major negative regulator of iron uptake
Produced in liver in response to iron load and inflammation
Down-regulates ferroportin

Question 11

Describe iron absorption in the duodenum

Answer 11

DMT 1- Transports iron into the duodenal enterocyte
Ferroportin: facilitates iron export from enterocyte, passed onto transferrin for transport elsewhere
Hepcidin: down-regulates ferroportin

Question 12

What are the consequences of -ve iron balance?

Answer 12

Exhaustion of iron stores
Iron deficient erythropoiesis
Falling red cell MCV
Microcytic Anaemia
Epithelial changes- skin, Koilonychia, Angular stomatitis

Question 13

What does a hypochromic microcytic mean?

Answer 13

Deficient Hb synthesis

Question 14

What can iron deficiency be confirmed by?

Answer 14

A combination of anaemia (decreased haemoglobin iron) and reduced storage iron (low serum ferritin)

Question 15

What are the causes of iron deficiency?

Answer 15

Insufficient dietary intake to meet physiological requirements: particularly women and children, vegetarian diets
Losing too much - bleeding
Not absorbing enough – malabsorption (relatively uncommon)

Question 16

What are the causes of chronic blood loss?

Answer 16

Menorrhagia
Gastrointestinal- Tumours, Ulcers, NSAIDs, Parasitic infection
Haematuria

Question 17

What is iron malutilisation?

Answer 17

Anaemia of chronic disorders

Question 18

What occurs in red cell breakdown in inflammatory macrophage iron block?

Answer 18

Increased transcription of Ferritin mRNA stimulated by inflammatory cytokines so ferritin synthesis increased
Increased plasma Hepcidin blocks ferroportin-mediated release of iron
Results in impaired iron supply to marrow erythroblasts and eventually hypochromic red cells

Question 19

What is primary iron overload?

Answer 19

Long-term excess iron absorption with parenchymal rather than macrophage iron loading, and eventual organ damage

Question 20

What are the clinical features of hereditary haemochromatosis?

Answer 20

Weakness/fatigue
Joint pains
Impotence
Arthritits
Cirrhosis
Diabetes
Cardiomyopathy

Question 21

When does hereditary haemochromatosis usually present?

Answer 21

Middle age or later

Question 22

Describe mutations in HFE gene

Answer 22

1 in 8 of population carry C282Y mutation; 1 in 4 the H63D mutation
Patients are usually C282Y homozygotes; occasionally C282Y/H63D double heterozygotes
Main effect likely to be via reduced hepcidin synthesis
Account for 95% of hereditary haemochromatosis
Incomplete penetrance

Question 23

How is hereditary haemochromatosis diagnosed based on phenotype?

Answer 23

Risk of iron loading: transferrin saturation >50% (sustained on repeat fasting sample)‏
Iron load: serum ferritin >300 g/l in men or >200 g/l in pre-menopausal women

Liver biopsy: only if uncertain about iron loading or to assess tissue damage

Question 24

What can cause hereditary haemochromatosis?

Answer 24

Mutations in HFE gene
Mutations of other iron regulatory proteins, e.g.
Transferrin receptor, hepcidin, ferroportin very rare

Question 25

What is the treatment of hereditary haemochromatosis?

Answer 25

Weekly phlebotomy
- 450-500ml
- 200-250mg iron
Initial aim to exhaust 
 iron stores (ferritin <20 µg/l)‏
Thereafter keep ferritin below 50 µg/l

Question 26

What family screening occurs in hereditary haemochromatosis?

Answer 26

First degree relatives: especially siblings (risk 1 in 4)‏
Children – wait until they are adults able to give informed consent
HFE genotype and iron status- Ferritin and transferrin saturation

Question 27

Up until what point may haemochromatosis be asymptomatic?

Answer 27

Until irreversible organ damage has occurred

Question 28

What are the causes of iron-loading anaemias (secondary iron overload)?

Answer 28

Repeated red cell transfusions

Excessive iron absorption related to over-active erythropoiesis

Question 29

What are the iron-loading anaemias?

Answer 29

Massive ineffective erythropoiesis- Thalassaemia syndromes, Sideroblastic anaemias
Refractory hypoplastic anaemias- Red cell aplasia, Myelodysplasia (MDS)

Question 30

Why may transfusions cause iron-loading anaemias?

Answer 30

Each unit of blood contains 200-250mg iron
Patients with thalassaemia may require transfusion every 2-3 weeks lifelong
Transfusion need in MDS highly variable

Question 31

Up until what point may the risk of excess intestinal iron absorption in regular transfusions be hidden?

Answer 31

Until tissue damage becomes symptomatic

Question 32

What is the treatment for secondary iron overload?

Answer 32

Treatment by venesection not an option in already anaemic patients
Iron chelating agents:
Desferrioxamine (s.c. or IV infusion)‏
New oral agents 	
Deferiprone
Deferasirox