Iron in health and disease

Question 1

What is iron required for in the body?

Answer 1

Oxygen transport (reversible oxygen binding by haemoglobin)
Electron transport (mitochondrial production of ATP)

Question 2

What substances in the body contain iron?

Answer 2

Haemoglobin
Myoglobin
Enzymes e.g. cytochromes

Question 3

How can iron harm the cells?

Answer 3

Oxidative stress

Question 4

How is iron excreted by the body?

Answer 4

There is no mechanism for active excretion

There is passive loss through old cells being shed e.g. skin cells, menstruation

Question 5

How are iron levels controlled by the body?

Answer 5

By controlling iron absorption

Question 6

Where is most of the body’s iron found?

Answer 6

In haemoglobin

Question 7

How much iron is absorbed and lost a day from the body?

Answer 7

1mg

Question 8

How much iron is present in a) the plasma b) the erythroid marrow c) red cell haemoglobin d)macrophage stores and e) parenchymal tissues?

Answer 8

a) 4mg
b) 150mg
c) 2500 mg
d) 500mg
e) 500mg

Question 9

What are the three components of assessment of iron status, and how are they measured?

Answer 9

1. Functional iron, measured by haemoglobin concentration
2. Transport iron/iron supply to the tissues, measured by Transferrin saturation
3. Storage iron, measured by serum ferritin and tissue biopsy (Bone marrow for Fe deficiency, liver for Fe overload)

Question 10

What is transferrin?

Answer 10

A protein with 2 binding sites for iron atoms
It transports iron from donor tissues (macrophages, intestinal cells and hepatocytes) to tissues expressing transferrin receptors (especially erythroid marrow).

Question 11

What does % transferrin saturation measure?

Answer 11

Iron supply

Question 12

How is % transferrin saturation calculated?

Answer 12

Serum iron/transferrin x 100

Question 13

What is ferritin?

Answer 13

A large spherical intracellular protein

It can store up to 4000 ferric ions

Question 14

What is an indirect measure of storage iron?

What can it tell you?

Answer 14

Serum ferritin
Low serum ferritin always indicated iron deficiency but a normal level does not guarantee normal stores as ferritin is increased in chronic inflammation and liver disease.

Question 15

Name three groups of factors that regulate iron absorption.

Answer 15

Intraluminal factors
Mucosal factors
Systemic factors

Question 16

What intraluminal factors regulate iron absorption?

Answer 16

Solubility of inorganic iron

Reduction of ferric (Fe3+) to ferrous (Fe2+)

Question 17

What mucosal factors regulate iron absorption?

Answer 17

Expression of iron transporters:

• DMT-1 (divalent metal transporter) at mucosal surface which transports iron into the duodenal enterocyte
• Ferroportin at mucosal surface which facilitates iron export from the enterocyte, which is passed on to transferrin.

Question 18

What systemic factor regulates iron absorption?

How does it do this?

Answer 18

Hepcidin
It is the major negative regulator of iron uptake.
It is produced in the liver in response to iron load and inflammation.
It down regulates ferroportin, which transports iron from the enterocyte into the systemic circulation.

Question 19

What types of disorders of iron metabolism can we have?

Answer 19

Iron deficiency
Iron malutilisation
Iron overload

Question 20

What are the consequences of a negative iron balance?

Answer 20

Exhaustion of iron stores
Iron deficient erythropoiesis
Microcytic anaemia
Epithelial changes (skin, koilonychia, angular stomatitis)

Question 21

Name some causes of iron deficiency

Answer 21

Insufficient dietary intake (particularly women and children, vegetarian diets)
Losing too much - bleeding
Malabsorption - relatively uncommon

Question 22

Give an example of a cause of iron malutilisation

Answer 22

Anaemia of chronic disease

Question 23

Is haem iron or non-haem iron better absorbed? Why?

Answer 23

Haem iron is better absorbed because there is a specific pathway for this process.

Question 24

Describe the mechanism of inflammatory macrophage iron block ad how it leads to anaemia.

Answer 24

There is increased transcription of ferritin mRNA stimulated by inflammatory cytokines.
As old red blood cells are broken down the iron is taken up by macrophages and stored in ferritin.
There is increased plasma hepcidin which blocks ferroportin mediated release of iron from the macrophages.
This results in impaired iron supply to marrow erythroblasts and eventually hypochromic red cells.

Question 25

What is primary iron overload?

Answer 25

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

Question 26

What are the clinical features of hereditary haemochromatosis?

Answer 26

Weakness/fatigue
Joint pains
Impotence
Arthritis
Cirrhosis
Diabetes
Cardiomyopathy
Usually present in middle age or later
Iron overload over 5g

Question 27

Which mutations account for >95% of hereditary haemochromatosis?
What is the penetrance?
What is the mechanism of disease?

Answer 27

Mutations of the HFE gene
C282Y and H63D mutations
Incomplete penetrance
Main effect is likely to be via reduced hepcidin synthesis.

Question 28

How can the diagnosis of haemochromatosis be made by phenotype?

Answer 28

Assess the risk of iron loading by measuring transferrin saturation: >50% sustained on repeated fasting sample
Assess iron load by measuring serum ferritin: >300ug/l in men or >200ug/L in pre-menopausal women
Liver biopsy: only if unsure about iron loading or to assess liver damage

Question 29

What is the most common cause of primary iron overload?

Answer 29

Hereditary haemochromatosis

Question 30

Who is screened for hereditary haemochromatosis?

How is screening carried out?

Answer 30

First degree relatives
Children - wait until they are adults and can give informed consent.
HFE genotype and iron status (ferritin and transferrin saturation)

Question 31

What is secondary iron overload?

Answer 31

Iron overload caused by iron-loading anaemias (either through treatment of anaemia by repeated transfusions or by excessive iron absorption related to over-active erythropoiesis)

Question 32

What disorders can lead to secondary iron overload?

Answer 32

Thalassaemia syndromes or sideroblastic anaemia causing massive ineffective erythropoiesis
or refractory hypoplastic anaemias e.g. red cell aplasia or myelodysplasia.

Question 33

What is the definition of iron overload?

Answer 33

Total iron >5g or liver iron >15mg/g dry weight

Question 34

How much iron can be absorbed per day?

Answer 34

Up to 5mg/day

Question 35

How is secondary iron overload treated?

Answer 35

Venesection not really an option in already anaemic patients.
Treated with iron chelating agents e.g. desferrioxamine (s.c./IV), deferiprone (oral) deferasirox (oral)

Question 36

Why is iron overload serious?

Answer 36

Once symptomatic it is life-threatening.

Question 37

What is the treatment of hereditary haemochromatosis?

Answer 37

Weekly phlebotomy (450-500ml which equates to 200-250mg of iron)
Initial aim is to exhaust iron stores (ferritin