Iron metabolism and iron overload

Question 1

What are the 2 main processes that iron is essential for ?

Answer 1

• Oxygen transport - its a component of Hb
• Electron transport (e.g. mitochondrial production of ATP)‏

Question 2

What are the 2 forms iron can be found in ?

Answer 2

Fe3+ and Fe2+

Question 3

What substances is iron found in the body ?

Answer 3

• Haemoglobin – where most is found
• Myoglobin
• Enzymes eg cytochromes involved in ATP production

Question 4

How is iron dangerous and therefore how is it managed?

Answer 4

• It can result in oxidative stress
• No mechanism for excretion

Question 5

Describe the process of iron exchange

Answer 5

1. Absorbed iron absorbed goes into the plasma
2. Then it mainly goes to the erythroid marrow (small amount put into storage in parenchymal tissue mainly the liver)
3. Then into Hb
4. Then into imacrophage stores
5. Then back into the plasma where again most goes back to the erythroid marrow but some of the plasma content will be stored

Whilst in storage in parenchymal tissue 1mg of iron is lost per day (this balances the 1mg of iron absorbed from food per day)

Question 6

Where is the largest proportion of iron in the body ?

Answer 6

In red cell haemoglobin

Question 7

Where specifically is iron absorbed into the body ?

Answer 7

In the duodenum

Question 8

Describe the process of iron absorption into the body mentioning the specific iron transporters

Answer 8

1. DMT (divalent metal transporter) -1; Transports iron into the duodenal enterocyte
2. Ferroportin - Facilitates iron export from the enterocyte and Passes iron on to transferrin for transport elsewhere

Question 9

What is the function hepicidin and when is it produced ?

Answer 9

• The major negative regulator of iron uptake
• Produced in liver in response to iron load and inflammation
• Down-regulates ferroportin
• Causing Iron to become ‘trapped’ in duodenal cells and macrophages (recticuloendothelial system)

Question 10

What are the 3 ways in which you can measure iron in the body and what does each of the tests tell you about iron in the body specifically ?

Answer 10

Functional iron:

• Haemoglobin concentration

Transport iron/iron supply to tissues:

• Measured by % saturation of transferrin with iron

Storage iron:

• Measured by serum ferritin

Question 11

What is the protein responsible for transport of iron in the body ?

Answer 11

Transferrin - It transports iron from donor tissues (macrophages, intestinal cells and hepatocytes) to tissues expressing transferrin receptors

Question 12

How many iron atoms can bind to one transferrin molecule ?

Answer 12

2 iron atoms

Question 13

Describe how % saturation of transferrin with iron is calculated and what are the normal levels of % transferrin saturation?

Answer 13

Transferrin saturation measures iron supply:

• Take the serum iron/total iron binding capacity(to transferrin) x 100 %

% levels = 20-50%

Question 14

What do high and low % transferrin levels indicate ?

Answer 14

1. High levels indicate iron overload
2. Low levels indicate iron deficiency

Question 15

What is the function of ferritin ?

Answer 15

Storage protein of iron

Question 16

How many ferric (Fe3+) ions can be stored per ferritin molecule ?

Answer 16

4000

Question 17

How does serum ferritin correlate to iron storage levels ?

Answer 17

A tiny amount of ferritin is in the serum ==> a higher the serum ferritin reflects a higher level of ferritin synthesis and ==> greater iron storage

Question 18

What is the problem with serum ferritin ?

Answer 18

Also acts as an acute phase protein so goes up with infection, malignancy etc

Question 19

What are the 3 main disorders affecting iron in the body ?

Answer 19

1. Iron deficiency (this is covered in microcytic anaemia so wont talk about this here)
2. Iron malutilisation – ‘anaemia of chronic disease’
3. Iron overload

Question 20

Describe the normal process of Hb recycling

Answer 20

Normally - Once red cell reaches end of lifespan they are broken down into there sub-components, the iron gets mainly recycled back to the marrow erythroblasts (transported by transferrin), and some of it will be stored as ferritin

Question 21

Describe mal-utilisation of iron ‘anaemia of chronic disease’

Answer 21

Anemia of chronic disease, also called the anemia of inflammation, is a condition that can be associated with many different underlying disorders including chronic illnesses such as cancer, certain infections, and autoimmune and inflammatory diseases such as rheumatoid arthritis or lupus.

Question 22

Describe the process of how anaemia of chronic disease results in problems with iron metabolism

Answer 22

In any kind of inflammatory disorder you get increased inflammatory cytokine production these have a number of effects:

• They upregulate ferritin production so more iron will be stored ==> iron deficiency
• You get increased hepcidin which blocks relase of iron from macrophages and enterocytes
• This all results in impared iron supply to erythroid marrow

Question 23

What are the causes of iron overload ?

Answer 23

Primary:

• Hereditary haemochromatosis

Secondary:

• Transfusional
• Iron loading anaemias

Question 24

What is hereditary haemachromatosis and what mutation causes it ?

Answer 24

Haemochromatosis is an inherited (genetic) disorder causing the body to absorb too much iron from the diet. The excess iron is then stored in various organs, mainly the liver. The excess iron may also be stored in the pancreas, heart, testicles (testes)/ovaries, skin and joints.

There is also a decrease in hepcidin production

It is due to mutations in HFE gene

Question 25

What can the accumulation of iron in heredtiary haemachromatosis result in ?

Answer 25

End-organ damage

Question 26

What are the symptoms/signs of haemachromatosis ?

Answer 26

Initially presents with:

• Weakness/fatigue
• Pains in the joints and in the abdomen
• Impotence in men, can cause menstrual problems in women
• Bronzing of the skin

As organ damage occurs:

• Arthritis - if present in the knuckle and 1st joint of the first 2 fingers this is very suggestive
• Cirrhosis
• Diabetes
• Cardiomyopathy

Question 27

Describe the diagnostic approach to hereditary haemachromatosis

Answer 27

1st - check serum ferritin (>300 in men and >200 in women) and % tranferrin (>50%) - this is suggestive of iron loading

Diagnosis then made by testing for HFE mutation

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

Question 28

What is the treatment of haemachromatosis ?

Answer 28

1. Initially weekly venesections to exhaust iron stores continue this until - serum ferritin <20 µg/L
2. The carry out maintance venesections 3-4 times per year - to keep serum ferritin below 50 µg/l

Question 29

When we discover someone has hereditary haemachromatosis, what is offered to 1st degree family members ?

Answer 29

Testing for HFE mutation and iron status checked with serum Ferritin and % transferrin saturation

Question 30

How do iron loading anaemias result in iron overload ?

Answer 30

• Require repeated red cell transfusions
• Excessive iron absorption related to over-active erythropoiesis

Question 31

What are the disorders associated with iron overload

Answer 31

Massive ineffective erythropoiesis:

• Thalassaemia syndromes
• Sideroblastic anaemias

Refractory hypoplastic anaemias:

• Red cell aplasia
• Myelodysplasia (MDS)

Question 32

How does iron overload occur in these disorders ?

Answer 32

• You are giving patinets tranfusions of red blood cells which contain 250mg per unit
• This may be given every 3-4 weeks (variable between conditions)
• The body isnt able to excrete iron (only looses 1mg per day) so this results in a build up of iron as you give more and more transfusions
• Also these conditions cause anaemia which upregulates iron absoroption into the body so will also be taking in more iron per day

Question 33

What is the treatment/prevention of iron overload?

Answer 33

1st line = Desferrioxamine (subcut or IV infusion)‏

Newer oral agents:

• Deferiprone – 1% can get agranulotosis
• Deferasirox