Iron metabolism and homeostasis

Question 1

What is iron needed for?

Answer 1

Formation of haemoglobin, and other metabolic processes in the body

Question 2

What is the total body content of iron?

Where is this distributed?

Answer 2

4g
3g is in bone marrow and RBCs.
The rest is in RES, myoglobin, and enzymes e.g. cytochromes, peroxidases.

Question 3

What happens to serum ferritin levels in IDA and in iron overload?

Answer 3

In IDA, ferritin levels decrease.

In iron overload, ferritin levels increase.

Question 4

What kind of molecule is transferrin?

Answer 4

A glycoprotein made in hepatocytes. More is made in low iron levels, and vice versa.

Question 5

What happens when serum iron levels drop?

Answer 5

Iron from the ferritin pool is then removed and taken via transferrin in the plasma to where its needed.

Question 6

What do transferrin molecules have high affinity for?

How does transferrin get iron into RBCs to become haem?

Answer 6

Transferrin receptors on RBC precursor membranes in bone marrow.
Ingested by endocytosis, and transferrin delivers iron to the mitochondria where haem is synthesised.

Question 7

Why is regulating iron absorption so important?

Answer 7

There’s no physiological mechanism for iron excretion, so absorption has to be tightly regulated to maintain iron balance

Question 8

Where does iron absorption principally occur?

Answer 8

Duodenum

Question 9

What type of iron is more easily absorbed?

Answer 9

Haem iron, rather than non-haem iron.

Question 10

How is non-haem iron released from food?

Answer 10

By acid digestion and proteolytic enzymes in the stomach. It has to be reduces from ferric to ferrous form by duodenal cytochrome B1, which is enhanced by vitamin C and alcohol.

Question 11

What receptor mediates non-haem iron absorption into enterocytes?

Answer 11

Divalent metal transporter 1 (DMT1). DMT1 is an electrogenic pump and it’s expression is upregulated in iron deficiency.

Question 12

How is iron exported from the enterocyte to the plasma?

Why is this important

Answer 12

Via ferroportin (transmembrane protein) and hepcidin (hormone). 
The interaction between the 2 is the single most important regulator of iron absorption and of RES iron release.

Question 13

Describe the difference in haem iron and non-haem iron absorption from the small intestine.

Answer 13

Haem iron is taken into the cells by endocytosis.
Non-haem iron has to be converted from ferric (Fe3) to ferrous (Fe2) by duodenal cytochrome B1, and then binds to the DMT1 receptor and is taken into enterocytes.

Question 14

What does iron do once it’s in the cell?

Answer 14

Either is stored as ferritin for when it’s needed, or is taken via ferroportin into the blood.

Question 15

What happens to iron once in the blood?

Answer 15

Iron is converted back into ferric form by hepcidin, which is upregulated in response to increased body iron stores.
Iron then binds back to transferrin.

Question 16

How is iron stored in the RES?

Answer 16

Once RBCs become effete after 120 days, RES macrophages turn haem into iron (and bilirubin) and iron is stored as ferritin or haemosiderin.

Question 17

How is RBC iron recycled?

Answer 17

The iron from effete RBCs is released from the RES to transferrin in the plasma, which is then taken up by transferrin receptors on RBC precursors.

Question 18

What are the main causes of IDA?

Answer 18

Menorrhagia, pregnancy, GI tract malignancy, oesophagitis, GORD, coeliac disease.

Question 19

What kind of anaemia is IDA?

Answer 19

Microcytic and hypochromic

Question 20

What are the symptoms of IDA?

Answer 20

Fatigue, headache, dyspnoea, palpitations, koilonychia, angular chelitis, glossitis

Question 21

What investigations should be carried out in IDA?

Answer 21

Bloods: decreased ferritin, decreased iron, increased iron binding capacity

Question 22

What treatment is available for IDA?

Answer 22

Treat the cause; iron supplement e.g. ferrous sulphate

Question 23

What haematinic (things which increase haemoglobin) deficiencies are seen in coeliac disease?

Answer 23

1. Folate deficiency (most likely)
2. Iron deficiency
3. Vitamin B12 deficiency (unlikely)

Question 24

How does hepcidin help to regulate plasma iron concentrations?

Answer 24

Hepcidin binds to ferroportin and degrades it, meaning that iron is sequestered in cells instead of absorbed into blood. This occurs in enterocytes and in macrophages (RES).

Question 25

What is haemochromatosis?

Answer 25

An autosomal recessive condition caused by excess iron absorption.

Question 26

What gene is mutated in haemochromatosis?

Answer 26

HFE gene. Homozygous 282Y mutation
Also, H63D.
Less transferrin molecules which are saturated with iron.

Question 27

How is iron homeostasis disturbed in haemochromatosis?

Answer 27

When HFE is mutated, the intestines constantly interpret a strong transferrin signal as if the body were deficient in iron. This leads to maximal iron absorption from ingested foods and iron overload in the tissues.
Hepcidin production is decreased, meaning the body can’t sense its own iron stores.

Question 28

Which tissues are susceptible to damage due to high iron levels?

Answer 28

Liver: cirrhosis
Pancreas: diabetes
Skin: bronzing
Joints: arthritis

Question 29

How is haemochromatosis treated?

Answer 29

Venesection: 500ml blood gives 250mg iron
Monitor ferritin levels and transferrin saturation
Prevent or limit organ damage

Question 30

What is sideroblastic anaemia?

Answer 30

Characterised by abnormal ringed sideroblasts (RBC precursors containing iron granules).
RBCs take in iron, but doesn’t transfer it into haem. Iron is locked as haemosiderin in mitochondria which are paralysed around the nucleus.