Absorption of Iron and Gastrointestinal Diseases

Question 1

List 4 roles of iron in human biology.

Answer 1

1 - Oxygen transport and storage.

2 - Electron transport.

3 - Used in a plethora of enzymes.

4 - Cell cycle control.

Question 2

What are the two forms of iron that are available in the diet?

Which is absorbed the most?

Answer 2

• Inorganic and haem.

- Equal absorption of both.

Question 3

Why is <10% of consumed iron absorbed?

Answer 3

Inorganic iron (the majority of dietary iron) is not absorbable.

Question 4

How does iron absorption efficiency change throughout the bowel?

Answer 4

There is a gradient of absorption from the small to large bowel.

Question 5

Describe the stages of luminal enterocyte Fe3+ uptake.

Answer 5

• Fe3+ -> Fe2+ by Dcytb (duodenal cytochrome b) membrane protein.
• Fe2+ enters the cell through the DMT1 (divalent metal transporter 1) transmembrane protein.
• Fe2+ is stored in the intracellular ferritin protein.

Question 6

Describe the stages of luminal enterocyte Haem-Fe uptake.

Answer 6

• Haem-Fe enters the cell through the HCP1 (haem carrier protein 1) transmembrane protein.
• The intracellular HO1 (haem oxygenase-1) protein degrades the Haem-Fe to Fe2+.
• Fe2+ is stored in the intracellular ferritin protein.

Question 7

How is Fe2+ transported out of the enterocyte?

Answer 7

Through FPN (ferroportin) at the basal membrane.

Question 8

How is Fe2+ converted back into Fe3+ once transported out of the enterocyte?

What does Fe3+ then bind to?

Answer 8

Using the transmembranous protein hephaestin.

Fe3+ then binds to Fe-transferrin.

Question 9

What is hereditary haemochromatosis?

Why is this an issue?

Answer 9

A type 1 autosomal recessive disease characterised by excessive intestinal absorption of dietary iron resulting in an increase in total body iron stores.

• An issue because humans have no way of actively excreting iron, and excess iron can lead to damage to the liver and pancreas (manifesting as diabetes mellitus and liver failure).

Question 10

Explain the pathophysiology of haemochromatosis.

Answer 10

• Normally, the HFE protein facilitates the binding of transferrin, (iron’s carrier protein in the blood).
• Transferrin levels are typically elevated at times of iron depletion (low ferritin stimulates the release of transferrin from the liver).
• When transferrin is high, HFE works to increase the intestinal release of iron into the blood.
• When HFE is mutated, the intestines perpetually interpret a strong transferrin signal as if the body were deficient in iron so there is always high intestinal release of iron into the blood.

Question 11

What is a potential treatment for hereditary haemochromatosis?

Answer 11

PPIs (evidence that acid can reduce Fe3+ to Fe2+).

Question 12

What is involved in non-enterocyte iron transport?

Answer 12

• Erythroid precursors.
• Transferring receptor-mediated endocytosis.
• Involves the transferrin receptor, DMT-1 and ferric reductase.

Question 13

Where does iron end up after binding to transferrin after the enterocyte?

Answer 13

In bone marrow (in developing red blood cells).

Question 14

Describe uptake of Hb by macrophages after haemolysis.

What happens to the iron after this?

Answer 14

• Hb binds to haptoglobin (Hp).
• Hp binds to the CD163 receptor on macrophages.
• This causes the Hb to be taken up by the macrophages.
• The macrophages return the Fe (from the Hb) to the bone marrow.

Question 15

Describe uptake of Hb by hepatocytes after haemolysis.

What happens to the iron after this?

Answer 15

• Haem from haemoglobin enters the hepatocyte.
• The intracellular HO1 (haem oxygenase-1) protein degrades the Haem-Fe to Fe2+ and biliverdin IX.
• Biliverdin IX is converted into bilirubin IX by biliverdin reductase.
• Porphyrin (breakdown product) is transported out of the hepatocyte to the bile.
• The Fe is returned to bone marrow.

Question 16

What is haemolytic anaemia?

Answer 16

A low blood haemaglobin concentration due to defective haemolysis.

Question 17

Where are the major stores of iron in the body?

Answer 17

1 - Liver.

2 - Spleen.

3 - Bone marrow.

Question 18

How do the iron stores of the body communicate with the small bowel?

Answer 18

• Via hepcidin.

- Hepcidin binds to iron-exporting cells to prevent exporting of iron.

Question 19

What happens to iron in the blood when hepcidin is elevated in response to inflammation / infection?

Answer 19

Iron is sequestered in the endothelium, resulting in anaemia despite adequate body iron.

Question 20

What concentration of iron is required for a person to be anaemic?

Answer 20

• Below 13g/dL in men.
• Below 12g/dL in women.
• Below 11g/dL in pregnant women.

Question 21

Why is it beneficial for hepcidin to increase in response to infection?

Answer 21

It creates an environment low in free iron, impeding bacterial survival.

Question 22

How does infection increase blood hepcidin concentration?

Answer 22

• Activated macrophages release cytokines, specifically interleukin-6.
• IL-6 is an inducer of hepcidin expression.

Question 23

How can you discriminate between anaemia of chronic disease and iron deficiency anaemia?

Answer 23

• If ferritin concentrations are <30ng/mL, it is iron deficiency anaemia.
• If ferritin concentrations are >100ng/mL, it is anaemia of chronic disease.
• If [Ferritin] is in between 30-100 ng/mL, it is anaemia of chronic disease with iron deficiency.

Question 24

List 7 types of anaemia.

Answer 24

1 - Iron deficiency anaemia.

2 - Vitamin deficiency anaemia.

3 - Anaemia of chronic disease.

4 - Aplastic anaemia (bone marrow and the hematopoietic stem cells that reside there are damaged).

5 - Anaemia associated with bone marrow disease.

6 - Haemolytic anaemia.

7 - Sickle cell anaemia.

Question 25

What does total iron capacity measure?

Answer 25

The blood’s capacity to bind iron with transferrin (an indirect measure of transferrin.

Question 26

How is transferrin saturation calculated?

Answer 26

The ratio of serum iron and total iron-binding capacity, multiplied by 100.

Question 27

List 8 symptoms of anaemia.

Answer 27

1 - Chronic fatigue / tiredness.

2 - Muscular weakness.

3 - Shortness of breath.

4 - Nausea.

5 - Palpitations.

6 - Tachycardia.

7 - Increased susceptibility to infection.

8 - Menorrhagia (heavy menstrual bleeding).

Question 28

How does iron cause damage to cells?

Answer 28

• Fenton reactions:
  (1) Fe2+ + H2O2 → Fe3+ + OH· + OH−
  (2) Fe3+ + H2O2 → Fe2+ + OOH· + H+
• Free radicals cause damage.

Question 29

What is coeliac disease?

Answer 29

• An autoimmune disease of the small bowel.
• Reaction to gliadin (a gluten protein).
• In coeliac disease, the enzyme ‘tissue transglutaminase’ modifies gliadin.
• This causes an immune inflammatory reaction, causing villous atrophy.

Question 30

List 5 symptoms of coeliac disease.

Answer 30

1 - Iron deficiency anaemia.

2 - Diarrhoea.

3 - Weight loss.

4 - Stunted growth in children.

5 - Fatigue.

Question 31

How is coeliac disease treated?

Answer 31

With a gluten free diet.

Question 32

How is coeliac disease tested for?

Answer 32

• Test for the anti-tissue transglutaminase antibody.

- Small bowel biopsy.

Question 33

Why does ulcerative colitis cause anaemia?

How is anaemia due to UC treated?

Answer 33

• Inflammation impedes iron absorption.
• Intestinal bleeding causes a loss of red blood cells in the stools.
• Intravenous oral iron supplementation.