L8 - iron metabolism and microcytic anaemia

Question 1

Microcytic anemia is caused either by a reduction in haem synthesis or reduced globin synthesis. The only way we can get a microcytic anaemia (low MCV/small RBC’s) in this case is via a thalassaemia (alpha or beta). There are four ways of getting one from reduce haem synthesis, what are they?

Answer 1

Anaemia of chronic disease (ACD)
Iron deficiency (most common)
Lead poisoning
Sideroblastic anaemia

NOTE - the causes of microcytic anaemia can be remembered by the mnemonic TAILS

NOTE - microcytic anaemias are often hypochromic (paler than normal) as well

Question 2

We need 10-15mg/day of iron in our diet. Give two examples of good dietary sources of haem and non-haem iron

Answer 2

haem iron (think animal products) - Liver/kidney/chicken/duck/salmon

non-haem iron - raisins/beans/figs/rice/iron-fortified cereals/oats

Question 3

free iron is toxic because it can cause generation of free radicals. The body however has no mechanism for regulating excretion of iron so it needs to be properly absorbed and utilised. What is it used for in the body, give two examples?

Answer 3

Haemoglobin and myoglobin production/as a co-factor with cytochromes, krebs cycle enzymes, catalase (protects against oxidative damage)

Question 4

There are two forms of iron, ferrous (Fe2+) and ferric (Fe3+) . Under what conditions is Fe3+ reduced to Fe2+?

Answer 4

Reduction in acidic (low) pH of Fe3+ to Fe2+

Oxidation of Fe2+ to Fe3+ takes place in alkaline (high) pH

Question 5

What areas of the small intestine does iron absorption occur?

Answer 5

Duodenum and jejunum

Question 6

Briefly iron absorption into the bloodstream and to the requiring tissues starting from the chyme in the duodenum

Answer 6

1) haem iron is directly absorbed into the enterocyte (hence why it is considered better)
2) The Fe3+ components of the non-haem iron are reduced to Fe2+ by a vitamin C dependent enzyme
3) The Fe2+ is now absorbed into the enterocyte via DMT1
4) From here iron can either be stored in ferritin or released into the bloodstream via ferroportin
5) Once in the bloodstream the iron is then oxidated again to the ferric form and transported via transferrin to the necessary tissues

Question 7

What are the constituents of haem and non-haem iron separately?

Answer 7

Haem - Ferrous iron only (Fe2+)

Non-haem - Ferrous and ferric iron (Fe2+ and Fe3+)

Question 8

Give 2 factors that promote the absorption of non-haem from the blood and 2 factors that inhibit it. Hint - This would be important dietary advice for iron deficient patients

Answer 8

Inhibit - Tannins in tea/pulses/fibre/ANTACIDS

Promote - vitamin C/ citrate

Question 9

Total iron can be divided into ‘funcitonal’ (available) iron which is available to our tissues to use and stored iron. Stored iron can be in a soluble or insoluble form, what are the names of each?

Answer 9

Soluble store - Ferritin

insoluble store - haemosiderin (accumulates in macrophages)

Question 10

Once transferrin takes ferric iron to the tissues how is it absorbed for use?

Answer 10

At the cells the transferrin is endocytosed, it then encounters an acidic microenvironment which reduces it to the Fe2+ form. Fe2+ is then transported into the cytosol via DMT1 just as it was at the enterocyte level. From here it is then stored in ferritin or used by the mitochondrial cytochrome enzymes

Question 11

Although we need a dietary source or iron, the majority of our requirements are fulfilled by iron already in the body via iron recycling. Explain this concept

Answer 11

1) Old RBC’s are phagocytosed by macrophages in the spleen and liver (Kupffer cells)
2) The macrophages catabolise the haem released from the RBC’s

Question 12

It is important to regulate our iron absorption from the diet depending on the need for iron. Dietary iron levels are sensed by the enterocytes, what is then done to regulate absorption?

Answer 12

Regulation of ferroportin
Regulation of transferrin receptor
Hepcidin (in liver, inhibits ferroportin) - hepcidin is upregulated in iron overload

Question 13

What causes a downregulation of the protein hepcidin which inhibits and degrades ferroportin

Answer 13

high erythropoietic activity - realises that iron is needed for this

Question 14

Considering hepcidin, explain how anaemia results from chronic inflammatory conditions in Anaemia of chronic disease (ACD)

Answer 14

Inflam condition -> release of pro-inflammatory cytokines (e.g. IL-6) -> this causes increased production of hepcidin in the liver -> This means increased inhibition of ferroportin -> iron can’t be released from it’s stores and iron absorption is decreased -> reduced plasma iron -> inhibition of erythropoiesis in the bone marrow

Question 15

Although we can’t regulate the excretion of iron, how do we lose it involuntarily?

Answer 15

bleeding/sweat/pregnancy/sudden growth

Question 16

What organ contains most of our iron stores?

Answer 16

liver

Question 17

What is the most common nutritional disorder worldwide?

Answer 17

iron deficiency

Question 18

Name three major causes of iron deficiency

Answer 18

insufficient iron in the diet/Bleeding (menstrual cycle problems/internal bleed)/ACD/pregnancy/malabsorption of iron i.e. vegan or vegetarian diet

Question 19

You take a patients blood after suspecting anaemia and notice that they are iron deficient, what are some questions to ask them?

Answer 19

• Are you vegan/vegetrarian?
• Have you had any trauma/ how is your menstruation? Are there any bleeds?
• What’s your diet like?
• Do you have any inflammatory diseases you are aware of?

Question 20

What groups are most at risk of iron deficiency?

Answer 20

Infants/children/women of child bearing age/older people

Question 21

Name two common symptoms of anaemia and two common signs of anaemia specifically linked to iron deficiency

Answer 21

Anaemic symptoms - tired/pale/reduced exercise tolerance (due to less haemoglobin)/palpitations/headache/dizzy

Iron deficient signs - Cold extremities/ epithelial changes such as ‘spoon nails’ glossy tongue (smooth centre), angular chelitis (inflammation of corners of mouth) / pica (cravings for srange substanves

Question 22

You suspect a patient is iron deficient and send for a FBC. What are the results you expect back if he is?

Answer 22

most importantly - Low ferritin, low iron and high transferrin (TIBC) in serum obviously
-also low MCV/ low MCHC (mean cell haemoglobin concentration)/often elevated platelet count/low reticulocyte haemoglobin content (CHr)

Question 23

To confirm an iron deficiency you send off a blood smear, what do you see if they are?

Answer 23

• RBC’s are microcytic and hypochromic
• Change in size and shape
• Sometimes we see pencil cells and target cells (LOOK AT THESE)

Question 24

CHr (reticulocyte haemoglobin content) is the test recommended by NICE to order to diagnose iron deficiency anaemia. What patients can you not use this in however?

Answer 24

-Patients with thalassaemia’s as their CHr is low
also note - CHr remains low in inflammatory responses

So this is the main test

Question 25

Reduced plasma ferritin definitively indicates an iron deficiency HOWEVER normal or increased ferritin does not exclude iron deficiency. Why would these be normal or high in such a patient?

Answer 25

infection/cancer/inlfalmmation/liver disease/ alcoholism

Question 26

What are the treatments for mild and severe iron deficiencies?

Answer 26

Mild - dietary advice/ oral iron supplements

severe - intramuscular iron injections/IV iron/ blood transfusion

Question 27

excess iron can be bad to as it promotes free radical formation and organ damage via deposition as haemosiderin in end organs. How could excess iron occur?

Answer 27

Hereditary haemochromatosis (mutation in the HFE gene which should negatively regulate the transferrin receptor, treated with regular venesection) or transfusion associated haemosiderosis (repeated blood transfusions can cause a build up of iron )

Question 28

what are the symptoms of haemochromatosis?

Answer 28

Hyperpigmentation of skin/ cardiomyopathy/arthropathy/liver cirrhosis (all to do with end organ damage/hypogonadism