L8: Fe Metabolism

Question 1

State two uses of Fe in the body

Answer 1

• Oxygen carrier (in Hb & myoglobin)
• Co-factor for enzymes (e.g. cytochromies in oxidative phosphorylation, CP450 in detoxification, catalase, Krebs cycle enzymeS)

Question 2

Why is free Fe potentially very toxic to cells?

Answer 2

It can participate in Fenton reaction to form free radicals leading to oxidative stress which can cause damage e.g. to DNA & lipids

Question 3

Does the body have a mechanism for excreting Fe?

Answer 3

No

Question 4

Why does microcytic anaemia occur (generally)?

Answer 4

There is a reduced rate of haemoglobin synthesis, which can be for various reasons, that results in erythrocytes being smaller than normal. Due to reduced rate of Hb synthesis erythroytes tend to be both microcytic & hypochromic (pale due to lack of Fe)

Question 5

State the 5 main causes of microcytic anaemia

Answer 5

Question 6

Describe the 5 maint types of microcytic anaemia (in terms of why they occur)

Answer 6

Question 7

Statet the two most cmmon states Fe is found in

Answer 7

• Fe²⁺ = ferrous state
• Fe³⁺= ferric state

Question 8

Define:

• Haem Fe
• Non-haem Fe

Answer 8

• Haem Fe= Fe²⁺
• Non-haem= Fe²⁺ & Fe³⁺

Question 9

Dietary Fe consists of haem & non-haem Fe; which source is best?

State some example haem & non-haem foods

Answer 9

Haem Fe is the best source

Haem (animal based)

• Liver
• Beef steak
• Chicken
• Salmon/tuna

Non-haem (plant based)

• Fortified cereals
• Raisins
• Figs
• Potatoes

Question 10

Fe ion undergoes changes in acidic and alkaline conditions; state these changes and state why they are beneficial to absorption

Answer 10

Acidic

Fe³⁺ + e^- -> Fe^{2+ <em></em>}Beneficial as only Fe2+ can be absorbed and stomach has acidic conditions</em></sup>

Alkaline

Fe²⁺ -> Fe³⁺ + e^-

Remember OILRIG

Question 11

Describe the absorption of dietary Fe

Answer 11

Occurs in duodenum & upper jejunum

1. Ferric Fe reduced to ferrous Fe in intestinal lumen by duodenal cytochrome B reductase (vitamin C helps reduction). Ferrous Fe just absorbed via DMT1 straight away
2. Ferrous Fe taken into enterocytes by DMT1 (divalent metal transporter 1)
3. Fe either stored as ferritin (in Fe³⁺ state) or released into bloodstream via ferroportin
4. Hephaestin oxidises Fe²⁺ to Fe³⁺
5. Ferric Fe then binds to transferrin (2 per transferrin molecule) and is transported in blood to sites where it is required or stored (most of Fe goes to bone marrow for erythropoiesis or is taken up by macrophages in RES as storage)

Question 12

Where does absorption of dietary Fe specifically occur?

Answer 12

Duodenum & upper jejunum

Question 13

How much Fe is required per day from diet?

Answer 13

10-15mg/day

Question 14

1. Where is hepcidin produced?
2. Describe it’s main role
3. State how the synthesis is affected by:

• Iron overload
• High erythropoietic activity

Answer 14

1. Liver
2. Prevent Fe absorption
3. In:

• Fe overload: increase synthesis
• High erythropoietic activity: decrease synthesis

Question 15

Describe the two ways in which hepcidin can decrease Fe absorption

Answer 15

• Bind to ferroportin: cause internalisation & degradation of ferroportin transporter to prevent Fe leaving enterocytes
• Inhibit transcription of DMT1 gene: downregulation of DMT1 hence less Fe uptake from lumen of duodenum & upper jejunum

Question 16

What we ingest can have a positive or negative influence on the absorption of Fe; state some examples of each and where possible explain why it has such effect

Answer 16

Positive Influence/Increase Absorption

• Vitamin C: aids reduction of Fe³⁺ to Fe²⁺ & prevents formation of insoluble Fe compounds
• Citrate: prevents formation of insolube Fe compounds

Negative Influence/Decrease Absorption

• Tannins (in tea)
• Phyates (in chapattis, pulses)
• Fibre
• All 3 can bind to non-haem Fe in intestine and reduce absorption*
• Antacids: decrease pH so decrease reduction of Fe³⁺?

Question 17

Fe absoprtion is depedent on what three things?

State 4 mechanisms which control Fe absorption

Answer 17

• Dietary factors
• Body Fe stores
• Erythropoiesis

Four mechanisms:

• Regulation of transporters e.g. ferroportin
• Regulation of receptors e.g. transferrin & HFE protein
• Hepcidin & cyokine production
• Crosstalk between enterocytes & other cells e.g. macrophages

Question 18

Describe cellular Fe uptake (how Fe taken from bloodstream into cells)

Answer 18

1. Trasnferrin, with Fe³⁺ bound, binds to transferrin receptor and enters cytosol via receptor mediated endocytosis
2. Fe³⁺ released from transferrin and reduced to Fe²⁺ due to the acidic envrionment of endosome
3. Fe²⁺ transported from endosome to cytosol via DMT1
4. Fe²⁺ is then either:

• Stored in ferritin as Fe³⁺
• Exported by ferroportin
• Taken up by mitochondria for use in cytochrome enzymes in oxidative phosphorylation

Question 19

Why is only a small amount of Fe required from diet?

Answer 19

Body obtains most of Fe from the recycling of damaged or senescent RBCs

Question 20

Describe how RES recycles the Fe in damaged or senescent RBCs

Answer 20

Macrophages of RES, mainly splenic macrophages or kupffer cells, take up damaged or senescent RBCs

Macrophages then catabolise the haem

Possible fates:

• Amino acids re-used
• Fe exported to blood (and bind to transferrin)
• Fe returned to storage pool, mainly in liver, as ferritin in macrophages (haemosiderin)

Question 21

Give an overview of Fe homeostasis

Answer 21

Question 22

What is the most common deficiency in the world?

Answer 22

Fe deficiency

Question 23

Fe deficiency is not a diagnosis hence you must always seek to find underlying cause; state some possible underlying causes

Answer 23

• Insufficient Fe uptake
• Malabsorption
• Bleeding
• Increased requirement e.g. pregnancy
• Anaemia of chronic disease

Question 24

Put the following categories of people in order of Fe requirement (start with highest):

• Females menstruating
• Adult males & menopausal women
• Children
• Pregnant women
• Lactating women

Answer 24

1. Pregnant women
2. Females menstruating
3. Lactating women
4. Children
5. Adults males & menopausal women

Question 25

Describe the aetiology of anaemia of chronic disease

Answer 25

Question 26

Describe signs & symptoms which aid diagnosis of Fe deficeincy anaemia

Answer 26

* **Usual anaemia signs** *(fatigue, pallor, reduced exercise tolerance, tachypnoea, headache, light-headed)* * **Pica** *(unusual craving for non-nutritional substance)* * **Cold hands & feet** * **Epithelial changes:** *angular cheilitis, glossy tongue with atrophy of lingual papillae, koilonychia*

Question 27

Describe: * Angular cheilitis * Glossy tongue with atrophy of lingual papillae * Koilonychia

Answer 27

* Inflammation of one or both corners of mouth * Smooth glossy tongue that can be quite tender * Spoon nails: abnormally thin nails that have lost their convexity so are flat or even concave

Question 28

State and describe two tests we can do to diagnose Fe deficiency anaemia, include: * Test * How it works * Result that indicates Fe deficiency anaemia * Associated problems with test

Answer 28

**Plasma Ferritin** * Ferritin usually cytosolic but small amount secreted into blood and acts as an Fe carrier * Low/reduced = Fe deficiency anaemia * Levels also increase in cancer, infection, inflammation, liver disease & alcoholism hence normal or increased levles of plasma ferritin do not exclude Fe deficiency **CHr (reccommended by NICE)** * Reticulocyte Hb content * Low/reduced = Fe deficiency anaemia * Levles are low during inflammatory respones and in patients with thalassaemia

Question 29

Describe the FBC results for someone with Fe deficiency anaemia: * MCV * MCHC * Platelet count * WBC * Serum/plasma ferritin * Serum Fe * % transferrin saturation * TIBC * CHr

Answer 29

* MCV (mean corpuscular volume): low * MCHC (mean corpuscular Hb concentration): low * Platelet count: elevated *\*\*\*don't know why* * WBC: normal or elevated * Serum ferritin: low * Serum Fe: low * % transferrin saturation: low * TIBC (total iron binding capacity=bloods ability to bind to Fe & transport it around body): raised * CHr (low reticulocyte Hb count)

Question 30

Describe the peripheral blood smear for someone with Fe deficiency anaemia

Answer 30

* Microcytic erythrocytes * Hyochromic erythrocytes

Question 31

State four treatment options for Fe deficiency anaemia

Answer 31

* Dietary advice (to increase dietary Fe and not eat foods that have negative influence) * Oral Fe supplements (taken with orange juice NOT MILK OR TEA) * Intramuscular injections (if there's a problem absorbing the Fe) * Blood transfusions

Question 32

Why do many patients not comply with oral Fe treatment?

Answer 32

Causes GI upset

Question 33

What rise in Hb wouldyou expect to see in 3 weeks to assure you that treatment is working?

Answer 33

20g/L rise in Hb in 3 weeks (AND IMPROVED SYMPTOMS)

Question 34

What happens to Fe if it is in excess and why is this dangerous?

Answer 34

If Fe in excess it can exceed binding capaccity of transferrin and hence the excess Fe is either: * Deposited in organs as haemoisiderin particuarly in **heart, liver, adrenal glands, joints & pancreas** * Used in Fenton reaction to form free radicals

Question 35

State two examples of when iron overload can occur

Answer 35

* Transfusion associated haemosiderosis * Hereditary haemochromatosis

Question 36

Describe: * How transfusion associated haemosiderosis can occur * Consequences of accumulation of Fe/haemosiderin * How it is treated

Answer 36

* If patient needs repeated blood transfusions, e.g. for t**ransfuion dependent anaemia such as thalassaemia & sickle cell**, then it can lead to gradual accumualtion of Fe and body has no mechanism to excrete it. * Haemosiderin in liver, heart & endocrine organs can cause: liver cirrrhosis, diabetes mellitus, hypogonadism, cardiomyopathy, arthropathy, increased skin pigmentation Treatment: **iron chelating agents e.g. desferrioxamine** (delay effects of Fe overload but overload is inevitable)

Question 37

Explain hereditary haemochromatosis, include: * Inheritance pattern * Mechanism of disease * Consequences/signs/symptoms * Treatment

Answer 37

* Autosomal recessive * **Mutation on HFE gene** on chromosome 6; **HFE usually interacts with transferrin receptor and reduces it's affinity for Fe bound transferrin**. Mutated HFE protein can't bind to transferrin receptor and hence can't exert a negative effect on binding; consequently, t**oo much Fe taken up into cells.** * Fe deposition/**haemosiderin** can cause damage: * Liver cirrhosis * Diabetes mellitus * Hypogonadism * Cardiomyopathy * Arthropathy (disease of joints) * Increased skin pigementation * Treatment: **venesection**

Question 38

What is the total Fe in body? How much of that is stored and how much is functionally available?

Answer 38

* Total Fe= 3350mg * Stored= ~1000mg * Functionally available= ~2350mg *(most of functionally available Fe is in Hb, then myoglobin, then enzymes, then in serum)*

Question 39

Describe two ways in which Fe can be stored, for each state: * What composed of * Soluble or insoluble

Answer 39