Lecture 13: Iron homeostasis

Question 1

What is the function of iron in the body?

Answer 1

Important in the formation of:

• the haem part of heamoglobin (See picture)
• Other essential elements of the body including myoglobin, cytochromes, peroxidase, catalase etc

Question 2

What is the total quantity of iron in the body?

Answer 2

Averages 4-5 grams of iron

Question 3

Which part of the body has the biggest iron stores?

Answer 3

Bone marrow and haemoglobin (approx 3g)

2nd is the reticulo-endothelial system (200-500mg)

3rd myoglobin (200-300mg)

4th enzymes (100mg)

Question 4

List some of the essential enzymes that have an iron component?

Answer 4

Cytochromes

Cytochrome oxidase

Peroxidases

Xanthine oxidase

Catalases

RNA reductase

Question 5

Which cells of the body take up iron?

Answer 5

All cells of the body

Question 6

Describe haemosiderin?

Answer 6

• Iron-storage complex
• When the body has enough iron, when haemoglobins are broken down, and the iron is released, the body stores the excess iron in haemosiderins
• Most commonly found in macrophages
• Occurs when storage of iron in ferritin is exceeded

Question 7

What is the difference between the level of iron in the serum ferritin vs iron stores?

Answer 7

Tiny amount of iron in serum

Large amount of iron in stores in the body

Question 8

Where is the GI tract is iron absorbed?

Answer 8

In the small intestine from ingested foods

Question 9

Describe the recycling of iron by the body?

Answer 9

Iron is essential in the formation of haemoglobins

RBCs have a lifespan of 120 days, after which they must get broken down by the reticulo-endothelium system.

The iron released from the break down of RBC is recycled back into the body (not lost).

Question 10

What happens to iron once its absorbed by the small intestine?

Answer 10

Iron is immediately combined in the blood with transferrin

This complex is then transported in the plasma.

Question 11

Describe transferrin?

Answer 11

• Glycoprotein
• Synthesised in hepatocytes i.e. the liver
• Has two iron binding domains
• Iron is loosely bound and consequently can be released to any tissue cell in the body

Question 12

How is iron transported in the plasma?

Answer 12

Bound to transferrin

Question 13

What percentage of transferrin is:

A) saturated with iron

B) free from iron

Answer 13

A) 30% are saturated with iron (either with 1 or 2 irons)

*remember transferrin has 2 iron binding domains so can bind to a maximum of 2*

B) 70% are free from iron

Therefore, the majority of transferrin is free from iron

Question 14

What is the serum ferritin level (Therefore ferritin production) in the following situations:

A) Iron deficiency anemia

B) when levels of iron is in excess

C) Tissue inflammation

Answer 14

A) Decrease in iron deficiency anemia (because less iron is taken up, therefore less ferritin needed to transport it)

B) Rise when levels of iron is in excess (because you want to transport the excess iron and store in)

C) Rise in tissue inflammation

Question 15

Describe ferritin production and how it gets to the small intestine to bind to iron?

Answer 15

** apotransferritin + iron = ferritin **

• The hepatocytes in the liver synthesis apotransferritin.
• The liver secretes the apotransferrin into the bile
• The bile flows through the bile duct into the duodenum.
• In the duodenum, the apotransferritin binds to free iron and other iron compounds, forming transferritin.

Question 16

Describe how the body excretes excess iron?

Answer 16

No mechanism to excrete excess iron. Hence, why iron homeostasis is so important.

Little amounts of iron (1-2mg per day) are lost from the body via urine, faeces, sweat and cells sloughed from the skin and GI tract.

Question 17

The amount of iron lost for males is 1mg per day while for females is 2mg per day.

Why is this?

Answer 17

Women lose an additional amount via menstrual blood.

*REMEMBER ERYTHROCYTES CONTAIN THE IRON IN THE HAEM COMPONENT*

Question 18

The western diet is ___ in iron

Answer 18

Rich

around 15-20mg per day

The daily requirement is only 1-2mg per day

Not all of the iron from the diet is absorbed

Question 19

Where does the majority of iron required by the body come from?

Answer 19

Majority comes from the body stores

Little comes from dietary sources

Question 20

Give examples of rich sources of iron?

Answer 20

• Meat (red meat particularly)
• Liver
• Shellfish
• Egg yolk
• Beans
• Nuts
• Cereals
• Lots more

Question 21

The body has a considerable store of iron. One of these stores is in the liver. Here, the excess iron is bound to___?

Answer 21

Ferritin

Question 22

What is the rate of iron absorption in the intestines?

Answer 22

Extremely slow

Maximum rate of 1 or 2 mg of iron absorbed per day.

Question 23

What are the two types of iron in meat?

Answer 23

Haem and non-haem

Question 24

Compare heam and non haem iron in the diet:

Giving examples of the types of food these types of iron are found in.

Comparing the efficiency of absorption in the body?

Answer 24

Haem group:

• Found in red meat, chicken and fish
• Easily absorbed by the body

Non-haem group:

• Found in plant foods such as vegetables, cereals, beans and lentils.
• Not absorbed well by the body

Question 25

The non-heam iron is not easily absorbed by the body. Describe the body's mechanism of action of non-haem iron so the iron can be abosrbed?

Answer 25

* Non-haem must be reduced from the **ferric** to the **ferrous** **form** by **duodenal** **cytochrome** **B1**. * Fe³⁺ -\> Fe²⁺ * The process is influenced by **vitamin** **C** * Duodenal cytochrome B1 activity increases when vitamin C is present

Question 26

Give a basic step by step approach to iron absorption?

Answer 26

* Once iron is reduced into Fe²⁺ it is taken into enterocytes via **divalent** **metal** **transporter 1** (DMT1). * Once in the enterocyte, it joins the labile iron pool. * The labile iron pool serves the processes ofthe cell itself e.g. mitochondria. * However the labile iron pool is small therefore the majority of the iron is incorporated into **ferritin,** which functions as an intracellular iron store. * The iron from the labile iron pool can also be released to the plasma bound to **transferrin**.

Question 27

Most of the iron is incorporated into \_\_\_, a protein-iron complex that functions as an intracellular iron store

Answer 27

Ferritin

Question 28

Iron circulates throughout the body bound to \_\_\_\_, a plasma protein?

Answer 28

transferrin

Question 29

Describe what happens to the iron when erythrocytes are broken down?

Answer 29

Erythrocytes are broken down by macrophages in the reticulo-endothelial system. If the body has plenty of iron then these macrophages store the iron as ferritin. The iron gets released from these reticulo-endothelial system macropages to the plasma in response to ferroportin and hepcidin.

Question 30

How much iron is stored by the reticulo-endothelial system?

Answer 30

Around 500mg of iron is stored by the RE system macrophages

Question 31

Which cells of the body have ferritin receptors?

Answer 31

All cells of the body Therefore all cells can store iron

Question 32

Ferritin binds to iron where? Transferrin binds to iron where?

Answer 32

_Ferritin_: in the cell as an intracellular iron store. _Transferrin_: bound in the circulation

Question 33

Transferrin is synthesised in the?

Answer 33

Liver

Question 34

Iron released from the __ and ___ is transported in the circulation by the plasma protein \_\_\_?

Answer 34

1. Enterocyte 2. Reticulo-endothelial system macrophages 3. Transferrin

Question 35

How many iron atoms can each transferrin molecule bind?

Answer 35

2

Question 36

How is iron delivered to tissues?

Answer 36

The transferrin-iron complex binds to transferrin receptors on the cell surface. The higher the concentration of transferrin receptors the more iron it takes up. Found particularly on red blood cell precursors

Question 37

Describe the process of iron being turned into haem?

Answer 37

* Iron is in plasma bound to transferrin. * **Transferrin** **receptors** on the **erythroblast** surface takes the iron from the iron-transferrin complex. * The iron is transported to the mitochondria where it is used to produce haem. * Excess iron is stored in ferritin as an intracellular iron store * Process is complete within **minutes**

Question 38

Describe the following image?

Answer 38

* Iron is absorbed in enterocytes in the GI * The iron is excreted by enterocytes into the circulating plasma. * The iron is bound to transferrin. * The iron is taken to be stored and/or used in other tissues * e.g. Bone marrow, myoglobin, enzymes. * In tissues such as joints, heart etc. * The bone marrow forms erythrocytes (which has an iron component) * The erythrocytes after 120 days are degraded by the reticulo-endothelial system. * The iron is released and stored by the RE system macrophages. * The iron can be released by these macrophages back into the plasma bound to transferrin. * Iron is lost by the loss of cells in the GI and by menstrual loss.

Question 39

Define ferroportin and what is its function?

Answer 39

* Transmembrane protein * Function is to transport iron from the cell to the plasma. * The only iron exporter.

Question 40

Ferroportin is regulated by?

Answer 40

Hepcidin

Question 41

The interaction between ___ and ___ controls systemic iron homeostasis?

Answer 41

Hepcidin and Ferroportin

Question 42

Where is ferroportin located?

Answer 42

Ferroportin is found on the **basolateral** **membranes** of intestinal epithelia I.e. in the cell surface of enterocytes, macrophages and hepatocytes

Question 43

Define hepcidin and its function in iron homeostasis?

Answer 43

* Hepcidin is a peptide hormone produced by the liver and secreted into the circulation. * It is a regulator of the iron metabolism. * Hepcidin directly binds to ferroportin * After binding, ferroportin was internalized and degraded * Therefore reducing its functional activity * Leading to a decrease in iron cellular export in the **enterocytes and macrophages**

Question 44

Describe iron deficiency anaemia?

Answer 44

* Common form of anaemia * Caused by a lack of iron, usually when iron is getting lost or when iron demand is too much. * Most common cause is blood loss or could be due to chronic PPI use. * RBC configuration: microcystic hypochromic (pale and small) * Hypochromic: the RBC appear paler due to low levels of haemoglobin (outside ring is thin- as this is the haem part) * Microcystic: appears smaller

Question 45

What is the golden rule in regards to iron deficiency anaemia in males and postmenopausal females?

Answer 45

The cause of the iron deficiency anaemia is due to GI blood loss until proven otherwise

Question 46

What is the golden rule in regards to iron deficiency anaemia in young women?

Answer 46

Due to menstrual blood loss or/and pregnancy. GI blood loss is only investigated if the patient has GI symptoms or blood in stool. Complete opposite to males and post menopausal females

Question 47

Where is iron absorbed in the gi tract?

Answer 47

The **duodenum** is the chief area where iron absorption takes place

Question 48

Why is coeliac disease commonly associated with iron malabsorption?

Answer 48

In coeliac disease, the mucosa is characterised by villus atrophy, enlarged hyperplastic crypts and inflitration of inflammatory cells into the lumen. This impairs the ability of the enterocytes to absorb iron

Question 49

What are the most likely haematinic deficiency in coeliac disease?

Answer 49

_Most likely_: folate deficiency _2nd most likely:_ iron deficiency _Unlikely:_ Vitamin B12 deficiency

Question 50

What happens to the incoming iron when the iron levels in the blood is plentiful?

Answer 50

* The increased concentration of free iron in the plasma and intestinal epithelial cells leads to an **increased** **transcription** of the gene encoding the ferritin protein * Leads to an icnreased **synthesis** **of** **ferritin**. * Leads to increased binding of iron in the intestinal epithelial cells * Reduced amount of iron released into the blood

Question 51

What happens to the incoming iron when the iron levels in the blood is scarce?

Answer 51

* The reduced concentration of free iron in the plasma and intestinal epithelial cells leads to a decrease in the trnascription of the gene encoding the ferritin protein. * Reduction in synthesis of ferritin. * Leads to a decrease in the amount of iron bound to ferritin * Thereby, increasing the unbound iron released into the blood

Question 52

The control mechanisms for iron absorption tend to maintain the iron content in a narrow haemostatic range. A very large ingestion of iron can overwhelm them. What does this lead to?

Answer 52

Leads to an increased deposition of iron in tissues This can produce toxic effects such as changes to the skin pigmentation, diabetes mellitus, liver failure, heart failure etc

Question 53

Describe the mechanism behind hereditary haemochromatosis?

Answer 53

* An autosomal recessive disorder of iron metabolism causing iron overload * Caused majority of the time by abnormalities in the HFE gene * HFE gene is required for the synthesis of hepcidin. * Therefore in HH there is a reduction in hepcidin production. * Therefore, there is no mechanism to limit ferroportin (a protein used for the export of iron from enterocytes and macrophages into the plasma) * Results in iron overload * The transferrin can bind to iron, but with a high concentration of iron there are high transferrin saturation and leading to some iron not being bound (non-transferrin bound iron). This free iron can cause tissue damage

Question 54

Fill in the table for the labatory findings for iron deficiency anaemia and hereditary haemochromatosis?

Answer 54

Question 55

Describe haemochromatosis?

Answer 55

Condition in which extra iron is absorbed by the GI, which increases the iron levels slowly builds up in the body over multiple years. For example, extra intake of 3mg per day. Over 18 years that will be an excess of 20g of iron (remember the iron stores in the body at any time is 4g) This excess iron is bound to transferrin. Eventually the transferrin become saturated, leading to unbound iron, which can cause damage to tissues.

Question 56

Excess iron can damage other tissues. What is the effect in the following tissues: ## Footnote A) Liver B) Pancreas C) Skin D) Joints

Answer 56

A) Can cause cirrhosis of the liver. B) Damage to pancreas can lead to diabetes mellius C) Bronzing of the skin (as iron stimulates melanin production) D) Arthritis of the joints

Question 57

Describe the epidemiology of haemochromatosis?

Answer 57

Haemochromatosis most often affects people of **white** **northern** **European** **background** and is particularly common in countries where lots of people have a **Celtic** **background**, such as Ireland, Scotland and Wales.

Question 58

What are the possible treatments of haemochromatosis?

Answer 58

* **phlebotomy** – frequent blood if withdrawn, which removes iron contained in erythrocytes from the body. * **chelation** **therapy** – medication to reduce the amount of iron in your body; this is only used if it's not easy to regularly remove some of your blood