Iron metabolism

Question 1

Why do we need iron?

Answer 1

• red blood cells

- huge part in general metabolism as part of essential enzymes

Question 2

How much iron does an average person have?

Answer 2

Total body content 4 grams

Question 3

Which cells require and store iron?

Answer 3

All cells

Question 4

What forms can iron be stored in?

Answer 4

• ferritin

- haemosiderin

Question 5

What is ferritin?

Answer 5

 Soluble form of iron
 Iron is safe and readily available from macrophages in RES
 Serum Ferritin
 Tiny amount in serum  (directly relates) to amount of iron in RES stores

Question 6

What is haemosiderin?

Answer 6

 Insoluble conglomerates of ferritin

 Iron is only slowly available in this form

Question 7

What investigation is used to determine iron levels?

Answer 7

Serum Ferritin

Question 8

Describe the serum ferritin levels in iron deficiency anaemia (IDA)

Answer 8

Decreased

- indicates patient has little or no iron stores (indisputable)

Question 9

Describe the serum ferritin in iron overload

Answer 9

Increased
o NB: Ferritin is an acute phase protein. This means it is increased in tissue inflammation/infection/damage
o Elevated serum ferritin therefore does not always indicate iron overload

Question 10

How is iron transported?

Answer 10

transferrin is used as a transport protein

Question 11

Where is transferrin made?

Answer 11

Synthesised in hepatocytes; plasma protein

Question 12

What controls the synthesis of transferrin?

Answer 12

controlled by level of iron
o Low levels of iron results in increased production of Transferrin
o Conversely, increased levels of iron result in decreased production of transferrin

Question 13

How is iron transported with transferrin?

Answer 13

Each transferrin molecule can bind 2 iron atoms (it has 2 iron binding domains)

Question 14

What is teh daily iron need?

Answer 14

1-2mg/day needs to be absorbed from GI tract to maintain
balance
o 1mg for men
o 2mg for women (to compensate for menstrual loss)

Question 15

What is the main variable of iron levels?

Answer 15

absorption as iron is locked in circulation

Question 16

What are the sources of iron in the western diet?

Answer 16

 Occurs as haem iron in red meat.

 Non-haem iron is found in white meat, green vegetables, cereals and fortified bread.

Question 17

How are iron levels maintained?

Answer 17

Regulation of dietary iron absorption is the single physiological mechanism responsible for
maintaining our iron balance
o There is no excretory mechanism for excess iron

Question 18

Where in the GI tract is iron absorbed?

Answer 18

Absorption predominantly in duodenum

Question 19

What cells are responsible for iron absorption?

Answer 19

duodenal enterocytes

Question 20

Which form of iron is easily absorbed?

Answer 20

haem iron

Question 21

Which form of iron is more difficult to absorb?

Answer 21

non-haem iron

Question 22

How is non-haem iron absorbed?

Answer 22

o Needs to be released from foodstuffs by acid digestion and proteolytic enzymes in stomach
o Non-haem iron must be reduced from the ferric (Fe 3+ ) to the ferrous form (Fe 2+ ) by duodenal
cytochrome b1(dCytb1)
o This process (reduction of ferric = ferrous) is influenced by vitamin C and by alcohol

Question 23

How is iron taken up into the enterocyte?

Answer 23

through the divalent metal transporter 1 (DMT1).
o DMT1 is an electrogenic pump.
o Its expression is upregulated in states of iron deficiency, to increase iron absorption

Question 24

How is iron exported from the enterocyte?

Answer 24

Iron is exported from the enterocyte to the circulating plasma through ferroportin and Hepcidin
(hormone).
o Ferroportin is a transmembrane protein on the internal side of duodenal cell
o This interaction is also essential for the release of iron from macrophages in the RES

Question 25

Describe iron release from RES

Answer 25

 RES macrophages acquire iron from effete RBCs  In the macrophage: o Haem is broken down to iron & bilirubin o Globin is broken down to amino acids, which are realised into the amino acid pool  RES iron is stored as ferritin (or haemosiderin)  Iron release from RES macrophages to plasma is controlled by Ferroportin and Hepcidin.

Question 26

What is hepcidin?

Answer 26

low iron hormone

Question 27

How is RBC iron recycled?

Answer 27

 Effete red blood cells are removed by the macrophages of the reticuloendothelial system (RES).  The RES stores around 500mg of iron.  RES Iron is stored in ferritin / haemosiderin.  RES releases iron to Transferrin in plasma.  Tf-iron is taken up by cells via Tf receptors (located on erythroblasts, hepatocytes etc.)

Question 28

Describe the transport of iron

Answer 28

Iron released from enterocytes and RES is transported in the circulation by transferrin.  Each transferrin molecule can bind 2 iron atoms.  Only 4mg of iron is bound to transferrin at any one time but up to 50mg of iron is transported by this method each day (over the course of 24 hours).  Iron is delivered to tissues by binding of the transferrin-iron complex to transferrin receptors found on the cell surface.

Question 29

Where is the highest concentration of transferrin receptors

Answer 29

(~80% of total TfRs) are found on red blood cell precursors o The liver is the next most major site of TfRs

Question 30

How is iron taken up by RBC?

Answer 30

 Transferrin iron is recognised by tf receptors on RBC surface  Iron is taken up  Most taken to mitochondrion  Converted to haem by ALA-S2  Very efficient process, occurs within minutes

Question 31

What is the role of Haem?

Answer 31

 Hb able to reversibly bind O 2 without undergoing oxidation or reduction  Only oxidised under extreme circumstances; forms Met Hb o iron in the heme group is in the Fe³⁺ state, not the Fe²⁺ of normal hemoglobin. o Methemoglobin cannot bind oxygen, unlike oxyhemoglobin

Question 32

What are the two types of iron metabolism disorders

Answer 32

- deficiency | - excess

Question 33

What are the microscopic appearances of iron deficiency anaemia?

Answer 33

 RBC are hypochromic and microcytic |  (Pale and small)

Question 34

What is IDA in males and post-menopausal females a sign of?

Answer 34

due to GI blood loss until proven otherwise

Question 35

What is IDA in young women a sign of?

Answer 35

often attributable to menstrual blood loss  pregnancy (causes loss of 500mg) o GI investigations only carried out in this group for GI symptoms or blood in stool.

Question 36

What is the effect of coeliac disease on iron levels?

Answer 36

Because of malabsorption, patients can become | deficient in haematinics

Question 37

Describe the features of coeliac disease

Answer 37

 Subtotal villus atrophy – blunting of villi and lymphocytic infiltrate in lamina propria  Gluten sensitivity  Folate deficiency is common o High daily requirements of folic acids but poor absorption  Because of malabsorption, patients can become deficient in haematinics

Question 38

Describe the likely causes of haematinic deficiency in coeliac disease

Answer 38

- folate deficiency (most likely) - iron deficiency (second most likely) - vitamin B12 deficiency (unlikely)

Question 39

What are the sources, requirements and stores of folate?

Answer 39

o Dietary source: green veg, orange fruit, liver o Daily requirements: high 150mg o Body stores: low 15mg (will run out in ~3 months if no intake)

Question 40

What are the sources, requirements and stores of iron?

Answer 40

o Dietary source: haem, non haem o Daily requirements: 1mg (20mg in diet) o Body stores : 200-500mg

Question 41

What are the sources, requirements and stores of Vitamin B12?

Answer 41

o Dietary source: meat and dairy, not vegetables daily o Requirements: 1-3mg/d o Body stores: 3mg (will run out in ~3-5 years if no intake) o Daily requirements low, and body stores B12 extremely efficiently

Question 42

What are the microscopic features of coeliac disease?

Answer 42

- target cells - howell-jolly bodies - irregularly contracted RBCs

Question 43

What are target cells?

Answer 43

(look like a bulls eye target) | o an abnormal form of red blood cell which appears as a dark ring surrounding a dark central spot

Question 44

What are Howell-Jolly bodies?

Answer 44

(HJs) – dots seen in cells o Clusters of DNA o Can indicate that the bone marrow does not produce enough healthy blood cells (myelodysplasia) or that the spleen has been removed

Question 45

How is iron metabolism regulated?

Answer 45

Hepcidin is the most important influence of iron metabolism. ‘Low iron’ hormone; it reduces the levels of iron in plasma. o Reduces iron absorption o Reduces iron release form RES

Question 46

How does hepcidin work?

Answer 46

by binding to ferroportin binds ferroportin and degrades it – reducing GI iron absorption (enterocyte) and reducing macrophage iron release from the RES.

Question 47

Where is hepcidin synthesised?

Answer 47

liver (requires HFE)`

Question 48

What is the result of hepcidin loss?

Answer 48

o Increased GI iron absorption o Increased RES iron release o Increased Tf % saturation - this parenchymal iron overload (HH) as body cells take up more iron

Question 49

What is Hereditary haemochromatosis

Answer 49

is an autosomal recessive disorder of iron metabolism causing iron overload. 1 in 8 Scots are carriers for HH (heterozygous C282Y)

Question 50

What causes Hereditary haemochromatosis?

Answer 50

 Abnormalities of the HFE gene are responsible for the vast majority of cases.  Homozygous C282Y mutation of the HFE gene is most common (H63D).  Mutations in HFE are thought to cause HH principally by reducing hepcidin production.  Condition is much more severe in males.  Females protected from iron overload by menstruation and child birth.  Only 50% of patients with the genetic predisposition (homozygous) will actually develop iron overload

Question 51

Describe transferrin levels in iron deficiency anaemia?

Answer 51

reduced iron levels cause increased levels of transferrin (% saturation falls)

Question 52

Describe transferrin levels in hereditary haemochromatosis

Answer 52

= decreased Tf production (% saturation increases) sometime to over 100% = some iron not bound to Tf, very toxic

Question 53

Describe the lab findings in IDA

Answer 53

- decreased transferrin saturation - decreased iron - decreased ferritin

Question 54

Describe the lab findings in HHC

Answer 54

- increased transferrin saturation - increased iron - increased ferritin

Question 55

What is the outcome of excess iron in the liver?

Answer 55

``` Cirrhosis  excess fibrous tissue  disruption of normal lobule  Iron stains blue  High risk of developing hepatocellular cancer ```

Question 56

What is the outcome of excess iron in the pancreas

Answer 56

Diabetes: caused by deposition in pancreas

Question 57

What is the outcome of excess iron in the skin

Answer 57

Skin Pigmentation: Iron deposited in skin iron stimulates melanin production

Question 58

What is the outcome of excess iron in the joints

Answer 58

Arthritis: Iron predominantly affects MCP joints

Question 59

What is the outcome of iron deposition in the heart?

Answer 59

restrictive cardiomyopathy

Question 60

What is the treatment of haemochromatosis

Answer 60

Venesection – Removal of red cells o Initially up to weekly o Removal of around 500mls whole blood = 250mg iron o Monitor ferritin and transferrin saturation. o Prevent or limit organ damage.

Question 61

Where is the excess iron found in haemochromatosis

Answer 61

Excess iron needs to be redirected to other tissues, causing many complications

Question 62

How is diagnosis of HHC made?

Answer 62

diagnosis is very difficult to make. Mostly picked up as a result of a random sample taken by GP, and then by family screening.

Question 63

What is another form of iron overload?

Answer 63

Blood transfusion | o 20L of blood ~ 5g IRON

Question 64

What is Sideroblastic Anaemia?

Answer 64

 Bone marrow produces ringed sideroblasts (erythroblasts with iron-loaded mitochondria) rather than healthy red blood cells   Erythroblasts in bone marrow take in iron but will not transfer it to haem  Iron is locked away in mitochondria  Mitochondria become paralysed around the nucleus (perinuclear ring)