Iron metabolism Flashcards
Why do we need iron?
- red blood cells
- huge part in general metabolism as part of essential enzymes
How much iron does an average person have?
Total body content 4 grams
Which cells require and store iron?
All cells
What forms can iron be stored in?
- ferritin
- haemosiderin
What is ferritin?
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
What is haemosiderin?
Insoluble conglomerates of ferritin
Iron is only slowly available in this form
What investigation is used to determine iron levels?
Serum Ferritin
Describe the serum ferritin levels in iron deficiency anaemia (IDA)
Decreased
- indicates patient has little or no iron stores (indisputable)
Describe the serum ferritin in iron overload
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
How is iron transported?
transferrin is used as a transport protein
Where is transferrin made?
Synthesised in hepatocytes; plasma protein
What controls the synthesis of transferrin?
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
How is iron transported with transferrin?
Each transferrin molecule can bind 2 iron atoms (it has 2 iron binding domains)
What is teh daily iron need?
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)
What is the main variable of iron levels?
absorption as iron is locked in circulation
What are the sources of iron in the western diet?
Occurs as haem iron in red meat.
Non-haem iron is found in white meat, green vegetables, cereals and fortified bread.
How are iron levels maintained?
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
Where in the GI tract is iron absorbed?
Absorption predominantly in duodenum
What cells are responsible for iron absorption?
duodenal enterocytes
Which form of iron is easily absorbed?
haem iron
Which form of iron is more difficult to absorb?
non-haem iron
How is non-haem iron absorbed?
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
How is iron taken up into the enterocyte?
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
How is iron exported from the enterocyte?
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
Describe iron release from RES
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.
What is hepcidin?
low iron hormone
How is RBC iron recycled?
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.)
Describe the transport of iron
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.
Where is the highest concentration of transferrin receptors
(~80% of total TfRs) are found on red blood cell
precursors
o The liver is the next most major site of TfRs
How is iron taken up by RBC?
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
What is the role of Haem?
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
What are the two types of iron metabolism disorders
- deficiency
- excess
What are the microscopic appearances of iron deficiency anaemia?
RBC are hypochromic and microcytic
(Pale and small)
What is IDA in males and post-menopausal females a sign of?
due to GI blood loss until proven otherwise
What is IDA in young women a sign of?
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.
What is the effect of coeliac disease on iron levels?
Because of malabsorption, patients can become
deficient in haematinics
Describe the features of coeliac disease
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
Describe the likely causes of haematinic deficiency in coeliac disease
- folate deficiency (most likely)
- iron deficiency (second most likely)
- vitamin B12 deficiency (unlikely)
What are the sources, requirements and stores of folate?
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)
What are the sources, requirements and stores of iron?
o Dietary source: haem, non haem
o Daily requirements: 1mg (20mg in diet)
o Body stores : 200-500mg
What are the sources, requirements and stores of Vitamin B12?
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
What are the microscopic features of coeliac disease?
- target cells
- howell-jolly bodies
- irregularly contracted RBCs
What are target cells?
(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
What are Howell-Jolly bodies?
(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
How is iron metabolism regulated?
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
How does hepcidin work?
by binding to ferroportin
binds ferroportin and degrades it – reducing GI iron absorption (enterocyte) and reducing
macrophage iron release from the RES.
Where is hepcidin synthesised?
liver (requires HFE)`
What is the result of hepcidin loss?
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
What is Hereditary haemochromatosis
is an autosomal recessive disorder of iron metabolism causing iron overload.
1 in 8 Scots are carriers for HH (heterozygous C282Y)
What causes Hereditary haemochromatosis?
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
Describe transferrin levels in iron deficiency anaemia?
reduced iron levels cause increased levels of transferrin (% saturation falls)
Describe transferrin levels in hereditary haemochromatosis
= decreased Tf production (% saturation increases) sometime to over 100% = some iron not bound to Tf, very toxic
Describe the lab findings in IDA
- decreased transferrin saturation
- decreased iron
- decreased ferritin
Describe the lab findings in HHC
- increased transferrin saturation
- increased iron
- increased ferritin
What is the outcome of excess iron in the liver?
Cirrhosis excess fibrous tissue disruption of normal lobule Iron stains blue High risk of developing hepatocellular cancer
What is the outcome of excess iron in the pancreas
Diabetes: caused by deposition in pancreas
What is the outcome of excess iron in the skin
Skin Pigmentation: Iron deposited in skin iron stimulates melanin production
What is the outcome of excess iron in the joints
Arthritis: Iron predominantly affects MCP joints
What is the outcome of iron deposition in the heart?
restrictive cardiomyopathy
What is the treatment of haemochromatosis
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.
Where is the excess iron found in haemochromatosis
Excess iron needs to be redirected to other tissues, causing many complications
How is diagnosis of HHC made?
diagnosis is very difficult to make. Mostly picked up as a result of a random sample taken by GP, and then by
family screening.
What is another form of iron overload?
Blood transfusion
o 20L of blood ~ 5g IRON
What is Sideroblastic Anaemia?
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)
