Week 1 - H - Iron - Absorption, Storage, Measurement, Deficiency, Malutilisation, Overload (Primary and secondary)

Question 1

What is the function of iron in the body - name two functions?

Answer 1

It transports oxygen as part of the haemgolobin molecule It also transports electrons for mitochondiral production of ATP

Question 2

How much iron is absorbed and excreted on a daily basis?

Answer 2

1mg of iron is absorbed and 1mg is excreted on a daily basis

Question 3

Where is the majority of body iron found? What is it bound to this iron (ie where the majority of iron is found)? WHat enzyme catalyses the addition of these two molecules

Answer 3

The majority of iron in the body is in the haemoglobin (approx 1mg iron in the blood for every 2mls of blood) The iron in Hb is bound to a prophyrin ring The enzyme ferrochelatase catalyses the addition of iron to protoporhyrin IX

Question 4

Most of the body iron is found in the haem Where does the incoportation of the iron atom into the centre of the porphyrin ring take place? Where else can iron be found?

Answer 4

This takes place in the mitochondria of the cells Iron can also be found in the plasma, erythroid marrow, macrophages and reticuloendothelial system (liver particularly)

Question 5

Where does iron absorption mainly take place? What is the protein in the duodenum that facilitates iron absorption into the duodenal enterocyte?

Answer 5

Iron absorption mainly takes place in the duodenum The DMT-1 (divalent metl transporter - 1) facilitates the absorption of iron into the dudodenal enterocyte

Question 6

Iron absorption takes place mainly in the duodenum The protein - divalent metal transporter 1 (DMT-1) abosrbs iton from the gut into the duodenal enterocyte What is the name of the transport protein that is responsible for export of iron from the enterocyte to the rest of the blood? What does this protein allow for iron to bind to?

Answer 6

The transport protein ferroportin allows iron to be exported from the enterocyte by allowing it to bind to transferrin to be carried in the blood

Question 7

What is the predominant protein which inhibits iron absorption? (it blocks the export of iron from duodenal enterecotyes)

Answer 7

Hepcidin is the protein that blocks the action of ferroportin preventing iron leaving the entercoyte and binding to transferrin This protein also acts to prevent iron leaving macrophages

Question 8

Iron absorption is regualted by intraluminal factors, mucosal factors and systematic factors What type of conditions intraluminally facilitate iron absorption? What type of iron is easier absorbed?

Answer 8

Acidic conditions intraluminally facilitate the absorption of iron Haem bound iron is easier absorbed into the dudeoenum also

Question 9

The expression of iron transporters (mucosal factors regulating iron absortion) is needed for the transport of iron into the blood WHat is the iron transporter at the mucosal surface that enables aborption of iron into the duodenal enterocyte? What is the iron transproter at the serosal surface that allows ion to be exported from the eneterocyte?

Answer 9

DMT-1 (divalent metal transporter-1) - enables aborption of iron into enterocyte Ferroportin - enables iron to be exported from the enterocyte

Question 10

Systematic factors What is the major negative regulator of iron uptake ? Where is it produced and in response to what? What does it down regulate? Where does it cause iron to be trapped?

Answer 10

Hepcidin Produced in the liver in response to iron overload and inflammation (removing iron from circulation helping to kill bacteria - need iron to survive) Down regulates the action of ferroportin Causes iron to be trapped in duodenal enterocyte and macrophages

Question 11

There are three compartments which can be used to assess the iron in the body These are the functional iron, transport iron supply to tissues and storage iron What are the good ways of assessing each of these? What is the main way of assessing iron deificiency anaemia?

Answer 11

Haemoglobin concentration - gives a rough idea if there is any decrease in iron %transferrin stauration - lets you know the percentage of iron in transport (not in haem) and the supply to tissues Serum ferrtin - lets you know the storage iron - best way of assessing the iron in iron deficiency anaemia

Question 12

What is the main iron transporter? How many iron atoms can bind to one transferrin atom? Where does this molecule carry iron from? once it picks up the iron from the donor tissues it binds to transferrin receptors Which part of the body is especially rich in transferrin receptors?

Answer 12

This would be transferrin Allows for the binding of two iron atoms Transferring carries iron from donor tissues (like macrophages, intestinal cells and hepatocytes) to tissues expressing transferrin receptors The erythroid marrow is especially rich in transferrin receptors

Question 13

Measuring transferrin saturation allows the total iron being transported in the blood to be measured How is this measurement carried out? What is the normal transferrin saturation numbers?

Answer 13

The measurement is carried out by measuring the serum iron bound to transferrin and knowing the total iron binding capacity (ie the total transferrin in the blood) Normal transferrin saturation is around 20-50%

Question 14

What is bound transferrin known as? What is abound transferrin known as?

Answer 14

When iron is bound to transferrin, it is known as holotransferrin When the transferrin is unbound it is known as apotransferrin

Question 15

What happens to the transferrin sats in iron overload? When might iron overload occur? What happens to the transferrin saturations in iron deficiency?

Answer 15

The transferrin saturations will increase in iron overload - eg in haemachromatosis and in multiple transfusions without the use of iron chelating agents The tranferrin saturations decrease in iron deficinecy anaemia

Question 16

Ferritin is a spherical protein Up to how many iron ions can bind to one large spherical molecule? What does serum ferritin allow an indirect measure of? Apart from iron deificnecy anaemia, when else is serum ferritin elevated?

Answer 16

One large spherical ferritin protein can bind up to 4000 iron ions Serum ferritin allows an indirect measure of the storage iron levels Serum ferritin is an acute phase protein and therefore may be raised in inflammation, malignancy etc, may also be raised in iron overload

Question 17

Disorders of iron metabolism include iron deficiency, iron malutilisation and iron overload What causes iron malutilisation?

Answer 17

Anaemia of chronic disease - is a form of anemia seen in chronic infection, chronic immune activation, and malignancy.

Question 18

What does chronic diseases eg chronic infection, immune activation and malignancy, produce that affect hepcidin? Anaemia of chronic disease also has other mechansims playing a role in the anaemia What effect will hepcidin cause?

Answer 18

These chronic conditions all produce a massive increase in IL-6 in response to inflammatory cytokines IL-6 stimulates hepcidin production in the liver which acts against the action of ferroportin resulting in iron being unable to leave the enterocytes and bind to transferrin Iron therefore able to form proper haemoglobin to transport oxygen

Question 19

Talking about iron deficiency What are the consequences of the ongoing negative iron balance? (ie how does it lead to anaemia) State the symptoms and what the late sign is

Answer 19

There will be exhaustion of the iron stores Leading to iron deficient anaemia This will cause the mean cell volume to volume and cells to become hypochromic - microcytic hypochromic anaemia Symptoms - get the normal anaemic symptoms Signs - angular stomatitis, atrophic glossitis (get the beefy tongue in B12/folate), and koilonychia - late sign

Question 20

Hypochromic microcytic anaemias =deficient haemoglobin synthesis Usually due to haem or globin deifiencies NAme causes of both

Answer 20

Haem Iron deficiency anaemias - storage iron levels are low Anaemia of chronic disease - storage iron levels are normal Sideroblastic anaemias - prophyrin synthesis problem Globin Thalassemia

Question 21

What causes sideroblastic anaemia? (see sideorblasts on blood film) What is the specific tests for staining the sideroblasts? What is the treatment?

Answer 21

Sideroblastic anaemia Caused by ALA synthase enzyme mutation Prussian blue stain can stain the sideroblasts Treatment is vit B6 (pyrodoxine)

Question 22

When suspecting someone with iron deficiency anaemia, what can be done to diagnose this?

Answer 22

Iron deficiency can be confirmed by a combination of anaemia (decreased haemoglobin iron) and reduced storage iron (low serum ferritin)

Question 23

What are the causes of blood loss resulting in iron deficiency? (list the GI causes)

Answer 23

MEnorrhagia - blood loss greater than 60mls during menses GI * Malignancy * NSAIDs * Ulcers * Parasitic disease * Malabsorption - coeliacs / crohns Dietary intake also may cause this as well as pregnancy

Question 24

What is occult blood loss?

Answer 24

Fecal occult blood (FOB) refers to blood in the feces that is not visibly apparent Occult blood loss refers to hidden blood loss that isnt visible to the naked eye in the faces

Question 25

Occult blood loss Gastrointestinal blood loss of 8-10 ml per day can occur without any symptoms or signs of bleeding How much iron would be lost if there were 8-10mls of blood lost per day? What is the maximum dietary absorption of iron daily?

Answer 25

8-10mls of blood loss per day can cause 4-5mg of iron lost per day As the max absorption of iron daily is 4-5mg, there will be negative iron balance here

Question 26

What is the main cause of iron deficiency anaemia in the tropics? It is caused by a parasite that leads to chronic blood loss

Answer 26

The infection of a parasitic worm (helminths) known as hookworm is the most common cause of iron deifiency anaemia in the tropics

Question 27

Iron malutilisation is due to anaemia of chronic disease Normally red cells have a 120 day life span, once they reach the end of this span they are broken down by the reticuloendoethial system and the iron from the haem is recylced (some goes to ferritin) but most will bind to transferrin What protein gets the iron out of the reticuloendoethial cells? Where expresses a huge amount of transferrin receptors?

Answer 27

Ferroportin will get the iron out of the reticuloendothelial cells and the iron will bind to transferrin here The trnsferrin will take the iron back to the marrow (which is rich in transferrin receptors)

Question 28

In anaemia of chronic disease the pathway of iron recycling is abnormal Any kind of inflammatory disorder eg sepsis, malignancy etc, inflammatory cytokines are increased, especially which one? These cytokines have number of effects (3 main effects)

Answer 28

INterleukin 6 is one of the main inflammatory cytokines produced here

Question 29

What are the three main effects of the increase in inflammatory cytokines due to chronic disease?

Answer 29

There is the upregulations of ferritin production so iron is directed to ferritin There are increased hepcidin levels which blocks ferroportin - this prevents the export of iron from macrophages or other storage sites (liver) causing the iron to no longer be available to be transported to the marrow The impaired iron supply to the marrow resulting in less red cells produced

Question 30

What would happen to these blood results in anaemia of chronic disease: * Hb? * MCV? * MCH? * Serum iron? * TIBC? * Transferrin saturation? * Serum ferritin?

Answer 30

Hb - low (anaemic) MCV - low (microcytic) MCH - low Serum iron (this is bound transferrin) - low (iron is in storage) TIBC - reduced- cytokines have an effect on transferrin Transferrin saturation - low- iron mostly in storage Serum ferritin - increased

Question 31

What are the primary and secondary causes of iron overload?

Answer 31

Primary Haematomachrosis Secondary Transfusional Iron loading anaemias (eg chronic haemolysis)

Question 32

Primary iron overload - Long-term excess iron absorption with parenchymal rather than macrophage iron loading What is the commonest gene mutation in haemacrhomatosis? What is the mode of inheritance of this condition?

Answer 32

It is in the HFE gene The mode of inheritance in this condition is autosomal recessive

Question 33

What does the HFE gene mutation in haemachromatosis decrease the synthesis of? What does this result in?

Answer 33

This decreases the synthesis of the hepcidin protein resulting in no inhibition due increased iron exportion by the action of ferroportin Results in gradual iron accumulation with risk of end-organ damage The decreased in hepccidin leads to an increase in iron absorption in the duodenum

Question 34

WHat are the clinical features of hereditary haemachromatosis? What are the organs in which the iron usually deposits?

Answer 34

There are depositions in the heart, liver, pituitary, pancreas, adrenals, joints and skin Symptoms include - joint pain, weakness and fatigue, impotence, diabetes, cardiomyopathy

Question 35

Presentation usually in middle age or later Iron overload > 5g Why does iron overload tend not to affect woman until later in life?

Answer 35

This is because menstrual loss is protective against too much iron

Question 36

Mutations of HFE gene Account for 95% of hereditary haemochromatosis Where do the mutations in the HFE gene usually occur? Are the patients usually homo or heterozygotes for the gene mutations if showing clincial symptoms?

Answer 36

The mutations usually occur in the C282Y region of the gene or the H63D region 1 in 8 of population carry C282Y mutation; 1 in 4 the H63D mutation * Patients are usually C282Y or H63D homozygotes; occasionally C282Y/H63D compound heterozygotes resulting in incomplete penetrance

Question 37

The diagnosis of haemochromatosis is often made following the incidental finding on routine blood screening of elevated serum liver enzymes or elevation of the transferrin saturation. Usually the phenotype and blood tests are used to diagnose the disease Transferrin saturation greater than what percentage and serum ferritin levels greater than what are indicative/diagnostic or haemachromatosis?

Answer 37

Transferrin saturation greater than 50% sustained on a repeated fasting sample and Serum ferritin levels >300micrograms in men and 200micrograms in pre-menopasual women are highly indicative

Question 38

In the past before genetic testing was available, if uncertain about diagnose liver biopsy were taken for diagnosis Now can check for what mutations? What stain would be used for liver biopsy?

Answer 38

Check for C282Y or H63D mutations Pearl stain was used in liver biopsy to see iron deposits

Question 39

What is the mode of treatment of hereidtary haemachromatosis? What are the serum ferritin and transferrin levels again?

Answer 39

Main mode of treatment - venesection Serum ferritin levels - men >300micrograms of ferritin and women >200microgams of ferritin in pre-menopasual women and Transferrin saturation >50%

Question 40

Weekly venesection - 450-500ml - 200-250mg iron Initial aim to exhaust iron stores (ferritin <20 µg/l)‏ After this initial exhasution, what are the serum ferritin levels aimed to be kept at?

Answer 40

Aim to keep serum ferritin levels at <50micrograms

Question 41

What are the causes of death in hereditary haemachromatosis? If there is liver cirrhosis due to haemachromatosis, what cancer is the patient at an increased risk of?

Answer 41

Diabetic death Cardiac failure Hepatic failure - bleeding varices Infections If there is liver cirrhosis, this puts the patient at an increased risk of hepatocellular carcinoma

Question 42

What tumour marker is raised in hepatocellular carcinoma? If a patient has hereditary haemachromatosis, what family is screened for the disease? What is the risk in siblings of having the disease?

Answer 42

Elevated levels of AFP are associated with active HCC disease First degree relatives of cases: especially siblings (risk 1 in 4)‏ Children – wait until they are adults able to give informed consent HFE genotype and iron status Ferritin and transferrin saturation

Question 43

Haemochromatosis may be asymptomatic until irreversible organ damage has occurred. This underlines importance of family studies: population screening remains controversial In patients with the conditon who are intolerant or contrainidcated to phlebotomy (venesection), what can be given?

Answer 43

Can give the iron chelating agent Desferrioxamine

Question 44

Each unit of blood given to a patient contains how much iron?

Answer 44

Each unit of blood contains 250mg of iron Patients with thalassaemia may require transfusion every 2-3 weeks lifelong Therefore iron levels will increase dramatically

Question 45

Iron overload is inevitable and predictable with regular red cell transfusions, but risk of excess intestinal iron absorption may be hidden until tissue damage becomes symptomatic. Why is treatment by venesection not an option? What is the treatment option? NAme some of the drugs?

Answer 45

Venesection is not an option as the patients are already anaemic Treatment option is iron chelating agents Desferrioxamine (subcut or IV infusion)‏ Newer oral agents Deferiprone Deferasirox