1.08 Iron in health and disease

Question 1

Functions of iron

Answer 1

transport oxygen reversibly
electron transport- Fe3+ and Fe2+
haemoglobin, myoglobin, and enzymes- cytochromes

Question 2

Where is iron integrated into the protoporphyrin ring?

Answer 2

in the mitochondrion

Question 3

where is the biggest store of iron in the body?

Answer 3

Red cell haemoglobin (2500mg)

Question 4

what is storage iron?

Answer 4

serum ferritin

tissue biopsy - bone marrow for Fe deficiency, liver biopsy for tissue overload

Question 5

what is transferrin?

Answer 5

protein with 2 binding sites for iron atoms for transport
transfers iron from donors to reciepients
-donors: macrophage, intestinal cell, hepatocyte
-recipient: having transferrin receptors- erythroid marrow

Question 6

what does % saturation of transferrin mean?

Answer 6

mean the iron supply

reflects proportion of diferric transferrin- high affinity for cellular transferrin receptors

Question 7

what is ferritin and how many iron ions does it store?

Answer 7

large intracellular protein
stores up to 4000 ferric ions
indirect measure of storage iron

Question 8

what are intraluminal factors that regulate iron absorption?

Answer 8

solubility of inorganic iron

reduction of ferric to ferrous 2+

Question 9

mucosal factors regulating iron absorption

Answer 9

expression of iron transporters

1. divalent metal transporter 1 at the mucosa
2. ferroportin at serosa - down regulated by HEPCIDIN

Question 10

systemic factors regulating iron absorption

Answer 10

HEPCIDIN

• major negative regulator of iron uptake
• made in liver in response to iron load and inflammation
• action: downregulates FERROPORTIN

Question 11

where does DMT-1 work?

Answer 11

duodenum

transports iron into the enterocyte

Question 12

where does ferroportin work?

Answer 12

enterocyte serosa

passes iron onto transferrin

Question 13

how much iron do we need in stores?

Answer 13

4g

Question 14

consequences of

Answer 14

used up iron stores
iron deficiency anaemia 
microcytic anaemia
skin changes 
koilonychias 
angular stomatitis

Question 15

iron deficiency anaemia a cytoplasmic defect?

Answer 15

Yes

Question 16

what are the causes for hypochromic microcytic anaemias?

Answer 16

haem deficiency

• iron deficiency
• chronic disease
• congenital sideroblastic anaemia

globin deficiency

Question 17

how do you confirm iron deficiency?

Answer 17

anaemia- decreased hb iron

reduced storage iron- serum ferritin

Question 18

causes of iron deficiency

Answer 18

not enough intake for needs- women, children, vegetarian
losing too much- bleeding
not absorbing enough- malabsorption

Question 19

causes of chronic blood loss

Answer 19

menorrhagia
GI= tumours, ulcers, NSAIDS, parasites
haematuria

Question 20

what is the maximum dietary intake of iron?

Answer 20

4-5mg per day

Question 21

what is the inflammatory macrophage iron block?

explain the process

Answer 21

activated macrophages phagocytose old red cells
there is increased storage of iron in ferritin, with decreased transferrin

due to:

• inflammatory cytokines
• increased ferritin mRNA transcription
• increased plasma hepcidin
• blocks ferroportin mediated release of iron
• impaired iron supply to marrow erythroblasts
• results in hypochromic red cells

Question 22

primary iron overload

Answer 22

long term
excess iron absorption
parenchymal not macrophage iron loading
eventual organ damage

Question 23

clinical features:

hereditary haemochromatosis

Answer 23

weakness 
fatigue
joint pain 
impotence
arthritis
cirrhosis
diabetes
cardiomyopathy 

usually middle age or later

Question 24

What iron stores may indicate hereditary haemochromatosis:?

Answer 24

iron overload >5g

Question 25

what is the inheritance pattern for hereditary haemachromotosis?
What are the 2 common mutations?

Answer 25

autosomal recessive, incomplete penetrance
1/8 carry C282Y mutation; chromosome 6
1/4 carry the H63D mutation; chromosome 6

may be homozygote for C282Y or double heterozygote
reduced hepcidin synthesis
cause 95% of HH

Question 26

what are rare mutation targets for hereditary haemochromatosis?

Answer 26

transferrin receptor
hepcidin
ferroportin

Question 27

how do you make the diagnosis of hereditary haemochromatosis?

Answer 27

transferrin saturation >50% - sustained on repeat fasting sample
serum ferritin >300uL/ in men; >200 ug/L in women
liver biopsy- only if uncertain about iron loading or worried about tissue damage

Question 28

treatment of hereditary haemochromatosis

Answer 28

weekly phlebotomy- 450-500mL= 200-250mg iron (about 2:1 ratio of blood in mL: iron in mg)

1st goal: exhaust iron stores- ferritin

Question 29

what is the most common cause of death now in hereditary haemacrhomatosis?

• diabetes
• infection
• organ failure
• hepatoma

Answer 29

hepatoma

Question 30

who to screen in hereditary haemachromatosis?

Answer 30

1st degree relatives- esp siblings (risk = 1/4)
children- wait until adult to give consent
HFE genotype and iron status- ferritin and transferrin saturation

Question 31

iron loading - external causes

Answer 31

repeated red cell transfusion

Question 32

iron loading anaemias

Answer 32

overactive erythropoiesis - excess iron absorption
thalassaemia/sideroblastic anaemias
red cell asplasia
myelodysplasia

Question 33

How much iron will a 400-500mL bag of red blood cells contain?

Answer 33

200-250mg

Question 34

what is iron overload by grams

• total
• liver

Answer 34

total >5g

liver >15mg/g dry weight

Question 35

iron overload causes damage to which organs in particular?

Answer 35

liver
heart
endocrine glands

Question 36

treatment of iron overload

Answer 36

iron chelation
-desferrioxamine- SC or IV
desferiprone, deferasirox- oral, expensive, less evidence of safety and efficacy

Question 37

which one is usually more fatal

• iron deficiency
• iron overload

Answer 37

iron overload- life threatening once symptomatic (affects 5 million)
iron deficiency is usually not fatal (affects 1 BILLION)