Iron metabolism and its disorders
Physiological functions of iron
• Iron is present in haem
- haemoglobin/myoglobin
- cytochromes
- enzymes
• e.g. catalase, peroxidase, ribonucleotide reductase, nitric oxide synthase
- Fe is necessary for the cell cycle (transition from Gl -> S phase)
- ROS formation in white blood cells
• Free Fe is highly reactive - it catalyses Fenton reaction
• Fe2+ + H202 -> Fe3+ + OH* + OH-
- most iron is in the complex form to minimize negative effects
- with organic anions
- with ferroproteins
- stored bound to ferritin (or hemosiderin)
• As no specific excretory mechanism exists, the absorption of Fe is tightly regulated
Fe balance
35 - 45mg of Fe per 1 kg of body weight in an adult
- 60 - 70% is part of Hb in erythrocytes
- 10% is contained in myoglobin, cytochromes and iron-containing enzymes
- 20 - 30% is stored bound to ferritin and hemosiderin in hepatocytes and macrophages
The total amount of Fe is constant in an adult, there is a balance between the intake and the losses
- the daily supply of food contains approximately 10 - 20mg of iron
- only 5 - 10% of iron gets to organism
- average daily losses are 0.5-lmg in men 1-2mg in women of fertile age
Intake of iron occurs in the duodenum and proximal jejunum
Monocyte-macrophage system
RBC 1 cfeslruct«on\
20 mg darfy
RBC producfjon
Bone marrow
Absorption 1-2 mg daily
20 mg daly
5 mg daily
\
* Loss 1-2 mg daily
\
Myoglobfi and respratory enzymes 300 mg
Distribution of iron in the organism
circulation of Fe and its cellular uptake
— transferrin - liver-produced protein with 2 binding sites for Fe3+
— the ratio of monoferric to diferric transferrin is normally approx. 2:1 (30% saturation)
— transferrin receptors (TfRl and 2) at cellular membrane enables the cellular uptake of Fe driven by momentary needs
• It is most abundant in the membrane of erythroblasts, but not mature erythrocytes
storage and recycling of Fe
• In the liver (hepatocytes) and in macrophages
— Fe is bound to cellular or serum ferritin (up to 4000 Fe atoms)
- hemosiderin (aggregated molecules of of ferritin)
excretion
— There is no specific mechanism of iron excretion
• desquamation of cells (GIT, skin)
• menstruation in women
Absorption of Fe and its release into the
circulation
eme /tv
Lumen
Fe,Tf
Blood
Maturation of the enterocyte
Small intestinal villus
Post-transcriptional regulation of gene
expression by Fe
IRP binding stabilizes mRNA
IRP binding inhibits translation
ron
5'
IRP
-0- 3' * lr°n 5'
3'
IRE
^ Iron 5'
Fe-S cluster ■| 3'       ^ Iron 5J
Fe binds to IRP (iron-responsive proteins) and deactivates them by changing their conformation
When intracelular levels of iron are low, IRP bind to IRE (iron-responsive elements) at 5' or 3' untranslated region of mRNA
- 5' IRE (low translation)
• e.g. ferritin
- 3' IRE (inhibits mRNA degradation -> high translation)
• e.g. DMT1 orTfR
Iron metabolism regulation
Disorders of iron metabolism
Iron deficiency anemia (IDA)
- decreased absorption / increased losses
- nI/ ferritin, 1s transferrin, ^ transferrin saturation, 1s sTfR
Anemia of chronic diseases (ACD)
- normal total amount of Fe in organism, but Fe is stored in macrophages instead of being part of haem
- 1s ferritin, ^ transferrin, ~/4, transferrin saturation, ^ sTfR
Hemochromatosis
Acquired
- increased parenteral intake
• repeated transfusions
• excessive supplementation - rare
- excessive hemolysis
• hemolytic anemias - often treated by transfusions
Hereditary
- excessive absorption
• autosomal recessive monogenic disorder (1:200 - 400 in northern Europeans)
• mutation in the HFE gene (6th chromosome) - inducer of hepcidin expression
- mostly C282Y or H63D mutations
Clinical presentation
- iron deposits in various organs (liver, heart, pancreas, joints) and their dysfunction
- ^ ferritin, ^ transferrin, ^ transferrin saturation, ^ sTfR, ^ non-transferrin bound iron (reactive)
- skin pigmentation („bronze diabetes")
- in most cases, non-specific symptoms are present (tiredness, hepatopathy, endokrinopathy, diabetes, artralgias...)
- treatment - phlebotomy