Iron Homeostasis

Iron is an essential element for many living organisms.
In humans it is required for oxygen transportation (in
haemoglobin and myoglobin) and electron transfer
Approximately two-thirds of the body’s iron is found
in erythrocytes, and a further 15% is in muscle and
cellular enzymes. The remaining iron is excess to needs
and stored primarily as ferritin or hemosiderin in the
liver and within macrophages in the reticuloendothelial
system. Iron recycling through the mobilisation of these
stores means that most human diets can account for
minor daily losses from the sloughing of epithelial cells
or insignificant blood losses.
Absorption of iron from the small intestine and its
release from macrophages is tightly controlled, as free
iron has the potential to cause tissue damage through
the production of reactive oxygen species. Maintaining
low levels of free iron also aids resistance to infection,
as bacteria constantly scavenge for iron from their
environment for growth.

Hepcidin, a 25 amino acid peptide produced by the
liver, is the principal iron-regulatory hormone pro-
viding the link between iron metabolism and innate

Hepcidin production is stimulated by both iron load-
ing and infection/inflammation — conditions where the
body aims to limit the uptake of iron and its availabil-
ity to invading organisms. 

high serum iron and infection/inflammation 
increases HEPCIDIN which 
- iron absorption
- release of stored iron into circulation
- withholding of iron within macrophages and liver)

-  infection/inflammation can lead to a DROP in serum iron levels resulting in ANEMIA. 

-  high serum iron occurs with hemochromatosis = iron overload. 
This is due to increased ferroportin mediated iron efflux from storage and increased gut iron absorption.


HEPCIDIN mutations lead to less effective hepcidin action, leading to juvenile haemochromatosis. 

hepcidin synthesized primarily in liver, and smaller quantities in fat cells

HEP-   synthesis in liver
-CIDIN  bacteriCIDAL properties
discovered in 2000.

Hepcidin acts by binding ferroportin, a transmem-
brane protein involved in exporting iron from mac-
rophages, erythrocytes and enterocytes.
This interaction leads to ferroportin degradation.
This in turn leads to decreased dietary iron absorption,
sequestration of iron into macrophages and decreased
circulating iron concentrations. Stimulated produc-
tion of hepcidin is also seen in the anaemia of chronic
disease, where body iron stores are not deficient but
simply not available for red cell production.
Conversely, in response to increased iron demand
(iron deficiency, hypoxia and haemorrhagic or haemo-
lytic anaemias), hepcidin production is suppressed, re-
sulting in a release of stored iron and increased dietary
iron absorption.
In hereditary iron overload syndromes, mutations
in genes such as HFE cause a deficiency in hepcidin.
It is likely that the liver, although exporting iron, has
a greater ability to take up the increased plasma iron
resulting in hepatic iron deposition.
Ferritin and other iron studies
Serum iron studies typically include measurement of
serum ferritin, iron, transferrin or Total Iron Binding
Capacity (TIBC), and the calculation of transferrin
Iron studies are usually requested to diagnose iron
deficiency or iron overload, but interpretation can be
difficult because of the relationship shared by iron
metabolism and inflammation.
Ferritin is an intra-cellular storage protein with the
capacity to store up to 4000 iron atoms.
The concentration of ferritin in serum correlates well
with the amount of storage iron as proven by phle-
botomy trials. Hence, serum ferritin is a good marker
of total body iron stores.
A low serum ferritin is almost only seen in iron
In the presence of conditions such as inflamma-
tion, infection, malignancy (haematological and solid
tumours), or liver or kidney disease, serum ferritin
concentrations do not reflect iron stores alone and are
typically higher than otherwise expected.
In addition, higher ferritin levels are seen with
increasing BMI and post-menopause. In all these set-
tings, a normal or elevated serum ferritin level does not
exclude iron deficiency nor diagnose iron overload.
Serum iron concentration is a poor measure of iron
status in the body.
In an individual, levels fluctuate significantly due to
diurnal variation and fasting status.
Even when blood collection is standardised to morn-
ing samples in fasting patients, iron is an acute phase
reactant and low levels may be seen as a consequence
of acute inflammation.
Transferrin is often referred to as the circulating car-
rier protein for iron. In fact, this describes apotransfer-
rin, which, when bound to either one or two atoms of
iron, is then named transferrin.
Monoferric or diferric transferrin has high affinity
for the transferrin receptor allowing cellular uptake by
endocytosis. Iron is then utilised or stored by the cell
and apotransferrin returned to the circulation.
Liver synthesis further contributes to apotransferrin
levels so that high serum transferrin concentrations

may be induced in iron deficiency or high oestrogen
states (eg, pregnancy, oral contraceptive pill use).
Low levels may be in response to iron loading or
due to liver disease with poor synthetic function. Like
serum iron, transferrin is also a negative acute phase
Transferrin saturation is a calculated ratio between
serum iron and TIBC. Because of this, it is influenced
by the analytical, physiological and pathological fac-
tors that affect these components.
TIBC may be measured directly or derived from
measuring unsaturated iron binding capacity (UIBC)
or transferrin. Measuring transferrin is generally more
expensive for laboratories compared with TIBC or
UIBC, but there is less variation in results between dif-
ferent assays.
Hepcidin, despite its importance in iron metabolism,
is yet to have an established role in diagnostic testing
and is not routinely available.
Iron deficiency
Iron deficiency is the most common nutritional defi-
ciency worldwide, with anaemia only one part of the
clinical spectrum.
It is now recognised that deficiency without overt
anaemia is common, and can adversely affect growth,
cognitive performance and behaviour in children and
adolescents. It can also reduce immunity to infections,
and decrease work capacity and performance in all age
During pregnancy, iron deficiency with anaemia is
associated with increased risk of maternal and infant
In industrialised nations where poor nutrition and
parasitic infestations are uncommon, the diagnosis
of iron-deficiency anaemia in adult males and post-
menopausal females warrants further investigation
for a source of blood loss, particularly gastrointestinal