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Iron regulation and determination of iron
stores
Sean Lynch
Eastern Virginia Medical School
USA
Function and toxicity
Selected Functions
• Oxygen transport and storage
• Oxidative metabolism
• Cellular growth and proliferation
• Neuroreceptor function
Red cells: 2300 mg
Functional tissues: 500 mg
Store: 1000 mg
Excretion: 1 mg
Absorption: 1 mg
Toxicity
• Free radical formation, particularly OH·
• Increased pathogen virulence
Stores 1000 mg
Liver
Spleen
Erythrocytes
Transferrin 3mg
Exchange 35 mg
Fe
Heme
Duodenum
Absorption 1mg
Functional
iron 2800 mg
Bone marrow and
other tissues
Ferroportin
• Ferroportin, a transmembrane iron transporter, is the
cornerstone of the internal iron circuit
It exports iron into the plasma from the duodenum
(control of absorption), macrophages and
hepatocytes (control of release of iron recovered
from red blood cell catabolism and from stores); the
iron is then bound to transferrin
It regulates the plasma iron concentration so that
transferrin is ~ 35% saturated with iron (average
early morning value)
Hepcidin
• Hepcidin, a 25 amino acid peptide produced primarily in hepatocytes,
is the key regulator of iron homeostasis
It is a negative regulator of iron release from macrophages (red
cell processing and iron recovery, iron store), hepatocytes
(iron store) and enterocytes (iron absorption)
It binds to cell-surface ferroportin, triggering tyrosine
phosphorylation and ubiquitin-mediated degradation in
lysosomes; iron transport to circulating transferrin is
reduced
• Hepcidin synthesis is induced independently by increasing
storage iron, and inflammation (IL 6)
• Hepcidin synthesis is suppressed by iron deficiency, anemia,
hypoxemia and accelerated ineffective eythropoiesis
Spleen
FPN
HEPCIDIN
TfR
FPN
Liver
Erythrocytes
Plasma
Fe-Tf
FPN
Duodenum
Tf R
FPN: Ferroportin
Tf: Transferrin
TfR: Transferrin receptor
Iron transport
Bone marrow
Cellular iron uptake
• Plasma iron bound to transferrin is delivered to all cells
where transferrin binds to specific transferrin receptors
and then transports the iron into the cell; the apotransferrin
returns to the cell surface to be released back into the
plasma and reutilized
• The rate of iron uptake is again regulated at the cellular
level; the number of transferrin receptors on the cell
surface is determined by the individual cell’s requirements
IRP-Fe
IRP
Tf - Fe
Tf-Fe-TfR
TfR
Fe
Tf-TfR
Functional
iron
Ferritin
Tf
IRP-Fe
IRP-Fe
Iron sufficient cell
IRP
IRP
Tf - Fe
Tf-Fe-TfR
TfR
Fe
Tf-TfR
Functional
iron
Ferritin
Tf
IRP-IRE
IRP-IRE
Iron deficient cell
Absorption, transfer across the placenta and uptake by the
nervous system are more complicated processes.
Iron absorption
IRP-Fe
DMT 1 – DCytb
IRP-IRE
Fe
Heme oxygenase
Heme
?
Transferrin
Ferroportin
Hephaestin
Ferritin
Hepcidin
Lumen
Duodenal enterocyte
Systemic disorders of iron metabolism
(balance and distribution)
• With the exception of iron deficiency (most often nutrtional or due to
chronic blood loss), the common disorders of iron metabolism are all
linked to hepcidin or ferroportin
• Hepcidin “insufficiency” and ferrportin abnormalities cause iron
overload:
Primary: HFE hemochromatosis
Hemochromatosis types 2 and 3
Ferroportin disease
Secondary: Iron overload associated with hemolysis,
thalassemias
• Hepcidin “excess”
Anemia of inflammation (anemia of chronic disease)
Evaluation of body iron status
• Iron overload
Serum iron concentration, percentage transferrin saturation
Serum ferritin concentration
Bone marrow iron
Computed tomography (CT scan)
Magnetic resonance imaging (MRI)
Liver biopsy
Magnetic susceptometry employing the superconducting
quantum interference device (SQUID)
• Iron deficiency
Most of the laboratory tests are related to red blood cell
production
Iron deficiency indicators



Storage iron depletion
Stainable bone marrow iron
Serum ferritin concentration
Increased total iron binding capacity (TIBC)
Early functional iron deficiency (Iron deficient erythropoiesis)
Reduced serum iron, transferrin saturation, raised TIBC
Increased serum transferrin receptor level
Increased zinc protoporphyrin level
Reticulocyte hemoglobin, proportion of hypochromic red cells
Established functional iron deficiency (Iron deficiency anemia)
Hemoglobin, hematocrit, erythrocyte count
Red cell indices (MCV, MCH, MCHC, RDW)
Red cell morphology (hypochromia, microcytosis, anisocytosis)
Iron store
Erythron iron
BMI
SF
TFS
N
N
N
ZPP STfR
MCV Hgb
Normal iron status
N
N
N
N
Storage iron depletion
N
N
N
N
N
Early functional iron deficiency
N
Established functional iron deficiency
N
Calculated iron store
• Transferrin receptor / ferritin ratio
 Provides a measure of iron status over the full
spectrum from iron overload to iron deficiency
 Other biomarkers such as hemoglobin are not required
to establish the severity of iron deficiency
 Standardization of the transferrin receptor assay is
pending
Unresolved issues
• Serum ferritin is the most commonly employed indicator of the size of
iron stores
1 ug/L serum ferritin = ~ 8 mg storage iron in normal adults and
those with uncomplicated iron deficiency or iron overload
Serum ferritin <12 ug/L is specific for iron deficiency (absent
iron stores)
• Serum ferritin values in the normal and above normal ranges are a
measure of the size of iron stores, but are also affected (increased) by
inflammation
• There is no satisfactory method for correcting serum ferritin values for
the effect of inflammation
• In field studies C-reactive protein is often measured concurrently and
samples with high values excluded from the serum ferrtin analysis
Unresolved issues (cont)
Serum ferritin values are:
 Higher in diabetics
 Directly correlated with markers of insulin resistance
 Directly correlated with body mass index
Unresolved issues (cont)
Indicators of functional iron deficiency are related to erythropoiesis
 It is possible that the supply to other tissues may be suboptimal
despite an adequate supply to the bone marrow or in situations in
which bone marrow demand is high
 All tissues may not compete equally for available iron
 Physical performance may be reduced by iron deficiency in the
absence of anemia
 Increased erythropoieses due to hypoxia is associated with downregulation of myoglobin in skeletal muscle in short term studies
(Robach et al., Blood, 109:4724, 2007)
 Mental, motor and emotional development of infants may be
impaired in the presence of iron deficiency without anemia