Transcript Iron Significance - Australian Centre for Blood Diseases

Iron Metabolism
New insights
By
Dr Mark Dawson
Iron Significance
Essential Element
Key functional component of
• O2 transportation & storage molecules (Hb, Mb)
• Many redox enzymes (cytochromes)
• Production of various metabolic intermediates
• Host defence (NADPH oxidase)
Iron Balance
Strictly regulated
Minimal loss 1 – 2mg/d
Total body iron of 3 – 4g
Erythropoietic iron requirement only 20mg/d
Absorption is appropriately attenuated in dietary iron excess
Important homeostatic mechanisms prevent excessive iron
absorption in duodenum and regulate rate of iron release from
RES
Iron is toxic to human cells and essential for pathogens
Control of Iron Metabolism
Cellular Iron Homeostasis
Concerned with each cells requirements for iron
Systemic Iron Homeostasis
Concerned with the body’s need for iron
What we knew about iron
Balance
Intestinal iron absorption increases with
Decreased iron stores
Increased erythropoietic activity
Anaemia
Hypoxia
Intestinal iron absorption decreases in inflammation
Excess iron absorption relative to body iron stores is
the hallmark of hereditary haemochromatosis
Overview of Normal Iron
Metabolism
Iron Absorption (into enterocyte)
Luminal surface
– Dietary free iron (Fe3+) is reduced to Fe2+
– Occurs at brush border by duodenal ferric reductase
(Dcytb)
Transluminal transport
– DMT1/Nramp2 (divalent metal transporter 1)
– Dietary haeme iron via transporter and released from
haeme or absorbed into the circulation.
Understanding Heme Transport - N.C Andrews - New England Journal of Medicine:353;23 - 2508
Overview of Normal Iron
Metabolism
Iron Absorption (out of enterocyte)
Shed
Basolateral absorption via ferroportin or haeme transporter.
Hephaestin facilitates enterocyte iron release
Released by way of ferroportin into the circulation
Ferroportin
Present on the basolateral membrane of enterocytes
Present on macrophages and other RES cells
Present on hepatocytes
Fleming, R. E. et al. N Engl J Med 2005;352:1741-1744
Overview of Normal Iron
Metabolism
Iron Tansport
Via transferrin
Iron Storage (Hepatic - major site)
Hepatic uptake of transferrin bound Fe via
classic transferrin receptor TfR1 (& homologous TfR2)
Hepatocytes are storage reservoir for iron
Taking up dietary iron from portal blood
Releasing iron into the circulation via ferroportin in times of increased
demand
Iron Utilisation
Erythropoiesis for haem synth / general cellular respiration
via TfRs on erythroid precursors and other cells
Generic Cellular Iron
Uptake
Generic Cellular Iron
Uptake
Generic Cellular Iron
Regulation
The IRE/IRP Regulatory System
Each cell has the capacity to regulate its own utilisation of
iron.
This is co-ordinated via Iron regulatory proteins (IRP) and
their binding to Iron regulatory elements (IRE) which are
presents on nucleic acids.
In this manner proteins involved in iron storage, erythroid
haeme synthesis, the TCA cycle, iron export, and iron uptake
are coordinately regulate.
IRP act as the cell sensor to iron availability
Who is in charge of all this
Sites involved in iron homeostasis (absorption,
recycling, storage & utilisation) are distant from each
other
Humoral regulation inflammatory / cytokine
involvement in iron regulation
Molecular basis of these signals was elusive for many
years until a series of converging and serendipitous
discoveries = Hepcidin
Hepcidin
25 aa peptide. Identified 2000
Antimicrobial activity. Hepatic bacteriocidal protein
Master iron regulatory hormone
Factors regulating intestinal iron absorption also regulate the
expression of hepcidin
Decreased iron stores
Increased erythropoietic activity
Anaemia
Hypoxia
Iron Balance – General Comments
Discovery of iron regulating hormone hepcidin provides
cohesive theory to explain the pathophysiology of HH
and ACD
Cellular targets of hepcidin are villous enterocyte, RE
macrophage and hepatocyte
There are no substantial physiologic mechanisms that
regulate iron loss
Iron homeostasis is dependant on regulatory feedback
between body iron needs and intestinal iron absorption
Hepcidin
Hepcidin
Intestinal iron absorption varies inversely with
liver hepcidin expression
Hepcidin decrease the functional activity of
ferroportin by directly binding to it and
causing it to be internalised from the cell
surface and deregulated
• Decreases basolateral iron transfer and thus dietary
iron absorption
• Decrease in iron export by hepatocyte and
macrophage and a resultant increase in stored iron
Interplay of Key Proteins in Iron
Homeostasis
Hepcidin Response
• TFR2 Transferrin receptor 2 may serve as a sensor of
circulating transferrin-bound iron, thereby influencing
expression of the iron regulatory hormone hepcidin
• The hepcidin response is also modulated by HFE and
hemojuvelin.
• Inflammatory cytokines including IL-6 and LPS increase
hepcidin secretion
Interplay of Key Proteins in Iron Homeostasis
Fleming, R. E. et al. N Engl J Med 2005;352:1741-1744
Disrupted Iron
Homeostasis
Hepcidin Deficiency:
Hereditary Haemochromatosis:
Absorb excessive iron relative to body stores implying the
‘set-point’ for the ‘stores regulator’ is altered.
Ineffective erythropoiesis:
Increased destruction of erythroid precursors (eg;
thalassemia's) but this is coupled to increased iron
absorption.
Hepcidin Excess:
Anaemia of Chronic disease:
Infection/inflammation induce iron sequestration in macrophages
and decrease intestinal absorption
Haemochromatosis
The field has expanded rapidly since the discovery of the HFE
gene.
The iron loading phenotype seen with mutations in the HFE gene
are also seen in patients without mutations in this gene.
The iron loading phenotype which is gradual in adults is seen in
Africans with autosomal dominant inheritance.
Children with severe iron overload disorders have also been
identified
Haemochromatosis
It is very difficult to predict what the likelihood of clinical
expression of the haemochromatosis phenotype.
There are a number of host factors and environmental factors
that influence the expression of the disease
It is liklely that the disorder is more polygenic than originally
thought.
The major players
• HFE:
Normal HFE binds to B2M and associates with transferrin receptor 1.
In patients with a HFE mutation (C282Y) a di-sulfide bond necessary for
HFE & B2M interaction is disrupted leading to impaired expression of HFE.
The original hypothesis was that HFE directly competed with Tfr1 and
decreased iron absorption.
Infact now we now HFE actually facilitates Tfr1 mediated iron absorption
We also know that people with HFE have decreased levels of circulating
hepcidin. HFE influence transcription of HAMP
The crypt programming model and HFE-HAMP model of
haemochromatosis
The major players
Transferrin receptor 2:
Very little is known about its function.
A homologue of Tfr1
Highly expressed in hepatocytes
It is thought to be a sensor for iron stores and able to
regulate HAMP gene
Haemojuvelin:
Highly expressed in hepatocytes
Thought to also be a sensor for iron reserve and
regulate HAMP (Hepcidin)
Anaemia of Chronic
Disease
This is a very common disorder and thought to be also closely
related to abnormalities in hepcidin.
This is a syndrome of Hepcidin excess. The hallmark is the
increased uptake and retention of iron within the RES
Inflammatory mediators:
Increase - DMT1, Ferritin, Hepcidin
Decrease- Transferrin, Ferroportin
Iron absorption from the GIT is decreased, iron availability for
erythropoiesis is decreased, circulating transferrin with bound
iron is decreased
Weiss, G. et al. N Engl J Med
Summary
Much has been learned re regulation of iron homeostasis
Many questions remain
Molecular mechanisms how HFE, TFR2 & HJV influence
hepcidin expression are unknown
Additional gene products involved in iron metabolism have not
been identified (eg: proteins participating in intracellular
trafficking and how the systemic control of iron metabolism links
to and influences the cellular control)
Drug therapy - Hepcidin analogues and inhibitors