Transcript Hepcidin

‫به نام یگانه هستی بخش‬
MODERN INSIGHTS INTO
ANEMIA
Hepcidin,the key regulator of
iron metabolism
 Dr.Hossein Ghaziasgar
IRON
 An essential element ,must be precisely
regulated
 Intestinal absorption is essential for the
iron balance ,but the precise
mechanism of its regulation was
unknown
Conservation of iron
 Recycling from Hb .(about 20 mg/day)
 Iron absorption in the duodenum
 Deposition in the liver (hepatocytes)
The coordination is essential
and vital
BUT
 Humans and other mammals lack
effective mechanisms to excrete excess
iron (the daily loss of iron from the body
is 1-2mg/day)
Intestinal iron absorption is the
sole means of iron balance
Excess iron
 Is deposited in the liver, endocrine
glands ,the heart and the skin
Tissue damage (in hereditary
hemochromatosis)
Question
 Who is playing the central role in
“orchestration” on iron metabolism?
?
Answer
 Hepcidin ,the key regulator of iron
metabolism
What is Hepcidin?
 Was first identified in human urine and
plasma in June 2000
 A 25-amino acid disulfide-rich peptide
 Molecular weight about 2 KDa
 Is highly folded and cationic amphipathic
What is Hepcidin?
 It was recognized as an antimicrobial
peptide ( Defensin-like) and is produced
in the liver and excreted in urine.
 Of course recent studies detected
Hepcidin synthesis in bacteria-activated
neutrophils and macrophages (at a
lower level)
What is Hepcidin?
 In addition to the 25-amino acid form ,the
urine also contains 20- and 22-amino
acid forms (but the role is not identified)
 Hence the bioactive form is the 25-amino
acid form which contains 4 disulfide
bands (Hepcidin 20- has been found in
serum too, in 2007 )
Hepcidin gene
 Is named HAMP
 Contains 3 exons :
 produces 84-amino acid preprohepcidin
60-amino acid prohepcidin
25-amino acid hepcidin
 Has also been identified in other
vertebrates like mice , rats , pigs and
several species of fish.
Hepcidin
 Controls extracellular iron by regulating:
1. Intestinal absorption
2. Recycling by macrophages
3. Releasing from stores
4. Placental transport
The Mechanism
The major mechanism of Hepcidin function
is “the regulation of transmembrane iron
transport”.
HOW?
 Hepcidin binds to its receptor, protein
FERROPORTIN , which serves as a
transmembrane iron channel enabling
iron efflux from cells.
THEN
 The Hepcidin-Ferroportin complex is
degraded in lysosomes and iron is
locked inside the cells (mainly
enterocytes, hepatocytes and
macrophages)
So
 Hepcidin lowers iron absorption in the
intestine ,lowers iron releasing from
hepatocytes and macrophages
Serum iron is decreased.
Ferroportin
 The sole protein exporter is located on:
1.
2.
3.
4.
the intestinal cells
hepatocytes
macrophages
placental cells
The second role
 Hepcidin is an acute phase protein type
2 and is increased in inflammation.
Hormonal activity of Hepcidin
 Lack of Hepcidin results in
Hemochromatosis (iron deposition in the
liver ,pancreas and macrophages)
 Hepcidin excess results in severe iron –
deficiency (blocking intestinal iron uptake
and iron releasing from hepatocytes and
macrophages and inhibiting the placental
transport of iron too)
Continue
 Injected synthetic 25-amino acid
Hepcidin causes 75% decrease in serum
iron levels within 1 hour persisting for
more than 2 days.
 By a decrease in Hepcidin level ,
erythroid regulation can increase iron
uptake 40mg/day(normal 1-2 mg/day).
Regulation of Hepcidin
synthesis by iron
 Dietary iron induces Hepcidin synthesis
 Urinary Hepcidin concentrations are
greatly increased within less than 1 day
after iron ingestion.
But
 The mechanism is not known
completely yet:
 In the liver the proteins:
1. HFE
2. Transferrin receptor 2
3. Hemojuvelin
may be involved in mediating this signal
Regulation of Hepcidin synthesis
by anemia and hypoxia
 Oxygen
Hepcidin
Uptake of diet iron
Iron release from hepatocytes
Iron release from macrophages
Continue
 Erythropoietic signal
 Tissue iron
Hepcidin
differic transferrin
Hepcidin
Regulation of Hepcidin
synthesis by inflammation
 Interleukin-6
iron
Hepcidin
anemia of chronic disease
The role of Hepcidin in
hereditary hemochromatosis
 Hereditary hemochromatosis:
-excessive intestinal iron absorption
-Saturation of transferrin
-Iron deposition in vital organs
Continue
 Mutations in:
-HFE gene: most common form
-TfR2 gene: much rarer
-HAMP gene: Severe phenotype
-HJV gene: Severe phenotype
The role of Hepcidin in anemia
of inflammation
 This anemia results from:
-Chronic infections
-Noninfectious generalized inflammatory
disorders
-Some cancers
-Sepsis
Continue
IL-6
Hepcidin
Hypoferremia
anemia of inflammation
The role of Hepcidin in ironloading anemias
 Ineffective erythropoiesis
 Increased intestinal iron absorption
 Increased ferritin
 Decreased Hepcidin
Hepcidin in differential
diagnosis
Increased Hepcidin
Decreased Hepcidin
High iron stores
Iron deficiency
Anemia of chronic disease
Increased and/or ineffective
erythropoiesis
Classical, ,juvenile and TfR2
HH
Ferroportin disease(?)
Hepcidin assays
 Immunoassay (urine ,UCLA)
 Mass spectrometry (urine ,serum)
 Elisa (for Prohepcidin)
Hepcidin assays
 Serum Prohepcidin:50-150 ng /mL
 Serum Hepcidin
:1-500 ng/mL
(based on 2007 findings)
Continue
 Hepcidin in urine is affected by multiple
freeze/thaw cycles. Serum is more
stable.
 High diurnal variation of especially
serum Hepcidin.
 Use of internal standard:Hepcidin-24 to
control for matrix influences and
instrumental settings.
Overall summary
 Hepcidin
-Is a recently discovered liver produced 25 aminoacid peptide
-Is a regulator of iron metabolism that controls iron
absorption and macrophage iron release.
-Is regulated by erythropoietic needs( ) ,body
iron stores( ) and inflammation( )
Overall summary
 MS Hepcidin assay for urine and serum:
-Precludes the need for Hepcidin specific
antibodies
-Will provide:
-information on etiology of iron
metabolism disorders
-leads for new therapeutic strategies
-novel diagnostic approaches