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Ulm
Pontchaillou University Hospital
National reference centre for rare
genetic iron overload diseases
Pierre Brissot
April, 23 2015
Rennes (France)
Haemochromatosis: A changing world
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HFE
HFE-related Haemochromatosis
C282Y/C282Y
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Evolving concepts and practices
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Patho-physiology
Diagnosis
Treatment
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Hepcidin
Ferroportin
C282Y/C282Y
Ferroportin
Fe
Fe
Fe
Bone marrow
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HFE mutation
(C282Y/C282Y)
Fe
TransferrinFe
Fe
Bone marrow
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HFE mutation
(C282Y/C282Y)
Fe
Fe
Fe
Bone marrow
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HFE mutation
(C282Y/C282Y)
Fe
Fe
Fe
Bone marrow
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HFE mutation
(C282Y/C282Y)
Fe
Bone marrowFe
Fe
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HFE mutation
(C282Y/C282Y)
Fe
Bone marrowFe Fe
NTBI
(non-transferrin bound iron)
Brissot P Biochem Biophys Acta 2010
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HFE mutation
(C282Y/C282Y)
Bone marrowFe Fe
Fe NTBI
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HFE mutation
(C282Y/C282Y)
Fe
Bone marrow
LPI
(labile plasma iron)
Cabantchik ZI Best Pract Res Clin Haematol 2012 Le Lan C Blood 2005
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HFE mutation
(C282Y/C282Y)
Bone marrow
Fe LPI
Cabantchik ZI Best Pract Res Clin Haematol 2012 Le Lan C Blood 2005
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HFE mutation
(C282Y/C282Y)
Bone marrow
Fe
Cabantchik ZI Best Pract Res Clin Haematol 2012 Le Lan C Blood 2005
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Brissot P Trends Mol Med 2011
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30% M 1% F
70% M 99% F
Allen KJ N Engl J Med 2008
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Phenotypic
variability
Iron overload Visceral target
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Fe
Hepcidin
Hepcidin
promoter
(Island ML
Haematologica
2009)
Low CD8
(Costa M
Plos One
2013)
(Dostalikova-Cimburova M
J Cell Mol Med 2014)
(Girelli D J Hepatol 2009)
(Detivaud L Blood 2005)
EPO
(Liu Q JCI 2012)
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Fe
Hepcidin
TMPRSS6
(Guo S JCI 2013)
(Desgrippes R Hepatology 2013)
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Phenotypic
variability
Iron overload Visceral target
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cirrhosis
PCSK7
Stickel F
Hum Mol Genet
2014
PNPLA3
Valenti L
WJG 2013
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Patho-physiology
Diagnosis
Treatment
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Clinical
exam.
Biology
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Biochemical
analyses
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Fe
Transferrin saturation > 60%
LPI = labile plasma iron.
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Fe
LPI = labile plasma iron.
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Fe
Transferrin saturation > 75%
LPI = labile plasma iron.
LPI (Labile Plasma Iron)
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Clinical
exam.
Biology
Imaging
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MRI
Hernando J Magn Reson Imaging 2014
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(www.radio.univ-rennes1.fr)
black liver + white spleen
=parenchymal iron overload
black liver + black spleen
=macrophagic iron overload
Hernando J Magn Reson Imaging 2014
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Clinical
exam.
Biology
Imaging
Biopsy
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Patho-physiology
Diagnosis
Treatment
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Bone
marrow
Hepatocyte
RBC
B
L
O
O
D
Fe
Venesection
RBC
RBCRBC
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Deferasirox
Phatak P Hepatology 2010
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Clip
Hepcidin
supplementation...
Ramos E Blood 2012 Camaschella C N Engl J Med 2013
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Bardou-Jacquet E Hepatology 2014
Liver transplantation cures…the liver
and the disease !r
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HFE
HFE-related Haemochromatosis
C282Y/……..
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C282Y /……
Frequent HFE mutation
Hepcidin
H63D
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C282Y / H63D
Hepcidin
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C282Y /……
Rare HFE
mutation
Hepcidin
C282Y/R226G
(Cézard C
Blood Cell Mol Dis
2014)
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Rare HFE-Haemochromatosis
(C282Y/rare mutation)
«Classical» HFE-Haemochromatosis
(C282Y/C282Y)
Hepcidin deficiency
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Rare HFE-
haemochromatosis
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Non HFE-related
Haemochromatoses
Camaschella C Curr Opin Pediatr 2011 Pietrangelo A Semin Liver Dis 2011
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Increased iron entry
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HJV
(hemojuvelin)
HAMP
(hepcidin)
TFR2
(transferrin
receptor2)
Hepcidin deficiency
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Hepcidin
supplementation...
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HJV
(hemojuvelin)
HAMP
(hepcidin)
TFR2
(transferrin
receptor2)
Increased iron entry
Camaschella C Curr Opin Pediatr 2011 Pietrangelo A Semin Liver Dis 2011
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Decreased iron exit
Fe
Fe Fe
Fe
Fe
Fe
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Decreased iron exit
Ferroportin disease
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Fe
Ferroportin
(export
dysfunction)
Ferroportin
mutations
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NTBI
Ferroportin
mutations (type A)
Hepatocytic
iron
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LPI
Ferroportin
mutations (type A)
Visceral
toxicity
Le Lan C Gastroenterology 2011
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Fe
B
L
O
O
D
Macrophage
Bone
marrow
Venesection
RBC
RBCRBC
RBC
Fe
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Decreased iron exit
Aceruloplasminemia
Anemia ferritin
Chelation