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