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Iron and hepcidin: a story of recycling and balance
Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo, Azienda Ospedaliera Universitaria Integrata VERONA)
Special ConferenceIl Patient Blood Management: non solo una questione di ferro e anemiaRoma, 15 ottobre 2015
Il sottoscritto DOMENICO GIRELLI, in qualità di Relatore dichiara che
nell’esercizio della Sua funzione e per levento in oggetto, DI NON ESSERE in alcun modo portatore di interessi commerciali propri o di terzi; e che gli eventuali rapporti avuti negli ultimi due anni con soggetti portatori di interessi commerciali non sono tali da permettere a tali soggetti di influenzare le mie funzioni al fine di trarne vantaggio.
NOTHING TO DISCLOSE
outline
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 3
Overview of iron metabolism and its regulation by the hepatic hormone hepcidin
The 3 main signals regulating hepcidin (iron status, inflammations/infections, and iron requirements from BM erythroid precursors)
The recent discovery of the erythroferrone (ERFE), the long sought “eryhtroid regulator” of iron metabolism
Possibile usefulness of hepcidin assay (in iron deficiency)
Future Targeted Treatments through pharmacological modulation of hepcidin
Iron: essential but potentially dangerous
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 4
easily exchange electronsFe3+ Fe2+
useful redox properties
key-component of enzymes crucial for O2 transport and
energy production (Hb, cytochromes…)
free radicals generation (Fe2++ H202 Fe3+ + OH- + OH•)
strict regulation of body iron content needed
anemianeuromuscolar impairment
iron overloadtoxic organ damage
low excess
IRON “ECOLOGY”
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 5
≈2 g
≈600 mg
Erythroid precursors in Bone Marrow
Fe3+
Fe3+
Fe3+
FERROPORTIN
Splenic macrophages
Circulating RBCsPlasma Transferrin
losses (1-2 mg/day)mucosal exfoliation,
menses
duodenal absorption
(1-2 mg/day)
enterocytes
intestinal lumenFe3+
Fe3+FERROPORTIN
Liver 1000 mg
hepcidin
_
_
Physiology
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 6
Castagna A, J Proteomics 2010 (adapted)
Red blood cells
Bone marrow
Fe-Transferrin
Reticuloendothelial macrophage
Hepcidin
plasma Fe ↑+
Inflammation
‐
↑ Erythropoietic drive
O2 ↓
Fe Fe
Hypoxia
IL-6
Physiology
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 7
Red blood cells
Bone marrow
FeTransferrin
Reticuloendothelial macrophage
Hepcidin
plasma Fe ↑+
Inflammation
‐
↑ Erythropoietic drive
O2 ↓
Fe Fe
Hypoxia
IL-6
Fe-TfFinal effect: negative feedback
Castagna A, J Proteomics 2010 (adapted)
The iron-sensing machinery in the liver
8
Iron transferrin from portal vein enters the sinusoids BMP6 production by SC, KC and HSC.
Both iron transferrin and BMP6 activate a multi-molecular signaling complex, composed of several molecules like BMP receptors, HJV (co-receptor), HFE and TFR2.
Pietrangelo A, Gastroenterology 2015
Special Conference SIMTI – Rome, October 15, 2015 – D.G.
hepcidin transcription
Pathology
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 9
Red blood cells
Bone marrow
FeTransferrin
Reticuloendothelial macrophage
Hepcidin
Inflammation
-
↑ Erythropoietic drive
O2 ↓
Fe Fe
Hypoxia
IL-6
Fe-Tf
Castagna A, J Proteomics 2010 (adapted)
HFE C282Y +/+
Pathology
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 10
Red blood cells
Bone marrow
FeTransferrin
Reticuloendothelial macrophage
Hepcidin
Inflammation
-
↑ Erythropoietic drive
O2 ↓
Fe Fe
Hypoxia
IL-6
Fe-Tf
XIntestinal absorption of Fe
Expanded plasma Fe pool TS% tissue Fe accumulation(Fe total 3-5 g >20 g)
Castagna A, J Proteomics 2010 (adapted)
HFE C282Y +/+
Non-transferrin bound iron (NTBI) in hemochromatosis
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 11
100%
30%
Normal: NoNTBI produced
Subsequent formation of
NTBI in plasma
Fe
FeFe
FeFe
FeFe
Iron overload
Transferrin saturation occurs due to
continuously increased iron absorption
Uncontrolled iron loading of organs,
such as:
The spectrum of genetic dysregulation of hepcidin
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 12
Hepcidin levelsIron stores
Normal homeostasis
Hereditary hemochromatosis (HH)
Iron Refractory Iron Deficiency Anemia (IRIDA)
Post-natal microcytic hypochromic anemia with low TS%
Refractoriness to oral iron Slow response to i.v. iron Sometimes diagnosed in adulthood Normal/high hepcidin levels (diagnosis)
HFE, TFR2, SLC40A1, HAMP, HJV
TMPRSS6
HEP-(atic) CIDIN (antimicrobial)
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 13
Ganz T, Physiol Rev 2013
• small (25 aa) peptide
• defensin-like (innate immunity-related peptides with natural antimicrobial acitvity)
A second level of balance in pathological conditions: the host-pathogen battle for iron
14Special Conference SIMTI – Rome, October 15, 2015 – D.G.
essential essential
hepcidin
Fe3+
Fe3+
Fe3+
FERROPORTIN
LPS
A second level of balance in pathological conditions: the host-pathogen battle for iron
15Special Conference SIMTI – Rome, October 15, 2015 – D.G.
essential essential
hepcidin
iron sequestration into macrophages
Fe3+
Fe3+
FERROPORTIN
_Fe3+
Fe3+
Fe3+
LPS
ANEMIA OF CHRONIC DISEASE OR “ANEMIA OF INFLAMMATION”
Impaired iron metabolism(hepcidin-induced“macrophage blockand hypoferremiareducing iron availability to invading pathogens)
Cytokine-inducedimpaired proliferationof erythroidprogenitors
Blunted EPO responseWeiss G, N Engl J Med 2005
Signals regulating hepcidin
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 17
Ganz T, Physiol Rev 2013 (adapted DG)
Pathophysiological meaning:1 (+) iron sequestering (during infections)2 (+) classic homeostatic loop3 (-) matching iron absorption with erythropoiesis requirementsrr
The “erythroid regulator” of iron metabolism
19
Ferrokinetic studies in humans:
Normal iron absorption = 1-2 mg/day
Pts. with Iron deficiency anemia receiving therapeutic doses of iron can absorb > 20 mg/day
Similar amount can be absorbed by subjects with normal iron stores when erythropoiesis is stimulated (i.e. after blood loss or by EPO administration)
Finch C, Blood 1994
Special Conference SIMTI – Rome, October 15, 2015 – D.G.
BLOOD LOSS SUPPRESSES HEPCIDIN TO INCREASE IRON AVAILABILITY FOR “STRESS” ERYTHROPOIESIS
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 20
Fe-Transferrin
Reticuloendothelial macrophage
Hepcidin
Fe ↑+
Inflammation
‐
↑ Erythropoietic drive
O2 ↓
Fe Fe
Hypoxia
IL‐6
Adapted from Castagna A, J Proteomics 2010
Western diet:~15 mg Fe/dieonly ~ 10% absorbed!
Bone Marrow
RBCs precursors
normal erythropoiesis
RBCs
BLOOD LOSS SUPPRESSES HEPCIDIN TO INCREASE IRON AVAILABILITY FOR “STRESS” ERYTHROPOIESIS
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 21
Fe-Transferrin
Reticuloendothelial macrophage
Hepcidin
Fe ↑+
Inflammation
‐
↑ Erythropoietic drive
O2 ↓
Fe Fe
Hypoxia
IL‐6
Adapted from Castagna A, J Proteomics 2010
Western diet:~15 mg Fe/dieonly ~ 10% absorbed!
Bone Marrow
RBCs precursors
normal erythropoiesis
blood loss
RBCs
BLOOD LOSS SUPPRESSES HEPCIDIN TO INCREASE IRON AVAILABILITY FOR “STRESS” ERYTHROPOIESIS
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 22
Fe-Transferrin
Reticuloendothelial macrophage
Hepcidin
Inflammation
‐
↑ Erythropoietic drive
O2 ↓
Fe Fe
Hypoxia
IL‐6
Bone Marrow
RBCs precursors
hyperplasia
Adapted from Castagna A, J Proteomics 2010
blood loss
RBCs
Western diet:~15 mg Fe/dieonly ~ 10% absorbed!
Erythroid regulator
-
BLOOD LOSS SUPPRESSES HEPCIDIN TO INCREASE IRON AVAILABILITY FOR “STRESS” ERYTHROPOIESIS
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 23
Fe-Transferrin
Reticuloendothelial macrophage
Hepcidin
Inflammation
‐
↑ Erythropoietic drive
O2 ↓
Fe Fe
Hypoxia
IL‐6X
20‐fold Fe absorbed!
Bone Marrow
RBCs precursors
hyperplasia
Adapted from Castagna A, J Proteomics 2010
blood loss
RBCs
Erythroid regulator
-
Erythroferrone (ERFE) the newly identified erythroid regulator Proposed mechanism of action
24
Kautz L , Nemeth, E Blood 2014
Kautz L, Nat Genet 2014
ERFE clearly involved in hepcidin suppression in response to acute “stress erythropoiesis” (after hemorrage/EPO administration)
Further work needed to confirm whether it is the long-sought erythroid regulator responsible for chronic hepcidin suppression in ILAs.
Special Conference SIMTI – Rome, October 15, 2015 – D.G.
“IRON LOADING ANEMIAS” (ILAs)
Genetic disorders leading to systemic Iron overload
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 25
Fleming RE, NEJM 2012
26
normal erythropoiesis
Bone Marrow
RBCs precursors
Ineffective/expanded erythropoiesis
anemia
X↑ Iron absorptionhepcidin
↑“eryhtroid regulator”(ERFE?) overrides signal from iron stores
Pathophysiology of iron overload in ILAs
Portal vein
Special Conference SIMTI – Rome, October 15, 2015 – D.G.
27
normal erythropoiesis
Bone Marrow
RBCs precursors
Ineffective/expanded erythropoiesis
anemia
X↑ Iron absorptionhepcidin
↑“eryhtroid regulator”(ERFE?) ) overrides signal from iron stores
Pathophysiology of iron overload in ILAs
Portal vein
Special Conference SIMTI – Rome, October 15, 2015 – D.G.
Hepcidin is suppressed in iron deficiency
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 28
Drakesmith H, Prentice AM, Science 2012
Hepcidin assays (ELISA and MS-based)
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 29
Kulaksiz H, Gut 2004
pro-hepcidin and N-terminus truncated isoforms in urine and serum
0
5
10
15
20
2191.7+H
2435.3+H
2788.3+H
30
Hepcidin 25 Hepcidin 22 Hepcidin 20
m/z Castagna A, J Proteom 2010
Bozzini C, BCMD 2008
Promise of hepcidin assay in the clinic:predict nonresponsiveness to oral iron in IDA
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 30
-Substudy of a phase III clinical trial-NR= Hb < 1 g/dl after 14 days-hepcidin >20 ng/ml = 81.4% Positive Predictive Value of NR -NR majority subsequently respondedto i.v. iron
Bregman DB, Am J Hematol 2013
Iron deficiency anemia in elderly: revisited in the hepcidin era
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 31
Busti F, Front Pharmacol 2014
The MOST promising application of hepcidin assay(from a global health perspective)
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 32
Sazawal S, Lancet 2006
• I.D. major health problem in children from low-incoming countries.• The “Pemba” trial: “routine” iron supplementation is not the solution, but rather can mortality due to infections.
• Hepcidin is the major predictor of RBC iron incorporation in anemic African (Gambia) children, indicating iron utilization for children’s growth rather than for the growth of infectious agents.
Prentice AM, Blood 2012
Hepcidin as a point-of-care index guiding “safe” and effective iron therapy
Pharmacology of hepcidin
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 33
Ruchala P & Nemeth E, Trends Pharmacol Sci 2014
Il “Gruppo Interdisciplinare per le Malattie del Ferro” (AOUI Verona)
Special Conference SIMTI – Rome, October 15, 2015 – D.G. 34
U.O.C. partecipanti: 1. Medicina Generale a indirizzo Immuno-Ematologico ed Emocoagulativo 2. Laboratorio Analisi 3. Servizio Trasfusionale4. Radiologia5. Anatomia Patologica6. Fisica per Tecnologie Biomediche
http://www.gimferverona.org