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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 Conference Il Patient Blood Management: non solo una questione di ferro e anemia Roma, 15 ottobre 2015

Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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Page 1: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 2: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 3: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 4: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 5: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

_

_

Page 6: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 7: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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)

Page 8: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 9: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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 +/+

Page 10: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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 +/+

Page 11: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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:

Page 12: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 13: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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)

Page 14: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 15: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 16: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 17: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 18: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,
Page 19: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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.

Page 20: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 21: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 22: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

-

Page 23: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

-

Page 24: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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.

Page 25: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

“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

Page 26: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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.

Page 27: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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.

Page 28: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

Hepcidin is suppressed in iron deficiency

Special Conference SIMTI – Rome, October 15, 2015 – D.G. 28

Drakesmith H, Prentice AM, Science 2012

Page 29: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 30: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 31: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 32: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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

Page 33: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

Pharmacology of hepcidin

Special Conference SIMTI – Rome, October 15, 2015 – D.G. 33

Ruchala P & Nemeth E, Trends Pharmacol Sci 2014

Page 34: Iron and hepcidin: a story of recycling and balance · Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo,

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