3e Giornate Gastro-Epatologiche Cuneesi

Casa Regina Montis Regalis - Vicoforte (CN)

19/20 febbraio 2010

Iperferritinemia: algoritmo

diagnostico

Antonio Piga

S.C.D.U. Pediatria – Centro regionale di riferimento per le talassemie ed Hbpatie

Azienda Ospedaliera Universitaria S. Luigi Gonzaga – Orbassano - tel. 011 9026851

Centro SQUID

Azienda Ospedaliera OIRM-S.Anna – Torino - tel. 011 3134771

Dipartimento di Scienze Cliniche e Biologiche, Università di Torino

email: antonio.piga@unito.it

Cell iron storage = ferritin

• Ferritin is a shell protein, made of 24 subunits

• It may store up to 4.500 atoms of iron

• In vertebrates ferritins are made of different proportions of 2 types of subunits: H chain and L chain, with 50% identity

• Ferritins incorporate iron with avidity in vivo e in vitro

1 g/L

Serum ferritin

8-10mg Fe

Iron stores

Thalassemia CentreUniversity of Torino

Zacharski LR, 2000

ALT and FERRITIN Pattern

in a Patient (G.F.) with Sickle Anemia and Hepatitis C

1990 1991 19920

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

0

200

400

600

800

1000

1200

1400

1600

1800

2000

ALT

FERRITIN

Thalassemia Centre

University of Torino

Serum ferritin

Direct correlationwith iron load

Jacobs, 1972

Brittenham, 1993

Influenced by

hepatitis Prieto, 1975

infection Konijn, 1977

inflammation Worwood, 1980

hemolysis Baynes, 1986

hemochromatosis Finch, 1986

vit C deficiency Nienhuis, 1981

Easy to be performed

Bothwell, 1979

Multiple assessmentare needed

PROs CONs

Thalassemia Centre

University of Torino

Thalassemia Centre

University of Torino

y = 0,456x + 381,8R² = 0,115

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000

Seru

m F

err

itin

mic

rog

/L

LIC by SQUID microg/g liver

Serum Ferritin and LIC in 571 patients with hyperferritinemiaPrevalence of Iron Overload (LIC > 1000) = 18%

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Andrews NC. Blood. 2008;112:219-230.

HEPCIDIN: A KEY IRON REGULATOR

DNA: 2.5 Kb, 3 exons - cDNA: 0,4 Kb

84 aa propeptide -> 20-25aa mature peptide

Liver product

4 S-S bonds

Hairpin structure

(antimicrobial peptide)

Andrews NC. Blood. 2008;112:219-230.Classes of Hemochromatosis

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Deugner Y, 2002

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Deficit Cp

XFe2+ (ferritin)

Fe3+ (transferrin)

Tissue ironoverload

ACERULOPLASMINEMIAIron overload physiopathology

plasmatic Fe deficiency

Increased Fe absorbtion

Anemia(microcytic)

MICROCYTIC ANEMIA AND HEPATIC IRON OVERLOAD

Aceruloplasminemia

DMT1 mutations

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Hereditary Hyperferritinemia-CataractSyndrome (HHCS)

• Autosomal dominant, rare

• Mutations in the IRE of L-ferritin

• Deregulation of L-ferritin synthesis

• High levels of serum ferritin

• Normal transferrin saturation

• Absence of iron overload

• Bilateral cataract

AAAA

5’

AAAA

5’AAAA

5’

5’AAAA

UNSTABLE

STABILE

HIGH TRANSLATION

NO TRANSLATION

transferrin receptor mRNA ferritin mRNA

IRP1,IRP2

low

affinity

form

high

affinity

form

- IRON+ IRON

IRE-IRP POST-TRANSCRIPTIONAL REGULATION

OF CELLULAR IRON

AAAA

5’

AAAA

5’AAAA

5’

5’AAAA

UNSTABLE

STABILE

HIGH TRANSLATION

NO TRANSLATION

transferrin receptor mRNA ferritin mRNA

IRP1,IRP2

low

affinity

form

high

affinity

form

- IRON+ IRON

X

IRE-IRP POST-TRANSCRIPTIONAL REGULATION

OF CELLULAR IRON

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

Sat TfN o ↓

Non anemia

TransaminasiN

PRC ↑↑-flogosi-Infezioni

Markerstumorali ++Neoplasie

Cataratta ++-S. iperferritinemia-cataratta

Transaminasi ↑↑

-Epatiti croniche virali

-Epatiti esotossiche

-NASH

AnemiaAceruloplasminemia

Sat Tf↑↑

Non anemia-Emocromatosi-Accumulo iatrogeno

Anemia-Talassemie

Thalassemia Centre

University of Torino

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

LICN

-Neoplasie

Flogosi

Infezioni

S. iperferritinemia-cataratta

LIC↑↑

Emocromatosi-Accumulo iatrogeno

-Talassemie

Aceruloplasminemia

LIC

↑

Epatiti croniche virali

NASH

Epatiti esotossiche

Thalassemia Centre

University of Torino

Isom HC, 2009

Causes of hepatic iron overload

Wallace DF, 2008

The role of iron in liver disease

NORMAL

RANGE OF

BODY IRON

STORES

(g Fe)

60

0

15

30

45

< 1.5 g1.5 to < 5 g

5 - 60 g

MODEST MARKED

Brittenham, 2001

Superconductive Quantum Interference Device

Josephson effect

V

I

Ic-Ic

IS S

0.8

0.06

0

0.1

0 42 6 8temperature (°K)

0.16

0.2

0.26

Conductive Superconductive

Superconductivity

Meissner effect

T>Tc T<Tc T<Tc

Normal(nonsuperconducting)

Flux expulsion(superconducting state)

Persistant current(superconducting state)

Resis

tance (

ohm

)

Thalassemia Centre

University of Torino

SQUID biomagnetic susceptometer

Liquidheliumdewar

Superconductingmagnet coils SQUID

sensors

Second derivative gradiometer detection coils

Water reservoir

Bed

Water bag

Patient

SQUID biomagnetic susceptometer

Thalassemia Centre

University of Torino

Liquidheliumdewar

Superconductingmagnet coilsSQUID

sensors

Second derivative gradiometer detection coils

Water reservoir

Bed

Water bag

Patient

Paramagnetic ferritin

fer = 1660 * 10-6 [SI]

SQUID biomagnetic susceptometer

Thalassemia Centre

University of Torino

Superconductingmagnet coils

Thalassemia Centre

University of Torino

OaklandNew York

Hamburg

Torino

SQUID biomagnetic susceptometers

Thalassemia Centre

University of Torino

Ultrasonic

transducer

Vibrator

Probe

Ribs

Liver

Hepatic elasticity measurement (Fibroscan)

Liver sample

T2

Spin Echo, Gradient-Echo sequences

Signal Intensity Ratio (SIR)

Thalassemia Centre

University of Torino

T2*Gradient-echo sequences

ms

R2Gradient-echo sequences

s-1

5ms 6ms 7ms 8ms 9ms 11ms 13ms 15ms 17ms

Deriving Myocardial T2*

0

20

40

60

80

100

0 4 8 12 16 20

TE

Sig

na

l

Signal = Ke-

TE/T2*

Anderson LJ. Eur Heart J 2001; 22: 2171-9

Scatterplot of LIC mg/g/dw 5.83 against Heart T2* (ms)

N=691 r=0.20 p<0.001

0 10 20 30 40 50 60 70 80

Heart T2* (ms)

0

5

10

15

20

25

30

35

40

45

50

55

LIC

mg

/g/d

w 5

.83

Thalassemia Centre

University of Torino

Normals

Liver

iron overload

Heart

iron overload

Liver & Heart

iron overload

Liver and Heart Iron Load in Thalassemia

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

LICN

-Neoplasie

Flogosi

Infezioni

S. iperferritinemia-cataratta

LIC↑↑

Emocromatosi-Accumulo iatrogeno

-Talassemie

Aceruloplasminemia

LIC

↑

Epatiti croniche virali

NASH

Epatiti esotossiche

Thalassemia Centre

University of Torino

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

LICN

-Neoplasie

Flogosi

Infezioni

S. iperferritinemia-cataratta

LIC↑↑

Emocromatosi-Accumulo iatrogeno

-Talassemie

Aceruloplasminemia

LIC

↑

Epatiti croniche virali

NASH

Epatiti esotossiche

Thalassemia Centre

University of Torino

Algoritmo per la valutazione dei pz con iperferritinemia

Iperferritinemia

LICN

-Neoplasie

Flogosi

Infezioni

S. iperferritinemia-cataratta

LIC↑↑

Emocromatosi-Accumulo iatrogeno

-Talassemie

Aceruloplasminemia

LIC

↑

Epatiti croniche virali

NASH

Epatiti esotossiche

Thalassemia Centre

University of Torino