Post on 21-Feb-2019
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