Magnetic Iron Detector - Uno strumento per misurare l'eccesso di ferro nel fegato

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NI Medical Innovation SummitJune 15, 2010

MAGNETIC IRON DETECTOR

Mauro Marinelli

Physics Dept. University of Genova and INFN, Italy

[email protected] 320 433 0989
mailto:[email protected]:[email protected]


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Assessment of the body iron burden is essential formanagement of diseases producing systematic ironoverload .

Long-term transfusion therapy (thalassemia major or otheranemias) or increased dietary iron absorption (hereditary

hemochromatosis) provide excessive amounts of iron stored inthe endocrine organs, heart and liver leading to cardiacdisease, cirrhosis and even to death.

The liver needle biopsy is an invasive method for themeasurement of liver-iron concentration, susceptible of largeerrors due to the heterogeneous distribution of iron depositionin the liver.


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Magnet Pickup

B B B

The magnetic field flux , threaded with thepickup, is slightly modified by the

diamagnetic (mainly from water) andparamagnetic (iron) properties of tissues .

MID measures the total iron overload

present the liver region

710B

BisysensitivitrequiredThe

Iron magnetic susceptibilityMagnetic susceptibility arises from

competition between the aligning effect ofthe applied field and thermal vibrations .

TC)(

)mKg

K1081.2( 3

5-2

Fe

p/

p iron effective magnetic moment(Bohr magneton)

deoxyhemoglobin (Hb) p = 5.2-5.5 oxyhemoglobin (HbO8) p = 0 Ferritin-Hemosiderin iron p 4 Ferric iron ion Fe 3+ p = 5.9

C

~ 0.4 mg/cc normal value

0.4 1 mg/cc light overload

> 2 mg/cc severe overload

for C = 0.5 mg/cc, p = 4, T = 310 K (37 C)the iron susceptibility is ~ 7 10 -7


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US patent n. 7,412,275European patent n. 1 644 730


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The symmetry, the mechanical stability and theaccurate temperature control of the

complete apparatus gives the sensitivity,better than 10 -7, necessary to detect the ironquantity of interest.

All of the susceptometer components operateat room temperature

Since February 2005, about 800 patients and100 healthy volunteers have been measured

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r d r gV

)r()(

Q is the total amount of iron inside the liver region .

The numerical coefficient is calculated assigning to the ironatoms a magnetic moment of 4 Bohr magneton.The liver temperature is 37 C.

QdV r gV Kg

m

V

)(10145.1 36

= magnetization signal of the iron atoms= magnetic susceptibility of the iron atoms

g = MID weight functionV = liver volume


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Inside the accessible region themagnetic field is lower than 1.9 10 -2 T(CEI EN 60601-2-3, 1997- 02)

Fiberglasssupportingstructure

Thermalshield

The signal of asmallersusceptometer,measuring rats,with andwithout thethermal shield .

with

without


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Inner magnets

Outer magnets Magnet construction


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11MagnetsPickup


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This bodyposition is toscan the liver

region .Simply shiftingthe body, alongthe stretcher,allowsmeasuring themagneticsignal of otherbody parts .

x

rail

The stretcher moves on rails . To account for the changes of theenvironment magnetic properties, we average a few differences betweenthe signals, with the stretcher in and out of the sensitivity region.


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The signal has two sources : an overall magnetic background of the torso and apossible contribution from liver iron excess

The background signal is calculated, from the patient anthropometric data, bya model based on the statistical analysis of the control data.Liver-iron overload is then determined by subtraction of the worked out

background signal from the measured signal of the patient.

Small holes are evenly distributedon each of the phantom plasticslices.We poured paramagnetic powder,equivalent to 3g of Fe 3+ and 15g

of Fe3+

, inside the holes placed inthe phantom liver region .

Because of ~100 nV error, the minimum quantity ofdetectable iron inside the entire liver region of the

phantom is ~130 mg of Fe3+

or ~270 mg of iron withan effective magnetic moment of 4 Bohr Magneton.

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0

5

10

-20 -15 -10 -5 0 5 10 15 20

Magnetic field axis relative to the phantom center

no addedpowder

3 g of Fe 3+

15 g of Fe 3+

x [cm]

V


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The signal of a patient,with about 9 g of ironoverload in the liver,is compared with theone of a healthyvolunteer, having closeanthropometric data.

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0

1

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Volunteer059

V

x [cm]

Patient

108

Liver

Magnetic field axis relative to the torso center


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-2

0

2

-20 -10 0 10 20

Volunteer059

Patient108

x [cm] M I D S i g n a l [

V ]

A B

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0

5

10

-20 -10 0 10 20

noaddedpowder

3 gFe3+

15 gFe3+


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At the low frequency (234 Hz) of the oscillating magneticfield, the magnetic moment of the iron atoms oscillates withthe same phase of the applied magnetic field and the phaselag, of the eddy currents within the human body, relative to

the induced electric field is negligible. So the magneticsignal of the oscillating iron atoms and theone of the induced eddy currents are out ofphase by one fourth of period.

Magnetic flux from thebody magnetization

Magnetic flux from thebody eddy currents

EDDY CURRENT SIGNAL

Magnetizationsignal

Eddy Current signal

y

x

B


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Variando la concentrazione diNaCl in soluzione con 2l acquadeionizzata si osserva:

il diamagnetismo del sale sulsegnale in fase

le correnti parassite sulsegnale in quadratura

h=15cm

r=7.75cm


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J. F. Schenck, E. A. Zimmerman, Review Article High -field magneticresonance imaging of brain iron: birth of a biomarker?, N.M.R. Biomed , no.17, pp. 433-445, 2004 The concentration of iron in the tissues as free aqua ions is not significant

In all the patient measurements we never noticed, on the eddy currentsignal, the iron-overload skew shape of the magnetization signal .

THE EDDY CURRENT SIGNAL DOES NOT DEPEND ON THE IRON

The eddy current signal of the patient, with 9 g of liveriron overload, does not show any skew shape.

The eddy current signal of the patient P029 isalmost the same before and after theremoval of his spleen, containing about 2.7gof iron .

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Volunteer 059magnetizationsignal

Patient 108magnetizationsignal

Patient 108eddy current

signal

Volunteer 059

eddy currentsignal -5

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Magnetizationsignal before the splenectomy

Eddy current

signal before the splenectomy

Magnetizationsignal after splenectomy

Eddy current

signal after the splenectomy


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Both the eddy current and magnetization signals of a personwithout iron overload have a similar dependence on the body size.

The estimation of the background signal of thepatient, is based on his/her eddy current signal andanthropometric data.

x0

A few anthropometric data of V037Height 1.57 mWeigh 48 KgBMI 19 Kg/m 2

Area of the torso cross-section 452 cm 2 Torso mean thickness 16.2 cmx coordinate of the liver center -10 cm

A few anthropometric data of V010Height 1.84 mWeigh 90 Kg

BMI 27 Kg/m2

Area of the torso cross-section 819 cm2 Torso mean thickness 23.3cmx coordinate of the liver center -12 cm

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x [cm]

V010 Torso Profilecm

0

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x [cm]

V037 Torso Profilecm

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Eddy CurrentSignal

Magnetization Signal

x [cm]

Healty Volunteer V010V

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-2

0

2

-20 -15 -10 -5 0 5 10 15 20

Eddy CurrentSignalMagnetizationSignal

x [cm]

Healty Volunteer V037

V


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-4

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0

2

-20 -10 0 10 20

V001 Waterman

V001 Measured Signal

x [cm]

S i g n a

l [ V ]


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LIVER SPLEEN

BEFORE splenectomyJune 05

Background SignalJune 05

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AFTER splenectomySept 05

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Eddy CurrentSignals

M a g n e

t i c s

i g n a

l [ V ]

x [cm]

Spleen : 14 slicesmg Fe /g dw

9.122.53.16.8

24.73.2

18.66.61.01.54.2

1.31.37.6

According with thechemical analysis of thecut off spleen (1350 g),

the held iron wasabout 2.7g .

Liver biopsyNo iron overload

in the liver

The expected magnetization signal, obtained before thesplenectomy, using the eddy current signal and the otherpatient's anthropometric data.


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Patient (P003) affected by Hemochromatosis.The iron is removed by the phlebotomy therapy

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Data of 15 hemochromatosis patients.(A)The iron removal estimated from phlebotomy therapy is

compared to the iron reduction measured by MID.The slope of the linear fit (R= 0.89) is 0.49 .

(B) Iron absorption by the diet during the course of phlebotomies iscalculated from the difference between the iron removalestimated from phlebotomy therapy and the measured reductionby MID. The net iron absorption is 4.9 mg/day with astatistical error of 0.3 mg/day (R=0.90).

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The measured iron reduction is always smaller thanits assessment by the phlebotomy therapy

Iron absorption during phlebotomyThe effective magnetic moment of the iron , is smaller than

the one (p = 4) we are using to calculate the iron overload .

Literature reports values ranging between 3.3 and 4.7 [1,2,3]. We obtained 3.6 from the susceptibility of excised rat livers.A more recent work [4], measuring a lysate of tissue with iron overload,

obtained an iron magnetic moment of 4.2.

1. Bothwell TH et al (1998) Semin. Hematol. 35 (1), 55-712. Michaelis L et al. Ferritin.III. (1943) J. Biol. Chem . 148 , 463-4803. Shoden A, Sturgeon P. (1960) Acta haemat. , 23 , 376-3924. Wang ZJ et al. 1/T2 and Magnetic Susceptibility Measurements in a Gerbil Cardiac Iron

Overload Model. Radiology 2005; 234:749 755


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Thalassemia patient under therapy with L1+DFO. The firstmeasurement was on February 2005 and the last one on March 2010.(C) Therapy administration. (D) Serum ferritin concentration.


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1055 iron overload measurements (age >18 years) have been done fromFebruary 2005 to February 2009. The present MID sensitivity (~0.8g) depends

mainly on the error of the background signal calculation .

0

50

100

150

200

-4 0 4 8 12 16 20g

Total1055

3g16%


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We obtain the iron concentration in the wet tissue dividing the MID measurementby the weight of the liver and adding the basal iron concentration (0.3 mg/g ww) of thehealthy liver. However, this procedure over-estimates the LIC in patients with a liverenlargement. Our liver volume assessment is based on the body weight [4].

The biopsy gives the iron concentration in dry tissues.

The references [1] of 1982 and [2] of 2005 assume that liver is 70% water,so the ratio between the wet and dry tissue is 3.3, but the reference [3] of 2006 claims that this ratio is 5.8 .

1. Brittenham GM et al. N Engl J Med. 1982;307:1671-1675

2. St Pierre et al. Blood. 2005;105:855-861.3. Fischer R et al. Does liver biopsy overestimate liver iron concentration? Blood.

2006;108:1775-1776 4. Vauthey JN et al. Body surface area and body weight predict total liver volume in Western

adults. Liver Transpl. 2002;8:233-240

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The liver biopsy is not required to calibrate the MID .


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SQUID Susceptometer

R. Fisher, E. Eich, R.Engelhardt, H. C.Heinrich, M. Kesslerand P. Nielsen, Thecalibration problemin liver ironsusceptometry in

Advances in

biomagnetism , S.J.Williamson et al. ,Ed. New York, 1990,pp. 501 504.

SQUID


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SQUID susceptometer

The geometry of SQUID susceptometr renders the measurements mostlydependent on the magnetic properties of few centimeters of tissues

immediately below the abdominal wall [10]. In the reference [5] we readIn effect, the susceptometer provides an automated magnetic biopsyof liver ferritin and hemosiderin iron.

To measure the body iron overload it is necessary the sensitivity to detect the small(about 10 part in 1 billion) change of the applied field, produced by the iron contribution

to the tissue susceptibility. Even in the presence of this very small relative modificationof the magnetic field, the absolute change of the magnetic field flux, produced bythe human body and threaded with the pickup, is equivalent to millions ofmagnetic flux quantum (2.07 10 15 Wb), so it is not necessary using the SQUID todetect it and a simpler room temperature pickup coil can be used.

5. Brittenham GM et al. Noninvasive measurement of iron: report of an NIDDK workshop. Blood .2003 ;101:15-19.6. Farrell DE et al. ( 1980 ) IEEE Trans. on Magnetics. 16(5), 818-8237. Brittenham GM et al. ( 1982 ) N. Eng. J. Med. 307, 1671-16758. Paulson DN et al. ( 1991 ) IEEE Trans. on Magnetics. 27(2), 3249-32529. Nielsen P et al. ( 1995 ) Br.J.Haemat . 91, 827-83310. Fisher R. et al ( 1989 ) In: Advances in Biomagnetism , eds . Williamson S.J. et al . (Plenum Press, New

York), pp. 501-50411. Brittenham GM et al. ( 2001 ) Semin Hematol 38 (suppl1) :37.56 .


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(A) The LIC in wet tissue of 50 patients (64 measurements) measured by the SQUIDand the MID susceptometers (R =0.79).

(B) Bland Altman plot showing the differences between LIC measured by MID andSQUID susceptometers.

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(A) 666 blood serum-ferritin (BSF) concentration tests are compared with the LIC inwet tissues calculated by the iron overload measured by MID (R =0.72).

(B) Comparison between the total iron amount in the liver measured by MID and theR2* value measured by the MRI on the same patients.

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MID 2 with CE stamp

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BOTTIGLIETTA con 0.5 L di LCWin un angolo della bacinella (8L Fisiologica)

B001 PKI SegnaleB001 PKI C90

B002 PKI SegnaleB002 PKI C90

PKIS

e

V)

Posizione Asse X (cm)

BOTTIGLIETTA LCWSOLO BACINELLA FISIOLOGICA

Magnetization Signal

SQUID S


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SQUID Susceptometer

R. Fisher, E. Eich, R.Engelhardt, H. C.Heinrich, M. Kesslerand P. Nielsen, Thecalibration problemin liver ironsusceptometry in

Advances in

biomagnetism , S.J.Williamson et al. ,Ed. New York, 1990,pp. 501 504.

SQUID susceptometer


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SQUID susceptometer

The geometry of SQUID susceptometr renders the measurements mostlydependent on the magnetic properties of few centimeters of tissues

immediately below the abdominal wall [10]. In the reference [5] we readIn effect, the susceptometer provides an automated magnetic biopsyof liver ferritin and hemosiderin iron.

To measure the body iron overload it is necessary the sensitivity to detect the small(about 10 part in 1 billion) change of the applied field, produced by the iron contribution

to the tissue susceptibility. Even in the presence of this very small relative modificationof the magnetic field, the absolute change of the magnetic field flux, produced bythe human body and threaded with the pickup, is equivalent to millions ofmagnetic flux quantum (2.07 10 15 Wb), so it is not necessary using the SQUID todetect it and a simpler room temperature pickup coil can be used.

5. Brittenham GM et al. Noninvasive measurement of iron: report of an NIDDK workshop. Blood .2003 ;101:15-19.

6. Farrell DE et al. ( 1980 ) IEEE Trans. on Magnetics. 16(5), 818-8237. Brittenham GM et al. ( 1982 ) N. Eng. J. Med. 307, 1671-16758. Paulson DN et al. ( 1991 ) IEEE Trans. on Magnetics. 27(2), 3249-32529. Nielsen P et al. ( 1995 ) Br.J.Haemat . 91, 827-83310. Fisher R. et al ( 1989 ) In: Advances in Biomagnetism , eds . Williamson S.J. et al . (Plenum Press, New

York), pp. 501-504

11. Brittenham GM et al. ( 2001 ) Semin Hematol 38 (suppl1) :37.56 .


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Method Measurement Unit Limits andSource of Errors

BIOPSY Local ironconcentration in drytissues obtained from

chemical analysis of essicated sample

mg/g dry tissue Invasive The measurement depends on the local distribution of the iron in the liver The result of the analysis depends on the treatment of

the sample before its exsiccation: the wet-to-dry ratiodepends on the treatment of the sample before itsanalysis

SQUID Local ironconcentrationin in wettissues

mg/g wet tissue Non-invasive The measurement depends on the local distribution of the iron in the liver ( magnetic biopsy ) The iron concentration is obtained by comparing thehuman tissues with water

MRI Local ironconcentration in drytissues

mg/g dry tissue Non-invasive It measures the decreasing of proton transverserelaxation in the presence of iron. The result of themeasurement is the relaxation time T2 (s). The T2 is evaluated in a selected region of interest(local measurement ) The conversion from T2 to iron concentration (drytissue) is performed using a calibration curve. Thebiopsy is needed to construct the calibration curve .

MID Iron overload withinthe whole liver region

g wet tissue Non-invasive The iron overload in the whole liver region isobtained dividing the difference between the signal of the patient and its basal one (i.e. the magnetic signal of the patient without the iron burden) by the contributionof 1 g of iron evenly distributed in the patient liver. The basal signal is obtained from the patientanthropometric characteristics and the magnetic

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Magnetic Iron Detector - Uno strumento per misurare l'eccesso di ferro nel fegato

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