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MAGNETIC IRON DETECTOR (MID)MAGNETIC IRON DETECTOR (MID)

WHOLE LIVER IRON OVERLOAD MEASUREMENT WHOLE LIVER IRON OVERLOAD MEASUREMENT BY A NON CRYOGENICBY A NON CRYOGENIC

MAGNETIC SUSCEPTOMETERMAGNETIC SUSCEPTOMETER

Mauro Marinelli1,2, Piergiorgio Beruto1, Barbara Gianesin1,2, Antonella Lavagetto3, Martina Lamagna3, Eraldo Oliveri2, Maria Luigia Saccone1, Giuliano Sobrero2, Laura Terenzani3, Gian Luca Forni3

1Physics Dept. University of Genova, Italy, 2National Institute of Nuclear Physics (INFN) Genova, 3Centro della Microcitemia e Anemie Congenite, Ospedali Galliera, Genova, Italy

SIF 06 - XCII Congresso Nazionale Società Italiana di Fisica

Torino, 18 – 23 Settembre 2006

THALAS

2

Accurate assessment of body-iron accumulation is essential for managing therapy of iron-overload in diseases such as thalassemia, hereditary hemochromatosis and other forms of severe congenital or acquired anemias.

At present, the gold standard to determine liver-iron concentration (LIC) is the invasive liver needle biopsy; it might lead to large error in assessing iron burden due to the heterogeneous distribution of iron deposition in the liver.

E. Butensky et al., Am J Clinical Pathology 2005; 123; 146-152 "Although chemical analysis of liver biopsy samples is considered the gold standard for determining the Liver Iron Concentration ..concern has been raised that variability in the distribution of liver iron deposition exists and might lead to errors as high as 200% in assessing body iron burden by biopsy."

The distribution of the Liver Iron Concentration (LIC), obtained from the post-mortem examination of a thalassemic-patient liver, ranges from 10 (mg/g)* to 35 (mg/g)*

10 20 30 40

LIC (mg/g)*

* Dry weight

1 2 3 4

5 6 7 8

9 10 11

Sample LIC (mg/g)*

Sample LIC (mg/g)*

F1 35 F7 34 F2 27 F8 21 F3 29 F9 35 F4 33 F10 27 F5 23 F11 10

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Magnet Pickup

B

BB

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

diamagnetic (mainly from water) and paramagnetic (iron) properties of tissues.

It measures the iron overload in the whole liver

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3

2

35-

Fe

107islitysusceptibiironthe

K310T,4p,cc/mg5.0CFor

overloadseverecc/mg2

overloadlightcc/mg14.0C

valuenormalcc/mg4.0

9.5p)Fe(ionironFerric

4pironnHemosideriFerritin

0p)8HbO(binoxyhemoglo

5.52.5p)Hb(lobindeoxyhemog

)magnetonBohr(

momentmagneticeffectiveironp

T

C) (p)

m/Kg

K10 81.2(

litysusceptibimagneticIron

710B

B

isysensitivitrequiredThe

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The symmetry, the mechanical stability and the accurate temperature control of the complete apparatus gives the sensitivity, better than 10-7, necessary to detect the iron quantity of interest.

All the susceptometer components operate at room temperature

Since February 2005, about 150 patients and 90 healthy volunteers have been measured.

volumebodyV

functionweightingMID)r(g

ility susceptibmagneticbody )r(

signalmagnetic

rd)r()r(gV

Pickup

Pickup

Magnet

5

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

Fiberglass supportingstructure

Thermal shield

The signal of a smaller susceptometer, measuring rats, with and without the thermal shield.

with

without

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This body position is to scan the liver region. Simply shifting the body allows measuring the magnetic signal of other body parts, for instance the head.

The stretcher moves on rails.

We average a few differences between the signals, with the stretcher in and out of the sensitivity region, to account for the changes of the environment magnetic properties.

x

rail

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The signal picked up by the susceptometer has two sources: an overall magnetic background of the torso and a possible contribution from liver iron excess.

After measuring the magnetic signature of a patient, statistical analysis methods and neural-network simulations (trained using the control data) are employed to estimate the background signal given the patient anthropometric data. Liver-iron overload is then determined by subtraction of the estimated background from the total measured signal.

Small holes are evenly distributed on each of the phantom plastic slices. We poured paramagnetic powder, equivalent to 3g of Fe3+ and 15g of Fe3+, inside the holes placed in the phantom liver region.

Because of ~100 nV error, the minimum quantity of detectable iron inside the entire liver region of the phantom is ~130 mg of Fe3+ or ~270 mg of iron with an effective magnetic moment of 4 Bohr Magneton.

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0

5

10

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Magnetic field axis relative to the phantom center

no addedpowder

3 g of Fe3+

15 g of Fe3+

x [cm]

V

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The signal of a patient, with 12.4±1 g of iron overload in the liver, is compared with the one of a healthy volunteer, having close anthropometric data.

The abscissa x (cm) is the position of the center of the human body relative to the magnetic field axis.

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Volunteer 059

V

x [cm]

Patient 108

Liver

Magnetic field axis relative to the torso center

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Because of the inductance of the eddy currents loops within the human body and the tissue resistivity, the delay of the eddy currents relative to the induced electric field is negligible.

Magnetic flux from the body magnetization

Magnetic flux from the body eddy currents

EDDY CURRENT SIGNALEDDY CURRENT SIGNAL

Magnetization signal

Eddy Current signal

y

x

B

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• J. F. Schenck, E. A. Zimmerman, “Review Article High-field magnetic resonance 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 the iron overload skewness on the eddy current signal.

THE EDDY CURRENT SIGNAL DOES NOT DEPEND ON THE IRONTHE EDDY CURRENT SIGNAL DOES NOT DEPEND ON THE IRON

The eddy current signal of the patient P108, with more than 12g of liver iron overload, does not show any skewness

The eddy current signal of the patient P029 is almost the same before and after the removal of his spleen, containing a large amount of iron.

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Volunteer 059magnetizationsignal

Patient 108 magnetizationsignal

Patient 108 eddy current signal

Volunteer 059eddy current signal -5

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Magnetization signal 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 person without iron overload have a similar dependence on the body size.

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A few anthropometric data of V037 Height 1.57 m Weigh 48 Kg BMI 19 Kg/m2

Area of the torso cross-section 452 cm2 Torso mean thickness 16.2 cm x coordinate of the liver center -10 cm

A few anthropometric data of V010 Height 1.84 m Weigh 90 Kg BMI 27 Kg/m2

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

The estimation of the signal of the patient, supposed depleted by the iron overload (background signal), is based on his eddy current signal and anthropometric data.

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x [cm]

V010 Torso Profilecm

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x [cm]

V037 Torso Profilecm

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Eddy Current Signal

Magnetization Signal

x [cm]

Healty Volunteer V010V

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0

2

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Eddy Current SignalMagnetization

Signalx [cm]

Healty Volunteer V037

V

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The expected magnetization signal, obtained before the splenectomy, using the eddy current signal and the other patient's anthropometric data.

Spleen: 14 slicesmgFe/gdw

9.122.53.16.8

24.73.2

18.66.61.01.54.21.31.37.6

According with the chemical analysis of the cut off spleen (1350 g), the held iron was

about 2.7g.

Liver biopsyNo iron overload

in the liver

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V

x [cm]Liver Spleen

magnetization signal before the splenectomy (June 20, 05)

magnetization signal after the splenectomy (Sept 06, 05)

Expected magnetizationsignal(June 20, 05)

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x [cm]

March 7, 05

(b)

(a)

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May 27, 05

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Oct 19, 05

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Feb 21, 06

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x [cm]

(a)

(b)

June 7, 06

P 003

Measured (a) and Background (b) signals of two patients affected by Congenital Hemocromatosis.

The iron depletion is obtained with the phlebotomy therapy.

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x [cm]

Feb 07, 06

(a)

(b)

V

x [cm]

Dec 01, 05

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x [cm]

May 09, 06

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June 28, 06

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P 068

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The iron overload measurements of the two Hemochromatosis patients

The iron reduction, measured by MID, is compared with the assessment of the iron depletion obtained with the phlebotomy

therapy

Measured Liver Iron Overload [g] Date P003 P068

March 7, 05 10.1 ± 1 May 27, 05 7.4 ± 1 Oct 19, 05 5.8 ± 1 Feb 21, 06 1.1 ± 1 June 7, 06 1.5 ± 1

Dec 01, 05 7.5 ± 1 Feb 07, 06 7.9 ± 1 May 09, 06 6.2 ± 1 June 28, 06 5.2 ± 1

0

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05/Feb 05/Jun 05/Oct 06/Feb 06/Jun 06/Oct

P068 P003g

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y = -0.62 + 0.95x R= 0.94

MID

Therapy assessment

g

g

15

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x [cm]

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(b)

Feb. 22, 05

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x[cm]

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July 12, 05

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Oct 27, 05

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June 7, 06

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x [cm]

(a)

(b)

June 16, 05

Measured (a) and Background (b) signals of a Thalassemia Major patient, treated, 5 days per week, with 45mg/Kg of DFO and, 7 days a week, with 75mg/Kg of

Deferipron.

Date Iron Overload [g] Feb 22, 05 10.0 ± 1 June 16, 05 7.5 ± 1 July 12, 05 7.1 ± 1 Oct 27, 05 5.7 ± 1 June 7, 06 4.1 ± 1

0

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05/Feb 05/Jun 05/Oct 06/Feb 06/Jun 06/Oct

Liver Iron Overload [g]

P002

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The MID sensitivity is about 1g (1SD)The MID sensitivity is about 1g (1SD). It depends on the model to calculate the background signaldepends on the model to calculate the background signal. .

The reproducibility of the iron overload of the same patients, measured after a relatively short lapse of time, is better than 0.5 g

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Healthy Volunteers

Iron Overload [g]

86Number

- 0.12 gMean1.0 gStd Deviation

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Patients Not Detectable [<1g]Moderate [1-3g]Severe [>3g]

Iron Overload [g]

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The Liver Iron Concentration (LIC) of 7 patients from the MID and the Biopsy of

their liver

Liver volume = (25cc/Kg) x (Patient’s body weight)

(Ratio between dry-weight and wet-weight iron concentrations) = 5.83

The LIC, measured by MID, is compared with the LIC measured by SQUID (Dr. A. Piga, Turin, Italy)

on the same patients

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2 103

4 103

6 103

8 103

1 104

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y = -265 + 1.5x R= 0.86

LIC (MID) [g/gwet weight

]

LIC (SQUID) [g/gwet weight

]

0

1 103

2 103

3 103

0 1 103 2 103 3 103

MID Liver Iron Concentration [g/100mg

dry weight]

y = 210 + 0.86x R= 0.89

Biopsy Liver Iron Concentration [g/100mg

dry weight]

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Conclusion

• This susceptometer measures the iron overload in the whole liver. • All of its components operate at room temperature. It is simpler to operate and more affordable than competing techniques. • It is currently used by the “Centro per la Talassemia e Anemie Congenite E.O. Ospedali Galliera Genova” for the diagnosis of the liver iron overload and for the follow-up of the iron reduction therapies. Since February 2005 about 150 patients and 90 healthy volunteers have been measured

• Recently the Ethics Committee allowed measuring also under age people.