NI Medical Innovation Summit

June 15, 2010

MAGNETIC IRON DETECTOR

Mauro Marinelli
Physics Dept. University of Genova and INFN, Italy

marinelli@ge.infn.it 320 433 0989

Assessment of the body iron burden is essential for
management of diseases producing systematic iron
overload.

Long-term transfusion therapy (thalassemia major or other

anemias) or increased dietary iron absorption (hereditary
hemochromatosis) provide excessive amounts of iron stored in
the endocrine organs, heart and liver leading to cardiac
disease, cirrhosis and even to death.

The liver needle biopsy is an invasive method for the

measurement of liver-iron concentration, susceptible of large
errors due to the heterogeneous distribution of iron deposition
in the liver.
2
The magnetic field flux, threaded with the Iron magnetic susceptibility
pickup, is slightly modified by the Magnetic susceptibility arises from
diamagnetic (mainly from water) and competition between the aligning effect of
paramagnetic (iron) properties of tissues. the applied field and thermal vibrations.

K (p2 C)
Fe (2.81 10 -5
3
)
Magnet Pickup Kg / m T

B B B p iron effective magnetic moment
(Bohr magneton)

deoxyhemoglobin (Hb) p = 5.2-5.5

oxyhemoglobin (HbO8) p=0
Ferritin-Hemosiderin iron p4
Ferric iron ion Fe3+ p = 5.9
MID measures the total iron overload
~ 0.4 mg/cc normal value
present the liver region
C 0.4 1 mg/cc light overload
> 2 mg/cc severe overload
The required sensitivity is
B for C = 0.5 mg/cc, p = 4, T = 310 K (37 C)
107 the iron susceptibility is ~ 7 10-7
B
US patent n. 7,412,275
European patent n. 1 644 730

4
5
6
 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 of the susceptometer components operate

at room temperature

Since February 2005, about 800 patients and

100 healthy volunteers have been measured
7

g ( r ) ( r ) dr
V
= magnetization signal of the iron atoms
= magnetic susceptibility of the iron atoms
g = MID weight function
V = liver volume

1
1.45 1 0 6 m

3
g ( r ) dV Q
Kg V
V

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

The numerical coefficient is calculated assigning to the iron

atoms a magnetic moment of 4 Bohr magneton.
The liver temperature is 37 C.
8
 Inside the accessible region the
Fiberglass magnetic field is lower than 1.9 10-2 T
supporting (CEI EN 60601-2-3, 1997- 02)
Thermal
structure
shield

The signal of a
smaller
without
susceptometer,
with measuring rats,
with and
without the
thermal shield. 9
Inner magnets

Magnet construction 10
Outer magnets
Magnets Pickup
11
The stretcher moves on rails. To account for the changes of the
environment magnetic properties, we average a few differences between
the signals, with the stretcher in and out of the sensitivity region.

This body
position is to
scan the liver
region.
Simply shifting
the body, along
the stretcher, x
allows
measuring the
magnetic
rail
signal of other
body parts.

12
The signal has two sources: an overall magnetic background of the torso and a
possible contribution from liver iron excess
10
V

3+
15 g of Fe
5

3+
3 g of Fe
0

no added
powder
Small holes are evenly distributed x [cm]
-5
on each of the phantom plastic -20 -15 -10 -5 0 5 10 15 20

slices. Magnetic field axis relative to the phantom center

We poured paramagnetic powder, Because of ~100 nV error, the minimum quantity of
equivalent to 3g of Fe3+ and 15g detectable iron inside the entire liver region of the
of Fe3+, inside the holes placed in phantom is ~130 mg of Fe3+ or ~270 mg of iron with
the phantom liver region. an effective magnetic moment of 4 Bohr Magneton.

The background signal is calculated, from the patient anthropometric data, by

a 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. 13
 3
The signal of a patient, V Volunteer
with about 9 g of iron Patient
2 059 108
overload in the liver,
is compared with the 1
one of a healthy 0
volunteer, having close
anthropometric data. -1

-2

-3

-4
Liver x [cm]
-5
-20 -15 -10 -5 0 5 10 15 20
Magnetic field axis relative to the torso center

14
A 10 B
2
Patient
15 g 108
Fe3+
5 0
MID Signal [V]

3g
Fe3+ -2
0 Volunteer
no
added 059
-4
powder
-5
-20 -10 0 10 20 -20 -10 0 10 20
x [cm]

15
 EDDY CURRENT SIGNAL

y
B Magnetization
signal

Eddy Current
signal

Magnetic flux from the

body magnetization
At the low frequency (234 Hz) of the oscillating magnetic
field, the magnetic moment of the iron atoms oscillates with
the same phase of the applied magnetic field and the phase
lag, of the eddy currents within the human body, relative to
the induced electric field is negligible. So the magnetic
signal of the oscillating iron atoms and the
Magnetic flux from the one of the induced eddy currents are out of
body eddy currents
phase by one fourth of period.

16
Variando la concentrazione di
NaCl in soluzione con 2l acqua
deionizzata si osserva:

il diamagnetismo del sale sul

segnale in fase
le correnti parassite sul
segnale in quadratura

r=7.75cm

h=15cm

17
 THE EDDY CURRENT SIGNAL DOES NOT DEPEND ON THE IRON
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, on the eddy current
signal, the iron-overload skew shape of the magnetization signal.
3 3
Volunteer 059 Patient 108 Magnetization
2 magnetization magnetization 2 signal before
signal signal Magnetization the splenectomy
1 1 signal after
splenectomy
0 0
-1 -1
-2 -2
-3 -3
Patient 108
-4 eddy current Volunteer 059 -4 Eddy current Eddy current
signal eddy current signal before signal after
-5 signal -5 the splenectomy the splenectomy
-20 -15 -10 -5 0 5 10 15 20 -20 -15 -10 -5 0 5 10 15 20

The eddy current signal of the patient, with 9 g of liver
iron overload, does not show any skew shape.
The eddy current signal of the patient P029 is
almost the same before and after the
removal of his spleen, containing about 2.7g
of iron.
18
 Both the eddy current and magnetization signals of a person
without iron overload have a similar dependence on the body size.
2 A few anthropometric data of V010
V Healty Volunteer V010 30
Height 1.84 m
cm V010 Torso Profile
0 25 Weigh 90 Kg
BMI 27 Kg/m2
Magnetization Signal
20
Area of the torso cross-section 819 cm2
-2 Torso mean thickness 23.3cm
15
x coordinate of the liver center -12 cm
10
-4
Eddy Current 5

-6
Signal x [cm]
0
x [cm] -20 -15 -10 -5 0 5 10 15 20

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

0 x
2
Healty Volunteer V037 30
cm V037 Torso Profile
0 25

20
V
-2
15

10
-4 Eddy Current A few anthropometric data of V037
Magnetization Signal 5
Height 1.57 m
-6 Signal x [cm] Weigh 48 Kg
0
x [cm] -20 -15 -10 -5 0 5 10 15 20
BMI 19 Kg/m2
-20 -15 -10 -5 0 5 10 15 20 Area of the torso cross-section 452 cm2
Torso mean thickness 16.2 cm
The estimation of the background signal of the x coordinate of the liver center -10 cm

patient, is based on his/her eddy current signal and

19
anthropometric data.
20
 2

0
V001 Waterman

Signal [V]
-2

-4

V001 Measured Signal

-6
-20 -10 0 10 20
x [cm]

21
The expected magnetization signal, obtained before the Spleen: 14 slices
splenectomy, using the eddy current signal and the other mgFe/gdw
9.1
patient's anthropometric data. 22.5
3.1
6.8
2 AFTER splenectomy 24.7
BEFORE splenectomy Sept 05 3.2
1 June 05 18.6
6.6
Magnetic signal [V]

1.0
0 1.5
4.2
-1 1.3
1.3
-2 7.6
Background Signal
According with the
June 05 chemical analysis of the
Eddy Current
-3 Signals cut off spleen (1350 g),
the held iron was
-4 about 2.7g.
LIVER SPLEEN Liver biopsy
-5
No iron overload
-20 -15 -10 -5 0 5 10 15 20 in the liver

x [cm]
Patient (P003) affected by Hemochromatosis.
The iron is removed by the phlebotomy therapy

23
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 is
calculated from the difference between the iron removal
estimated from phlebotomy therapy and the measured reduction
by MID. The net iron absorption is 4.9 mg/day with a
statistical error of 0.3 mg/day (R=0.90).
24
 The measured iron reduction is always smaller than
its assessment by the phlebotomy therapy

Iron absorption during phlebotomy

The 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), 55-71

2. Michaelis L et al. Ferritin.III. (1943) J. Biol. Chem. 148, 463-480
3. Shoden A, Sturgeon P. (1960) Acta haemat., 23, 376-392
4. Wang ZJ et al. 1/T2 and Magnetic Susceptibility Measurements in a Gerbil Cardiac Iron
Overload Model. Radiology 2005; 234:749755
25
Thalassemia patient under therapy with L1+DFO. The first
measurement was on February 2005 and the last one on March 2010.
(C) Therapy administration. (D) Serum ferritin concentration.
 200
1055 Total
150 47% <1g
37% 1g-3g
100 16% >3g

50
g
0
-4 0 4 8 12 16 20
1055 iron overload measurements (age >18 years) have been done from
February 2005 to February 2009. The present MID sensitivity (~0.8g) depends
mainly on the error of the background signal calculation.
27
 Theiron overload of each patient has been calculated from the difference
between the measured signal and the background signal, assuming that the
effective magnetic moment of the iron present inside the alive liver is 4
Bohr magneton.

The model to calculate the background signal has been calibrated

measuring 84 healthy volunteers and checked with the same data set by the
leave one out technique. The standard deviation of the distribution of the
differences, between the magnetization and the background signals is
0.8 g.
The leave one out technique calculates the model parameters using the data set of
83 volunteers and, by this model, the background signal of the removed volunteer.
The procedure is repeated 84 times, each time leaving a different volunteer out.

The reproducibility of the iron overload of the same patients is better

than 0.5 g. It has been assessed measuring the same patients within a lapse of time of one
or two weeks.

28
(A) The LIC in dry tissue obtained from 26 liver biopsies is correlated
with the LIC in wet tissue calculated by the iron overload measured by
MID (R =0.62).
(B) Bland Altman plot showing the differences between MID-LIC and
biopsy. The wet-to-dry conversion factor of 5.8 was used to convert
the LIC measured by biopsy in mg/gww. 29
The liver biopsy is not required to calibrate the MID.

We obtain the iron concentration in the wet tissue dividing the MID measurement
by the weight of the liver and adding the basal iron concentration (0.3 mg/gww) of the
healthy liver. However, this procedure over-estimates the LIC in patients with a liver
enlargement. 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

30
 SQUID Susceptometer

R. Fisher, E. Eich, R.
Engelhardt, H. C.
Heinrich, M. Kessler
and P. Nielsen, The
calibration problem
in liver iron
susceptometry in
Advances in
biomagnetism, S.J.
Williamson et al. ,
Ed. New York, 1990,
pp. 501504.

31
 SQUID susceptometer

The geometry of SQUID susceptometr renders the measurements mostly

dependent on the magnetic properties of few centimeters of tissues
immediately below the abdominal wall [10]. In the reference [5] we read
In effect, the susceptometer provides an automated magnetic biopsy
of 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 modification
of the magnetic field, the absolute change of the magnetic field flux, produced by
the human body and threaded with the pickup, is equivalent to millions of
magnetic flux quantum (2.07 1015 Wb), so it is not necessary using the SQUID to
detect 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), 818-823
7. Brittenham GM et al. (1982) N. Eng. J. Med. 307, 1671-1675
8. Paulson DN et al. (1991) IEEE Trans. on Magnetics. 27(2), 3249-3252
9. Nielsen P et al. (1995) Br.J.Haemat. 91, 827-833
10. Fisher R. et al (1989) In: Advances in Biomagnetism, eds. Williamson S.J. et al. (Plenum Press, New
York), pp. 501-504
32
11. Brittenham GM et al. (2001) Semin Hematol 38 (suppl1):37.56.
(A) The LIC in wet tissue of 50 patients (64 measurements) measured by the SQUID
and the MID susceptometers (R =0.79).
(B) Bland Altman plot showing the differences between LIC measured by MID and
SQUID susceptometers.
33
(A) 666 blood serum-ferritin (BSF) concentration tests are compared with the LIC in
wet 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 the
R2* value measured by the MRI on the same patients.
34
MID 2 with CE stamp

35
36
 BOTTIGLIETTA con 0.5 L di LCW
in un angolo della bacinella (8L Fisiologica)
2

-2

Magnetization Signal

PKI Segnale (V)

-4

-6

-8

-10

-12
BOTTIGLIETTA LCW
SOLO BACINELLA FISIOLOGICA
-14
-16 -12 -8 -4 0 4 8 12 16
Posizione Asse X (cm)

B001 PKI Segnale B002 PKI Segnale

B001 PKI C90 B002 PKI C90

37
 SQUID Susceptometer

R. Fisher, E. Eich, R.
Engelhardt, H. C.
Heinrich, M. Kessler
and P. Nielsen, The
calibration problem
in liver iron
susceptometry in
Advances in
biomagnetism, S.J.
Williamson et al. ,
Ed. New York, 1990,
pp. 501504.

38
 SQUID susceptometer

The geometry of SQUID susceptometr renders the measurements mostly

dependent on the magnetic properties of few centimeters of tissues
immediately below the abdominal wall [10]. In the reference [5] we read
In effect, the susceptometer provides an automated magnetic biopsy
of 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 modification
of the magnetic field, the absolute change of the magnetic field flux, produced by
the human body and threaded with the pickup, is equivalent to millions of
magnetic flux quantum (2.07 1015 Wb), so it is not necessary using the SQUID to
detect 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), 818-823
7. Brittenham GM et al. (1982) N. Eng. J. Med. 307, 1671-1675
8. Paulson DN et al. (1991) IEEE Trans. on Magnetics. 27(2), 3249-3252
9. Nielsen P et al. (1995) Br.J.Haemat. 91, 827-833
10. Fisher R. et al (1989) In: Advances in Biomagnetism, eds. Williamson S.J. et al. (Plenum Press, New
York), pp. 501-504
39
11. Brittenham GM et al. (2001) Semin Hematol 38 (suppl1):37.56.
 Method Measurement Unit Limits and
Source of Errors
BIOPSY Local iron mg/g dry tissue Invasive
The measurement depends on the local distribution of
concentration in dry the iron in the liver
tissues obtained from The result of the analysis depends on the treatment of
chemical analysis of the sample before its exsiccation: the wet-to-dry ratio
depends on the treatment of the sample before its
essicated sample analysis

SQUID Local iron mg/g wet tissue Non-invasive

The measurement depends on the local distribution of
concentrationin in wet the iron in the liver (magnetic biopsy)
tissues The iron concentration is obtained by comparing the
human tissues with water

MRI Local iron mg/g dry tissue Non-invasive

It measures the decreasing of proton transverse
concentration in dry relaxation in the presence of iron. The result of the
tissues measurement 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 (dry
tissue) is performed using a calibration curve. The
biopsy is needed to construct the calibration curve.

MID Iron overload within g wet tissue Non-invasive

the whole liver region
The iron overload in the whole liver region is
obtained 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 contribution
of 1 g of iron evenly distributed in the patient liver.
The basal signal is obtained from the patient
anthropometric characteristics and the magnetic
signal of a population of healthy volunteers.
Liver biopsy is not required to calibrate the MID.