John M. Gomoni, MD Liora Komnreich, MD Joseph Ben-Meir, PhD Eliezer A. Rachmilewitz,

Hepatic Quantitative

a a

Gadi Homey, MD a Hannah Tamary, MD a Judith Zandback, MD Rina Zaizov, MD #{149} Enrique Freud, MD a Oliver Krief, MD a #{149} Haim Rotem, MSc #{149} Mario Kuspet, PhD a Phillip Rosen, PhD MD #{149}Elia Loewenthal, PhD #{149} Raphael Gorodetsky, PhD

Iron

terms:

Anemia,

eases,

761.594,

761.652

761.652

Liver,

a

ic resonance

#{149} Liver,

MR studies,

(MR),

Radiology

761.652

1991;

Liver,

a

iron

T

HE regular and frequent administration of med blood cell transfusions to patients with /3-thalassemia major has prolonged survival and eliminated the consequences of the severe anemia. However, the price of this therapeutic gain has been the exacerbation of the difficult problem of tissue iron overload. Excessive iron deposition occurs in sideroblastic and other anemias, idiopathic hemochnomatosis, and dietary iron overload. In many of these cases, the iron is metamed mainly in the parenchymal tissues. In /3-thalassemia and in other cases of transfusional iron load, a greaten proportion of iron is retained in the neticuloendothelial system, concurrently with the more hazardous parenchymal deposits. The transition from iron deposition in the melatively benign neticuloendothelial system to the parenchyma has not been thoroughly studied. The parenchymal iron deposits lead to damage of the heart, endocrine glands, and liven (1). The ability to determine accurately the iron stones of an individual organ and the total iron burden in each patient would help to relate the iron deposition to the clinical manifestations and to evaluate chelation therapy regimens. The detection of iron overload has been difficult. Hemosidenin and fermitin, the iron storage proteins, are mostly intracellular. An increased serum femnitin concentration is usually regarded as a crude parametem indicating increased total body iron. However, it may also me-

dis-

content,

761.1214

comparative

a

Magnet-

studies

179:367-369

flect inflammation or hepatic damage (2). Presently, the most accepted way to estimate total body iron overload is the direct evaluation of hepatic iron concentration by needle biopsy. These measurements correlate with the total amount of blood transfused, and the pathologic examination of the biopsy specimens indicates the severity of the subsequent hepatic fibrosis (3). However, this invasive procedure cannot be repeated for the routine follow-up of the iron ovenload in these patients. Other methods proposed for the assessment of body iron load include hepatic computed tomogmaphic (CT) attenuation measurements (attenuation coefficient) (4-6), bulk magnetic susceptibility (7), nuclear resonance scattering of gamma nays (8,9), and noninvasive evaluation of skin iron by means of diagnostic x-ray fluonescence spectrometry (iO,1 1). It has been shown that in vitro hepatic 1 /T2 measurements made by means of magnetic resonance (MR) imaging or nuclear MR spectroscopy correlate well with liver iron content in iron-overloaded experimental animals (12,13). The purpose of the present study was to assess in vivo 1/ T2 measurements obtained by means of MR imaging as a measure of liver iron content in hemosiderotic patients and compare them with hepatic CT attenuation measurements.

MATERIALS Ten mia

I

From

the

Departments

of Radiology

(EAR.),

Hadassah

University

Pediatric Surgery

Radiology (G.H., L.K.), (E.F.), Beilinson Medical

Hospital, Pediatric Center,

(J.M.G.,

O.K.),

Oncology

(EL.,

P0

12000,

Jerusalem

91120,

Box

Hematology-Oncology Petach Tikva, Israel;

HR., M.K., P.R.). Received September 28, 1990; revision February 7, 1991; accepted February 12. R.G. supported grant. Address reprint requests to J.M.G. (. RSNA, 1991 See

also

this issue.

the

article

by

Siegelman

a

Overload: MR Imaging’

Iron deposits demonstrate characteristically shortened T2 relaxation times. Several previously published studies reported poor correlation between the in vivo hepatic 1/T2 measurements made by means of midfield magnetic resonance (MR) units and the hepatic iron content of iron-overloaded patients. In this study, the authors assessed the use of in vivo 1/T2 measurements obtamed by means of MR imaging at 0.5 T using short echo times (13.4 and 30 msec) and single-echo sequences as well as computed tomographic (CT) attenuation as a measure of liver iron concentration in 10 severely iron-overloaded patients with $-thalassemia major. The iron concentrations in surgical wedge biopsy samples of the liver, which varied between 3 and 9 mg/g of wet weight (normal, 0.5 mg/g), comelated well (r .93, P .0001) with the preoperative in vivo hepatic 1/ T2 measurements. The CT attenuation did not correlate with liver iron concentration. Quantitative MR imaging is a readily available noninvasive method for the assessment of hepatic iron concentration in ironoverloaded patients, reducing the need for needle biopsies of the liver. Index

a

et a! (pp

361-366)

and

R.G.), Israel;

(H.T., Elscint

R.Z.), Ltd.

requested November by a Hadassah Research

and

the

editorial

by

Stark

and

Hematology

the

Departments

of

Pathology (J.Z.). and Haifa, Israel (J.B.M., 9; revision received and Development

(pp

333-335)

AND

METHODS

transfusion-dependent

major

patients

scheduled

for

creased

transfusion

mL/kg/y), All the

were patients

aged

/3-thalasse9-20

splenectomy

years, because

requirements included in were imaged

of in-

(>250 this by

study. means

MR and CT preoperatively. Since 1982, we have given subcutaneously administemed deferoxamine (Desfemioxamine, Ciba-Geigy, Basel, Switzerland) (140 mg/

in

Abbreviation:

TE

=

echo

time.

of

kg per night) age of 4 years. piiance

to all patients reaching However, the overall

with

treatment

case,

a surgical

from

the

of the

inferior

liver

is poor.

wedge

the

after

surgery.

liver

The

unprocessed

the

direct

their examiwithin 24

content

was

assayed

measurement

concentrations

sues and in vitro,

for the analysis as previously

tissue matic,

The

samples gauze,

of major

trace-

in superficial

tis-

of tissue described

elements

are excited low-energy

samples in detail

examined

by a focused, x-ray beam.

in the monochmoThe char-

actemistic x-ray fluorescence are detected concurrently

energy with the

of the

incident

beam,

serves

as an internal

normal

excitation

mg/g of wet weight or less. MR imaging was performed Gyrex (Elscint, Haifa, Israel) images

repetition

were

time

times separate tion,

images

msec with echo after 18.4 msec dient

and

were

after

the

a C

with

and

a

0;

echo

a

in two In addi-

echo.

of

The

sinc lobes

suppression

pulse of the was

complete

tance from the section section thickness. The tamed

with

phase

14.4

Fe

1 /T2 and assuming upper hepatic chymal CT

regions

(E!scint) 10-mm kV,

35-cm

in the

and

breathhold).

sumements

were

(normal

the

liver

is 40-80

sections

that

HU)

to

regions

of

lobe away hila and were

normalized for each 0.9% sodium chlo-

was

simultaneously

concentrations were compared

Radiology

mea-

at three

homogeneous hepatic

X 340

time

attenuation

They were with a standard

lated 1 /T2 and CT attenuation

a

acquisition

in the right nonparenchymal

ride solution scanned. The iron specimens

340

CT

in three

1-cm-square

averaged. section

of view,

2-second

made

interest from

The parameters thickness, 350 mAs,

field

(single

368

decay,

of interest

imager. section

matrix,

five

calculated,

1 /T2* values measurements.

of the surgical with the ca!cu-

and

with

the

analysis-that significance with

.05 for the upper .66 and P .04 for

is, correlations tests-was

SPSS/PC+

software

10000

Biopsy

(igIg)

liver

iron

content

the CT

(r

.62 and

segment the lower

and seg-

r

ment).

Chicago).

The results of the MR imaging and CT measurements and the liven iron concentrations in the 10 patients studied are presented in the table. The iron content of the hepatic biopsy specimens correlated well with the 1 /T2 and 1 /T2* of both the supenor and inferior portions of the night hepatic lobe. The correlation was best with the i/T2 of the lower segment (near the biopsy site); the correlation coefficient r was .93 (P .0001) (Figure), leading to the following equation: hepatic iron concentration = [a 1 /T2] + b, where a 46 g - sec /g ± 7, b = 400 g - sec/g ± 900, and the iron is in micrograms per gram (wet weight) and 1 /T2 in seconds ‘. Generally, the 1 /12* values were approximately four times the 1 /T2 values. But, the 1 /T2* values were noisier and had a worse correlation with

Iron

biopsy sample from the lower segment of the right heof wet weight versus the 1 /T2 (a) and 1 /T2* (b) values of the right hepatic lobe. The 1 /T2 versus iron content meof the right hepatic lobe is shown in a.

RESULTS

Elscint).

and lower segments of the right lobe, away from the nonpamenhila. images were obtained on an Excel

1800 were 120

performed

(SPSS,

5000



Liver

b.

Statistical with two-tailed

of This



(gIg)

a.

at a dis-

option;

values were monoexponential

in i-cm-square

Iron

Plots of liver iron concentration in patic lobe in micrograms per gram the lower and higher segments of gression line of the lower segment

cycle-dependent

(Freeze

1 /T2* simple

Liver

edge of 30% of the images were ob-

respiratory

encoding

0

10000

field

with suppression section profile.

almost

a

#{176}

I-

a

of view was 30 or 35 cm, the acquisition matrix was 200 X 256, and two excitations were performed. The section thickness was 10 mm with a 3- or 5-mm intersection gap. The sections were excited with a modified the side

500

-J

at a TE

spin

C

C

The is 0.5

a i-msec delay of the gradient the spin echo and at a TE of with a 5-msec delay of the gra-

echo

a

Lower

#{176}

on a 0.5-T imager. Axial

30 msec sequences.

obtained

i-

which

obtained

of 500 msec

(TEs) of 13.4 single-echo

1000

lines scatter

calibration (ii). liver iron content

nonheme

spin-echo

in

by means of diagnostic a method designed

element

(10,11,14).

lobe dur-

iron

samples

nondestructively x-ray spectrometmy,

right

obtained

and kept on ice until which was performed

the

for

sample

of

g) was

ing the splenectomy. The were placed on saline-soaked sealed, nation, hours

In each

biopsy

portion

(0.5-1.5

the corn-

P

There was liven iron attenuation

no correlation concentrations measurements.

between and the

DISCUSSION In the tients

follow-up

with

of thalassemic

severe

of other iron-overloaded iron level in needle of the liver has been

major

indicator

overload. sy of the not

of total

body

to

iron

routine

monitor

biop-

iron

load

that

MR

is

desirable.

In vitro

studies

imaging -

patients, the biopsy samples adopted as the

Nevertheless, liver

pa-

and

hemosidenosis

the

may

suggest

the

be

noninvasive

hepatic

iron

correlation

best

evaluation load.

We

between

imaging

of

of

in

wedge

of the liven. Reticuloendothelial nitin and its denatured

the vivo

and

surgical

for severe

examined the

measurements

content

modality

MR

the

iron

biopsy

samples

sidemin, iron.

are They

the appear

deposits form,

major

of ferhemo-

store

of body

hypointense

on

May

1991

MR

images

caused

by

due the

hemosidenin

to an

increased

magnetic

and

1 /T2

properties

fennitin

of

(12,13,15-

18). This 1 /T2 increases quadratically with field strength (below magnetic saturation) and is sensitive to the coarseness of the distribution of the hemosidenin and fennitin deposits (18). There is good in vitro comrelation between 1 /T2 measurements and iron content of hemosiderotic livers and spleens (12,13,17). Howeven, the 1 /T2 due to the iron overload in spleens is lower per equivalent iron concentration (J.M.G., H.T., and R.G., unpublished data, 1989). This may reflect a difference in the distnibution of iron deposits between the spleen and liver. Clinical evaluation of MR images

by Hemnandez

et a! (19)

showed

that

nine healthy subjects and 12 others with mild to moderate iron overload, excluding a patient with high liver iron content. They used higher magnetic field strengths and multiple

short

TEs.

Despite

the

dependence

7.

8.

of

the 1 /T2 of iron deposits on field strength, they pooled measurements obtained at 1.0 T with those obtained at 1.5 T. They obtained a slope of the iron content of the hepatic needle bi-

opsy

samples

(dry

weight)

versus

1/

T2 six times ours (we used wet weight) with a correlation of r .98. In view of the different field strengths (ours 0.5 T, theirs 1.0 and

1.5 T) and

the

difference

between

crepancy

noisy

signal.

Our

use

for

with

field

quence,

and

particular

unit

strength, MR

im-

1.

2.

3.

4.

Number

2

noisy.

previous

5.

tissue

iron

17.

18.

19.

20.

21.

(4-6).

Computed

and

J Pathol

1975;

JL, Nienhuis

AW,

tomographic

analysis

307:1671-1675. Vartsky D, Ellis K), Hull DM, et a!. Nuclear resonant scattering of gamma rays: a new technique for in vivo measurement of body iron stores. Phys Med Biol 1979; 24:680-701. Wie!opolski L, Ancona RC, Mossey RT, et a!. Nuclear resonance scattering measurement of human iron stores. Med Phys 1985; 2:401404. Zeimer R, Be!kin M, Leitersdorff E, Rachmilewitz EA. A noninvasive method for the evaluation of tissue iron deposition in betathalassemia major. J Lab Clin Med 1978; 91:24-31. Corodetsky R, Goldfarb A, Dagan I, Rachmilewitz EA. Noninvasive analysis of skin iron and zinc levels in 3-thalassemia major and intermedia. J Lab Clin Med 1985; 105:4451. Stark DD, Moseley ME, Bacon BR, et a!. Magnetic resonance imaging and spectroscopy of hepatic iron overload. Radiology 1985; 154: 137-142. Israel J, Unger E, Buetow K, Brown T, Blum-

B, London

hepatic

WT.

Correlation

and Magn

R, Sherman

MA.

16.

The

studies

concentration

fibrosis in thalassemia. 95. Long JA, Doppman

magnetic Reson

22.

Magnetic

25.

imaging

MR.

of trans-

1990; 74:360-363.

Wismer CL, Buxton RB, Rosen BR, et a!. Susceptibility induced MR line broadening: applications to brain iron mapping. J Comput Assist Tomogr 1988; 12:259-265. Edelman RR, Johnson K, Buxton R, et a!. MR of hemorrhage: a new approach. AJNR 1986; 7:751-756. Young IR, Khenia S. Thomas DGT, et a!. Clinical magnetic susceptibility mapping of

the brain. 26.

resonance

U, Wexler

fusional hemosiderosis complicating thalassemia major. Radiology 1984; 150:767-77 1. Comori JM, Grossman RI, Goldberg HI, Zimmerman RA, Bilaniuk LT. Intracranial hematomas: imaging by high-field MR. Radiology 1985; 157:87-93. Gomori JM, Grossman RI, Drott HR. MR relaxation times and iron content of thalassemic spleens: an in-vitro study. AJR 1988; 150:567569. Gomori JM, Grossman RI. Mechanisms responsible for the MR appearance and evolution of intracranial hemorrhage. RadioGraphicy 1988; 8:427-440. Hernandez RJ, Samnaik SA, Land I, et a!. MR evaluation of liver iron overload. J Comput Assist Tomogr 1988; 12:91-94. Johnston DL, Rice L, Vick W, Hedrick TD, Rokey R. Assessment of tissue iron overload by nuclear magnetic resonance imaging. Am Med 1989; 87:40-47. Chezmar JL, Nelson RC, Malko JA, Bernardino ME. Hepatic iron overload: diagnosis and quantification by noninvasive imaging. Gastrointest Radio! 1990; 15:27-31. Kaltwasser JP, Gottschalk R, Schalk KP, Hart! W. Non-invasive quantitation of liver ironoverload by magnetic resonance imaging. Br

Haematol

24.

Y, Zagher

between resonance Imaging 1989;

11:2-6. Overmoyer Uniformity (storage)

Med

J Comput

Assist

Tomogr

1987;

BA, McLaren CE, Brittenham of liver density and nonheme iron distribution. Arch Patho!

GM. Lab

1987; 111:549-554.

116:83Mills

of beta-

thalassemia syndrome with hemochromatosis: pathologic findings with clinical and laboratory correlations. J Comput Assist Tomogr 1980; 4:159-165. Houang MT. Skalicka A, Arozena x, Huehns

ER, Shaw

a

more

Powell LW, Isselbacher KJ. Hemochromatosis. In: Braunwald E, Isse!bacher KJ, Petersdorf RC, Wilson JD, Martin JB, Fauci AS, eds. Harrison’s principles of internal medicine. New York: McCraw-Hil!, 1987; 1632-1635. Lifschits DA, Cook JD, Finch CA. A clinical evaluation of serum ferritin as an index of iron stores. N Eng! J Med 1974; 290:12131216. Ridson RA, Barry M, Flynn DN. Transfusional iron overload: the relationship be-

SR.

is necessary.

179

also

with

tween

se-

imaging

The accuracy of iron evaluation with MR imaging by means of 1/T2 measurement was also suggested recently in a communication by Kaltwasser et a! (22). They studied

Volume

ments

et a!. of hu-

1982;

15.

References

low 1evwhich

pulse

As expected, to

were

J Med

Gorodetsky R. Elevated concentrations of elements and abnormalities of neuromuscular functions in tongue muscles of Down’s syndrome. J Neurol Sci 1987; 79:315-326. Brasch RC, Wesbey CE, Gooding CA, Koerper

23.

have longer T2 relaxation times. This should be corrected by the acquisition of a sequence with a delayed echo, perhaps at a TE of 50 msec. Our data yield a calibration for the noninvasive quantitation of hepatic iron content by means of 1 /T2 measurement with our clinical MR imaging unit operating at 0.5 T. A study of the variation of the 1 /T2 of hemosideno-

tic liver

et a! (23).

JW,

measurements

N Eng!

Yarom

from

the 1 /T2* measurements proved be more sensitive to iron deposits (24,25); however, these measure-

DF, Harris

stores.

iron

14.

after

In conclusion, quantitative MR imaging is a readily available noninvasive method for the assessment of hepatic iron overload. U

of an earlier echo with a TE of 13.4 msec, and perhaps the use of singleecho sequences as well as respiratory cycle-dependent phase encoding, yielded less noisy measurements. However, our present MR imaging sequence is less sensitive els of hepatic iron overload,

of Wismer

echo

patterned

Farell

susceptibility

man

liver iron content imaging in rats. 7:629-634.

low-intensity,

that

echo

12.

GM,

Magnetic

berg

proved correlation with the liver iron content of the 1 /T2 value nearest the biopsy site suggests mild intrahepatic variation in iron content in iron-overloaded livers, unlike the uniformity observed in nonoverloaded livers (26). The lack of correlation between hepatic iron content and CT attenuation measurements is striking. We do not have an explanation for the dis-

the gradient was

spin

11.

13.

hepatic iron concentration did not correlate well with hepatic T2 measurements and correlated only poorly with the hepatic-to-muscle MR imaging intensity ratios. Their study was performed at 0.35 T with TEs of 28 and 56 msec. Johnston et a! (20) demonstrated only a qualitative comrelation with the liver-to-muscle MR imaging intensity ratios at 0.5 T with a TE of 35 msec. Similarly, Chezman et a! demonstrated no correlation with the liver T2 measurements and only a poor correlation with the liven-tomuscle intensity ratios at 0.5 T with a TE of 60 msec (21). It appears that their poor correlations were due to the relatively delayed first echo of greater than 30 msec, resulting in a

the

10.

the

dry weight and wet weight of liver samples, their results for moderate liver iron contents are compatible with ours for high liver iron loads. Our method of measuring 1 /T2*

by separating

9.

Brittenham

DC.

ed tomographic in thalassemia

Correlation

between

comput-

values and liver iron content major with iron overload. Lan-

cet 1979; 1:1322-1333. 6.

Olivieri

DJ, Rose

NF,

Crisaru

V. Freedman

D, Daneman

MH.

A, Martin

Computed

to-

mography scanning of the liver to determine efficacy of iron chelation therapy in thalassemia major. J Pediatrics 1989; 114:427-430.

Radiology

a

369

Hepatic iron overload: quantitative MR imaging.

Iron deposits demonstrate characteristically shortened T2 relaxation times. Several previously published studies reported poor correlation between the...
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