The evaluation of portal circulation is essential to afull understanding of the pathological conditions invarious liver diseases, and will allow more reasonabletreatment of patients with portal hypertension. In orderto study portal circulation, there have been many clinicalreports by per-rectum administration of radioactivetracers such as Na-24 (1 ), Na 131@ (2,3), Xe-i 33 (4),

99mTcO@(5), and ‘3NH@(6). However, none of thesetechniques has been widely applied routinely, becausemost of the radioactive tracers absorbed from the rectal

lumen pass rapidly through the liver and do not remain

there. This common biological behavior makes it corn

ReceivedApril 9, 1982;June23, 1982.For reprints contact: Norihisa Tonami, MD, Dept. of Nucl. Med.,

Schoolof Medicine,KanazawaUniv.,Takara-machiI 3-1, KanazawaCity 920,Japan.

plicated and difficult to obtain useful indices for theevaluation of a portal-to-systemic shunt.

While we have designed new clinical applications fortumor imaging using Tl-201 chloride (7,8), we understood that Tl-201 might be mainly distributed in itsinitial passage to a tumor according to the local bloodflow and the cell viability. Consequently, we thought thatifTl-20l is similarly subject to hepatic uptake, Tl-201might be an appropriate tracer to evaluate the rectumto-hepatic vascular pathways when given rectally.

This paper will present images of the liver and otherorgans by this new technique, using Tl-20l chloride innormal controls, in patients with hepatic cirrhosis withportal-systemic shunt, and in patients with other hepatocellular damage. The clinical results of the data areanalyzed for the evaluation of portal-systemic shunt invarious liver diseases.

965Volume 23, Number 11

A Noninvasive Method for Evaluating Portal Circulation by Administration of

11-201 per Rectum

Norihisa Tonami, Kenichi Nakajima, Kinichi Hisada, Nobuyoshi Tanaka, and Kenichi Kobayashi

Kanazawa University, Kanazawa, Japan

A newmethodforevaluatingportalsystemiccirculationbyadministrationofTI201 per rectumwas performedin 13 controlsubjectsand in 65 patIentswith vanous livendiseases. In normal controls,the liver was visualizedon the 0-5-mmimage whereas the imagesof other organssuch as the heart, spleen,and lungswere very poor. In patients with livencirrhosisassociatedwith portal-systemicshunt,andin manyotherpatientswithhepatocellulandamage,the livenwas notsoclearly visualized,whereasradIoactivityIn otherorgans,especiallythe heart, became evident.The heart-to-liveruptake ratio at 20 mm after administration(H/Iratio) was significantlyhigherin liver cirrhosIsthan in normalsand patientswithchronichepatitis(p

locationof ROlPatient

@cirrhosisPatient

2chronichepatitisPatient

3chronichepatitisPatient

4nonnalROI-2L310.220.140.17R0I-31.150.230.130.15R0I-41.000.230.140.23R0I-51.240.130.290.29R0I-61.180.180.@80.224

ROIswithoutR0I-5mean

1.16S.D. 0I3C.Y. 0.110.22

0.020.100.15

0.020.140.19

0.040.20

TONAMI, NAKAJIMA, HISADA, TANAKA, AND KOBAYASHI

lung. Each such ROI contains about 100 points (onepoint = 5.2 mm X 5.2 mm). Areas of these ROIs were

normalized. We then obtained time-activity curves ineach normalized ROI, and time-ratio curves for heartto liver, spleen to liver, and lung to liver. In this study,however, we used the heart-to-liver ratios at 20 mm(H/L ratio) after administration to evaluate the degreeof portal-systemic shunt. A background correction wasnot made since backgrounds in this study result mainlyfrom collateral circulation, and it is very difficult to estimate the backgrounds over the liver and heart, whichmight be quite different in the ROIs of the two organs.In patients showing very low Tl-201 activity in the livereven at 20—25mm, a liver scan with 0.2 mCi (7.4 MBq)of Tc-99m Sn colloid was performed before moving thepatient, to locate the liver precisely.

We first investigated whether an H/L ratio can beaffected by the selection of the ROI on the liver. In fourpatients, ROIs were placed on the liver at five different

areas: the lower part of the right lobe, the upper part ofthe right lobe, the middle part of the liver, the left lobe,and the whole liver. Since the results suggested that, ifone avoided the left lobe, the choice of ROt would makelittle difference to the H/L ratio (Table 2), we chose themiddle of the liver for our standard ROI. H/L ratios in21 of 23 patients with liver cirrhosis were investigatedat each state of esophageal varicosity, based on fiberoptic endoscopy. Two other patients were not included

here because endoscopy was not performed. Also H/Lratios were compared with the results of indocyaninegreen retention at I 5 mm (ICG), performed in 42 pa

tients with various diseases. To test for difference between the mean values, student's t-test was used. Correlations were assessed by standard linear regression.Results were considered significant when p

to 2fl MIN

CLINICAL SCIENCESDIAGNOSTIC NUCLEAR MEDICINE

@RATlO(20MlN)@(20MlN)0.13

2€

IC

ib 2b MINFIG.3. Time-ratiocurveforheartto liverinsamecontrolpatient.Curvebecomesrelativelyconstantbetween10and25 mm.H/L ratiointhiscontrolIs0.13.

heart-to-liver ratio curve became nearly constant afterabout 10 mm and held there up to 25 mm. (Fig. 3).Similarly constant time-ratio curves were observed inevery patient. In contrast to the normal controls, in mostof the patients with liver cirrhosis associated with portalsystemic shunt, liver activity was low and did not increase

much with time, whereas activity was seen in the heart,lungs, spleen, and stomach, probably related to collateralcirculation. The patients with portal-systemic shuntshowed prominent changes ofTl-20l distribution, clearlydifferent from the findings in normal controls (Fig. 4).As a matter of course, the activities of the heart, spleen,and lung increase rapidly with time (Fig. 5). A typical

.@.:;.@ .-

-..,@

SF'LEEH

1o@cii:

01'

HEART LUHG

ciiiFIG. 4. Sequentialscintigramsafteradministrationperrectumof0.5 mCi Tl-201 In a 65-year-oldwomanwith livercirrhosiswithportal-systemicshunt.Liver cannot be clearly visualized,whereasother organs such as heart, lungs,spleen, and stomach were observed, probablydue to collateral circulation.

967Volume 23, Number 11

5u-.1o,

1@:!@1..1@5—15' 15@.2O'

2O@-25'FIG. 1. SequentIalscintigramsafteradministrationperrectumof0.5 mCiTl-201 ina 66-year-oldmanwithoutliverdisease.LiverIsobservedon 0-5-mm imageand becomesclearer with time,whereas other organsare very faint even on the 20—25-mmimage.

RESULTS

In the normal controls the liver was visualized on the0- to 5-mm image and became clearer with time, whilethe accumulations in other organs (heart, spleen, andlung) were very small even on the 20—25-mmimage with0.5 mCi Tl-201 (Fig. 1). Time-activity curves for thenormalized ROIs in each organ showed that the liveractivity increased rapidly with time, but the activities ofother organs increased much more slowly (Fig. 2). The

lb 2IMIN 1@ @MIN

FIG.2. @flme-actMtycurves in from normalizedROisof liver, heart,spleen,andlungincontrolof Fig.1.Liveractivftyincreasesrapidlywith time. whereasactivities of other organs Increasemuch moreslowly.

@s..$. N. M•anI s.d.@ 0.5 1.0 1.5H/LNormal

13 o.ietO.Oi..Cirrhosis

23 0.92±0.40I

S I

.@ . . .@ . . . . .. . .. ..cwrtio.I.e

hspatoma 9 O.78t0.25,@

I I•• @. • •..Clwonêc

hepatitis 14 0.25±0.17I

I @—@-I4@ •IAcuta

bep•t$tIs 9 0.43*0.31II I

•‘ I I S • •.ISubacuti

hepatitis 2 0.89*0.090.74

tO.30@;

@Hsp•tlc

m.t@t•sis 4 0.72 tO.20,I I

I I IIHspItoms

Scbvhosls I 0.83I

TONAMI, NAKAJIMA, HISADA. TANAKA, AND KOBAYASHI

LI'IER SPLEEN

801

701C01

40@301

3o@

901

tCi4

401

.?I3(

101CH I

90(

_________________‘.H‘ui 2bMIN

aos: HEHPT ,@J €;@LP LUNG;-o':@t;øC@ 6o@50E @—@‘

V ___CH? ____________ CH@ ____________1@ 2@MIN 1@ 2bM1N

FIG.5. TIme-activitycurvein normalizedROIsof liver,heart,spleen,and lung In patient of Fig. 4. Activities In heart, spleen, and lungIncrease rapidly with time.

curve for the heart-to-liverratio leveledoff at 1.4 after10 mm (Fig. 6); the mean value for normal controls was0.16 (Table 3).

In the patients with liver cirrhosis without esophagealvarices, liver activity was evident and became clearer

with time, while activities of other organs were lowerrelative to those in the patients with esophageal varices.Among the cirrhotics without varices, the highest H/Lratio was 0.49; the images (0.5 mCi Tl-20l) are shown

in Fig. 7. In other patients with hepatocellular damageshowing abnormally high H/L ratios, Tl-201 images

10 2@MIN

RATIO(2OMIN) 1.40

I ciL@1

ib @:b MINFIG. 6. Time-ratIocurvefor heartto liverInsamepatient.Curvebecomes constant between 10 and 25 mm. H/L ratio Is 1.40.

were similar to those of the patients with liver cirrhosisassociated with portal-systemic shunt. However, imagequality was somewhat different in each patient, sinceTl-20l activity can be affected by the absorption ratefrom the rectum and also by the dosage. Sample imagesare shown in Fig. 8 (cirrhosis, Stage 3 esoph. var., 0.5mCi Tl-201, H/L = 0.96); Fig. 9 (acute hepatitis, 0.5mCi, H/L = 0.87); and Fig. 10 (subacute hepatitis, 2mCi, H/L = 0.93). In the six patients who were given0.5- and 2-mCi doses ofTl-201 2 to 4 wk apart, the H/Lratios correlated well (r 0.98, p

CLINICAL SCIENCESDIAGNOSTIC NUCLEAR MEDICINE

FIG.9. SequentIalscintigramsafter administrationper rectum of0.5 mCiTl-201 ina 69-year-oldmanwithacutehepatitis.Liverisnot seenclearly,whereascardiacactivity becomesevident(arrow).Spleen is not visible. H/L ratio was 0.87.

FIG. 7. SequentIalscintigramsafteradministrationperrectumof0.5 mCiTI-201 Ina 35-year-oldmanwithlivercirrhosisnotassodated with esophageal varices. Livar Is visible but activities of heartand other organs are low. H/L ratio in this patient was 0.49.

higher than normal (p

H/L2.0

C.)EI0d i.oI-

0c;i

I-

Esophagealvarices N. Maan±s.d.0 0.5 1:0 1.5H/LAbsent

40.32±0.19IIStagel

3 0.71±0.10I IIStage

U 6 1.03±0.36cc I I IIStagelIl

8 1.21±0.20I II I I I I I

TONAMI. NAKAJIMA, HISADA, TANAKA. AND KOBAYASHI

ICG(%)

50

25

N:6Y:0.7 5X'O. I 0r:0.98

1.0 2.0Tl-201 2.0 mCI H/L

FIG. 11. Relationof H/L ratiosbetweendosesof 0.5 mCiand2.0mCi of Tl-201 chloride.

nificantdifferencebetweenstages1and 3 (p

CLINICAL SCIENCESDIAGNOSTIC NUCLEAR MEDICINE

evaluate the portal systemic circulation. Newman andCohen (JO) reported that “therectum-to-lung time―required to detect intrarectally administered ether in a

patient's expired air was longer in patients with cirrhosisthan in normal subjects. However, Giges (1 1) andWaldstein (12) indicated that this method did notdemonstrate a significant difference in portal circulation

time between normal subjects and patients with livercirrhosis. Deterling et al. (1) described a test of portalcirculation time using the appearance of radioactivity

over the brachial artery after administrating Na-24rectally. Castell et al. (4) presented a method usingXe- 133 given rectally with monitoring of radioactivityover the precordium. In this method the portal circulation time was estimated “visually―from the initialtracing or calculated from a semilogarithmic plot ofprecordial radioactivity against time. The slope of appearance of precordial radioactivity was also obtained.However, these findings can vary with the availabilityof absorbing areas from the rectum. Xenon-l 33 diffuseseasily into the descending or transverse colon as well asthe lower part of the rectum, making it difficult to establish the circulation route. Blondheim et al. (2) monitored the time-activity curve over the liver after administering radioiodine rectally and evaluated portal

hypertension by the shape and equilibration of the curveobtained. This equilibration over the liver is achievedafter I- 131 absorbed from the rectum has circulatedseveral times through the portal and systemic circulations and the analysis of the curve is therefore complicated and difficult. To overcome this shortcoming, Kuroki et al. (5) used [99mTc]pertechne@te as a radiotracerand obtained a relatively useful index of the liver-to

heart uptake ratio from the initial rising slope. Technetium-99m has very good physical characteristics forimaging and thus can provide visual information ofportal systemic circulation. However, since the mainfactor affecting the rise of radioactivity over the liver isdifferent in each disease (e.g., liver flow from portal veinin patients without portal hypertension vs. liver flow fromsystemic circulation in patients with portal hypertension), this index is not strictly reliable.

Caride (13) studied the dynamics of rectal absorptionof pertechnetate in dogs and concluded that pertechnetate is not the ideal tracer for studying portal circulationusing rectal entry, because a significant amount of radioactivity remains in the abdominal area followingadministration and induces considerable error. Nitro

gen-l 3 ammonia has been also applied to such studies(6). This radiotracer can accumulate in the liver as wellas the heart and stays for a while, thus affording a relatively good index of the heart-to-liver uptake ratio for

evaluation of the portal circulation. Its disadvantage isthat a cyclotron must be near the hospital for clinical use,so it is not widely suitable for routine study. An idealradioactive tracer for studying portal circulation by

rectal administration has to be rapidly absorbed and toaccumulate in each organ according to its blood flow,preferably without recirculation. The main advantageof Tl-201 over the other radiotracers studied is thecomparatively prolonged cellular retention of thallium,as is seen in myocardial imaging. Bradley-Moore et al.(14) reported the tissue distribution ofTl-201 given intravenously in goats, in which the greatest concentrationis in the kidneys, heart, and liver; the concentration remains high in these organs for at least the first two hours.This characteristic of Tl-20 1 makes possible a reliableindex of portal-systemic shunt, such as the H/L ratio inour study. From this point ofview, Tl-201 chloride seemsto be a reasonable tracer.

One of the problems with Tl-20l is the influence ofradioactivity distributed to the liver through the hepaticartery. It arises because Tl-20l is partly cleared from theliver through hepatic veins and some enters into thesystemic circulation through various collaterals. Ac

cording to the study of the biological behavior of Tl-20l

by Bradley-Moore et at. (14), the heart-to-liver uptakeratio is I .6 at 25 mm after intravenous injection. Thismeansthat thedistributionofTl-201throughthe hepaticartery should be considered in patients with portal-systemic shunt, and the H/L ratio calculated in our studymay be higher than the real one. However, the H/L ratiomay also be raised by decreased Tl-201 accumulationin the injured liver cells of patients with various hepaticdiseases. Although the real condition is uncertain, thereseem to be opposing errors in patients with hepatic disease. Another problem is the variation of myocardialuptake of Tl-20l between patients, which should beconsidered in those with heart disease. There is also apossibility that other diseases may affect Tl-20l distribution.

In ourstudy,the meanH/L ratio wassignificantlyhigher than normal in liver cirrhosis and in chronichepatitis. The cirrhotic patients with esophageal varicesshowed a significantly higher H/L ratio compared withthat in patients without esophageal varices, and therewas a significant difference between Stages 1 and 3 of

the endoscopy findings. In spite of some problems, then,this technique seems quite useful in evaluating noninvasively the degrees of portal-systemic shunt. However,the effects of hepatocellular damage on liver uptake ofTl-201 should be considered, since there was relativelygood correlation between the H/L ratio and ICG, andthe high ratios found in cirrhosis also occurred in threeof nine patients with acute hepatitis, two of two withsubacute hepatitis, three of three with biliary cirrhosis,four of four with hepatic metastases, and in one case ofprimary hepatoma without cirrhosis. It can be said thatthe H/L ratio is the result of portal blood flow and hepatic cell viability, assuming a normal myocardial uptake. Since there were many cirrhotic patients showingTl-201 images similar to those in patients with hepato

Volume 23, Number 11 971

TONAMI, NAKAJIMA, HISADA. TANAKA, AND KOBAYASHI

cellular damage and high H/L ratios, it seems to bedifficult to separate them on the Tl-201 images. Insubacute hepatitis and metastatic liver cancer, we assume that intrahepatic shunt formation may also accountfor the high H/L ratio. Although all ofthe patients withmetastatic liver cancer showed clear focal defects on the

Tc-99m Sn colloid liver scans, high H/L ratio in thesepatients indicates that this method may also have auseful diagnostic value to suggest the presence of diffusesmall metastatic livertumors. In the comparisonstudyregarding H/L ratio between the use ofO.5 mCi and 2.0mCi of Tl-20l chloride, the dosage of 0.5 mCi gave asatisfactory result. This encourages us to perform this

method routinely with less expense in patients withvarious liver diseases.

ACKNOWLEDGMENTS

We wish to thank Mr. M. Matsudaira, M. Yamada, H. Tsujii, andY. Kurata for their technicalassistanceandNihon Medi.-PhysicsCo.,Ltd., for kindly supplying the radionuclide.

REFERENCES

I . DETERLING RA, POWERS SR. BHONSLAY SB: The use ofradioactive sodium in the determination of patency of portacaval shunts. SurgForum 5:193-200, 1954

2. BLONDHEIM SH, BEN-PORATH M, BEN IsHAI Z, et at:Concentrationof rectally administeredradio-iodinein thecirrhotic liver: Preliminary report. Isr Med J 17:222—224,1958

3. LEWITUSZ, LAORJ: Thediagnosisof portalhypertensionwithl'31.JMedSciIsr4:41-46, 1968

4. CASTELLDO, GRACEND, WENNAR MH, et al: Evaluationof portal circulation in hepatic cirrhosis.A newmethodusing‘33Xe.Gastroenterology57:533—541,1969

5. KUROKI T, KIM K, KOBAYASHI K, et at: Study of portalcirculation with per-rectal portal scintigraphy. J Nuci Med(Jpn) 13:354, 1976 (abst)

6. HAZENBERG HJA, GIPS CH, BEEKHUISH, et al: Rectaladministration of 13N-ammonia in cirrhosis of the liver. AdaHepalo-Gastroenterol 23:308—318, 1976

7. TONAMIN, HISADAK:Clinicalexperienceoftumorimagingwith 201T1-Chtoride.C/in Nudi Med 2:75—81,1977

8. TONAMI N, HISADA K: 201T1scintigraphy in postoperativedetection of thyroid cancer: A comparative study with 1311Radiology136:461-464,1980

9. Report from the Japanesecommittee of the study for portalsurgery: Decision criteria of fiberoptic endoscopy findings inesophageal varices. Ada Hepatologica Japonica 17:566-568,1976

10. NEWMAN HF, COHEN IB: Estimation of the portal circulation time in man. J Lab C/in Med 34:674-676, 1949

I I. GIGES B, TESCHAN PE: The portal circulation time in cirrhosisofthe liverfollowingportacavalanastomosis.J LabC/inMed 40:537-540,1952

12. WALDSTEINSS,FORSYTHBT,JAHNKEEJ:An evaluationof the rectum-to-lung ether time test in shunt operations forportal hypertension and in liver disease. Gastroenterology26:781—788,1954

13. CARIDE Vi: Rectal absorptionof99mTc@pertechnetatein thedog.JNuclMed 14:600-603, 1973

14. BRADLEY-MOOREPR, LEBOWITZE, GREENEMW, et al:Thallium-201 for medicaluseII: Biological behavior.J NudiMed 16:156-160,1975

972 THE JOURNAL OF NUCLEAR MEDICINE

George Simon Memorial Fellowship AwardThe Fourth Annual George Simon Memorial Fellowship Award, given by the Fleischner Society for the best submittedworkrelatingto the imagingofthe respiratorysystem,hasbeengivento H. DirkSostmanof Yale Universityforhispaper“ExperimentalStudies with “IndiumLabeled Platelets in Pulmonary Embolism.―

Entries for the Fifth George Simon Award are now being accepted. The paper can represent the work of more than oneinvestigator, but the senior author should be the applicant and responsible for the majority of the work. Applicants shouldbe no olderthan 40 years. Paperswhichhave been publishedor submittedelsewhereare noteligible.The awardconsists of an all-expense-paid trip to the 1983 Fleischner Society Meeting, New York City in May, plus a cash prize. Allsubmissions must be in the form of a complete scientific paper, not longer than 25 pages (double spaced) and shouldbe sent in triplicate to:

Richard H. Greenspan, MDDept. of DiagnosticRadiology

Yale UniversitySchoolof Medicine333 CedarStreet

New Haven, CT 06510

Papers must be sent on or before January 1, 1983