ADJUNC11VE MEDICAL KNOWLEDGE

SchillingEvaluationof PerniciousAnemia:CurrentStatus

Lionel S. Zuckier and L. Rao Chervu

Albert Einstein College of Medicine, Bronx, New York

The Schlllingexaminationremainsa popularmeansofevaluatinginvivoabsorp tion of vitaminB12.When absorptionIs abnormallylow, the test may be repeated with addition of exogenous (IF) in order to correct the IF deficiency that characterizesperniciousanemia. A dual-isotopevariationprovidesa means ofperformingbothstagesofthetestsimultaneously,therebyspeedingupthetest and reducingdependenceon complete urine collection.The dual-tracertest de pendson noexchangeof B12moietiesonthe IF molecule.in vftrostudiessuggest that thisexchangedoestake place, in a mannerdependentontime, temperature, and pH. Furthermore,in vivo studiesindicate that, when administeredsimufta neously, the absorption of unbound B12 is elevated, and IF-bound B12 is reduced, in pernicious-anemiapatients, relative to the classic two-stage examination.A numberof clinical studiesindicate significantdifficultyin resolvingclinical diag noseswith the dual-tracertest. The potentialweaknessesof the test discussed hereincanbeovercomebytemporallyseparatingtheadministrationofthetwoB12 dosesandby treatingsecondarymalabsorptionwhereit exists.Analgorfthmis of fered for selectingthe mostsuitablevariationof the Schillingtest to improvethe accuracyof test resuftsandthe ease of performance.

J Nucl Med 25: 1032—1039,1984

The Schilling examination, originally introduced in have been introduced as alternative means of measuring 1953 (1 ), remains the mainstay of in vivo evaluation of vitamin B12 absorption, they all lack the precision and vitamin B12absorption. The test, as conceived, involves ease of administration of the Schilling test (Table 1). the ingestion of a physiologic quantity of radiolabeled Nonetheless, difficulties exist in the performance of the vitamin B12, followed by administration of a pharma Schilling examination, including critical dependence on cologic parenteral flushing dose and quantification of complete urine collection and an extended period before subsequent urinary B12 excretion. When absorption of completion of the two stages of the test. For the outpa the test dose is abnormally low, the examination is re tient, the test requires multiple visits to the nuclear peated with administration of exogenous intrinsic factor medicine department, and is often handicapped by poor (IF) in an attempt to correct the IF deficiency that compliance and an incomplete study. characterizes pernicious anemia (PA) and other IF In order to circumvent many of these problems, Katz deficiency states (e.g., after ). An interval et al. (11) in 1963 introduced a dual-tracer method using of 3—7days before repeat administration is advocated vitamin B12 labeled with Co-57 and Co-60, one admin in order to avoid interference by enterohepatic circula istered free and the other bound as an IF-saturated tion of the first flushing dose. complex. Quantification was performed much as in While measurements other than urinary excretion single-tracer tests, but the amount of each form of vita mm B12 was separately assessed and the ratio of IF Forreprintscontact L. Rao Chervu,PhD, Dept. of Nuclear Mcdi bound to free vitamin excretion calculated. This allowed cine, Albert Einstein College of Medicine, Bronx, NY 10461. simultaneous measurement of B12absorption with and

1032 THE JOURNAL OF NUCLEAR MEDICINE ADJUNCTIVE MEDICAL KNOWLEDGE

TABLE1.ABSORPTiONHepatictTESTSFOREVALUATIONOFB12

uptakeStoolt countingSerums countingWhole1 bodySchilling test Duration (days) 7 7 <1 7 Quantitative no yes no yes no Accuracy ++ +++ ++ +++ Availability yes yes yes no yes Sample handling none unpleasant acceptable none acceptable

. D*xationof single-stageof thetest. t Ref. 2,3. t Ref. 4,5. §Ref.6,7. I Ref.8. . . Ref. 1,9,10.

without the influence ofexogenous IF. Bell modified the 2. Although theoretically in the DIST the B/F ratio test to its present form by substituting Co-58 for Co-60, should be independent of renal excretion and com resulting in a reduced radiation dose (12). pleteness of urine collection, these remain desirable test The dual-isotope Schilling test (DIST) offers several prerequisites, since otherwise IF-mediated improvement advantages over the classic single isotope Schilling test in B12absorption may be incompletely expressed. Fur (SIST), including shortened study time and equivalence thermore, normal patients may have reduced bound and of urine collection for the two stages of the test. Never free B12 excretion, thus giving an erroneous malab theless, the intricacies of preparing and purifying the sorption-like picture. vitamin B12-IF complex prevented widespread clinical In addition to the quantification of urinary vitamin use before introduction of a commercial version (Table B12 excretion, the dual-tracer method of evaluating 2) that offered increased convenience, acceptance, and bound and free B12absorption has also found application standardization of the technique (13,14). The kit cur in whole-body counting, in plasma absorption tests, and rently consists of two capsules of radioactive B12, one stool analyses (8,15—17). The DIST remains the most containing 0.25 sg offree Co-58-B12 (0.8 sCi), and the convenient, reliable, and popular of all these test varia second containing 0.25 @sgof Co-57-B12(0.5 jzCi) bound tions. An 8-hr serum sample is sometimes useful in to human gastric juice. conjunction with urine collection for clarification of cases In the DIST, three values are generated: percent cx with suspicion of incomplete urine collection or those cretion of IF-bound B12(bound B12),percent excretion with renal insufficiency (16). The present discussion of free B12 (free B12) and the bound-to-free (B/F) ratio, focuses on use of DIST in evaluation of PA. which serves as an index of IF deficiency. While different Our experience using the DIST (Fig. 1), along with workers have chosen varying criteria to differentiate that of others (18), has led us to conclude that there is between normal, PA, and IF-refractory , a significant incidence of nondiagnostic test values the manufacturer's suggested ranges are given in Table leading to indeterminate diagnoses. While the results from some of these cases lie between the classic malab sorption and normal regions of the graph (B/F ratios TABLE2. INTERPRETATIONOF DUAL-TRACER approximating unity), these patients may be exhibiting SCHILLINGRESULTS minor degrees of malabsorption or have had incomplete urine collection. In other instances nondiagnostic values PerniciousMalabsorp Normal anemia tion with elevated B/F ratios may reflect a physiologic “gray area―of gradation from normal to clearly deficient IF FreevitaminB12 10—40 0—7 <6 secretion (5,19—22)or may in fact represent spurious test excretlon(%) results owing to experimental difficulties (vide infra). BoundvitaminB12 10—426-12 <6 excretion (%) Bound-to-freeratio 0.7—1.3 >1.7 0.7—1.3 THEORETICAL BACKGROUND AND IN VITRO VALIDATON

. Manufacturer's suggested ranges (Amersham Corpo The inherent assumptions of the DIST are (a) that one ration,ArlingtonHeights,IL60005). of the isotopically labeled B12s is administered com pletely bound to IF without presence of free vitamin, and

Volume 25, Number 9 1033 ZUCKIER AND CHERVU

B/F RATIOvsFREE58C0-B12EXCRETION

>50@ I @ 25 I I IF-DEFICIENCY . I U MALABSORPTION @ 10 0 I NORMAL @7/Eo,. % . S I . O••lOO . I . 0 • 0 I-. •• . U-

1.3-@—@-@----,0 0b •0• 1:•r@ • —— FIG.1.Dlstrlbutlonofdual-IsotopeSchlll :ii @o •lb•• Ingtestresultsln58patlentswlth24-hr 5•8 •• • urlnevolume >750 cc (closed cWcles) and • •0 • • • 23patlentswlthurlnevolume<750cc 0 •p •• III (openclrcles)obtalnedoverlast5yearsat i• 0(1'Institution.Numberedregionsreferto <0.7liIsliliIi@,4 I I I I manufacturer'ssuggesteciranges.t..age @ 0 2 4 6 8 10 20 30 40 50 (n= 16)ofIndeterminateresults FREE58C0-B12 EXCRETION(S INGESTEDDOSE) occix withthIsmethod.

(b) that, once ingested, there is no significant exchange bound vitamin, which suggested that exchange between between the bound and free forms ofvitamin B12(23). bound and free vitamin B12was insignificant (24—26). The first requirement is met by combining a given Intrinsic factor does not bind dietary B12in the amount of IF with a surplus of B12,followed by dialysis at acid pH, but rather this binding occurs after both of the complex to remove any remaining unbound vita moieties transit into the more alkaline small bowel. mm (11,12). The validity of the second assumption was More direct and quantitative studies have since been established by studies on the relationship of IF-B12 performed to determine the physicochemical affinity binding to efficacy of IF in promoting absorption (Table between B12and IF (Table 3), with varying results. IF 3). The relative absorption of IF-bound and free B12was bound Co-60 B12was not significantly displaced by in assessed in postgastrectomy and PA patients lacking cubation for 1 hr with a fiftyfold excess of cold B12at endogenous IF, by comparing absorption of bound ra room temperature (27). At 4°C,less than 10% of the dioactive B12, administered with an equal amount of free labeled vitamin was displaced by unlabeled B12(20% of cold B12,with the absorption offree radioactive B12given the maximally possible exchange) in 24 hrs (29), and at with bound cold B12. It was shown that B12bound to 37°Cexchangewasnegligible(30). In 1963,Donaldson gastric juice was preferentially absorbed over the un Ct al. did describe a time- and temperature-dependent

TABLE3. PRELIMINARYAND IN VITROSTUDIESOF ThE DUAL-TRAcERSCHILUNGTEST PrelIminarystudIes Bishop (24) (1955)—Preferentlalabsorption of Bt to F* In a PG@pt Schilling(25)(1957)—Pref&entlalabsorptionof Bto F ina PGpt Toporek(26)(1960)—Preferentialabsorptionof Bto F In7 PGand5 PA pta Invitro studies Bunge(27)(1957)—BonlyslightlydIsplacedby50xexcessof F Donaldsopn(28)(1963)—TIme-andtemperature-dependentexchangeof B12ontoIF Highley (29) (1962)—<10% exchangeof B and F at 4°Cover 24 hr HI@iIey(30@(1964)—NeglIgIbleexchangeof BandFat 37°C Knudson( 16)(1974)—HI@dissocIationconstantfor IF-B12complex Fairbanks(23) (1983)—812exchange greater at low pH

. PA—PernIcIous anemia. t B—IF-Bound vitamin B12. t F—Free(unbound)vitaminB12. §PG—Postgastrectomy. B/F—Ratioof bound-to-freevitamin B12.

I034 THE JOURNAL OF NUCLEAR MEDICINE ADJUNCTIVE MEDICAL KNOWLEDGE

TABLE4. IN VIVO STUDIESOF EFFECTIVENESSOF THE DUAL-TRACERSCHILLINGTEST soup studies:comparisonof DISTto 81STIncomparablePA pt groups Bayly( 13)(1971)—BXintheDISTt70% of SIST •values.FXf Briedis(32)(1973)—4BX@andt FXtt withtheDIST Knudson( 16)(1974)—4InB/FratiowiththeDIST Individualpt studies: comparison of DISTto 81STin the same individuals @ Donaldson(28)(1963)—4BXand FXIn6 PApts@and2 PG@rats Briedls(32)(1973)—4BXandt FXIn 10/11PApta ClInicalcorrelationstudies:comparisonof DISTresultswithknownpt diagnoses Katz ( 11)(1963)—Nooverlap of FX or B/F ratios between 20 controls and 10 PA pts Bell(12)(1965)—NooverlapofFXorB/Fratiosbetween16control,4PG& 13PApts Bell(31)(1969)—1/38PAptawithnormal-rangeFX;I withnormalB/F ratio Bayly( 13)(1971)—Nooverlapof FXor B/F ratiosInearlyuseof commercialkit Payne( 14)(1972)—Moderateoverlapof FX;no intergroupoverlapof B/F ratiosin 40 pts Briedis(32)(1973)—Nooverlapof FXor B/F ratiosbetween37 PAand74 non-PAsubjects Knudson( 16)(1974)—Someoverlapof FXandB/Fratiosbetween26 control& 13PAsubjects @ Pathy(33)(1979)—MIldintergroupoverlapof FX& B/F ratiosin 246elderlywith B12 Domstad( 19)(1981)—98%specificityand83% sensItivityfor diagnosingPAin 65tests Fairbanks(23)(1983)—HIgh(46%) levelof misdiagnosisIn28 PApatients

•PA—Perniciousanemia. t DIST—DuaI-isotope Schilling test. @ BX—lF-Boundvit.B12excretion. §pt—Patient. I PG—post-gastrectomy. ••SIST—Single-tracerSchillingtest. tt FX—Free(unbound)vit. B12excretion. B/F—Ratioof bound-to-freevit. B12.

exchange of Co-60 B12 with Co-57 B12 on gastric juice IN VIVO STUDIES (28). When free and bound vitamin B12were mixed in The clinical efficacy of the DIST method has not been equal amounts at 37°Cand pH 6.8 to 7.0, 40% of the thoroughly documented (19). Several existing studies theoretically possible exchange occurred within 2 hr. pertain to overlapping patient groups (12,13,31). We When radioB12, bound to gastric juice, was incubated have classified the published in vivo evaluations of the with cobalt sulfate for 24 hr, the amount of bound ac DIST into three subgroups (Table 4): (a) group studies tivity did not decrease, indicating that the observed ex where DIST results in a series of PA patients were sta change between free and bound B12 involved the entire tistically compared with classic 51ST results in a com B12moiety rather than the cobalt atoms. Fairbanks et parable patient series; (b) individual patient studies a!. (23) showed that exchange ofvitamin B12 is depen comparing the results of the DIST with the 51ST in in dent on the pH of the medium: in simulated acid gastric dividual patients; and (c) clinical studies where the DIST juice, Co-57 B12 equilibrated completely with IF-Co-58 results were evaluated against independently determined B12within 10 mm, whereas in simulated intestinal or clinical diagnoses. achlorhydric gastric juice (0.155% NaC1), exchange was Groupstudies,The rangesof boundandfreevitamin only 64% or 38% complete, respectively, after 90 mm. B12excretion by the 51ST and DIST were studied in The dissociation constant for the IF-B12complex at pH similar groups of patients. In the DIST method, the 7 and 25°Cis reported as 0.005/sec; dissociation of the mean free B12excretion was significantly higher, and the complex and subsequent exchange of the forms of B12 IF-bound B12 excretion conversely lower, than in the is anticipated under these conditions (16). In PA patients classic 51ST method (13,16,32). Knudson and Hippe with achlorohydria, as well as in post-gastrectomy pa (16), using a double dose of the commercial test in 13 tients (groups that we tend to study for IF deficiency), patients with PA, reported that 8-hr plasma levels of free higher gastrointestinal pH would tend to minimize the B12were also higher, and bound B12levels lower, than confounding effects of B12exchange. We may now re those reported for the 2-stage test. trospectivelly understand why early studies performed While lowering of the B/F vitamin B12absorption in these groups did not suggest this phenomenon. ratio was statistically demonstrated in patients with PA,

Volume 25, Number 9 1035 ZUCKIER AND CHERVU it was not tested whether this decrease causes overlap the manufacturer's suggested B/F cutoff ratio of 2.0, with normal patient values. Comparison of test results they found that 34% of the PA patients had B/F ratios in different and potentially nonequivalent populations below this value. By revising the cutoff to 1.4 they found is another limitation of these studies. Since as the corn only one false-negative and two borderline results. Of the parison groups were either a previous cohort of patients I 75 non-PA cases, nine (5%) gave false-positive results, (32) or a group described by other investigators (16), but four of these had a free Co-58 excretion level high there is no assurance that variation in patient variables enough to make misdiagnosis unlikely. The fifth case and experimental design did not cause the results represented an extreme situation oflow Co-57 and Co-58 noted. levels, possibly due to malabsorption, where the counting Individualpatient studies. A limited number of patients statistics did not allow determination of a valid ratio. were studied by both the 51ST and the DIST methods Fairbanks et al. (18) described their experience with a at an expense of increased cost, time and patient radia large number of indeterminate examinations in 388 tion dose (19). Donaldson and Katz (28) evaluated fecal consecutive DISTs. While increasing the range of free excretion in two gastrectomized rats and urinary B12 B12excretion considered normal decreased the incidence excretion in six PA patients. Compared with levels in the of false positives, any potential advantage was lost in an SIST, simultaneous administration of the two tracers increased false-negative rate. without prior incubation led to an increased absorption As in the single-tracer test (34—37), 8-hr serum of free B12 and a corresponding decrease in the absorp measurements of B12absorption are shown to be inferior tion of B12 bound to gastricjuice. This phenomenon was to 24-hr urine collections, with increased intergroup enhanced by incubation of free and bound B12 at pH overlap of serum-free B12 levels and B/F ratios 6.8—7.0at 37°C for 18—24hr before administration. (15,16,32). Fish et al. (17) compared absorption of si Using the DIST, Briedis et al. (32) showed relative dc multaneously administered Co-57 B12-IF, free Co-58 vation of free B12 levels, and depression of bound B12 B12,and Co-60 microspheres by incomplete stool sam absorption, in I 0 out of 1 1 PA patients. The absorption pling, whole-body measurement, and 6-8 hr plasma of free Co-58-B12 alone was reassessed in an additional values. The Co-60 microspheres (a nonabsorbable five patients following the initial DIST, and it dropped marker in the stool) served as an internal standard en from a mean of 5% to only 2.3%. Since these two series abling calculation of absolute absorption with partial are not randomized with regard to order of test perfor stool collection. Between PA patients and controls there mance, it is possible that prior administration of the was no overlap of the absorption ratios generated by ci 51ST may have biased the subsequent DIST. Further ther serum or whole-body counting methods. Normals more, as in the group studies, the diagnostic impact of and patients with PA had slightly overlapping B/F vi these findings was not measured. tamin 2 absorption ratios when based on partial stool Clinical correlation studies, Accuracy of the DIST was collection. assessed against independently confirmed clinical Two studies of dual-tracer B12 absorption using diagnoses. The ability of the dual-tracer test to resolve whole-body counting methods have been performed with diagnoses represents the most relevant measure of its a 1-hr delay between the administration of the B12 usefulness. Initially (11—13,32) it was thought that there tracers, during which the patients drank water to aid in would be a clear-cut separation of free-B12 excretion separating the B12 doses. No overlap of free B12 ab levels between normal patients and those with malab sorption (8,38), nor of B/F ratios (38), between clinical sorption (including PA), but subsequent investigators groups was reported, though the B/F ratios were found found this parameter unreliable due to intergroup lower than in two-stage tests. A short pause between overlap (14,16,23,31,33). The most useful value gen administration of the forms of vitamin B12 has been crated by the test was seen to be the B/F absorption applied in urinary excretion tests as well. A 1-hr interval ratio, which, in the setting of a decreased free B12 ab between B12 doses was used in an early study by sorption, is an indicator for the presence of PA. While McCurdy (39), with clear differentiation between PA initial evaluation of this ratio was promising, with absent patients and other subjects. Breidis et al. (32) repeated (11—14,32)or only occasional (16,31 ,33) overlap be urinary dual-tracer studies in five patients, with a 2-hr tween clinical groups, greater overlap between controls interval between administration of the two labeled B12 and PA patients has since been described (18,23). moieties. In four of the five patients, the B/F ratio in Several studies appear to use retroactively assigned creased towards values obtained in the classic two-stage cutoff values designed to optimize discimination between test. diagnostic groups (14,16,32). Other authors have di rectly evaluated readjustment of the cutoff levels in DISCUSSION improving the test accuracy. Pathy et al. (33) were un The in vivo group and individual-patient studies dis able to demonstrate a sharp delineation between 7 1 PA cussed above show reduced B/F ratios in patients with and 175 other elderly subjects with low B12levels. Using PA using the DIST method compared with the SIST.

I036 THE JOURNAL OF NUCLEAR MEDICINE ADJUNCTIVE MEDICAL KNOWLEDGE

DIAGNOSTIC SGIILLING ALGORITHM

FIG.2. DiagnostIcalgorithmforselectingmostsuitablevariationof theSchillingtestto retaingreatesteaseof administrationandaccixacy ofresults.MDISTrefersto modifieddual-isotopeSchillingtest with2-hrpausebeforeadministrationofsecondformofB12.Algorithm assumesadequateurinecollectionandrenalfunction.

Several clinical studies demonstrate significant difficulty In the standard single-tracer procedure, the flushing dose in resolving diagnoses with this test. While the possibility given in the initial portion of the test may act therapeu of a physiologic “grayarea―of absorption may be in tically to reverse, partially or totally, any secondary yoked to explain the presence of nondiagnostic test re malabsorption that exists before initiation of the second suits (5,19—22), this does not explain the differences stage of the test (43). In the DIST test, the two stages observed between the standard 51ST and the DIST of the test are performed simultaneously, thereby pre methods. cluding any therapeutic effect of the flushing dose on the A number of authors cite the phenomenon of lability absorption ofthe IF-bound vitamin B12.PA patients with of the B12-IF bond to explain these findings secondary malabsorption may therefore not correct their (13,16,18,23,28,32). In vitro data generally support the B12absorption with exogenous IF, and hence might have hypothesis of a time-, temperature-, and pH-dependent atypical and nondiagnostic test results. In support of this exchange ofvitamin B12bound to IF (Table 3). Since the hypothesis, Knudson and Hippe ( 16) described three majority of cases of elevated B/F ratios are expected in patients with PA who had low IF-bound 2 absorption patients with elevated gastrointestinal pH (secondary levels in the DIST, which increased on repeat testing to achlorohydria or gastrectomy), the incidence of B12 after B12 treatment. exchange would be reduced under these circumstances. Though the DIST test will on occasion yield a nondi Where gastric or intestinal transit are abnormally de agnostic result, the classic 51ST may also lead to unin layed, one would anticipate an increased incidence of this terpretable or erroneous conclusions. In the latter, one occurrence (11,23). may never be certain that the two halves of this test were The presence of secondary malabsorption in patients carried out under comparable experimental and clinical with PA (40—43) could also lead to a reduced absorption conditions (1 1 ), and the incomplete collection of urine of IF-bound B12in the DIST relative to the 51ST (16). may not only lead to uninterpretable and invalidated

Volume 25, Number 9 1037 ZUCKIER AND CHERVU results but may simulate malabsorption or PA where it 2. GLASSGBJ: Scintillation measurementsof the uptake of does not occur (44,45). In a DIST, even with partial loss radioactive vitamin 2 by the in normal humans and patients with perniciousand other macrocytic anemias. Bull ofsample, the ratio of IF-bound to free vitamin B12 ab NYAcadMed 30:717—718,1954 sorption remains preserved, thereby allowing differen 3. GLASS GBJ, BOYD U, GELLIN GA et al: Uptake of ra tiation of PA from normal [diagnosis of IF-independent dioactive vitamin B12by the liver in humans: test for mea malabsorption, with depressed B12 absorption but a surement of intestinal absorption ofvitamin B12and intrinsic normal B/F ratio, cannot be ascertained without corn factor activity. Arch Biochem Biophys 51:251—257,1954 4. HEINLE RW, WELCH AD, SCHARF V, Ct al: Studiesof plete and reliable collection of samples (11,14)]. Fur excretion (and absorption) of @°Co-labeledVitamin B12 in thermore, decreased patient compliance and an increased perniciousanemia. Trans Assoc Am Physicians 65:214-222, incidence of incomplete tests has a detrimental bearing 1952 on the SIST performance. These not insignificant factors 5. CALLENDERST, TURNBULLA, WAKI5AKAG: Estimation must be weighed against the decreased sensitivity of the of intrinsic factor of Castle by use of radioactivevitamin B12. BrMedJ 1:10—13,1954 DIST technique. 6. BOOTHCC, MOLLIN DL: Plasma,tissueand urinary ra We have presented an algorithm (Fig. 2) that main dioactivity after oral administration of 56Co-labeledvitamin tains the advantages of convenience, brevity, and con B12.BrfHaematol 2:223—236,1956 gruity of samples in the DIST while minimizing the 7. DOSCHERHOLMEN A, HAGEN PS: Radioactivevitamin B12 possibility of spurious results. The examination need be absorption studies: Results of direct measurement of radio activity in the blood. Blood 12:336—346,1957 repeated only once in the event of an initially indeter 8. REIZENSTEINPG, CRONKITEEP, COHNSH: Measure minate test. Where the initial DIST yields a nondiag ment of absorption of vitamin B12 by whole-body gamma nostic result, repeat testing with a greater separation spectrometry. Blood 18:95—101, 1961 between administration of the two forms of B12is ad 9. ELLENBOGENL, WILLIAMS WL, RABINERSF, Ctal: An vocated to minimize the possibility of exchange of vita improved urinary excretion test as an assay for intrinsic factor. ProcSoc ExperBiolMed 89:357-362,1955 mmonIF.Ifthe51STisnottechnicallyfeasible,we 10. CALLENDERST, EVANS JR: The urinary excretion of la suggest providing a 2-hr separation between the B12 belied vitamin B12.C/in Sci 14:295—302,1955 doses in the manner of Breidis et al. (32), who proposed 11. KATZ JH, DIMASE J, DONALDSONRM: Simultaneous that a short interval between administration of the administration ofgastricjuice-bound and free radioctive cy tracers improves the test resolution. On the other hand, anocobalamin:rapid procedurefor differentiatingbetween intrinsic factor deficiency and other causes of vitamin B12 Nickoloff has stated that regardless of which capsule is malabsOrption.J Lab Clin Med 61:266-27 1, 1963 administered first, the first tracer will be preferentially 12. BELLTK, BRIDGESJM, NELSONMG: Simultaneousfree excreted, perhaps because of the presence of a contarn amd bound radioactive Vitamin B12urinary excretion test. inant, the hydroxycobalamin analog of vitamin B12 (46). JClinPatho/18:611-613,1965 She maintains that the 2-hr capsule separation does not 13. BAYLY Ri, BELLTK, WATERS AH: A dual isotope mcdi ficationofthe Schillingtest. Nuc/Medizin Supp/ 9:911—915, invariably clarify concerns about the simultaneous assay 1971 results. While delaying the administration of the second 14. PAYNE RW, FINNEY RD: An evaluation of the double B12will minimize the potential for B12crossover, care isotopetest in the diagnosisof perniciousanemia. Scott Med must be taken to obtain complete urine collection, as any I 17:359—363,1972 loss of sample will disproportionately affect the two B12 15. FINNEY RD. PAYNE RW: Plasma radioactivity following simultaneousoral administrationof intrinsicfactor-boundand moieties. Where secondary malabsorption is suspected free radioactive vitamin B12.Acta Haemaiol 48:137—144, as having caused an indeterminate DIST response, a 1972 repeat study should not be performed until after vitamin 16. KNUDSENL, HIPPEE: Vitamin B12absorption evaluated B12therapy. by a dual-isotope test (Dicopac). Scand J Haemto/ 13: A thorough understanding of the dual-tracer test is 287—293,1974 17. FISH MB, POLLYCOVEM, WALLERSTEINRO, et al: critial for the maximizing of its unique diagnostic use Simultaneous measurement of free and intrinsic factor (IF) fulness and for avoiding its potential diagnostic pit bound vitamin B12(B12)absorption: absolute quantitation falls. with incomplete stool collection and rapid relative measure ment using plasma B12(IF):B12 absorption ratio. JNucl Med ACKNOWLEDGMENTS 14:568—575,1973 18. FAIRBANKSVF, WAHNERHW, PHYLIKYRL: Testsfor TheauthorsthankDrs.M. DonaldBlaufox,Ira Sussman,Lawrence perniciousanemia:The “Schillingtest―.Mayo C/in Proc P. Davis, and Kwang J. Chun for their constructivecomments and 58:541—544,1983 suggestions regarding the manuscript. 19. DOMSTADPA, CHOY YC, KIM EE, et al: Reliability of the dual-isotope Schilling test for the diagnosis of pernicious REFERENCES anemia or malabsorption syndrome. Am J C/in Patho/ 75: 723—726,1981 I. SCHILLING RF: Intrinsic factor studies II. The effects of 20. LAMARC, MCCRACKENBH, MILLERON, etal: Experi gastricjuice on the urinary excretionof radioactivityafter the ences with the Schilling test as a diagnostic tool. Am J C/in oral administration of radioactive vitamin B12.J Lab C/in Med Nutr 16:402-411,1965 42:860-866, 1953 21. ESTEN5, WASSERMANLR: Perniciousanemia.I. Remis

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Announcement from the Editor's Office On January1, 1985,ThomasP.Haynie,M.D.will assumethe Editorshipof TheJournalof NuclearMedicine.Toensure a smoothtransitionof duties,It is necessarythat Dr.Haynieinitiatemanuscriptprocessingin September,1984.Beginning September15,1984,all manuscripts,original submissions,and revisions,shouldbe forwardedto: ThomasP.Haynie,M.D. UT M.D.AndersonHospital 6723 Bertner Avenue, Box 83 Houston, TX 77030 Frank H. DeLand, M.D. Editor

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