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Technetium thyroid uptake ratios in pediatric Graves disease
Technetium thyroid uptake ratios in pediatric Graves disease Patients with Graves disease were prospectively followed by means o f three 99mtechnetium thyroid uptake ratios. These three ratios were >90% sensitive and specoqc for the detection o f hyperthyroidism in the patient with untreated Graves disease. Twelve of 15 patients experienced prolonged remission after normalization o f the ratios. These ratios exhibit significant linear correlation with serum thyroxine and triiodothyronine concentrations (r = 0.4-0.6, P <0.01) and are a very sensitive index o f medical oversuppression o f thyroid function. (J PEDIATR 1985;I07:905-909)
Stephen C. Duck, M.D., and J. Sty, M.D. Milwaukee,
Wisconsin
TREATMENT of pediatric Graves disease has often required continuous treatment for 18 to 24 months with propylthiouracil or methimazole, followed by discontinuation to determine whether remission has occurred. Discontinuation of antithyroid medication is usually a benign procedure, but could place the patient with compromised cardiac function in jeopardy. A simple test is needed to assist in determining whether the disease is in remission. HLA typing of adult patients with Graves disease may identify a population not likely to experience remission? Thyroid-stimulating immunoglobulin titers also can correlate with disease activity and may indicate that clinical remission has occurred?,3 However, both of these laboratory tests are expensive and imperfect. 99mTechnetium pertechnate thyroid uptake percentages and ratios are abnormally elevated in 90% or more of pediatric and adult patients with untreated Graves disease?, 5The 99mTcuptake values in general are strongly and positively correlated with serum thyroxine and triiodothyronine concentrations, decrease with effective therapy, and normalize before long-term remissionY 2 Further, the From the Departments o f Pediatrics, Pediatric Endocrinology. Medical College o f Wisconsin, and Pediatric Radiology, Milwaukee Children's Hospital. Supported in part by Grant 80/14 from Milwaukee Children's Hospital. Submitted for publication March 4, 1985; accepted June 12, 1985. Reprint requests: Stephen C. Duck, M.D., Associate Professor o f Pediatrics, Department o f Pediatrics, Milwaukee Children's Hospital, 1700 W. Wisconsin Ave., Milwaukee, WI 53233.
99mWcuptake testing protocols are as valid as radioactive iodine uptake in T3 suppression testing?, ~0,~-~499rnTchas a distinct advantage compared with radioactive iodine in that it can be measured while the patient is receiving full therapeutic dosages of P T U / M M I , because technetium is essentially trapped and not organified and coupled? ~ Our experience with 99mTcratios in children with Graves disease leads us to believe that this procedure is easy, safe, and useful in indicating when antithyroid drug therapy may be discontinued. ANOVA MMI PTU T3 T, 99mTC
TSAB TSH '
Analysis of variance Methimazole Propytthiouracil Triiodothyronine Thyroxine 99mTechnetium pertechnetate radionuclide Thyroid-stimulating immunoglobulin Thyroid-stimulating hormone
METHODS We used a Picker Thyroid Uptake Spectroscaler 4R system with a single-channel Magnaprobe (Picker Corp., Highland Heights, Ohio), set at 1 MeV full-scale energy range. The pulse height analyzer was set so as to use both the lower- and upper-level energy windows. The lower level was at 130 keV, and the upper level at 150 keV, with 140 keV energy of 99mTcat the center of the window. The high voltage was easily fine-tuned before the examination to assure an exact peak, The timer was set for 60 seconds. The patient was positioned under the scintillation probe,
The Journal o f P E D I A T R I C S
905
906
Duck and Sty
The Journal of Pediatrics December 1985
Table I. Laboratory data in 33 children with Graves disease
Thyroid hormone* T4 0*g/dl) T3 (ng/dl) TSH (#U/ml) Thyroid antibody* Antithyroglobulin (U/mt) Microsomal (U/ml) 99raTe ratio* Tel0 Tel5 TcP
Observed (X +_1 SD)
Normal (range)
21.1 _+ 6.7 539 _+ 197 <1.0
5.1-11.6 94-241 ~<5
407 _+ 565 4057 _+ 2774
<10 <20
1.32 + 0 . 2 2 12.78 _+ 9 . 0 3 17.49 + 13.97
0.86-1.22 1.92-5.96 1.52-6.75
*P <0.05 comparedwith normalcontrolsby multiplerangetesting (LSD procedures).
with the thyroid gland 17 cm from the fiat-field collimator face of the uptake probe, or 28 cm from the probe crystal. A bolus of 3 mCi 99mTcpertechnetate/1.7 m 2 surface area (minimum 0.5 mCi) was administered intravenously. In a 10- to 15-year-old population, the estimated radiation dose per test to the thyroid gland was 0.2 rads, and to the whole body was 0.007 rads. Total counts were obtained over the thyroid area at 2, 10, and 15 minutes after injection. Total counts were obtained over the thigh at 16 minutes. The three uptake ratios were calculated as follows: Tcl0 = 10minute thyroid count/2-minute thyroid count; Tel5 = 15minute thyroid count/thigh count; and TcP = Tcl0 • Tel5. 5 Twenty-three patients had newly diagnosed, untreated Graves disease at enrollment. Another 10 had previously received medical treatment, had no evidence for remission, and were thyrotoxic without therapy. Another 12 were first examined while receiving antithyroid medication; the diagnosis had been confirmed previously. The 37 girls and eight boys ranged in age from 5 to 17 years (mean 11.6 years, median 11 years). All received treatment for 24 months or until 99mTcratios were normal.4 Each was examined by one of us (S.C.D.). T3, T4, and TSH were assessed by standard RIA methods, as were antithyroid antibodies (Nichols Institute). Age-related normal values were usedJ 6 Diagnostic mI uptake was assessed at 24 hours (normal <25%). The diagnosis of Graves disease required clinical signs and symptoms of hyperthyroidism and the elevation of serum T3 and T4 values, increased n3Iodine uptake, and suppression of serum TSH. The study was approved by the Human Research and Review Committee of the Medical College of Wisconsin. Enrollment in the study required prospective, serial 99mTc
Table II. Sensitivity and specificity for determining hyperthyroidism in untreated Graves disease by 99mTc uptake ratios, 2 X 2 table format*
Sensitivity(%) " I Tcl0 Tcl 5 Tcl 0 with Tcl 5 TcP
52 94 94 90
Specificity(%) 93 85 79 90
*Chi-squareanalysis(P <10 ~): euthyroidpatients (n = 65), hypothyroid patients (n = 29), hyperthyroidpatients(n = 33). ratios to be performed once every 4 months (maximum six times) until discontinuation of antithyroid medication. Statistical analysis included linear regression analysis, Pearson correlation coefficients, and one-way ANOVA/multiple range testing (Student-NewmanKeuls and modified least significant difference procedures). RESULTS Biochemical criteria for each of the 33 children clinically toxic with Graves disease while receiving no therapy are listed in Table I. The mean 123Iuptake at 24 hours was 79% (range 54% to 99%). By linear regression analysis, no correlation existed between the 24-hour ~23Iuptake value of Tcl 5 or TcP. The mean of each 99mTcuptake was significantly elevated. Table II indicates that sensitivity for diagnosing hyperthyroidism in patients with untreated Graves disease by 99rnTc uptake was >90% when Tcl5 was considered alone and together with Tcl0 (Figure) or by the product TcP. Specificity for diagnosis by 991nTc uptake using Tel0 or TcP was ~90%. The T3 and T4 levels correlated significantly With Tcl5 and TcP (r = 0.4-0.6, P <0.01). The r values improved consistently with log/log transformation of the data prior to linear regression analysis, suggesting that the sample was skewed. During the period of observation, 12 patients entered and remained in remission for >2 years, and another five patients entered and remained in remission for >6 months. Twelve others underwent subtotal thyroidectomy; three were lost to follow-up; and 13 continued with antithyroid medication. Of the 17 patients experiencing clinical remission for _>6 months, t4 were evaluated at termination of medical treatment or within 4 weeks of discontinuation (Table III). All of their Tc15 and TcP values were within the normal range; only one Tel0 value was abnormal at 1.3. Eight of these 17 patients in remission were examined before therapy (Table IV); their Serum values did not differ
Table III. Tc uptake ratios obtained at discontinuation of medical therapy in 14 patients who remain in prolonged remission after termination of medical therapy
Tcl0 Tcl5 TcP
907
99mTc ratios in Graves disease
l~olume 107 Iiumber 6
Remission (~ • l SD)
Expected normal (range)
1.06 +- 0.09 4.26 _+ 0,73 4.51 • 0.93
0.86-1.22 1.92-5.96 1.52-6.75
56
9
II
52 28 24 20
Table IV. Tc uptake ratios in eight patients, at enrollment and at start of prolonged remission
6o
18
(..) I-
16
m
12
is
XxY=6Y5
n
i
8 Diagnosis
Tcl0 TcI5 TcP
1.29 • 0.06* 9.95 • 3.36 12.93• 4.82
Remission
D(fJ'erence
P
t.09 _+ 0.12 0.20 • 0.12 0.001 4.31 _+ 0.67 5.64 • 3.10 <0.001 4.69 • 0.86 8.24 _+ 4.37 <0.001
4 ,~j
0.0
I
I
0.6 0.8
I
1.0
I
1.2
I
1.4
I
1.6
I
I
I
1.8 2.0 2.2
TCIO
V a l u e s r e p r e s e n t m e a n _+ 1 S D .
significantly from those of the rest of the group (Table I). During remission, each Tcl 5 and TcP value and all but one T e l 0 value were within the normal euthyroid range. With prolonged clinical remission, a highly significant improvement was noted by paired t testing (Table IV). During the study period three patients had a return to normal of 99mTc ratios; they experienced remission for >6 months, but then relapsed. The 99mTc ratios at the time of relapse were no different than the ratios at-the time of initial diagnosis. Medical therapy for Graves disease often induces a state of relative hypothyroidism (T4 <5 ~g/dl or T S H >5 #U/ml). Among our patients, 19 episodes of hypothyroidism were noted in 13 patients in whom pretreatment uptakes were known. Highly significant increases occurred in Tcl5 and TcP (Table V) in response to excessive medical suppression. In seven of these patients the study obtained 4 months later was done while they were euthyroid with corrected medical treatment. Among these seven, highly significant decreases of Tcl5 and TcP were noted (Table IV). Overall, the 99roTe uptakes in patients with iatrogenic hypothyroidism in Graves disease were much greater than values in a cohort of children with acquired or congenital hypothyroidism? DISCUSSION Administration of PTU or M M I is the treatment of choice for most pediatric patients with Graves disease? 5 Controversy remains as to how long medical therapy should be sustained before considering cessation of treatment. Twelve to 24 months of continuous biochemical c o n t r o l is generally (but not universally) recommended. No reliable biochemical test provides the clinician with
Figure. Tcl 0 and Tcl5 for each patient (n = 33) before treatment. Box represents mean • 2 SD for Tcl0 and Tcl5. Curve (X • Y = 6.75) represents mean • 2 SD for TcP. adequate specificity for detection of remission. Patients with Graves disease who are positive for HLA-B8 and HLA-DR3 phenotypes were thought to be at greater risk for relapse after therapy was discontinued, but this conclusion has been refuted, and at best specificity was 66%?,~5 Research laboratories and a few commercial reference laboratories now can assay the IgG class immunoglobulin thought to cause thyrotoxicosis by direct stimulation of the TSH receptor or membrane-bound adenylate cyclase system. Decreasing titers of TSAb can suggest remission of disease, but sensitivity and specificity of these titers are not adequate for clinical use}, 3,15 An in vivo assay for TSAb is the 99mTcthyroid uptake. Regardless of which cell surface pathway is stimulated to increase generation of thyroid cyclic adenosine monophosphate, the iodine trapping mechanism and therefore the 99mTC uptake value should be stimulated. 4 That 99mTc is only trapped and not organified, as is iodine, is not a liability. Indeed, because of this limitation, the uptake can be measured during treatment? ~ ~2,t3.15.~%20Assurance that remission had occurred before stopping antithyroid medication would be a significant advantage. In our patients, the mean99mTc values were uniformly elevated at the time of diagnosis and of relapse. Although not completely accurate, the use of either T c l 0 with Tcl 5 or TcP alone was 90% to 94% sensitive and 79% to 90% specific for confirmation of hyperthyroidism, and equal to the percentages found in adults?, 5 When the test was used to determine only whether our patients were hyperthyroid or euthyroid, specifici(y rose to 91% to 98%. Several authors have observed that 99mTc uptake or
908
Duck and Sty
The Journal o f Pediatrics December 1985
Table V. Graves disease and effect of excessive and appropriate medical treatment
Tel0 Tcl5 TcP
No treatment
Excessive treatment (n = 19)
Mean difference
1.28 _+ 0.17" 9.90 • 3.64 13.11 • 6.01
1.28 +_ 0.17 20.62 • 7.19 27.59 • 13.07
0.001 • 0.21 -10.72 + 9.01 -14.47 • 14.71
P
Excessive treatment
NS 1.23 _+ 0.15 < 0 . 0 0 1 21.07 • 8.49 <0.01 26.79 _+ 13.01
Corrected treatment (n = 7)
Mean difference
P
1.24 • 0.19 8.11 • 1.35 10.25 • 3.05
-0.0l • 0.10 12.96 • 7.79 16.54 _+ 11.41
NS <0.01 <0.005
Values representmean • 1 SD.
ratios correlate well with serum T3 and T 4 levels, and suggest that 99mTc values could be used prospectively to determine when medical treatment can be discontinued safely.6-9,14 Gossage et al. 6 noted that 99mTc absolute percentage values did not correlate with their assay method for TSAb titers at diagnosis, but did show significant correlation with the TSAb titers during treatment. The lack of correlation between 99mTc values and 24hour iodine uptake was also found by those who evaluated patients with Graves disease as a separate g r o u p . 4,13,21 Correlation was significant only when patients with euthyroid diseases and those with hyperthyroid diseases were analyzed together. 4 The explanation for this discrepancy is unknown. Fifteen (88%) of 17 patients in whom 99mTc uptake ratios normalized remained in remission for at least 6 months, with the majority in remission for >2 years. One of two patients who relapsed within 3 months of discontinuation of ant• medication received treatment for an additional 8 months. She once again normalized, 99mTc uptakes ratios once again normalized, and the patient has been in remission for >6 months without medication. Few others have prospectively followed patients with Graves disease, but they have found that as 99mTcvalues normalized, long-term remission often follows. 6,1~ This test cannot be expected to predict who will experience permanent remission, because it is an in vivo indicator of TSAb activity?, ~oOur results suggest that with normalization of 99mTc uptakes, ant• medication can be safely stopped.6,~0, u Failure to normalize 99mTcvalues indicates that the patient will likely rapidly relapse. 6,t~ Medical treatment is children can involve drug dosage adjustment to maintain euthyroidism or complete thyroid suppression followed by addition of L-thyroxine replacement. Because the former approach was used and because the disease varied unpredictably, states of relative hypothyroidism (T4 <5 #g/dl, TSH >5 ~zU/ml) were induced in several patients. The highest values of Tcl5 and TcP were seen secondary to this iatrogenic hypothyroid state, and resulted from a combination of endogenous TSH plus TSAb activity. However, in seven patients examined 4 months later, during appropriate drug therapy, the magni-
tude of the fall in 99mTcuptake ratios was related presumably to TSH alone. Indeed, the order of magnitude of the rise or fall in Tel5 (10.7 to 13.0) and TcP (14.5 to 16.5) secondary to TSH is approximately two times the rise caused by TSAb alone (Tables IV and V). Others have studied the impact of PTU and TSH on 99mTc values. 8,tS'2~ Those showing no effect of P T U / M M I in normal subjects administered the drug to patients for only 3 daysJ 8,2~A standard 3-day stimulation test with TSH increased the 99mTc value by up to three-fold (mean of one-fold).8,18 We believe, but cannot prove, that any marked elevation of Tcl5 and TcP observed in our patients who were receiving treatment and euthyroid represents TSH-dependent trapping activity. If 99mTc uptake ratios are used to assess the time for discontinuation of P T U / M M I treatment, then we suggest that not only the thyroid activity be suppressed but also that the patient be given replacement L-thyroxine therapy. This would preclude any TSH-dependent activity as measured by 99mTC uptake. Double drug treatment regimens should eliminate any ambivalence as to whether disease or TSH-dependent activity caused a change in 99roTevalues. Goolden et alJ 2 observed a rebound elevation in 99rnTc values a month after discontinuation of both ant• drugs and orally administered T3. We did not administer T3 orally, and saw no such rebound except in those individuals who relapsed. Several have commented that this test can give misleading results in patients with subacute thyroiditis, nodular hyperthyroidism, or relapse of Graves disease after unsuccessful 13~Iablation?, 7,2~,23 The precise biochemical explanations are unproved. Where these occur, the 99mTc test should not be used. Care should be taken to establish whether increased 99roTe values in pretreated Graves disease are TSH dependent. Limited information is available on the impact of drugs and other agents (i.e., iodine-containing compounds) known to alter radioiodine uptake values. 99mTcratios are less adversely affected by iodine containing contrast dyes. 5 Diagnosis is not the major indication for 99mTc ratio
Volume 107 Number 6
determination in patients with Graves disease. S e r u m T3 and T4 levels and the clinical presentation are usually sufficient for establishing the diagnosis. If thyroid uptake determination is clinically indicated in an unusual patient, ~23Iodine remains the a g e n t of choice, with determinations done approximately 2, 6, and 24 hours after administration. 99mTc ratios are useful at diagnosis primarily for establishing a baseline value, 99mTc ratios are principally useful when obtained prospectively to assess clinical remission while the patient continues to receive treatment. As a n in vivo test of T S A b titer, the ratio does not establish the presence of long-term remission. Our work indicates t h a t normalization of all three ratios is a very favorable index for remission. If 99mTc ratios are to be followed, concomitant L-thyroxine t r e a t m e n t is suggested in those patients whose thyroid activity was first suppressed by P T U a n d MMI. REFERENCES 1. Allannic H, Fauchet R, Lorcy Y, Gueguen M, LeGuerrierA-M, Genetet B. A prospective study of the relationship between relapse of hyperthyroid Graves' disease after antithyroid drugs and HLA haplotype. J Clin Endocrinol Metab 1983;57:719-222. 2. Madec AM, Laurent MC, Lorcy Y, LeGuerrier AM, Rostagnat-Stefanutti A, Orgiazzi J, Allannic H. Thyroid stimulating antibodies: an aid to the strategy of treatment of Graves' disease. Clin Endocrinol 1984;21:247-255. 3. Hensen J, Kotulla P, Finke R, Badenhoop K, Koppenhagen K, Meinhold H, Schleusener H. Ten years experience with consecutive measurement of thyrotropin binding inhibiting antibodies. J Endocrinol Invest 1984;7:215-220. 4. Duck SC, Sty J. 99mTechnetium throid uptake ratios in a pediatric population with suspected common diseases (unpublished data). 5. Schneider PB. Simple, rapid thyroid function testing with 99mTc-pertechnetate thyroid uptake and neck/thigh ratio. A JR 1979;132:249-253. 6. Gossage AAR, Crawley JCW, Copping S, Hinge D, Himsworth RL. Graves' disease: thyroid function and immunologic activity. J Nucl Med 1982;23:973-977. 7. Marion MA, Ronai PM, Pain RW, Wise PH. Simultaneous assessment of thyroid structure and function with the gamma camera using perteehnetate: a comparison with radioiodine and biochemical diagnosis. Aust NZ J Med 1974;4:379384. 8. Atkins HL, Richards P. Assessment of thyroid function and
99roTe ratios in Graves disease
9. 10.
11.
12.
13.
14.
15. 16.
17. 18.
19.
20.
21.
22.
23.
909
anatomy with technetium-99m as pertechnetate. J Nucl Med 1967;9:7-15. Van't Hoff W, Pover GG, Eiser NM. Technetium-99m in the diagnosis of thyrotoxicosis. Br Med J 1972;4:203-206. Van't Hoff W, Pover GG, Drury PL. Technetium uptake in the management of thyrotoxicosis. Clin Endocrinol 1978;8: 327-333. Maisey MN, Natarajan TK, Hurley P J, Wagner HN Jr. Validation of a rapid computerized method of measuring 99mTc pertechnetate uptake for routine assessment of thyroid structure and function. J Clin Endocrinol Metab 1973; 36:317-322. Goolden AWG, Glass HI, Williams ED: Use of 99mTcmfor the routine assessment of thyroid function. Br Med J 1971 ;4:396399. Kirkegaard C, Friis TH, Molholm Hansen JE, SiersbackNielsen K. The diagnostic and prognostic value of the 20 rain 99mTc-uptake in the thyroid gland. Acta Endocrinol 1973;74:659-665. Higgins HP, Ball D, Eastham S. 20-rain 99myc thyroid uptake: a simplified method using the gamma camera. J Nucl Med 1974;14:907-911. Cooper DS. Antithyroid drugs. N Engl J Med 1984;311:13531362. Fisher DA, Sack J, Oddie TH, Pekary AE, Hershman JM, Lam RW, Parslow ME. Serum T4, TBG, T3 uptake, T3, reverse T3 an d TSH concentrations in children 1 to 15 years of age. J Clin Endocrinol Metab 1977;45:191-198. Wilson MA, Hurley PJ, White BM, John MB. Thyroidal pertechnetate uptake [abst]. Aust N Z J Med 1975;5:175. Atkins H L.Technetium-99m pertechnetate uptake and scanning in the evaluation of thyroid function. Semin Nucl Med 1971;1:345-355. Sucupira MS, Camargo EL, Nickoloff EL, Alderson PO, Wagner HN Jr: The role of 99mTcpertechnetate uptake in the evaluation of thyroid function. Int J Nucl Med Biol 1983; 10:2%33. Hays MT, Wesselossky B. Simultaneous measurement of thyroidal trapping (99mTco4) and binding (~311-):clinical and experimental studies in man. J Nucl Med 1974;14:785-792. Selby JB, Buse MG, Gooderatne NS, Moore Do. The Anger camera and the pertechnetate ion in the routine evaluation of thyroid uptake and imaging. Clin Nucl Med 1979;4:233237. Kuba J, Widerlnann M, Komenda S. Zur problematik der 99mTc-Pertechnetatspeicherung in der Schilddruse. Nuklearmedizin 1967;6:6t-64. Preston D. Additional experience with pertechnetate as a test of thyroid hyperfunction [abst]. South Med J 1970; 64:1373.
Stephen C. Duck, M.D., and J. Sty, M.D. Milwaukee,
Wisconsin
TREATMENT of pediatric Graves disease has often required continuous treatment for 18 to 24 months with propylthiouracil or methimazole, followed by discontinuation to determine whether remission has occurred. Discontinuation of antithyroid medication is usually a benign procedure, but could place the patient with compromised cardiac function in jeopardy. A simple test is needed to assist in determining whether the disease is in remission. HLA typing of adult patients with Graves disease may identify a population not likely to experience remission? Thyroid-stimulating immunoglobulin titers also can correlate with disease activity and may indicate that clinical remission has occurred?,3 However, both of these laboratory tests are expensive and imperfect. 99mTechnetium pertechnate thyroid uptake percentages and ratios are abnormally elevated in 90% or more of pediatric and adult patients with untreated Graves disease?, 5The 99mTcuptake values in general are strongly and positively correlated with serum thyroxine and triiodothyronine concentrations, decrease with effective therapy, and normalize before long-term remissionY 2 Further, the From the Departments o f Pediatrics, Pediatric Endocrinology. Medical College o f Wisconsin, and Pediatric Radiology, Milwaukee Children's Hospital. Supported in part by Grant 80/14 from Milwaukee Children's Hospital. Submitted for publication March 4, 1985; accepted June 12, 1985. Reprint requests: Stephen C. Duck, M.D., Associate Professor o f Pediatrics, Department o f Pediatrics, Milwaukee Children's Hospital, 1700 W. Wisconsin Ave., Milwaukee, WI 53233.
99mWcuptake testing protocols are as valid as radioactive iodine uptake in T3 suppression testing?, ~0,~-~499rnTchas a distinct advantage compared with radioactive iodine in that it can be measured while the patient is receiving full therapeutic dosages of P T U / M M I , because technetium is essentially trapped and not organified and coupled? ~ Our experience with 99mTcratios in children with Graves disease leads us to believe that this procedure is easy, safe, and useful in indicating when antithyroid drug therapy may be discontinued. ANOVA MMI PTU T3 T, 99mTC
TSAB TSH '
Analysis of variance Methimazole Propytthiouracil Triiodothyronine Thyroxine 99mTechnetium pertechnetate radionuclide Thyroid-stimulating immunoglobulin Thyroid-stimulating hormone
METHODS We used a Picker Thyroid Uptake Spectroscaler 4R system with a single-channel Magnaprobe (Picker Corp., Highland Heights, Ohio), set at 1 MeV full-scale energy range. The pulse height analyzer was set so as to use both the lower- and upper-level energy windows. The lower level was at 130 keV, and the upper level at 150 keV, with 140 keV energy of 99mTcat the center of the window. The high voltage was easily fine-tuned before the examination to assure an exact peak, The timer was set for 60 seconds. The patient was positioned under the scintillation probe,
The Journal o f P E D I A T R I C S
905
906
Duck and Sty
The Journal of Pediatrics December 1985
Table I. Laboratory data in 33 children with Graves disease
Thyroid hormone* T4 0*g/dl) T3 (ng/dl) TSH (#U/ml) Thyroid antibody* Antithyroglobulin (U/mt) Microsomal (U/ml) 99raTe ratio* Tel0 Tel5 TcP
Observed (X +_1 SD)
Normal (range)
21.1 _+ 6.7 539 _+ 197 <1.0
5.1-11.6 94-241 ~<5
407 _+ 565 4057 _+ 2774
<10 <20
1.32 + 0 . 2 2 12.78 _+ 9 . 0 3 17.49 + 13.97
0.86-1.22 1.92-5.96 1.52-6.75
*P <0.05 comparedwith normalcontrolsby multiplerangetesting (LSD procedures).
with the thyroid gland 17 cm from the fiat-field collimator face of the uptake probe, or 28 cm from the probe crystal. A bolus of 3 mCi 99mTcpertechnetate/1.7 m 2 surface area (minimum 0.5 mCi) was administered intravenously. In a 10- to 15-year-old population, the estimated radiation dose per test to the thyroid gland was 0.2 rads, and to the whole body was 0.007 rads. Total counts were obtained over the thyroid area at 2, 10, and 15 minutes after injection. Total counts were obtained over the thigh at 16 minutes. The three uptake ratios were calculated as follows: Tcl0 = 10minute thyroid count/2-minute thyroid count; Tel5 = 15minute thyroid count/thigh count; and TcP = Tcl0 • Tel5. 5 Twenty-three patients had newly diagnosed, untreated Graves disease at enrollment. Another 10 had previously received medical treatment, had no evidence for remission, and were thyrotoxic without therapy. Another 12 were first examined while receiving antithyroid medication; the diagnosis had been confirmed previously. The 37 girls and eight boys ranged in age from 5 to 17 years (mean 11.6 years, median 11 years). All received treatment for 24 months or until 99mTcratios were normal.4 Each was examined by one of us (S.C.D.). T3, T4, and TSH were assessed by standard RIA methods, as were antithyroid antibodies (Nichols Institute). Age-related normal values were usedJ 6 Diagnostic mI uptake was assessed at 24 hours (normal <25%). The diagnosis of Graves disease required clinical signs and symptoms of hyperthyroidism and the elevation of serum T3 and T4 values, increased n3Iodine uptake, and suppression of serum TSH. The study was approved by the Human Research and Review Committee of the Medical College of Wisconsin. Enrollment in the study required prospective, serial 99mTc
Table II. Sensitivity and specificity for determining hyperthyroidism in untreated Graves disease by 99mTc uptake ratios, 2 X 2 table format*
Sensitivity(%) " I Tcl0 Tcl 5 Tcl 0 with Tcl 5 TcP
52 94 94 90
Specificity(%) 93 85 79 90
*Chi-squareanalysis(P <10 ~): euthyroidpatients (n = 65), hypothyroid patients (n = 29), hyperthyroidpatients(n = 33). ratios to be performed once every 4 months (maximum six times) until discontinuation of antithyroid medication. Statistical analysis included linear regression analysis, Pearson correlation coefficients, and one-way ANOVA/multiple range testing (Student-NewmanKeuls and modified least significant difference procedures). RESULTS Biochemical criteria for each of the 33 children clinically toxic with Graves disease while receiving no therapy are listed in Table I. The mean 123Iuptake at 24 hours was 79% (range 54% to 99%). By linear regression analysis, no correlation existed between the 24-hour ~23Iuptake value of Tcl 5 or TcP. The mean of each 99mTcuptake was significantly elevated. Table II indicates that sensitivity for diagnosing hyperthyroidism in patients with untreated Graves disease by 99rnTc uptake was >90% when Tcl5 was considered alone and together with Tcl0 (Figure) or by the product TcP. Specificity for diagnosis by 991nTc uptake using Tel0 or TcP was ~90%. The T3 and T4 levels correlated significantly With Tcl5 and TcP (r = 0.4-0.6, P <0.01). The r values improved consistently with log/log transformation of the data prior to linear regression analysis, suggesting that the sample was skewed. During the period of observation, 12 patients entered and remained in remission for >2 years, and another five patients entered and remained in remission for >6 months. Twelve others underwent subtotal thyroidectomy; three were lost to follow-up; and 13 continued with antithyroid medication. Of the 17 patients experiencing clinical remission for _>6 months, t4 were evaluated at termination of medical treatment or within 4 weeks of discontinuation (Table III). All of their Tc15 and TcP values were within the normal range; only one Tel0 value was abnormal at 1.3. Eight of these 17 patients in remission were examined before therapy (Table IV); their Serum values did not differ
Table III. Tc uptake ratios obtained at discontinuation of medical therapy in 14 patients who remain in prolonged remission after termination of medical therapy
Tcl0 Tcl5 TcP
907
99mTc ratios in Graves disease
l~olume 107 Iiumber 6
Remission (~ • l SD)
Expected normal (range)
1.06 +- 0.09 4.26 _+ 0,73 4.51 • 0.93
0.86-1.22 1.92-5.96 1.52-6.75
56
9
II
52 28 24 20
Table IV. Tc uptake ratios in eight patients, at enrollment and at start of prolonged remission
6o
18
(..) I-
16
m
12
is
XxY=6Y5
n
i
8 Diagnosis
Tcl0 TcI5 TcP
1.29 • 0.06* 9.95 • 3.36 12.93• 4.82
Remission
D(fJ'erence
P
t.09 _+ 0.12 0.20 • 0.12 0.001 4.31 _+ 0.67 5.64 • 3.10 <0.001 4.69 • 0.86 8.24 _+ 4.37 <0.001
4 ,~j
0.0
I
I
0.6 0.8
I
1.0
I
1.2
I
1.4
I
1.6
I
I
I
1.8 2.0 2.2
TCIO
V a l u e s r e p r e s e n t m e a n _+ 1 S D .
significantly from those of the rest of the group (Table I). During remission, each Tcl 5 and TcP value and all but one T e l 0 value were within the normal euthyroid range. With prolonged clinical remission, a highly significant improvement was noted by paired t testing (Table IV). During the study period three patients had a return to normal of 99mTc ratios; they experienced remission for >6 months, but then relapsed. The 99mTc ratios at the time of relapse were no different than the ratios at-the time of initial diagnosis. Medical therapy for Graves disease often induces a state of relative hypothyroidism (T4 <5 ~g/dl or T S H >5 #U/ml). Among our patients, 19 episodes of hypothyroidism were noted in 13 patients in whom pretreatment uptakes were known. Highly significant increases occurred in Tcl5 and TcP (Table V) in response to excessive medical suppression. In seven of these patients the study obtained 4 months later was done while they were euthyroid with corrected medical treatment. Among these seven, highly significant decreases of Tcl5 and TcP were noted (Table IV). Overall, the 99roTe uptakes in patients with iatrogenic hypothyroidism in Graves disease were much greater than values in a cohort of children with acquired or congenital hypothyroidism? DISCUSSION Administration of PTU or M M I is the treatment of choice for most pediatric patients with Graves disease? 5 Controversy remains as to how long medical therapy should be sustained before considering cessation of treatment. Twelve to 24 months of continuous biochemical c o n t r o l is generally (but not universally) recommended. No reliable biochemical test provides the clinician with
Figure. Tcl 0 and Tcl5 for each patient (n = 33) before treatment. Box represents mean • 2 SD for Tcl0 and Tcl5. Curve (X • Y = 6.75) represents mean • 2 SD for TcP. adequate specificity for detection of remission. Patients with Graves disease who are positive for HLA-B8 and HLA-DR3 phenotypes were thought to be at greater risk for relapse after therapy was discontinued, but this conclusion has been refuted, and at best specificity was 66%?,~5 Research laboratories and a few commercial reference laboratories now can assay the IgG class immunoglobulin thought to cause thyrotoxicosis by direct stimulation of the TSH receptor or membrane-bound adenylate cyclase system. Decreasing titers of TSAb can suggest remission of disease, but sensitivity and specificity of these titers are not adequate for clinical use}, 3,15 An in vivo assay for TSAb is the 99mTcthyroid uptake. Regardless of which cell surface pathway is stimulated to increase generation of thyroid cyclic adenosine monophosphate, the iodine trapping mechanism and therefore the 99mTC uptake value should be stimulated. 4 That 99mTc is only trapped and not organified, as is iodine, is not a liability. Indeed, because of this limitation, the uptake can be measured during treatment? ~ ~2,t3.15.~%20Assurance that remission had occurred before stopping antithyroid medication would be a significant advantage. In our patients, the mean99mTc values were uniformly elevated at the time of diagnosis and of relapse. Although not completely accurate, the use of either T c l 0 with Tcl 5 or TcP alone was 90% to 94% sensitive and 79% to 90% specific for confirmation of hyperthyroidism, and equal to the percentages found in adults?, 5 When the test was used to determine only whether our patients were hyperthyroid or euthyroid, specifici(y rose to 91% to 98%. Several authors have observed that 99mTc uptake or
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Duck and Sty
The Journal o f Pediatrics December 1985
Table V. Graves disease and effect of excessive and appropriate medical treatment
Tel0 Tcl5 TcP
No treatment
Excessive treatment (n = 19)
Mean difference
1.28 _+ 0.17" 9.90 • 3.64 13.11 • 6.01
1.28 +_ 0.17 20.62 • 7.19 27.59 • 13.07
0.001 • 0.21 -10.72 + 9.01 -14.47 • 14.71
P
Excessive treatment
NS 1.23 _+ 0.15 < 0 . 0 0 1 21.07 • 8.49 <0.01 26.79 _+ 13.01
Corrected treatment (n = 7)
Mean difference
P
1.24 • 0.19 8.11 • 1.35 10.25 • 3.05
-0.0l • 0.10 12.96 • 7.79 16.54 _+ 11.41
NS <0.01 <0.005
Values representmean • 1 SD.
ratios correlate well with serum T3 and T 4 levels, and suggest that 99mTc values could be used prospectively to determine when medical treatment can be discontinued safely.6-9,14 Gossage et al. 6 noted that 99mTc absolute percentage values did not correlate with their assay method for TSAb titers at diagnosis, but did show significant correlation with the TSAb titers during treatment. The lack of correlation between 99mTc values and 24hour iodine uptake was also found by those who evaluated patients with Graves disease as a separate g r o u p . 4,13,21 Correlation was significant only when patients with euthyroid diseases and those with hyperthyroid diseases were analyzed together. 4 The explanation for this discrepancy is unknown. Fifteen (88%) of 17 patients in whom 99mTc uptake ratios normalized remained in remission for at least 6 months, with the majority in remission for >2 years. One of two patients who relapsed within 3 months of discontinuation of ant• medication received treatment for an additional 8 months. She once again normalized, 99mTc uptakes ratios once again normalized, and the patient has been in remission for >6 months without medication. Few others have prospectively followed patients with Graves disease, but they have found that as 99mTcvalues normalized, long-term remission often follows. 6,1~ This test cannot be expected to predict who will experience permanent remission, because it is an in vivo indicator of TSAb activity?, ~oOur results suggest that with normalization of 99mTc uptakes, ant• medication can be safely stopped.6,~0, u Failure to normalize 99mTcvalues indicates that the patient will likely rapidly relapse. 6,t~ Medical treatment is children can involve drug dosage adjustment to maintain euthyroidism or complete thyroid suppression followed by addition of L-thyroxine replacement. Because the former approach was used and because the disease varied unpredictably, states of relative hypothyroidism (T4 <5 #g/dl, TSH >5 ~zU/ml) were induced in several patients. The highest values of Tcl5 and TcP were seen secondary to this iatrogenic hypothyroid state, and resulted from a combination of endogenous TSH plus TSAb activity. However, in seven patients examined 4 months later, during appropriate drug therapy, the magni-
tude of the fall in 99mTcuptake ratios was related presumably to TSH alone. Indeed, the order of magnitude of the rise or fall in Tel5 (10.7 to 13.0) and TcP (14.5 to 16.5) secondary to TSH is approximately two times the rise caused by TSAb alone (Tables IV and V). Others have studied the impact of PTU and TSH on 99mTc values. 8,tS'2~ Those showing no effect of P T U / M M I in normal subjects administered the drug to patients for only 3 daysJ 8,2~A standard 3-day stimulation test with TSH increased the 99mTc value by up to three-fold (mean of one-fold).8,18 We believe, but cannot prove, that any marked elevation of Tcl5 and TcP observed in our patients who were receiving treatment and euthyroid represents TSH-dependent trapping activity. If 99mTc uptake ratios are used to assess the time for discontinuation of P T U / M M I treatment, then we suggest that not only the thyroid activity be suppressed but also that the patient be given replacement L-thyroxine therapy. This would preclude any TSH-dependent activity as measured by 99mTC uptake. Double drug treatment regimens should eliminate any ambivalence as to whether disease or TSH-dependent activity caused a change in 99roTevalues. Goolden et alJ 2 observed a rebound elevation in 99rnTc values a month after discontinuation of both ant• drugs and orally administered T3. We did not administer T3 orally, and saw no such rebound except in those individuals who relapsed. Several have commented that this test can give misleading results in patients with subacute thyroiditis, nodular hyperthyroidism, or relapse of Graves disease after unsuccessful 13~Iablation?, 7,2~,23 The precise biochemical explanations are unproved. Where these occur, the 99mTc test should not be used. Care should be taken to establish whether increased 99roTe values in pretreated Graves disease are TSH dependent. Limited information is available on the impact of drugs and other agents (i.e., iodine-containing compounds) known to alter radioiodine uptake values. 99mTcratios are less adversely affected by iodine containing contrast dyes. 5 Diagnosis is not the major indication for 99mTc ratio
Volume 107 Number 6
determination in patients with Graves disease. S e r u m T3 and T4 levels and the clinical presentation are usually sufficient for establishing the diagnosis. If thyroid uptake determination is clinically indicated in an unusual patient, ~23Iodine remains the a g e n t of choice, with determinations done approximately 2, 6, and 24 hours after administration. 99mTc ratios are useful at diagnosis primarily for establishing a baseline value, 99mTc ratios are principally useful when obtained prospectively to assess clinical remission while the patient continues to receive treatment. As a n in vivo test of T S A b titer, the ratio does not establish the presence of long-term remission. Our work indicates t h a t normalization of all three ratios is a very favorable index for remission. If 99mTc ratios are to be followed, concomitant L-thyroxine t r e a t m e n t is suggested in those patients whose thyroid activity was first suppressed by P T U a n d MMI. REFERENCES 1. Allannic H, Fauchet R, Lorcy Y, Gueguen M, LeGuerrierA-M, Genetet B. A prospective study of the relationship between relapse of hyperthyroid Graves' disease after antithyroid drugs and HLA haplotype. J Clin Endocrinol Metab 1983;57:719-222. 2. Madec AM, Laurent MC, Lorcy Y, LeGuerrier AM, Rostagnat-Stefanutti A, Orgiazzi J, Allannic H. Thyroid stimulating antibodies: an aid to the strategy of treatment of Graves' disease. Clin Endocrinol 1984;21:247-255. 3. Hensen J, Kotulla P, Finke R, Badenhoop K, Koppenhagen K, Meinhold H, Schleusener H. Ten years experience with consecutive measurement of thyrotropin binding inhibiting antibodies. J Endocrinol Invest 1984;7:215-220. 4. Duck SC, Sty J. 99mTechnetium throid uptake ratios in a pediatric population with suspected common diseases (unpublished data). 5. Schneider PB. Simple, rapid thyroid function testing with 99mTc-pertechnetate thyroid uptake and neck/thigh ratio. A JR 1979;132:249-253. 6. Gossage AAR, Crawley JCW, Copping S, Hinge D, Himsworth RL. Graves' disease: thyroid function and immunologic activity. J Nucl Med 1982;23:973-977. 7. Marion MA, Ronai PM, Pain RW, Wise PH. Simultaneous assessment of thyroid structure and function with the gamma camera using perteehnetate: a comparison with radioiodine and biochemical diagnosis. Aust NZ J Med 1974;4:379384. 8. Atkins HL, Richards P. Assessment of thyroid function and
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