The triiodothyronine suppression test

The Triiodothyronine Suppression Test*

GERALD BURKE, M.D.

Chicago, Illinois

The results of the triiodothyronine suppression test, as performed in one hundred fifty-five patients with suspect thyroid dysfunction, are recorded. The clinical utility of this procedure as an adjunct to the laboratory diagnosis of hyperthyroidism is confirmed. The results of the present study support the validity of the criteria for normal (thyroidal) suppressibility originally set forth by Werner and Spooner. A clearly abnormal response to triiodothyronine was noted in six of twenty-one patients with nontoxic nodular goiter; this finding suggests that the usual criteria for normal suppressibility do not obtain in this group. The diagnostic and/or prognostic value of the triiodothyronine suppression test in the treated hyperthyroid patient remains the subject of conflicting opinion. The small number of patients in this category included in the present report precludes a definitive statement, but only a limited correlation between the response to triiodothyronine and recurrence of clinical hyperthyroidism was observed. Long-term clinical assessment of euthyroid patients with exophthalmos in this series indicates that a normal response to triiodothyronine militates against the ultimate development of clinical thyrotoxicosis. The recent demonstration of long-acting thyroid stimulator activity in the serum of a euthyroid exophthalmic patient unresponsive to triiodothyronine raises a number of theoretical considerations and underscores the significance of abnormal suppressibility in such cases. The importance of post-triiodothyronine 1131 uptake studies in the assessment of thyroid-stimulating hormone (TSH)-(in)dependence of hyperfunctioning thyroid nodules has been noted; the necessity for both quantitative and topographic 1131 uptake studies in these cases is emphasized.

T HE administration of exogenous thyroid hormone inhibits thyroidal radioiodine uptake

in euthyroid subjects but does not appreciably alter P uptake in hyperthyroid patients [ 7-31. More than a decade has passed since Werner and Spooner [4] systematically applied this difference in response to a clinical test as an adjunct in the diagnosis of hyperthyroidism. These investigators noted that following eight days of oral administration of 1-triiodothyronine in daily doses of 75 or 150 pg., twenty-four hour thyroidal 1131 uptake in euthyroid patients was uniformly depressed to levels of 20 per cent or less; in contrast, no value under 35 per cent was obtained in hyperthyroid patients studied in this manner.

Subsequent to this initial report a number of workers [5-701 have documented the clinical usefulness of triiodothyronine suppression studies in the differental diagnosis of hyperthyroidism. The purpose of this report is to detail our experi-

ence with the triiodothyronine suppression test as performed in the course of routine laboratory investigation of patients with clinically suspect thyroid dysfunction. The results obtained attest to the diagnostic utility of this procedure, and confirm the validity of the criteria for normal suppressibility originally set forth by Werner and Spooner.

CLINICAL MATERIALS AND METHODS

We have performed triiodothyronine suppression tests in (1) patients in whom the results of 1131 uptake studies and plasma protein-bound iodine determina- tions were at variance (patients with elevated 1131 uptakes and normal plasma protein-bound iodine levels constitute the great majority of this group, and, in fact, of the entire study population); (2) clinically hyperthyroid patients with normal or minimally elevated baseline twenty-four hour thyroidal P uptake studies; (3) the evaluation of treated hyperthyroid patients; (4) the evaluation of euthyroid patients with exophthalmos; and (5) in euthyroid

* From the Radioisotope Laboratory, Division of Metabolism and Endocrinology, Department of Medicine, Michael Reese Hospital and Medical Center, Chicago, Illinois. Manuscript received May 9, 1966.

600 AMERICAN JOURNAL OF MEDlCINE

Triiodothyronine Suppression Test--Burk-e

0 10 20 30 40 50 60 70 80 90 100

PER .CENT

24-HOUR THYROIOAL 113’ UPTAKE

FIG. 1. Histograms depicting distribution of initial twenty-four hour 113’ uptake values in euthyroid and hyperthyroid patients.

patients with solitary hyperfunctioning thyroid nodules.

These diagnostic categories constitute a patient population of one hundred fifty-five subjects in whom triiodothyronine suppression tests were performed. The results obtained and an analysis of their diagnostic validity in the laboratory assessment of suspect thyroid dysfunction comprise the subject matter of this report.

Each of the patients studied was evaluated by at least one physician in our laboratory as well as by the referring physician. A history and physical examination directed to the assessment of thyroid function was performed in each instance.

Patients listed as “normal” were obviously highly selected. They were chosen from a euthyroid patient population referred to the Radioisotope Laboratory for evaluation of clinically suspect thyroid disease; in all, one or more studies of thyroid function yielded values in or near the hyperthyroid range. Hence their baseline In1 uptake studies do not necessarily reflect the values to be obtained in a “random” or unselected euthyroid population.

Patients listed as “hyperthyroid” were either clearly thyrotoxic on clinical grounds at the time of initial evaluation or overt hyperthyroidism developed subsequent to the performance of the suppression test.

Patients with (autonomous) hyperfunctioning thyroid nodules were selected according to the criteria originally proposed by Cope et al. [77] and more recently discussed by Sheline and McCormack [72].

Twenty-four hour thyroidal uptake of radioiodine

VOL. 42, APRIL 1967

was performed in the manner of Newburger et al. [ 731. Plasma protein-bound iodine was determined by the method of Barker and associates [ 741 as modified by Grossman and Grossman [ 751.

Dosage of triiodothyronine for the suppression test was 25 pg. three times a day for eight days (total of 600 pg). Background neck counts were obtained prior to the administration of the second tracer dose of In1 to correct for any thyroidal radioactivity remaining from the initial test.

RESULTS

As can be seen from Figure 1, thyroidal P’ uptake in the clinically euthyroid patients was usually in the 40 to 60 per cent range (63 per cent of cases). Twenty-four hour uptake values in the clinically hyperthyroid population, on the other hand, were fairly evenly distributed through the 40 to 90 per cent range. The area of overlap is obviously extensive, clearly neces- sitating further studies.

Since 82 per cent of hyperthyroid patients had uptake values in excess of 50 per cent (the upper limits of normal in our laboratory), and nearly two-thirds had values over 60 per cent, the indication(s) for triiodothyronine suppression studies in this group must be examined in detail. Twelve patients in this group of thirty-four deemed clinically hyperthyroid had uptake values in the high normal or borderline elevated range (40 to 55 per cent), and this

602 Triiodothyronine Suppression Test--Burke

TABLE I

EFFECT OF TRIIODOTHYRONINE ON THYROIDAL +- UPTAKE

IN EUTHYROID AND HYPERTHYROID PATIENTS

Thyroidal Uptake of P*

Diagnosis Before Tt After Ta Decrease

(%) (%) (%)

Euthyroid 53 f15.5 14 zIzl2.4 71 f23.6 (89 cases)

Hyperthyroid 67 f 16.8 65 + 17.9 1 f21.1 (34 cases)

* Mean b 1 standard deviation.

served as the indication for confirmatory suppression studies. In the remainder protein-bound iodine values were high normal ranging from 7.0 to 8.0 pg. per 100 ml. (normal, 3.5 to 8.0 pg. per 100 ml.) despite clearly elevated Ii31 uptake studies; in each instance the triiodothyronine suppression test was employed to resolve the discrepancy between normal protein- bound iodine and elevated 1131 uptake values.

As can be seen from Table I, the thyroidal

FIG. 2. Average suppression of IL31 uptake after administration of triiodothyronine (Ta) in euthyroid patients without goiter, with diffuse and nodular goiter, and in hyperthyroid patients.

response to an eight day course of 75 pg. of triiodothyronine daily clearly differentiated between a euthyroid and a hyperthyroid population. Of the eighty-nine euthyroid patients studied, eight showed no significant suppression, and these will be discussed in detail. In seventy- one euthyroid subjects, thyroidal twenty-four hour 1131 uptake fell to 20 per cent or less, i.e., a definitely “normal” response [4]. Post-triiodothyronine uptakes in the remaining ten euthyroid patients ranged from 21 to 30 per cent. Although these data might be termed equivocal, the per cent suppression of uptake in five of these cases exceeded 50 per cent, satisfying the criteria of Silver [16] for a normal response to triiodothyronine. Six of the ten patients with post-triiodothyronine uptake values of 20 to 30 per cent had goiters, and in four of these the per cent suppression of 1131 uptake was less than 50 per cent.

Baseline twenty-four hour uptake values in the eight euthyroid patients with abnormal response to triiodothyronine ranged from 34 to 72 per cent (mean, 52 per cent). Post-triiodothyronine uptake values ranged from 35 to 62 per cent (mean, 46 per cent) and the average per cent suppression of thyroidal Im uptake was only 10 per cent. Of interest is the fact that six of these eight patients had long-standing multinodular goiters of varying size.

An attempt was made to differentiate between baseline uptake values in our euthyroid population without thyromegaly and those obtained in patients with nontoxic goiter. The data were entirely comparable in that the average baseline uptake value for the nongoitrous euthyroid population was 54 per cent (+ 14.5 S.D.) and that in euthyroid patients with goiter 52 per cent (f 16.8 SD.).

The euthyroid patient population was further subdivided into those without thyromegaly, those with diffuse goiters, and those with multinodular goiters to determine whether any meaningful differences in the response to triiodothyronine existed between group(s).

As can be seen from Figure 2, the post- triiodothyronine uptake data in the nongoitrous euthyroid group is virtually identical with that obtained in euthyroid patients with diffuse goiter. However, the per cent suppression of Im uptake by triiodothyronine in the patients with multinodular goiter is significantly different (p < 0.05) from either of the preceding groups. (As noted earlier, six of the eight euthyroid

AMERICAN JOURNAL OF MEDICINE

Triiodothyronine Suppression Test--Bwkr 603

TABLE II

EFFECT OF TRIIODOTHYRONINE ON THYROIDAL 1131 UPTAKE IN TREATED HYPERTHYROID PATIE I’>

Baseline Thyroid Function Studies

Protein- Post-T3 Decrease 1’31 Bound 1131 in 1i3i Prior Therapy and

Case Uptake Iodine Uptake uptake Time Interval Clinical Diagnosis nnd

No. (X1 (pg. 5) (%I (%I (yr.) Additional l’herapy

1 46 8.0 35 24 Surgery, 33 Euthyroid, none 2 73 5.2 28 62 Radioactive iodine, 7 Euthyroid, none 3 45 8.0 38 16 Surgery, 3 Hyperthyroid, radioactive iodine 4 52 7.4 47 10 Surgery, 1 Hyperthyroid, radioactive iodine 5 51 6.6 37 27 Surgery, 3 Euthyroid, none 6 56 8.8 31 45 Radioactive iodine, 1 Hyperthyroid, radioactive iodine

“nonresponders” are included in the group of twenty-one patients with multinodular goiter.)

,411 but two of the thirty-four clinically hyperthyroid patients had post-triiodothyronine twenty-four hour uptake values in excess of 40 per cent; in none was the per cent suppression of 1131 uptake greater than 35 per cent (per cent suppression in all but four hyperthyroid patients was <20 per cent, and the mean per cent suppression of Ii31 uptake in the group as a whole was only 1 per cent.). Post-triiodothyronine Im uptake value in one patient was 32 per cent and in another 35 per cent.

Six patients in this series had triiodothyronine suppression studies from one to thirty-three years after surgical or radioactive iodine treatment of hyperthyroidism. They had been referred to the Radioisotope Laboratory for study because of the clinical suspicion of recurrent hyperthyroidism and/or as part of a general medical evaluation by the referring physician. The clinical diagnosis and the decision regarding

(additional) radioactive iodine treatment was based on the findings on physical examination, as well as on the results of in vitro isotopic tests of thyroid function [ 77, IS] and basal metabolic rate. As can be seen from Table II, only a limited correlation between clinical status and the results of the triiodothyronine suppression tests could be made out. Abnormal post-triiodothyronine uptake values were obtained in euthyroid patients as well as in those with recurrent hyperthyroidism. Although per cent suppression of Ir31 uptake appears greater in the former, the small number of cases studied precludes an) definitive statement.

Eight patients with unilateral exophthalmos underwent triiodothyronine suppression tests after exclusion of nonendocrine causes of propto- sis (Table III). All were clinically euthyroid at the time of study, with baseline 1131 uptakes ranging from 28 to 56 per cent. Of these, six patients have remained euthyroid for periods from three to eleven years. Post-triiodothyronine twenty-

TABLE III

EFFECT OF TRIIODOTHYRONINE ON Ila’ UPTAKE IN EUTHYROID PATIENTS WITH EXOPHTHALMOS

Case Age No. (yr.)

1 59 2 55 3 22 4 45 5 39 6 66 7 55 8 30

Baseline Thyroid Function Studies

Protein- 1’31 Bound Post-T2 Change in Follow-up

Uptake Iodine 1’s’ Uptake Ii3i Uptake Period

(%) (ccg. %) (%I (%I Goiter (yr.1

56 5.6 62 +11 Diffuse l/6 44 8.0 25 -43 0 6 41 3.7 30 -27 0 l/2 44 4.7 26 -41 Diffuse 11 36 5.6 14 -61 0 6 36 . . . 03 -92 Diffuse 3 32 6.6 11 -66 0 10 28 . . 05 -83 Diffuse 11

VOL. 42, APRIL 1967

604 Triiodothyronine Suppression Test-Burke

TABLE IV

EFFECT OF TRIIODOTHYRONINE ON THYROIDAL Ilsl UPTAKE AND THYROID SCAN IN PATIENTS WITH

A HYPERFUNCTIONING NODULE*

Case No.

Initial Uptake Change in Ini Within Nodule

Uptake After Tt I’si Uptake Initial Scan

(%I (%I (%I Scan After Ta

Ini in Remaining Thyroid Tissue

Initial Scan Scan After T)

1 38 40 2 36 42 3 29 31 4 38 13 5 43 25 6 44 40 7 20 13 8 32 21 9 45 35

10 65 65 11 44 44 12 37 43 13 48 33 14 52 33 15 46 31 16 38 19 17 59 49 18 66 29

Mean 43 34 SD. 11.8 13.1

+05 $17 +07 -66 -42 -09 -35 -34 -22

0 +1:

-31 -36 -33 -50 -17 -56

-21 25.1

All No change None No change All No change None No change All No change None No change All No change None No change

Nearly all No change Very little Slight decrease All No change None No change

Nearly all Slight decrease Very little Slight decrease Nearly all No change Very little No change

All Slight decrease None No change All No change None No change All No change None No change All No change None No change All Slight decrease None No change All No change None No change All No change None No change All No change None No change

Nearly all No change Very little No change All No change None No change

* All patients in this group were euthyroid and had a characteristic response to exogenous TSH with moderate to marked increase in Pai uptake by extranodular thyroid tissue.

four hour uptakes in this group ranged from

26 to 3 per cent, and suppression of In1 uptake varied from 41 to 92 per cent. Two patients studied recently have shown little (Case 3) or no (Case 1) response to triiodothyronine. Case 1, a fifty-nine year old woman with a diffuse goiter antedating the onset of unilateral exophthalmos by six months, is of particular interest because of the presence of long-acting thyroid stimulator [ 791 in her serum (see “Comments”).

Twenty-four hour I13i uptake studies as well as thyroid scintiscans were performed prior to and following an eight day course of 600 pg. of triiodothyronine in eighteen patients with hyperfunctioning solitary thyroid nodules. All patients studied were clinically euthyroid and had normal plasma protein-bound iodine levels.

As would be anticipated [77,72], the P uptake pattern on scintiscan was uniformly un- affected by triiodothyronine administration. In four instances, however (Cases 4, 5, 16 and 18), this was accompanied by a decrease in the twenty-four hour Ii31 uptake ranging from 42 to 66 per cent of the pretriiodothyronine value (Table rv). Since in all these instances 1’” uptake was essentially restricted to the palpable

nodule only, the decrease in the twenty-four hour uptake value reflects intranodular response and suggests partial TSH dependence of the “autonomous” nodules in these four patients

( see “Comments”). Baseline twenty-four hour Im uptake values were found to range from a low normal of 20 per cent to a “hyperthyroid” level of 66 per cent, confirming the wide spread in 1131 uptake values noted in previously published reports [ZO]. There was no correlation between initial uptake values and clinical status (all patients were euthyroid), nor was there any relationship between baseline Ii3i uptake and the degree of suppression (if any) by administered triiodothyronine. The mean post-triiodothyronine uptake value and per cent suppression of 1131 uptake in this group, although abnormal by Werner’s [4] and Silver’s [76] criteria, differed significantly from the hyperthyroid population (p <0.05) as well as from the euthyroid population as a whole (p <0.05).

COMMENTS

Lack of suppression of thyroid function by exogenous thyroid hormone is a characteristic finding in spontaneous hyperthyroidism [2],


Triiodothyronine Suppression Test-Burke GO5

although the mechanism(s) involved remain(s) to be fully elucidated [21]. In any event, the concept that virtually all thyrotoxic patients demonstrate this failure of functional suppression by administered thyroid hormone underlies the potential diagnostic value of a practical clinical test which would clearly place a maxi- mum number of euthyroid subjects in the “suppressible” categor>-.

In 1948 Skanse and Riggs [22] noted that in factitious hy-perthy-roidism resulting from the excessive ingestion of thyroid extract in obese patients the amount of administered radioiodine excreted in the urine was increased, in marked contrast to the low urinary 1131 excretion in spontaneous hyperthyroidism. Subsequently, LVerner and co-workers [I] established that, in contrast to normal euthyroid subjects, a series of seventeen thyrotoxic patients showed no modification of thyroidal P uptake, despite the daily ingestion of more than 700 mg. of thyroid extract for periods varying from one to eight weeks. The studies of Greer and Smith 123,241 confirmed these findings. These investigators administered 3 gr. of thyroid extract daily for a one week period to euthyroid subjects as well as to patients with Graves’ disease. Twenty-four hour thyroidal 1131 uptake in the euthyroid population fell to levels below 20 per cent whereas in hyperthyroid patients the change in 1131 uptake was minimal, even though in some instances larger doses of thyroid extract were used.

The subsequent use of purified l-thyroxine, instead of thyroid extract, yielded entirely comparable data. Oddie et al. [25] showed that a daily 0.4 rng. dose of l-thyroxine for twenty-one da)-s effectively separated the mode of response of euthyroid from hyperthyroid patients, although a zone of overlap between a few euthyroid goitrous subjects and some hyperthyroid patients was noted.

Because of its greater potency and particularly because of a shorter biologic half-life, triiodothyronine was introduced as a test agent for thyroidal suppression studies by Werner and Spooner [4] in 1955. This diagnostic procedure has undergone many years of trial, and the results obtained [26] have on the whole confirmed Werner’s initial conclusion that “. . . the difference in the response to triiodothyronine between patients with active Graves’ disease and those with other related conditions provides a useful diagnostic test.”

TABLE v

REPORTED PROTOCOLS FOR TRIIODOTHYKONINE

SUPPRESSION TEST

Source

Daily Dose Duration

(pg.1 (days)

Werner, Spooner [4] 75 8 Perlmutter, Slater [5] 35-75 14 McConahey, Owen [CT] 2.5-140 3-5 Derome et al. [7] 75-200 10 Dresner, Schneeberg [8] 300 2 Hales et al. [Q] 120-150 7 Villela Pedras et al. [RI] 80-l 00 S-10

As can be seen from Table v, the daily dose of triiodothyronine and the duration of the test have varied in the hands of different workers. Dresner and Schneeberg [8] described good statistical separation of hyperthyroid from euthyroid patients following the administration of 300 pg. of triiodothyronine for two days. Although the data of Bakke et al. [27] indicate that the human pituitary is depleted of thyrotropin by the administration of lesser doses of triiodothyronine over the same period, there is ample clinical evidence [9,70,28] that a significant number of euthyroid patients require a longer duration of triiodothyronine therapy, even at doses of this magnitude, for adequate suppression of 1131 uptake. Even with daily doses of 450 pg. of triiodothyronine, Hales et al. [9] noted instances in which euthyroid patients remained unresponsive after four days of treatment, although smaller quantities of hormone were effective in reducing the 1131 uptake in seven days. It would seem, therefore, that within practical limits, duration is more important than dosage in the triiodothyronine suppression test. It is generally agreed [26] that for careful investigative purposes the protocol (75 pg. triiodothyronine daily for eight days) originally proposed by Werner and Spooner represents the method of choice.

The multiplicity of modifications in this original protocol, however, has in itself been a limiting factor in the long-term assessment of Werner’s original criteria for normal siippressi- bility. Thus in a recent review Sisson [26] has stated: “For best results, the criteria for normal and abnormal suppressibility should be developed in the individual laboratory.” It was thought therefore, that a re-evaluation of the diagnostic validity of Werner’s criteria em-


ploying the regimen he and Spooner originally reported might be of some interest.

The present study indicates that the effect on twenty-four hour thyroidal 1131 uptake of an eight day regimen of 75 pg. of triiodothyronine effects a clear-cut separation between thyrotoxic patients and euthyroid subjects without thyroid disease. All but two of the thirty-four thyrotoxic patients in this series had post-triiodothyronine twenty-four hour uptake values in excess of 40 per cent, and in only one instance was the final uptake less than the 35 per cent value cited by Werner as the lowest obtained in a hyperthyroid population.

As was noted earlier, euthyroid subjects without thyromegaly could not be differentiated from those with diffuse goiter by their response to triiodothyronine ; in this group of sixty-eight patients, post-triiodothyronine twenty-four hour uptake values of 25 per cent or less were obtained in fifty-nine; of the remainder only two had values exceeding 30 per cent. Werner 1291 and Silver [76] have recently suggested that an additional criterion for normal suppressibility is that the 1131 uptake after hormonal treatment should be less than half the baseline value; such was the case in all but four of the sixty- eight euthyroid subjects (with or without diffuse goiter) in this series.

In their original publication, Werner and Spooner noted that even though patients with nontoxic diffuse goiter responded like normal subjects to the administration of triiodothyronine, five of twenty-one patients with nontoxic nodular goiter showed no response to triiodothyronine administration, even though the initial uptake values were within the normal range. Therefore it is of interest that of the twenty-one euthyroid patients with multinodular goiter in our series, no less than six showed no response to triiodothyronine and thus represent the basis for distinguishing this group from the remainder of the euthyroid population. As noted earlier, these patients also account for all but two of the eight euthyroid subjects with “abnormal suppressibility” (post-triiodothyronine twenty-four hour uptakevalues in excess of 35 per cent). This finding has been confirmed by others but the pathogenesis of an abnormal pituitary- thyroid axis in (some) patients with nontoxic multinodular goiter remains obscure [ 70,281.

In their initial review, Werner and Spooner noted that a normal response to triiodothyronine was obtained in all but two of twelve treated

hyperthyroid patients, and that in these two overt hyperthyroidism developed shortly. It was therefore suspected that the use of triiodothyronine might have prognostic as well as diagnostic value, although in a subsequent series [30] Werner cautioned: “The possibility that the response to triiodothyronine may be abnormal despite euthyroidism in patients previously treated for hyperthyroidism must be taken into account when the triiodothyronine test is used in the diagnosis of recurrent hyperthyroidism.” As might be anticipated, reports in the years that followed have been conflicting. Thus Hales [37] and Cassidy [32,33] have reported that persistence of unsuppressible thyroid function following the treatment of hyperthyroidism (by any modality) is often associated with continuing or recurrent disease, whereas normal suppressibility has a good correlation with permanent cure. On the other hand, e)sterg$rd Kristensen et al. [34] have indicated that glandular function following sub- total thyroidectomy in previously thyrotoxic patients frequently cannot be suppressed. As already mentioned, Werner [30] obtained varying results in the nine treated patients studied, even though all remained clinically euthyroid. Most recently, Friis [35] has concluded that the triiodothyronine suppression test has only limited prognostic value in estimating the likelihood of recurrence of hyperthyroidism after discontinu- ation of antithyroid medication.

Only six patients with treated hyperthyroidism are included in the present series. Post- triiodothyronine uptake values were abnormal in euthyroid subjects as well as in those patients with recurrent thyrotoxicosis, but the small number of cases studied precludes any definitive statement as to the diagnostic and/or prognostic validity of the triiodothyronine suppression test in treated hyperthyroidism. This limited experience reflects a greater reliance in our laboratory on other indices of thyroid function [77,18,36] in the assessment of the treated hyperthyroid patient.

The diagnostic value of triiodothyronine suppression studies in euthyroid patients with the early eye signs of Graves’ disease has been well documented [3,4,6]. Suppression tests, if abnormal in such patients, permit delineation of what may initially appear as obscure eye dis- orders and may be of value in predicting the onset of clinical thyrotoxicosis. Of the six patients with (unilateral) exophthalmos subject to long-


Triiodothyronine Suppression Test---Rztrke Ml7

term follow-up in the present series, all demonstrated normal or near normal response to triiodothyronine and all have remained euthyroid. (The presence or absence of goiter in these cases appears to be of no diagnostic or prognostic significance.). The clear-cut lack of suppressibility recently demonstrated in the patient with serum long-acting thvroid stimulator activity is of manifest interest, since the production of this abnormal humoral substance has been suggested as a pathogenetic mechanism in Graves’ disease [27], and it has been speculated that this factor is responsible for the unsuppressible thyroid function found in this disorder. Moreover, long-acting thyroid stimulator activity is re- portedly more frequently demonstrable in the serums of hyperthyroid patients with ophthal- mopathy than in those without eye signs [37]. Thus, although the patient in question is pres- ently euthyroid, the likelihood of the ultimate development of clinical toxicity appears great.

The diagnosis of the autonomous hyperfunctioning solitary thyroid nodule, in which function is independent of pituitary thyrotropin, is based, in part, on the lack of response to triiodothyronine administration as determined by twenty-four hour 1131 uptake and scintiscan [72,X7]. Molnar et al. [ZO] have pointed out that thyroidal accumulation of radioiodine in patients with a hyperfunctioning nodule can be meaningfully evaluated only by localization as well as quantitation. It is evident from the initial uptake data in the present series that routine In1 uptake studies would frequently have been misleading without accompanying scintiscans. Note should be made, however, of the marked decrease in (intranodular) In1 uptake following triiodothyronine administration despite lack of change in thepattern of radioiodine accumulation observed in four of these cases. These findings suggest that the diagnosis of complete autonomy in a hyperfunctioning thyroid nodule must be accepted with reservations if based on the post- triiodothyronine scintiscan only. The present study indicates that “hot” thyroid nodules with sufficient hyperfunction in the adenoma to cause suppression of function in extra-adenoma- tous tissue may exhibit variable degrees of TSH-dependence, and emphasizes the necessity for both quantitative and topographic Pi uptake studies before and after triiodothyronine administration. (As was noted earlier, all patients with hyperfunctioning nodules in our study group were clinically euthyroid; a detailed

VOL. 42. APRIL 1967

account of our clinical experience with this entity will be reported elsewhere ],?X].)

REFERENCES

1. WERNER, S. C., HAMILTON, H. and NLMETH, M.

Graves’ disease: hyperthyroidism or hyper- pituitarism? J. Clin. Endocrinol., 12: 1561, 1952.

2. WERNER, S. C. and HAMILTON, H. Pituitary-thyroid relations. Lam&, 1: 796, 1953.

3. WERNER, S. C. Euthyroid patient with early eye signs of Graves’ disease. Their response to l-triiodothyronine and thyrotropin. Am. .J. 3fed., 18: 608, 1955.

4. WERNER, S. C. and SPOONER, M. A new and simple test for hyperthyroid&m employing I-triiodothyronine and the twenty-four hour Iul uptake method. Bull. New York Acad. Med., 31: 137, 1955.

5. PERLMUTTER, M. and SLATER, S. Use of thyroid hormone to differentiate between hyperthyroidism and euthyroidism. J.A.M.A., 158: 718, 1955.

6. MCCONAHEY, W. M. and OWEN, C. A., JR. Studies of the inhibitory effect of 1-triiodothyronine on thyroidal Im uptake in euthyroid persons and patients with exophthalmic goiter. \1. Clin. Endo- crinol., 16: 1480, 1956.

7. DEROME, G., MAHAUX, J. and HENRY, J. A. L’tpre- uve d’inhibition de la captation thyroidienne d’iode 131 par la 1-triiodothyronine chez les hyperthyroidies et chez les cuthyroidiens. Ann. d’Endocrinol., 18: 1030, 1957.

8. DRESNER, S. and SCHNEEBERG, N. G. Rapid radioiodine suppression test using triiodothyronine. J. Clin. Endocrinol., 18: 797, 1958.

9. HALES: I. B., MYHILL, J., ODDIE, T. H. and CLOY- DON, M. Quantitative observations with the triiodothyronine suppression test of thyroid function. J. Clin. Endocrinol., 21: 189, 1961.

10. VILLELA PEDRAS, J. A., PENNA FRANC:A, E. and PENNA FRANCA, H. Our experience with the suppression test in the diagnosis of thyroid dysfunc- tions (415 tests). Nuclear-Medirin, 3: 263, 1963.

11. COPE, O., RAWSON, R. W. and MCARTHUR, J. W. The hyperfunctioning single adenoma of the thyroid. Surg. Gynec. & Obst., 84: 415, 1947.

12. SHELINE, G. E. and MCCORMACK, K. Solitary hyperfunctioning thyroid nodules. J. Clin. Eadocrinol., 20: 1401, 1960.

13. NEWBURGER. R. A., SILVER, S., YOIIALEM, S. B. and FEITELBERG, S. Uptake and blood level of radioactive iodine in hyperthyroidism. ~l%ru England J. Med., 253: 127, 1955.

14. BARKER, S. B., HUMPHREY, M. J. and SOLEY, M. H. The clinical determination of protein-bound iodine. J. Clin. Inuest., 30: 55, 1951.

15. GROSSMAN, A. and GROSSMAN, G. F. Protein-bound iodine by alkaline incineration and a method for producing a stable cerate color. J. Clin. Endo- crinol., 15: 354, 1955.

16. SILVER, S. The thyroid gland and Im. In: Radio- active Isotopes in Medicine and Biology (Medi- cine), 2nd ed., p. 52. Philadelphia, 1962. Lea ;Ur Febiger.

17. STERLING, K. and TABACHNIK, M. Resin uptake of Im-triiodothyronine as a test of thyroid function. J. Clin. Endocrinol., 21: 456, 1961.


18. BURKE, G., METZGER, B. E. and GOLDSTEIN, M. S. Routine clinical application of an electrophoretic method for characterizing thyroid function. J. Lab. &F Clzn. Med., 63: 708, 1964.

19. MCKENZIE, J. M. Studies on the thyroid activator of hyperthyroidism. J. Clin. Endocrinol., 21 : 635, 1961.

20. MOLNAR, G. D., WILBER, R. O., LEE, R. E., WOOL- NER, L. B. and KEATING, F. R., JR. On the hyperfunctioning solitary thyroid nodule. Proc. Staff Meet. Mayo Clin., 40: 665, 1965.

21. MCKENZIE, J. M. Review: pathogenesis of Graves’ disease: role of the long-acting thyroid stimulator. J. Clin. Endomnol., 25: 301, 1965.

22. SKANSE, B. N. and RIGGS, D. S. Thyrotoxicosis factitia (alimentary thyrotoxicosis). Its differentia- tion from spontaneous thyrotoxicosis with the aid of radioactive iodine. J. Clin. Endocrinol., 8: 532, 1948.

23. GREER, M. A. The effect on endogenous thyroid activity of feeding desiccated thyroid to normal human subjects. New England J. Med., 244: 385, 1951.

24. GREER, M. A. and SMITH, G. E. Method of increas- ing the accuracy of the radioiodine uptake as a test for thyroid function by the use of dessicated thyroid. J. Clin. Endocrinol., 14: 1374, 1954.

25. ODDIE, T. H., RUNDLE, F. F., THOMAS, I. D., HALES, I. and CATT, B. Quantitative observations with the thyroxine suppression test of thyroid function. J. Clin. Endocrinol., 20: 1146, 1960.

26. SISSON, J. C. Principles of, and pitfalls in, thyroid function tests. J. Nuclear Med., 6: 853, 1965.

27. BAKKE, J. L., KAMMER, H. and LAWRENCE, N. Ef- fect of thyroid hormone on human pituitary thyroid-stimulating hormone content. J. Clin. Endocrinol., 24: 281, 1964.

28. GUINET, P. and DESCOUR, C. Etude critique du test de Werner. Rev. Lyon Mid., 11: 501, 1962.

29. WERNER, S. C. Diagnostic uses of thyroid and triiodothyronine. In: The Thyroid, p. 223. Edited by Werner, S. C. New York, 1962. Hoeber Medical Division, Harper & Row.

30. WERNER, S. C. Response to triiodothyronine as an index of persistence of disease in the thyroid rem- nant of patients in remission from hyperthyroidism. J. Clin. Invest., 35: 57, 1956.

31. HALES, L. B., MYHILL, J., ODDIE, T. H. and RUNDLE, F. F. Thyroid suppressibility after therapy for thyrotoxicosis. J. Clin. Endocrinol., 21: 569, 1961.

32. CASSIDY, C. E. and VANDERLAAN, W. P. Thyroid- suppression test in the prognosis of hyperthyroidism treated by anti-thyroid drugs. New Eng- land J. Med., 262: 1228, 1960.

33. CASSIDY, C. E. Use of a thyroid suppression test as a guide to prognosis of hyperthyroidism treated with anti-thyroid drugs. J. Clin. Endocrinol., 25: 155, 1965.

34. @STERGKRD KRISTENSEN, H. P., DYRBYE, M. and KORSGKRD CHRISTENSEN, L. Trijodtyroninsup- pressionstestens diagnostiske vaerdi ved hyper- tyreose. Ugeskr. Laeg., 125: 10, 1963.

35. FRIIS, T. The triiodothyronine suppression test in hyperthyroid patients on antithyroid medication. In: Current Topics in Thyroid Research, p. 719. New York, 1965. Academic Press, Inc.

36. BURKE, G. The radiothyroxine turnover study in the diagnosis of thyroid disease. Ann. Int. Med., 64: 1208, 1966.

37. KRISS, J. P., PLESHAKOV, V. and CHIEN, J. R. Isolation and identification of the long-acting thyroid stimulator and its relation to hyperthyroidism and circumscribed pretibial myxedema. J. Clin. Endocrinol., 24: 1005, 1964.

38. SILVERSTEIN, G. E., COGAN, S. R. and BURKE, G. The natural history of the autonomous hyperfunctioning thyroid nodule. (In preparation.)

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The triiodothyronine suppression test