Radiol Oncol 19%; 3(): 2.5.5-9.
Follow-up study of autonomous thyroid adenoma treated with I-131
Vera Dolgova-Korubin, Nina Simova, Vukosava Bogdanova, Nikola Serafimov,
Isak S. Tadzer
Institute of Pathophysiology and Nuclear Medicine, Medical Faculty, Skopje, Macedonia
Twenty seven ¡lalients with autonomously functioning thyroid adenoma (AFTA), clinically and laboratory euthyroid were treated with 1-131. A acriterion for the therapy was the scintigraphic appearance of AFTA "hot", and suppressed TRH response of the patients. The mean weight of AFTA was 50.03 ± 28.5 g, administered radioactivity was 13.3 ± 6.1 MBq per g tissue, and estimated radiation was 262.2 ± 129.9 Gy. Examinations in the follow-up period of 2-36 months included clinical and laboratory testing, TRH test and thyroid scintigraphy.
After the therapy. AFTA became impalpable in 14 (51.8 %) patients, decreased in 7 (26.0 %) and did not change in 6 (22 %). All patients remained euthyroid by all criteria, with normal TRH test in 26 (96 %) of them. Two months afier the therapy, transitory suppression or exaggeration of TRH test, was found in 3 and
1 patienl resp, but spontaneous rl'slilution occurred later in ali but one, where TRH remained suppressed (3.7 % ofall). AFTA appeared cold oil the scan of'92.6 % of the treated patients. There was no hypothyroidism afier the therapy. This and the achievement of ablation or reduction of the nodules in most of the patients, support the opinion that patients with AFTA and suppressed TRH test, even when euthyroid, should be treated with 1-131.
Key words: thyroid neoplasms: adenoma-therapy; iodine radioisotopes; follow-up studies
Introduction
Plummer's disease is a thyroid disorder in which a part of the tissue is functioning autonomously and the rest of the gland is normally responding to feedback mechanisms. It is presented by a spectrum of structural and functional abnormalities which include solitary or multiple nodules, or numerous autonomous centers, and autonomous production of hormones in normal or excessive quantity.12 The last is crucial for the clinical presentation of the disorder. When an autonomously functioning thyroid adenoma (AFfA) produces clinically overt hyperthyroidism, the therapy should be radically-
Correspondence lo: Prof'. Vera-Dolgova-Korubin, M.D., Ph.D., Medical Faculty Skopje. Institute of' Pathophysiology and Nuclear Medicine, Bodnjanska 17. 9100 Skopje, Macedonia.
UDC: 616.44l-"6.6-08:849.2
surgical or with radio iodine, sometimes after a short-lasting medicamentous treatment.2
The treatment of AFrA in euthyroid patients rises many questions: is it necessary, in which cases and when, and what kind of therapy? Euthyroid clinical picture may be associated with different biological behavior of AFrA: compensated or decompensated, i.e. scintigraphically presented as iso-fixant or hiperfixant - "warm" or "hot" nodule, comparing to surrounding tissue.) Normal serum levels of T4, T3 and even TSH, may be associated with a suppressed response to TRH stimulation as a first sign of disorder.5 Keeping in mind the slow evolution of AFrA and the possibility of spontaneous destruction of adenomatous tissue45 many clinicians hesitate to choose a radical therapy. But the follow-up studies of many cases show steady progression of the disease in some patients, which may cause heart damage,1'' and Belfiore et al.7 found that it happened in a higher percent of patients from
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Do/gova-Korubin Vet al.
iodine deficient regions than in those from other regions.
Here we present results of radioiodine treatment of euthyroid patients with AFfA and our attitude to that problem.
Material and methods
The study includes 27 patients with AFTA, clinically, euthyroid, who were treated with 1-131 and subsequently followed-up. The diagnosis of AFTA and evaluatiion of clinical status were based on clinical, laboratory and scintigraphic examinations. Biologic behavior of AFTA was assessed by TRH-test response, as the serum thyroxine (T4) and triiodothyronine (T3) were in normal range. The therapy was accomplished by oral application of radio-iodine dose, calculated according to the weight of AFfA and 24h-uptake of 1-13 l. Follow-up evaluation included clinical and laboratory estimation of the thyroid function (T4 and T3 determination, TRH response), as well as scintigraphy of the gland.
A group of 20 patients who were healthy and with palpatory and scintigraphically normal thyroid, were tested for TRH response. They were considered as a control group in this study.
T4 and T3 were determined with RIA (kits produced by "Vinca", thyrotropine (TSH) in serum was determined with IRMA (CIS) (first generation). Normal values for T4 in T3 serum concentrations: 64-160 nmol/L resp. 1,5-3,4 nmol/L. Thyroid scintigraphy was performed mostly with 1-131, after 24h of an oral do.se of 1850 KBq, or with 800 MBq of Tc-99 m, 30--40 minutes after i.v. application. The weights of the nodules were determined by calculating their volumes as ellipsoids (diameters were measured by the scintigraphic imaging of the gland). This method had been proven by comparing the weights of operated nodules with calculated ones by their scans8 (before introduction of ultrasound measurement). TRH test was performed by i.v. application of 200 pg Relefact TRH (Hoechst, AG) and serum TSH was determined in 0,30 and 60 min. after the application.
the patients was 36-72 years, mean 53.48 ± 7.96, and the age of the control patients 40.38 ± 10.89 years. In 23 (85 %) patients there was a solitary nodule and in 4 (15 % of ali) there were 2 nodules. The nodules in ali patients were "hot" by scintigra-phy and surrounding tissue was completely suppressed. Most of the patients were clinically normal and some of them only with mild and common complaints, as slight nervousness of fatigue. T4 na T3 serum levels were in normal range. but their mean values were statistically higher that in controls (Figure 1). TSH values were in normal range as well, ranging 0.5-0.4 pU/ml. TRH test was abnormal - unresponsive in ali: no increase of TSH serum level was recorded after 30 or 60 min. of TRH injection, or the increase was minimal, not exceeding 1.5 pU/ml over basal level in 13 patients. As a normal response to TRH stimulation (positive response) it is considered an increasing of TSH level after 30 min. or more than 3 but less than 25 pU/ml, a criterion accepted by many authors.3- "■ 10 TRH test in the contol group showed an average elevation of TSH of 10.81 ± 4.2 pU/ml.
nmol/1 150 p 135 -120 -105 -BOOS -060 -45 -30 -15 -0 t
T4
T3
*	rn
II	
0
nmol/ ■3 4.6
-	4.1
-	3.7
-	3.2
-	2.8
-	2.3
-	1.8
-	1.4
-	0.9
-	o.s Jo.O
p<0.05 1 - Controls. 2 -
Before treatment. 3
p<0.01 -After treatment
Figure l. T4 and T3 in CONTROLS and in AFTA BEFORE AND AFfER 1-U I TREATMENT
The data on the weights of AFfA and the applied radiotherapy are given on Table 1. The follow-up period after the therapy was 2-36 months (mean 14.J ± 12.0).
Table l. 1-131 Treatment of autonomously functioning thyroid adenoma (AFTA). 27 patients.
Results
Only two of the patients with AFTA were men (7 %), so that women/men ratio was 12,5/1. Age of
	Mean±SD		Range
Weight of AFTA (g)	50.0 ±	28.5	19-32
24h 1-131 uptake	44.5 ±	12.1	27-78
Dose ofi-131 (MBq)	1090.8	± 244.2	740-1850
1-131/g AFTA (MBq)	i 2.i ±	6.1	3.4-23
Radiation in AFTA (Gy/g)	262.2 :	± 129.8	73.5-508
Follow-up .study of autonomous thyroid adenoma Heated with /-13!
257
The clinical state in all patients remained euthyroid. The change of the size and scintigraphic appearance of AFTA is presented on Table 2. T4 and T3 levels decreased and although remained in normal range, their mean value, did not differ significantly from that of the control group (Figure 1).
Table 2. Follow-up of 27 patients with AFTA: findings of palpation. thyroid scintigraphy and TRH test (alter the therapy).
Reduction ofAFTA size (by palpation):		
Not palpable any more	14	51.8
Reduced in size	7	26.0
Remained unchanged	6	22.2
Scintigraphic appearance:		
Cold nodule	25	92.6
lsofixant nodule	2	7.4
Hot nodule	o	o
TRH -Test:		
(Elevation ofTSH levels -.30 min.)		
Normal (.3-25 |jU/ml)	26	96.3
Negative (.3 |jU/ml)	1	3.7
TRH test was performed in the follow-up period in all patients, at different times. It was normal in 22 of them and abnormal in 4: in 3 it was negative (increase of TSH less than 3 pU/ml at 30 min.), and in one, basal TSH was elevated and the test was exaggerated (Table 3). These patients were tested two months alter the therapy, as were other 9 patients whose TRH test was normal. Repeated testing of those with abnormal test alter 4-36 months, did not show abnormality in three of them and only one patient had a suppressed TRH response, even alter 36 months. The nodule of the patient weighted 132 g and it received a lower radiation doses (86.5 Gy), but in spite of that, the nodule became impalpable and "cold" on scan.
Table 3. Patients with abnormal TRH response two months alter 1-1.31 therapy.
Pat. No.	1-131 dosis	Radiation	No. monlh	TRH le M	TSH (pUliiil)	
			aller 1-1U			
	(MBq/g)	(GyIg)		Basal	30 min.	Mî min.
J.D.	10.5	227.0	2	0.5	3.4	1.9
			22	3.2	10.4	8.1
M.A.+	4.0	86.5	2	0.5	0.6	0.6
			36	2.3	3.8	3.3
J.S.	3.6	77.9	2	2.4	5.1	4.5
			15	1.6	12.7	9.7
G.S.	14.3	309.0	2	16.0	46.0	40.0
			36	0.5	11.8	8.8
+ - the patient wilh persistent suppressed TRH response
Discussion
It is generally accepted that AFTA which causes hyperthyroidism should be treated radically - by surgical or radioiodine treatment. The data of many studies show that relapses and hypothyrosis after the treatment are very rare, in contrast to Graves' disease, where they occur in much higher per-cent.2-5 '" '' The treatment of euthyroid patients with AFTA (solitary or multiple) is a matter of individual consideration, depending on different factors.12 Since the early and later application of TRH test, has shown that it can discover subclinical hyperthy-roidism'1"'1" and so to help in decision-making for therapy. Discovering a disturbed thyroid function at its very beginning by TRH-test, is not of pure academic interest. Correcting it, an overt thyrotoxicosis may be prevented (which in older age is usually oligosymptomatic, manifested as a heart disease). Although progression of euthyroid AFTA to toxic nodule and hyperthyroidism is slow and not very frequent/" we observed it in 35 out of 181 euthyroid patients, followed-up during a period of 0,5-15 years, with statistical probability of 6,65 % to become hyperthyroid.5 At last, one can not exclude the possibility of "Tissue hyperthyroidism" although not proved by laboratory findings.
All of our patients were euthyroid, with serum concentrations of T4, T3 and TSH in normal range (although statistically higher than in controls), but TRH test and scintigraphy revealed abnormal biological behavior of AFfA. Even in that case one may pose the question of the reason for therapy. Treatment of clinically and laboratory euthyroid patients if they are not young and their AFTA is large, is recommend by McConahey.12 Our choice of radioiodine treatment for these patients was not wrong by our consideration, which could be supported by the results of the therapy:
-	all treated patients remained euthyroid, with restituted physiological regulation of the thyroid, but one. None of the patients became hypothyroid. One patient who showed a transitory, subclinical hypothyroidism (exaggerated TRH response). recovered spontaneously.
-	ablation ol' AFTA was achieved with lower doses of 1-131 than those we5 or other authors1 iJ) usualy use for treatment of AFTA in hyperthyroid patients.
-	the percentage of markedly reduced nodules is very high (77.8 % of all), so that this therapy offers also an esthetic effect and possible relief of com-
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Dol<w>va-Korubin Vet al
pressive effect of AFTA (if it were present). So, these effects, otherwi.se expected from surgical treatment, may be achieved by radiotherapy, without surgical risks.
A support of our approach to radioiodine treatment of euthyroid palients with AFTA, we found also in the excellent study of 87 thyroidectomized patients wilh Plummer's disease by WienerY He found in ihe follow-up period an unexpectedly high percenl of postoperative thyroid autonomy in the residual tissue and this suggested that radioiodine treatment could be more effective that surgical treatment.
The amount of administered radioactivity is a matter of consideration in many sludies. Although there is some relation between the dose and the success of lhe therapy (i.e. the incidence of hy-pothyroidism and failure of the therapy,"-"'1-'' many authors,1112-15 found that the incidence of hypothy-rosis is not related to the dose per gram of nodular tissue. By their experience, for its prevention is the most important: the scintigraphic appearance ofthe extra nodular tissue before the administration of 1-131 should be sufficienlly suppressed, with minimal iodine uptake. We agree wilh them and all of our patients were scanned shorlty before the therapy.
The finding of temporary exaggerated TSH response after the therapy in one patient, was surprising. It may be supposed that the suppressed extra-nodular tissue which was functioning below its normal capacity before the therapy, need more time for its functional recovery. There is a possibility that extranodular tissue was moderately irradiated and is in temporary hypofunction. These both possibili-lies do not exclude each other.
It is more difficult to explain the persistence of suppressed TSH response after the therapy. At two months after the therapy maybe the effecl of radiation was not compleled yet, but in the case when the nodule became cold, long time after lhe therapy the finding is unusual. As a coincidence of Grave's disease and AFTA in lhe same gland has been reported1" it may be supposed that a thyroid autonomy of surrounding lissue developed during post-treatment period.
Our experience from this study is that examinations of clinically euthyroid patienls with AFTA should be completed with TRH-test (or ultrasensitive measurement of TSH which is in use nowadays) and if it is suppressed the therapy may be taken in consideration.
Conclusions
1.	AFTA decompensated on scan could be treated if TRH test is negative, in spite of euthyroid clinical and laboratory findings.
2.	Radioiodine therapy is effective in curing the autonomy and very often in reducing the size of the nodules in doses of 3.4-23.0 MBq per g AFTA tissue.
3.	About two months after the therapy a normal TSH response is achieved in most of the treated patients. Only in few patients it restores later and for evaluation of therapeutic effect TRH-test should be repeated.
4.	Hypothyroidism after 1-131 treatment of Plummer's disease is very rare, even in euthyrotic patients with AFTA.
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