Department of Endocrinology, Diabetes and Metabolism and Department of Medical Physics, “Evangelismos” Hospital, Athens, Greece
Radioactive iodine is a widely used treatment for hyperthyroidism caused by solitary autonomously functioning thyroid nodule (toxic adenoma). The aim of this retrospective analysis is to report the long term effects of this therapy on the thyroid function of patients with toxic adenoma treated in our department. Between 1968 and 1996, 160 patients received a single dose of 131I (range 25-40 mCi) for hyperthyroidism caused by toxic adenoma. In 126 of these (110 females, 26 males), follow-up was feasible either in our Endocrine Outpatient Clinic or through correspondence. The mean observation period was 5.3 years (range 1-21 years, median 4.0). Post treatment evaluation revealed that: a) 57 patients became euthyroid and remained free of disease up to the last visit (mean observation period 5.76±0.52 years, range 1-21 years, median 5 years), b) 69 patients developed hypothyroidism, all within 1 to 12 months (5.9±0.49 months), c) persistence or recurrence of the disease (ie. thyrotoxicosis) was not observed, d) the 131I dose, or the 131I pretreatment TSH levels were not different between patients who developed hypothyroidism and those who became and remained euthyroid. CONCLUSION: 131I administration in the above-mentioned dose to patients with toxic adenoma: a) was a safe and very effective therapy, and b) led to hypothyroidism which developed within the first year after 131I administration in 55% of the patients.
Toxic adenoma ,131I treatment, hypothyroidism
Solitary, autonomously functioning thyroid nodules are nodules clearly demarcated from the rest of the thyroid tissue, with autonomous function, independent of the physiological pituitary-thyroid feedback mechanism1. Autonomous hormonal secretion by the nodule suppresses pituitary TSH production, leading to various degrees of functional reduction of the remaining thyroid tissue. Thus, thyroid scintigraphy (with 131I or 99mTc) depicts a region of increased radionuclide uptake as compared to the normal extranodular thyroid tissue (i.e. hot nodule)2,3. The diagnosis of toxic adenoma is established in the presence of a “hot” thyroid nodule along with the complete suppression of the remaining thyroid tissue on scintigraphy, in combination with biochemical evidence of hyperthyroidism. The natural history of a solitary, autonomously functioning thyroid nodule, is variable; in this respect, both stability in size and function and slow increase of the size with development of clinical hyperthyroidism (toxic adenoma), are possible4,5. In rare cases, spontaneous degeneration of the nodule may occur4,5.
Treatment of toxic adenoma includes in surgical excision or ablation with 131I6-8. Both options are equally effective. Iodine administration is widely used and it has certain advantages (easy administration, avoidance of surgical intervention with potential complications, especially in the elderly), while surgery remains the treatment of choice for children and adolescents, as well as for large nodules (>3 cm)9 which are relatively radioresistant10.
In this retrospective study we present our 28-year experience of the therapeutic administration of 131I and its long term effects on thyroid function in patients with toxic adenoma.
PATIENTS AND METHODS
Of the total number of patients with toxic adenoma treated in our Department during the period 1968 - 1996, 160 patients were treated with a therapeutic dose of 131I, while the remaining had surgical treatment. Radioiodine treated patients received a single therapeutic dose of 131I. In all patients the pertechnetate 99mTc (2-3 mCi) or 131I (15-30 μCi) thyroid scanning revealed a solitary "hot" nodule with suppressed radioiodine uptake in the extanodular thyroid tissue. The selection of patients for 131I administration was based on the size of the toxic adenoma (<3 cm), unless the presence of a medical condition precluded surgery. With the exception of 20 patients treated in the initial years of our study (before 1980), all patients had received carbimazole (mean dose 15 mg daily for 4-6 months) or/and propranolol, according to the severity of thyrotoxicosis. Most patients were given low dose antithyroid drugs for a rather long period waiting for their admittance to the special ward for radiation treatment of our department. Treatment was discontinued 5 days prior to 131I administration. On the day of 131I administration, 128 patients were euthyroid and 32 were marginally hyperthyroid with slightly increased serum total T3 and/or suppressed TSH (the latter available in 1980) levels. Post treatment follow-up was feasible for 126 patients (100 women and 26 men with a mean age of 62.6±0.9 years, 97 of them were treated between 1986 and 1996). 85 patients regularly attended our outpatient clinic, while 41 patients were traced through correspondence. For the remaining 34 patients, no follow-up information could be obtained.
All 126 patients received a therapeutic dose of 25-40 mCi 131I (mean 33.9±0.6, median 30 mCi). Patients were previously informed about the possibility of post-treatment hypothyroidism and the resulting need for life-long replacement therapy with thyroxin. Post treatment follow-up ranged from 1to 21 years, (mean 5.3±0.4, median 4 years) and consisted of clinical and biochemical assessment, with TSH, T3 and T4 measurements, approximately every 2 months during the first year and at longer intervals afterwards, or until hypothyroidism was detected and life-long treatment with l-thyroxin was initiated. During the follow-up period, no patient had evidence of other disease on clinical grounds and routine biochemical screening, and none was taking medication known to interfere with thyroid function.
Serum TSH was measured by a radioimmunoassay (RIA) during the 1970s, (normal range 1-10 mU/L) an immunoradiometric assay (IRMA, International CIS, Gif-sur-Yvette, France, normal range 0.5-4.5 mU/L) from 1985-1995 and a sensitive IRMA method (Henning, Berlin, GMBH) with analytical sensitivity of 0-03 mU/L (normal range 0.3-4.0 mU/L) thereafter. T3 and T4 were measured using commercial RIA kits.
Unpaired t-test was performed for comparisons of the means of several parameters. Probability at the 5% level (P<0.05) was considered statistically significant. All results are expressed as mean±standard error of the mean. The statistical calculations were performed with the SPSS+5 version (Statistical Package for Social Science, +5, SPSS Inc, Chicago).
From the 160 patients with hyperthyroidism due to toxic adenoma, none was found hyperthyroid 2 months following 131I treatment (1st follow up visit). From the 126 patients with long term follow up (mean 5.3±0.4, median 4 years) post 131I administration, 69 (54.8%) developed hypothyroidism within the 1st post treatment year (mean 5.9±0.5 months, median 4). In 22 of these individuals hypothyroidism was evident in their 1st follow up visit (2 months after treatment). The remaining 57 patients (45.2%), who were euthyroid at 12 months, remained so for the whole follow-up period (5.76±0.5, median 5 years). No clinical and biochemical evidence of hypothyroidism and no relapse of the hyperthyroidism was observed during this period. More specifically, for 52 euthyroid patients follow-up was longer than 2 years and for 33 patients longer than 5 years.
No differences were observed between patients who became hypothyroid and those who remained euthyroid after 131I treatment of toxic adenoma, as regards age at the time of treatment, the 131I dose administered, the size of the adenoma, or pre 131I treatment TSH levels. Of the 57 patients who remained euthyroid after treatment, 54 were euthyroid on the day of 131I administration, while 3 were subclinically hyperthyroid.
Of the 69 patients who developed hypothyroidism, 40 (58.4%) were euthyroid on the day of 131I administration and 29 (41.6%) were subclinically hyperthyroid. Hypothyroidism developed earlier in patients who were euthyroid before 131I administration (within 3.63±0.64 months) than in the subclinically hyperthyroid patients, who became hypothyroid within 6.82 ±0.57 months (P=0.001). No difference was found between the two patient groups of individuals with post radiation hypothyroidism as regards age at the time of treatment, 131I dose administered and size of the adenoma (smaller or larger than 3 cm). None of our patients developed any malignancy during the follow up period.
This retrospective analysis demonstrated that a complete cure of hyperthyroidism was achieved in 100% of the 126 patients with toxic adenoma treated with an ablative dose of 131I (25-40 mCi, median 30 mCi) and no recurrence was observed during a mean follow-up period of 5.3 years. Hypothyroidism developed in approximately 55% of the patients (n=69), exclusively within the first year after radioiodine treatment, while 45% of the patients (n=57) remained euthyroid for the total duration of the follow-up.
The treatment rate of toxic adenomas and the frequency of post 131I treatment hypothyroidism vary widely, and this variability seems to correlate with the administered dose of radioiodine but not entirely (11-20, Table 1). Hence other factors must be sought for the variable responses. In the present study, we demonstrated higher treatment rates (100%) than the ones reported by others as well as higher incidence of post treatment hypothyroidism (55%), using 25-40 mCi 131I. O’Brien et al.11 using 19.7-100 mCi 131I, reported a 8.7 % recurrence rate of hyperthyroidism in 23 patients with typical toxic adenoma after 131I, while hypothyroidism developed in approximately 35% of the patients within 3 months to 16.3 years post-treatment. In another study of 29 patients, using 10-40 mCi, the recurrence rate was 52% and hypothyroidism developed in 17% of the subjects in 10 years and 44% in 20 years of follow-up12. Finally, in the study by Goldstein & Hart13, hypothyroidism occurred in 36% of the 23 patients followed for 8.5 years and treated with a dose of 23±10 mCi. The lower treatment rate and incidence of post treatment hypothyroidism in the above studies as compared to our results, could be attributed to the lower dose of 131I used, to the fact that some patients were on antithyroid drugs before 131I treatment, and to the fact that patients with “hypotoxic” nodule were included. It should be stressed that in one study a dose of 131I of 10-15 mCi resulted in persistence or relapse of the hyperthyroidism in 100% of the patients (15, Table 1). This observation is in concordance with the well known radioresistance of adenomatous tissue due to the presence of medium and large follicles with much more colloid which reduces the effect of beta-radiation of 131I on the follicular cells10.
The finding that in our patients who were subclinically hyperthyroid on the treatment day, post radiation hypothyroidism developed less frequently and also later, as compared to patients who were euthyroid, can be explained by the protective effect of the functional suppression of the extranodular thyroid tissue by the hyperfunctioning toxic adenoma leading to a lower iodine uptake of the normal thyroid cells at the time of the 131I administration. The lack of correlation between TSH levels immediately before treatment and the development of hypothyroidism is probably due to the less sensitive radioimmunoassays for TSH determination during the early years of the study (before 1990). However, most of the patients in our study that remained euthyroid were euthyroid on the 131I treatment day (54 out of 57) and presumably with normal 131I uptake potential. Thus the avoidance of hypothyroidism in almost half of our patients can be only partially attributed to the above mentioned protective effect6,7,20. Apart from the incomplete suppression of the extranodular normal thyroid, or the possibility of some 131I uptake by the thyroid tissue which appeared suppressed on the scanning21, other factors participate in the development of hypothyroidism as well. It has also been proposed that autonomously functioning micronodules which may accompany toxic adenoma may degenerate and predispose to hypothyroidism post 131I8,22. Finally, hypothyroidism may be part of the natural history of toxic adenoma due to autoimmune dysfunction of the extranodular thyroid tissue3 as it is shown that patients with antithyroid antibodies have a higher incidence of hypothyroidism post 131I18.
In accordance with others13, post treatment hypothyroidism in our patients did not correlate with the adenoma size, patient’s age or 131I dose. None of our patients developed any malignancy during the follow-up period, in agreement with reports of no increased risk for thyroid malignancy23, other cancers24, and leukemia25 post 131I treatment.
The main argument against the use of 131I versus the surgical approach in the treatment of toxic adenoma is the possible coexistence of thyroid cancer. Nevertheless our data26 and those of others27-29, indicate that such a risk is very low (»1.5 %), although rates as high as 2.5-5.4% have been reported30-31. It should be noted that the incidence of thyroid carcinoma in the general population following operation or post mortem is reported to range from 0.11%32 to 2.8%33. Nevertheless, lobectomy, which is the surgical treatment of choice for toxic adenoma, offers only partial protection due to the well documented multifocality, especially in papillary carcinoma where microscopical foci of cancer are detected in the opposite lobe in 30-82% of patients34.
In conclusion, our findings suggest that treatment of toxic adenoma with 131I in the dose of 25-40 mCi is a well tolerated therapy, with no side effects, leading to rapid relief of hyperthyroid symptoms. Hypothyroidism is a permanent disease that needs life long treatment and regular follow-up once or twice a year, but it cannot be considered a major side effect, as the replacement therapy with thyroxine is easy, safe and cost-free. In addition, the observation that hypothyroidism in all our patients developed within one year post treatment is of major importance. Since our follow-up is 1-21 years, we suggest that if hypothyroidism does not develop within the first year, the likelihood of developing it later is very small, so that follow- up visits should be less frequent past the first year.
1. Hamburger J I. 1975 Solitary autonomously functioning thyroid lesions: Diagnosis, clinical features and pathogenic considerations. Am J Med 58: 740-748.
2. Tollin SR, Fallon EF, Mikhail M, Goldstein H Yung E. 2000 The utility of thyroid nuclear imaging and other studies in the diagnosis and treatment of underlying thyroid abnormalities in patients with endogenous subclinical thyrotoxicosis. Clin Nucl Med 25:341-347
3. Taylor HC, Pillay I. 1984 Thyroid function after treatment of solitary autonomous thyroid nodule. New Eng J Med 310:1392- 1395
4. Mc Cormack KR, Sheline GE. 1967 Long-term studies of solitary autonomous thyroid nodules. J Nucl Med 8:701-708.
5. Silverstein GE, Burke G, Cogan R. 1967 The natural history of autonomously hyperfunctioning thyroid nodule. Ann Int Med 67: 539-548.
6. Skillern PG, Mc Cullagh EP, Clamen M. 1962 Radioiodine in diagnosis and therapy of hyperthyroidism: Hyperthyroidism caused by hyperfunctioning thyroid adenoma. Arch Int Med 110: 888-897
7. Horst W, Rosler H, Schneider C, Labbart A. 1967 306 cases of toxic adenoma: clinical aspects, findings in radioiodine diagnostics, radiochromatography and histology; results of 131I and surgical treatment. J Nucl Med 8:515-528.
8. Freitas JE 2000 Therapeutic options in the management of toxic and non toxic goiter Semin Nucl Med 30:88-97
9. Hay ID, Morris JC. 1996 Toxic adenoma and toxic multinodular goiter. In: Braverman LE, Utiger RD eds. Werner & Ingbar’s The Thyroid Philadelphia: Lippincott-Raven: 713-734
10. Miller JM. 1975 Plummers’ disease. Med Clinics of North America 59:1203-1218.
11. O’Brien T, Gharib H, Suman VJ, van Heerden J.A. 1992 Treatment of toxic solitary thyroid nodules: Surgery versus radioactive iodine. Surgery 112: 1166-1170.
12. Fontana B, Curti, G., Biggi A, Fresco G. 1980 The incidence of hypothyroidism after 131-I therapy for autonomous hyperfunctioning thyroid nodule evaluated by means of life-table method. J of Nucl Med Al Sci 24:85-91.
13. Goldstein R, Hart IR. 1983. Follow up of solitary autonomous thyroid nodules treated with 131-I. New Engl J Med, 309:1473-1476.
14. Eyre-Brook IA, Talbot CH. 1982 The treatment of autonomous functioning thyroid nodules. Br J Surg 6:577-579
15. Blum M, Shenkman L, Hollander CS. 1975 The autonomous nodule of the thyroid: correlation of patient’s age, nodule size, and functional status. Am J Medical Sci 269:43-50.
16. Ross DS, Ridgway EC, Daniels GH. 1984 Successful treatment of solitary toxic thyroid nodules with relatively low dose iodine-131, with low prevalence of hypothyroidism. Ann Int Med 101, 488-490
17. Hegedus L, Veiergang D, Karstrup S, Hansen JM. 1986 Compensated 131I therapy of solidary autonomous thyroid nodules: effect of thyroid size and early hypothyroidism. Acta Endocrinol (Copenh) 113:226-232.
18. Mariotti S, Martino E, Francesconi M, Ceccarelli C, Grasso L, Lippi F, Baschieri L, Pinchera A. 1986 Serum thyroid autoantibodies as a risk factor for development of hypothyroidism after radioactive iodine therapy for single thyroid “hot” nodule. Acta Endocrinol.(Copenh.) 113:500-507.
19. Ratcliffe GE, Cooke S, Fogelman I, Maisey MN. Radioiodine treatment of solitary functioning thyroid nodules. 1986 Br J Rad 59:385-387.
20. Huysmans DA, Corstens FH, Kloppenborg PW. 1991 Long term follow up in toxic solitary autonomous thyroid nodules treated with radioactive iodine. J Nucl Med 32:27-30.
21. Gorman CA, Robertson, JS. 1978 Radiation dose in the selection of 131-I or surgical treatment for toxic thyroid adenoma. Ann Int Med 89: 85-90
22. Miller, JM. 1678 Hyperthyroidism from the thyroid follicle with autonomous function. Thyrotoxicosis. Clin Endocr Metab 177-178.
23. Holm LE, Dahlqvist I, Israelsson A Lundell G. 1980 Malignant thyroid tumors after iodine-131 therapy: A retrospective cohort study. New Eng J Med 303:188-191.
24. Sheppard MC. 1988 Radioiodine therapy for thyrotoxicosis and risk of malignancy. In: Rubery E, Smales E eds Iodine prophylaxis following nuclear accidents. London, Pergamon: 111-118
25. Hall P, Boice JD, Berg G, Bjelkengren G, Ericsson, VB, Hallquist A, Lindberg M, Lundell G, Mattsson A, Tennvall J. 1992 Leukemia incidence after iodine-131 exposure. Lancet 340:1-4.
26. Tzavara I, Vlassopoulou B, Alevizaki C, Koukoulis G, Tzanela M, Koumoussi P, Sotsiou F, Thalassinos N. C. 1999. Differentiated thyroid cancer: a retrospective analysis of 832 cases from Greece. Clin Endocrinol, 50: 643-654.
27. Alder-Razzak M, Christie JH. 1979 Thyroid carcinoma in an autonomously functioning nodule. J Nucl Med 20:1001-1002.
28. Croom RD, Thomas CG, Reddick RL, Tawil MT 1987. Autonomously functioning thyroid nodules in childhood and adolescence. Surgery 102: 1101-1108.
29. Studer H, Derwahl M. 1995 Mechanisms of nonneoplastic endocrine hyperplasia-a changing concept: a review focused on the thyroid gland. Endocrine Rev 16:411-426.
30. Ashcraft MW, Van Herbe AJ. 1981 Management of thyroid nodules 2: Scanning techniques, thyroid suppressive therapy and Fine Needle Aspiration. Head and Neck Surg 3:297-322.
31. Pacini F, Elisei R, Di Coscio GC. 1988 The thyroid carcinoma in thyrotoxic patients treated by surgery. J Endocrinol Invest 11:107-111.
32. Holm LE, Wiklund KE, Lundell GE, Bergman NA, Bjelkengren G, Cederquist ES, Ericsson UB, Larsson LG, Lidberg ME, Lindberg RS. 1988. Thyroid cancer after diagnostic doses of iodine-131:a retrospective cohort study. J Nat Canc Inst 80:1132-1138.
33. Mortensen JD, Woolner LB, Bennett W.A. 1955. Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol 15:1270-1276.
34. Siperstein AE, & Clark OH. 1996 Carcinoma of follicular epithelium. Surgical therapy. In: Braverman LE, Utiger RD eds. Werner & Ingbar’s The Thyroid Philadelphia: Lippincott-Raven. 916-922.
Address correspondence and requests for reprints toN.C. Thalassinos,
Department of Endocrinology, Diabetes anMetabolism, "Evangelismos" Hospital,
45-47 Ipsilantou St.GR 106 75, TEL: (031) 7201825-26, FAX: (031) 7249476,
Received 15-12-2001, Revised 03-02-2002, Accepted 01-03-2002