2-1999

Radioactive iodine treatment for benign thyroid disease

Laszlo Hegedüs, Odense, Denmark 

Contents:

Introduction

Toxic goitre

Diffuse toxic goitre

Multinodular toxic goitre

Solitary toxic nodule

Non-toxic goitre

Diffuse non-toxic goitre

Multinodular non-toxic goitre

Solitary non-toxic nodule (autonomous nodule)

Future aspects

References
 

Introduction

Various aspects of radioiodine (131I) treatment have almost exhaustively been dealt with in recent reviews1–4. Despite being in use for more than 50 years, initially for hyperthyroidism and shortly thereafter for thyroid carcinoma, and an overwhelming number of publications, it is surprising that so many fundamental questions remain unanswered (1–5).

While much information is available with regard to 131I-treatment of toxic goitre (mainly Graves’ disease), this review will highlight present knowledge of 131I-treatment also in benign non-toxic goitre and focus on aspects needing further research. Recently, the cancer risk after diagnostic and therapeutic use of 131I in thyroid disorders has thoroughly been reviewed in e.g. Thyroid International6. Present knowledge indicates that the marginally increased mortality among hyperthyroid patients the first year after diagnosis is not related to the 131I-therapy but the underlying disease5,6. Consequently, the main focus of this review will be on other aspects of 131I-treatment in benign thyroid disorders. Indications and contraindications for 131I-therapy are listed in Table 1 and 2, respectively.

Toxic goitre

Hyperthyroidism is a very common clinical condition. The lifetime risk has been estimated at up to 5% in women (5). Subtype of hyperthyroidism is mainly determined by the level of iodine intake in the region. Nodular toxic goitre is most prevalent in iodine insufficient regions as opposed to diffuse toxic goitre (Graves’ disease) in iodine sufficient regions (7). Since surgery for hyperthyroidism is infrequently used in any part of the world, and since only a minority of patients on antithyroid drugs (ATD) will remit, it is not surprising that millions of patients have been treated with 131I since its introduction in the 1940s (1, 5).

Diffuse toxic goitre

There is still no consensus on the best treatment for Graves’ disease. In the USA 131I is the preferred therapy in adults, while ATD are favored in Europe and Japan (8), although less than 50% will achieve long-term remission by this therapy. 131I is thought to be the most cost-effective therapy. Advantages and disadvantages are given in table 3.

Generally, oral 131I doses of 100 µCi (3.7 MBq) per gram thyroid tissue corrected for a 100% 24 h 131I uptake have been given (9). This will approximately render 70% of patients euthyroid within 3 months, given that antithyroid drugs are not resumed. Roughly 70% are cured with one dose and 90% with two doses. It is generally believed that pretreatment as well as post treatment with ATD decreases the effect of 131I4. Prospective randomized studies on how many days ATD have to be withdrawn, if at all, and whether there is a difference between carbimazole, methimazole and propylthiouracil are lacking.
 

 The risk of hypothyroidism depends on the 131I dose. The lower the dose, the lower the incidence of hypothyroidism within the first year of therapy and the higher the frequency of persistent hyperthyroidism. Using the above dose-algorithm some 20% of patients will become hypothyroid within the first year, while myxedema incidence beyond the first year seems at large uninfluenced by 131I dose at 2–3% per year (9,10). The risk of hypothyroidism is roughly 50% after 10 years and if given at a young age inevitably causes hypothyroidism (5,9,10). Based on the existing information, it could be speculated whether a meticulously calculated 131I dose is cost-effective and worth while (10,11).

Thyroid size reduction has received little attention. Thyroid volume – determined ultrasonically – can be reduced by approximately 50–60% within one year (9), with little subsequent reduction. Roughly, half of this decrease is seen within 3 months of therapy (9). There is no significant acute increase in thyroid volume or obstructive symptoms, after 131I administration12. Normalization of thyroid volume – irrespective of initial thyroid size (9) – is the rule, and secondary increase in thyroid volume should not be anticipated, except in the patient affected by radiation thyroiditis, which is rare. The initial 131I dose reduces thyroid volume in all patients, also in patients needing subsequent 131I doses due to persistent hyperthyroidism. The dose can be repeated and additional thyroid volume reduction expected. Thyroid volume reduction is generally higher in patients becoming hypothyroid than in those remaining eu- or hyperthyroid (9).

Radiation thyroiditis is seen in few percent within the first months of 131I-therapy and easily treated with salicylates or corticosteroids. Recent evidence unequivocally demonstrates that 131I-treatment in Graves’ disease carries a risk of development or worsening of ophthalmopathy in 15% of patients (5% needing treatment) (13). This worsening is often transient and can be prevented by the administration of prednisolone (13). While this study may indicate that the combination of 131I and prednisolone should have a more prominent place in the therapy of Graves’ hyperthyroidism with eye-symptoms, only 6% of European Thyroid Association (ETA) members would prefer this treatment14. Active ophthalmopathy is thus regarded by most ETA members as a relative contraindication for 131I-therapy.

The overwhelming majority of young patients with hyperthyroidism have Graves’ disease (15). Since remission rates on ATD are lower in young subjects than in adults, 131I-therapy has been used also in children (15). Although used down to the age of 5 by some, and the rarity of thyroid malignancy in 131I-treated children (4 reported cases) (15), we are reluctant to administer this therapy for subjects below 20 years of age. However, as data on side-effects accumulates we, as have others, have treated younger and younger subjects. There is at present no consensus as to a lowest age limit.

Multinodular toxic goitre

The fact that remission of hyperthyroidism on ATD cannot be expected, in addition to the relatively high risk of surgical complications, even in eligible patients (16), has lead a number of centers (including ours) to offer radioiodine as the first choice of therapy in the majority of patients. 131I is considered safe and appropriate in nearly all types of hyperthyroidism, especially in elderly patients, as is most often the case with multinodular toxic goitre (17). Compared to that in Graves’ disease, surprisingly little data is available regarding effects and side-effects of 131I-therapy in multinodular toxic goitre (Table 3).

Most often oral 131I doses of 100–150 µCi (3.7–5.55 MBq) per gram thyroid tissue corrected for 100% 24 h 131I uptake, is recommended. Again, many do not use meticulously calculated dose-algorithms but prefer fixed maximum outpatient doses. There is at present no evidence of one regime being better than the other10. Only 50% of patients become euthyroid within 3 months of 131I-therapy, given that ATD are not administered (16,18). Twenty to forty percent need additional 131I-therapy and even up to 5 treatment sessions will not cure all patients (18). As with Graves’ disease, the role of pre- and post radioiodine treatment with ATD on the effect of 131I is not known.

Thyroid volume can be halved within 1–2 years of 131I-therapy with approximately two thirds of this reduction becoming evident within 3 months of therapy (18). Even 131I doses that do not cure the patients will reduce thyroid volume by 25% on average (18). The reduction is independent of pretreatment with antithyroid drugs (18) and no additional reduction beyond two years can be expected. There is no clinically significant acute increase in thyroid volume or obstructive symptoms after 131I treatment (12,19). In fact, a relief of compressive symptoms, a decrease in upper airway obstruction – as estimated by pulmonary functioning testing and flow-volume loops – and an increasing cross-sectional area of the tracheal lumen, can be expected in most patients (19,20). Also patients with monstrous (150 ml) and partly intrathoracic goitres have been treated with beneficial results (19,20). In these patients very large doses of 131I are needed. Treatment is given on an in-patient basis and 131I dose calculated using 96 h 131I uptake measurement and thyroid volume determination by MR-scan (19). Isolation for 1–2 weeks is often necessary (but may depend on local regulations) making this a cumbersome alternative in the few patients not found suited for thyroidectomy (19,20). In these monstrous goitres a 30–40% volume reduction within one year can be expected (19,20). The treatment can be repeated with an expected additional volume reduction (18,21). Normalization of thyroid volume is rare, as is secondary increase in thyroid size.

Radiation thyroiditis is an infrequent complication18. Graves’ like hyperthyroidism has been demonstrated in 5 of 100 patients (5%) with multinodular toxic goitre (22) or similar to that described in non-toxic multinodular goitre (23). It is related to appearance of TSH-receptor(TSHR)-ab and typically occurs 3–6 months after 131I-therapy. The risk of hypothyroidism is lower than in Graves’ disease since only part of the gland takes up 131I. In the only long-term (median 6 years) follow-up of a large population (130 subjects) the risk of hypothyroidism was found to be 14% after 5 years (18) or similar to that found in non-toxic multinodular goitre (21). Pretreatment presence of anti-TPOab seems to confer an increased risk of developing both Graves’ like hyperthyroidism (10%) and hypothyroidism (30%) as compared to 0.8% and 5%, respectively, in anti-TPOab negative subjects (22).

• Low risk of radiation thyroiditis. Risk of hypothyroidism ~ 10% after 5 years.
• For all subtypes it is evident that thyroid volume reduction is much slower and less pronounced than with surgery.
• There is a theoretical risk of overlooking or inducing malignancy and of inducing or worsening ophthalmopathy.

Solitary toxic nodule

Hyperthyroidism caused by a solitary toxic nodule can be treated with ATD, this however, does not result in lasting remission. Therefore, the treatment of choice, in most centers, is often 131I (3,24) (Table 3).

Most often oral 131I doses of 100–150 µCi (3.7–5,55 MBq) per gram thyroid tissue corrected for 100% 24 h 131I uptake is recommended. There is at present no consensus on the best dose-algorithm and as previously stated many have given up dose calculation and give fixed low (5 mCi/185 MBq) or high (15 mCi/555 MBq) doses. Only 75% of patients become euthyroid within 3 months of 131I-therapy, given that ATD are not given25. 10–20% need additional 131I doses due to persistent or recurrent hyperthyroidism (24,25) and some need up to 5 treatment sessions25. As with the other types of hyperthyroidism the role of ATD on the effect of 131I is not clarified.

Thyroid volume is reduced by 35% within 3 months and 45% after 2 years (25,26). The reduction is independent of pretreatment with antithyroid drugs (25) and no additional reduction beyond 2 years of therapy can be expected. There is no clinically significant acute increase in thyroid volume or obstructive symptoms after 131I administration (25). The treatment can be repeated with an expected additional volume reduction (25). This volume reduction is generally satisfactory and only extremely rarely is subsequent surgery required. The risk of hypothyroidism depends on the 131I dose. Using the above dose-algorithm it is generally believed to be less than 10% after 5 years, although higher figures have also been reported (24,25). These relatively low figures are due to most of the 131I being taken up by the hyperfunctioning nodule, while the suppressed extranodular tissue is in part protected. The fact that the prevalence of hypothyroidism after 131I is not nil, is supported by studies demonstrating extranodular uptake of 131I and a significant effect on extranodular volume (26).

Radiation thyroiditis is rare (< 5% of patients)24,25. Graves’ like hyperthyroidism has been demonstrated in 1 of 49 patients (2%) with a solitary toxic nodule22. Pretreatment presence of anti-TPOab seems to confer an increased risk of developing both Graves’ like hyperthyroidism22 and hypothyroidism (22,27).

The fact that 13 out of 149 (9%) consecutive patients with clinically and scintigraphically nodular (both solitary and multinodular) toxic goitre had pretreatment presence of TSHRab illustrates that it is not always easy to discriminate between nodular toxic goitre and Graves’ disease (22). Some of these patients could in fact have had simultaneous presence of Graves’ disease and nodular goitre (Marine-Lenhart syndrome). Since pretreatment presence of TSHRab and elevated anti-TPOab levels are associated with a significantly increased risk of developing post 131I hyper- and hypothyroidism, it could be speculated whether these antibodies need being measured before treatment, to give a better risk estimate.

Non-toxic goitre

The well established treatment of symptomatic non-toxic goitre is surgery. Due to the questionable efficacy of L-thyroxine therapy and the fact that many patients decline surgical therapy or are poor surgical candidates, a number of centers have started offering 131I-therapy to an increasing number of patients (2). Extent of this therapy and the pretreatment work-up of such a patient is presently debated. There is clearly no consensus on this, which will undoubtedly be demonstrated by the results of an ongoing ETA questionnaire investigation, to be presented at the ETA meeting in Milan, Italy, August 1999. Advantages and disadvantages of this therapy are given in table 4.

• For all subtypes it is evident that thyroid volume reduction is much slower and less pronounced than compared with surgery. Given the choice, the majority of Danish patients will choose 131I and not surgery. There is a theoretical risk of overlooking or inducing malignancy and of inducing ophthalmopathy.

Diffuse non-toxic goitre

Very little is known of the effects and side-effects of 131I in diffuse non-toxic goitre. Only reports on a total of 21 highly selected subjects and 12 months of follow-up are available28,29. These suggest that thyroid volume can be reduced by 62% within 12 months, leading to a normalization of thyroid volume in 15 of 21 (71%) of the patients. Additional 131I-therapy allows further reduction of thyroid volume (29).

Side effects were hypothyroidism in 3 patients (14%), two of whom were anti-TPOab positive before treatment and one case of post 131I-therapy Graves’ disease related to appearance of TSHRab (28,29). The place of this therapy is at present not clarified. Much larger series followed for longer periods are needed. Controlled studies comparing L-T4 therapy or surgery with 131I are the next step. Presently, I believe it to be an alternative in patients who have an unsatisfactory effect of L-T4 therapy, who are poor surgical risks or who refuse surgery.
 

Multinodular non-toxic goitre

This condition is common, especially in iodine-deficient regions. Most of these goitres do not cause significant symptoms and are best left untreated. When treatment is warranted, the fact that L-T4 is of questionable effect, whether before30 or after surgery (31), in addition to a number of patients declining surgery, has led a number of centers (including ours) to offer 131I-therapy to an increasingly number of patients (2,3,21). Starting with highly selected patients who were ineligible for or refused surgery (20,32), the treatment is now the preferred one for the vast majority of patients in Denmark (2). Only relatively few and small studies with less than 10 years of follow-up are available (2,3), and the role of this therapy is still discussed (Table 4).

Generally, oral 131I doses of 100–150 &micro;Ci (3.7–5,5 MBq) per gram thyroid tissue corrected for 100% 24 h. 131I uptake have been given. There is at present no evidence of one regime being better than the other, and since most countries have a relatively low maximum upper limit of out-patient 131I dose, many patients receive less than the intended doses. This should logically lead to a suboptimal thyroid volume reduction. This is, however, at present unsolved since it is not known whether there is a linear dose response relationship between 131I dose and thyroid volume reduction. In monstrous long-standing goitre this does not seem to be the case (19).

Thyroid volume can be reduced by approximately 40% after one year (2,3,32) and by approximately 50–60% after two years without further reduction (3,21). 60% of this decrease is seen within the first 3 months of therapy (21). There is no significant acute increase in thyroid volume or obstructive symptoms after therapy (12,19). In fact, a relief of compressive symptoms, decrease in upper airway obstruction – as estimated by pulmonary functioning testing and flow volume loops – and an increasing cross-sectional area of the tracheal lumen, can be expected in most patients. This is also valid for monstrous goitres with intrathoracic extension (3,19,20). The treatment can be repeated and additional volume reduction can be achieved (21). Normalization of thyroid volume is rare due to the generally large pretreatment size. Secondary increase in thyroid volume has been seen, although uncommon, and should raise the suspicion of malignancy.

Radiation thyroiditis is seen in 3% within the first months of 131I-therapy (23) and easily treated with salicylates or corticosteroids. Graves’ like hyperthyroidism has been demonstrated in 9 of 191 patients (5%) (23). This is most likely triggered by 131I-related release of thyroid antigens and related to appearance of TSHRab. It can also be seen after surgery (33) or following subacute thyroiditis (34), and typically occurs 3 months after treatment. In principle, this could lead to development of thyroid associated ophthalmopathy, as evidenced by a recent case (35).

The risk of hypothyroidism, including subclinical cases, is approximately 20% after 5 years or similar to that found in toxic multinodular goitre (18). This figure is much lower than that found in Graves’ disease and in diffuse non-toxic goitre, which is explained by the 131I being taken up only in the functioning (hot/warm) areas of the gland. Pretreatment presence of anti-TPOab seems to confer an increased risk of developing both Graves’ like hyperthyroidism (22%), hypothyroidism (29%) and radiation thyroiditis (11%) as compared to 2%, 13% and 2%, respectively, in anti-TPOab negative subjects (23). The risk of inducing thyroid carcinoma is as yet a theoretical consideration. More important, the risk of pretreatment presence of thyroid carcinoma in multinodular non-toxic goitre is probably as high as in solitary cold nodules (36). This should be taken into consideration and, in my opinion, lead to a more liberal use of diagnostic imaging as well as fine needle aspiration biopsy in patients offered non-surgical treatment.
 

Solitary non-toxic nodule (autonomous nodule)

In this section only autonomous nodules, that is hot nodules with uptake in the nodule and various degrees of extranodular suppression, are considered. Cold solitary nodules are not believed to take up 131I to any significant degree and are therefore not treated with 131I. On the other hand it is evident from the treatment of multinodular non-toxic goitre that also areas with seemingly low/no uptake are reduced by 131I-therapy. In theory, reduction by 131I of cold nodules should be possible, however, no objective data on this is available.

Most subjects with autonomous non-toxic thyroid nodules have a suppressed s-TSH at time of diagnosis (subclinical hyperthyroidism). Most of these nodules do not substantially change in size with time, 86% remained stable during a follow-up period of 1–15 years  (37). 5% become hyperthyroid each year (37). At this time the nodule is usually 3 cm or more in diameter. Since many subjects have pressure symptoms, cosmetic complaints and subclinical hyperthyroidism – associated with increased morbidity – a number of centres (including ours) choose to recommend 131I-therapy to these subjects without waiting for clinical hyperthyroidism to occur.

Future aspects

In spite of being used for more than 50 years in the treatment of benign thyroid disorders, a number of questions remain (Table 5).

In the toxic patient, further studies are needed in order to reach a consensus on patient selection criteria and on the adequate investigations before offering 131I-therapy. In these patient categories, randomized studies on effects and side-effects as well as cost-benefit comparing ATD, 131I, and surgery in prospective randomized trials are still needed. Further studies on the optimum dose calculation should be encouraged. The influence of pre- and post treatment with ATD on the effect of 131I should be studied. Although generally considered safe in the adult population, further studies on which is the lower age limit of treatment and whether large 131I doses, given to e.g. patients with monstrous goitre, are also safe, are needed.

In the non-toxic patient, additional studies are warranted in order to clarify which patients are best suited for 131I-therapy. Much work is needed before a consensus can be reached on adequate pretreatment investigations. Should fine needle biopsy routinely be performed? Should serum calcitonin be determined? To name but a few of the pressing questions. Randomized studies comparing L-T4, 131I and surgery are needed, as are studies on the optimum 131I dose calculation for treatment of various types of non-toxic goitre. The most recent reports suggest that side-effects are in no way negligible (hypothyroidism, radiation thyroiditis, insufficient effect) and further long-term follow-up data in larger groups of patients are awaited. Whether the risk of thyroid and non-thyroid malignancy is as low as in toxic goitre cannot be answered before much larger groups of patients have been followed for several decades.

While searching for preventive measures and awaiting treatment modalities, for toxic as well as non-toxic goitre, of a less destructive and a more physiologic nature, I hope that many colleagues will take on these and other challenges in order to optimize 131I-therapy in benign thyroid disorders. Little is known about effects and side-effects of 131I-therapy in this type of patient. If a dose is given, calculated according to that given for toxic solitary nodules,25,26 it is likely that the consequences of treatment are also similar (Table 4). Indeed, a short-term study suggests thyroid volume reduction to be similar26. Frequency of hypothyroidism depends on serum TSH level, thyroid autoantibody status and on degree of extranodular thyroid tissue uptake. Autoantibody positive subjects are more prone to develop hypothyroidism27 as are subjects with measurable TSH and evidence of extranodular uptake.

References:

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2. Nygaard B, Faber J, Hegedüs L, Hansen JM. 131I treatment of nodular non-toxic goitre. Eur J Endocrinol 1996; 134: 15-20.

3. Hermus AdR, Huysmans DA. Treatment of benign nodular thyroid disease. N Engl J Med 1998; 338: 1438-1447.

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5. Cooper DS. Radioiodine for hyperthyroidism. Where do we stand after 50 years? JAMA 1998; 280: 375-376.

6. Hall P. Hazards of diagnostic and therapeutic use of radioactive iodine in thyroid disorders. Thyroid International 1998; 1: 1-14.

7. Laurberg P, Pedersen KM, Vestergaard H, Sigurdsson G. High incidence of multinodular toxic goiter in the elderly population in a low iodine intake area vs. high incidence of Graves’ disease in the young in a high iodine intake area: Comparative surveys of thyrotoxicosis epidemiology in East-Jutland, Denmark and Iceland. J Intern Med 1991; 229: 415-420.

8. Wartofsky L, Glinoer D, Solomon B, et al. Differences and similarities in the diagnosis and treatment of Graves’ disease in Europe, Japan and the United States. Thyroid 1991; 71: 129-135.

9. Nygaard B, Hegedüs L, Gervil M, Hjalgrim H, Hansen BM, Søe-Jensen P, Hansen JM. Influence of compensated radioiodine therapy on thyroid volume and incidence of hyperthyroidism in Graves’ disease. J Intern Med 1995; 238: 491-497.

10. Hegedüs L, Faber J. Calculation of the ideal dose of radioiodine for treatment of thyroid disease. Eur J Endocrinol 1995; 132: 544-545.

11. Jarløv AE, Hegedüs L, Kristensen LØ, Nygaard B, Hansen JM. Is calculation of the dose in radioiodine therapy of hyperthyroidism worth while? Clin Endocrinol 1995; 43: 325-329.

12. Nygaard B, Faber J, Hegedüs L. Acute changes in thyroid volume and function following 131I therapy of multinodular goitre. Clin Endocrinol 1994; 41: 715-718.

13. Bartalena L, Marcocci C, Bogazzi F, Manetti L, Tanda ML, Dell’Unto E, Bruno-Bossio G, Nardi M, Bartolomei MP, Lepri A, Rossi G, Martino E, Pinchera A. Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. N Engl J Med 1998; 338: 73-78.

14. Weetman AP, Wiersinga WM. Current management of thyroid-associated ophthalmopathy in Europe. Results of an international survey. Clin Endocrinol 1998; 49: 21-28.

15. Rivkees SA, Sklar C, Freemark M. The management of Graves’ disease in children, with special emphasis on radioiodine treatment. J Clin Endocrinol Metab 1998; 83: 3767-3776.

16. Erickson D, Gharib H, Li H, van Heerden JA. Treatment of patients with toxic multinodular goiter. Thyroid 1998; 8: 277-282.

17. Vanderpump MPJ, Ahlquist JAD, Franklyn JA, Clayton RN. Consensus statement for good practice and audit measures in the management of hypothyroidism and hyperthyroidism. Br Med J 1996; 313: 539-544.

18. Nygaard B, Hegedüs L, Ulriksen P, Nielsen KG, Hansen JM. Radioiodine therapy of multinodular toxic goiter. Arch Intern Med 1999; in press.

19. Bonnema S, Bertelsen H, Mortensen J, Andersen P, Knudsen DU, Bastholt L, Hegedüs L. The feasibility of high-dose 131I-treatment as an alternative to surgery in patients with a monstrous goitre. Effect on thyroid function and size and pulmonary function. J Endocrinol 1998; 159 (Supplementum): abstract OC18.

20. Huysmans DAKC, Hermus Ad RMM, Corstens FHM, Barentsz JO, Kloppenborg PWC. Large compressive goiters treated with radioiodine. Ann Intern Med 1994; 121: 757-762.

21. Nygaard B, Hegedüs L, Gervil M, Hjalgrim H, Søe-Jensen P, Hansen JM. Radioiodine treatment of multinodular non-toxic goitre. Br Med J 1993; 307: 828-832.

22. Nygaard B, Faber J, Veje A, Hegedüs L, Hansen JM. Transition of nodular toxic goiter to autoimmune hyperthyroidism triggered by 131I therapy. Thyroid 1999; in press.

23. Nygaard B, Knudsen JH, Hegedüs L, Veje A, Hansen JEM. Thyrotropin receptor antibodies and Graves’ disease, a side-effect of 131I treatment in patients with non-toxic goiter. J Clin Endocrinol Metab 1997; 82: 2926-2930.

24. Ferrari C, Reschini E, Paracchi A. Treatment of the autonomous thyroid nodule: A review. Eur J Endocrinol 1996; 135: 383-390.

25. Nygaard B, Hegedüs L, Nielsen KG, Ulriksen P, Hansen JM. Long-term effect of radioactive iodine on thyroid function and size in patients with solitary autonomously functioning toxic thyroid nodules. Clin Endocrinol 1999; in press.

26. Hegedüs L, Veiergang D, Karstrup S, Hansen JM. Compensated 131I-therapy of solitary autonomous thyroid nodules: Effect on thyroid size and early hypothyroidism. Acta Endocrinol 1986; 113: 226-232.

27. Mariotti S, Martino E, Francesconi M, Ceccarelli C, Grasso L, Lippi F, Baschieri L, Pinchera A. Serum thyroid autoantibodies as a risk factor for development of hypothyroidism after radioactive iodine therapy for single thyroid "hot" nodule. Acta Endocrinol 1986; 113: 500–507.

28. Hegedüs L, Bennedbæk FN. Radioiodine for non-toxic diffuse goitre. Lancet 1997; 350: 409-410.

29. Nygaard B, Faber J, Veje A, Hansen JEM. Thyroid volume and function after 131I treatment of diffuse non-toxic goitre. Clin Endocrinol 1997; 47: 493-496.

30. Berghout A, Wiersinga WM, Drexhage HA, Smits NJ, Touber JL. Comparison of placebo with L-thyroxine alone or with carbimazole for treatment of sporadic non-toxic goitre. Lancet 1990; 336: 193-197.

31. Hegedüs L, Nygaard B, Hansen JM. Is routine thyroxine treatment to hinder postoperative recurrence of non-toxic goiter justified? J Clin Endocrinol Metab 1999; 84: in press.

32. Hegedüs L, Hansen BM, Knudsen N, Hansen JM. Reduction of size of thyroid with radioactive iodine in multinodular non-toxic goitre. Br Med J 1988; 297: 661-662.

33. Walfish PG, Caplan D, Rosen IB. Postparathyroidectomy transient thyrotoxicosis. J Clin Endocrinol Metab 1992; 75: 224-227.

34. Bennedbæk FN, Gram J, Hegedüs L. The transition of subacute thyroiditis to Graves’ disease as evidenced by diagnostic imaging. Thyroid 1996; 6: 457-459.

35. Nygaard B, Metcalfe RA, Phipps J, Wetman AP, Hegedüs L. Graves’ disease and thyroid associated ophthalmopathy triggered by 131I treatment of non-toxic goiter. J Endocrinol Invest 1999; in press.

36. Franklyn JA, Daykin J, Young J, et al. Fine-needle aspiration cytology in diffuse or multinodular goitre compared with solitary thyroid nodules. Br Med J 1993; 307: 240.

37. Hamburger JI. Evolution of toxicity in solitary nontoxic autonomously functioning thyroid nodules. J Clin Endocrinol Metab 1980; 50: 1089-1093.
 

Lazlo Hegedüs is an associate professor of Internal Medicine and Endocrinology at Odense University Hospital, Denmark. He is the author of approximately 150 journal articles mainly dealing with various clinical aspects of thyroid disorders. His main areas of research have been diagnostic imaging, regulation of thyroid size, radioiodine treatment and lately genetic and environmental aspects of thyroid disease as investigated in Danish twins. Within these fields of clinical thyroidology he is supervising several PhD students. He will be authoring textbook chapters in the forthcoming issue of Endocrinology, Thyroid, and Oxford Textbook of Endocrinology.

Laszlo Hegedüs, MD, Dr. Med. Sci. Associate professor of Internal Medicine and Endocrinology

Correspondance:
Laszlo Hegedüs, MD
Department of Endocrinology and Metabolism
Odense University Hospital
DK-5000 Odense C
Denmark

Phone: 0045 6541 3426
Fax: 0045 6591 9653
E-mail: [email protected]