Low failure rate of fixed administered activity of 400 MBq 131I with pre-treatment with carbimazole for thyrotoxicosis: the Gateshead Protocol

BACKGROUND: Thyrotoxicosis is associated with significant morbidity, therefore adequate control of the disease is paramount. The outcome of treatment of thyrotoxicosis using radioiodine shows variable failure rates depending, amongst other things, on the administered activity of radioiodine and the use of anti-thyroid drugs. Thus, management should follow an evidence based protocol, which has a low failure rate. METHOD: We prospectively analysed the outcome of treatment using our Gateshead protocol of a fixed administered activity of radioiodine therapy (400 MBq) given to 201 patients (including 140 with Graves' disease, 48 with toxic multinodular goitre (TMNG) and 13 with toxic nodule) followed up for a median period of 12 months (range, 6-77 months). Carbimazole was discontinued in patients rendered euthyroid 16 days prior to radioiodine. No routine anti-thyroid drugs or thyroxine were given following radioiodine unless hypothyroidism or thyrotoxicosis occurred. RESULTS: Following the Gateshead protocol led to a failure rate of 6.5% (eight females with Graves' disease, four females with TMNG and one female with toxic nodule), 29% euthyroidism and 64% hypothyroidism. The rates of hypothyroidism for women and for men were: in Graves' disease 77% and 79%, in TMNG 29% and 75%, in toxic nodule 42% and 0%, respectively. CONCLUSIONS: Our observations show that withholding an antithyroid drug in excess of just over 2 weeks prior to administering a fixed administered activity of radioiodine in patients with thyrotoxicosis leads to the lowest reported failure rate, irrespective of the underlying cause. One possible mechanism for this could be the avoidance of drug induced radio-resistance.     

Thyroid suppression and stimulation testing: The place of scanning in the evaluation of nodular thyroid disease

In the past, T3 suppression testing was often required to confirm the presence of autonomous thyroid function in patients with borderline clinical and laboratory findings suggestive of hyperthyroidism or in euthyroid patients with the stigmata of Graves' disease. Similarly, TSH stimulation testing was used to document the presence of "low thyroid reserve" in patients with borderline clinical and laboratory findings suggestive of hypothyroidism. The current availability of radioimmunoassays for triiodothyronine (T3) and thyrotorpin (TSH) plus the ability to evalate pituitary responsiveness by performing a TRH stimulation test permits a definitive diagnosis to be made in the majority of borderline situations without recourse to the more cumbersome suppression and stimulation tests. Suppression and stimulation thyroid scanning retain a unique position in the evaluation of localized areas in increased uptake of radionuclide (hot nodules), especially in patients who are euthyroid. Proof that such nodules are autonomously functioning thyroid adenomas (AFTN) greatly decreases the possibility that they represent malignant thyroid tumors. Suppression and stimulation scanning have a more limited role in the evaluation of patients with hyperthyroidism arising in a multinodular goiter, where TSH stimulation scanning may help to differentiate between toxic multinodular goiter and Graves' disease arising in a preexisting goiter.     

Therapeutic options in the management of toxic and nontoxic nodular goiter

Nodular goiter is present in 500 to 600 million people and is usually secondary to endemic iodine deficiency. Despite adequate iodine intake, 4% to 6% of American adults are goitrous. Sporadic nodular goiter ensues from the natural heterogeneity of thyroid follicular cells, which, when amplified by yet unidentified trophic stimuli, results in episodes of proliferating, rapidly dividing micronodules. The initial small diffuse goiter evolves into a multinodular goiter (MNG) with 1 or more dominant nodules that may or may not be autonomous. An autonomous functioning thyroid adenoma (AFTA) usually possesses a somatic gain-of-function mutation of the thyrotropin (TSH) receptor associated with rapid growth, hemorrhagic necrosis, and reparative fibrosis that accentuate goiter nodularity. Diagnostic evaluation consists of patient history and physical examination, serum TSH determination, free thyroxine and free triiodothyronine measurements, and imaging studies assessing goiter function, size, and anatomy. If treatment is required, L-thyroxine, thionamides, surgery, radioiodine (I-131), and percutaneous ethanol injection (PEI) are effective in selected patients. In euthyroid patients, L-thyroxine reduces goiter size in some patients, but continued therapy is required to prevent regrowth. Thionamides control the hyperthyroidism of toxic nodular goiter in preparation for more definitive therapy, but are rarely used long term. Surgery and I-131 are most commonly selected for definitive therapy for the toxic AFTA, and the toxic or euthyroid MNG, but PEI is effective in selected toxic AFTAs.     

Radioiodine-treatment (RIT) of functional thyroidal autonomy

Since 1942, therapy with radioiodine (RIT) has gained a major role in the treatment of benign thyroid disorders, notably hyperthyroidism caused by Graves' disease or toxic multinodular goitre (thyroid autonomy). In iodine deficient areas thyroid autonomy accounts for 40-50% of all cases with hyperthyroidism. RIT has become a cost-effective first-line procedure in autonomy-patients with latent or overt hyperthyroidism, especially in the absence of a large goitre, after thyroid surgery and in elderly patients with associated conditions who carry a high intra- or perioperative risk. Decisions concerning the definitive treatment of thyroid autonomy should take into account previous episodes of hyperthyroidism, objective parameters of risk stratification in euthyroid patients as well as concomitant diseases and the probability of iodine exposure in the future. In Central Europe the majority of investigators prefer to estimate the therapeutic activity individually by a radioiodine test. TCTUs (global 99m-Tc-pertechnetate thyroid uptake under suppression)-based dose concepts have been proven to be highly effective in the elimination of autonomy and carry a low (< 10%) risk of post-radioiodine-therapeutic hypothyroidism. Radioiodine therapy for autonomy has been found to be both effective and safe and without major early or late side effects. The most frequent complication is hypothyroidism requiring lifelong follow-up.     

Clinical role of TSH binding inhibiting antibodies (TBIAb) assay

Anti TSH-receptor antibodies (TBIAb) were measured by a radioreceptor assay in 277 patients with Graves' disease, 101 with autoimmune thyroiditis, 43 with autonomous adenoma, 15 with subacute thyroiditis, 15 with euthyroid ophthalmopathy, 155 with euthyroid multinodular goiter, 10 with amiodarone-induced hyperthyroidism and 2 with tumoral TSH hypersecretion. TBIAb were present at high titers in 74% of patients with untreated or relapsed Graves' disease and, at lower titers, in only 10% of patients who had recovered from Graves' disease, in 8% of patients with autoimmune thyroiditis and in 4% of patients with euthyroid goiter. TBIAb were absent in normal subjects as well as in the other groups studied. These findings suggest that TBIAb represent a specific marker of Graves' disease, particularly of the untreated form. Their presence in non Graves' patients may be considered expression of inactive or inhibiting antibodies.     

Thyroid cancer prevalence after radioiodine treatment of hyperthyroidism.

The definitive treatment of hyperthyroidism in Europe is quite different from that in the United States. In Europe, the surgical approach is often preferred and considered safer than radioiodine treatment. European doctors usually prefer to surgically remove the thyroid and perform a pathologic examination of it. They consider it to be an essential diagnostic tool to identify possible diseases that might be associated with hyperthyroidism and even to detect the rare thyroid tumors that might be associated with thyroid hyperfunction. The aim of this study was to evaluate whether radioiodine therapy could be a risk factor for the misdiagnosis of thyroid cancer. METHODS: We performed a retrospective revision of data we collected from 6647 patients (1171 [17.5%] men, 5476 [82.5%] women), all of whom underwent 1311 therapy for hyperthyroidism from 1970 to 1997. Of the whole group, 6.5% were younger than 40 y, 33.5% were 40-60 y old, and 60% were older than 60 y. Moreover, 5061 (76%) patients had either an autonomously functioning node or a toxic multinodular goiter. The other 1586 (24%) patients had Graves' disease. RESULTS: After treatment, thyroid cancer was discovered in 10 (0.15%) patients, none of whom belonged to the group of patients with Graves' disease. Five of these patients were treated during a period from 1970 to 1980, when sonography was not routinely available. The incidence of thyroid cancer in the series of radioiodine-treated patients (150/100,000 over a 27-y period) was not significantly different from its incidence in the general population. The expected rate is 124.88 per 100,000 over a 27-y period. CONCLUSION: An accurate preliminary evaluation (clinical examination, sonography, and cytologic evaluation of fine-needle aspiration) is fundamental for a proper choice between radioiodine and surgical therapy.     

Is thyroid scintigraphy necessary before I-131 therapy for hyperthyroidism? Concise communication

To assess the value of routine thyroid scintigraphy in the differential diagnosis of hyperthyroidism and as a guide to I-131 therapy, we prospectively examined 100 consecutive hyperthyroid patients referred for a 24-hr radioiodine uptake and I-131 therapy. The nuclear medicine physician recorded his preimaging diagnostic impression and therapeutic plan for each patient. After the [ 99mTc ] pertechnetate image, the patient was reassessed to determine whether the image induced any change in the diagnosis or therapeutic plan. Seventy-nine of 80 patients with diffuse goiter to palpation, had scintigrams demonstrating no discrete focal defects and were diagnosed as Graves' disease; thus the scintigram did not contribute useful information. In 17 of 20 patients with uninodular or multinodular goiters, the image was necessary to clarify the final diagnosis and therapeutic plan. Thus, selective use of thyroid scintigraphy should decrease the number of scintigrams performed before I-131 therapy for hyperthyroidism, without compromising diagnostic accuracy or therapeutic success.     

Functional results of radioiodine therapy with a 300-GY absorbed dose in Graves' disease

The aim of this study was to assess the results of high-dose radioiodine therapy given to 43 patients with recurrent hyperthyroidism due to Graves' disease between 1986 and 1992. We chose an intrathyroidal absorbed dose of 300 Gy and determined the applied activity individually, which ranged from 240 to 3120 MBq with a median of 752 MBq. Hyperthyroidism was eliminated in 86% of cases after 3 months and in 100% after 12 months. No patient required a second radioiodine treatment. The incidence of hypothyroidism was 63% after 3 months and 93% after 18 months. Neither the pretherapeutic thyroid-stimulating immunoglobulin level nor the degree of co-existing endocrine ophthalmopathy was correlated with the time at which hypothyroidism developed. Patients with previous radioiodine therapy developed hypothyroidism earlier than patients with previous thyroid surgery. The results show that ablative radioiodine therapy with a 300-Gy absorbed dose is a very effective treatment of hyperthyroidism in Graves' disease, but it should be restricted to patients with recurrent hyperthyroidism combined with severe co-existing disorders or episodes of unfavourable reactions to antithyroid drugs. Correspondence to: U.F. Willemsen     

Health effects of therapeutic use of 131I in hyperthyroidism.

Since 1942, therapy with radioiodine (Na131I) has gained a major role in the treatment of benign thyroid disorders, notably hyperthyroidism caused by Graves' disease or toxic multinodular goiter. The very large series of patients treated so far offer the opportunity for an assessment of both benign and malignant side effects. Hyperthyroidism is sometimes observed after radioiodine therapy due to radiation induced thyroid hormone or by an immunological mechanism. Despite the numerous attempts to design dosage schedules aiming at euthyroidism, hypothyroidism occurs in the majority of patients throughout life. Transient hypothyroidism may be observed within the first year after therapy and is caused by an immunological mechanism. Radioiodine therapy in Graves' disease may induce or worsen ophthalmopathy, which can be prevented by steroids effectively. Hypoparathyroidism and hyperparathyroidism have been reported after radioiodine therapy but probably do not exceed the normal incidence. Sialitis is commonly observed but mostly in patients treated with radioiodine for thyroid cancer. There are no indications for induction of genetic abnormalities after radioiodine therapy although no definite conclusion can be reached. Much attention has been paid to malignant disease. In very large series, no effects of radioiodine therapy on survival have been observed. Some studies report an increased relative risk for certain types of cancer (notably thyroid cancer, stomach cancer, bladder and kidney cancer or hematological malignancies). However, these observations were not confirmed by other large studies, so that no definite conclusion with respect to risk for certain types of malignant disease can be drawn. However, radioiodine therapy for benign thyroid disorders has generally been considered safe and without major side effects, hypothyroidism being the most frequent one.     

The role of thyroid scanning in hyperthyroidism

Radionuclide thyroid imaging was performed in 872 consecutive patients with hyperthyroidism. Of these, 84% were found to have diffuse toxic hyperplasia (Graves' disease), while 12% had autonomously functioning nodules (Plummer's disease), 3% had Graves' disease developing in a multinodular gland, and in the remaining 1%, either a clear diagnosis could not be established or the hyperthyroidism was due to thyroiditis or the Jod-Basedow phenomenon. It was found that a thyroid scan seldom provides additional diagnostic information in patients with Graves' disease when a diffuse goitre is present. However, if patients are to be treated with radioiodine (131I), thyroid imaging with tracer quantitation can replace a 24-h 131I uptake measurement, this having the advantages that the patients are required to attend only once, and that the gland size can be measured. In addition, visual confirmation of tracer uptake by the thyroid is obtained and patients with thyroiditis will not receive inappropriate therapy. When single or multiple thyroid nodules are palpated, a thyroid scan is crucial in establishing an accurate diagnosis, as it is not otherwise possible to differentiate between Plummer's disease and Graves' disease developing in a multinodular gland. Indeed, in 20 of our 63 patients (32%) with single autonomously functioning nodules, the initial clinical assessment had been incorrect.     

Indications for and basic principles of the surgical treatment of thyroid diseases

Surgical treatment is indicated for patients with nodular goiter if malignancy seems possible, if there are mechanical reasons, or on request from the patient. In patients with goiter and hyperthyroidism, surgery and radioiodine are alternatives. In contrast, thyroid autonomy always requires surgery. The treatment of patients suffering from differentiated thyroid cancer includes thyroidectomy and radioiodine, and in those with anaplastic thyroid cancer external radiation and surgery should be performed. Apart from the classic indications and surgical procedures, in recent years selective resection of multinodular goiter, more conservative surgery of small papillary thyroid cancer and surgical treatment of iodine-induced thyrotoxicosis have become established.     

The role of thyroid scanning in hyperthyroidism

Radionuclide thyroid imaging was performed in 872 consecutive patients with hyperthyroidism. Of these, 84% were found to have diffuse toxic hyperplasia (Graves' disease), while 12% had autonomously functioning nodules (Plummer's disease), 3% had Graves' disease developing in a multinodular gland, and in the remaining 1%, either a clear diagnosis could not be established or the hyperthyroidism was due to thyroiditis or the Job-Basedow phenomenon. It was found that a thyroid scan seldom provides additional diagnostic information in patients with Graves' disease when a diffuse goitre is present. However, if patients are to be treated with radioiodine (¹³¹I), thyroid imaging with tracer quantitation can replace a 24-h ¹³¹I uptake measurement, this having the advantages that the patients are required to attend only once, and that the gland size can be measured. In addition, visual confirmation of tracer uptake by the thyroid is obtained and patients with thyroiditis will not receive inappropriate therapy. When single or multiple thyroid nodules are palpated, a thyroid scan is crucial in establishing an accurate diagnosis, as it is not otherwise possible to differentiate between Plummer's disease and Graves' disease developing in a multinodular gland. Indeed, in 20 of our 63 patients (32%) with single autonomously functioning nodules, the initial clinical assessment had been incorrect.     

Changes in national insurance reimbursement with introduction of the DPC package payment system for 131I therapy for hyperthyroidism

The inpatient DPC package payment system lowers national insurance reimbursement as compared to the former fee-for-service payment system for inpatients, when an inpatient with hyperthyroidism or toxic multinodular goiter (TMNG) is admitted for 2-day radioiodine therapy. The differentials are 29,970 yen and 48,870 yen for a 2-day hospital stay for administration of 555 MBq and 925 MBq, respectively. We request the Health and Labor Ministry to newly establish the fee for 131I internal therapy for hyperthyroidism. Furthermore, the fee should be paid according to the fee-for-service payment system.     

Radioiodine treatment in patients with Graves' disease at outpatient clinic: special reference to safety and short-term outcome

PURPOSE: This retrospective study was aimed at revealing the safety and short-term outcome of radioiodine treatment in patients with Graves' disease at outpatient clinic. METHODS: From July 1999 to April 2002, 511 patients with Graves' disease were treated with radioiodine at the outpatient clinic of Tajiri Thyroid Clinic, Kumamoto. Of them, 73 patients dropped out or were referred to another medical institution. In the remaining 438 patients [100 men and 338 women; 44.6 +/- 15.4 (mean +/- SD) (14-82) years old], the safety of radioiodine treatment at the outpatient clinic and the treatment outcome until April 2003 was examined. The dosage was determined based on radioactive iodine uptake (3 hours) and thyroid volume measured by ultrasound. The initial dosage was 6.7 +/- 3.3 (1.2-13.5) mCi. Five months later, it was evaluated whether or not radioiodine should be administered a second time. All patients were treated at the outpatient clinic. RESULTS: There was no particular problem associated with treatment. Patients with a large goiter could be successfully treated with divided doses. After 12-45 (30.1 +/- 9.3) months of radioiodine, thyroid function status was as follows; hyperthyroidism: 7 patients (1.6%), subclinical hyperthyroidism: 78 patients (17.8%), euthyroidism: 108 patients (24.7%), subclinical hypothyroidism: 116 patients (26.5%), hypothyroidism: 129 patients (29.4%). CONCLUSION: It was concluded that radioiodine treatment in patients with Graves' disease at outpatient clinic was safe and showed a satisfactory short-term outcome.     

Outpatient management of patients with large multinodular goitres treated with fractionated radioiodine

The efficacy of fractionated out-patient radioiodine therapy in 38 patients with compressive symptoms due to long-standing large multinodular goitres was assessed. The diagnosis was established by clinical assessment in addition to technetium-99m pertechnetate thyroid scan or computed tomography scan of the thyroid and mediastinum. Oral iodine-131 therapy was administered as a 2.22 GBq (60 mCi) cumulative dose over 4 months (555 MBq per month). All patients were monitored with serum thyroid-stimulating hormone and free thyroxine (± free tri-iodothyronine) assays before the treatment and after each dose fraction. Clinical and biochemical follow-up was performed on all patients and ranged from 6 to 45 months after therapy. The patients consisted of 35 female and three male patients with a median age of 59 years (range 37–87 years). Prior to treatment 20 patients were biochemically hyperthyroid and 18 were euthyroid. Overall, 71% of patients reported a subjective improvement in compressive symptoms and 29% reported no change. Clinically assessed reduction in goitre size occurred in 92% of patients while there was no change in 8%. At 3 months of follow-up, 31% of patients had become hypothyroid and at 18 months 66% were hypothyroid. Seven hyperthyroid patients (35%) became euthyroid and 13 hyperthyroid patients (65%) became hypothyroid. Three patients who became hypothyroid experienced neck soreness (transient in one patient, persistent in two patients). There were no differences in outcome between patients who were hyperthyroid and those who were euthyroid prior to treatment. Fractionated out-patient radioiodine therapy showed excellent short- and medium-term safety, was very well tolerated and offered a satisfactory alternative treatment to surgery. Received 23 May and in revised form 11 August 1997     

Long-term results of two schedules of radioiodine treatment for toxic multinodular goitre

The long-term effects of two schedules of radioiodine therapy in patients with toxic multinodular goitre were evaluated. Forty-five patients (group A) were treated with low doses and 58 patients (group B) with calculated doses adjusted for thyroid weight (1.85–3.70 MBq/g) and radioactive iodine uptake. Follow-up (mean ± SEM) was 4.3 ± 0.2 years and 5.2 ± 0.3 years, respectively (P>0.1). At the end of follow-up, hyperthyroidism was successfully reversed in 73% (group A) and 88% (group B). In each group, hypothyroidism was present in 7%. The total dose per gram of thyroid tissue was not significantly different in groups A and B (2.1 ± 0.2 vs 2.7 ± 0.2 MBq/g). However, for patients treated with calculated doses the number of ¹³¹I administrations was significantly lower (1.3 ± 0.1) than for patients treated with low doses (2.2 ± 0.2), and the percentage of patients who were adequately treated with a single dose was more than twice as high (66% in group B versus 27% in group A). Euthyroidism was reached within a significantly shorter time after treatment with calculated doses (median time 0.6 years in group B vs 1.5 years in group A; life table analysis). It is concluded that radioiodine is an effective treatment for toxic multinodular goitre with a low risk of post-treatment hypothyroidism and that calculated (higher) doses appear to be preferable to low doses.     

Concomitant hyperthyroidism in patients with thyroid carcinoma and the effects of iodine supplementation in an iodine-deficient area

Objectives of this study were to investigate the occurrence and aggressiveness of differentiated thyroid carcinoma (DTC) in patients with hyperthyroidism and to explore the influence of the changes in dietary iodine intake on the association of hyperthyroidism and DTC. Clinical records of 1,800 patients with DTC were reviewed. The characteristics of DTC cases with and without thyrotoxicosis and their thyroid tumors were comparatively assessed.In the current series, 76 patients (4.2%) presented with hyperthyroidism before thyroid surgery. The most common type of goiter among 76 patients was toxic multinodular goiter. Presence of lymph node metastasis and recurrence was only observed in patients with toxic diffuse goiter. When DTC cases with and without thyrotoxicosis were compared irrespective of the type of goiter, aggressiveness of thyroid carcinoma was not higher in the thyrotoxic group. Hyperthyroidism and thyroid carcinoma coexisted in 3.3% and 4.7% in cases diagnosed before and after national iodine supplementation program, respectively (P = 0.04). Clinical course of the disease was not different in the diagnosis of these cases. As a result of no significant difference in complete remission ratio, we conclude that there is no need for a different DTC treatment protocol in cases with coexisting hyperthyroidism.     

Radioiodine treatment of solitary functioning thyroid nodules

Forty-eight patients with hyperthyroidism due to a single toxic nodule have been treated with radioiodine (131I). The mean follow-up period is 37 months. All patients were rendered euthyroid and no cases of hyperthyroidism have been observed. Forty patients required only one dose of 131I to render them euthyroid, six patients required more than one dose and two patients initially rendered euthyroid relapsed during follow-up and required further 131I treatment. It is concluded that a single fixed dose of 131I is a simple, effective treatment for a solitary toxic thyroid nodule and does not cause hypothyroidism.     

甲状腺本身病变所致甲亢的核素显像特征

目的甲状腺功能亢进症具有多种病因、临床表现和治疗方法。应用核素显像对甲状腺自身病变所致甲状腺功能亢进症病因进行正确的诊断,指导选择相对应合适的治疗方法。方法319例临床拟诊甲亢患者,治疗前进行甲状腺显像（thyroid radionuclide imaging）,对甲亢病因做分型。结果甲状腺显像特征分类Grave’s病（GD）259例（合并结节66例）,81．2％;毒性腺瘤（TA）36例,11．3％;毒性多结节性甲状腺肿（TMNG）9例,2．8％;亚急性甲状腺炎15例,4．7％。结论甲状腺核素显像在甲状腺功能亢进症的分类和指导治疗中起重要的基础作用,可为临床提供合理及最佳的临床实践。