|Year : 2014 | Volume
| Issue : 2 | Page : 60-65
Empirical 131 Iodine therapy in thyrotoxicosis based on 99mTechnetium thyroid scan and gamma camera based uptake values
Ajit S Shinto1, Koramadai K Kamaleshwaran1, P Velayudham2, Suresh Damodharan2, A Prem Kumar3
1 Department of Nuclear Medicine, Kovai Medical Center and Hospital, Coimbatore, Tamil Nadu, India
2 Department of Endocrinolgy, Kovai Medical Center and Hospital, Coimbatore, Tamil Nadu, India
3 Department of Endocrinolgy SKS Hospital, Salem, Tamil Nadu, India
|Date of Web Publication||31-Mar-2014|
Ajit S Shinto
Department of Nuclear Medicine, Kovai Medical Center and Hospital, Coimbatore - 641 014, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Objective: Radioactive iodine-131 (RAI) has been established in the treatment of patients with various etiologies of hyperthyroidism. However, the short term and long term clinical outcome of patients receiving RAI is different in various studies. The aim of this study was to assess clinical outcome one year after RAI therapy and identify factors associated with a good response. Materials and Methods: In this experimental study among patients with Graves' disease, referred to the Nuclear Medicine Department and had indication for RAI therapy, 164 consecutive subjects were enrolled for the study. Radioiodine dose was calculated based on the uptake of the thyroid gland by routine pertechnetate thyroid scan done on a gamma camera. Patients with less than 10% uptake of injected dose were given 10 mCi of oral Na-I 131 and if uptake was higher than 10%, a dose of 15 mCi was administered. Patients were monitored closely clinically and with blood investigations after treatment for one year. Results: Among the 158 patients, who completed follow-up, 96.2% recovered and 3.8% remained thyrotoxic. Among patients who recovered, 77.6% became hypothyroid and 22.4% euthyroid. The incidence of hypothyroidism was 32.2% in first trimester, 58.5% in second trimester, 5.1% in third trimester and 4.2% in fourth trimester. Conclusion: In our study, a good result was seen in more patients than other studies and it might relate to higher absorption of radioactive iodine in our region . According to our result, incidence of hypothyroidism was the most in second trimester, and so patients should be carefully followed in this period.
Keywords: Graves′ disease, hyperthyroidism, hypothyroidism, outcome, radioiodine therapy,
|How to cite this article:|
Shinto AS, Kamaleshwaran KK, Velayudham P, Damodharan S, Kumar A P. Empirical 131 Iodine therapy in thyrotoxicosis based on 99mTechnetium thyroid scan and gamma camera based uptake values. Thyroid Res Pract 2014;11:60-5
|How to cite this URL:|
Shinto AS, Kamaleshwaran KK, Velayudham P, Damodharan S, Kumar A P. Empirical 131 Iodine therapy in thyrotoxicosis based on 99mTechnetium thyroid scan and gamma camera based uptake values. Thyroid Res Pract [serial online] 2014 [cited 2020 Jun 5];11:60-5. Available from: http://www.thetrp.net/text.asp?2014/11/2/60/129727
| Introduction|| |
Radioiodine therapy has enjoyed increasing popularity since its use in the 1960s for hyperthyroidism because of its efficacy and few side effects. Hyperthyroidism is a state of increased function of the thyroid gland leading usually to a clinical status of thyrotoxicosis. Graves' disease, an autoimmune disease, caused by an antibody active against the thyroid stimulating hormone receptor, is the most common cause of hyperthyroidism accounting for 60 to 80 percent of all cases. Other common causes include toxic multinodular goiter and toxic adenomas.  Antithyroid drugs (ATD), radioactive iodine (RAI) and surgery are the main treatment options for persistent hyperthyroidism. ,, RAI-131, a radioactive isotope of iodine, is the treatment of choice for most patients with Graves' disease and toxic nodular goiter. It is inexpensive, highly effective, easy to administer, tissue specific and safety has been proven in all age groups.  The primary goal of radioiodine therapy in Graves' disease is to cure the hyperthyroidism. It is controversial, however, whether radioiodine should be given in sufficient dose to induce hypothyroidism or in a lower dose in an attempt to achieve a euthyroid state. Controversy also exists regarding the optimal dosing regimen of radioiodine to ablate the thyroid gland. However, it is clear that most patients ultimately develop hypothyroidism after therapy. Administration of relatively low doses of RAI-131 designed to restore euthyroidism, but not cause hypothyroidism, may simply delay this or fail to cure the hyperthyroidism. , Most patients who become euthyroid soon after radioiodine therapy will eventually develop hypothyroidism at a rate of approximately 5 percent per year. 
The aim of treatment is to destroy sufficient thyroid tissue to cure hyperthyroidism by rending the patients' euthyroid or hypothyroid in the long term. Although it is highly effective with a cure rate approaching 100% after one or more treatments depending on the dose administered and various other factors,  some complications have been reported like delayed control of symptoms, post-treatment hypothyroidism, and in majority of patients with Graves' disease, regardless of dosage (82 percent after 25 years); transient neck soreness, flushing and decreased taste, radiation thyroiditis in 1 percent of patients, may exacerbate Graves's ophthalmology, may require pretreatment with ATDs in older or cardiac patients.  Previously there was concern that this form of therapy might also produce thyroid carcinoma, leukemia, or an increase in mutation rates. However, in more than seven decades in which RAI has been in use, no increased prevalence of thyroid or other carcinoma in treated patients has been noted. ,
The most important side effect is hypothyroidism, though many of the treating physicians state that it is the inevitable outcome to be achieved. Many reports have documented that the incidence of hypothyroidism is significant during the first year or two after treatment with RAI and continue to increase at a rate of approximately 5% per year therefore. Studies have reported the incidence of post RAI hypothyroidism at 5 th year to be between 30-50% depending on dosage and geographical factors, although values as high as 70% have been reported. 
About 1% of patients who receive RAI may experience radiation thyroiditis 5-10 days later with pain over the thyroid area and possibly associated hyperthyroidism due to release of stored hormone and sometimes may progress to post-treatment thyroid storm.  There has also been reluctance to use RAI in women of childbearing years because of the genetic damage in future offspring. Long term follow-up of patients has not validated these concerns. , The aim of this study was assessment outcome one year after RAI therapy.
| Material and Methods|| |
In this study, among hyperthyroid patients with Graves' disease, referred to the Nuclear Medicine department for RAI therapy, 164 consecutive subjects were enrolled for the study. All the patients had been given a trial of standard ATD regimen and none of them were ever exposed to RAI therapy.
Exclusion criteria were pregnancy, breast feeding, severe Graves 'ophthalmopathy and age under 20 years. Iodine containing medications were discontinued several weeks before therapy and ATDs withdrawn at least 5 days before RAI therapy. Most of the patients were put on pre-treatment beta blockers and was continued for approximately 2 weeks post-therapy. Doses were calculated on the basis of the gamma camera based uptake of the thyroid gland at 20 minutes after intravenous injection of 3-5 mCi of sodium per technetate. Patients with total thyroid uptake less than 10% of injected dose were given 10 mCi of 131-I orally and if it the uptake was greater than 10%, they received 15 mCi of 131-I orally. Patients were recommended to avoid physical contact and transfer of secretion for several days after treatment. Patients were monitored closely, clinically and biochemically, at frequent outpatient visits for one year after therapy.
A good result was considered as hypothyroidism or euthyroidism after RAI therapy.
Informed consent was obtained from all subjects and the research had the approval of the institutional review board and ethics committee of the Institute and was carried out in accordance with the Declaration of Helsinki.
For statistical analysis, categorical variables were compared with Chi-square and Fisher exact test. Continuous variables that are normally distributed were expressed as mean ± SD. Statistical calculation was performed using a commercial computer package (Statistical Package for Social Sciences for Windows version 13.0; (SPSS)).
| Results|| |
At first 164 subjects were enrolled but only 158 patients completed follow-up for 1 year. All the patients had a clinical diagnosis of Graves' disease, based on clinical, biochemical, antibody, thyroid ultrasound as well as nuclear thyroid scan evidence. All the patients received ATD before RAI therapy and of these patients 75.9% treated for more than one year. 52% had one recurrence after stopping ATD's, 7% two recurrences and 1.2% had three recurrences before RAI therapy [Table 1].
Among these patients, 96.2% (n = 152) recovered (hypothyroidism or euthyroidism) and 3.8% (n = 6) remained hyperthyroid. Among patients who recovered, 77.6% (n = 118) became hypothyroid and 22. 4% (n = 34) euthyroid.
Among the patients who became hypothyroid, the incidence of hypothyroidism was 32.2% in first trimester, 58.5% in second trimester, 5.1% in third trimester and 4.2% in forth trimester [Table 3].
96.5% women and 95.5% men obtained pleasant result and unpleasant result (persistent hyperthyroidism) was noted in 3.5% women and 4.5% men. No significant association was observed between sex and cure rate (P = 0.9). Pleasant result was observed in 94.9% of subjects aged less than 35 and 97.8% of subjects aged more than 35 years (P = 0.2). 97.6% of subjects who received antithyroid medications less than one year and 95.7% received medication more than one year obtained pleasant result (P = 0.10) [Table 2]. Pleasant result was seen in 95.9% of patients who received RAI less than 10 mCi and in 97.6% of patients who received 15 mCi, but this correlation was not significant (P = 0.6) [Table 2].
| Discussion|| |
Although RAI is widely used for the treatment of patients with thyroid disorders, particularly hyperthyroidism, outcome of patients receiving RAI is different in studies. In our study, pleasant result was seen in 96. 2% of patients with Graves' disease, when a standard empirical dose of oral 131-I was given to the patient based on the percentage uptake by the thyroid gland at 20 minutes post injection of 3-5 mCi of pertechnetate. Hypothyroidism was seen in 77.6% patients treated with RAI in one year and just 4 patients (2.5%) needed second dose and 2 patients (1.2%) needed third dose.
In our study, a good result was seen in more patients than other studies and it might relate to higher absorption of radioactive iodine in our region. Taylor et al. studied 225 patients who were treated with 555 MBq (15 mCi) RAI for hyperthyroidism, and to ablate the thyroid and induce early hypothyroidism. With this fixed-dose regimen only 5.6% failed to become euthyroid within one year of treatment. Ten patients (4.4%) required a second dose of 555 MBq 131-I since they were still hyperthyroid one year after treatment and three of these required a third dose. 
Our patients received 10 mCi or 15 mCi of oral 131-I on the basis of the % uptake of the thyroid gland by standard gamma camera imaging. The optimal method for determining iodine-131 treatment doses remains controversial. Techniques have varied from fixed doses ,, to more elaborate calculations that are based upon gland size (estimated either clinically or from imaging), iodine uptake, and sometimes iodine turnover. ,,, Leslie et al., studied 88 patients with Graves' hyperthyroidism who had not been previously treated with radioactive iodine, were randomized to one of four dose calculation methods: low-fixed, 235 MBq; high-fixed, 350 MBq; low-adjusted, 2.96 MBq (80-Ci)/g thyroid adjusted for 24 h RAI uptake; and high-adjusted, 4.44 MBq (120-Ci)/g thyroid adjusted for 24 h RAI uptake. Subjects were followed for mean of 63 months for assessing clinical outcomes. Mean treatment doses were similar in the different outcome groups. They could not demonstrate any advantage to using an adjusted dose method. Survival analysis did not demonstrate any difference in the time to outcome between the fixed and adjusted dose methods.  Mazzaferri et al., in their study on 813 hyperthyroid patients, divided them in two groups. First group received 185 MBq and second group received 370 Mbq. Incidence of hypothyroidism was 41.3% in first group and 60.8% in second group at the end of their study period. 
Most dosimetric methods have the benefit of including a measure of thyroid size in their formulas, thereby administering a dose of RAI proportional to size of the gland and theoretically increasing the probability of cure. In addition, the use of isotope uptake measurements, as part of the dose calculation protocol, can confirm the absence of thyroiditis and identify patients with extremes of isotope uptake or turnover, which may predict failure of RAI treatment.  Despite these potential benefits of calculated doses, several studies have failed to demonstrate improvements in cure rate over fixed doses. ,, Furthermore, there is little evidence that using a calculated dose has any advantage over a fixed-dose regimen, in terms of preventing hypothyroidism,  so many centers use a single-fixed dose. 
We administered RAI of approximately 15 mCi in subjects with higher uptakes based on the premise that these glands are usually larger, are more active, iodine hungry and have a faster turnover of organified iodine, thus reducing the intra glandular residence time, lessening the therapeutic effect. Thus, higher dose is required for a consistent therapeutic benefit, though it has not been proven conclusively in various studies as well as meta analyses.
Our results showed that there was no difference in cure rate between the two different doses of RAI, though the size of the gland was different in the two groups and hence the results cannot be universally applied. Allahabadia et al., reported that in patients given a single dose of 370 megabequerels, a higher cure rate was achieved than those given 185 megabequerels, (84.6% vs. 66.6%) but an increase in hypothyroidism incidence at 1 yr (60.8% vs. 41.3%). 
About effect of age in Allahabadia study, younger patients (<40 yr) had a lower cure rate than patients over 40 yr old (68.9% vs. 79.3%).  Our results showed a cure rate of 94.9% in patients below 35 years and 97.8% in patients aged above 35 years. Although no statistically significant difference was noted between the two age groups, there was a trend of higher cure rate in the older age group. It could also be noted that there was good treatment response in younger age group with no compliance issues and no significant side effects. According to this, RAI can be offered earlier in younger patients in the treatment of their disease.
We did not observe any significant association between cure rate and sex. Gender has not been demonstrated to be a significant prognostic factor to response RAI treatment in many studies but Allahabadia et al., showed males had a significantly lower cure rate, after one dose of RAI, than females. 
Several studies have demonstrated that patients with larger volume thyroid glands are more likely to fail to respond to a single dose of RAI.  Though we did not use the size of the thyroid gland as a variable, it was noticed that the patients with a higher uptake percentage tended to have bigger thyroid glands. So the patients with higher uptake and bigger gland size were administered higher doses compared to patients with similar gland size but lower uptakes and our results show that both groups of patients did equally well.
Our findings also showed no significant correlation between pretreatment ATDs duration and cure rate. Many studies have shown a reduction in response rate to RAI , if patients have received pretreatment with thyroid drugs, but others have shown no effect  or an effect confined to propylthiouracil.  Alexander et al., treated 261 patients with hyperthyroidism caused by Graves' disease with 131-I [mean dose, 14.6 mCi (540 MBq)]. Patients pretreated with antithyroid medication for greater than 4 months were at higher risk for treatment failure.  Also some studies demonstrated that ATDs pretreatment may cause to exacerbate and recurrence of hyperthyroidism. , But our results are similar to Braga and Andrade et al., who demonstrated that methimazole pretreatment has no effect on final result or the time required for cure or the 1-yr success rate of 131-I therapy. , Ahmad et al., demonstrated the frequency of hypothyroidism was lower in patients treated with ATDs prior to RAI compared with patients who did not received anti thyroid drug. Hypothyroidism after RAI was reported from 2 months to 20-30 years after therapy. The study identified Graves' disease, presence of thyroid autoantibodies, no antithyroid treatment given prior to RAI, non-palpable goiter and high RAI dose as significant independent risk factors. In the absence of all risk factors, there is a 11.9% probability of developing hypothyroidism; which increases linearly to a 96.4% probability in the presence of all factors. 
In our study, hypothyroidism was seen in 77.6% of subjects mostly in second trimester post therapy. Similarly, in a study by Nebesio et al., hypothyroidism was observed in 75% patients 40-90 days after RAI.  In Ahmad's study the cumulative incidence of hypothyroidism following RAI treatment was 38.2% after 6 months; this increased to 55.8% after 1 year and 86.1% at 10 years.  In Taylor study, the modal time to hypothyroidism was three months, and 64% of patients were hypothyroid at one year. 
These data suggest cure rate in our patients was more than other studies. This may be contributed by the higher absorption of RAI in our patients due to regional iodine insufficiency compared with iodine sufficient region and probably low sample size. No significant association was observed between cure rate and gender, ATDs pretreatment, duration of ATDs pretreatment and RAI dose. Only correlation between age and the final result could be considered significant. According to our result incidence of hypothyroidism was the most in second trimester, so patients should be carefully followed in this period.
Ideally, the rate of euthyroidism should correlate with the applied activities of radioiodine, whereas too low activities would result in persistent hyperthyroidism and overdosing would induce hypothyroidism, in between these extremes, an ideal activity would be observed. However, the ideal way to determine activity does not exist, mainly because treatment success depends on the absorbed dose and not on the applied activity. Individualized methods make important assumptions with respect to the kinetics of radioiodine. All reported studies used the 24-h radioactive iodine uptake to determine activity. However, this uptake method may be inaccurate because the biological half-life of radioiodine is variable and that it assumes a first-order kinetic model, which may be too simplistic.  Moreover, dosimetric formulas take into account individualized iodine metabolism, but ignore several other factors also known to affect treatment outcome, such as patient age, gender and severity of hyperthyroidism. Further, the individual thyroid metabolism seems to fluctuate overtime. Thus, the uptake of a test activity of radioiodine does not necessarily correlate with the uptake of the therapeutic activity several days to weeks later.  Since there will always be sometime between the application of the uptake measurement and the therapy with I-131, this problem cannot be overcome with dosimetry. These considerations make clear that also calculated methods to determine activity may not be optimal.
It is important to consider what the main goal of I-131 therapy should be: long-term euthyroidism or cure from hyperthyroidism. If the main goal is cure from hyperthyroidism (ablative procedures), higher activities may be applied in order to prevent a prolonged hyperthyreotic state. However, induction of hypothyroidism, necessitating lifelong supplementation therapy, may be accompanied by intrinsic imperfection of hormonal replacement therapy. The goal of nonablative procedures is the adequate treatment of hyperthyroidism, without induction of hypothyroidism in a large proportion of patients. It was not the aim of the paper to decide on the goal of I-131 treatment. Irrespective of the treatment goal, radioactive treatments should be performed according to the ALARA ('as low as reasonable achievable') principle. This means for a predefined therapeutic goal, the lower the administered activity the better the treatment. This principle protects from unnecessary high administered activities. Both goals should be taken into account when considering the goal for radioactive iodine therapy in hyperthyroidism: The best clinical effect with the lowest possible activity. A high therapeutic success rate in our study, could potentially emphasize the fact that more cumbersome calculations might be replaced with a simple gamma camera based uptake.
The calculation method is a relatively time consuming procedure compared with estimation methods, requiring at least one extra visit to an outpatient clinic, adding to the complexity and cost of the procedure. On the other hand, no optimal fixed dose exists as the absorbed dose depends on geographical conditions and patient characteristics, and is variable especially in Graves' disease. Theoretically, some of these factors that determine the absorbed dose can be adjusted for in calculated methods but need not translate in better treatment outcomes.
| Limitations of the Study|| |
One of our limitation is the sample size was relatively small so our negative result may reflect lack of power. Further studies to confirm our result with longer follow-up and lager sample size is suggested. In addition, the hypothesis that the better cure rate was due to higher iodine absorption is not verified due to the lack of an iodine uptake probe. However, an association between the gamma camera calculated thyroid uptake and cure rates is to be studied to establish the relation between better cure rates and high absorption.
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[Table 1], [Table 2], [Table 3]