Radioiodine Therapy of Graves' Disease and the Uptake Paradox.

PURPOSE OF THE STUDY: Radioiodine (131I) therapy is approved and well-accepted modality for the treatment of hyperthyroidism. The dosage of 131I for successful treatment is based on many factors; however, an objective tool to determine the dose was missing. In a retrospective study, we found that high 131I uptake values required more dose to achieve desirable results contrary to the belief.
MATERIALS AND METHODS: Clinically and scintigraphically proven Graves' disease patients with high 131I uptake (>50%) were accrued for this study and block randomized into low-dose (Group I) and high-dose (Group II) groups. Low activity (5 mCi) was administered in Group I and higher activity (10 mCi) in Group II. The patients were followed up after 3 months with thyroid function tests to determine the outcome.
RESULTS: A total of 344 patients were analyzed at the end of 3 months, with 174 in low-dose group and 170 in high-dose group. Euthyroidism/hypothyroidism was achieved in significantly higher number of patients as compared to the low-dose group.
CONCLUSION: The higher dose of 131I is required to achieve euthyroidism/hypothyroidism in patients with high 131I uptake. Copyright:

Introduction

Graves' disease, also known as Parry's/Basedow's disease, is the most common cause of hyperthyroidism in the world. The prevalence of Graves' disease is about 0.2% in males and 1.3%–2% in females in the US and UK and ranges from 0.6% to 1.6% in India.[1234] The therapeutic options available for the treatment are antithyroid drugs, radioiodine (131I) therapy, and surgery.[5] Depending on many factors, including socioeconomic and cultural factors, physicians and patients prefer one modality over the other, although all three modalities have been proved to be equally effective. In several parts of the world including the US, radioiodine has become the most commonly used therapeutic modality. The required activity of radioiodine to be administered is calculated using many methods such as gland size, thyroid uptake, and T4 level. However, controversies remain in calculating the correct dose to achieve euthyroidism or hypothyroidism.[678] An objective tool to calculate the effective dose is missing. Radioactive iodine uptake (RAIU) test is one such tool used to estimate the dose required and also helps in the differential diagnosis of thyrotoxicosis. It was firmly believed that higher the RAIU, lower is the activity of 131I required to administer for successful treatment, as indicated by the following standard formula used to calculate the dose.

However, recently in a retrospective study from our institute (duration: 1987–2006) made a paradoxical observation that higher the RAIU, higher is the dose required for successful treatment.[9] Therefore, to address this controversy, we designed a prospective randomized control trail, with 90% power (alpha = 0.05, n = 171 in each arm) to test the radioiodine therapy and high-RAIU paradox in patients with Graves' disease.

Materials and Methods

The current study was approved by the Institutional Ethics Committee. Patients were informed in the local language about the study and consent obtained for participation. All consecutive Graves' disease patients who were referred for radioiodine therapy were recruited for the study. [Chart 1]

Chart 1

Overview of the study. RAIU - Radioactive iodine uptake

Inclusion and exclusion criteria

Patients clinically and scintigraphically (uniformly increased99m Tc-pertechnetate) diagnosed with Graves' disease were included in the study. Patients <18 years of age, pregnant or lactating women, and those with active moderate-to-severe orbitopathy were excluded from the study.

Baseline evaluation

Prior to radioiodine therapy, all patients underwent detailed clinical and biochemical evaluation. For the clinical assessment, a full-detailed history, prior antithyroid drug treatment or of any other medications, and signs and symptoms of Graves' disease were evaluated. For biochemical assessment, serum total T3, T4, and thyroid-stimulating hormone (TSH) were measured using radioimmunometric assay.

RAIU measurement

If the patients were on antithyroid drugs, they were asked to stop the drugs for a minimum of 1 week. All patients were administered a standard dose of 5 μCi of 131I orally on empty stomach. Patients were asked not to consume food for the next 2 h. RAIU was measured at 2 and 24 h after 131I administration. Measurements were done using a standard thyroid uptake probe (Biodex Atomlab 950, Oakville, Ontario, Canada). The uptake was measured with 25–30 cm between the face of the crystal and the anterior neck or phantom. Neck counts, lower thigh counts (body background), counts of a calibrated standard in a neck phantom, and room background counts were obtained at each counting session (in cpm – counts per minute). RAIU was calculated with the following formula:

Randomization and radioiodine therapy

Patients with 24 h RAIU >50% were block randomized into two groups – Group 1 patients were administered a fixed activity of 5 mCi (185 MBq) and Group 2 were administered 10 mCi (370 MBq) of 131I. Those patients with 24 h RAIU <50% were excluded from this study. All patients were put on beta blockers or calcium-channel blocker (if beta blockers were contraindicated) for the control of sympathetic symptoms.

Follow-up evaluation

All patients were reassessed clinically and biochemically (T3, T4, and TSH) 3 months after radioiodine therapy. They were classified into euthyroid, hypothyroid, or persistently toxic states. Hypothyroidism was defined as T3 <70 ng/dl, T4 <4.5 μg/dl, and TSH >4.5 IU/ml. The first-dose cure rate was defined as either euthyroidism or hypothyroidism at 3 months follow-up. Subclinical hyperthyroidism and overt hyperthyroidism were considered as not cured. Patients were then followed up for an average period of 12 months.

Statistical analysis

Statistical analysis was performed using the SPSS software version 11.5 (SPSS Inc., Chicago, Illinois, USA), and the groups were compared using two-sample Wilcoxon rank-sum (Mann–Whitney) to test the continuous variables. Results were compared using the student paired t-test. P < 0.05 was considered statistically significant.

Results

A total of 415 Graves' disease patients who fulfilled the inclusion and exclusion criteria were randomized into Group I (n = 204) or Group II (n = 211). Cent percent recruitment was achieved; however, 71 patients went back to their treating endocrinologist/physician after receiving first dose of 131I, and we could not get further information on them in spite of repeated attempt to contact the patients, thus were excluded from the analysis (30 from Group I and 41 from Group II). The final analyses were made on 344 patients (174 in Group I and 170 under Group II) – 103 males, mean age 38.9 ± 11.18 and 37.6 ± 11.94, mean 24 h RAIU–63.15 ± 10.08 and 66.32 ± 10.71 in Group I and Group II, respectively. Both groups were matching in their baseline characters (age, gender, RAIU, T3, T4, and TSH values). The patients' characteristics and pretherapy investigation results are shown in Table 1. Prior antithyroid drug intake varied from 3 months to 13 years in both the groups (P = 0.72).

Table 1

Demographic profile of the recruited Graves’ disease patients

	Group 1 (5 mCi fixed activity)	Group 2 (10 mCi fixed activity)	P
n	174	170
Age (mean)	38.9±11.18	37.6±11.94	0.382
Females	119	122	0.495
Males	55	48
T3 (normal 70-180 ng/ml)	324.19±126.23	312.91±141.96	0.436
T4 (normal 4.5-12 µg/dl)	18.63±6.61	19.09±9.49	0.612
TSH (normal 0.5-4.5 mIU/l)	0.119±0.153	0.126±0.143	0.647
2 h RAIU	36.05±17.91	39.98±19.83	0.328
24 h RAIU	63.15±10.08	66.32±10.71	0.997
Patients on previous antithyroid medication	143	142	0.723

TSH: Thyroid-stimulating hormone, RAIU: Radioiodine uptake, T3: Triiodothyronine, T4: Thyroxine

First-dose overall success rate at the end of 3 months was 237/344 (68.9%); significantly higher (P = 0.005) in Group II (76.5% [n = 130]) as compared to Group I (61.5% [n = 107]) [Figure 1]. In view of persistent hyperthyroidism in 107 patients, additional doses of radioiodine were administered for 67 patients of Group I and 40 of Group II.

Figure 1

Pie chart depicting significantly higher single-dose cure rate in Group II (76.5%) as compared to Group I (61.5%) (P = 0.005). P < 0.05 was considered statistically significant

After the second administration of radioiodine, 22 patients (11 patients each in Group I and Group II) went back to their referring endocrinologist/physician for subsequent management and did not report to us, thus considered lost to follow-up. Median total follow-up time was 18 months in Group I and 13 months in Group II. At the time of reporting, there were 59 patients in Group I and 51 in Group II were found euthyroid and 104 and 108 patients were hypothyroid, respectively. No serious adverse effects were reported in any of the patients.

Discussion

The optimal and effective administered activity of radioiodine for the successful treatment of Graves' has been debated over decades. Many tools to estimate the same have been proposed. The important variables noted are thyroid gland volume, thyrotropin receptor antibody level, thyroglobulin level, and radiation-absorbed dose to the thyroid gland. However, the outcome of therapy is not dependent upon any single-measured variable but multiple factors which play role in it.[10] Another important influencing factor is the length of pretreatment with antithyroid drugs.[11121314] In our study, both groups had similar percentage of patients who were on antithyroid medication; hence, interference if any would not be unilateral, ruling out influence on the final outcome. Regarding thyroid gland volume, a factor which has found to have a significant role in predicting the outcome of RAI therapy.[15] To test this hypothesis, Haase et al. divided patients into three groups – thyroid volume(<15, 15–25, and >25 ml) and adjusted administered activity according to volume. The authors reported a significant correlation between thyroid volume and treatment outcome.[16] However, it is well known that even smaller glands can secrete a high amount of hormones based on the thyrotropin receptor antibody level present and taking only anatomical factor may not give a complete understanding of the disease. Individualized treatment based on target absorbed dose is also proposed rather than administering a fixed dose, but optimum absorbed dose is still debatable, and there is no consensus.[17] Orsini et al. concluded, in their study, that dosimetric approach method based on thyroid-mass reduction instead of a fixed activity or an activity calculated based on a fixed value of the radiation dose to the gland, allows to personalize the 131I activity to be administered in patients on an individual basis depending on personal parameter such as thyroid volume and thyroidal iodine kinetics.[18]

Coming to dosimetry, RAIU value is another factor used to estimate the dose and predict the outcome. There was a strong belief that higher the uptake, lower the dose necessary for successful therapy, with many claiming that high uptake is necessary for better outcome.[14] However, recently, there have been reports that high-uptake values are predictors of poor outcome[1920] including a retrospective analysis done at our institute which showed that 24 h RAIU of more than 50% was associated with higher failure rate.[9] Hence, it was hypothesized that higher uptake values may demand higher administered activity of 131I for successful treatment with single administration.

In this study, we recruited a total of 415 Graves' patients who had 24 h RAIU >50% and randomized into two groups. Outcome at the end of first assessment at 3 months showed that higher uptake values were significantly associated with higher failure rates when relatively low amount of radioiodine (5 mCi fixed activity) was administered, and better outcome in high-activity (10 mCi) group which was comparable to other studies in which absorbed dose or thyroid volume was used to estimate the amount of administered activity. It can be argued that higher uptake is because of increased gland volume and so requires higher activity; however, uptake is not just based on the gland volume, rather depends on many factors including thyrotropin receptor-stimulating antibody levels. RAIU is a comprehensive measure of the disease status and may very well correlate with the present state of Graves' gland and the disease activity, as shown elegantly in this randomized control trial.

Conclusion

From this randomized control trial, we conclude that contrary to the belief, the patients of Graves' disease with higher 24 h RAIU (>50%) need higher administered activity of radioiodine to cure the disease with the single administered activity of 131I. The good old 24h RAIU seems a fairly reliable tool for guiding the administered activity and predicting the outcome of single dose 131I therapy in Graves' disease patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.