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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0608
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 12 6536-6540
Copyright © 2005 by The Endocrine Society

BRIEF REPORT

Effect of Iopanoic Acid on Radioiodine Therapy of Hyperthyroidism: Long-Term Outcome of a Randomized Controlled Trial

C. S. Bal, Ajay Kumar and Prem Chandra

Departments of Nuclear Medicine (C.S.B., A.K.) and Biostatistics (P.C.), All India Institute of Medical Sciences, New Delhi, India, 110029

Address all correspondence and requests for reprints to: Dr. C. S. Bal, M.B.B.S., M.D., D.N.B., Professor, Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India, 110029. E-mail: csbal{at}hotmail.com.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Telepaque [iopanoic acid (IA)] is believed to rapidly ameliorate hyperthyroidism; however, it may preclude subsequent 131I therapy, possibly delaying it for several months.

Objective: Our objective was to see how early patients, made euthyroid with Telepaque, can be treated with 131I and to compare their short- and long-term outcome with patients treated with 131I, after making them euthyroid with carbimazole and ß-blockers.

Design: We conducted a randomized controlled trial.

Setting and Patients: We studied 200 hyperthyroid patients at a tertiary care teaching institute.

Interventions: The IA group received Telepaque, 500 mg/d orally, for 7 d and then no medication for 1 wk followed by 131I therapy if radioiodine neck uptake had recovered. The control group received 30–40 mg oral carbimazole daily until patients became euthyroid followed by 131I.

Main Outcome: After 1 wk of Telepaque therapy and 6 wk of carbimazole, almost all patients became clinically and biochemically euthyroid, and 86 and 94% of patients were ready for 131I therapy after 1 and 2 wk off Telepaque, respectively. The cure rate, defined as euthyroid plus hypothyroid, after the first dose of 131I in controls and the IA group was 80 and 76.2%, respectively (P = 0.54). Thirty-two percent among controls and 25% in the IA group became hypothyroid within 1 yr (P = 0.33); thereafter, the annual rate of hypothyroidism was about 2% in both groups. After a mean follow-up duration of 11 yr, 58% of patients in the control group and 51% in the IA group were hypothyroid.

Conclusions: Telepaque rapidly ameliorates hyperthyroidism without jeopardizing the subsequent radioiodine therapy, and the outcome of radioiodine therapy in this subset of patients is in no way different compared with those prepared by carbimazole.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
RADIOIODINE THERAPY IS considered a major treatment modality in hyperthyroidism. In high-risk patients such as elderly thyrotoxic patients with severe thyrotoxic features, patients with impending thyroid storm, and patients suffering from thyrocardiac disease, rapid reduction of thyroid hormone level is desired or even imperative before radioiodine is administered to avoid rare events such as thyroid storm in the postablation period. Conventional preparation with antithyroid drugs such as thionamides takes 4–6 wk to achieve euthyroid status. Similarly, an alternative is required when conventional therapy is contraindicated (e.g. development of agranulocytosis with propylthiouracil or hypersensitivity to thionamides). The ability to swiftly and profoundly make patients clinically and biochemically euthyroid makes oral cholecystographic agents (OCAs) such as iopanoic acid (IA) (Telepaque) and ipodate (Oragrafin) an extremely attractive and invaluable tool in such conditions (1, 2, 3, 4, 5, 6, 7, 8).

The plasma inorganic iodine value is raised to a significant level because of release of a large quantity of iodine from OCAs. It was believed that their use may preclude subsequent radioiodine (131I) therapy, possibly delaying it for several months. In a pilot study, we had earlier demonstrated that iodine kinetics in hyperthyroid patients is significantly different from euthyroid individuals and that the majority of them are ready for 131I therapy after just 1 wk off OCA (5), results similar to that shown by Shen et al. (6). However, both these studies had small numbers of patients, and there was no literature available regarding the long-term outcome of patients treated with radioiodine after OCA as adjuvant. Therefore, we planned a randomized clinical trial to see how early patients, made euthyroid with Telepaque, can be treated with 131I and to compare their short- and long-term outcome with patients treated with 131I, after making them euthyroid with carbimazole and/or ß-blockers.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Sample size

In our experience of treating more than 3000 hyperthyroid patients with radioiodine over three decades, the first-dose radioiodine success rate is roughly 80%. The sample size, calculated by using the formula for comparing the two proportions with a level of significance ({alpha}) of 0.05 and power (1 – ß) of 90%, was found to be 170 (85 in each arm) to achieve the objective. A simple randomization method (200 random numbers were generated through a random number table) with concealment was used for allocating the patients to two groups in this prospective study. Because the stable iodine released from a contrast agent might decrease the radioactive iodine uptake in the thyroid (RAIU), which may lead to a lower success rate, even a 60% success rate with the first dose of radioiodine in patients receiving Telepaque as an adjuvant, was assumed to be a clinically acceptable tradeoff for the quick control of thyrotoxic features.

Two hundred consecutive hyperthyroid patients, who did not fulfill the exclusion criteria, were recruited into this randomized controlled trial from January 1991 to December 1996 after giving informed written consent. Patients with severe Graves’ ophthalmopathy or previous treatment of hyperthyroidism with radioiodine or surgery, those with hypersensitivity to iodine, pregnant and lactating women, and patients unwilling to give informed written consent were excluded from the study.

The patients were randomized into two groups with 100 patients in each arm. 1) The control group received 131I after they were made euthyroid conventionally with an antithyroid drug (carbimazole tablets, 30–60 mg in two to three divided doses, tapered to 10–20 mg once daily) with or without ß-blockers (propranolol, a nonselective ß-blocker; 120 mg/d in three divided doses). 2) The IA group, 100 drug-naive patients, who were assigned to the intervention group, were administered 500 mg/d Telepaque orally for 7 d as monotherapy and then no medication for 1 wk followed by 131I therapy if RAIU had recovered to baseline.

The patients were evaluated with complete clinical examination, thyroid function tests [T3 (normal, 70–200 ng/dl), T4 (normal, 4.2–13 µg/dl), free T3 (normal, 1.4–4.4 pg/ml), free T4 (normal, 0.8–2.0 ng/dl), TSH (normal, 0.4–4.4 µIU/ml), thyroid scan, and 2- and 24-h RAIU (normal, 5–15 and 15–35%)], and urinary iodine estimation (normal, 5–10 µg/dl) at baseline. In the IA group, a thyroid hormone profile and RAIU was done at the end of Telepaque treatment, at 1 wk off Telepaque, and weekly thereafter (until RAIU recovered), making background correction for residual 131I activity in the body. In controls, a thyroid hormone profile was repeated fortnightly. The trial profile is given in Fig. 1Go.



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  		FIG. 1. Trial profile. *, Patient did not come for follow-up (FU) after receiving first dose of 131I. ATD, Antithyroid drug; RCT, randomized controlled trial.

 
All patients were clinically and biochemically euthyroid at the time of radioiodine therapy. Antithyroid treatment was stopped 72–96 h before the radioiodine therapy in controls and was never reintroduced throughout the study. Similarly, Telepaque was not prescribed again. Radioiodine (150 µCi/g of thyroid tissue, corrected for 24-h RAIU) was administered after obtaining informed written consent from the patients. Thyroid mass was estimated by thyroid scan or manual palpation.

Post-radioiodine-therapy assessment was done at 3-monthly intervals for the first year and 6- to 12-monthly thereafter until patients became hypothyroid. Another dose of radioiodine was administered to patients with persistent hyperthyroidism at the end of the 3-monthly follow-up period and was repeated until patients became either euthyroid or hypothyroid. Although hypothyroidism was considered the endpoint, patients were considered cured when they became stably euthyroid or developed permanent hypothyroidism. Euthyroidism was considered stable when it persisted for at least 12 months after the first evidence.

Statistical analysis

Quantitative values are expressed as mean ± SD. Under univariate analysis, unpaired t test and {chi}2 was applied to compare quantitative and qualitative independent variables with outcome, respectively. Paired t test was applied to look for any significant change in RAIU and thyroid function tests in the IA group between various time points. A Kaplan-Meier survival curve was plotted to show the euthyroid fraction (patients remaining euthyroid) at various points in time in both groups, and subsequently the log-rank test was applied to look for any significant difference between these two groups. A P value smaller than 0.05 was considered as statistically significant. Statistical packages SAS 8.2 and SPSS 10.5 were used for the statistical analyses.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Fifteen patients among controls and 16 patients from the IA group were lost to follow-up (did not come for additional evaluation after the first dose of 131I). Therefore, data were analyzed for 85 patients among controls and 84 patients in the IA group. The patients were followed up for the mean duration of 11 yr (range, 8–13 yr). There was no significant difference in clinical and demographic profiles of the two groups (given in Table 1Go). As expected, most of the patients presenting with hyperthyroidism were diagnosed with Graves’ disease. Graves’ disease was diagnosed according to already established criteria (9).


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  		TABLE 1. Clinical and radioiodine therapy profile

 
After 1 wk of Telepaque therapy and 6 wk of carbimazole, almost all patients became clinically and biochemically euthyroid. Although RAIU was severely decreased at the end of Telepaque therapy, it recovered quickly, and within 2 wk, almost all patients were ready for radioiodine treatment (Table 2Go). Radioiodine therapy details and outcome are given in Table 1Go. The cure rate (euthyroid plus hypothyroid) after the first dose of 131I in controls and the IA group was 80 and 76.2%, respectively (P = 0.54). After a mean follow-up duration of 11 yr, 49 and 51% of patients in the IA group and 42 and 58% of controls were euthyroid and hypothyroid, respectively (P = 0.39). Thirty-two percent of patients among controls and 25% in the IA group became hypothyroid within 1 yr; thereafter, the annual rate of hypothyroidism was about 2% in both groups. Figure 2Go depicts the Kaplan-Meier survival curve showing the euthyroid fraction (patients remaining euthyroid) at various points in time in both groups. The log-rank test showed that there was no significant difference (P = 0.40) in the euthyroid proportion between the two groups at various time points.


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  		TABLE 2. Thyroid hormone and RAIU profile in the two groups

 


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  		FIG. 2. Euthyroid fraction (patients remaining euthyroid) at various points in time. Median euthyroid time (time period for which patients remained euthyroid after 131I treatment) was 58 months in controls and 70 months in IA group (log-rank test statistic = 0.70; P = 0.40).

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
OCAs act by altering thyroid hormone metabolism in several ways, namely inhibition of type I, II, and III deiodinases, competitive inhibition of T3 binding to the nuclear receptor, blocking of thyroid hormone secretion, by displacing T4 and T3 from their protein binding sites, and reducing the conversion of T4 to T3 (10, 11, 12, 13, 14, 15). They can achieve rapid reduction of thyroid hormone levels and euthyroid status in cases of thyrotoxicosis. Although serum T3 levels can decrease up to 77% as early as 12 h and can become normal in 1–5 d, serum T4 levels decrease progressively and more modestly, approximately 20% in the first 24 h with nadir reduction in 1–2 wk (4, 5, 6, 7, 8). Similarly, all our patients became euthyroid after only 1 wk of Telepaque therapy. T3 and T4 values reached a nadir at the end of Telepaque treatment (P = 0.001) and then showed some slight elevation (statistically not significant).

With OCA metabolism, large amounts of inorganic iodine are released into the circulation, reflected by increased serum total and inorganic iodine content and by increased urinary iodine excretion. This had been the basis of the assumption that no radioiodine therapy is possible if patients are pretreated with OCAs. Furthermore, some authors argue that using OCAs in hyperthyroidism may possibly worsen the thyrotoxic features and/or develop resistance to more conventional therapy (16, 17). However, our study demonstrated that although mean urinary iodine value increased from 6.6 ± 2.9 µg/dl (at baseline) to 1650 ± 237 µg/dl (at the end of Telepaque treatment) and remained very high (1100 ± 212 µg/dl at 1 wk thereafter) in the IA group, RAIU recovered in 86 and 94% of patients within 1 and 2 wk, respectively (mean urinary iodine value among controls was 6.9 ± 3.3 µg/dl). The further course and outcome in these patients were also similar to those treated with radioiodine after making them euthyroid with carbimazole. The mean first dose and mean cumulative dose of radioiodine administered in both groups of patients were statistically not different from each other. Furthermore, there was no statistically significant difference in the outcome of radioiodine therapy; be it the outcome of a single dose of radioiodine therapy, the final outcome at the end of the study, or hypothyroid rate. Because these patients have been followed up for a sufficiently long duration, it can be reasonably concluded that pretreatment with Telepaque does not change the biological characteristic and behavior of the disease and the long-term clinical outcome of radioiodine therapy.

Although various adverse effects of OCA treatment such as rash, thrombocytopenia, headache, nausea, vomiting, diarrhea, dysuria, uricosuria, and renal insufficiency have been reported (18, 19, 20), we encountered none of these serious side effects except complaints of mild nausea and vomiting in a few patients. The reasons probably were the use of a low dose of Telepaque (only 500 mg per day) and for too short a duration (for only 1 wk).

In summary, we conclude that Telepaque can be used for rapid control of hyperthyroidism without any significant adverse effects or jeopardizing the subsequent radioiodine therapy, and the long-term outcome of radioiodine therapy in this subset of patients is in no way different compared with controls prepared by conventional methods.


   Footnotes
 
Part of this work was presented at the 49th Annual Meeting of the Society of Nuclear Medicine, Los Angeles, CA, June, 2002.

First Published Online September 27, 2005

Abbreviations: IA, Iopanoic acid; OCA, oral cholecystographic agent; RAIU, radioactive iodine uptake in the thyroid.

Received March 18, 2005.

Accepted September 19, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Burgi H, Winpfheimer C, Buerger A, Zaunbauer W, Rosler H, Lemarchand-Beraud T 1976 Changes of circulating thyroxine, triiodothyronine, and reverse triiodothyronine after radiocontrast agents. J Clin Endocrinol Metab 43:1203–1210[Abstract/Free Full Text]
  2. Wu SY, Chopra IJ, Solomon DH, Bennett LR 1978 Changes in circulating iodothyronines in euthyroid and hyperthyroid subjects given ipodate (Oragrafin), an agent for oral cholecystography. J Clin Endocrinol Metab 46:691–697[Abstract/Free Full Text]
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  5. Bal C, Nair N 1990 The therapeutic efficacy of oral cholecystographic agent (iopanoic acid) in the management of hyperthyroidism. J Nucl Med 31:1180–1182[Abstract/Free Full Text]
  6. Shen DC, Wu SY, Chopra IJ, Shian LR, Florsheim W, Solomon DH 1991 Further studies on the long-term treatment of Graves’ hyperthyroidism with ipodate: assessment of a minimal effective dose. Thyroid 1:143–146[Medline]
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