Long Term Treatment of Graves5 Hyperthyroidism with Sodium Ipodate*

DER-CHUNG SHEN, SING-YUNG WU, INDER J. CHOPRA, HAN-WEN HUANG, LEE-REN SHIAN, TYZZ-YANG BIAN, CHII-YUAN JENG, AND DAVID H. SOLOMON Department of Medicine, Tri-Service General Hospital, Taipei, Taiwan; the Departments of Nuclear Medicine and Medicine, Veterans Administration Medical Center, Long Beach, California 90822; and UCLA Center for the Health Sciences, Los Angeles, California 90024

ABSTRACT. To investigate the long term usefulness of so- radioiodine (RAI) uptake values increased serially in four pa- dium ipodate (Oragrafin) in the management of Graves' hyper- tients and were similar to pretreatment values: pretreatment, 74 thyroidism, we studied the effects of ipodate (500 mg, orally, ± 6% (±SEM); after 7 days, 66 ± 8%; after 14 days, 71 ± 7%; daily for 23-31 weeks) on serum T3, T4) rT3, and some clinical after 28 days, 69 ± 7%. The fifth patients's RAI uptake was 12- parameters in five newly diagnosed Graves' hyperthyroid pa- 16% (vs. a pretreatment value of 48%) from 7-28 days after the tients. Mean pretreatment serum T3, T4, and rT3 concentrations end of a 31-week course of ipodate. He remained euthyroid were 780 ng/dl, 25.4 /xg/dl, and 118 ng/dl, respectively. One day without further treatment for the subsequent 4 months. after the first dose of ipodate, serum T3 decreased by 62% (P < We conclude that 1) ipodate (500 mg daily) reduces serum T4 0.01), and it was within the normal range thereafter throughout and T3 levels as fast and as much as does the 1-g daily dose treatment. The serum T4 concentration decreased by 20% (P = studied previously; 2) long term use (for 23-31 weeks) of ipodate 0.09) at 24 h and by 43% (P < 0.05) at 14 days. Subsequently, for the treatment of Graves' hyperthyroidism is clinically feasi- serum T4 was 41-65% lower than before treatment throughout ble; no adverse effects occurred during or after ipodate treat- the study; rT3 increased 24 h after the first dose of ipodate (118% ment; and 3) RAI uptake returns to pretreatment levels as early above baseline; P = 0.1), remained elevated (97-109%) for 10 as 7 days after the discontinuation of ipodate. Hence, use of weeks, and then gradually decreased to the pretreatment level. ipodate does not prevent use of 131I therapy for those patients A marked gain in body weight [5.1 ± 1.1 (±SEM) kg] occurred in for whom it is otherwise desirable. (J Clin Endocrinol Metab 61: all patients. After discontinuation of ipodate, mean thyroid 723,1985)

HE ADMINISTRATION of sodium ipodate re- Subjects and Methods duces serum T and T concentrations rapidly in T 3 4 Patients and studies with ipodate patients with hyperthyroidism due to Graves' disease (1, 2). The effect of ipodate on circulating thyroid hormones Five patients with newly diagnosed hyperthyroidism due to is presumably due to a combination of inhibition of Graves' disease (four men and one woman, ranging in age from 21-55 yr) were studied. The protocol had been approved by the peripheral T4 to T3 conversion and inhibition of thyroid hospital (TSGH) Clinical Research Committee, and written hormone release, possibly a result of iodine release from informed consent was given by all patients after they had been the metabolism of ipodate in vivo. More recently, we informed of the nature and risks of the study. The daily iodine reported that ipodate (1 g, orally, daily) compared favor- intake in the area in which the patients lived approximated ably to propylthiouracil (200 mg, orally, three times a 100 ng (4). The diagnosis of hyperthyroid Graves' disease was day) in early reduction of serum T3 and T4 as well as based on clinical examination demonstrating diffuse goiter,

clinical improvement in Graves' hyperthyroid patients elevated serum T4 and T3 concentrations, and increased 24-h when either was given for 3 weeks (3). In this report, we thyroid radioiodine (RAI) uptake. The patients were hospital- present the results of treatment of five newly diagnosed ized for 2 weeks at the beginning and for 4 weeks after the Graves' hyperthyroid patients with 500 mg ipodate, or- completion of ipodate treatment and were followed weekly ally, once daily for 23-31 weeks. during the study in the out-patient clinic. All patients were given 500 mg sodium ipodate (E. R. Squibb and Sons, Inc., Received February 21, 1985. Princeton, NJ), orally, as a single dose daily for 23-31 weeks Address requests for reprints to: Sing-yung Wu, M.D., Ph.D., Nu- (two patients were treated for 31 weeks, and one patient each clear Medicine Service, Veterans Administration Medical Center, Long was treated for 23,25, and 28 weeks, respectively). The patients Beach, California 90822. received no other medication during these studies. One to three * This work was supported in part by grants from the V.A. and USPHS Grant AM-16155. blood samples were obtained in the 24-h period before ipodate

723

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 March 2014. at 11:38 For personal use only. No other uses without permission. . All rights reserved. 724 SHEN ET AL. JCE & M • 1985 Vol 61 • No 4 administration, and one blood sample was obtained on days 1, 1). Serum TSH was not abnormally elevated in patients 3, and 7 of treatment and then once weekly throughout the while they were taking ipodate (Table 1). study. Body weight and resting pulse were measured before The data on 24-h thyroid RAI uptake before and after each blood sample was taken. All patients also were questioned ipodate treatment are shown in Table 2. After the dis- about symptoms of hyperthyroidism, including palpitation, nervousness, weakness, and heat intolerance during each visit. continuation of ipodate, mean RAI uptake in four pa- They also were questioned frequently for other symptoms, such tients was similar to uptake before treatment. It was 66 as nausea, vomiting, and skin rash, that could be side effects of ± 8% 7 days after ipodate, 71 ± 7% 14 days after ipodate, ipodate. and 69 ± 7% 28 days after discontinuation of ipodate compared to 74 ± 6% before treatment. The fifth (no. 5) Laboratory studies patient's RAI uptake was 12-16% (vs. a pretreatment value of 48%) 7-28 days after the end of a 31-week course Serum T3, T4, and rT3 concentrations were measured by RIAs described previously (5-7). The normal range (mean ± 2 of ipodate. He remained euthyroid without further treatment for the subsequent 4 months and then was treated SD) for was 126 ± 66 ng/dl for T3, 8.4 ± 4 Mg/dl for T4, and 41 ± 20 ng/dl for rT3. All samples from each individual patient with low doses of methimazole (5-10 mg, daily) and were stored frozen and assayed at the same time. Complete propranolol (20 mg, three times a day) when his serum blood count, electrolytes, and hepatic and renal function pa- T3 and T4 levels were 140 ng/dl and 10.5 /ng/dl, respec- rameters were evaluated before and periodically during treat- tively. He remained euthyroid for 14 months until his ment. Thyroid 131I uptake (normal range, 8-30%) was measured hyperthyroid symptoms relapsed and his serum T3 and in all patients before ipodate administration and 7, 14, and 28 T concentrations increased to 180 ng/dl and 17 /ng/dl, days after the end of treatment. Serum total and inorganic 4 respectively. iodine were determined by BioScience Laboratory (Van Nuys, CA) using methods described previously (8, 9). The changes in Serum T3, T4, and rT3 were determined in patients 1, values at various times of study were examined statistically by 2, 4, and 5 1 week after discontinuation of ipodate (Table analysis of variance (10). The P value is based on Bonferroni t 2). Patient 5 was clearly euthyroid clinically and chemi- test. cally. Patient 1 had a slight increase in serum T4 and a large increase in serum T3, from 130 to 210 ng/dl. Pa- Results tients 2 and 4 were clearly hyperthyroid 1 week after stopping ipodate. In the subsequent 3 weeks, serum T4 Table 1 shows the serum T3, T4, and rT3 results from remained elevated in patients 1, 2, and 4, but at no time each patient before and during the 23- to 31-week treat- during the first 28 days after discontinuation of ipodate ment period. The mean ± SEM pretreatment serum T3 did serum T3 or T4 exceed pretreatment values. During level was 780 ± 229 ng/dl; it was 209 ng/dl at 24 h and the last weeks of ipodate treatment, serum total and 170 ng/dl on day 3. These changes represented 62% (P inorganic iodine content were 1082 ±114 and 110 ± 43 < 0.01) and 69% (P < 0.01) decreases, respectively, in Mg/dl, respectively, in four patients. Unfortunately, sin- serum T3 from the pretreatment value (Fig. 1). Mean gle samples from only two patients were available for serum T3 levels subsequently stayed within the normal serum iodine determinations in the postipodate period, range throughout treatment. Patient 2 had a borderline and each sample was a pool of serum obtained from 7- elevated serum T3 concentration between 24-31 weeks 21 days after treatment. Inorganic iodine levels in these of treatment even though serum T4 concentrations were samples were 10 and 12 /ng/dl, suggesting rapid clearance normal, and patient 4 had persistently elevated serum of free iodine and the absence of residual ipodate stores T3 concentrations, although they were 77-83% below the available for deiodination. baseline value. The changes in body weight and resting pulse rate The mean ± SEM baseline serum T4 level was 25.4 ± during ipodate therapy are shown in Fig. 2. The increase 2.6 /ng/dl. It decreased by 20% (P = 0.09) at 24 h and by in body weight gain was significant after 10 weeks (3.3 43% (P < 0.05) at 14 days (Fig. 1). Subsequently, serum ± 0.6 kg; P < 0.01 vs. baseline). The total gain in body T4 was 41-65% lower than before treatment throughout weight averaged 5.1 kg after 23 weeks of treatment. The the study. It was within the normal range in four patients resting pulse rate decreased gradually to 87% of the after 10 weeks of treatment. Serum T4 in the fifth (i.e. pretreatment mean value of 90 ± 5 (±SEM) beats/min (P no. 4) patient remained supranormal throughout the = 0.25) after 20 weeks of ipodate treatment. study, but was 31-56% below the pretreatment value of Improvement in subjective symptoms of hyperthyroid- 35 /ig/dl (Table 1). Serum rT3 increased 24 h after the ism, including perspiration, nervousness, palpitation, first dose of ipodate [118% above the mean pretreatment tremor, and weakness, was reported by all patients. No value (118 ± 25 ng/dl); P = 0.1], remained somewhat abnormal results were found on periodic blood tests for elevated (78-109%) for the 10 weeks of treatment, and complete blood count, electrolytes, and hepatic and renal then decreased gradually to the pretreatment level (Fig. function during and after ipodate treatment. Chest ra-

TABLE 1. Effect of long term treatment of Graves' hyperthyroidism with ipodate (500 mg, orally, daily)

After ipodate treatment Patient no. Serum cone, of Pretreat- Day Weeks ment 1 3 7 2 5 10 15 20 25 31

1 T4 (Mg/dl) 27 17 16.5 14 12 14.5 13.5 7.5 6.8 8.5 T3 (ng/dl) 340 200 155 105 110 175 170 210 155 130 rT3 (ng/dl) 58 160 270 205 190 205 220 130 130 110 TSH OiU/ml) <2.5 3.0 3.5 2.5 2.7

2 T4 23 23 23 13 19 17 11.5 6.0 7.2 9.2 9.6 T3 875 240 140 140 160 205 205 110 160 235 215 rT3 84 175 170 170 190 240 160 97 80 98 110 TSH <2.5 <2.5

3 T4 21 24 21.2 17 14.5 11 8.8 6.6 5.6 5.3 T3 235 160 145 155 165 140 130 140 97 120 rT3 205 240 130 130 60 96 68 54 70 <10 TSH <2.5 4.7

4 T4 35 30 29 21 13 15 26 21 20 T3 1500 300 300 235 165 250 225 290 340 rT3 140 470 345 345 190 280 410 92 110 TSH <2.5 3.0 <2.5

5 T4 21 12 10.5 10.5 10.5 7.5 9.2 6.0 9.0 7.5 9.2 T3 950 125 110 105 110 90 95 60 95 145 150 rT3 105 160 125 190 180 105 150 105 130 54 45 TSH <2.5 3.5 3.5

Mean ± SEM T4 25.4 ± 2.6 21.2 ± 3.1 20.0 ± 3.4 15.2 ± 1.7 14.0 ± 1.0° 13.2 ± 1.6° 14.0 ± 1.4° 9.4 ± 2.9* 9.8 ± 2.6* 7.5 ± 0.8* T3 780 ± 229 209 ± 34* 170 ± 33* 148 ± 24* 142 ± 13* 172 ± 27* 165 + 24* 162 ± 40* 169 ± 45* 158 ± 26* rT3 118 ± 25 241 ± 59 218 ± 39 208 ± 36 162 ± 26 185 ± 36 202 ± 59 96+12 104 ± 12 68 ±23 Ipodate was given as a single dose daily after the morning blood sample was taken. ° P < 0.05 us. baseline values [the P value is based on Bonferroni t test for multiple comparisons (10)]. * P < 0.01 us. baseline values.

eral as well as thyroidal T4 to T3 conversion (11-13), curtail the tissue effect of thyroid hormones (14-16), and inhibit the release of thyroid hormones, possibly a result of iodide liberated during the metabolism of ipodate in vivo. The present study demonstrates that ipodate (500 mg, orally, daily) was just as fast and effective in reducing serum T3 and T4 in Graves' hyperthyroid patients as treatment with 1 g daily reported previously (3). The slopes of decline in serum T3 and T4 after ipodate treatment were virtually identical in these two studies. The

0 13 7 2 5 peak increases in serum rT3 at 72 h were 144 ± 84% and

Days 276 ± 65% in the current 500 mg study and the previous 1 g ipodate study, respectively (not statistically signifi- FIG. 1. Mean ± SEM percent changes in serum T4, T3, and rT3 concentrations in five hyperthyroid patients before and during ipodate treat- cant). ment (500 mg, orally, once daily) for 23 weeks. P values were deter- The present study provides data on long term use of mined using analysis of variance for multiple comparisons and Bonfer- ipodate. Serum T4 was within normal range in four of roni t test (10). the five patients after 10 weeks of treatment. The mean diograms were normal in all patients before and after the T3 level stayed within the normal range after day 3 of study. treatment, although it was slightly elevated in some patients. Using 1.5 g tyropanoate (Bilopaque) daily, No- Discussion guchi et al. (17) reported a similar (63%) reduction of T3 after 1 week treatment in seven hyperthyroid patients; Recent studies suggest that ipodate is as good as or serum T3 remained decreased at the same level without better than propylthiouracil in controlling hyperthyroid- escape throughout the study period of 10-16 weeks. ism during the first 3 weeks of treatment (3). The effect Serum T4, on the other hand, decreased in only two of ipodate may be related to its ability to reduce periph- patients and was unchanged or increased in the other

TABLE 2. Changes in 24-h thyroid RAI uptake and serum T4, T3, rT3, and total and inorganic iodine concentrations after discontinuation of ipodate treatment

24 h thyroid RAI uptake (%)° Serum cone* Serum iodine (/ig/dl)

Patient Pretreat- ^ 7 days 14 days 28 days During therapy After therapy 28 days ment J no. T4 T3 rT3 T4 T3 rT3 T4 T3 rT3 Total Inorganic Total Inorganic 1 83 83 84 73 11 210 47 15 280 50 16 290 54 1380 230 480 10 2 83 75 78 81 15 400 62 15 68 880 70 3 57 44 52 48 1140 110 4 75 62 69 75 24 700 125 28 1000 125 19 550 130 80 12 Mean 74 + 6 66 ± 8 71 ± 7 69 ± 7 ± SEM

48 12 16 13 11 96 930 30 ° Twenty-four-hour thyroid RAI uptakes were measured using 10 /iCi Na131I, administered orally. Special care was taken to correct the appreciable background activity in repeated measurements. Normal values ranged from 8-30%. * The concentration of T4 is in micrograms per dl, T3 and rT3 are in nanograms per dl. c Serum iodine concentrations were determined by BioScience Laboratory. Normal values for serum total iodine ranged from 4.5-9.0 /ig/dl and for inorganic iodine ranged from 0.5-1.0 Mg/dl. d Samples were pooled to provide adequate amounts of serum for these determinations. Samples were pooled from 20-30 weeks of treatment or 7-21 days after discontinuation of ipodate.

6- Body Weight patients with Graves' disease. We specifically excluded

5- patients with toxic nodular goiter from this study because they are prone to Jod-Basedow and are less sensitive to 4- 1 1 the antithyroid effect of iodine (18). However, we do not 3- know the relative importance of free iodine released from 2- ipodate metabolism in vivo and the various other above- 1 - -co.oi f clb" mentioned antithyroid effects of ipodate to the overall /^ - 0- • • i ii i i beneficial effects of ipodate therapy in hyperthyroidism. A systematic future study of the usefulness (or lack Pulse Rate thereof) of ipodate treatment in hyperthyroidism due to 90 I causes other than Graves' disease should be interesting. r One obvious criticism of using iodine-containing T-, agents for treating hyperthyroidism has been concern 80- 1 T""T that large increases in serum inorganic iodine (63% of rl ipodate by weight is iodine) derived from ipodate metab- 70- olism that would make a subsequent treatment with radioiodine (131I) impossible for a prolonged period. How- " ever, the data of our study suggest that this concern may 10 15 20 25 not be well founded; the RAI uptake of our patients Weeks returned to pretreatment levels as early as 7 days after FIG. 2. Mean ± SEM changes in body weight and resting pulse rate in the discontinuation of ipodate treatment. This early five hyperthyroid patients given ipodate (500 mg, orally, once daily). return of high thyroid RAI uptake appears to coincide The statistical evaluation of the data was performed by analysis of with rapid clearance of inorganic iodine from blood after variance for multiple comparisons, as described in Fig. 1. the discontinuation of ipodate. These data suggest that it should be feasible to administer 131I within a week five. By comparison, ipodate appeared to give better after withdrawal of 500 mg/day ipodate. They also indi- therapeutic results at a lower daily dose in the long term cate that remission of Graves' disease had not occurred. treatment of Graves' hyperthyroid patients, as presented It was intriguing to find increased thyroid uptake in the current study. values in the postipodate period at a time when the In the 23- to 31-week treatment with ipodate, we found serum inorganic iodine level was still elevated (10-12 /ng/ no adverse effects. However, the safety of long term use dl vs. normal, 0.5-1.0 Mg/dl). Addition of stable iodide to of ipodate in the treatment of hyperthyroid patients, who the dose of radioiodine has been shown in previous have no contraindications to treatment with traditional studies to markedly reduce the uptake of radioiodine. medications, i.e. propylthiouracil or methimazole, should This effect of stable iodine is more pronounced in hyper- be further evaluated. It should be emphasized that our thyroid patients with Graves' disease than in euthyroid studies pertain only to the use of ipodate in hyperthyroid patients (19, 20). Thus, thyroid 131I uptake is inhibited

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 March 2014. at 11:38 For personal use only. No other uses without permission. . All rights reserved. LONG TERM IPODATE IN HYPERTHYROIDISM 727 at a serum iodide level below 5 /zg/dl in hyperthyroid for measurement of triiodothyronine in human serum. J Lab Clin Med 80:729 patients, whereas this effect in euthyroicj patients re- 7. Chopra IJ 1972 A radioimmunoassay for measurement of thyroxine quires iodide levels greater than 10-12 Mg/dl. However, in unextracted serum. J Clin Endocrinol Metab 34:938 the situation in these acute studies with stable iodide 8. Riley M, Gochman N 1969 Fully automated method for the determination of serum protein bound iodine. In: Technicon Autoanal- may not apply to our patients, who had received sodium izer Methodology, method file N-56. Technicon, Tarryton ipodate for many weeks. The thyroid iodine concentra- 9. Truesdell W, Smith PJ 1975 Automatic determination of iodide or tion mechanism may have been altered during this pe- iodate in solution by catalytic spectrophotometry. Analysis riod, and there may have occurred an escape from the 10. Glantz SA 1981 Primer of Biostatistics. McGraw-Hill, New York, acute inhibitory effects of iodide (21). One patient in the pp 30-93 present study, whose RAI uptake after treatment was 11. Chopra IJ, Solomon DH, Chopra U, Wu SY, Nakamura Y, Fisher DA 1978 Pathways of metabolism of thyroid hormones. Recent 12-16% (pretreatment, 48%), remained euthyroid with- Prog Horm Res 34:521 out further treatment for 4 months, but hyperthyroidism 12. England ML, Hershman JM, Pekary AE, Feng DA, DiStefano JJ, later recurred. Whether the several months remission T4 and T3 kinetics in patients taking sodium ipodate. 60th Annual Meeting of the American Thyroid Association, New York, NY, was due to spontaneous fluctuation in the severity of his 1984, p T-6 (Abstract) Graves' disease or can be attributed to ipodate is not 13. Wu SY 1983 Thyrotropin-mediated induction of thyroidal iodothy- known. ronine monodeiodinases in the dog. Endocrinology 112:417 14. DeGroot LJ, Rue PA 1979 Roentgenographic contrast agents inhibit triiodothyronine binding to nuclear receptors in vitro. J Clin Acknowledgments Endocrinol Metab 49:538 15. Felicetta JV, Green WL, Nelp WB 1980 Inhibition of hepatic We thank Ms. Debbie S. Burmeister, Ms. Carol E. Wright, and Dr. binding of thyroxine by cholecystographic agents. J Clin Invest Yan-qiu Yu for able technical assistance. 65:1032 16. Chopra IJ, Huang TS, Hurd RE, Solomon DH 1984 A study of cardiac effects of thyroid hormones: evidence for amelioration of References the effects of thyroxine by sodium ipodate. Endocrinology 114:2039 1. Wu SY, Chopra IJ, Solomon DH, Bennett LR 1978 Changes in 17. Noguchi K, Suzuki H, Nakahata M, Long term treatment of circulating iodothyronine in euthyroid and hyperthyroid subjects hyperthyroidism with tyropanoic acid. 2nd Meeting of the Asian- given ipodate (Oragrafin), an agent for oral cholecystography. J Oceanic Thyroid Association, Tokyo, Japan, 1982 p 15 (Abstract) Clin Endocrinol Metab 46:691 18. Braverman LE 1978 Disorders of iodine excess and deficiency. In: 2. Wu SY, Chopra IJ, Solomon DH, Johnson DE 1978 The effect of Werner SC, Ingbar S (eds) The Thyroid, ed 4. Harper and Row, repeated administration of ipodate (Oragrafin) in hyperthyroidism. Hagerstown, pp 528-536 J Clin Endocrinol Metab 47:1358 19. Childs DS, Keating FR, Rail JE, William MMD, Power MH 1950 3. Wu SY, Shyh TP, Chopra IJ, Huang HW, Chu PC 1982 Compar- The effect of varying quantities of inorganic iodide (carrier) on the ison of sodium ipodate (Oragrafin) and propylthiouracil in early urinary excretion and thyroidal accumulation of radioiodine in treatment of hyperthyroidism. J Clin Endocrinol Metab 54:630 exophthalmic goiter. J Clin Invest 29:726 4. Chan I 1946 Iodine intake of Formosan population: investigation 20. Feinberg WD, Hoffman DL, Owen CA 1959 The effects of varying of the iodine deficiency problem in the goitrous regions in Formosa, amounts of stable iodide on the function of the human thyroid. J part 5. Formosa Med Assoc J 45:36 Clin Endocrinol Metab 19:567 5. Chopra IJ 1974 A radioimmunoassay for measurement of 3,3',5'- 21. Emerson CH, Anderson AJ, Howard WJ, Utiger RD 1975 Serum triiodothyronine (reverse T3). J Clin Invest 54:583 thyroxine and triiodothyronine concentration during iodide treat- 6. Chopra IJ, Ho RS, Lam R 1972 An improved radioimmunoassay ment of hyperthyroidism. J Clin Endocrinol Metab 40:33