The Therapeutic Efficacy of Oral Cholecystographic Agent (lopanoic Acid) in the Management of Hyperthyroidism

Chandrasekhar Bal and Narendra Nair

Radiation Medicine Centre, (B.A.R.C.), Tata Memorial Centre Annexe, Parel, Bombay, India

this point by asking patients to undergo radioiodine Five randomly chosen patients with thyrotoxicosis were uptake after stopping iopanoic acid given for rapid administered 1 gm of the oral cholecystographic agent control of thyrotoxicosis. iopanoic acid daily for 21 days. There was a marked fall in T3 levels by 75% of the pretherapy value by 96 hr; values MATERIALSANDMEThODS remained normal over the 21-day period. T4 values fell The criteria for inclusion in the study included: significantly by seven days of therapy, and the decreased values were sustained. FT3 and FT4I also showed corre 1. No form of prior treatment taken for hyperthyroidism. sponding decreases in value. All subjects showed dinical 2. Initialclinicaland biochemicalprofileas wellas iodine improvement by both subjective and objective criteria. 131(13h1)uptakes confirmed hyperthyroidism (Table 1). During therapy, escape from the effect of iopanoic acid was not encountered. However, after stopping the drug The nature and risk of the study were explained to all the for 2—4wk, the patients' iodine-i 31 uptake become as patients and informed consent was obtained. Five patients high as the pretherapy level, enabling them to undergo were given 1 g each iopanoic acid (Telepaque) orally as a radiolodine treatment for thyrotoxicosis. The treatment single dose daily for 21 days. Serial blood samples were strategy can be aimed at achievingquick euthyroidism and collectedon Day ‘0'and subsequentlyon Days 1,2, 4, 7, 14, in planning radiolodine treatment as early as possible in and 21. All serum samples were stored at —20°Cand assayed high risk patients. This treatment may also be useful in together to reduce interassay variability. Standard 24-hr up preoperative control of thyrotoxicosis. take was measured during the 2-4 post-treatment weeks using a thyroid uptake probe. The thyroid gland volume was mess J NuciMed 1990;31:1180—1182 ured from the 1311scan using the formula described by Good winet al. (9). On each visit,patientswereclinicallyexamined and signs and symptoms were recorded. Laboratory Studies he management of hyperthyroidism per se is a Serum T3, T4, and T3 charcoal uptake ratios, and thyroid challenging field. Several modalities of treatment are stimulatinghormone (TSH) were measured in duplicate by currently available. However, controversy exists as to radioimmunoassay (RIA) and immunoradiometric assay the optimum therapy in different types of patients. (IRMA) using kits obtained from Isopharm Division, Long-term medical management with antithyroid drugs B.A.R.C.,Bombay,India. The normal rangeswereT3 = 70- takes several days or weeks to bring hormone values to 200 ng/dl; T4 = 4.2-13.0 @tg/dl,T3 charcoal uptake = 85%- euthyroid level. 113%, and TSH = 0.25-4.3 nu/ml. Free T3 was measured by Oral cholecystographic contrast media when admin SephadexColumn method asdescribedby Rajan and Samuel istered to normal subjects results in a sharp and rapid (10). decrease in the serum T3 concentration with modest The antithyroglobulin antibodies (ATA) and antimicro sonal antibodies (AMA)were measured using kits obtained increase in serum T4 and reverse T3 (rT3) concentra fromWellcomeDiagnostics,Dartford,England.The freehor tion (1-5). In contrast to normal subjects, hyperthyroid mone indices were calculated. Statistical analyses of paired patients taking sodium ipodate show marked decrease data were done using two-tailed Student's t-test. in serum T3 and moderate decrease in T4 concentra tions (6—8).The question often asked is: Can these RESULTS patients receive definitive treatment of radioiodine and Serial thyroid hormone proffles ofthese five patients ifyes, what is the earliest time? We wanted to investigate are shown in Table 2. All values are depicted as mean ±standard error of mean (s.c.m.). Twenty-four hours ReceivedAug.9, 1989;revisionacceptedJan.16,1990 Forreprintscontact:N.Nair,MD,RadiatiOnMedidneCentre,(B.A.R.C.), after the first dose of treatment, T3 levels decreased by Tata MemorialCentre Annexe, Parel, Bombay - 400 012, India. 55%, and by 96 hr to 75% of pretherapy values (p <

1180 The Journal of Nuclear Medicine •Vol. 31 •No. 7 •July 1990 TABLE 1 Pretherapy Clinical and LaboratoryData of Five Hyperthyroid Patients on lopanoic Acid* Post-treatmentSr. 24-hr TA atno. Sex/ Pulse RAIU Thyroidt T3 T4 FT3 Goiter 1311uptake (%)@1Age rate (%) wt (9) ATA AMA (ng/dl) (zg/dl) (pg/mL) FT4I grade 24 hr 60(2)2F/45 90 60 27.5 — + >800 >20 >60.0 >36.2 III (2)3 F/38 116 60 10.3 + + 328 >20 26.9 32.6 I 57 74(4)4F/38 120 72 18.1 — + 406 >20 50.4 23.9 II 56(4)5F/32 88 59 35.2 + + 226 >20 20.5 38.7 III 73(4). F/35 124 68 14.0 — + 447 >20 53.6 32.6 Il

days.tDose: I g administered orally for 21 @zU/ml).*Standard paper Scan method was used (9). TSH values were below the lower limit of detectability (0.05 Numbers inparentheses indicateweeks afterdiscontinuingiopanoic acid.

0.05). Throughout the study period, the T3 concentra in pulse pressure and weight gain were not appreciable. tion remained within the laboratory normal range. No side-effects of Telepaque therapy were observed During treatment a significant decrease in serum T4 except in one patient who had 4—5loose bowel motions concentration (p < 0.01) was observed and the nadir per day from the second day of therapy. Her stool was reached on the 7th day of therapy. Pretherapy free examination revealed no pathogenic organism and the T3, which is an indicator ofactive circulating hormone, diarrhea was controlled with loparamide for 2 days. was decreased by 50% on Day 1, and by 48 hr it further declined to 69% of pretreatment level (p < 0.05). Free DISCUSSION hormone indices followed the pattern oftotal hormone. Sodium ipodate acid and iopanoic acid are similar in The Ff31 significantly correlated (r = 0.9879) with free structure and both of them rapidly reduce the T3 level. T3, measured by Sephadex Column method. Serum They have structural homology with thyroxine and TSH concentration was below the limit of detectability behave as competitive inhibitors of 5'-monodeiodinase, (0.05 @U/ml) in all subjects throughout the study an enzyme responsible for T4 to T3 conversion. This period. Radioiodine uptake (RAIU) measurements substrate competition is not seen with other contrast were not statistically significant, as pretreatment and agents, though all ofthem contain 3-6 iodine atoms per post-treatment values were 64.0 ±26% and 63.8 ± molecule. These effects are more likely to be related to 4.0%, respectively. Post-treatment values are included the chemical structure rather than their iodine content in Table I. (3). Wu et al. (8) have compared sodium ipodate (ora Changesin ClinicalSymptomsand Signsof grafin) with propylthiouracil (PTU) and concluded that Hyperthyroidism ipodate may serve as a useful adjunct in the early All subjects reported improvement in clinical symp treatment of hyperthyroidism (8). However, Roti et al. toms, such as nervousness, palpitation, and tremor. The have compared the effects of sodium ipodate and solu resting pulse rate dropped from the mean pretreatment tion ofsaturated potassium iodide (SSKI) in 15 patients value of 108 ±9 to 82 ±7 (p < 0.05) by 48 hr. Change with Graves' disease and concluded that though de crease in hormone values was sharp, the rebound phe nomenon observed after withdrawal of ipodate was TABLE2 severe as opposed to iodine (11). The escape of the Response of Serum T3, T4, FT3 Concentration and FT4I to lopanoic Acid in Five Hyperthyroid Patients thyroid gland to iodine block is well known. Hence, SSKI should have produced more rebound effect than Day T3 (ng/dl) T4 (@@g/dl)FT3(pg/mI) FT4I sodium ipodate. We can infer that slow and sustained 04412.81185±2215.9±2.421.5±6.825.0±4.52147±108>20t42.2 ±8.732.8 ± release of iodine, from contrast agents, has a more stimulatory effect on thyroid gland than high doses 3.741 ±1714.9 ±2.113.2 ±3.522.5 ± from SSKI. Wang et al. have treated 40 patients with 3.27102±1611.3±1.010.0±2.815.6±3.11412012±1414.7 ±2.09.9 ±3.020.3 ± Graves' disease with a single agent, iopanoic acid 500 3.121155±912.5 ±2.08.2 ±2.615.6 ± mg daily for 1—12mo (12). Similar long-term follow ±2112.1 ±1.410.4 ±2.015.0 ±2.2 up data also has been published by Shen et al. (13). Their reports indicated that iopanoic acid is not an

. Dose: 1 g administered orally for 21 days. Each value is effective agent for long-term treatment of Graves' dis expressedasmean±s.e.m. ease. Karpman and his colleagues have recently re t All laboratory values were reported as >20 @@g/dl; for statis ported an excellent response to sodium ipodate in neo ticalanalysisit wastakenas 20 ,@g/dI. natal hyperthyroidism (14).

Therapeutic Efficacy of lopanoic Acid •Bal and Nair 1181 A small daily dose is as effective as pulsed high-dose pituitary thyroid axis. Ada Endocrinologica 1979; 92:477— therapy viz. 3 g every third day, as advocated by Wu et 488. 3. Kleinmann RE, Vagenakis AG, Braverman LE. The effect of al. (6). In our series, TSH was never above the detect iopanoic acid on the regulation of thyrotropin secretion in able limit (0.05 @U/ml);in contrast, Kleinmann et al. euthyroid subjects. J Clin Endocrinol Metab 1980;5l:399— (3) havereporteda riseasearly asDay 5 following 3 g 403. iopanoic acid in euthyroid volunteers. Although the 4. Beng CG, Wellby ML, Symons RG, et al. The effect of ipodate number of individuals in both study groups was com on the serum iodothyronine pattern in normal subjects.Ada Endocrinologica1980;913:175—178. parable, their physiologic statuses were quite different. 5. Suzuki H, Noguchi K, Nakahata M, et al. Effect of iopanoic The ultrasensitive pituitary regulatory mechanism may acid on the pituitary-thyroid axis: time sequence of changes be excessively suppressed in hyperthyroidism, which in serum iodothyronines, thyrotropin and prolactin concen can explain this discrepancy in the results. trations and responseto thyroid hormones. J Clin Endocrinol The observation ofRAIU following the iopanoic acid Metab 1981;53:779—783. 6. Wu SY, Chopra U, Solomon DH, Benett LR. Changes in is very encouraging and agrees with the published data circulatingiodothyroninesin euthyroid and hyperthyroidsub ofShen et al. for a similar number ofpatients (13). We jectsgivenipodate(oragrafin):an agentfor oral cholecystog treated all five patients ofthis protocol with iodine-l3 1. raphy. J Clin EndocrinolMetab 1978;46:691—697. They are currently under follow-up, and are doing well. 7. Wu SY, Chopra U, Solomon DH, Johnson DE. The effect of Hence, there is no doubt that these patients can be repeated administration of ipodate (oragrafin) in hyperthy roidism. J Clin EndocrinolMetab 1978;47:1358—1362. treated with radioiodine after 2-4 wk of withdrawal of 8. Wu SY, Shyh TP, Chopra U, Ct al. Comparison of sodium iopanoic acid/sodium ipodate. ipodate (oragrafin)and propylthiouracil in early treatment of This study indicates that hyperthyroid patients may hyperthyroidism.J Clin EndocrinolMetab 1982;54:632—634. be quickly stabilized to a euthyroid state so that a 9. Goodwin WE, Cassen B, Bauer FK. Thyroid gland weight definite modality like radioiodine or surgery can be determination from thyroid scintigram with postmortem ver ification.Radiology 1953;61:88—92. offered. This may be of particular value, where early 10. Rajan MGR, Samuel AM. Adapting the total T3 RIA kits to and rapid control is required, such as in high risk measure serum free T3. Ini JMedRes 1988;87:179—185. patients, thyrocardiac disease in the elderly, and pre 11. Roti E, Robuschi G, Manfredi A, et al. Comparative effects paring for surgery. of sodium ipodate and iodide on serum thyroid hormone concentrations in patients with Graves' disease. Clin Endo REFERENCES crinol 1985;22:489—496. 12. Wang YS, Tsou CT, Lin WH, Hershman JM. Long-term I. Biirgi H, Wimptheimer C, Berger A, et al. Changes of circu treatment of Graves' disease with iopanoic acid (Telepaque). lating thyroxine, triiodothyronine and reverse triiodothyro J C/in Endocrino/Metab 1987;65:679—682. nine after radiographic contrast agents. J Clin Endocrinol 13. Shen DC, Wu SY, Chopra U, et al. Long-term treatment of Metab 1976;43:1203—1210. Graves' hyperthyroidism with sodium ipodate. J C/in Endo 2. Suzuki H, Kadena N, Takeuchi K, Nakagawa S. Effects of crinolMetab1985;61:723—727. three-dayoral cholecystographyon serum iodothyroninesand 14. Karpman BA, Rapoport B, Filetti 5, Fisher DA. Treatment TSH concentrations:comparison ofeffects among some cho of neonatal hyperthyroidism due to Graves' disease with lecystographicagents and the effectsof iopanoic acid on the sodium ipodate. J Clin EndocrinolMetab 1987;64:119—123.

1182 The Journal of Nuclear Medicine •Vol. 31 •No. 7 •July 1990