Clinical Endocrinology ( 1 986), 25, 293-30 1

PROLONGED TREATMENT OF HYPERTHYROIDISM WITH SODIUM TYROPANOATE,

AN ORAL CHOLECYSTOGRAPHIC AGENT: A RE-EVALUATION OF ITS CLINICAL UTILITY

K. NOGUCHI, H. SUZUKI, M. NAKAHATA, S . KUROSAWA AND S . NAKAGAWA

The Second Department of Medicine, Hokkaido University School of Medicine, Sap- poro, Japan, 060

(Received 27 January 1986; returned for retiision I I March 1986;Jinally revised 28 April 1986; accepted 20 Ma.v 1986)

S U M M A R Y

To re-evaluate the clinical utility of the prolonged management of hyperthyr- oidism with sodium tyropanoate (TP), an oral cholecystographic agent, we studied the changes in the scoring of thyrotoxic signs and symptoms (thyrotoxic index; TI), serum concentrations and binding of thyroid hormone, and circulating TSH receptor antibodies (TRAb) in two groups of patients with Graves’ disease; seven patients (TP group) received TP (1.5 g daily) alone for 14 weeks, and six patients (TP+ MMI group) received methimazole (MMI; 30 mg daily) in addition to TP for 8 weeks and MMI alone thereafter. In the TP group, the TI reduced significantly, but it failed to reach a euthyroid level in all except one. Serum total T4 (TT4), free T4 (FT4), and T3 uptake (T3U) values declined by the third week of treatment, but an ‘escape’ occurred thereafter. Serum rT3 and T4 binding globulin (TBG) levels were increased. The TRAb titres were increased slightly but significantly. Serum T3 levels fell within a week but remained higher than normal during the treatment.

In the TP+ MMI group, all patients achieved a normal TI by the end of the treatment. Serum TT4, FT4 and T3U fell more significantly than those in the TP group, indicating no escape from the effect of TP. The serum TRAb decreased significantly. Serum T3 levels showed a greater reduction than those in the TP group, and remained decreased even after withdrawal of TP. In a further 9 patients receiving TP alone for 4-14 weeks (7.3 +_ 5.0 weeks on the average), TP was withdrawn and replaced by MMI. A rebound of TI and serum T3 occurred within a week. These data suggest that, in the chronic treatment of hyperthyr- oidism, doses of combined TP and thionamide drug may have the advantage over those of TP alone both for achieving a more significant improvement of thyrotoxicosis and for precluding the recurrence of hyperthyroidism after cessation of TP therapy.

Correspondence: Dr Kazuya Noguchi, Hokubukai Hokuto Hospital, Nishiku Teine Hontyo 3-4-2-5, Sapporo, Japan, 006.

293

294 K . Noguchi et al.

Some oral cholecystographic agents (OCA), such as iopanoic acid, sodium ipodate, iobenzamic acid and sodium tyropanoate, induce a marked decrease in serum T3, marked increases in rT3 and in basal as well as TRH-stimulated TSH, and a slight increase in T4 concentrations in normal subjects (Biirgi et al., 1976; Wu er al., 1978; Suzuki et al., 1979, 1981; Beng er al., 1980; Kleinmann et al., 1980). Additionally, recent studies have shown that repeated doses of ipodate reduce circulating T3 and T4 levels and improve thyrotoxic signs and symptoms in patients with Graves’ disease (Wu et al., 1978, 1982).

There are several uncertainties, however, about the therapeutic usefulness of the agents for the treatment of hyperthyroidism. First, it is not clear whether sustained amelioration of thyrotoxicosis could be obtained by prolonged administration of the drugs, since previous studies were confined to short-term observations of up to 3 weeks. Second, recent studies in hyperthyroid patients have shown a more striking reduction in serum T3 concentration by doses of ipodate than by propylthiouracil (PTU) (Wu et al., 1982), or by combined doses of ipodate, PTU and propranolol than by those of PTU and propranolol (Sharp et al., 1981). Little is known, however, as to whether the effect of treatment with combined doses of an OCA and a conventional antithyroid drug would compare favourably with that of OCA alone. Third, little if any data is available as to how the withdrawal of OCA would affect clinical and laboratory manifestations of hyperthyr- oidism (Wu et af., 1978; Sharp et al., 1981).

We have, therefore, studied the chronic effects of sodium tyropanoate (TP) on clinical signs and symptoms of thyrotoxicosis, serum concentrations and binding of thyroid hormone, and thyrotrophin receptor antibody (TRAb) activity in hyperthyroid patients. The effects of TP alone were compared with those of combined TP and I-methyl-2- mercaptoimidazole (methimazole; MMI). Furthermore, the changes in the clinical features of thyrotoxicosis and thyroid hormone concentrations were observed after withdrawal of TP administration. We chose TP because our previous study showed that this agent was the most potent of the OCA examined in reducing serum T3 concentration in normal subjects (Suzuki et al., 1979).

SUBJECTS A N D METHODS

Patients and study protocol

Twenty-two out-patients, seven men and 15 women, aged from 22 to 61 years, with newly diagnosed hyperthyroidism due to Graves’ disease were included in the study. The diagnosis of Graves’ disease was based on the presence of diffuse goitre, thyrotoxic signs and symptoms, high 24-h-radioiodine uptake, elevated T3U, elevated serum T4 and T3 concentrations, and undetectable TSH concentrations (Table 1). All patients had positive TRAb. After informed consent was obtained, the patients were randomly allocated to the following groups: (A) Seven patients (TP group) were given TP (Tyropaque, Torii Yakuhin Co., Tokyo) at a fixed dosage of 1.5 g daily for 14 weeks; (B) six patients (TP+ MMI group) received TP as employed for the TP group, plus MMI 30 mg daily. Since all patients achieved normal T4 concentrations by the eighth week, TP was withdrawn and the doses of MMI were continued; (C) 9 patients (TP-withdrawal group) received TP in the same dosage as the TP group for &14 weeks (mean 7-3 k 5.0 weeks), and then TP was withdrawn and the doses of MMI, as in the TP+ MMI group, were given as a substitute for TP.

Tyropanoate and methimazole in hyperthyroidism 295

Table 1. Mean baseline laboratory data in three groups of hyperthyroid patients under study

Group Age 24-h- T3U T4 T3 TRAb** (n) (years) RAIU*(%) rA) (nmolil) (nmol/l) (%)

TP (7) Range 22-61 30.2-71.5 43.5-56.8 220.0-567.6 5.35-12.40 27.W31.2 Mean 34.3 58.4 48.9 380 8.30 56.8 SD 12.8 16.3 5.8 I l l 2.90 21.1

T P f M M I (6) Range 3Wf 66.8-88.6 45.656.1 2604H04.1 4.90-14.70 25.8-70.5 Mean 34.5 75.0 50.1 312 1 1.20 43.2 SD 5.4 7.9 3.7 53 3.60 16.6

TP withdrawal (9) Range 29-60 41473.0 37.5-54.7 2124444.0 5.20-12.60 29.0-79.7 Mean 39.8 64.8 46.8 314 7.50 54.0 SD 9.8 9.3 5.0 nn 2.50 I 8.2

Serum TSH concentration was undetectable ( < I .25 pU/ml) in all patients. * Radioactive iodine uptake; ** TSH receptor antibody.

Clinical evaluation of therapeutic eflects

The patients were questioned and examined weekly for the following signs and symptoms; hyperhidrosis, palpitations, nervousness, increased appetite, hand tremor, and resting pulse rate. Each of the signs and symptoms was scored according to the severity of thyrotoxicosis on a scale; 0 (normal or none), 1 (moderate), and 2 (severe). The resting pulse rate was scored as 0 ( < 90/min), 1 (91-1 IO/min), and 2 (> 11 l/min). The sum of the scores for each parameter was arbitrarily referred to as the ‘thyrotoxic index’ (TI) in this study.

The patients were monitored weekly for possible adverse reactions to TP (Doerge & Wilson, 1977) on the basis of clinical symptoms and signs, and the following laboratory data were obtained with an autoanalyser; complete blood count, serum concentrations of urea nitrogen, creatinine, glutamic oxaloacetic transaminase, glutamic pyruvic transami- nase, alkaline phosphatase and electrolytes.

Assays

Serum T3, TT4, FT4, rT3, TBG and TSH concentrations were measured by commercial RIA kits (T3, TT4 and rT3: Dainabot Radioisotope Laboratory, TF4: Clinical Assays- Japan Travenol Co., TBG: Hoechst Japan Co., TSH: Daiichi Radioisotope Laboratory, respectively) and T3U was measured with Triosorb S kit (Dainabot Radioisotope Laboratory). All serum samples were assayed concurrently. Normal ranges for adults in this laboratory are 2638% for T3U, 1.38-2.95 nmol/l for T3, 64-167 nmol/l for TT4, 1 1 &29.6 pmol/l for FT4,O. 17-0.67 nmol/l for rT3, 1 4 3 1 pg/ml for TBG, and 1.25-6.00 pU/ml for TSH. TRAb activity was measured by the method of Smith and Hall (Mukhatar et al., 1975) using the kit provided from Japan Travenol Co., originally

296 K. Noguchi et al.

prepared by R.S.R. Ltd. (Cardiff, UK). TRAb assay was performed using unextracted sera according to the kits’ instruction. Sera from normal subjects gave TRAb values ranging from - 10 to + 10%.

Statistical analysis

The data are presented as the mean f SD. Comparisons between values were made using Student’s t-test for paired and unpaired data and one-way analysis of variance, as appropriate.

RESULTS

Comparison of the efects between the TP group and TP+MMIgroup

As shown in Table 1, there was no statistical difference in the mean of initial laboratory data between the TP group and the TP + MMI group. The time sequence of changes in the mean TI, serum T3U values, TT4, FT4, T3, rT3 and TBG concentrations, and TRAb values in both groups is summarized in Fig. 1.

The mean TI revealed a significant decrease one week after the initiation of treatment in both groups. After the seventh week, however, the reduction became significantly greater in the TP + MMI group than in the TP group. After the eleventh week, the TI fell to zero in all patients in the TP+ MMI group but in only one patient in the TP group.

The serum T3U in the TP group decreased significantly from the baseline value, reached the nadir at the third week, and then returned toward the baseline. In contrast, the T3U values in the TP+MMI group revealed a persistent decrease, indicating significantly lower levels than corresponding values in the TP group after the sixth week. By the end of the study, all patients in the TP+ MMI group achieved normal T3U values (26-32%), while all patients in the TP group still showed high values (39-52%).

The time course of changes in serum TT4 and FT4 were similar to that of T3U; both TT4 and FT4 values showed an initial fall and subsequent return toward the baseline in the TP group, whereas the values in the TP+ MMI group showed a gradual decrease. At the end of the study, all patients in the TP + MMI group achieved normal TT4 and FT4 values, while all patients in the TP group still showed high values (TT4: 170-498 nmol/l, FT4: 64-1 13 pmol/l).

The changes in serum T3 concentration displayed a similar trend in both groups; the T3 levels decreased within one week of the initiation of each treatment, and the change persisted throughout the period of the study. After the eleventh week, however, the serum T3 showed significantly greater reduction in the TP + MMI group than the corresponding values in the TP group.

Serum rT3 concentrations in the TP group increased rapidly, reached a peak at the first week, and a plateau thereafter. In contrast, the rT3 in the TP+MMI group did not change until the sixth week, and then gradually decreased toward a normal value. After the seventh week, there were significant differences in the corresponding values between the two groups.

Serum TBG concentrations in the TP group rose significantly from the second week to the seventh week, and then gradually declined toward the baseline. In the TP+MMI

Tyropanoate and methimazole in hyperthyroidism 297

T

.. .. .+ ** tf

,. I I I I I I I I I I I I I I I I

0 2 4 6 8 1 0 1 2 1 4 0 2 4 6 8 1 0 1 2 14

Time (weeks) Time (weeks)

Fig. I . Time sequence of changes in thyrotoxic index, serum T3U values, TT4, FT4, T3, rT3 and TBG concentrations, and TRAb in the T P group (solid line) and in the T P + MMI group (dotted line). Each point represents the mean f SD. Crosses indicate significant difference from the baseline value (+ ; P i 0.05; + +, P< 0,01), and asterisks indicate significant differences between the two groups (*; P ~ 0 . 0 5 ; **: PiO.01).

group, however, the TBG levels persistently increased, showing a significant difference from the corresponding values in the TP group after the eighth week.

The initial values of TRAb were 56.8 f 2 I . 1 % for the TP group and 43.2 & 16.6% for the TP+ M M I group on the average, showing no significant difference. After treatment, there was a gradual decline in the TRAb values in the TP+ MMI group, whereas the TRAb values in the TP group were unchanged or rather increased. The mean TRAb values at the end of the study were 15.5 f 1 1.5% for the TP+ MMI group, and 70.3 9.2% for the TP group, showing a significant difference between the groups.

Serum TSH concentrations were undetectable in all patients throughout the study (data not shown).

298 K. Noguchi et al.

Withdrawal eflects after chronic TP treatment

As shown in Table 1, there was no significant difference in the mean values of initial laboratory data between the TP+ MMI group and TP withdrawal group. Initial TI in the TP withdrawal group was 11.0 k0.9 on the average. In the TP-withdrawal group, the changes of serum T3U values, TT4 and T3 concentrations, and the TI during TP- treatment showed a similar pattern to those observed in the TP group.

One week after the discontinuance of TP, both the mean serum T3 levels and the TI rose again, as shown in Fig. 2. By contrast, as shown in Fig. 1, such a rebound of serum T3 and the TI was not demonstrated in the TP+MMI group after TP was withdrawn at the eighth week.

Adverse reaction to TP

No adverse reactions to OCA, such as skin rash, liver damage, nausea, vomiting, or dysuria were noted in any patients under study.

DISCUSSION

In the present study, chronic administration of TP alone to hyperthyroid patients clearly demonstrates sustained decreases in serum T3 levels and thyrotoxic index for up to fourteen weeks. Moreover, our study disclosed an initial fall and subsequent rise of serum T4 concentration during the chronic TP treatment. Such an 'escape' of serum T4 has not been reported in the previous short-term studies with ipodate (Wu et al., 1978, 1982).

Wu et al. (1982) showed that repeated doses of ipodate caused about 50% reduction in serum T4 below the baseline at the third week. In the present data obtained with TP, however, the reduction of T4 at the third week was only 14.6+ 12.0%. The reason for this difference remains unexplained, but might be related to the differences in the OCA employed, or sensitivity of the patients to the drugs due to the severity of thyrotoxicosis or dietary iodine intake.

r"*-l p,

I I I I c, II

Fig. 2. The changes in serum T3 concentration and thyrotoxic index in TP withdrawal group (**; P<0.005): I, the basal value; 11, at the time of TP-withdrawal; 111, at one week after TP- withdrawal.

Tyropanoate and methimazole in hyperthyroidism 299

The escape of serum T4 during chronic TP treatment cannot be explained merely by the observed elevation in serum TBG concentrations, since both serum T3U and FT4 levels were increased concomitantly with the increases in serum T4 levels. Likewise, an increment ofTSH secretion, previously shown in normal subjects given OCA (Burgi et al., 1976; Suzuki et al., 1979), is not responsible for the escape of serum T4, since no appreciable increase in serum TSH concentration was found after TP treatment.

Most OCA are known as a potent inhibitor of peripheral 5’-monodeiodination of T4 and rT3 in vitro (Chopra, 1978; Kaplan & Utiger, 1979; Larsen et al., 1979). Ipodate decreases T3 binding to hepatic nuclei in virro (DeGroot & Rue, 1979). Studies in uiuo have shown that TP reduces the hepatic uptake of T4 (Felicetta et al., 1980) and ipodate decreases the degradation of T4 (Wu el al., 1978). Moreover, metabolism of OCA in vivo releases iodide, which usually causes a transient inhibition of thyroid hormone secretion in hyperthyroid patients (Emerson et al., 1975). Thus, the reciprocal changes in serum T3 and rT3, as well as the transient fall of T4 levels, during TP treatment could be best explained by the additive effects of TP itself and of iodide liberated from TP.

Recently, Sharp et al. (198 1) have shown that in hyperthyroid patients combined doses of ipodate, PTU, and propranolol cause a greater reduction in serum free T3 index than PTU and propranolol alone. To compare the effects of TP plus MMI and MMI alone, 10 patients with Graves’ hyperthyroidism received MMI solely. The reduction of serum T3 concentration two weeks after the initiation of treatment was greater in the TP+MMI group than in the MMI group (Fig. 3). We feel, therefore, that the combination therapy compares favourably with the therapy with thionamide alone.

The present data showed that the therapy with combined TP and MMI appears to have the clinical advantage over that with TP alone in the following aspects. Firstly, the combined therapy produced more prompt and sustained improvement of thyrotoxicosis as evidenced by the reduction in the TI and serum concentration of T3, the most

0 2 4 6 8 14

Time (weeks)

Fig. 3. The mean percent change in serum T3 concentration in TP+ MMI group (dotted line) and ten hyperthyroid patients treated with MMI above (solid line). Each point represents the meankSD. Asterisks indicate significant differences between the two groups (*, P<O.OI; **, P < 0.00 I ).

300 K. Noguchi et al.

metabolically active thyroid hormone. Secondly, the reduction of serum TRAb activity was demonstrated only in the TP+MMI group. Recent studies emphasize the role of autoantibodies against TSH receptor in ultimate clinical expression as Graves’ hyperthyr- oidism (Teng & Yeung, 1980; Endo et al., 1981; Strakosch et al., 1982). In addition, several (Wall et al., 1976; McGregor et al., 1980; Weiss & Davies, 1981), though not all (Wenzel & Lente, 1984), studies support the hypothesis that some thionamide drugs may have an immunosuppressive effect upon the production of such antibodies. It is conceivable, therefore, that the decline in the TRAb activity in patients on TP+MMI might reflect remission of the underlying immunological disturbance in Graves’ disease. Thirdly, a rebound of serum T3 concentration and thyrotoxic index occurred after withdrawal of TP in the patients who received TP alone, but not in those given TP + MMI. In view of the peripheral 5’-monodeiodination of T4 as the major source of circulating T3, hyperthyroxinaemia as observed in the patients treated only with TP would provide a large amount of substrate for T3 unless the production or secretion of thyroid hormone is blocked. In this regard, therapy with a combination of thionamide and OCA could preclude a rise of serum T3 which may occur after an abrupt cessation of TP treatment.

Finally, in agreement with previous short-term studies with ipodate (Wu et al., 1982) and ipodate with combined PTU and propranolol (Sharp et al., 1981), no adverse reactions to chronic administration of TP plus MMI were observed in the present study. These findings imply the potential usefulness of the combined therapy for long-term management of hyperthyroidism, although further experience is needed to warrant the safety of the therapy.

Taken together, we conclude that the combination of OCA and thionamide therapy may be of clinical benefit at least in a selected group of patients with Graves’ disease.

ACKNOWLEDGEMENTS

The authors wish to thank Dr Sidney H. Ingbar at the Thorndike Laboratory (Beth Israel Hospital, Boston, Massachusetts, USA) for his critical reading of the text and helpful advise. We are also grateful to Torii Yakuhin Co., Tokyo for providing TP, to Dainabot Radioisotope Laboratory for providing rT3 RIA kits, and to Japan Travenol Co. for providing free T4 RIA kits and TRAb RRA kits.

A part of this study was presented in abstract form at the Second Asia & Oceania Thyroid Association Meeting, Tokyo, Japan, August 19-22, 1982, at the 57th Annual Meeting of the Japan Endocrine Society, Tokyo, Japan, May 18-20, 1984, and at the 9th International Thyroid Congress, Sao Paulo, Brazil, September 1-6, 1985.

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