J. Endocrinol. Invest. 14: 847-851 , 1991
Therapy of Graves' disease with sodium ipodate is associated with a high recurrence rate of hyperthyroidism E. Martino*, S. Balzano*, L. Bartalena**, A. Loviselli*, V. Sica*, L. Petrini*, L. Grasso**, M. Piga*, and L.E. Braverman*** *Cattedra di Endocrinologia, Universita di Cagliari, Cagliari; **Istituto di Endocrinologia, Universita di Pisa, Pisa, Italy, and ***Division of Endocrinology and Metabolism , University of Massachusetts Medical School, Worcester, MA, USA patients were treated with methimazole (20-30 mg/day, initial dose), but the therapeutic response was poor and delayed. Two patients were still hyperthyroid after 6 months of methimazole treatment. Elevated serum FT3 concentrations were observed in the Group 2 patients at 21 days following the early normalization of serum FT 3 concentrations. No changes in serum thyroglobulin and thyroid microsomal and TSH-receptor autoantibody titers were observed in either groups during IPO therapy. In conclusion, the results of the present study demonstrate that IPO rapidly restores euthyroidism, but its prolonged administration is associated with a high rate of relapse of hyperthyroidism and a poor response to subsequent methimazole treatment and that long-term IPO administration does not affect humoral markers of thyroid autoimmunity.
ABSTRACT. To evaluate the long-term efficacy of sodium ipodate (IPO) in the treatment of hyperthyroid Graves' disease, we studied 12 consecutive patients with Graves'hyperthyroidism treated only with 500 mg IPO po daily for several weeks to 22 months. Serum thyroid hormone concentrations markedly decreased and serum free T 3 values normalized in all patients within 7 days of therapy. Five patients (42%, Group 1) were euthyroid after 6 weeks of IPO treatment and remained so until IPO was discontinued after 22 months. Recurrence of hyperthyroidism after drug withdrawal occurred in only one of these Group 1 patients, who was promptly responsive to a second course of IPO. In contrast, seven of 12 patients (58%, Group 2) relapsed with recurrent hyperthyroidism between 14 and 42 days of IPO therapy. After IPO was withdrawn, these Group 2
INTRODUCTION
roidism due to Graves' disease. We conclude that long-term IPO therapy is associate with a high recurrence rate of hyperthyroidism and does not affect humoral markers of thyroid autoimmunity.
The short-term administration of iodine-containing oral cholecystographic agents, such as sodium ipodate (IPO) , iopanoic acid and sodium tryopanoate, has been reported to rapidly control hyperthyroidism due to Graves' disease (1-5) . The efficacy of these drugs depends upon their ability to decrease the peripheral conversion of T4 to T3 by inhibiting 5'-deiodinase activity and the direct effect of iodine on blocking hormone release from the thyroid. On the other hand, the effectiveness of longterm therapy with these drugs is controversial since discrepant results have been obtained , possibly due to the selection of patients, drug and daily dose (6-8). In the present study, we evaluated the therapeutic effect of prolonged IPO treatment of hyperthy-
MATERIALS AND METHODS Twelve consecutive patients with untreated hyperthyroidism due to Graves' disease (3 men, 9 women , age range 18-70 yr) were studied after obtaining their informed consent (Table 1). All patients lived in Southern Sardinia where the average iodine intake is low and ranges from 40 to 100 )lg/day. Patients were given IPO (Biloptin®, Schering, 500 mg/day po) . Biochemical and clinical evaluation was carried out before treatment and at various time intervals (3, 7, 14, 21 , and 42 days) during IPO administration. In patients who had a persistent remission of hyperthyroidism during IPO administration (Group 1), IPO was continued for 22 months. Recurrence of hyperthyroidism during IPO treatment was diagnosed on clinical grounds, as well as on the basis of persistently elevated serum total
Key-words: Graves' disease , sodium ipodate, hyperthyroidism. Correspondence: Prof. Enio Martino, Catted ra di Endocrinologi a, Universita di Cagliari, Vi a S. Giorgio 12, 09124 Cag liari, Italy.
Received March 4, 1991 ; accepted July 8,1991 .
847
E Martino. S Balzano. L. Bartalena. et al
RESULTS Five of the 12 patients with Graves' disease (42%) had a prolonged remission of hyperthyroidism during IPO treatment (Group 1). In contrast, hyperthyroidism recurred in the remaining 7 patients (58%) during the administration of the drug (Group 2). These different responses could not be explained by a difference in the degree of hyperthyroidism since mean serum total and free T4 and T3 concentrations prior to treatment were similar in the two groups (Table 1). TRAb were positive in four of 5 Group 1 patients and in five of 7 Group 2 patients. No differences in the prevalence or titer of MCHA or TGHA autoantibodies were apparent between the two groups (Table 1). The compliance of IPO therapy was excellent in all patients, as suggested by the marked increase in urinary iodine excretion found in all patients during treatment (data not shown). The mean serum FT 4 and FT 3 concentrations in Groups 1 and 2 at various time intervals during IPO treatment are shown in Figures 1 and 2, respectively. In Group 1, mean serum FT4 and FT3 values rapidly and significantly decreased within 3 days, and serum FT3 normalized after 7 days. Serum FT4 did not return to normal in all patients despite the restoration of clinical euthyroidism and normal serum FT3 concentrations. Serum FT 4 and FT3 concentrations in Group 1 patients remained stable up to 42 days. The serum FT 4 concentrations returned
T3 (TI3) and free T3 (FT3) concentrations. In patients with recurrent hyperthyroidism (Group 2), IPO was eventually withdrawn and methimazole was begun (20-30 mg/day, initial dose). Serum total T4 (TI 4) and TT 3 concentrations were measured by specific radioimmunoassay (Byk Gulden SpA, Milan, Italy). Serum thyroglobulin (Tg) was determined by an immunoradiometric assay (Becton Dickinson and Ames Italia SpA, Milan, Italy). Serum TSH was measured by an ultrasensitive immunoradiometric assay (Sorin Biomedica, Saluggia, Italy) having a limit of detection of 0.07 mUll. Serum free T4 (FT 4) and FT 3 were assayed by the Lisophase FT4 and FT3 kits (Sclavo SpA, Siena Italy), according to Romelii et al. (9). Normal values in our laboratory are as follows: TI4, 51.6-144.5 /-lmol/l; TI3, 1.5-3.2 /-lmol/l; FT 4, 8.4-21.3 pmol/l; FT 3, 3.9-8.5 pmol/l; TSH, 0.4-4.0 mUll; Tg, 3-20 mg/l. Thyroid microsomal (MCHA) and thyroglobulin (TGHA) autoantibodies were determined by passive hemagglutination (Fujizoki, Inc., Tokyo, Japan), and TSH receptor autoantibodies (TRAb) by radioreceptor assay (THYBIA assay, Mallinckrodt, Inc., Mannheim, FRG). Urinary iodine excretion was evaluated by a colorimetric method, using an automated analyzer (Technicon Co.). Statistical analyses were carried out by paired and unpaired Student's t test and analysis of variance (AN OVA) as appropriate.
Table 1 - Thyroid function tests prior to sodium ipodate administration. Patient (no.)
TT4 (/lmol/I)
TT3 (/lmol/I)
197 180 153 245 236 202 17
4.3 3.3 3.5 34 6.1 4.2 0.5
172 172 201 317 253 275 250 234 21
4.5 2.2 5.6 6.7 3.2 3.3 5.6 4.5 0.6
FT3 (pmol/I)
TSH (mU/I)
61.3 37.8 53.8 30.8 64.5 49.7 6.6
30.2 20.1 26.0 13.8 29.5 23.9 3.1
26.9 20.7 764 25.5 35.9 84.3 91.8 51.8 11.7
20.9 8.6 22.1 32.2 19.2 25.9 34.9 234 3.3
FT4 (pmol/I)
24 h RAIU % of dose
MCHA
TGHA
Tg (mg/I)
< 0.07 < 0.07 < 0.07 < 0.07 < 0.07
1/1600 1/1600
Neg Neg Neg Neg Neg
274 5 527 35 6
90 65 58 62 42 64.3 7.7
< < < < < <
Therapy of Graves' disease with sodium ipodate is associated with a high recurrence rate of hyperthyroidism E. Martino*, S. Balzano*, L. Bartalena**, A. Loviselli*, V. Sica*, L. Petrini*, L. Grasso**, M. Piga*, and L.E. Braverman*** *Cattedra di Endocrinologia, Universita di Cagliari, Cagliari; **Istituto di Endocrinologia, Universita di Pisa, Pisa, Italy, and ***Division of Endocrinology and Metabolism , University of Massachusetts Medical School, Worcester, MA, USA patients were treated with methimazole (20-30 mg/day, initial dose), but the therapeutic response was poor and delayed. Two patients were still hyperthyroid after 6 months of methimazole treatment. Elevated serum FT3 concentrations were observed in the Group 2 patients at 21 days following the early normalization of serum FT 3 concentrations. No changes in serum thyroglobulin and thyroid microsomal and TSH-receptor autoantibody titers were observed in either groups during IPO therapy. In conclusion, the results of the present study demonstrate that IPO rapidly restores euthyroidism, but its prolonged administration is associated with a high rate of relapse of hyperthyroidism and a poor response to subsequent methimazole treatment and that long-term IPO administration does not affect humoral markers of thyroid autoimmunity.
ABSTRACT. To evaluate the long-term efficacy of sodium ipodate (IPO) in the treatment of hyperthyroid Graves' disease, we studied 12 consecutive patients with Graves'hyperthyroidism treated only with 500 mg IPO po daily for several weeks to 22 months. Serum thyroid hormone concentrations markedly decreased and serum free T 3 values normalized in all patients within 7 days of therapy. Five patients (42%, Group 1) were euthyroid after 6 weeks of IPO treatment and remained so until IPO was discontinued after 22 months. Recurrence of hyperthyroidism after drug withdrawal occurred in only one of these Group 1 patients, who was promptly responsive to a second course of IPO. In contrast, seven of 12 patients (58%, Group 2) relapsed with recurrent hyperthyroidism between 14 and 42 days of IPO therapy. After IPO was withdrawn, these Group 2
INTRODUCTION
roidism due to Graves' disease. We conclude that long-term IPO therapy is associate with a high recurrence rate of hyperthyroidism and does not affect humoral markers of thyroid autoimmunity.
The short-term administration of iodine-containing oral cholecystographic agents, such as sodium ipodate (IPO) , iopanoic acid and sodium tryopanoate, has been reported to rapidly control hyperthyroidism due to Graves' disease (1-5) . The efficacy of these drugs depends upon their ability to decrease the peripheral conversion of T4 to T3 by inhibiting 5'-deiodinase activity and the direct effect of iodine on blocking hormone release from the thyroid. On the other hand, the effectiveness of longterm therapy with these drugs is controversial since discrepant results have been obtained , possibly due to the selection of patients, drug and daily dose (6-8). In the present study, we evaluated the therapeutic effect of prolonged IPO treatment of hyperthy-
MATERIALS AND METHODS Twelve consecutive patients with untreated hyperthyroidism due to Graves' disease (3 men, 9 women , age range 18-70 yr) were studied after obtaining their informed consent (Table 1). All patients lived in Southern Sardinia where the average iodine intake is low and ranges from 40 to 100 )lg/day. Patients were given IPO (Biloptin®, Schering, 500 mg/day po) . Biochemical and clinical evaluation was carried out before treatment and at various time intervals (3, 7, 14, 21 , and 42 days) during IPO administration. In patients who had a persistent remission of hyperthyroidism during IPO administration (Group 1), IPO was continued for 22 months. Recurrence of hyperthyroidism during IPO treatment was diagnosed on clinical grounds, as well as on the basis of persistently elevated serum total
Key-words: Graves' disease , sodium ipodate, hyperthyroidism. Correspondence: Prof. Enio Martino, Catted ra di Endocrinologi a, Universita di Cagliari, Vi a S. Giorgio 12, 09124 Cag liari, Italy.
Received March 4, 1991 ; accepted July 8,1991 .
847
E Martino. S Balzano. L. Bartalena. et al
RESULTS Five of the 12 patients with Graves' disease (42%) had a prolonged remission of hyperthyroidism during IPO treatment (Group 1). In contrast, hyperthyroidism recurred in the remaining 7 patients (58%) during the administration of the drug (Group 2). These different responses could not be explained by a difference in the degree of hyperthyroidism since mean serum total and free T4 and T3 concentrations prior to treatment were similar in the two groups (Table 1). TRAb were positive in four of 5 Group 1 patients and in five of 7 Group 2 patients. No differences in the prevalence or titer of MCHA or TGHA autoantibodies were apparent between the two groups (Table 1). The compliance of IPO therapy was excellent in all patients, as suggested by the marked increase in urinary iodine excretion found in all patients during treatment (data not shown). The mean serum FT 4 and FT 3 concentrations in Groups 1 and 2 at various time intervals during IPO treatment are shown in Figures 1 and 2, respectively. In Group 1, mean serum FT4 and FT3 values rapidly and significantly decreased within 3 days, and serum FT3 normalized after 7 days. Serum FT4 did not return to normal in all patients despite the restoration of clinical euthyroidism and normal serum FT3 concentrations. Serum FT 4 and FT3 concentrations in Group 1 patients remained stable up to 42 days. The serum FT 4 concentrations returned
T3 (TI3) and free T3 (FT3) concentrations. In patients with recurrent hyperthyroidism (Group 2), IPO was eventually withdrawn and methimazole was begun (20-30 mg/day, initial dose). Serum total T4 (TI 4) and TT 3 concentrations were measured by specific radioimmunoassay (Byk Gulden SpA, Milan, Italy). Serum thyroglobulin (Tg) was determined by an immunoradiometric assay (Becton Dickinson and Ames Italia SpA, Milan, Italy). Serum TSH was measured by an ultrasensitive immunoradiometric assay (Sorin Biomedica, Saluggia, Italy) having a limit of detection of 0.07 mUll. Serum free T4 (FT 4) and FT 3 were assayed by the Lisophase FT4 and FT3 kits (Sclavo SpA, Siena Italy), according to Romelii et al. (9). Normal values in our laboratory are as follows: TI4, 51.6-144.5 /-lmol/l; TI3, 1.5-3.2 /-lmol/l; FT 4, 8.4-21.3 pmol/l; FT 3, 3.9-8.5 pmol/l; TSH, 0.4-4.0 mUll; Tg, 3-20 mg/l. Thyroid microsomal (MCHA) and thyroglobulin (TGHA) autoantibodies were determined by passive hemagglutination (Fujizoki, Inc., Tokyo, Japan), and TSH receptor autoantibodies (TRAb) by radioreceptor assay (THYBIA assay, Mallinckrodt, Inc., Mannheim, FRG). Urinary iodine excretion was evaluated by a colorimetric method, using an automated analyzer (Technicon Co.). Statistical analyses were carried out by paired and unpaired Student's t test and analysis of variance (AN OVA) as appropriate.
Table 1 - Thyroid function tests prior to sodium ipodate administration. Patient (no.)
TT4 (/lmol/I)
TT3 (/lmol/I)
197 180 153 245 236 202 17
4.3 3.3 3.5 34 6.1 4.2 0.5
172 172 201 317 253 275 250 234 21
4.5 2.2 5.6 6.7 3.2 3.3 5.6 4.5 0.6
FT3 (pmol/I)
TSH (mU/I)
61.3 37.8 53.8 30.8 64.5 49.7 6.6
30.2 20.1 26.0 13.8 29.5 23.9 3.1
26.9 20.7 764 25.5 35.9 84.3 91.8 51.8 11.7
20.9 8.6 22.1 32.2 19.2 25.9 34.9 234 3.3
FT4 (pmol/I)
24 h RAIU % of dose
MCHA
TGHA
Tg (mg/I)
< 0.07 < 0.07 < 0.07 < 0.07 < 0.07
1/1600 1/1600
Neg Neg Neg Neg Neg
274 5 527 35 6
90 65 58 62 42 64.3 7.7
< < < < < <
