Exp. Clin. Endocrinol. Vol. 97, No. 2/3, 1991, pp. 261-264
J. A. Barth, Leipzig
Department of Endocrinology, Hospital Servidor Publico Estadual de Sao Paulo, IAMSPE, Sao Paulo, Brazil
J. H. ROMALDINI, M. C. WERNER, N. BROMBERG and R. S. WERNER
Introduction
The introduction of antithyroid drugs (ATD) 40 years go changed the treatment of hyperthyroidism (Astwood et al., 1945); however, the high incidence of adverse effects associated with the thiouracil led to its substitution in favour of propylthiouracil (PTU), methimazole (MMI) and carbimazole, which have a lower frequency of these adverse effects (Amrehein et al., 1954). These drugs are still the first choice for the treatment of Basedow's disease (Glinoer et al., 1987), but the relationship between daily doses and the adverse effects of PTU and MMI remains unclear. We have used large doses of ATD for treatment of hyperthyroidism for more than 10 years and with this regimen we obtained an elevated remission-rate in Basedow's patients (Reis et al., 1979). During this period no significant differences regarding the doses could be noted (Romaldini et al., 1q83). Recently, we observed that adverse effects of PTU or MMI were similar in hyperthyroid patients receiving either high or low doses of ATD (Werner et al., 1989). Patients and Methods Adverse effects were studied in 194 Basedow's hyperthyroid patients who received between 40 to 120 mg of MMI daily (mean ± SD, 60 ± 19mg) and 92 patients who received 728 ± 216 mg daily of PTU (high dose group) associated with 50-75 tg of
T3 daily. The second group was treated with lower doses: up to 35 mg of MMI (23 ± 10 mg daily) in 64 patients and 255 ± 35 mg daily of PTU in other 39 patients (low dose group). The 2 groups of patients were observed in both high and low doses regimen. Recently, Meyer-Gebner et al. (1989) found high toxicity rate in patients taking over 20 mg of thiamazol or over 30 mg daily of carbimazole. It is very difficult to find a satisfactory explanation for the discrepancy between our findings and the data of Meyer-Gebner et al. (1989). They studied a population of hyperthyroid patients that included toxic multinodular goiter that are often older than Basedow's disease patients. Regarding the major adverse effects our incidence was slightly higher than some data
Downloaded by: University of Connecticut. Copyrighted material.
Adverse Effects Related to Antithyroid Drugs and their Dose Regimen
262
Exp. Clin. Endocrino!. 97 (1991) 2/3
reported in the literature (Cooper, 1984; Amrehein et al., 1970; Chevalley et al., 1954; Ducornet and Duprey, 1988) and it was the same in high and low dose groups. Although no significant difference was obtained, there were more patients taking high doses of ATD with minor adverse effects and most of them were on MMI therapy. We also found an elevated prevalence of thyroid microsomal antibody in patients with skin rash than other adverse effects. Probably these patients were prone to get skin hypersensibility. By far the most well-known and life-risk adverse effects of antithyroid drugs is agranulocytosis that is a severe condition and sometimes lethal. It has been estimated to of leucopenia and granulocytopenia that would have to overestimate the incidence. In a study involving patients from Israel and 7 regions of Europe (Retsagi et al., 1988) the quantitative risk of agranulocytosis for ATD was calculated to be lower than previous estimates and not so different from other drugs (Braun, 1988). In contrast with the findings of Cooper et al. (1983) in our comparable for age and sex were treated for 16 ± 8 months (range: 13 to 43 months). Hematologic and hepatic enzymatic determinations were made every 3 weeks for the first 3 months and then every two months until the end of treatment. We warned the patients to report any complaints immediately. Granulocytopenia was defined as a total granulocyte count lower than 1,500/mm3 and agranulocytosis was considered as total leukocyte count of 1 ,000/jnm3 or less and granulocyte count of 250/mm3 or less. Hepatic damage was diagnosed on clinical and laboratorial grounds and by liver biopsy. Results No statistical difference in the frequency of adverse effects could be noted between the
2 groups. Major effects (agranulocytosis, granulocytopenia and hepatic damage) were observed in 11 (3 Wo) patients. Minor effects (arthralgia, skin rash and gastric intolerance) were observed in 52(13 Wo) patients. Among major effects in high doses group, patients on PTU had significan't more adverse effects (n = 4, 4.3 Wo) than those treated with MMI (n = 3, 1 .5Wo). Hepatotoxicity related to the PTU treated patients was responsible for this
difference. The total minor adverse effects showed no difference between the type of thionamide drugs used. Arthralgia was the most frequent minor effect found (21: 5.3 Wo of patients). In high dose group, arthralgia was noted in 5.8Wo and in 3.9Wo of patients from low dose group. Most of the patients (79 Wo) were on MMI-therapy. Skin rash was observed in 4.lWo of patients from high group and in 3.9Wo of patients from low dose group. Fifty nine percent of these patients were treated with MMI. Gastric intolerance was observed in 3.8Wo of the patients; 4.5 Wo from high dose group and 1.9Wo from low dose group. Forty two (26.5 Wo) of the patients with minor adverse effects were taking MMI and only 10 (7.6Wo) on PTU (Fischer's Exact Test; P > 0.05) and most of these effects occurred after the third month of treatment. We found 4 patients with agranulocytosis (1 Wo), 2 (0.7Wo) of them were taking larger doses of MMI (60 and 80 mg daily) and the other 2 (1 .9Wo) patients with low doses of MMI (30 mg) or PTU (250 mg daily). The mean age was 29.5 ± 3.8 years (25 to 34 years). Agranulocytosis occurred between the first and the third month of therapy and these patients were still thyrotoxic. Also we found 2 patients with granulocytopenia both from high dose group (0.5 Wo) receiving 90mg and 600 mg daily of MMI and PTU, respectively.
Downloaded by: University of Connecticut. Copyrighted material.
occur among 0.5 to 1 Wo of users (Ducornet and Duprey, 1988) but this included mild cases
J. H. R0MALruNI et. al., Adverse Effects of Antithyroid Drugs
263
Full recovery was achieved in all the cases after discontinuation of the drugs. There was no significant difference between the 2 groups or the 2 types of ATD. Hepatic injury was observed inS (1.3Wo) cases, 4 of these patients were on high PTU
doses and the last one on 15 mg of MMI (P < 0.05 by Fischer's Exact Test). The hepatotoxicity occurred after the 3rd month to the 12th month of treatment. All patients were euthyroid and no age dependence was found. The patients' age was below 39 years.
In 2 patients, with the change of the drug from PTU to MMI after normalization of hepatic enzymatic tests, no liver disfunction was further noted 24 months of MMI therapy.
The adverse effects of ATD during therapy of Basedow's disease study, there was no relation between the incidence of agranulocytosis and the age of patients (29 ± 3 years). A reason for this difference was the kind of hyperthyroid patients studied. Cooper et al. (1984) studied patients with Basedow's disease (age: 39 ± 15 years, n = 7) and toxic
multinodular goiter (age: 61 ± 8.5 years, n = 8). As it is known patients with toxic multinodular goiter usually are older than Basedow's patients and in Cooper's work they
needed larger doses of ATD (50 ± 18 mg) than Basedows patients (32 ± 8.6 mg). Besides, the age of the Basedow's patients in their study was not different from ours. Although not strictly dose related, agranulocytosis and granulocytopenia were most frequent in patients taking high doses of ATD and related to thyrotoxic status but not agedependent. Hepatic damage is a rare reaction of ATD. We found 45 cases in the english literature (Vitug and Goldman, 1985; Ducornet and Duprey, 1988). However some of these cases did not have liver biopsies or had other etiologies of liver disfunctions. There is a difference between PTU AND MMI doses that cause hepatotoxicity, 12 out of 21 patients on MMI were taking more than 40 mg while only 10 out 24 cases were taking more than 400 mg o1 PTU. Furthermore the evolution of liver enzymatic tests in our patients showed that they were elevated before treatment and came down to normal during ATD treatment. These changes suggest an influence of hyperthyroidism per se and should be considered in the diagnostics of hepatic adverse effects of ATD. In our study, ATD induced hepatotoxicity was related to high dose of PTU, duration of treatment and attributed to drug hypersensitivity. In conclusion, Basedow's disease treatment with any dosage of ATD demands a strict follow-up to avoid undesirable adverse effects. High ATD doses should be used, particularly in severe Basedow's patients as thyroid-associated ophthalmopathy.
References AMRHEIN, J. A.; KENNY, F. M.; Ross, D.: Granulocytopenia, lupus-like syndrome and other com-
plications of propyithiouracil therapy. J. Pediatr. 76 (1970) 54-63. AsTwooD, E. B.; VANDERLAAN, W. P.: Thiouracil derivates of greater activity for the treatment of
hyperthyroidism. J. Clin. Endocrinol. Metab. 5 (1945) 424-430. BRAUN, VON, J.: Risiken des Analgetikagebrauchs. Fortschr. Med. 106 (1988) 618-622.
Downloaded by: University of Connecticut. Copyrighted material.
Discussion
264
Exp. Clin. Endocrinol. 97 (1991) 2/3 CIrEVALLEY, J.; MCGAVACK, T. H.; KENIBERG, S.; PEARSON, S.: A four year study of the treatment of
hyperthyroidism with methimazole. J. Clin. Endocrino!. Metab. 14 (1954) 948-960. COOPER, D. S.; GOLDMINZ, D.; LE WIN, A. A.; LADERSON, P. W.; DANIELS, G. H.; MOLntiI, M. E.;
RIDGWAY, E. C.: Agranulocytosis associated with antithyroid drugs: effects of patients age and drug dose. Ann. Intern. Med. 98 (1983) 26-29. COOPER, D. S.: Antithyroid drugs. N. EngI. J. Med. 318 (1984) 1353-1360. DUCORNET, B.; Dupny, J.: Effects secondaires des antithyroidiens de synthese. Ann. Med. Interne. 139 (1988) 410-431. GLINOER, D.; HESCH, D.; LAGASSE, R.; LAUBERG, P.: The management of hyperthyroidism due to
Graves' disease in Europe in 1986. Results of an international survey. Acta Endocrinol. (Copen.) Suppl. 185 (1897). MEYER-GEBNER, M.; BENKER, G.; OLBEICHT, ils.; WINDECK, R.; Cissnwsiu, K.; REINERS, CHR.;
REIS, L. C. E; ROMALDINI, J. H.; BROMBERG, N.: High remission-rate in hyperthyroidism: correla-
tion with "total thyroidal rest therapy." Braz. J. Med. Biol. Res. 10 (1977) 311-318. RETSAGI, G.; KELLY, P. J.; K .JFMAN, W.: Risk of agranulocytosis and aplastic anaemia in relation
to use of antithyroid drugs. International agranulocytosis and aplastic anaemia study. Br. Med. J. 297 (1988) 261-264. ROMALDINI, J. H.; BROMBERG, N.; WERNER, R. S.; TANAKA, L. M.; RODRIGUES, H. E; WERNER,
M. C.; FARÁN, C. S.; REIS, L. C. E: Comparison of effects of high and low dosage regimens of an-
tithyroid drugs in the management of Graves' hyperthyroidism. J. Clin. Endocrino!. Metab. 57 (1983) 563-570. Vrruo, A. C.; GOLDMAN, J. M.: Hepatotoxicity from antithyroid drugs. Hqmone Res. 21 (1985)
229-234.
WERNER, M. C.; ROMALDINI, J. H.; BROMBERG, N.; WERNER, R. S.; FARÁN, C. S.: Adverse effects
related to thionamide drugs and their dose regimen. Am. J. Med. Sci. 297 (1989) 216-219. Author's address: J. H. ROMAJ.Dmn, M. D., Department of Endocrinology, HSPE, IAMSPE, Caixa Postal 8570, 01000 Sao Paulo, Brazil
Downloaded by: University of Connecticut. Copyrighted material.
REINWEIN, D.: Nebenwirkungen der antithyreoidalen Therapie der Hyperthyreose. Eine Untersuchung an 1 256 fortlaufend betreuten Patienten. Dtsch. med. Wschr. 114 (1989) 166-171.
J. A. Barth, Leipzig
Department of Endocrinology, Hospital Servidor Publico Estadual de Sao Paulo, IAMSPE, Sao Paulo, Brazil
J. H. ROMALDINI, M. C. WERNER, N. BROMBERG and R. S. WERNER
Introduction
The introduction of antithyroid drugs (ATD) 40 years go changed the treatment of hyperthyroidism (Astwood et al., 1945); however, the high incidence of adverse effects associated with the thiouracil led to its substitution in favour of propylthiouracil (PTU), methimazole (MMI) and carbimazole, which have a lower frequency of these adverse effects (Amrehein et al., 1954). These drugs are still the first choice for the treatment of Basedow's disease (Glinoer et al., 1987), but the relationship between daily doses and the adverse effects of PTU and MMI remains unclear. We have used large doses of ATD for treatment of hyperthyroidism for more than 10 years and with this regimen we obtained an elevated remission-rate in Basedow's patients (Reis et al., 1979). During this period no significant differences regarding the doses could be noted (Romaldini et al., 1q83). Recently, we observed that adverse effects of PTU or MMI were similar in hyperthyroid patients receiving either high or low doses of ATD (Werner et al., 1989). Patients and Methods Adverse effects were studied in 194 Basedow's hyperthyroid patients who received between 40 to 120 mg of MMI daily (mean ± SD, 60 ± 19mg) and 92 patients who received 728 ± 216 mg daily of PTU (high dose group) associated with 50-75 tg of
T3 daily. The second group was treated with lower doses: up to 35 mg of MMI (23 ± 10 mg daily) in 64 patients and 255 ± 35 mg daily of PTU in other 39 patients (low dose group). The 2 groups of patients were observed in both high and low doses regimen. Recently, Meyer-Gebner et al. (1989) found high toxicity rate in patients taking over 20 mg of thiamazol or over 30 mg daily of carbimazole. It is very difficult to find a satisfactory explanation for the discrepancy between our findings and the data of Meyer-Gebner et al. (1989). They studied a population of hyperthyroid patients that included toxic multinodular goiter that are often older than Basedow's disease patients. Regarding the major adverse effects our incidence was slightly higher than some data
Downloaded by: University of Connecticut. Copyrighted material.
Adverse Effects Related to Antithyroid Drugs and their Dose Regimen
262
Exp. Clin. Endocrino!. 97 (1991) 2/3
reported in the literature (Cooper, 1984; Amrehein et al., 1970; Chevalley et al., 1954; Ducornet and Duprey, 1988) and it was the same in high and low dose groups. Although no significant difference was obtained, there were more patients taking high doses of ATD with minor adverse effects and most of them were on MMI therapy. We also found an elevated prevalence of thyroid microsomal antibody in patients with skin rash than other adverse effects. Probably these patients were prone to get skin hypersensibility. By far the most well-known and life-risk adverse effects of antithyroid drugs is agranulocytosis that is a severe condition and sometimes lethal. It has been estimated to of leucopenia and granulocytopenia that would have to overestimate the incidence. In a study involving patients from Israel and 7 regions of Europe (Retsagi et al., 1988) the quantitative risk of agranulocytosis for ATD was calculated to be lower than previous estimates and not so different from other drugs (Braun, 1988). In contrast with the findings of Cooper et al. (1983) in our comparable for age and sex were treated for 16 ± 8 months (range: 13 to 43 months). Hematologic and hepatic enzymatic determinations were made every 3 weeks for the first 3 months and then every two months until the end of treatment. We warned the patients to report any complaints immediately. Granulocytopenia was defined as a total granulocyte count lower than 1,500/mm3 and agranulocytosis was considered as total leukocyte count of 1 ,000/jnm3 or less and granulocyte count of 250/mm3 or less. Hepatic damage was diagnosed on clinical and laboratorial grounds and by liver biopsy. Results No statistical difference in the frequency of adverse effects could be noted between the
2 groups. Major effects (agranulocytosis, granulocytopenia and hepatic damage) were observed in 11 (3 Wo) patients. Minor effects (arthralgia, skin rash and gastric intolerance) were observed in 52(13 Wo) patients. Among major effects in high doses group, patients on PTU had significan't more adverse effects (n = 4, 4.3 Wo) than those treated with MMI (n = 3, 1 .5Wo). Hepatotoxicity related to the PTU treated patients was responsible for this
difference. The total minor adverse effects showed no difference between the type of thionamide drugs used. Arthralgia was the most frequent minor effect found (21: 5.3 Wo of patients). In high dose group, arthralgia was noted in 5.8Wo and in 3.9Wo of patients from low dose group. Most of the patients (79 Wo) were on MMI-therapy. Skin rash was observed in 4.lWo of patients from high group and in 3.9Wo of patients from low dose group. Fifty nine percent of these patients were treated with MMI. Gastric intolerance was observed in 3.8Wo of the patients; 4.5 Wo from high dose group and 1.9Wo from low dose group. Forty two (26.5 Wo) of the patients with minor adverse effects were taking MMI and only 10 (7.6Wo) on PTU (Fischer's Exact Test; P > 0.05) and most of these effects occurred after the third month of treatment. We found 4 patients with agranulocytosis (1 Wo), 2 (0.7Wo) of them were taking larger doses of MMI (60 and 80 mg daily) and the other 2 (1 .9Wo) patients with low doses of MMI (30 mg) or PTU (250 mg daily). The mean age was 29.5 ± 3.8 years (25 to 34 years). Agranulocytosis occurred between the first and the third month of therapy and these patients were still thyrotoxic. Also we found 2 patients with granulocytopenia both from high dose group (0.5 Wo) receiving 90mg and 600 mg daily of MMI and PTU, respectively.
Downloaded by: University of Connecticut. Copyrighted material.
occur among 0.5 to 1 Wo of users (Ducornet and Duprey, 1988) but this included mild cases
J. H. R0MALruNI et. al., Adverse Effects of Antithyroid Drugs
263
Full recovery was achieved in all the cases after discontinuation of the drugs. There was no significant difference between the 2 groups or the 2 types of ATD. Hepatic injury was observed inS (1.3Wo) cases, 4 of these patients were on high PTU
doses and the last one on 15 mg of MMI (P < 0.05 by Fischer's Exact Test). The hepatotoxicity occurred after the 3rd month to the 12th month of treatment. All patients were euthyroid and no age dependence was found. The patients' age was below 39 years.
In 2 patients, with the change of the drug from PTU to MMI after normalization of hepatic enzymatic tests, no liver disfunction was further noted 24 months of MMI therapy.
The adverse effects of ATD during therapy of Basedow's disease study, there was no relation between the incidence of agranulocytosis and the age of patients (29 ± 3 years). A reason for this difference was the kind of hyperthyroid patients studied. Cooper et al. (1984) studied patients with Basedow's disease (age: 39 ± 15 years, n = 7) and toxic
multinodular goiter (age: 61 ± 8.5 years, n = 8). As it is known patients with toxic multinodular goiter usually are older than Basedow's patients and in Cooper's work they
needed larger doses of ATD (50 ± 18 mg) than Basedows patients (32 ± 8.6 mg). Besides, the age of the Basedow's patients in their study was not different from ours. Although not strictly dose related, agranulocytosis and granulocytopenia were most frequent in patients taking high doses of ATD and related to thyrotoxic status but not agedependent. Hepatic damage is a rare reaction of ATD. We found 45 cases in the english literature (Vitug and Goldman, 1985; Ducornet and Duprey, 1988). However some of these cases did not have liver biopsies or had other etiologies of liver disfunctions. There is a difference between PTU AND MMI doses that cause hepatotoxicity, 12 out of 21 patients on MMI were taking more than 40 mg while only 10 out 24 cases were taking more than 400 mg o1 PTU. Furthermore the evolution of liver enzymatic tests in our patients showed that they were elevated before treatment and came down to normal during ATD treatment. These changes suggest an influence of hyperthyroidism per se and should be considered in the diagnostics of hepatic adverse effects of ATD. In our study, ATD induced hepatotoxicity was related to high dose of PTU, duration of treatment and attributed to drug hypersensitivity. In conclusion, Basedow's disease treatment with any dosage of ATD demands a strict follow-up to avoid undesirable adverse effects. High ATD doses should be used, particularly in severe Basedow's patients as thyroid-associated ophthalmopathy.
References AMRHEIN, J. A.; KENNY, F. M.; Ross, D.: Granulocytopenia, lupus-like syndrome and other com-
plications of propyithiouracil therapy. J. Pediatr. 76 (1970) 54-63. AsTwooD, E. B.; VANDERLAAN, W. P.: Thiouracil derivates of greater activity for the treatment of
hyperthyroidism. J. Clin. Endocrinol. Metab. 5 (1945) 424-430. BRAUN, VON, J.: Risiken des Analgetikagebrauchs. Fortschr. Med. 106 (1988) 618-622.
Downloaded by: University of Connecticut. Copyrighted material.
Discussion
264
Exp. Clin. Endocrinol. 97 (1991) 2/3 CIrEVALLEY, J.; MCGAVACK, T. H.; KENIBERG, S.; PEARSON, S.: A four year study of the treatment of
hyperthyroidism with methimazole. J. Clin. Endocrino!. Metab. 14 (1954) 948-960. COOPER, D. S.; GOLDMINZ, D.; LE WIN, A. A.; LADERSON, P. W.; DANIELS, G. H.; MOLntiI, M. E.;
RIDGWAY, E. C.: Agranulocytosis associated with antithyroid drugs: effects of patients age and drug dose. Ann. Intern. Med. 98 (1983) 26-29. COOPER, D. S.: Antithyroid drugs. N. EngI. J. Med. 318 (1984) 1353-1360. DUCORNET, B.; Dupny, J.: Effects secondaires des antithyroidiens de synthese. Ann. Med. Interne. 139 (1988) 410-431. GLINOER, D.; HESCH, D.; LAGASSE, R.; LAUBERG, P.: The management of hyperthyroidism due to
Graves' disease in Europe in 1986. Results of an international survey. Acta Endocrinol. (Copen.) Suppl. 185 (1897). MEYER-GEBNER, M.; BENKER, G.; OLBEICHT, ils.; WINDECK, R.; Cissnwsiu, K.; REINERS, CHR.;
REIS, L. C. E; ROMALDINI, J. H.; BROMBERG, N.: High remission-rate in hyperthyroidism: correla-
tion with "total thyroidal rest therapy." Braz. J. Med. Biol. Res. 10 (1977) 311-318. RETSAGI, G.; KELLY, P. J.; K .JFMAN, W.: Risk of agranulocytosis and aplastic anaemia in relation
to use of antithyroid drugs. International agranulocytosis and aplastic anaemia study. Br. Med. J. 297 (1988) 261-264. ROMALDINI, J. H.; BROMBERG, N.; WERNER, R. S.; TANAKA, L. M.; RODRIGUES, H. E; WERNER,
M. C.; FARÁN, C. S.; REIS, L. C. E: Comparison of effects of high and low dosage regimens of an-
tithyroid drugs in the management of Graves' hyperthyroidism. J. Clin. Endocrino!. Metab. 57 (1983) 563-570. Vrruo, A. C.; GOLDMAN, J. M.: Hepatotoxicity from antithyroid drugs. Hqmone Res. 21 (1985)
229-234.
WERNER, M. C.; ROMALDINI, J. H.; BROMBERG, N.; WERNER, R. S.; FARÁN, C. S.: Adverse effects
related to thionamide drugs and their dose regimen. Am. J. Med. Sci. 297 (1989) 216-219. Author's address: J. H. ROMAJ.Dmn, M. D., Department of Endocrinology, HSPE, IAMSPE, Caixa Postal 8570, 01000 Sao Paulo, Brazil
Downloaded by: University of Connecticut. Copyrighted material.
REINWEIN, D.: Nebenwirkungen der antithyreoidalen Therapie der Hyperthyreose. Eine Untersuchung an 1 256 fortlaufend betreuten Patienten. Dtsch. med. Wschr. 114 (1989) 166-171.
