Agranulocytosis associated with antithyroid drugs. Effects of patient age and drug dose

The records of all patients with antithyroid drug-related agranulocytosis at two Boston hospitals (Group 1, 14 patients), as well as the published case reports of 36 patients with this syndrome (Group 2) were reviewed. The clinical characteristics of these patients were then compared with those of 50 hyperthyroid patients who had taken antithyroid medication without untoward hematologic reactions (Group 3). The mean ages of patients in Group 1 and Group 2 were significantly greater than that of Group 3 (50.6 +/- 16 years versus 35.7 +/- 13.7 years, p less than 0.001; 46.3 +/- 18.7 years versus 35.7 +/-- 13.7 years, p less than 0.02). By chi-square analysis, the relative risk of developing agranulocytosis in patients over age 40 was 6.4 times that among younger patients (p less than 0.001). The mean doses of methimazole in Group 1 and Group 2 were significantly higher than that in Group 3 (43.8 +/- 9.9 mg/d versus 29.5 +/- 10.4 mg/d, p less than 0.001; 40.7 +/- 15.7 mg/d versus 29.5 +/- 10.4 mg/d, p less than 0.02), with and 8.6-fold increased risk of agranulocytosis with doses greater than 40 mg/d (p less than 0.01). In contrast, the mean doses of propylthiouracil did not differ among the three groups. These data suggest that antithyroid drugs should be administered cautiously to patients over age 40. Because no cases of agranulocytosis were seen with methimazole doses less than 30 mg/d, low-dose methimazole therapy may be safer than high-dose therapy or treatment with conventional doses of propylthiouracil.     

Adverse effects related to thionamide drugs and their dose regimen

The authors studied 389 Graves' hyperthyroid patients receiving either high propylthiouracil (PTU) or methimazole (MMI) daily doses or low doses to evaluate whether adverse effects were related to the thionamide drugs or its daily dose regimen. Group 1 patients (n = 286) received high PTU (728 +/- 216 mg/day, n = 92) or MMI (60 +/- 19 mg/day, n = 94) doses, and group 2 patients (n = 103) were treated with low PTU (255 +/- 85 mg/day, n = 39) or MMI (23 +/- 10 mg/day, n = 64) doses. Major adverse effects were observed in 11 (2.8%) patients. Of these, four (1.0%) had agranulocytosis, two (0.5%) were granulocytopenic and five (1.3%) had hepatotoxicity. Agranulocytosis occurred in two patients from each group, 0.7% and 1.9%, respectively from group 1 and group 2. There was no significant difference between the groups or the types of thionamide. There also was no correlation with the patients' age. All of the patients were hyperthyroid, and its onset occurred in the first to third month of treatment. Full recovery was achieved in all cases after drug withdrawal. Four of 5 patients with hepatotoxicity were treated with high PTU doses, and one patient received low MMI doses (p less than .05). All patients were euthyroid. Arthralgias, skin rash and gastric intolerance, the minor adverse effects of thionamides studied, were observed in 52 (13.4%) of the patients. Although no significant differences were found, most of the patients experiencing side effects were from group 1 an received MMI therapy. These adverse effects did not demand drug withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)     

The relation of initial methimazole dose to the incidence of methimazole-induced agranulocytosis in patients with Graves' disease

The relation between the incidence of methimazole (methylmercaptoimidazole; MMI)-induced agranulocytosis and initial MMI dose was evaluated in a group of 514 patients with Graves' disease who were treated between 1995 and 2005. One hundred and forty-six (28.40%) patients had received an initial dose of 30 mg MMI and 277 (53.89%) patients had been treated with 15 mg MMI. Nine patients (1.75%) developed agranulocytosis due to MMI treatment. Six (4.11%) of 146 patients who received an initial dose of 30 mg MMI, two (4.54%) of 44 patients given an initial dose of 20 mg MMI, and one (0.36%) of 277 patients given an initial dose of 15 mg MMI developed agranulocytosis. There was a statistically significant difference in agranulocytosis incidence between patients receiving an initial dose of 30 mg MMI and those who received an initial dose of 15 mg. Although 8 (4.10%) of 195 patients in the high-dose group (20 mg or higher) developed agranulocytosis, only 1 (0.31%) of 319 patients in the low-dose group (15 mg or lower) did. In conclusion, the incidence of agranulocytosis with low-dose MMI therapy was ten times lower than that of the high-dose regimen.     

Thyroid function in breast-fed infants is not affected by methimazole-induced maternal hypothyroidism: results of a retrospective study

For many years, breast-feeding was forbidden if methimazole (MMI) was being used. However, a few studies have demonstrated the relative safety of MMI. The purpose of this study was to evaluate thyroid function of breast-fed infants whose lactating mothers became hypothyroid while taking methimazole. Between 1990 and 2001, 134 thyrotoxic lactating mothers received MMI while breast-feeding. MMI therapy was initiated between 2-8 months postpartum, 10-30 mg for the first month and 5-10 mg from the second until the twelfth month. In 16 mothers, TSH was increased at the end of one month of MMI therapy (Group 1). Infants of 18 mothers whose serum TSH was normal at the end of the first month were included as controls (Group 2). Mothers and their infants were clinically evaluated and serum T4, T3 and TSH were measured before and at 1, 2, 4, 8 and 12 months after MMI therapy. Serum MMI was measured in 8 infants 2 h after breast-feeding. Mean +/- SD of FT4I and FT3I were not statistically different between the two groups of mothers before MMI therapy. In all 34 mothers thyroid indices decreased one month after MMI therapy; FT4I: Group 1 from 19.8 +/- 4.3 to 6.0 +/- 4.8 (p<0.001) and Group 2 from 20.3 +/- 4.7 to 11.4 +/- 4.1 (p<0.001); FT3I: Group 1 from 602 +/- 56 to 146 +/- 52 (p<0.001) and Group 2 from 562 +/- 42 to 186 +/- 39 (p<0.001). The difference in FT4I, FT3I and TSH (20 +/- 18 vs 2.1 +/- 1.1 mU/l, p<0.001) between the 2 groups was significant at the end of the first month of MMI therapy. There was no significant difference in thyroid function of infants of these two groups one month after MMI therapy and all tests remained within the normal range during 12 months of treatment of their lactating mothers. Serum MMI levels were less than 0.03 in 6 and 0.03 and 0.035 microg/ml in the other 2 infants. The results further indicate the safety of MMI therapy in breast-feeding thyrotoxic women.     

Treatment with propylthiouracil is associated with appearance of antineutrophil cytoplasmic antibodies in some patients with Graves' disease.

The use of propylthiouracil (PTU) for the treatment of Graves' disease is associated with few adverse effects such as skin eruptions, liver dysfunction, and agranulocytosis. Furthermore, recent studies described the development of antineutrophil cytoplasmic antibody (ANCA)-related glomerulonephritis and vasculitis in patients treated with PTU. Here we investigated whether PTU therapy per se is associated with the appearance of ANCA in patients with Graves' disease. We analyzed 119 serum samples from 117 patients with Graves' disease treated with either PTU (n = 56), or methimazole (MMI) (n = 21), as well as untreated patients (n = 42). Myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA were tested by enzyme-linked immunosorbent assay (ELISA) kits. MPO-ANCA was negative in all patients treated with MMI therapy and untreated patients. However, MPO-ANCA was detected in 21 (37.5%) of 56 patients treated with PTU therapy. Furthermore, two patients who were negative for MPO-ANCA became positive after PTU therapy. The proportion of patients positive for MPO-ANCA increased with the prolongation of PTU therapy, but did not correlate with age, gender, and positive antithyroperoxidase (TPO) antibody. Among 21 MPO-ANCA positive patients, 12 had no symptoms, but 9 patients complained of myalgia, arthralgia, or common cold like symptoms after the appearance of MPO-ANCA. Three patients developed agranulocytosis or granulocytopenia, but none showed abnormal urinary findings. Our results suggest that PTU per se is associated with the production of MPO-ANCA in patients with Graves' disease.     

Benefit of short‐term iodide supplementation to antithyroid drug treatment of thyrotoxicosis due to Graves’ disease

Objective Combined treatment with anti‐thyroid drugs (ATDs) and potassium iodide (KI) has been used only for severe thyrotoxicosis or as a pretreatment before urgent thyroidectomy in patients with Graves’ disease. We compared methimazole (MMI) treatment with MMI + KI treatment in terms of rapid normalization of thyroid hormones during the early phase and examined the later induction of disease remission. Design and patients A total of 134 untreated patients with Graves’ disease were randomly assigned to one of four regimens: Group 1, MMI 30 mg; Group 2, MMI 30 mg + KI; Group 3, MMI 15 mg and Group 4, MMI 15 mg + KI. For easy handling, KI tablets were used instead of saturated solution of KI. KI was discontinued when patients showed normal free thyroxine (FT4) levels but MMI was continued with a tapering dosage until remission. Remission rate was examined during a 4‐ to 5‐year observation. Measurements Serum FT4, FT3 and TSH were measured by chemiluminescent immunoassays. TSH receptor antibody (TRAb) was assayed with TRAb‐ELISA. Goitre size was estimated by ultrasonography. Results After 2 weeks of treatment, normal FT4 was observed in 29% of patients in Group 1 and 59% (P < 0·05) of patients in Group 2. Furthermore, normal FT4 after 2 weeks of treatment was observed in 27% of patients in Group 3 and 54% (P < 0·05) of patients in Group 4. Similarly, FT3 normalized more rapidly in Groups 2 and 4 than in Groups 1 and 3. None of the patients showed an increase in thyroid hormones or aggravation of disease during combined treatment with MMI and KI. The remission rates in Groups 1, 2, 3 and 4 were 34%, 44%, 33% and 51%, respectively, and were higher in the groups receiving combined therapy but differences among four groups did not reach significance. Conclusions Combined treatment with MMI and KI improved the short‐term control of Graves’ hyperthyroidism and was not associated with worsening hyperthyroidism or induction of thionamide resistance.     

MATERNAL HYPERTHYROIDISM AND CONGENITAL MALFORMATION IN THE OFFSPRING

Six hundred and forty-three neonates from mothers with Graves' disease were examined for major malformations of external organs to compare the influence of maternal hyperthyroidism vs. ingestion of methimazole (MMI) during the first trimester on the incidence of congenital malformations. The subjects were divided into four groups according to maternal therapy and thyroid status during the first trimester as follows: (1) infants whose mothers did not receive MMI and were hyperthyroid (Group 1), (2) infants whose mothers did not receive MMI and were euthyroid (Group 2), (3) infants whose mothers received MMI and were hyperthyroid (Group 3) and (4) infants whose mothers received MMI and were euthyroid (Group 4). The prevalence of malformed infants in these four groups was 6.0% (three of 50), 0.3% (one of 350), 1.7% (two of 117) and 0.0% (none of 126), respectively. The incidence in Group 1 was significantly higher than that in Group 2 (P less than 0.01). There was no discernible dose dependency of MMI on the occurrence of malformations. These findings suggest that maternal uncontrolled hyperthyroidism may cause congenital malformations and that the beneficial role of MMI treatment outweighs its teratogenic effect, if any.     

In vitro immunoreactivity to propylthiouracil, methimazole, and carbimazole in patients with Graves' disease: a possible cause of antithyroid drug-induced agranulocytosis

Studies of in vitro immunoreactivity to propylthiouracil (PTU), methimazole (MMI), and carbimazole (CARB), as assessed by peripheral blood lymphocyte transformation and 2 antibody tests, were carried out in 12 patients with Graves' hyperthyroidism who had developed agranulocytosis during treatment with PTU (11 patients) or CARB (1 patient) from 1 week to 10 yr earlier. Significant lymphocyte transformation responses to antithyroid drugs (stimulation indices greater than mean +/- 2 SD for normal subjects) were found in 5 of 6 patients tested, in 1 patient to PTU only, in 3 patients to MMI only, and in 1 patient to both PTU and MMI, but in none of 10 patients currently being treated with PTU who did not develop agranulocytosis. Circulating antibodies causing neutrophil agglutination in the presence of antithyroid drugs were demonstrated, using the indirect Coombs test, in 5 of 7 patients tested, in 2 patients to PTU only, in 3 patients to CARB only and in 1 patient (the only one tested with MMI) to PTU and MMI. Lymphocyte transformation and antibody tests to PTU were both carried out in 6 patients. Of these, both tests were positive in one patient, both negative in 3 patients, and 1 negative and 1 positive in 2 patients. In the 1 patient in whom both tests were carried out with CARB (patient 3), tests were negative, whereas in the 1 patient in whom both tests were carried out with MMI (patient 3), 1 test was positive, whereas the other was negative. Thus, in patients in whom both tests were carried out using the same drug, correlation between lymphocyte transformation responses and the detection of neutrophil antibodies was found in 5 of 6 cases. Antibodies reactive with neutrophils were also detected in 2 of the 5 patients tested using an enzyme-linked immunosorbent assay. In this test antibodies to PTU or MMI were not demonstrated. Possible mechanisms for the neutrophil depression in relation to these findings are discussed. It is concluded that patients with Graves' disease may be prone to develop this complication of antithyroid drug therapy because of underlying immunological abnormalities.     

Cost-effectiveness of the clinical treatment of Grave's disease in a public University Hospital: a retrospective analysis and prospective projection for a therapeutic approach

The aim of the present study was to evaluate a new proposal for increasing compliance to the clinical management of patients with Graves' disease (GD) in a large and public University Hospital. The patients were carefully selected (no previous GD treatment, goiter volume less than 6 mL must be living in the metro area of S?o Paulo), received medication at no cost, were contacted frequently by the social worker and alerted for the date of consultation and only referred to a single endocrinologist during all phases of treatment. We recruited 229 patients with GD that were initially treated with methimazole (MMI--60 mg q.d) in a single daily dose followed by a combination of MMI (20 mg) plus L-T4 (100 microg) daily for 24 months. Only 83 patients (36.2%) completed the protocol and were subdivided in: Group 1 (n= 34) that were in remission for 3 years after discontinuation of the MMI and Group 2 (n= 49) that presented recurrence of GD between 2 and 36 months without MMI. Predictive factors associated with remission were: decrease of the glandular volume, serum TG< 40 ng/mL and normal TRAb values. We concluded that in spite of a careful protocol planned to increase compliance, more than 60% of patients with GD did not complete the therapeutic trial and were referred for radioiodine treatment. The solution for this low therapeutic success for GD should be the possible identification of factors that would indicate patients that are not inclined to follow a long period of clinical therapy.     

Deferiprone‐induced agranulocytosis: 20 years of clinical observations

Use of the iron chelator deferiprone for treatment of iron overload in thalassemia patients is associated with concerns over agranulocytosis, which requires weekly absolute neutrophil counts (ANC). Here, we analyze all episodes of agranulocytosis (n = 161) and neutropenia (n = 250) during deferiprone use in clinical trials (CT) and postmarketing surveillance programs (PMSP). Rates of agranulocytosis and neutropenia in CT were 1.5% and 5.5%, respectively. Of the agranulocytosis cases, 61% occurred during the first 6 months of therapy and 78% during the first year. These events appeared to be independent of dose, and occurred three times more often in females than males. Their duration was not significantly shortened by use of G‐CSF. No patient with baseline neutropenia (n = 12) developed agranulocytosis during treatment, which raises questions about the validity of prior neutropenia as a contraindication to use. Only 1/7 novel neutropenia cases in CT progressed to agranulocytosis with continued treatment, indicating that neutropenia does not necessarily lead to agranulocytosis. The agranulocytosis fatality rate was 0% in CT and 15/143 (11%) in PMSP. Rechallenge with deferiprone produced agranulocytosis in 75% of patients in whom the event had already occurred, and in 10% with previous neutropenia. Weekly ANC monitoring allows early detection and interruption of therapy, but does not prevent agranulocytosis from occurring. Its relevance appears to decrease after the first year of therapy, when agranulocytosis occurs less often. Based upon analysis of data collected over the past 20 years, it appears that patient education may be the key to minimizing agranulocytosis‐associated risks during deferiprone therapy. Am. J. Hematol. 91:1026–1031, 2016. © 2016 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.     

The course of Graves' ophthalmopathy is not influenced by near total thyroidectomy: a case-control study

OBJECTIVE: The relationship between the method of treatment of hyperthyroidism due to Graves' disease and the course of Graves' ophthalmopathy is debated. Antithyroid drug therapy is associated with no change, or even amelioration, of ophthalmopathy. Although controversial, radioiodine may be followed by progression of eye disease, preventable by glucocorticoid administration. Whether thyroidectomy affects the course of ophthalmopathy is uncertain. DESIGN: In a case control study, the course of non-severe Graves' ophthalmopathy after thyroidectomy was investigated and the results compared with those observed in patients treated with methimazole. PATIENTS: Thirty patients with Graves' hyperthyroidism and non-severe/absent ophthalmopathy were treated with near-total thyroidectomy (Group 1, Tx), after achievement of euthyroidism with methimazole. After surgery, all patients started levothyroxine replacement therapy. Sixty patients treated with methimazole, matched for age, sex, duration of hyperthyroidism, degree of ocular involvement and smoking habits, were used as controls (Group 2, MMI). MEASUREMENTS: Patients were seen every 1-2 months for 12 months for thyroid tests and ocular evaluation. RESULTS: In Group 1, ocular parameters did not change in 17 of 18 patients with pre-existing ophthalmopathy, and in 12 patients without ophthalmopathy. Eye manifestations worsened only in one (3.3%) patient with pre-existing ophthalmopathy. In Group 2, ocular parameters did not change in 58 patients (33 with, and 25 without ophthalmopathy), while new ophthalmopathy occurred in two without pre-existing eye disease. One of the 30 patients treated by surgery (3.3%) had permanent hypoparathyroidism. CONCLUSIONS: Treatment of Graves' hyperthyroidism with near-total thyroidectomy in patients with non-severe or absent pre-existing ophthalmopathy is not associated in the short term with significant effects on the course of ophthalmopathy.     

Change in serum G-CSF levels in patients with Graves' disease by treatment with methimazole]

We evaluated the determination of serum G-CSF in the diagnosis of granulocytopenia due to methimazole (MMI) in 54 patients with Graves' disease, while they were being treated with MMI, by way of measuring WBC counts and serum levels of G-CSF, thyroid hormones, IgE, and interleukin-2. Serum TSH was measured by immunoradiometric assay, serum G-CSF was done by enzyme immunoassay, thyroid hormones and IgE were done by radioimmunoassay, and serum Interleukin-2 was done by enzyme-linked immunosorbent assay. The population whose G-CSF levels were higher than the minimum detectable level (30pg/ml) was 6 (30%) in normal subjects, 4 (22%) in patients with untreated Graves' disease, 2 (12%) in patients with treated euthyroid Graves' disease, 3 (23%) in patients with Graves' disease who had gone through agranulocytosis, and 2 (33%) in patients with Graves' disease complicated with granulocytopenia. There was no significant change in WBC counts for 4 weeks, but there was a significant difference between WBC counts before treatment and those at 8 weeks after treatment. We observed no significant change of serum G-CSF levels in patients with Graves' disease under treatment. However, there were significantly high levels of serum G-CSF and significantly low counts of WBC in patients with Graves' disease complicated with granulocytopenia induced by MMI, compared with those in normal subjects, patients with untreated Graves' disease, patients with treated euthyroid Graves' disease, and patients with euthyroid Graves' disease who had gone through agranulocytosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum concentrations of granulocyte colony-stimulating factor (G-CSF) in antithyroid drug-induced agranulocytosis

Granulocyte colony-stimulating factor (G-CSF) levels in serum were determined by a highly-sensitive chemiluminescent enzyme immunoassay (limit of detection, 0.5 pg/ml) in 54 patients with Graves' disease including 6 patients complicated with methimazole-induced agranulocytosis. Serum G-CSF levels in patients with Graves' disease were not different from normal subjects and did not correlate with serum FT4 level or circulating neutrophil counts. Before the onset of agranulocytosis, there was no difference in serum G-CSF level between the patients complicated with agranulocytosis and the uncomplicated patients. When circulating neutrophil counts decreased to less than 0.5 x 10(9)/L, serum G-CSF level elevated with the mean of 106.8 +/- 82.2 (SD) pg/ml, but the level did not correlate with the duration of agranulocytosis. Interestingly, maximum serum G-CSF level during the treatment with recombinant human G-CSF (100 microg/day) was related to bone marrow finding at the onset of agranulocytosis and correlated with the duration of agranulocytosis (r = 0.824, p < 0.05). In conclusion, measuring serum G-CSF levels with a highly-sensitive chemiluminescent enzyme immunoassay revealed that 1) thyrotoxicosis does not affect serum G-CSF level, 2) serum G-CSF level during antithyroid drug treatment does not play an important role in development of agranulocytosis, 3) the maximum serum G-CSF level in the course of agranulocytosis is related to the responsiveness of bone marrow to G-CSF and the recovery time from agranulocytosis.     

Treatment with lithium prevents serum thyroid hormone increase after thionamide withdrawal and radioiodine therapy in patients with Graves' disease

Serum thyroid hormone concentrations increase after radioiodine (RAI) therapy for Graves' disease. This phenomenon has been ascribed to either antithyroid drug withdrawal before RAI therapy or release of preformed thyroid hormones into the bloodstream from the RAI-damaged thyroid. Lithium blocks the release of iodine and thyroid hormones from the thyroid, thus enhancing the effectiveness of RAI therapy. Changes in serum-free thyroxine (FT4) and triiodothyronine (FT3) levels after methimazole (MMI) discontinuation and RAI therapy were evaluated in a prospective, randomized, control study of 36 patients with Graves' disease. After a 3- to 4-month course of MMI, patients were assigned to one of three groups: G1 (RAI alone); G2 (RAI plus lithium for 6 d starting on the day of RAI therapy); or G3 (RAI plus lithium for 19 d starting on the day of MMI withdrawal). G1-G2 patients had an increase in serum FT4 and FT3 levels from 13.5 +/- 6.5 to 19.8 +/- 9.2 pmol/liter and 5.0 +/- 2.0 to 8.0 +/- 4.8 pmol/liter, respectively (P < 0.0001), 2-5 d after MMI withdrawal, but G3 patients showed no changes. In the 30 d after RAI therapy, mean serum FT4 values increased in G1 patients (P = 0.02), peaking at 3-7 d (P < 0.05) but not in G2 and G3 patients. Serum FT3 levels decreased in G1, G2, and G3 (P = 0.03, P = 0.001, P = 0.02, respectively). Hyperthyroidism was cured in 8 of 12 G1 patients, 11 of 12 G2 patients, and 11 of 12 G3 patients (P = 0.31). Control of hyperthyroidism was prompter in G2 (P = 0.08) and G3 (P < 0.05) than in G1 patients. Patients in the three groups received a similar dose of RAI, but the committed radiation to the thyroid was higher in G3 (563 +/- 174 Gray) and G2 (588 +/- 347 Gray) than in G1 (429 +/- 204 Gray) (P < 0.03). In conclusion, the results of the present study demonstrate that: 1) MMI withdrawal is associated with a slight rise in serum thyroid hormone levels; 2) a further increase occurs after RAI therapy; 3) changes in serum thyroid hormone concentrations are prevented by lithium; and 4) the increased effectiveness of RAI therapy in lithium-treated patients is related to the increased RAI retention in the thyroid gland. Accordingly, a short course of lithium therapy can be considered a useful adjunct to RAI therapy to obtain a prompter control of thyrotoxicosis and avoid its transient exacerbation because of MMI withdrawal and RAI administration.     

Myocardial infarction and normal coronary arteriography: a 10 year clinical and risk analysis of 74 patients

Myocardial infarction with normal coronary arteries was identified in 74 patients with a mean age of 43 years (range 19 to 66). A mean follow-up period of 10.5 years after documented myocardial infarction and 8.6 years after cardiac catheterization was obtained. The survival rate was 85% (n = 63). There were no statistical differences in age or clinical risk factor prevalence between survivors and nonsurvivors. Moderate (55%) to severe (27%) left ventricular impairment was more common in nonsurvivors. Nine of 11 deaths were cardiovascular, 6 were sudden and 8 occurred in patients with moderate to severe global left ventricular impairment. Seventy-six percent of survivors were asymptomatic and 86% were fully active at follow-up. Two survivors and three nonsurvivors experienced a second myocardial infarction. The clinical risk factors of the study group (Group I) were compared by age, sex and year of catheterization with risk factors in two matched groups. Group II consisted of 74 patients with coronary occlusive disease and myocardial infarction and Group III consisted of 148 patients with normal arteriograms. Group I differed from Group II in having fewer clinical risk factors (p = 0.01 to less than 0.0001). Cigarette smoking did not differ significantly between Group I (72%) and Group II (69%) but was less common in Group III (45%) (p less than 0.001). Hormone therapy or the peripartum state was more common in women in Group I (34%) than in women in Group III (14%) (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of long-term continuous methimazole treatment of hyperthyroidism: comparison with radioiodine

OBJECTIVE: To investigate the long-term effects of continuous methimazole (MMI) therapy. DESIGN AND METHODS: Five hundred and four patients over 40 years of age with diffuse toxic goiter were treated with MMI for 18 months. Within one year after discontinuation of MMI, hyperthyroidism recurred in 104 patients. They were randomized into 2 groups for continuous antithyroid and radioiodine treatment. Numbers of occurrences of thyroid dysfunction and total costs of management were assessed during 10 years of follow-up. At the end of the study, 26 patients were still on continuous MMI (group 1), and of 41 radioiodine-treated patients (group 2), 16 were euthyroid and 25 became hypothyroid. Serum thyroid and lipid profiles, bone mineral density, and echocardiography data were obtained. RESULTS: There was no significant difference in age, sex, duration of symptoms and thyroid function between the two groups. No serious complications occurred in any of the patients. The cost of treatment was lower in group 1 than in group 2. At the end of 10 years, goiter rate was greater and antithyroperoxidase antibody concentration was higher in group 1 than in group 2. Serum cholesterol and low density lipoprotein-cholesterol concentrations were increased in group 2 as compared with group 1; relative risks were 1.8 (1.12-2.95, P<0.02) and 1.6 (1.09-2.34, P<0.02) respectively. Bone mineral density and echocardiographic measurements were not different between the two groups. CONCLUSION: Long-term continuous treatment of hyperthyroidism with MMI is safe. The complications and the expense of the treatment do not exceed those of radioactive iodine therapy.     

Thyroid function and intellectual development of infants nursed by mothers taking methimazole

For many years, breast-feeding was forbidden if antithyroid drugs were being used. Recently, limited studies have shown the relative safety of propylthiouracil and methimazole (MMI). It is not known whether MMI therapy of lactating mothers for 1 yr is safe for breast-fed infants and does not cause alterations in thyroid function and intellectual development. Between 1988 and 1998, 139 thyrotoxic lactating mothers and their infants were studied. Fifty-one thyrotoxic lactating mothers were treated with MMI during pregnancy, and MMI was continued during breast-feeding. Eighty-eight mothers were given 10 mg MMI (n 46) or 20 mg MMI (n = 42) daily for 1 month, 10 mg daily for the second month, and 5-10 mg daily thereafter. Serum T4, T3, and TSH concentrations were measured in thyrotoxic lactating mothers and their infants, before and at 1, 2, 4, 8, and 12 months. Serum MMI was measured in the infants of thyrotoxic lactating mothers taking 20 mg MMI. Thyroid function, urinary iodine, thyroid antibodies, intelligence quotient (IQ), verbal and functional components (Wechsler and Goodenough tests) were performed on 14 children of thyrotoxic lactating mothers between 48 and 74 months of age and on 17 controls. Mean +/- SD of FT4I in thyrotoxic lactating mothers treated with 10 mg MMI for 1 month decreased from 19.4 +/- 4.1 to 11.6 +/- 4.4 and from 20.5 +/- 4.7 to 9.8 +/- 1.5 when treated with 20 mg MMI. Values for FT3I decreased from 462 +/- 52 to 194 +/- 52 with 10 mg MMI and from 481 +/- 92 to 171 +/- 38 with 20 mg MMI. FT4I and FT3I were normal from the third to the twelfth months. In all infants FT4I, FT3I, and TSH concentrations were normal before and up to 12 months of MMI therapy in their lactating mothers. The lowest T4 and T3 values were 108 and 1.87 nmol/L, and the highest TSH value was 4.0 mU/L. Serum MMI levels in infants were less than 0.03 microg/mL. Six mothers receiving 20 mg MMI had increased serum TSH concentrations ranging from 26-135 mU/L after 1 month of treatment. Their infants were euthyroid with serum TSH values less than 2.6 mU/L. At 48-74 months of age, height, weight, FT4I, FT3I, TSH, and antithyroid antibody titers were not different than controls. The mean IQ was 107 +/- 14 vs. 106 +/- 16 (Goodenough test) and 103 +/- 10 vs. 103 +/- 16 (Wechsler test) for infants of thyrotoxic lactating mothers and control infants, respectively. Similarly, there was no difference in verbal and performance IQ and their components between infants of thyrotoxic lactating mothers and control children. No deleterious effects occur in thyroid function and physical and intellectual development of breast-fed infants whose lactating mothers were treated with doses of MMI up to 20 mg daily.     

Comparison of effects of high and low dosage regimens of antithyroid drugs in the management of Graves' hyperthyroidism

We compared the effects of high and low dosages of antithyroid drugs in 113 patients with Graves' hyperthyroidism. The patients were randomly divided into 2 groups. In group A, 65 patients received either methimazole (MMI): 60 +/- 14.5 mg/day (mean +/- SD); range 40-100 mg/day, or propylthiouracil (PTU): 693 +/- 173 mg/day; range 500-1200 mg/day. These high doses were maintained throughout treatment with later addition of 50-75 micrograms T3 daily. Forty eight patients (group B) were treated with lower doses of MMI or PTU without thyroid hormone addition. The maintenance dose of MMI was 13.6 +/- 7 mg/day (range 5-25 mg/day) and that of PTU was 180 +/- 58 mg/day (range 100-300 mg/day). The treatment period was 15.1 +/- 4.2 (range 10-30) months for group A and 13.5 +/- 2.2 (range 12-20) months for group B. Remission occurred in 75.4% patients from group A and in 41.6% patients from group B (P less than 0.001). The mean follow-up was 42 +/- 14 months (17-81 months). The free T4 index (FT4I) in group A remained below the normal range during treatment. The mean FT4I, obtained during the course of treatment, of patients who went into remission from group A was significantly (P less than 0.001) lower than in relapsed patients (4.8 vs. 6.5). Moreover, there was an inverse correlation between mean FT4I and maintenance daily dose of either MMI (r = -0.567; P less than 0.001), or PTU (r = -0.379; P less than 0.01). A fall in microsomal antibody (MCHA) titer occurred mainly in remission patients, and was more significant (P less than 0.05) in group A patients. In contrast, 11 (7 from group B) of the 16 patients with an increase of microsomal antibody levels relapsed. The frequency of negative tests of thyroid-stimulating antibody was higher in group A patients (71%) than in group B (29%) at the end of therapy (P less than 0.01). No correlation was found between thyroid T3 suppressibility and either mean FT4I or thyroid-stimulatory antibody activity during treatment. Our findings show that patients treated with high doses of PTU or MMI throughout treatment have a higher remission rate when compared to those treated with a more conventional regimen. These results support the hypothesis that large antithyroid drug doses may have greater immunosuppressive effects than low dosage regimens. Furthermore, a high dosage regimen could permit the restoration of the immune surveillance mechanisms and, thus, lasting remission of Graves' disease.     

Safety profile of the oral iron chelator deferiprone: a multicentre study

In previous trials, the orally active iron chelator deferiprone (L1) has been associated with sporadic agranulocytosis, milder forms of neutropenia and other side-effects. To determine the incidence of these events, we performed a multicentre prospective study of the chelator. Blood counts were performed weekly, and confirmed neutropenia mandated discontinuation of therapy. Among 187 patients with thalassaemia major, the incidence of agranulocytosis (neutrophils < 0.5 x 109/l) was 0.6/100 patient-years, and the incidence of milder forms of neutropenia (neutrophils 0.5-1.5 x 109/l) was 5.4/100 patient-years. All cases of neutropenia resolved after interruption of therapy. Neutropenia occurred predominantly in non-splenectomized patients. Nausea and/or vomiting occurred early in therapy, was usually transient and caused discontinuation of deferiprone in three patients. Mild to moderate joint pain and/or swelling did not require permanent cessation of deferiprone and occurred more commonly in patients with higher ferritin levels. Mean alanine transaminase (ALT) levels rose during therapy. Increased ALT levels were generally transient and occurred more commonly in patients with hepatitis C. Persistent changes in immunological studies were infrequent, although sporadic abnormalities occurred commonly. Mean zinc levels decreased during therapy. Ferritin levels did not change in the overall group but decreased in those patients with baseline levels > 2500 microgram/l. This study characterized the safety profile of deferiprone, and, under the specific conditions of monitoring, demonstrated that agranulocytosis is less common than previously predicted.     

Quinidine syncope in children

Quinidine syncope and factors associated with it are well known among adult patients treated for cardiac arrhythmias. To define factors that may influence the occurrence of syncope in children taking quinidine, the clinical, anatomic, electrocardiographic, roentgenographic and pharmacologic data were compared in six patients with syncope (Group A) and 22 patients without syncope (Group B). There was a significant (chi-square = 10.2, p = 0.001) relation between heart disease and quinidine syncope: all six Group A (syncopal) patients had heart disease whereas 15 of the 22 Group B (non-syncopal) patients had no structural heart disease. In contrast, no significant difference was noted between Group A and Group B patients in mean age (11.4 versus 11.4 years), mean quinidine serum concentration (2.9 versus 2.3 micrograms/ml), mean corrected QT interval before quinidine (0.43 versus 0.40 second) or mean corrected QT interval during quinidine therapy (0.46 versus 0.46 second) or between those taking digitalis and those not. Two of the six Group A (syncopal) patients died during therapy, one 6 days after initiating therapy and one suddenly at home 6 months after beginning quinidine. Another two of the six Group A patients exhibited hypokalemia (both 2.9 mEq/liter) at the time of syncope, 2 weeks and 6 months, respectively, after initiation of quinidine therapy; both survived. Syncope occurred within 8 days of initiation of quinidine therapy in three of the six patients. Sustained ventricular tachycardia was observed during quinidine associated arrhythmia in three of six patients with syncope; nonsustained ventricular tachycardia or complex ventricular ectopic activity while on this therapy was observed before syncope in the other three patients in Group A.(ABSTRACT TRUNCATED AT 250 WORDS)