Serum thyrotropin receptor antibodies concentrations in patients with Graves' disease before, at the end of methimazole treatment, and after drug withdrawal: evidence that the activity of thyrotropin receptor antibody and/or thyroid response modify during the observation period.

AIM AND METHODS: We performed a quantitative retrospective analysis of serum thyrotropin receptor antibody (TRAb) concentrations measured by a second-generation radioreceptor assay in 58 patients with Graves' disease (GD) at the onset of the disease, at the end of 18 month methimazole (MMI) treatment, and after MMI withdrawal in order to evaluate the correlation between the presence of these antibodies and the relapse of hyperthyroidism. Sixty healthy subjects were enrolled as a control group. RESULTS: Before MMI treatment the best cutoff TRAb value for identifying patients with GD was 1.45 UI/L (specificity, 100%; sensitivity, 98.3%). At the end of MMI treatment, serum TRAb concentrations were significantly lower (p < 0.001) than those measured at baseline, but they were still significantly higher (p < 0.001) than those found in the control subjects. At the end of MMI treatment, 44 patients (75.9%) had positive TRAb values (>1.45 UI/L). After MMI withdrawal (median, 15 months), 34 patients (58.6%) became hyperthyroid, 4 patients (6.9%) became hypothyroid, and 20 patients (34.5%) remained euthyroid. There was a significant correlation between serum TRAb concentrations at the end of MMI treatment and the percentage of patients who became hyperthyroid (r: 0.56; p < 0.001) and the time of appearance of hyperthyroidism (r: -0.38; p = 0.03). All 4 patients with TRAb values below 0.9 UI/L at the end of MMI treatment remained euthyroid throughout the follow-up period. Among the 27 patients who had serum TRAb values higher than 4.4 UI/L, 23 developed hyperthyroidism and 4 hypothyroidism. The TRAb values between 0.9 and 4.4 UI/L did not discriminate between the 27 patients (46.6%) who remained euthyroid from those who had relapse of hyperthyroidism. Thus a different TRAb end of treatment cutoff was calculated to identify patients who became again hyperthyroid. This TRAb cutoff value was 3.85 UI/L (sensitivity, 85.3%; specificity, 96.5%). All but 1 patient who had serum TRAb values above 3.85 UI/L became hyperthyroid after MMI was withdrawn (positive predictive value, 96.7%). In these patients, relapse of hyperthyroidism was independent of the changes in serum TRAb concentrations (r: 0.27; p = 0.15) and occurred after a median period of 8 weeks (range, 4-48). Hyperthyroidism also developed in 5 of 24 patients who had serum TRAb concentrations lower than 3.85 UI/L at the end of MMI treatment. In these 5 patients the relapse of hyperthyroidism occurred after a median period of 56 weeks (range, 24-120) and was always accompanied by an increase in serum TRAb concentrations. CONCLUSIONS: TRAb persist in the blood of most patients with GD after 18 months of MMI treatment. Both the frequency and the time of appearance of hyperthyroidism are closely correlated with serum TRAb concentrations at the end of MMI treatment. Our data would suggest that TRAb maintain stimulating activity after a full course of MMI treatment in the large majority of patients with GD. However, it is likely that the potency of these antibodies and/or the thyroid response to them change during treatment, as suggested by the different values measured in euthyroid control subjects and in euthyroid patients after MMI treatment.     

Thyroid function in breast-fed infants whose mothers take high doses of methimazole

Recently, a few studies have shown the safety of methimazole (MMI) therapy of thyrotoxic lactating mothers on thyroid function of their infants. However, it is not known whether the effect of moderately high doses of MMI therapy on lactating mothers can be dangerous for breast-fed infants. Eighty-eight thyrotoxic lactating mothers and their infants were studied. 46 received 20 mg MMI and 42 were given 30 mg MMI during the first month, 10 mg for the second and 5-10 mg for additional 10 months of therapy. Serum T4, T3 and TSH concentrations and in hyperthyroid MMI treated mothers and their RT3U were measured in hyperthyroid MMI treated mothers and their infants, before and at 1, 2, 6, and 12 months after initiation of therapy. Serum MMI was measured in the infants of thyrotoxic mothers taking 20-30 mg MMI. Mean+/-SD of free T4 index (FT4I) in thyrotoxic mothers treated with 20 and 30 mg MMI for one month decreased from 20.1+/-4.2 to 9.7+/-1.5 (p<0.001) and from 20.6+/-4.8 to 8.6+/-3.0 (p<0.001), respectively. Values for free T3 index (FT3I) decreased from 587+/-53 to 180+/-39 (p<0.001) and from 610+/-49 to 151+/-31 (p<0.001) in those treated with 20 and 30 mg MMI, respectively. By the end of one month 5 had elevated FT4I or FT3I or both and 12 had elevated TSH. The dose of MMI was adjusted and thyroid function remained normal up to 12 months of MMI therapy in thyrotoxic lactating mothers. Serum T4, T3 and TSH concentrations of breast-fed infants were normal before and up to 12 months of MMI therapy of their breast-feeding mothers. The lowest T4 and T3 and the highest TSH values were 101 nmol/l, 1.8 nmol/l and 4.1 mU/l, respectively. Serum MMI levels were <0.03 in 7 and 0.03, 0.034 and 0.035 microg/ml in the other 3 infants. We conclude that the treatment of hyperthyroid lactating mothers with doses of 20-30 mg MMI day does not cause deleterious effects on thyroid function of their breast-fed infants.     

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.     

125I therapy in Graves' disease. Long-term results in 355 patients.

Because of the physical and radiobiologic differences between 125I and 131I, a trial using 125I to treat hyperthyroidism was undertaken in the hope of controlling hyperthyroidism without causing subsequent hypothyroidism. Three hundred fifty-five patients with diffuse toxic goitres were treated and have been under review for an average of 49.4 months: 63.4% are euthyroid, 33.5% are hypothyroid, and 3.1% remain hyperthyroid. Different groups of patients received a wide range of doses of 125I (4.0 to 56.0 mCi), and the lowest incidence of hypothyroidism (23%) was in the group that received between 6.0 and 10.5 mCi. Sixty-three percent of the patients whose initial dose was greater than 20.0 mCi are hypothyroid. Persistent hyperthyroidism was common in patients who received small doses. Because of the high incidence of posttreatment hypothyroidism in this series and because 131I has stood the test of time, we believe that 131I is the radionuclide of choice for the routine treatment of hyperthyroidism.     

Pregnancy-associated changes in the thyroid-stimulating antibody of Graves' disease and the relationship to neonatal hyperthyroidism

Assays for the thyroid-stimulating antibody (TSAb) of Graves' disease were performed with serum obtained from 17 women with 20 pregnancies who either had or had had Graves' disease, or who had delivered a child with neonatal hyperthyroidism. Ten of the children, of eight women, were diagnosed as being hyperthyroid; all eight mothers had high concentrations of TSAb, as measured by adenylate cyclase stimulation. In the infants with neonatal hyperthyroidism, a minimum 500% increase in cAMP was found on assay of maternal immunoglobulin G, and no such high values were associated with a euthyroid infant. Blood samples for TSAb assay were available from 11 mothers on both the day of delivery and at least 1 other time in the pre- or postpartum period. In 7 mothers, the lowest value (negative in 4) was obtained coincident with delivery, and in the remaining 4, there was no pregnancy-associated change. Thus, a pattern, related to pregnancy, of a decline in TSAb concentration or a subsequent postpartum increase was observed in the majority of subjects. Apparently, neonatal hyperthyroidism due to transplacental passage of TSAb occurred only when this decline did not reduce the concentration to a low value.     

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)     

Serum thyroid-stimulating antibody, thyroglobulin levels, and thyroid suppressibility measurement as predictors of the outcome of combined methimazole and triiodothyronine therapy in Graves' disease.

The value of the criteria used to anticipate the outcome of treatment of Graves' hyperthyroid patients with methimazole (MMI) remains controversial. We have reported that high MMI doses combined with T3 administration was correlated with higher remission rates. In this study, we used the lowest MMI dose able to control the hyperthyroidism, keeping the free T4 index (FT4I) values below the normal range throughout treatment, and compared the results with patients treated with a high MMI regimen. Both groups received T3. We also evaluated the usefulness of goiter size, serum thyroid-stimulating antibody (TSAb: adenylate cyclase stimulation in human thyroid membrane), thyroglobulin (Tg) levels, and the T3 suppressibility of 24 h RAIU as prognostic markers for the outcome of Graves' disease therapy. Twenty-four Graves' hyperthyroid patients were treated with high MMI dose (mean +/- SD 60 +/- 19, range 40-120 mg daily), and 25 patients received low MMI dose (17 +/- 4.3, 5-20 mg daily). T3, 75 micrograms daily, was given to both groups of patients for 15 +/- 4 (13-22) months of treatment. After cessation of drug therapy, 31 patients (63%) remained euthyroid for 18 +/- 3 (13-49) months of follow-up, 15 (62.5%) and 16 (64%) patients in the high and low dose groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucagon binding autoantibodies in a patient with hyperthyroidism treated with methimazole

A 47-yr-old woman who had previously received methimazole (MMI) treatment for hyperthyroidism was found to have glucagon binding autoantibodies in plasma. She had never received glucagon. The binding substances were detected in plasma at the time of a glucagon RIA. [125I]Glucagon binding was inhibited only by porcine glucagon and porcine glicentin, and dissociated at acid pH. The substances proved to be glucagon binding antibodies (immunoglobulin G, L-chain K-type), as determined by ammonium sulfate and radioprecipitation. There were no clinical manifestations related the presence of these autoantibodies. In a survey of 91 patients with thyroid disease, 3 patients whose plasma bound [125I]glucagon were identified among 41 with hyperthyroidism who were receiving MMI treatment. Such binding was not found in plasma from untreated hyperthyroid patients, those receiving propylthiouracil or those with chronic thyroiditis. These findings suggest that the development of glucagon antibodies in hyperthyroidism may be associated with MMI treatment.     

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.     

Effect of maternal hyperthyroidism during late pregnancy on the risk of neonatal low birth weight

OBJECTIVE: Hyperthyroidism in pregnancy occurs with a prevalence of 0.05--0.2% and has been shown to affect neonatal outcomes. Fetal weight increases markedly during the third trimester of pregnancy. This retrospective study was performed to examine the effect of maternal hyperthyroidism during late pregnancy on neonatal birth weight (NBW). DESIGN: Medical and obstetric records of 293 pregnant women with present and past history of hyperthyroidism were retrospectively reviewed. PATIENTS: There were 188 records of 181 patients with adequate data for inclusion in the analysis. The patients were divided into two groups according to the maternal thyroid function during the third trimester of pregnancy: hyperthyroidism (HT; 35 cases) and euthyroidism (ET; 153 cases). MEASUREMENTS: Maternal thyroid function tests were periodically evaluated before and during the third trimester of pregnancy. Neonatal thyroid function tests and birth weight of the newborn infants were also assessed. RESULTS: There was no significant difference of maternal age between HT and ET groups mean +/- SD (27.6 +/- 5.5 vs. 29.2 +/- 5.4 years). The NBW of the HT group was not significantly different from that of the ET group (2880 +/- 590 vs. 3019 +/- 426 g). However, the prevalence of infants with low birth weight (LBW) defined as NBW of lower than 2500 g in HT group was 22.9% which was significantly higher than the 9.8% in the ET group (P = 0.039, OR = 2.7, 95%CI = 1.1--7.1) and 9.7% of infants born to healthy mothers at Siriraj Hospital (control group) between 1991 and 1995 (P = 0.01, OR = 2.7, 95%CI = 1.3--6.1). The 90% CI for the true difference between the prevalence of LBW infants born to ET and HT mothers was 0.7--25.4. There was no significant difference in the prevalence of LBW infants in ET and control groups. Multiple logistic regression analyses showed that maternal hyperthyroidism during the third trimester of pregnancy was an independent factor associated with increased prevalence of LBW infants (P = 0.037, OR = 4.1, 95%CI = 1.1--15.0). CONCLUSIONS: Maternal hyperthyroidism during the third trimester of pregnancy independently increases the risk of low birth weight by 4.1-fold. Appropriate management of hyperthyroidism throughout pregnancy is essential in the prevention of this undesirable neonatal outcome.     

STUDIES ON THYROTROPHIN RECEPTOR ANTIBODIES IN PATIENTS WITH EUTHYROID GRAVES'' DISEASE

Thyroid stimulating antibodies (TSAb) and TSH-binding inhibitor immunoglobulins (TBII) were assessed in 30 patients with euthyroid Graves' disease. TSAb were detected in 24 cases (80.0%), the incidence being not significantly different from that in hyperthyroid Graves' disease (29/30, 97.6%). On the other hand, the incidence of TBII in patients with euthyroid Graves' disease (12/30, 40.0%) was significantly lower than that in patients with hyperthyroid Graves' disease (30/30, 100.0%). The mean TSAb and TBII activities in the euthyroid patients were significantly lower than in the hyperthyroid patients (P less than 0.005 and P less than 0.001, respectively). Both TBII and, more closely, TSAb activities correlated with T3-nonsuppressibility and inhibition of serum TSH response to TRH stimulation. The findings supported the stimulation in vivo of the thyroid by these antibodies. Both antithyroglobulin and antimicrosomal antibody titres in euthyroid Graves' disease were significantly lower than in hyperthyroid Graves' disease (P less than 0.05, P less than 0.01, respectively). Goitre size was significantly smaller (P less than 0.001), and 99mTc thyroid uptake was significantly lower (P less than 0.001) in the euthyroid than in the hyperthyroid group. Thus, the reduced mass of thyroid tissues responding to the stimulators was considered to be one of the factors responsible for the euthyroidism despite the presence of TSAb. The high incidence of TSAb and relatively low incidence of TBII in euthyroid Graves' disease indicate that the presence of TSAb does not necessarily lead to hyperthyroidism and that the development of overt thyrotoxicosis may require augmentation of both TSAb and TBII.     

Thyroid function in wholly breast-feeding infants whose mothers take high doses of propylthiouracil

BACKGROUND: Propylthiouracil (PTU) might theoretically be preferred over methimazole (MMI) during breast-feeding because of its lower milk/serum concentration ratio (0.1 vs. 1.0). The problem is that Graves' disease often relapses during the postpartum period, and high doses of PTU are sometimes needed to control maternal hyperthyroidism) during breast-feeding. However, there are virtually no data on the effects of maternal PTU on thyroid status of infants whose mothers take more than 300 mg PTU daily and who are wholly breast-feeding. OBJECTIVES: To investigate whether mothers can breast-feed without adverse effects on infants' thyroid status while taking 300 mg or more daily of PTU. SUBJECTS AND DESIGN: Eleven infants who were wholly breast-fed while their mothers took PTU 300-750 mg daily for Graves' hyperthyroidism were included in this study. In one of the 11 infants, the mother also took iodine 6 mg daily for a limited period. Thyroid status in these infants was evaluated. MEASUREMENTS: Free T4 (FT4), thyrotrophin (TSH), and TSH binding inhibiting antibody (TBIAb) concentrations were examined at least once in the age range 6 days to 9 months. Maternal blood was also examined for FT4 and TBIAb on the same day, or within a week, of the infants' blood tests. FT4, TSH and TBIAb concentrations at birth were examined, using cord blood, in cases where antithyroid drugs had been continued through delivery. RESULTS: Three of the 11 infants had TSH concentrations higher than the normal range for adults. In one of the three infants, the TSH concentration, which was determined 19 weeks after birth, was just above the normal range. In the remaining two infants whose mothers had taken PTU through delivery, TSH concentrations, determined within 7 days after birth, were distinctly high, but they became normal while maternal PTU doses were the same as or higher than those at the initial examination. Maternal PTU doses or FT4 concentrations were not significantly correlated with infants' TSH concentrations. CONCLUSION: Mothers can breast-feed while taking propylthiouracil at doses as high as 750 mg daily without adverse effects on thyroid status in their infants.     

孕母自身免疫性甲状腺疾病对婴儿甲状腺功能影响的多因素分析

目的探讨孕母患自身免疫性甲状腺疾病对婴儿甲状腺功能的影响。方法通过浙江省新生儿疾病筛查网络系统,从2001年7月～2003年6月对78例母亲患自身免疫性甲状腺疾病的婴儿甲状腺功能进行追踪观察,采用病例对照分析的方法对可能影响婴儿甲状腺功能的因素进行非条件logistic回归分析。结果(1)78例孕母患自身免疫性甲状腺疾病的婴儿,其甲状腺功能正常37例,先天性甲低7例,甲亢1例,高TSH血症33例,与同期健康母亲的婴儿相比差异有显著性。(2)经多因素非条件logistic回归分析筛选出孕期母亲甲状腺功能状态、孕母患自身免疫性甲状腺疾病的种类、婴儿体内TSH受体抗体(TRAb)与婴儿甲状腺功能异常有关(均P<0.05)。结论孕母患自身免疫性甲状腺疾病对婴儿甲状腺功能有影响。为减少婴儿甲状腺功能异常的发生率,必须加强孕母妊娠期甲状腺功能的监测。     

METHIMAZOLE-INDUCED AGRANULOCYTOSIS IN JAPANESE PATIENTS WITH GRAVES'' DISEASE

We reviewed the records of approximately 7000 Japanese patients whose hyperthyroidism was treated with methimazole (MMI) alone. Four patients (Group I) developed agranulocytosis during a second course of MMI therapy and eight patients (Group II) during an initial course. Six patients (three in each group) received less than 30 mg MMI daily. Agranulocytosis occurred after more than 2 months of therapy (12 weeks-1 year) in five patients. Seven patients were less than 40 years of age. One patient displayed a gradual protracted development of agranulocytosis. These results indicate that agranulocytosis after MMI may occur irrespective of dose, age, duration of treatment, and with a second exposure.     

Bone histomorphometry of lactating and no lactating hyperthyroid rats

The objective of this study was to verify if hyperthyroidism potentiates the osteopenia lactational. 24 adult female rats were distributed in four groups: euthyroid no lactating (control), euthyroid lactating, hyperthyroid no lactating and hyperthyroid lactating. 20 days after gestation, all the animals were necropsied. The thoracic and lumbar vertebrae, the femur and tibia were decalcified and processed for histomorphometric analysis. The euthyroid lactating group presented intense osteopenia in the studied bones. In the hyperthyroid no lactating group, there was not any change in trabecular bone percentage in none of the analyzed bone. In the hyperthyroid lactating group, there was osteopenia in the tibia and femur, similar to the one in the euthyroid lactating group. But the trabecular bone percentage in all the vertebral bodies was significantly larger in comparison with the euthyroid lactating group. It was concluded that the hyperthyroidism does not potentiate the osteopenia lactational in female rats, but it minimizes the vertebral osteopenia once it stimulates the osteoblastic activity.     

Congenital thyrotoxicosis in premature infants

OBJECTIVES: Graves' disease (GD) complicates 0.1% to 0.2% of pregnancies, but congenital thyrotoxicosis is rare occurring in one in 70 of these pregnancies independent of maternal disease status. Antenatal prediction of affected infants is imprecise; however, maternal history, coupled with a high maternal serum TSH receptor binding immunoglobulin index (TBII) predict adverse neonatal outcome. Mortality is reported to be as high as 25% in affected infants and would therefore be expected to be higher in premature infants. This study illustrates that in sick, premature, extreme low birth weight (ELBW) or intrauterine growth retarded (IUGR) infants, the diagnosis maybe overlooked especially in the absence of antenatal risk assessment and management of thyrotoxicosis in this setting is complex. DESIGN AND PATIENTS: The records of premature neonates born at the three main maternity units in Brisbane, between January 1996 and July 1998 diagnosed with congenital thyrotoxicosis were reviewed. Data were recorded on gestational age, birth weight (B Wt), maternal thyroid history and current status, and neonatal course. Thyroid function and TBII status was assessed using standard biochemical assays. RESULTS: Seven neonates from five pregnancies were identified (four female, three male). Mean gestational age was 30 week (25--36 week) and median B Wt was 1.96 kg (0.50--2.62 kg). Only one mother received formal antenatal counselling by a paediatric endocrine service and had a TBII (54%) measured prior to delivery. Three of five mothers had elevated TBII measured after diagnosis in their offspring (57%, 65%, 83%) and in one mother, a TBII was not performed. All mothers were biochemically euthyroid at delivery. Mean age at diagnosis was 9 days (1--16 days) and mean age at commencement of treatment was 12 days (7--26 days). Two infants received propylthiouracil and five received a combination of carbimazole and propranolol. Four became biochemically hypothyroid, in three this resolved with cessation of the antithyroid drug (ATD), and one required ongoing T4 supple-mentation. Only one infant required treatment for cardiac failure and there were no deaths in this cohort. CONCLUSIONS: This is a large series of extremely small and premature infants with neonatal thyro-toxicosis. Presentation was nonspecific. The diagnosis was delayed because of low birth weight, prematurity, multiple birth and/or an unrecognized maternal history of Graves' disease. The treatment of neonatal thyrotoxicosis was difficult in these extreme low birth weight infants yet no infant died and significant morbidity was confined to high output cardiac failure in one infant. With antenatal recognition of past or active Graves' disease, assessment of maternal TSH receptor binding immunoglobulin index prior to delivery and postnatal monitoring of cord TSH and venous fT4 and TSH on days 4 and 7 rapid treatment of affected infants may have further reduced neonatal morbidity.     

Intravenous methimazole in the treatment of refractory hyperthyroidism.

BACKGROUND: Management of a hyperthyroid patient unable to take oral or rectal medication is a difficult clinical problem. The need for an alternative parenteral route of antithyroid medication administration in thyrotoxic patients occurs in certain rare cases, such as emergent gastrointestinal surgery, bowel ileus or obstruction, or severe vomiting and diarrhea. We report a simple and successful protocol for the preparation and use of intravenous methimazole (MMI) for treatment of hyperthyroidism in patients intolerant of orally and rectally administered thionamides. METHODS: Five hundred milligrams of methimazole USP powder was reconstituted with pH-neutral 0.9% sodium chloride solution to a final volume of 50 mL using aseptic technique, then filtered through a 0.22-microm filter. MMI injection was administered as a slow intravenous push over 2 minutes and followed by a saline flush. CASES: A 76-year-old man, intolerant of oral and rectal medications because of an ileus and intractable diarrhea, who developed worsening thyrotoxicosis after an emergent spinal cord decompression, and a 42-year-old man with chronic liver disease and hyperthyroidism, requiring emergent exploratory laparotomy and maintenance of complete bowel rest because of persistent gastrointestinal bleeding were rendered euthyroid using intravenous MMI. CONCLUSION: Two cases of hyperthyroidism successfully treated with a preparation of intravenous MMI are described.     

Serum paraoxonase activity before and after treatment of thyrotoxicosis

OBJECTIVE: Antioxidant effects of paraoxonase, a high density lipoprotein (HDL)-associated enzyme that inhibits low density lipoprotein cholesterol (LDL-C) oxidation in human serum, have been reported. Patients with thyroid dysfunction are more susceptible to oxidative stress, and may show enhanced LDL-C oxidation. The purpose of this study was to evaluate serum paraoxonase activity in patients with hyperthyroidism before and after treatment with methimazole (MMI). DESIGN AND PATIENTS: Twenty-four hyperthyroid patients (15 women and nine men, aged 43.0 +/- 12.9 years) and 23 age- and sex-matched healthy controls were studied. Serum paraoxonase activity, lipid, lipoprotein and apolipoprotein levels were measured in fasting samples. Patients were treated with MMI 20-30 mg daily for the first month, and 5-10 mg daily thereafter, and re-evaluated after 6-9 months of treatment. RESULTS: Significantly lower serum paraoxonase activity was present in hyperthyroid patients before treatment compared with the controls (43.4 +/- 21.9 vs. 72.6 +/- 41.2 U/ml, P < 0.005). After a mean follow-up of 7.3 months, 15 patients became euthyroid (treated) and nine were still hyperthyroid. After follow-up, serum paraoxonase activity had increased to 62.2 +/- 37.4 U/ml in those who became euthyroid (P < 0.05 compared with baseline). In patients who were still hyperthyroid serum paraoxonase was unchanged from baseline, at 43.2 +/- 23.2 U/ml. CONCLUSION: Serum paraoxonase is reduced in patients with hyperthyroidism and reverts to normal after euthyroidism is attained. Reduced serum paraoxonase activity in thyrotoxicosis might predispose lipids to oxidation.     

Effectiveness of radioiodine (131-I) as definitive therapy in patients with autoimmune and non-autoimmune hyperthyroidism

We evaluated the outcome of radioiodine (RAI) therapy in 100 consecutive patients treated in the period 2000-2001 for hyperthyroidism due to Graves' disease (GD), toxic adenoma (TA) and toxic multinodular goiter (TMG). Thyroid function was measured before and after therapy every 3-6 months up to 3 yr. Three years after therapy, 75% of TA patients were euthyroid, 18.7% were hypothyroid and 6.3% hyperthyroid. Of the TMG patients, 62.2% were euthyroid, 18.9% were hypothyroid and 18.9% hyperthyroid. In GD patients euthyroidism was achieved in 12.9% of the patients, hypothyroidism in 74.2% and hyperthyroidism persisted in 12.9%. Definitive hypothyroidism was significantly higher in GD (p<0.0001) than in TA and TMG patients. Overall, positive effect of RAI (definitive hypothyroidism or euthyroidism) was very high: 93.7% in TA, 81.1% in TMG and 87.1% in GD patients. Thyroid volume reduction was observed in all patients, but was higher in GD patients (mean reduction of 76%) and in TA patients (mean nodule reduction of 69%). In TMG, mean reduction was of 32%. The median activity of RAI received by the 86 cured patients was 555 MBq (15 mCi) compared to 407 Mbq (11 mCi) received by the 14 patients who remained hyperthyroid. No influence was found between outcome and clinical parameters at the moment of 131-I therapy. In conclusion, our results indicate that RAI therapy is highly effective and safe for the control of hyperthyroidism.     

Reevaluation of the effects of methylmercaptoimidazole and propylthiouracil in patients with Graves' hyperthyroidism

The effects of methylmercaptoimidazole (MMI) and propylthiouracil (PTU) were compared in patients with Graves' hyperthyroidism. Firstly, the duration of action of the drugs was studied by the perchlorate discharge test, which was performed 2, 12, or 24 h after administering a single dose of 15 mg MMI or 300 mg PTU. After 2 h, the 9 MMI-treated patients who were tested had marked discharge (mean +/- SD, 65.0 +/- 15.8%), as did the 6 patients treated with PTU (57.6 +/- 26.6%). The mean values for the percent discharge 12 and 24 h after drug administration were 34.9 +/- 31.9% (4 patients) and 36.5 +/- 26.9% (69 patients), respectively, in the MMI group and 19.1 +/- 11.7% (11 patients) and 8.6 +/- 10.5% (7 patients) in the PTU group, indicating that the effect of MMI lasted longer. Secondly, the clinical effects of long term administration of the drugs were compared in a different group of patients with Graves' hyperthyroidism. Within 5 weeks after the onset of treatment, 34 (52%) of 66 patients treated with MMI (10 mg, 3 times daily) were euthyroid, while only 1 of 17 patients treated with PTU (100 mg, 3 times daily) was euthyroid. The average time required to achieve euthyroidism, namely normal serum T3 and T4 levels, was significantly shorter in the MMI group [6.7 +/- 4.6 (+/-SD) weeks] than in the PTU group (16.8 +/- 13.7). In spite of the well known effect of PTU on the extrathyroidal conversion of iodothyronines, the serum T3 level normalized much faster with MMI than with PTU. These results indicate that in our patient population 15 mg MMI had a longer inhibitory effect on the organification of iodide than did 300 mg PTU, and that MMI was more rapidly effective in the treatment of Graves' hyperthyroidism.