Three Japanese patients from two families with generalized resistance to thyroid hormone with mutations in exon 9 of the thyroid hormone receptor beta gene.

Resistance to thyroid hormone (RTH) is a genetic disorder caused by mutations in the thyroid hormone receptor (TR) beta gene. The mutations are clustered in two regions: exon 9 and exon 10. To date, only one patient with an exon 9 mutation has been reported in Japan. We herein report three patients from two Japanese families with RTH and mutations in exon 9. A 52-year-old woman and her 18-year-old daughter, both with inappropriate secretion of TSH (SITSH) were diagnosed simultaneously with generalized RTH. Molecular analysis revealed a G345D mutation. An 11-year-old girl with SITSH, whose only manifestation was a goiter, had an R338W mutation, which is frequently associated with pituitary RTH. Thus, RTH with mutations in exon 9 of the TR beta gene is not so rare in Japan.

Toxic multinodular goitre in a patient with generalized resistance to thyroid hormone who harbours the R429Q mutation in the thyroid hormone receptor beta gene.

The association of resistance to thyroid hormone (RTH) due to a receptor defect with toxic multinodular goitre or with carcinoma of the thyroid has not been previously reported. Previous histopathological studies of the thyroid gland in patients with RTH have revealed changes similar to multinodular goitre, probably due to continuous stimulation by TSH. We report here a case of generalized resistance to thyroid hormone associated with a multinodular goitre, which became toxic. The patient was a 46-year-old Japanese woman who noticed a goitre although she had no symptoms of thyrotoxicosis. Initial examination revealed elevated serum thyroid hormone levels and a normal TSH level. Ultrasonography disclosed a multinodular goitre with cystic lesions. Three years later, the patient complained that the goitre had become larger and that she had developed symptoms of thyrotoxicosis such as palpitation and hyperhydrosis. Progressive hyperthyroxinaemia with relatively suppressed TSH, increased radioiodine uptake and negative anti-TSH receptor antibodies led to the diagnosis of toxic multinodular goitre. Subtotal thyroidectomy was performed, and pathological examination revealed a micropapillary carcinoma within the multinodular goitre. Occurrence of thyroid carcinoma should be considered in RTH because its incidence is high in multinodular goitre. Molecular examination revealed the R429Q mutation in the thyroid hormone receptor beta gene, which is one of the mutations usually manifesting as the pituitary resistance phenotype. That thyrotoxic manifestations appeared only during toxic stage of multinodular goitre in this case suggests that the phenotype of this type of mutation can be dependent on the amount of thyroid hormone.

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.

[The outcome of treatment with adjusted dose of 131I to thyroid weight for Graves' disease by estimation of effective half life using a single radioiodine uptake measurement].

In the determination of therapeutic 131I doses, it takes several days to measure effective half life (EHL) of radioiodine in thyroid glands (Ordinary method). We suggested the new method to estimate EHL by a single radioiodine uptake measurement (INDEX method). We evaluated the outcome of 131I treatment with these two methods in outpatients with Graves' disease. Eighty outpatients were treated with INDEX method (Group I) and 108 outpatients with Ordinary method (Group O). At the 5-yr follow up, the incidence of hypothyroidism in Group I was 22.5%, subclinical hypothyroidism 8.8%, euthyroidism 30.0%, subclinical hyperthyroidism 13.7% and hyperthyroidism 25.0%. In Group O, 17.6% of the patients were hypothyroid, 16.7% subclinical hypothyroid, 30.5% euthyroid, 9.3% subclinical hyperthyroid and 25.9% hyperthyroid. There were no significant differences between these two methods. We conclude that INDEX method surpasses Ordinary method in timesaver and is equal in effectiveness.

[Diagnosis and treatment of autoimmune thyroid disease (ATD) complicated by pregnancy].

During pregnancy, distinguishing TBII-negative Graves' disease from HCG-related thyrotoxicosis is important. There has been no convincing evidence for any adverse effects of maternal hyper- or hypothyroidism, or thionamides transferred from the mother on fetal organogenesis. In Graves' disease, maintaining maternal free T4 within normal range with thionamides may be preferable to fetal euthyroidism when toxemia of pregnancy or glucose intolerance develops, since there is little evidence indicating fetal hypothyroidism due to maternal ingestion of thionamides can cause intellectual retardation. TBII and/or TSAb levels should be determined by the 3rd trimester in patients with a history of ablative therapy for Graves' disease, and in patients with primary myxedema, in order to predict or treat fetal hyper- and hypothyroidism.

Prolonged suppressed thyroid-stimulating hormone levels in hyperthyroidism in a neonate born to a mother with Graves' disease.

We report here a case of neonatal hyperthyroidism born to a mother, whose pregnancy was complicated by poorly controlled Graves' disease. The patient demonstrated exophthalmos and marked goiter at birth, indicating the existence of thyrotoxicosis in utero. The mother's Graves' disease was well controlled in the third trimester, resulting in a slightly lower level of free thyroxine (FT4) in the umbilical cord blood serum; however, thyroid-stimulating hormone (TSH) was undetectable. Thyroid-stimulating hormone remained undetectable for 2 months, while FT4 levels varied in the course. This case suggests that severe and prolonged thyrotoxicosis in utero, due to poor control of pregnancy with Graves' disease, might induce unresponsiveness of the hypothalamo-pituitary system in the newborn.

TSH receptor antibody-associated thyroid dysfunction following subacute thyroiditis.

OBJECTIVE: Autoimmunity plays an important role in the development of thyrotrophin (TSH) receptor antibodies and the pathogenesis of Graves' disease and Hashimoto's thyroiditis. On the other hand, subacute thyroiditis is a self-limited inflammatory disease of presumed viral aetiology. The aim of this study was to examine whether subacute thyroiditis triggers TSH receptor antibody-associated thyroid disorders. PATIENTS: We reviewed 1,697 patients with subacute thyroiditis seen between 1985 and 1995. DESIGN AND MEASUREMENTS: We measured antibodies which inhibit the TSH binding to the TSH receptor (TBIAb), thyroid stimulating antibodies (TSAb) and antibodies that block TSH action (TBAb). Other thyroid autoantibodies were also determined. RESULTS: TBIAb became positive in 38 patients following subacute thyroiditis. Thyroid function after the development of TBIAb appeared to be influenced by the bioactivity of the antibody. Hyperthyroidism developed in the presence of TSAb, and so did hypothyroidism in the presence of TBAb, although 21 patients did not have thyroid dysfunction despite high titres of TBIAb. Fifteen out of 17 patients recovered from hyperthyroidism or hypothyroidism after the disappearance of TBIAb sometimes even without medication. TBIAb-positive patients had a high incidence of a family history of thyroid disease and positive anti-thyroid microsomal antibodies. An ophthalmopathy similar to Graves' disease was also observed in 3 patients. CONCLUSIONS: Subacute thyroiditis may trigger autoreactive B cells to produce TSH receptor antibodies, resulting in TSH receptor antibody-associated thyroid dysfunction in some patients.

Serum leptin concentrations in patients with thyroid disorders.

OBJECTIVE: Leptin, the obese gene product, is secreted exclusively by adipocytes and is thought to act as a lipostatic signal that regulates body weight homeostasis. We previously reported that thyroid hormone is one of the up-regulating factors of leptin in vitro. T3, at physiological concentrations, stimulates leptin mRNA expression and leptin secretion by 3T3-L1 adipocytes. The aim of this study was to explore the role of thyroid hormone in the regulation of leptin in humans. DESIGN AND PATIENTS: A total of 59 non-obese women aged 38.4 +/- 1.8 years (mean +/- SEM) were studied: 19 patients with hyperthyroidism, 17 patients with hypothyroidism, and 23 normal control subjects. The correlation between serum leptin concentrations and body mass index (BMI) was analyzed, and serum leptin levels were compared among the three groups. MEASUREMENTS: Serum leptin concentrations were measured by radioimmunoassay. RESULTS: Serum leptin concentrations after logarithmic transformation were correlated significantly (P < 0.05) with BMI in the hyperthyroid (r = 0.46), the hypothyroid (r = 0.84), and normal (r = 0.63) groups. Even though age, body weight, and BMI were similar in all groups, serum leptin levels in the hypothyroid patients (5.30 +/- 1.12 micrograms/l) were significantly (P < 0.05) lower than in the hyperthyroid and normal groups (6.87 +/- 0.66 and 6.58 +/- 0.68 micrograms/l, respectively). CONCLUSIONS: These results indicate that thyroid hormone may play an important role in the appropriate secretion of leptin in humans.

[Thyroid disease and reproduction dysfunction].

Thyroid disorders have been implicated in a broad spectrum of reproductive disorders ranging from abnormal sexual development to menstrual irregularities and infertility. Hyperthyroidism in the male is thought to cause gynecomastia. In the female hypo and hyperthyroidism results in changes in cycles length and amount of bleeding. The hypothyroidism in the male has less clear-cut effect on the reproductive system. Long-standing, untreated hypothyroidism is associated with galactorrhea. These abnormalities are reversible with adequate thyroid supplementation or collection of hyperthyroidism. Thus during the investigation of hirsurism, menstrual irregularity, infertility, galactorrhea, and gynecomastia, the possibility of thyroid dysfunction must always be considered.

Effects of propylthiouracil and methimazole on fetal thyroid status in mothers with Graves' hyperthyroidism.

Thionamide therapy is a mainstay of the treatment of hyperthyroidism complicated by pregnancy, but it can expose the fetus to hypothyroidism. In terms of fetal thyroid status, propylthiouracil (PTU) has been preferred over methimazole (MMI) based on experimental data on limited transplacental passage, and lower doses have been recommended. However, neither of these practices is supported by convincing clinical evidence. We compared the effect of maternal ingestion of PTU with that of MMI on fetal thyroid status using cord sera at delivery in 77 mothers with Graves' hyperthyroidism who were receiving thionamides and whose free T4 (FT4) levels were within the normal range. We also examined the dose effects on fetal thyroid status in these women. Thirty-four women were taking PTU (group P), and 43 were taking MMI (group M). Neither the mean fetal FT4 nor the mean fetal TSH level was significantly different between the two groups. No significant difference in the occurrence of low FT4 levels or high fetal TSH levels was found between group P and group M (low FT4, 6% vs. 7%; high TSH, 21% vs. 14%). Little relationship was observed between maternal doses and fetal thyroid status; in fact, when low doses of both PTU (100 mg daily or less) and MMI (10 mg daily or less) were administered, high TSH levels in the fetus were observed in 7 of the 34 fetuses (21%) and in 6 of the 43 fetuses (14%), respectively. Higher doses were associated with normal or low fetal TSH levels. These findings demonstrate that in terms of fetal hypothyroidism-inducing potential, there is little reason to choose PTU over MMI. Individualized, not uniformly low, doses of these drugs may prevent fetal hypothyroidism.

Bone mineral density after surgical treatment for Graves' disease.

Restoration of bone loss associated with thyrotoxicosis follows normalization of thyroid function. However, the extent of bone loss and restoration remain controversial. To clarify whether bone recovery is complete, we examined lumbar and femoral bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) in 14 thyrotoxic premenopausal women with Graves' disease and 31 premenopausal women treated for Graves' disease by subtotal thyroidectomy who had been in remission for at least 3 years. In the remission group, to exclude the influence of subclinical hyperthyroidism, thyrotropin (TSH) levels were followed and subjects with low levels excluded. Thus, all 31 subjects had normal thyroid hormone levels with transiently or persistently elevated TSH levels post-thyroidectomy. Data from the two study groups were compared with those from healthy premenopausal controls matched for age, height and weight. Mean lumbar (anterior-posterior and lateral), femoral neck, and trochanter BMDs were significantly lower in the thyrotoxic group than in controls (p < .05, all four BMDs). Mean lumbar (anterior-posterior), femoral neck and trochanter BMDs were significantly higher in the remission group than in controls (p < 0.05, all three BMDs). At the time of DXA, the 31 remission subjects showed a significant positive correlation between lumbar BMD and TSH (p < 0.05) and a significant negative correlation between femoral neck BMD and free triiodothyronine (FT3) (p < 0.05). These observations suggest: (1) in premenopausal women, bone loss associated with thyrotoxicosis due to Graves' disease is present but is fully restored when remission is reached after subtotal thyroidectomy; (2) subclinical hypothyroidism after subtotal thyroidectomy may result in higher BMD than that of controls.

[The outcome of adjusted accumulation dose of treatment of Graves' disease].

We evaluated the outcome of 131I treatment of Graves' disease in two different protocols (old and new protocol) of adjusted accumulation dose from 1988 to 1995. Adjusted accumulation doses of patients with above 50 g thyroid weights were increased by 5-20 Gy/g tissue in new protocol compared to those in old one. In 166 patients treated with single and plural doses of 131I treatment in 1990 (Group In), the therapeutic doses were calculated according to new protocol and in 130 patients in 1988 (Group Io), according to old one, modification of Quimby's formula. The patients treated with plural doses were classified as hyperthyroidism because the efficacies of the first treatments with 131I were insufficient. At the 5-yr follow up, the incidence of hypothyroid in Group In was 9%, subclinical hypothyroid 17%, euthyroid 30%, subclinical hyperthyroid 7%, hyperthyroid 37%. In Group Io, 11% of the patients were hypothyroid, 6% subclinical hypothyroid, 29% euthyroid, 3% subclinical hyperthyroid, 51% hyperthyroid. The incidence of hyperthyroid in Group In was lower than that in Group Io (p < 0.05). There were no significant differences in hypothyroid and euthyroid. In conclusion, we suggest that an adjusted dose of 131I in relation to the patients' thyroid weight shows some room for improvement.

Incidence of subacute thyroiditis recurrences after a prolonged latency: 24-year survey.

Subacute thyroiditis, which is considered to be a viral disease, rarely recurs after a complete recovery. We evaluated data on 3,344 patients with subacute thyroiditis who were seen at Ito Hospital between 1970 and 1993. Subacute thyroiditis recurred in 48 of 3,344 patients 14.5 +/- 4.5 yr after the first episode. Five patients experienced a third episode 7.6 +/- 2.4 yr after the second. The mean age of the patients at the first, second, and third episode was 38.4 +/- 6.3, 53.1 +/- 8.9, and 57.8 +/- 10.1 yr old, respectively. The mean incidence of a recurrence was 2.3 +/- 0.9% per year. The erythrocyte sedimentation rate and the duration of treatment were each significantly decreased at the second episode as compared with the first. Thus, recurrences of subacute thyroiditis do occur at least in 2% of patients and exhibited relatively mild clinical manifestations.

Defective organification of iodide causing congenital goitrous hypothyroidism.

A 26-yr-old Japanese woman with congenital goitrous hypo-thyroidism and sensorineural deafness underwent a thyroidectomy. Examination of the thyroid gland revealed characteristic features of multinodular goiter. The T3 and T4 content in thyroglobulin (Tg) were 0.03 and 0.02 mol/mol Tg, respectively. Iodide incorporation into Tg, using slices of the thyroid tissue, revealed that iodide organification of thyroid tissue from our patient was markedly lower than that of normal controls. Then, guaiacol and iodide oxidation activities of thyroid peroxidase (TPO) in our patient's thyroid tissue were lower than those of normal controls (guaiacol assay: 1.92 vs. 30.0 +/- 5.7 mGU/mg protein; iodide assay: 1.1 vs. 6.6 +/- 2.8 mIU/mg protein). Lineweaver-Burk plot analysis of the oxidation rates of guaiacol and iodide indicated that this patient's TPO had a defect in the binding of guaiacol and iodide, but the coupling activity of the patient's TPO was not decreased compared with those of two normal thyroids. In this case and in control subjects, Nothern gel analysis of TPO messenger RNA from unstimulated and TSH-stimulated thyroid cells revealed a 3.2 kilobase species in the former and four distinct messenger RNA species of 4.0, 3.2, 2.1, and 1.7 kilobases in the latter. Western blot analysis of TPOs obtained from this patient and from control subjects identified the same 107 kDa protein, using antimicrosomal antibody-positive serum. We analyzed the coding sequence in the patient's TPO gene by using polymerase chain reaction technique. A single point mutation of G-->C at 1265 base pair was detected only in the TPO gene, but this point mutation does not alter the amino acid residue. It is possible that posttranslational modification such as abnormal glycosylation may occur in the TPO molecules. Furthermore, it is possible that there are differences in the tertiary structures of the TPO molecules between our patient and normal subjects. The above abnormalities of TPO molecules may play an important role in our patient's dyshormonogenesis.

[Clinical significance of the measurement of the urinary concentration of iodine in differentiating silent thyroiditis from Graves' disease].

In order to differentiate silent thyroiditis (SLT) from Graves' disease, the usefulness of the measurement of the urinary concentration of iodine was evaluated in this study. The subjects employed were 39 patients with SLT and 40 patients with Graves' disease. Patients were advised to avoid any iodine-containing food or medication for a week before the examination. The urinary concentration of iodine (UI) and the serum concentration of thyroid hormones were determined. UI was calculated from the amount of iodine in the spot urine by multiplying it by the ratio of iodine to creatinine. Since the UI value thus obtained was significantly well correlated with the UI value for 24 hour urine, the former value was used instead of the latter value thereafter. Mean UI value in the patients with SLT was 482.4 +/- 296.4 mu g/day and that in the patients with Graves' disease was 169.8 +/- 75.2 mu g/day, the former value being significantly higher than the latter (p < 0.0001). A strong and significant correlation between UI and the serum concentration of FT4 or T3 (TT3) was found in the patients with SLT (r = 0.76, p < 0.0001 and r = 0.54, p < 0.02), but not in those with Graves' disease (r = 0.34, p = 0.07 and r = 0.24, p = 0.14) Mean UI/FT4 ratio and mean UI/TT3 ratio was significantly higher in patients with SLT than those with Graves' disease and the overlaps in the ratios between these two groups were very slight. These results indicate that both the ratios of UI/FT4 and UI/TT3 were useful parameters to differentiate SLT from Graves' disease. The higher UI value observed in the patients with SLT was thought to be due to the increase in the amount of inorganic iodine which was liberated from the iodinated material leaked from the damaged thyroid tissue by the deiodinating mechanism in the peripheral tissues.

[A five-year follow-up of two different 131I treatment methods for Graves' disease and the factors affecting the outcome].

We employed two different methods of 131I treatment for Graves' disease in 285 patients and compared the results between the two. (We also analyzed the factors affecting the treatment outcome.) A single dose of 131I adjusted to the patients' thyroid weight was administered to 180 patients in group 1, while a relatively lower dose of 131I (approximately 30Gy) was given repeatedly to 105 patients in group 2. A 5-year follow-up showed that in group 1, 34% of the patients were euthyroid, 11% hypothyroid, 11% subclinical hypothyroid and 44% still remained hyperthyroid. In group 2, 43% of the patients were euthyroid, 5% hypothyroid, 35% subclinical hypothyroid and 17% hyperthyroid. The factors affecting the outcome of the treatment in group 1 patients were their thyroid weight, the duration of the disease and TRAb levels. No significant correlation was observed between the efficacy of 131I treatment and the patients' sex, age, 24hr 131I-uptake, effective half life of administered 131I or titers of antithyroid antibodies. We conclude that the repeated low dose administration of 131I provides the best outcome in a 5-year follow-up. However, we suggest that an adjusted dose of 131I in relation to the patients' thyroid weight should be employed to obtain a faster therapeutic response.

[Studies on patients with a discrepancy between free thyroid hormones and thyrotropin values].

Thyroid function has been almost exactly evaluated by the measurement of serum free thyroxine (FT4), free triiodothyronine (FT3) and thyrotropin (TSH) concentrations. However, we occasionally experience patients who show a discrepancy between free thyroid hormones and TSH values, and the assessment of thyroid function in such cases is extremely difficult. Thyroid hormone autoantibodies (THAA) interfere with radioimmunoassay (RIA) of FT4 and FT3 by giving inappropriate values. To investigate the incidence of THAA, immune precipitation of patients' sera after incubation with labelled T4 (125I-T4) or T3 (125I-T3) analog tracer was done in 394 patients with thyroid diseases. 9 patients (2.3%) showed an increased binding of 125I-T4 or 125I-T3 analog. Heterophilic antimouse antibodies in a patient's serum (human antimouse immunoglobulin antibodies: HAMA) can interfere in two-site immunometric assays (IMA) using mouse monoclonal antibodies and result in spuriously increased serum TSH concentrations. Manufacturers now customarily add nonspecific mouse immunoglobulins into their assay kits to absorb HAMA and prevent such interference. This approach may not always be enough to prevent HAMA interference in all samples. In 14 thyrotoxic patients with inappropriately high TSH measured by an IMA kit, we measured the levels of TSH by the further addition of mouse serum into this kit. Their serum TSH levels were fully suppressed except for 2 patients with a syndrome of inappropriate secretion of TSH (SITSH). The presence of abnormal albumin in the serum also interferes with RIA of FT4 and FT3. We experienced a female case of Graves' disease treated with methimazole who showed an inappropriately high serum FT3 measured by an analog tracer RIA kit, whose serum FT4, FT3 and TSH were 1.31 ng/dl, 19.3 pg/ml and 1.9 mu U/ml respectively. Although the anti-T3 autoantibody was considered to be present initially, immune precipitation of her serum with 125I-T3 analog tracer gave a negative result. In order to elucidate this finding, Sephadex-G200 chromatography of her serum after incubation with 125I-T3 analog tracer was done. Radioactivity of her serum in albumin fraction was significantly higher than that of normal control serum to indicate the presence of abnormal albumin in the serum. In conclusion, to assess the thyroid function of a patient with a discrepancy between free thyroid hormones and TSH values, it is important to consider the presence of THAA, HAMA, or rarely, an abnormal albumin.

Relationship between silent thyroiditis and recurrent Graves' disease in the postpartum period.

We carried out a close follow-up study of 96 episodes of postpartum hyperthyroidism, which developed in women with a history of Graves' disease. Hyperthyroidism had developed 1-6 months (mean +/- SD, 2.3 +/- 1.4) after delivery. Radioiodine uptake (RAIU) values during the thyrotoxic phase, determined after a 1-week restriction of iodine-rich diet, ranged from very low to very high (1-70%). The group with low RAIU values (group L: < 10%, n = 26) and the normal group (group N: 10-40%, n = 33) showed significantly higher urinary excretion of iodine (UI) than the high group (group H: > 40%, n = 37), and UI in group L was comparable to that in patients with silent thyroiditis. TSH binding inhibiting antibody (TBIAb) values were determined in 87 patients at the RAIU testing, and were above normal in most of them: all in group H, 68% in group N, and 52% in group L. The mean TBIAb value in group H was significantly higher than that in group N or L (P < 0.0001 for both). Fifty-one patients in group L and group N were observed without treatment. Of these, hyperthyroidism resolved spontaneously in 39 patients (76%), in whom transient hypothyroidism developed with substantial frequency. Hyperthyroidism subsequently resumed in 18 (46%) of these 39 between 4 and 9 months (mean +/- SD, 7.1 +/- 2.1) after delivery and did not resume in the other 21. RAIU values, determined again during this later phase of hyperthyroidism, were high enough to indicate Graves' hyperthyroidism in all but one patient. During the postpartum period, TBIAb values increased and then declined in the majority of the patients irrespective of the course of hyperthyroidism. Of the 21 patients who maintained euthyroidism after spontaneous resolution of hyperthyroidism, transient increase in TBIAb was observed in 14. These findings suggest that silent thyroiditis commonly develops concomitantly with the activation of Graves' disease and delays or masks the development of Graves' hyperthyroidism.

Maternal hypothyroidism during early pregnancy and intellectual development of the progeny.

OBJECTIVE: To investigate whether maternal hypothyroidism before the onset of fetal thyroid function influences mental development of the offspring. DESIGN: We examined IQs in children in whom the mothers had been hypothyroid during early pregnancy (group 1). The IQs were compared with those of siblings who were not exposed to maternal hypothyroidism during gestation (group 2). PATIENTS: Group 1 consisted of eight children. Mothers were examined for thyroid status during the fifth to 10th gestational weeks and were found to have distinctly low thyroxine levels and high thyrotropin levels; the levels became normal after thyroxine supplementation by 13 to 28 weeks of gestation. Seven of the eight children had nine siblings who had not been exposed to maternal hypothyroidism during gestation (group 2). Ages at examination were 4 to 10 years in group 1 and 4 to 15 years in group 2. RESULTS: All children in group 1 showed normal IQs. There was no significant difference in the mean IQ between the children in group 1 who had siblings (112 +/- 11) and their siblings in group 2 (106 +/- 8). Even the subject whose mother had had the lowest thyroxine level (free thyroxine, 2.3 pmol/L) had an IQ similar to that of his sibling. CONCLUSION: These data provide evidence against the presence of adverse effects of maternal hypothyroidism during early pregnancy on the subsequent mental development of the offspring.

[Cases of Graves' disease with falsely high TSH values due to interfering substances which cross-link with mouse monoclonal antibodies in the TSH assay kits].

It has been reported that highly sensitive two-site immunometric assays occasionally indicate falsely high serum TSH values. A possible reason for this is that heterophilic antibodies interfere with these assays. Recently we had a patient in whom the Delfia TSH kit falsely indicated an elevated serum TSH value. A 29-year-old female was diagnosed as having Graves' disease and was referred to Ito Hospital for surgical treatment. Her thyroid hormone values were distinctly high two months before admission (FT3: 20.7pmol/L, FT4: 42.3pmol/L), but her serum TSH level was normal (1.1mU/l). She was clinically hyperthyroid, and T3 and T4 values determined after ethanol extraction and T3 or T4 analog binding rates did not indicate the presence of T3 or T4 antibodies. Her TSH value became undetectable when mouse IgG was added to the assay. These results suggested that the "normal" serum TSH value was caused by interfering substances such as anti-mouse IgG antibodies which had cross-linked with mouse monoclonal antibodies in the Delfia TSH kit. Another 12 patients who were suspected of having the interfering substances were examined because of the discordance between TSH values and thyroid hormone values. All of the serum TSH values measured using the DELFIA TSH kit decreased when mouse IgG was added. In another case, the presence of serum TSH could not be detected using the Delfia TSH kit but could be measured using the RIABEAD II TSH kit.(ABSTRACT TRUNCATED AT 250 WORDS)