Effects of Levothyroxine Treatment on Fertility and Pregnancy Outcomes in Subclinical Hypothyroidism: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Subclinical hypothyroidism, defined by elevated thyrotropin (TSH) and normal free thyroxine levels, is associated with adverse pregnancy outcomes, including preterm birth, pre-eclampsia, and small for gestational age. Despite the uncertainty regarding the effectiveness of levothyroxine (LT4) treatment on pregnancy outcomes in subclinical hypothyroidism, LT4 is widely administered with a pre-treatment threshold TSH level of 2.5 mU/L. The aim of this study is to investigate the efficacy of periconceptional LT4 treatment for subclinical hypothyroidism, including TSH levels >2.5 mU/L, and identify the characteristics of subclinical hypothyroidism that can benefit from LT4 treatment. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials from inception to February 2023. We analyzed the pooled effects of LT4 on subclinical hypothyroidism before and during pregnancy. The main outcomes before pregnancy were live birth, pregnancy, and miscarriage. The main outcomes during pregnancy were live birth, miscarriage, and preterm birth. We conducted subgroup analyses to compare the effects of LT4 on subclinical hypothyroidism with TSH levels of 2.5-4.0 and >4.0 mU/L. Results: Of the 888 studies identified, 27 full-text articles were screened for eligibility. Five studies on pre-conception treatment with 768 participants and eight studies on treatment during early pregnancy with 2622 participants were analyzed. One of the two studies on pre-conception treatment in subclinical hypothyroidism with TSH >4.0 mU/L had high risk of bias and the other was composed of 64 participants. Pre-conception LT4 treatment had no significant effect in improving rates of live births and pregnancies, or reducing miscarriages (risk ratio [RR], 95% confidence interval): 1.41 (0.84-2.36), 1.73 (0.88-3.39), and 0.46 (0.11-2.00), respectively. LT4 treatment during pregnancy was not significantly associated with higher rates of live births (RR 1.03, 0.98-1.09) nor decreased miscarriage rates (RR 1.01, 0.66-1.53). The effect of LT4 treatment on preterm birth during pregnancy was significantly different depending on the TSH values (p = 0.04); a positive effect was shown in the subclinical hypothyroidism subgroup with TSH >4.0 mU/L (RR 0.47, 0.20-1.10), while no significant effect was observed in the subgroup with TSH 2.5-4.0 mU/L (RR 1.35, 0.79-2.31). Conclusions: Pre-conceptional LT4 treatment for subclinical hypothyroidism does not improve fertility or decrease the incidence of miscarriages. However, further well-designed studies are needed for pre-conceptional treatment, especially in TSH >4.0 mU/L. LT4 treatment during pregnancy had a positive effect on preterm birth; nevertheless, this was only applicable to subclinical hypothyroidism with TSH >4.0 mU/L.

Graves' Disease with Thymic Hyperplasia: The Response of the Thyroid Function, Thyrotropin Receptor Autoantibody, and Thymic Size to Thiamazole Treatment.

We treated a 22-year-old woman suffering from Graves' disease and thymic hyperplasia. She was referred to our institution for a close investigation of thyrotoxicosis and thymic mass. Thyroid tests and magnetic resonance imaging resulted in a diagnosis of Graves' disease and thymic hyperplasia. The thyroid function and thyroid-stimulating hormone receptor antibody (TRAb) were normalized one and five months after thiamazole initiation, respectively. The thymic size began to decrease after 1 month and was further decreased after 5 months; it was normalized after 12 months. The correlation between TRAb titers and the thymic size (R2=0.99) suggested that the patient's autoimmunity might have contributed to the thymic hyperplasia.

Successful Re-administration of Low-dose of Methimazole (MMI) in Graves' Disease Patients Who Experienced Allergic Cutaneous Reactions to MMI at Initial Treatment and Had Received Long-term Propylthiouracil (PTU).

Objective When patients with Graves' disease show severe allergic cutaneous reactions, physicians often suggest that they undergo radioiodine therapy instead of receiving propylthiouracil (PTU), another antithyroid drug, because anti-neutrophil cytoplasmic antibody (ANCA) -related vasculitis can occur with PTU, especially with long-term use. However, some patients refuse radioiodine therapy and chose PTU. Sometimes PTU treatment may be prolonged. Since the frequency of adverse effects of methimazole (MMI) is dose-related, there is a possibility that we can re-administer a low dose without adverse effects to patients well-controlled with PTU who once experienced an allergic reaction to MMI. Methods I prospectively re-administered a low dose of MMI to patients who previously experienced an allergic reaction to MMI at initial treatment. The dose of re-administered MMI ranged from 5 mg twice a week to 5 mg daily. Patients Nine patients with Graves' disease who developed urticaria at initial treatment with MMI and had been treated with PTU for 6 to 21 years were recruited. Results Eight of the 9 patients were successfully controlled with MMI without allergic cutaneous reactions. Only one patient felt itchiness 2 days after switching to MMI. However, skin change was not observed. Conclusion If the patients show allergic cutaneous reactions as a side effect of MMI at the initial treatment for Graves' disease, then there is a strong possibility that such patients can tolerate a low dose of MMI without adverse effects after the disease activity has subsided.

Cytologic findings and differential diagnoses of primary thyroid MALT lymphoma with striking plasma cell differentiation and amyloid deposition.

We report two cases of thyroid mucosa-associated lymphoid tissue (MALT) lymphoma with associated amyloid protein deposition. While other primary thyroid neoplasms sush as medullary carcinoma and plasmacytoma with associated amyloid protein are known to occur and have been previously described by fine-needle aspiration cytology (FNAC), to our knowledge, the current cases are the first of thyroid MALT lymphoma with amyloid deposition to be detailed in the cytopathology literature. Case 1 was a 73-year-old female with chronic thyroiditis. FNAC suspected MALT lymphoma. The amyloid material was not noticed, nevertheless it existed. Case 2 was a 71-year-old female with a nodule of the thyroid. Malignant lymphoma and medullary carcinoma were suspected by FNAC. The possibility of medullary carcinoma was excluded by a measurement of serum calcitonin and carcinoembryonic antigen. After follow-up for two years, the nodule was diagnosed as MALT lymphoma associated with plasma cell differentiation and amyloidosis by the fourth FNAC. When we encounter small round cell tumors associated with amyloid in thyroid FNAC, we should consider not only medullary carcinoma but also MALT lymphoma.

Effect of L-thyroxine replacement on apolipoprotein B-48 in overt and subclinical hypothyroid patients.

Apolipoprotein B-48 (ApoB-48) is a constituent of chylomicrons and chylomicron remnants, and is thought to be one of the risk factors for atherosclerosis. We evaluated the effect of L-thyroxine (L-T(4)) replacement on serum ApoB-48 levels in patients with primary hypothyroidism. Eighteen patients with overt hypothyroidism (OH) and 18 patients with subclinical hypothyroidism (SH) participated in the study. The lipid profiles, including ApoB-48, were measured in patients with hypothyroidism before and 3 months after L-T(4) replacement. After L-T(4) replacement, the serum concentrations of all lipoproteins, exclusive of lipoprotein(a) (Lp(a)), were significantly decreased in patients with OH. In patents with SH, the serum levels of total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), remnant-like particle cholesterol (RLP-C), apolipoprotein B (ApoB), and ApoB-48 decreased significantly after L-T(4) replacement. The serum levels of triglycerides (TG), HDL-C, low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA-1), and Lp(a) did not change significantly. In all 36 patients, the reduction in the ApoB-48 levels correlated significantly with the reduction in TSH levels (r = 0.39, P<0.05). This study showed clearly that L-T(4) replacement might reduce serum levels of ApoB-48 in both OH and SH patients. Such altered serum levels of ApoB-48 in patients with OH and SH may be related to the disturbed metabolism of chylomicron remnants in patients with hypothyroidism.

Initial treatment with 15 mg of prednisolone daily is sufficient for most patients with subacute thyroiditis in Japan.

BACKGROUND: Oral glucocorticoids are administered in moderate and severe cases of subacute thyroiditis (SAT), providing dramatic relief from pain and fever. However, there have been no reports regarding the optimal dose of prednisolone (PSL) for treatment of SAT. In this study, we used 15 mg/day of PSL as the initial dosage and tapered it by 5 mg every 2 weeks. We assessed the effectiveness of this treatment protocol. METHODS: We examined 384 consecutive and untreated patients with SAT who visited our thyroid clinic between February 2005 and December 2008. We excluded patients who did not fit our protocol, and the final number of subjects was 219. When patients complained of pain in their neck or C-reactive protein (CRP) was still high, physicians were able to extend the tapering of the dose of PSL or increase it at 2-week intervals. The endpoint of the study was the duration of the PSL medication. We also compared the severity of thyrotoxicosis and rate of hypothyroidism after SAT between the short medication group (patients who recovered within 6 weeks) and long medication group (patients who recovered in 12 weeks or more). RESULTS: The number of patients whose thyroiditis improved within 6 weeks and did not recur was 113 (51.6%), and 61 (27.9%) improved within 7 to 8 weeks and did not have a recurrence. The longest duration was 40 weeks. Seven patients (3.2%) needed increases in the dosage of PSL. Thyroid hormone (free thyroxine and free triiodothyronine) levels measured at the initial visit in the short medication group were significantly higher than those in the long medication group (p<0.05). Serum CRP, male-to-female ratio, body weight, and age showed no differences between the two groups. There were no differences in the rate of hypothyroidism after SAT between the two groups (p=0.0632). CONCLUSIONS: The treatment protocol that we employed had 15 mg/day of PSL as the initial dosage for the treatment of SAT, with tapering by 5 mg every 2 weeks, and was effective and safe for Japanese patients. However, 20% of patients with SAT needed longer than 8 weeks to recover from the inflammation.

TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy.

OBJECTIVE: Thyroidal production of triiodothyronine (T(3)) is absent in patients who have undergone total thyroidectomy. Therefore, relative T(3) deficiency may occur during postoperative levothyroxine (L-T(4)) therapy. The objective of this study was to evaluate how the individual serum T(3) level changes between preoperative native thyroid function and postoperative L-T(4) therapy. METHODS: We retrospectively studied 135 consecutive patients with papillary thyroid carcinoma, who underwent total thyroidectomy. Serum free T(4) (FT(4)), free T(3) (FT(3)), and TSH levels measured preoperatively were compared with those levels measured on postoperative L-T(4) therapy. RESULTS: serum tsh levels during postoperative L-T(4) therapy were significantly decreased compared with native TSH levels (P<0.001). serum FT(4) levels were significantly increased (P<0.001). Serum FT(3) levels were significantly decreased (P=0.029). We divided the patients into four groups according to postoperative serum TSH levels: strongly suppressed (less than one-tenth of the lower limit); moderately suppressed (between one-tenth of the lower limit and the lower limit); normal limit; and more than upper limit. Patients with strongly suppressed TSH levels had serum FT(3) levels significantly higher than the native levels (P<0.001). Patients with moderately suppressed TSH levels had serum FT(3) levels equivalent to the native levels (P=0.51), and patients with normal TSH levels had significantly lower serum FT(3) levels (P<0.001). CONCLUSIONS: Serum FT(3) levels during postoperative L-T(4) therapy were equivalent to the preoperative levels in patients with moderately suppressed TSH levels. Our study indicated that a moderately TSH-suppressive dose of L-T(4) is required to achieve the preoperative native serum T(3) levels in postoperative L-T(4) therapy.

Histopathological diagnoses of "accessory" thyroid nodules diagnosed as benign by fine-needle aspiration cytology and ultrasonography.

BACKGROUND: Patients who have thyroidectomies for thyroid nodules that are suspected of being malignant, called here "main nodules," occasionally have second nodules, called here "accessory nodules" that are evaluated by ultrasonography (US) and fine-needle aspiration cytology (FNAC). Most accessory nodules are diagnosed as benign based on preoperative US and FNAC. To evaluate the accuracy of US and FNAC for a group of nodules which were likely to be mostly benign we evaluated procedures to diagnose accessory nodules. PATIENTS AND METHODS: In a total of 643 patients who underwent thyroidectomy for their main nodules, 866 accessory nodules were evaluated by US and/or FNAC preoperatively. All were evaluated by histopathological examination postoperatively. Of the 866 accessory nodules, 501 were evaluated by US only and 365 were evaluated by US and FNAC. RESULTS: While the 363 accessory nodules were diagnosed as malignant by histopathology, 235 nodules were malignant by US and histopathology and 115 nodules were malignant by FNAC and histopathology. Among the accessory nodules that were diagnosed as benign by histopathology, 7.2% were malignant by US, and 4.4% were malignant by FNAC. Among the accessory nodules that were diagnosed as benign by FNAC, 15.0% were malignant by histopathology. This was a significantly higher percentage than the value of 6.2% for the accessory nodules diagnosed as benign by US but malignant by histopathology. Accessory nodules with a benign cytology on FNAC that were malignant were significantly smaller than those with a benign cytology and histopathology. Among the 126 accessory nodules that were read as benign by both US and FNAC, only one (0.8%) was diagnosed as papillary thyroid carcinoma by histopathology. CONCLUSION: These data suggest that diagnostic accuracy of benign nodules based on both US and cytological evaluation was supported by the evidence of high-level histopathological compatibility in accessory nodules. FNAC and US have a low but not negligible false-negative diagnostic rate. When FNAC is combined with US the false-negative rate is probably very low.

Identification of independent risk loci for Graves' disease within the MHC in the Japanese population.

To identify genetic variants that confer the risk of Graves' disease (GD) in the Japanese population, we conducted a two-stage genome-wide association study (GWAS) using 1119 Japanese individuals with GD and 2718 unrelated controls, and a subsequent replication study using independent 432 GD cases and 1157 controls. We identified 34 single nucleotide polymorphisms (SNPs) to be significantly associated with GD in the GWAS phase. Twenty-two out of 34 SNPs remained positive in the replication study. All 22 SNPs were located within the major histocompatibility complex (MHC) locus on chromosome 6p21. No strong long-range linkage disequilibrium (LD) was observed among the 22 SNPs, indicating independent involvement of multiple loci within the MHC with the risk of GD. Multivariate stepwise logistic regression analysis selected rs3893464, rs4313034, rs3132613, rs4248154, rs2273017, rs9394159 and rs4713693, as markers for independent risk loci for GD. The analysis of LD between these seven SNPs and tagging SNPs for GD-associated human leukocyte antigen (HLA) alleles in the Japanese population (HLA-DPB1(*)0501 and HLA-A(*)0206) demonstrated that all of and five of seven SNPs were not in strong LD with HLA-DPB1(*)0501 and HLA-A(*)0206, respectively. Although causal variants remain to be identified, our results demonstrate the existence of multiple GD susceptibility loci within the MHC region.

The thyroid function of Graves' disease patients is aggravated by depressive personality during antithyroid drug treatment.

BACKGROUND: We previously reported that depressive personality (the scores of hypochondriasis, depression and psychasthenia determined by the Minnesota Multiphasic Personality Inventory (MMPI)) and daily hassles of Graves' disease (GD) patients treated long trem with antithyroid drug (ATD) were significantly higher in a relapsed group than in a remitted group, even in the euthyroid state. The present study aims to examine the relationship among depressive personality, emotional stresses, thyroid function and the prognosis of hyperthyroidism in newly diagnosed GD patients. METHODS: Sixty-four untreated GD patients responded to the MMPI for personality traits, the Natsume's Stress Inventory for major life events, and the Hayashi's Daily Life Stress Inventory for daily life stresses before and during ATD treatment. RESULTS: In the untreated thyrotoxic state, depressive personality (T-scores of hypochondriasis, depression or psychasthenia greater than 60 points in MMPI) were found for 44 patients (69%). For 15 (23%) of these patients, the scores decreased to the normal range after treatment. However, depressive personality persisted after treatment in the remaining 29 patients (46%). Normal scores before treatment were found for 20 patients (31%), and the scores were persistently normal for 15 patients (23%). The remaining 5 patients (8%) had higher depressive personality after treatment. Such depressive personality was not associated with the severity of hyperthyroidism. Serum TSH receptor antibody activity at three years after treatment was significantly (p = 0.0351) greater in the depression group than in the non- depression group. The remission rate at four years after treatment was significantly (p = 0.0305) lower in the depression group than in the non- depression group (22% vs 52%). CONCLUSION: The data indicate that in GD patients treated with ATD, depressive personality during treatment reflects the effect of emotional stress more than that of thyrotoxicosis and that it aggravates hyperthyroidism. Psychosomatic therapeutic approaches including antipsychiatric drugs and/or psychotherapy appears to be useful for improving the prognosis of hyperthyroidism.

Pathologic features of polycystic thyroid disease: comparison with benign nodular goiter.

Polycystic thyroid disease (PCTD) is characterized by multiple thyroid cysts detected by ultrasonography, the absence of thyroid autoantibodies, and susceptibility to the development of hypothyroidism due to a high iodine intake. It is necessary to obtain histopathological information on PCTD in order to clarify the cause of hypothyroidism. We retrospectively reviewed three patients with PCTD and small papillary thyroid cancer who underwent thyroidectomy. We observed the thyroid tissues pathologically in areas with and without multiple cysts, and compared them with those of multinodular goiter with cysts. In the patients with PCTD, there were multiple enlarged follicles that resembled enlarged normal follicles and differed from those found in multinodular goiter in terms of their shape. Huge follicles corresponded to the cysts that were detected by ultrasonography. Each follicle contained colloid. Follicular cells in enlarged follicles comprised low cuboidal epithelium that appeared normal. These findings were common in the 3 patients with PCTD. In Conclusion the PCTD patients had multiple enlarged follicles that seemed to decrease the total number of follicular cells, and may be a cause of hypothyroidism. We believe that PCTD is a new entity of thyroid disease based on the pathological findings.

Method-dependent HbA1c values in a family with hemoglobin Himeji.

BACKGROUND: Hb Himeji is variant hemoglobin associated with increased glycation in a mutated ß chain. We measured HbA1c using various methods in a family with Hb Himeji. METHODS: The proband was a 42-y female. While receiving treatment for Graves' disease, an oral glucose tolerance test showed normal glucose tolerance, but HbA1c by enzymatic assay was abnormally elevated (11.6%). Hemoglobin gene analysis identified Hb Himeji [ß140 (H18) Ala→Asp]. RESULTS: HbA1c values measured by high-performance liquid chromatography (HPLC; HLC-723G8 and HA-8160 instruments), immunoassay, enzymatic assay, affinity method, and electrospray ionization/mass spectrometry were 3.2%, 5.2%, 11.5%, 9.7%, 7.2%, and 9.6%, respectively. Glycation product of the variant hemoglobin measured by HPLC, using HLC-723G8 and HA-8160, was 9.1% and 4.5%, respectively. The proband's father with type 2 diabetes was the first reported case of Hb Himeji. HbA1c by affinity method was markedly elevated (18.0%), but it was 5.3% by HPLC. The proband's two sisters also had Hb Himeji variant and similar method-dependent discrepancies in HbA1c values were observed. CONCLUSIONS: In the patients with Hb Himeji, discrepancies occur between plasma glucose and HbA1c with all measurement methods because of differences in HPLC mobility, increased glycation, and antigenic changes of the variant ß chain.

The prevalence of polycystic thyroid disease in hypothyroid patients with negative thyroid autoantibodies.

BACKGROUND: We previously reported that multiple thyroid cysts may be a cause of hypothyroidism in patients with a relatively high iodine intake and we termed it polycystic thyroid disease (PCTD). The aim of this study was to investigate the prevalence of PCTD in patients who visited our thyroid center. We hypothesized that patients with PCTD are not rare in a region with a high iodine intake. METHODS: We retrospectively studied the cause of hypothyroidism based on medical histories and ultrasonography in new patients to our hospital from April 2008 to March 2009 whose serum tests for antithyroglobulin antibodies (TgAb) and thyroid peroxidase antibodies (TPOAb) were negative. Serum thyroid hormones, thyrotropin (TSH), TgAb, and TPOAb were measured in 8243 patients. Patients with four or more thyroid cysts, negative tests for TgAb and TPOAb, no evidence for thyroid diseases other than their thyroid cysts, and no exposure to thyroid-perturbing influences were defined as having PCTD. RESULTS: Three hundred seven patients had overt hypothyroidism (TSH level above 10.0 µU/mL and free thyroxine level below 0.7 ng/dL), of whom 71 patients were both TgAb and TPOAb negative. There were 546 patients with subclinical hypothyroidism (TSH level above 5.0 µU/mL and normal free thyroxine), of whom 193 patients were both TgAb and TPOAb negative. There were 24 patients with overt hypothyroidism and PCTD, accounting for 7.8% (24/307) of all causes of overt hypothyroidism. There were 42 patients with subclinical hypothyroidism and PCTD, accounting for 7.7% (42/543) of all causes of subclinical hypothyroidism. PCTD was more common among elderly people than young people. CONCLUSIONS: PCTD appears to be a minor but not negligible cause of hypothyroidism, at least in iodine-rich regions. PCTD with hypothyroidism may have been misdiagnosed as thyroid antibody-negative Hashimoto's thyroiditis in many reports.

Subclinical nonautoimmune hyperthyroidism in a family segregates with a thyrotropin receptor mutation with weakly increased constitutive activity.

BACKGROUND: Subclinical hyperthyroidism is usually associated with Graves' disease or toxic nodular goiter. Here we report a family with hereditary subclinical hyperthyroidism caused by a constitutively activating germline mutation of the thyrotropin receptor (TSHR) gene. METHODS: The proband was a 64-year-old Japanese woman who presented with a thyroid nodule and was found to be euthyroid with a suppressed serum TSH. The nodule was not hot. Although antibodies to thyroid peroxidase and thyroglobulin antibodies were present, TSHR antibodies were not detected by TSH-binding inhibition or by bioassay. Two of her middle-aged sons, but not her daughter, also had subclinical hyperthyroidism without TSHR antibodies. Without therapy, the clinical condition of the affected individuals remained unchanged over 3 years without development of overt hyperthyroidism. RESULTS: A novel heterozygous TSHR point mutation causing a glutamic acid to lysine substitution at codon 575 (E575K) in the second extracellular loop was detected in the three family members with subclinical hyperthyroidism, but was absent in her one daughter with normal thyroid function. In vitro functional studies of the E575K TSHR mutation demonstrated a weak, but significant, increase in constitutive activation of the cAMP pathway. CONCLUSION: Although hereditary nonautoimmune overt hyperthyroidism is very rare, TSHR activating mutations as a cause of subclinical hyperthyroidism may be more common and should be considered in the differential diagnosis, especially if familial.

Menstrual disturbances in various thyroid diseases.

The prevalence of menstrual disturbances, including secondary amenorrhea, hypomenorrhea, oligomenorrhea, hypermenorrhea, polymenorrhea and irregular menstrual cycle were prospectively examined in 586 patients with hyperthyroidism due to Graves' disease, 111 with hypothyroidism, 558 with euthyroid chronic thyroiditis, 202 with painless thyroiditis and 595 with thyroid tumor. In the overall patient group, the prevalence did not different from that in 105 healthy controls. However, patients with severe hyperthyroidism showed a higher prevalence of secondary amenorrhea (2.5%) and hypomenorrhea (3.7%) than those (0.2% and 0.9%, respectively) with mild or moderate hyperthyroidism. Moreover, patients with severe hypothyroidism had a higher prevalence (34.8%) of menstrual disturbances than mild-moderate cases (10.2%). Menstrual disturbances in thyroid dysfunction were less frequent than previously thought.

Multiple thyroid cysts may be a cause of hypothyroidism in patients with relatively high iodine intake.

BACKGROUND: Multiple cysts of the thyroid gland have not been recognized as one of the causes of hypothyroidism. Here we present six patients from a region with relatively high iodine intake in whom multiple cysts of the thyroid were associated with hypothyroidism or the development of hypothyroidism. SUMMARY: All patients were women and ranged in age from 49 to 71. Their thyroids were mildly enlarged, tests for thyroid autoantibodies were negative, and multiple cysts were detected in the thyroid by ultrasonography. By dietary questionnaire their iodine intake was estimated to range from 2 to 10 mg of iodine daily. Otherwise, there was no evidence for disorders or factors associated with hypothyroidism. All four patients who agreed to dietary iodine restriction became euthyroid at approximately 1 month after a low-iodine diet (less than 0.5 mg iodine per day) was started. CONCLUSIONS: Although these patients were from a region with high-iodine intake and had a relatively high intake compared with most regions of the world, this amount of iodine intake is not associated with hypothyroidism in otherwise healthy persons. Therefore, we propose that multiple thyroid cysts, which we have termed polycystic goiter, is probably a cause of hypothyroidism in patients with a relatively high iodine intake.

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.

Prevalence of TSH receptor and Gsalpha mutations in 45 autonomously functioning thyroid nodules in Japan.

Somatic mutations of the thyrotropin receptor (TSHR) gene and the gene encoding the alpha subunit of the stimulatory GTP-binding protein (Gsalpha) are the main cause for autonomously functioning thyroid nodules (AFTN) in iodine-deficient regions of the world. In iodine-sufficient regions, including Japan, the genetic relevance of AFTN is unclear. In a series of 45 Japanese subjects with AFTN, exons 9 and 10 of the TSHR and exons 7-10 of Gsalpha , where the activating mutations have been found, were analyzed using direct sequencing. We found 29 somatic mutations: 22 in the TSHR gene and 7 in the Gsalpha gene. The most frequent mutation in TSHR was Met453Thr (10 cases), followed by clustered residues from codons 630 through 633 on TSHR (7 cases). Mutations of Gsalpha were detected at codon 201 in 5 cases and at codon 227 in 2 cases. No patients had coexistent TSHR and Gsalpha mutations in the same nodule. All mutated residues but one, which was deleted at codon 403 on the TSHR gene, are constitutively active. The prevalences of a germline polymorphism of Asp727Glu on the TSHR gene and incidental papillary thyroid carcinoma in thyroid surgical specimens were similar to those reported in other studies. In the present study, more than half of the cases with AFTN had a somatic activating mutation either of the TSHR or Gsalpha gene, despite their high iodine intake.

Methimazole-induced agranulocytosis in patients with Graves' disease is more frequent with an initial dose of 30 mg daily than with 15 mg daily.

BACKGROUND: Antithyroid drugs (ATDs) are prescribed as the initial therapy for the majority of patients with Graves' disease in many areas of the world. Although, it is well known that agranulocytosis is one of the most serious side effects of ATDs, there has not yet been any conclusive evidence that the prevalence of agranulocytosis induced by ATDs is dose related. This study was performed to determine if the prevalence of agranulocytosis is different depending on the starting dosage of ATDs in patients with Graves' disease. METHODS: Until 1996, we had typically prescribed 30 mg/d of methimazole (MMI) as the initial dosage for the treatment of Graves' disease at our institution. We changed the initial MMI dosage to 15 mg/d as a general rule in 1997. As a consequence, we acquired two groups of patients with Graves' disease who received different dosages of MMI. We retrospectively compared the prevalence of MMI-induced agranulocytosis in patients who received 15 mg/d of MMI to those who received 30 mg/d of MMI. RESULTS: There were 2087 subjects treated with 30 mg/d of MMI and 2739 treated with 15 mg/d of MMI. The prevalence of agranulocytosis in the 30 mg/d group was significantly higher than in the 15 mg/d group (0.814% vs. 0.219%, respectively, p < 0.01). The prevalence of agranulocytosis plus neutropenia in the 30 mg/d group was also significantly higher than in the 15 mg/d group (1.581% vs. 0.474%, respectively, p < 0.001). CONCLUSIONS: It is very likely that MMI-induced agranulocytosis occurs with a larger dosage of MMI and is dose related. Considering both the effectiveness and the risk of serious side effects, we recommend 15 mg/d of MMI as the starting dosage for the treatment of Graves' disease.