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.

Utility of outpatient fractionated radioiodine therapy for Graves disease involving a large goiter measuring more than 100 mL in volume.

Contrary to large multinodular goiters, reports on 131I radioiodine therapy (RIT) for Graves disease (GD) involving a large goiter are scarce. We retrospectively reviewed a total of 71 consecutive patients (25 males, 46 females) with GD involving a large goiter (>100 mL) who had received RIT in our clinic. Patients with a history of thyroid surgery or with large thyroid nodules and those who had dropped out less than one year after the initial RIT session were excluded. A fixed 131I activity of 481 MBq was administered in most cases. RIT was repeated at intervals of 1-47 months, typically 3-6 months. The follow-up duration after the initial RIT session was 13-233 (median: 81) months. The thyroid volume was estimated using ultrasound. The number of 131I doses were 1 dose in 13 patients, 2 doses in 29, 3 doses in 17, 4 doses in 5, 5 doses in 5, 6 doses in 1, and 8 doses in 1. Sixty-six patients had remission from overt hyperthyroidism after RIT: overt hypothyroidism in 45 patients, subclinical hypothyroidism or euthyroidism in 13, and subclinical hyperthyroidism in 8. Their thyroid volume decreased from 101-481 (median: 126) mL to 1.4-37 (8.2) mL. Three patients still had overt hyperthyroidism under treatment with methimazole after one to three doses, and two dropped out less than six months after the third or sixth dose. Even in GD patients with a large goiter (>100 mL), repeated RIT with an activity of 481 MBq could sufficiently shrink goiters and remit overt hyperthyroidism.

Thyroid Function of Infants Breastfed by Mothers with Graves Disease Treated with Inorganic Iodine: A Study of 100 Cases.

CONTEXT: We previously reported that inorganic iodine therapy in lactating women with Graves disease (GD) did not affect the thyroid function in 25 of 26 infants despite their exposure to excess iodine via breast milk. OBJECTIVE: To further assess thyroid function in infants nursed by mothers with GD treated with inorganic iodine. DESIGN: Case series. SETTING: Tajiri Thyroid Clinic, Japan. PARTICIPANTS: One hundred infants of lactating mothers with GD treated with potassium iodide (KI) for thyrotoxicosis. MAIN OUTCOME MEASURES: Infant blood thyrotropin (TSH) and free thyroxine (FT4) levels were measured by the filter paper method. Subclinical hypothyroidism was defined as TSH ≥10 µIU/mL and ≥5 µIU/mL in infants aged <6 and ≥6 months, respectively. RESULTS: Overall, 210 blood samples were obtained from 100 infants. The median infant age was 5 (range, 0-23) months; median maternal KI dose, 50 (4-100) mg/day; median blood TSH level, 2.7 (0.1-12.3) µIU/mL; and median blood FT4 level, 1.04 (0.58-1.94) ng/dL. Blood TSH level was normal in 88/100 infants. Twelve infants had subclinical hypothyroidism; among them, blood TSH levels normalized after maternal KI withdrawal or stopping breastfeeding in 3 infants. In 7 infants, blood TSH levels normalized during KI administration without stopping breastfeeding. Two infants could not be followed up. CONCLUSION: In Japan, inorganic iodine therapy for lactating women with GD did not affect thyroid function in most of the infants. Approximately 10% of infants had mild subclinical hypothyroidism, but blood TSH level normalized during continued or after discontinuing iodine exposure in all followed up infants.

Long-Term Outcomes of Radioiodine Therapy for Juvenile Graves Disease with Emphasis on Subsequently Detected Thyroid Nodules: A Single Institution Experience from Japan.

OBJECTIVE: To investigate the long-term outcomes of radioiodine therapy (RIT) for juvenile Graves disease (GD) and the ultrasonographic changes of the thyroid gland. METHODS: All of 117 juvenile patients (25 males and 92 females, aged 10 to 18 [median 16] years) who had undergone RIT for GD at our clinic between 1999 and 2018 were retrospectively reviewed. Each RIT session was delivered on an outpatient basis. The maximum 131I dose per treatment was 13.0 mCi, and the total 131I dose per patient was 3.6 to 29.8 mCi (median, 13.0 mCi). 131I administration was performed once in 89 patients, twice in 26, and three times in 2 patients. Ultrasonography of the thyroid gland was regularly performed after RIT. The duration of follow-up after the initial RIT ranged from 4 to 226 (median 95) months. RESULTS: At the latest follow-up more than 12 months after RIT (n = 111), the patients' thyroid functions were overt hypothyroidism (91%), subclinical hypothyroidism (2%), normal (5%), or subclinical hyperthyroidism (2%). New thyroid nodules were detected in 9 patients, 4 to 17 years after initial RIT. Patients with newly detected thyroid nodules underwent RIT with lower doses of 131I and had larger residual thyroid volumes than those without nodules. None of the patients were diagnosed with thyroid cancer or other malignancies during the follow-up period. CONCLUSION: Over a median follow-up period of 95 months (range, 4 to 226 months), RIT was found to be effective and safe in juvenile GD. However, cumulative evidence from further studies is required to confirm the long-term safety of RIT for juvenile GD. ABBREVIATIONS: ATD = antithyroid drug; GD = Graves disease; KI = potassium iodide; LT4 = levothyroxine; MMI = methimazole; PTU = propylthiouracil; RAIU = radio-active iodine uptake; RIT = radioiodine therapy; 99mTc = technetium-99m; TSH = thyrotropin.

Congenital Primary Hypothyroidism with the Homozygous Nonsense Mutation P.K1374* in the Thyroglobulin Gene and a Normal-sized Thyroid Gland on Levothyroxine Replacement.

Thyroglobulin (TG) gene mutations cause thyroid dyshormonogenesis, which is typically associated with a congenital goiter. We herein report the case of a 64-year-old man with congenital primary hypothyroidism who had a normal-sized thyroid gland on levothyroxine replacement. He had short stature (-3.1 standard deviations) and mild intellectual impairment. Thyroid autoantibodies were all negative, and the serum TG levels were undetectable. Eventually, he was found to have the novel homozygous nonsense mutation p.K1374* in the TG gene. The possibility of TG mutation should be considered for patients with congenital primary hypothyroidism and a very low serum TG level, regardless of the thyroid size.

Effects of Inorganic Iodine Therapy Administered to Lactating Mothers With Graves Disease on Infant Thyroid Function.

CONTEXT: The effects of maternal inorganic iodine therapy on infant thyroid function are not well known. OBJECTIVE: This study investigated the effects on infant thyroid function of maternal inorganic iodine therapy when administered to lactating mothers with Graves disease. DESIGN AND SETTING: This study was a prospective case series performed at the Tajiri Thyroid Clinic, Kumamoto, Japan. PARTICIPANTS: Subjects were 26 infants of lactating mothers with Graves disease treated with potassium iodide (KI) for postpartum thyrotoxicosis. MAIN OUTCOME MEASURES: Infant blood levels of thyroid-stimulating hormone (TSH) and free thyroxine were measured using the dried filter-paper method. Iodine concentrations in breast milk and infant urine were measured on the same day. Subclinical hypothyroidism was defined as a blood TSH level of ≥10 or ≥5 µIU/mL in <6-month-old and 6- to 12-month-old infants, respectively. RESULTS: The median age of the infants was 3 months (range, 0 to 10 months). The median KI dose was 50 mg/d (range, 10 to 100 mg/d). High median iodine concentrations were detected in breast milk (15,050 µg/L; range, 831 to 72,000 µg/L) and infant urine (15,650 µg/L; range, 157 to 250,000 µg/L). Twenty-five of 26 infants had normal thyroid function. Although one infant had subclinical hypothyroidism (blood TSH, 12.3 µIU/mL), the TSH level normalized to 2.3 µIU/mL at 2 months after KI discontinuation. CONCLUSION: In Japan, where iodine intake is sufficient, administration of inorganic iodine to lactating mothers with Graves disease did not affect thyroid function in most infants despite high levels of exposure to iodine via breast milk.

Painful Radiation Thyroiditis after 131I Therapy for Graves' Hyperthyroidism: Clinical Features and Ultrasonographic Findings in Five Cases.

BACKGROUND: Radiation thyroiditis caused by 131I therapy for Graves' hyperthyroidism is asymptomatic in most patients and is rarely associated with pain or fever. Currently, there are few reports on the ultrasonographic findings of radiation thyroiditis after 131I therapy for Graves' hyperthyroidism. CASE REPORT: We herein report 5 cases with painful radiation thyroiditis (including 2 febrile cases) after 131I therapy for Graves' hyperthyroidism. The cases included 4 women, aged 49, 50, 76, and 81 years, and 1 man, aged 60 years. Anterior neck pain developed 0-10 days after 131I administration (fixed dose of 481 MBq). Each patient visited our clinic 0-4 days after the development of anterior neck pain. The thyroid glands were noticeably enlarged (increasing from 18 g at 131I administration to 35 g after the development of anterior neck pain in 1 patient, and from 20 to 33 g, 21 to 39 g, 21 to 51 g, and 40 to 51 g in the other patients) and tender. The echogenicity of the thyroid parenchyma was increased, and the parenchyma was more heterogeneous. Granular hyperechoic lesions were scattered throughout the thyroid gland in the most severe case. The border between the thyroid gland and the surrounding tissue was blurred, and the surrounding tissue was hyperechoic. CONCLUSION: Painful radiation thyroiditis should be reacknowledged as one of the complications of 131I therapy for Graves' hyperthyroidism. Ultrasonography demonstrated the characteristic changes caused by 131I-induced radiation thyroiditis.

Iodide Transport Defect and Breast Milk Iodine.

BACKGROUND: Iodide transport defect (ITD) is a dyshormonogenetic congenital hypothyroidism caused by sodium/iodide symporter (NIS) gene mutations. In the lactating mammary gland, iodide is concentrated by NIS, and iodine for thyroid hormone synthesis is thereby supplied to the infant in the breast milk. CASE DESCRIPTION: A 34-year-old Japanese woman was diagnosed with ITD caused by a homozygous NIS gene mutation T354P. She had begun treatment of primary hypothyroidism with levothyroxine at the age of 5. She delivered a baby at the age of 36. The iodine concentration in her breast milk was 54 µg/l. She took a 50-mg potassium iodide tablet daily to supply iodine in the breast milk, starting on the 5th day postpartum. Her breast milk iodine concentration increased to 90 µg/l (slightly above the minimum requirement level). The patient weaned her baby and stopped taking the daily potassium iodide tablet 6 weeks postpartum, and the baby began to be fed with relatively iodine-rich formula milk. The baby's thyroid function remained normal from birth until 6 months of age. CONCLUSION: Possible iodine deficiency in the infant breast-fed by an ITD patient should be kept in mind. Prophylactic iodine supplementation is essential for such infants in order to prevent severe iodine deficiency.

FREQUENCY OF FLAME SENSOR ACTIVATION IN PUBLIC PLACES AFTER ADMINISTRATION OF RADIOACTIVE IODINE TO TREAT GRAVES DISEASE: A RECENT SURVEY.

OBJECTIVE: Ultraviolet (UV)-perception-type flame sensors detect gamma rays emitted from iodine 131 ((131)I). Explaining the possibility of flame sensor activation to patients when they receive (131)I to treat Graves disease or other ablative purposes is important. We investigate the current situation of flame sensor activation after radioactive iodine (RAI) therapy. METHODS: A total of 318 patients (65 males and 253 females) with Graves disease who received RAI therapy at our clinic between November 2007 and June 2014 participated in this study. Patients were given both written and oral explanations regarding the possibility of flame sensor activation. Participants were surveyed with a questionnaire. The following question was asked: "Did the fire alarm (flame sensor) go off when you used a restroom in places like shopping centers within a few days after your isotope therapy?" To those who answered "yes," we asked where the fire alarm had gone off. RESULTS: Of the 318 patients, 19 (6.0%) answered "yes," 2 of whom were male while 17 were female. Of the 299 (94.0%) patients who answered "no," 63 were male and 236 were female. As to the place of restroom sensor activation, shopping centers were reported by 9 patients; supermarkets by 5; airports by 2; and a bookstore, the Kyushu Shinkansen (bullet train), and a hospital by 1 each. CONCLUSION: Explaining to patients the possibility of flame sensor activation after RAI therapy is important to avoid some complications, especially in security-sensitive areas. ABBREVIATIONS: (131)I = iodine 131 RAI = radioactive iodine UV = ultra-violet.

Development of Primary Thyroid Lymphoma during an Ultrasonographic Follow-up of Hashimoto's Thyroiditis: A Report of 9 Cases.

We herein experienced 9 patients with primary thyroid lymphoma that developed during 3-18 years of ultrasonographic follow-up of Hashimoto's thyroiditis. All nine patients had localized mucosa-associated lymphoid tissue (MALT) lymphoma. Two patients had diffuse type, one had mixed type, and six had nodular type according to the ultrasonographic classification. A clearly enlarging goiter was observed before the diagnosis of lymphoma in 3 patients. An enlarging goiter was not apparent in the remaining 6 patients with nodular type lymphoma, however, the emergence or enlargement of a hypoechoic nodular lesion was observed. Thyroid MALT lymphoma may be diagnosed early by an ultrasonographic follow-up of Hashimoto's thyroiditis.

Cell density impacts epigenetic regulation of cytokine-induced E-selectin gene expression in vascular endothelium.

Growing evidence suggests that the phenotype of endothelial cells during angiogenesis differs from that of quiescent endothelial cells, although little is known regarding the difference in the susceptibility to inflammation between both the conditions. Here, we assessed the inflammatory response in sparse and confluent endothelial cell monolayers. To obtain sparse and confluent monolayers, human umbilical vein endothelial cells were seeded at a density of 7.3 × 10(3) cells/cm(2) and 29.2 × 10(3) cells/cm(2), respectively, followed by culturing for 36 h and stimulation with tumor necrosis factor α. The levels of tumor necrosis factor α-induced E-selectin protein and mRNA expression were higher in the confluent monolayer than in the sparse monolayer. The phosphorylation of c-jun N-terminal kinase and p38 mitogen-activated protein kinase or nuclear factor-κB activation was not involved in this phenomenon. A chromatin immunoprecipitation assay of the E-selectin promoter using an anti-acetyl-histone H3 antibody showed that the E-selectin promoter was highly and specifically acetylated in the confluent monolayer after tumor necrosis factor α activation. Furthermore, chromatin accessibility real-time PCR showed that the chromatin accessibility at the E-selectin promoter was higher in the confluent monolayer than in the sparse monolayer. Our data suggest that the inflammatory response may change during blood vessel maturation via epigenetic mechanisms that affect the accessibility of chromatin.