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.

Hypoalbuminemia, influenza vaccination and other factors related to the development of pneumonia acquired outside hospitals in southern Japan: A case-control study.

AIM: Pneumonia is the third largest cause of death in Japan. Pneumonia continues to be one of the most common causes of morbidity, hospitalization and mortality, especially in the elderly. The aim of the present study was to evaluate the factors related to the development of pneumonia acquired outside hospitals among the Japanese elderly. METHODS: We carried out a hospital-based, case-control study. Cases were patients who had been newly diagnosed with pneumonia acquired outside hospitals. For each case, one to three controls were defined as outpatients with other diseases (not pneumonia) at the same hospitals. All participants (i.e. 50 cases and 110 controls) were aged 65 years and older. RESULTS: Compared with control participants, hypoalbuminemia (<3.5 g/dL) and low body mass index (<18.0) were more common in pneumonia patients, whereas the proportion of those who could go out by themselves (i.e. self-support in activities of daily living) and the vaccination rate of seasonal influenza were lower in patients with pneumonia than control participants. Even after controlling for age, sex, hospital and aforementioned four factors, hypoalbuminemia (OR 9.19, 95% CI 3.70-22.81) increased the risk of pneumonia, whereas seasonal influenza vaccination (OR 0.37, 95% CI 0.16-0.85) reduced the risk. Even after excluding those who lived in a nursing home, hypoalbuminemina (OR 12.19, 95% CI 4.29-34.63) increased the risk of pneumonia. CONCLUSIONS: Hypoalbuminemia might be a risk factor for pneumonia among the elderly living in the community.

Onset of reversible flaccid quadriplegia during treatment of thyrotoxic crisis.

Two unrelated women were hospitalized for thyrotoxic crisis complicated by multiple organ failure. Both patients were treated with antithyroid drugs and hydrocortisone, as well as insulin for hyperglycemia, and underwent mechanical ventilation with sedation. Flaccid quadriplegia became apparent after each patient completely recovered their level of consciousness once sedation was discontinued on days 6 and 15, respectively. Three to six months of rehabilitation was required for the muscle strength to fully improve in both cases. Thyrotoxicosis in addition to critical illness polyneuromyopathy and the administration of glucocorticoid therapy may have contributed to the onset of quadriplegia in these two cases. Flaccid quadriplegia is one of the serious neuromuscular conditions experienced during the treatment of thyrotoxic crisis.

Simultaneous occurrence of type 1 diabetes mellitus and Graves' disease: a report of two cases and a review of the literature.

Two unrelated Japanese women, 41 and 27 years of age, were admitted with histories of thirst, weight loss and palpitations of a few weeks' duration. Both were diagnosed to have diabetic ketosis or ketoacidosis with acute-onset type 1 diabetes (T1D) and Graves' disease (GD) (autoimmune polyglandular syndrome type 3 variant; APS3v), and were treated with intensive insulin therapy and anti-thyroid drugs. Human leukocyte antigen examinations showed that both cases had the HLA-A2, A24, B54, and DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype, which made them susceptible not only to APS3v, but also to both acute-onset T1D and GD. The genetic background of patients strongly contributes to the simultaneous occurrence of T1D and GD.

Isolated adrenocorticotropin deficiency associated with painless thyroiditis: a case report and review of the literature.

A 53-year-old Japanese man was admitted with a 3-month history of transient headache followed by general fatigue and weight loss. He had a history of ocular myasthenia gravis which had been in remission following thymectomy 30 years ago. He had a small diffuse goiter without tenderness, and was diagnosed as having painless thyroiditis with mild thyrotoxicosis on admission. Endocrinological studies showed he had isolated adrenocorticotropin deficiency. Magnetic resonance imaging of the pituitary gland revealed no abnormalities. His symptoms improved soon after replacement of glucocorticoid. After an episode of hypothyroidism, he spontaneously became euthyroid. It is likely that thyrotoxicosis uncovered adrenal insufficiency that had developed insidiously, and hypoadrenocorticism-induced immunological changes may have triggered the development of painless thyroiditis. Moreover, thymectomy might have facilitated the development of pituitary and thyroid autoimmunity.

Stress and thyroid autoimmunity.

While many studies have shown a connection between stress and autoimmune disease, most of the evidence for stress contributing to the onset and course of autoimmune disease is circumstantial and the mechanisms by which stress affects autoimmune disease are not fully understood. The best circumstantial evidence for an effect of stress on autoimmune thyroid disease is the well-known relationship between the onset of Graves' hyperthyroidism and major stress but even this is debated. However, most of the recent case-control studies have supported stress as a factor that affects the onset and clinical course of Graves' disease. On the other hand, there have been few reports concerning the possible relationship between stress and Hashimoto's thyroiditis. Because the onset and course of Hashimoto's thyroiditis is generally insidious, the effect of stress on Hashimoto's thyroiditis might be overlooked. Numerous human and animal studies have demonstrated that psychological and physiologic stressors induce various immunologic changes. Stress affects the immune system either directly or indirectly through the nervous and endocrine systems. These immune modulations may contribute to the development of autoimmunity as well as the susceptibility to autoimmune disease in genetically predisposed individuals. Stress can be one of the environmental factors for thyroid autoimmunity.