Determination of Capillary Blood TSH and Free Thyroxine Levels Using Digital Immunoassay.

Background: The remote performance of thyroid function blood tests is complicated because it requires blood collection. Objective: To compare TSH and free thyroxine (FT4) levels between capillary and venous blood and assess the adequacy of measuring each value in capillary blood. Methods: This prospective intervention study was conducted at Ito Hospital and was based on the clinical research method. The participants were 5 healthy female volunteers and 50 patients (41 females and 9 males) between the ages of 23 and 81 years. To measure TSH and FT4 levels in capillary and venous blood, a digital immunoassay (d-IA) method capable of measuring trace samples was used. Chemiluminescence measurements were used as controls. Values obtained for each assay system were compared using Spearman's correlation analysis. Capillary blood was collected using an autologous device (TAP II; not approved in Japan). Results: Capillary plasma volume obtained using TAP II was 125 µL or more in 26 cases, 25 µL to 124 µL in 24 cases, and less than 25 µL in 5 cases. Strong correlations were noted in the TSH and FT4 levels between capillary and venous blood, with correlation coefficients of rs = 0.99 and rs = 0.97, respectively. Conclusion: Capillary TSH and FT4 levels strongly correlate with venous blood values. Trace samples can be used in high-precision d-IA methods. These results may promote telemedicine in assessing thyroid function.

Role of Surgery in Patients with Stage IE Primary Thyroid MALT Lymphoma Staged by a Modified Classification System: The Tokyo Classification.

PURPOSES: To establish the appropriate staging system and assess the role of curative thyroidectomy alone (Surgery) vs. involved-site radiation therapy after open biopsy (OB-ISRT) in stage IE mucosa-associated lymphoid tissue (MALT) lymphoma. METHODS: We examined the Tokyo Classification as a modified classification. This retrospective cohort study included 256 patients with thyroid MALT lymphoma; 137 underwent standard therapy (i.e., OB-ISRT) and were enrolled for the Tokyo classification. Sixty stage IE patients with the same diagnosis were examined to compare Surgery with OB-ISRT. RESULTS: Overall survival (p = 0.0092) and relapse-free survival (0.00113) were significantly better in stage IE vs. stage IIE under the Tokyo classification. No OB-ISRT and Surgery patients died, but three OB-ISRT patients relapsed. The incidence of permanent complications was 28% in OB-ISRT (mainly dry mouth) and 0% in Surgery (p = 0.027). The number of painkiller prescription days was significantly greater in OB-ISRT (p < 0.001). During follow-up, the rate of the new appearance/change of the low-density area in the thyroid gland was significantly higher in OB-ISRT (p = 0.031). CONCLUSIONS: The Tokyo classification allows an appropriate discrimination between stages IE and IIE MALT lymphoma. Surgery can provide a good prognosis in stage IE cases; it also avoids complications, shortens painful periods during treatment, and simplifies ultrasound follow-up.

Adult Thyroid Outcomes of Congenital Hypothyroidism.

Background: More than 40 years have passed since the introduction of newborn screening (NBS) for congenital hypothyroidism (CH), and many early diagnosed patients have reached adulthood. Their thyroid morphology and function have been little studied. This cross-sectional, observational study was conducted to characterize the thyroid morphology and function of adult CH patients diagnosed in the framework of NBS for CH. Methods: A total of 103 adult CH patients born after 1979 were enrolled at Ito Hospital, Tokyo, Japan, and were classified into Goiter, Normal gland, and Dysgenesis groups based on ultrasonographic findings. For 60 patients, genetic analysis was performed. Thyroid function test results and the proportion of patients with thyroid nodules were compared among the three groups and between 56 female CH patients and 168 non-CH women matched for thyrotropin levels. Results: A significantly low serum free triiodothyronine/free thyroxine ratio (0.22) was observed in the Dysgenesis group. Thyroid nodules were detected in 14.3% (8/56) of female CH patients, more frequently than in non-CH women. Thyroid nodules were detected most frequently in the Goiter group (71%, 10/14). Genetic defects were identified in 89% (8/9) of patients belonging to the Goiter group, including thyroglobulin defect (33%, 3/9), thyroid peroxidase defect (33%, 3/9), and dual oxidase 2 defect (22%, 2/9). Conclusions: Our results suggest that adults with thyroid dysgenesis on levothyroxine replacement therapy have relative triiodothyronine deficiency. Most adults with goitrous CH have genetic dyshormonogenesis. They are at high risk of developing thyroid nodules. Our findings support the current guideline recommendation that CH patients with dyshormonogenesis should undergo periodic thyroid ultrasonography.

Incidence of and Risk Factors for Neonatal Hypothyroidism Among Women with Graves' Disease Treated with Antithyroid Drugs Until Delivery.

Background: The incidence of neonatal hypothyroidism among newborns born to mothers with Graves' disease (GD) who continued antithyroid drug (ATD) treatment until delivery has never been reported. Objective: Our primary objective was to investigate the incidence of neonatal hypothyroidism among newborns born to mothers with GD who were treated with ATD until delivery. Our secondary objective was to identify the cutoff ATD daily doses for neonatal hypothyroidism risk, based on maternal thyrotropin (TSH) receptor antibody (TRAb) levels. Methods: We conducted a retrospective cohort study. We included 305 pregnant women with GD who were treated with an ATD until delivery (63 treated with methimazole [MMI] and 242 treated with propylthiouracil [PTU]). Umbilical cord TSH, free thyroxine (fT4), and TRAb levels were measured at delivery, and we investigated the respective relationships between neonatal hypothyroidism at delivery and maternal fT4 levels, TRAb levels, and daily ATD doses during pregnancy. Neonatal hypothyroidism was diagnosed when the umbilical cord fT4 level was below the lower limit of the reference range. Results: The incidence of neonatal hypothyroidism at delivery was 19.0% ([confidence interval, CI, 11.2-30.4]; 12/63) in the MMI group and 12.8% ([CI, 9.2-17.6]; 31/242) in the PTU group. Neonatal goiter was observed in one neonate in the PTU group, and two infants in the PTU group required levothyroxine treatment. The daily ATD dose in the third trimester was the strongest predictor of neonatal hypothyroidism at delivery; the cutoff MMI dose was 10 mg/day, and the cutoff PTU dose was 150 mg/day. When the maternal TRAb level in the third trimester was above three times the upper limit of the normal range, the cutoff MMI dose was 20 mg/day, and the cutoff PTU dose was 150 mg/day. Conclusions: Maternal fT4 and TRAb levels were higher in the neonatal hypothyroid group, which suggested prolonged GD activity. Careful follow-up is necessary when maternal GD remains active and the ATD dose to control maternal thyrotoxicosis cannot be reduced.

The Mediation Role of Thyrotropin Receptor Antibody in the Relationship Between Age and Severity of Hyperthyroidism in Graves' Disease.

Background: The severity of hyperthyroidism in Graves' disease (GD) has been reported to be worse in younger patients and to gradually improve with advancing age, accompanied by declining thyrotropin (TSH) receptor antibody (TRAb) values. This study was conducted to explore the extent to which the declining TRAb production may contribute to a decrease in severe hyperthyroidism with advancing age in patients with GD. Methods: This study was a cross-sectional analysis of retrospectively reviewed data. The medical records of patients newly diagnosed with GD at Ito Hospital, between January 2005 and June 2019, were examined. Patients were divided into age-stratified groups for evaluation. Multivariable logistic regression was performed to estimate the odds ratio (OR) of severe hyperthyroidism by increasing age. Mediation analyses were also conducted to quantify the association between age and declining severity of hyperthyroidism mediated through decreased TRAb productivity. Results: A total of 21,018 patients with newly diagnosed GD (3848 male and 17,170 female) were included. A correlation was observed between TRAb value and thyroid hormone values in each age-stratified group, which became weaker with an increase in age. Patients aged <40 years had a higher risk of severe hyperthyroidism (free thyroxine [fT4] level >7.0 ng/dL [n = 5616], OR [confidence interval, CI] = 1.80 [1.68-1.92]; free triiodothyronine [fT3] level >25 pg/mL [n = 4501], OR [CI] = 2.06 [1.92-2.23]) than those aged ≧40 years. In examining the relationship between age and severe hyperthyroidism, the proportion mediated through TRAb productivity was 8.5% and 8.4% using fT4 and fT3 as an outcome index, respectively. Conclusions: Declining TRAb value mediated only 8.5% of the negative association between age and severity of hyperthyroidism. The presence of other underlying mechanisms, such as the decline in the reactivity of thyrocytes to TSH stimulation, requires further investigation.

The Relationship Between Primary Thyroid Lymphoma and Various Types of Thyroid Autoimmunity: A Retrospective Cohort Study of 498 Cases, Including 9 Cases with Graves' Disease.

Background: Primary thyroid lymphoma (PTL) is known to develop mostly in patients with Hashimoto's thyroiditis (HT), and it is rare for it to develop in patients with Graves' disease (GD). The objective of this study was to investigate the clinical features, pathological findings, and long-term outcomes of PTL patients, grouped according to the presence of GD, HT, or no autoimmune thyroid disease (AITDs). The GD group was of major interest due to limited knowledge of the relationship with PTL. Methods: In this single-center retrospective cohort study, we reviewed the medical records of all patients diagnosed with PTL between August 1979 and October 2021, and we characterized the patients according to the presence of HT, GD, or no AITDs. Pathological specimens were classified according to the World Health Organization classification. Staging was performed in accordance with the Ann Arbor classification. Results: During the 42-year period, 498 participants were diagnosed with PTL. The median age was 68 (interquartile range 61-76) years, and 221 patients were stage IE, whereas the remaining 277 patients were stage IIE. Of the PTL patients, 431 (86.6%) were diagnosed with HT, 9 (1.8%) were diagnosed with GD, and 58 (11.6%) did not have AITDs. All nine patients with GD were positive for anti-thyroglobulin antibody and/or anti-thyroid peroxidase antibody. All patients with GD were treated with anti-thyroid medication. There were no significant differences in the proportions of each subtype of PTL between the PTL patients with GD and all subjects with PTL (p = 0.51), PTL patients with HT (p = 0.51), or PTL patients without AITDs (p = 0.48). The median follow-up time was 6.2 (interquartile range 3.0-10.7) years after the diagnosis of PTL. The Kaplan-Meier curve analyses showed no significant differences in overall survival and event-free survival between PTL patients with GD and those with HT (p = 0.37), or between PTL patients with GD and those without AITDs (p = 0.43). Conclusions: The PTL was observed with HT in a majority of cases, and rarely with GD (1.8%). The proportions of each pathological subtype of PTL and the prognosis of PTL were not different between the patients with GD and those with HT or those without AITDs.

Clinical course and outcome of differentiated thyroid cancer patients with pregnancy after diagnosis of distant metastasis.

PURPOSE: There is no sufficient data about the clinical course and outcome in thyroid cancer patients who become pregnant after diagnosis of distant metastasis (DM). The current study was conducted to collect information regarding the clinical and reproductive characteristics, and outcomes in thyroid cancer patients who became pregnant after being diagnosed with DM. METHODS: Records of 125 differentiated thyroid cancer (DTC) patients with age ≤45 years at DM diagnosis who had visited Ito Hospital from January 2005 to June 2021 were retrospectively reviewed. Among those 125 patients, 28 who became pregnant after DM diagnosis were classified as pregnancy group, and the remained 97 patients were classified as comparator group. RESULTS: In pregnancy group, the median age at malignancy diagnosis, DM diagnosis, and first pregnancy after DM diagnosis was 25 years (range, 4-41 years), 27 years (range, 11-41 years), and 32 years (range, 25-45 years), respectively. Fifty-five pregnancies and 40 live births were reported. Other pregnancy outcomes were miscarriage (n = 14) and induced abortion (n = 1). The 10-year progression-free survival (PFS) rates of pregnant and comparator group were 92.1% and 74.4%, respectively (p = 0.018). The multivariate analysis showed that multiple 131I treatment was independent negative prognostic factor for PFS (p = 0.046). CONCLUSIONS: DTC patients with age ≤45 years at DM diagnosis had good survival even though they became pregnant. Our results add to the information required for counseling thyroid cancer patients who have concerns about their fertility in the future.

Delayed Follow-up Visits and Thyrotropin Among Patients With Levothyroxine During the COVID-19 Pandemic.

CONTEXT: The indirect effects of the COVID-19 pandemic on clinical practice have received great attention, but evidence regarding thyroid disease management is lacking. OBJECTIVE: We aimed to investigate the association between delayed follow-up visits during the pandemic and their serum thyrotropin (TSH) levels among patients being treated with levothyroxine. METHODS: This study included 25 361 patients who made a follow-up visit as scheduled (n = 9063) or a delayed follow-up visit (< 30 d, n = 10 909; ≥ 30 d, n = 5389) during the pandemic (after April 2020) in Japan. We employed modified Poisson models to estimate the adjusted risk ratio (aRR) of TSH greater than 4.5 mIU/L and greater than 10 mIU/L during the pandemic according to the 3 types of follow-up visit group (ie, as scheduled, delayed < 30 d, and delayed ≥ 30 d). The models included age, sex, city of residence, TSH levels, underlying thyroid disease, dose of levothyroxine, and duration of levothyroxine prescriptions. RESULTS: The mean age was 52.8 years and women were 88%. Patients who were older and had a higher dose or longer duration of levothyroxine prescriptions were more likely to make a delayed follow-up visit during the pandemic. Changes in TSH were larger among the delayed-visit groups than the scheduled-visit group. We found increased risks of elevated TSH levels during the pandemic among the delayed visit groups, particularly those with delayed visit of 30 or more days (TSH > 4.5 mIU/L, aRR [95% CI] = 1.72 [1.60-1.85]; and TSH > 10 mIU/L, aRR [95% CI] = 2.38 [2.16-2.62]). CONCLUSION: A delayed follow-up visit during the COVID-19 pandemic was associated with less well-controlled TSH among patients with levothyroxine.

Thyroid Hormone Plays an Important Role in Cardiac Function: From Bench to Bedside.

Thyroid hormones (THs) are synthesized in the thyroid gland, and they circulate in the blood to regulate cells, tissues, and organs in the body. In particular, they exert several effects on the cardiovascular system. It is well known that THs raise the heart rate and cardiac contractility, improve the systolic and diastolic function of the heart, and decrease systemic vascular resistance. In the past 30 years, some researchers have studied the molecular pathways that mediate the role of TH in the cardiovascular system, to better understand its mechanisms of action. Two types of mechanisms, which are genomic and non-genomic pathways, underlie the effects of THs on cardiomyocytes. In this review, we summarize the current knowledge of the action of THs in the cardiac function, the clinical manifestation and parameters of their hemodynamics, and treatment principles for patients with hyperthyroid- or hypothyroid-associated heart disease. We also describe the cardiovascular drugs that induce thyroid dysfunction and explain the mechanism underlying the thyroid toxicity of amiodarone, which is considered the most effective antiarrhythmic agent. Finally, we discuss the recent reports on the involvement of thyroid hormones in the regulation of myocardial regeneration and metabolism in the adult heart.

Thyroid MALT lymphoma: self-harm to gain potential T-cell help.

The development of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is driven by chronic inflammatory responses and acquired genetic changes. To investigate its genetic bases, we performed targeted sequencing of 93 genes in 131 MALT lymphomas including 76 from the thyroid. We found frequent deleterious mutations of TET2 (86%), CD274 (53%), TNFRSF14 (53%), and TNFAIP3 (30%) in thyroid MALT lymphoma. CD274 was also frequently deleted, together with mutation seen in 68% of cases. There was a significant association between CD274 mutation/deletion and TNFRSF14 mutation (p = 0.001). CD274 (PD-L1) and TNFRSF14 are ligands for the co-inhibitory receptor PD1 and BTLA on T-helper cells, respectively, their inactivation may free T-cell activities, promoting their help to malignant B-cells. In support of this, both the proportion of activated T-cells (CD4+CD69+/CD4+) within the proximity of malignant B-cells, and the level of transformed blasts were significantly higher in cases with CD274/TNFRSF14 genetic abnormalities than those without these changes. Both CD274 and TNFRSF14 genetic changes were significantly associated with Hashimoto's thyroiditis (p = 0.01, p = 0.04, respectively), and CD274 mutation/deletion additionally associated with increased erythrocyte sedimentation rate (p = 0.0001). In conclusion, CD274/TNFRSF14 inactivation in thyroid MALT lymphoma B-cells may deregulate their interaction with T-cells, promoting co-stimulations and impairing peripheral tolerance.

Does Age or Sex Relate to Severity or Treatment Prognosis in Graves' Disease?

Background: The prognosis of Graves' disease (GD) is reportedly related to sex, age, and genetic factors, although there is no consensus. The objective of this study was to investigate the relationship between severity and prognosis of GD and sex or age. Methods: Subjects were patients newly diagnosed with GD between January 2005 and June 2019, and medical records were retrospectively reviewed. Patients diagnosed between January 2009 and December 2010 and followed up for at least 12 months were enrolled. Patients were divided into nine age-stratified groups. Remission was defined as maintenance of a euthyroid state for more than one year after withdrawal of antithyroid drugs (ATDs). Results: Participants comprised 21,633 patients (3954 males, 17,679 females). Initial free triiodothyronine (fT3) and free thyroxine (fT4) levels significantly decreased with increasing age, including after sex stratification. fT4 was significantly higher in males than females aged 20-39 years. In 2191 patients treated with ATDs alone, median durations until remission were 37.7 and 30.6 months in males and females, respectively. Remission and recurrence were observed in 1391 patients (204 males, 1187 females) and 262 patients (37 males, 225 females), respectively. By Kaplan-Meier analyses, males required a significantly longer time to achieve remission than females (p < 0.0001), although there were no significant age-related differences (p = 0.08). Cox proportional hazard modeling showed a 41% higher hazard ratio (HR) for remission in females than males (adjusted HRs [aHR] confidence interval [CI] = 1.41 [1.21-1.64]), and each additional 10 years of age had a 14% lower rate of recurrence (age [per 10-year increase], aHR [CI] = 0.86 [0.78-0.94]); no significant relationship between recurrence rate and sex was identified. Conclusions: Severity of hyperthyroidism in GD was significantly higher in males in their 20s and 30s, declining with advancing age in both sexes. Females were more likely to achieve remission than males, and younger patients had a higher risk of recurrence, although recurrence was unrelated to sex.

Exposure to Propylthiouracil in the First Trimester of Pregnancy and Birth Defects: A Study at a Single Institution.

CONTEXT: Medical treatment of Graves disease during the first trimester has been the subject of controversy ever since treatment with an antithyroid drug during the first trimester was reported to possibly be associated with an increased risk of birth defects in newborns. OBJECTIVE: We investigated whether the incidence of birth defects among newborns born to mothers with Graves disease (GD) treated with propylthiouracil (PTU) during the first trimester of pregnancy was higher than in a control group that was not exposed to any medication. METHODS: We reviewed the cases of 1913 women with GD who gave birth between January 1, 2015, and May 31, 2019. Detailed information concerning the outcome of pregnancy and the presence of birth defects was collected at the first visit after the delivery and again 1 year after delivery. We classified the mothers and infants into 3 groups according to the treatment the mother had received for GD in the first trimester of pregnancy: a group in which the mothers had been treated with PTU alone (PTU group), a group in which the mothers had not been treated with any medication (control group), and a group in which the mothers had received some other medical treatment, such as thiamazole, potassium iodide, or 2 or more drugs (other treatment group). RESULTS: The incidence of malformed infant births was 5.5% (30/541 infants) in the PTU group and 5.7% (27/ 475 infants) in the control group. There were no specific birth defects in the PTU group, and there were no significant differences between PTU dosages or maternal thyroid function according to whether mothers had delivered a child with a birth defect. CONCLUSION: The results of our retrospective study showed that treatment with PTU during the first trimester of pregnancy did not increase the incidence of birth defects among newborns.

t(3;14)(p14.1;q32)/FOXP1-IGH translocation in thyroid extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma).

OBJECTIVES: MALT lymphoma occurs in various organs and has several characteristic genetic aberrations. Thyroid MALT lymphoma has been reported to include t(3;14)(p14.1;q32)/FOXP1-IGH as a specific genetic aberration, but the number of studies is limited. METHOD AND RESULTS: We examined 86 thyroid lymphoma cases using fluorescence in situ hybridization (FISH) for the detection of t(3;14)/FOXP1-IGH in formalin fixed paraffin-embedded tissue (FFPE). Histopathological diagnoses of the analyzed specimen were as follows: thyroid MALT lymphoma (n = 59), DLBCL (n = 23), follicular lymphoma (n = 4), and benign lesions (n = 14) included Hashimoto's thyroiditis (n = 13) and other (n = 1). Of the 100 analyzed cases, thirty-six (36 %) thyroid lymphoma cases were positive for t(3;14)/FOXP1-IGH. Thirty-three (55.9 %) of the 59 MALT lymphoma cases were positive for t(3;14)/FOXP1-IGH. Three (13.0 %) of the 23 DLBCL cases were positive for t(3;14)/FOXP1-IGH. All 4 follicular lymphomas examined were negative for t(3;14)/FOXP1-IGH. None of the benign cases was positive for t(3;14)/FOXP1-IGH, including Hashimoto's thyroiditis (0/13) and benign tissue (0/1). CONCLUSIONS: Our study found that t(3;14)/FOXP1-IGH was frequently found in thyroid MALT lymphoma. A detection of t(3;14)/FOXP1-IGH is extremely useful for the differential diagnosis between primary MALT lymphoma of the thyroid and other thyroid disorders.

Characteristics of Patients with Graves' Disease Whose Thyroid Hormone Levels Increase After Substituting Potassium Iodide for Methimazole in the First Trimester of Pregnancy.

Background: The clinical course of Graves' disease (GD) in women who switched from methimazole (MMI) to potassium iodide (KI) during the first trimester of pregnancy has never been reported in detail. Objective: To investigate the characteristics of GD patients whose thyroid hormone levels increase after substituting KI for MMI. Patients: Two hundred forty women with GD who had been treated with MMI and switched from MMI to inorganic iodide to control hyperthyroidism during the first trimester between January 1, 2005, and March 31, 2018. Results: In 133 (55.4%) of the GD patients, medication was completely tapered during pregnancy, and the other 107 (44.6%) GD patients were taking medication at delivery: 57 were taking KI alone and 50 were taking an antithyroid drug with or without KI. It was difficult to control the maternal thyrotoxicosis of 22 of the 107 patients with KI alone, and a higher dose of MMI compared with the dose at the time of conception was required (worsened group). Multivariate analysis revealed that the TRAb value at the time of switch from MMI to KI was the only factor that predicted continuation of the thyroid suppression medication, but none of the parameters was a predictor of the worsened group. Conclusions: It must be kept in mind that a certain proportion of GD patients escape from the antithyroid effect of iodide and that careful follow-up is necessary after switching a pregnant patient's medication to KI.

Painless destructive thyroiditis in a patient with resistance to thyroid hormone: a case report.

BACKGROUND: Resistance to thyroid hormone (RTH) usually features a syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH) without suppression of the typical high thyroid hormone levels. However, some patients with RTH show thyroid-stimulating hormone (TSH) suppression due to thyrotoxicosis. We report a case of painless thyroiditis in a patient with RTH that was misdiagnosed as Graves' disease because of TSH-suppressed thyrotoxicosis. CASE PRESENTATION: A sixteen-year-old boy consulted a local general physician for fatigue. He had a goiter, and biochemical analysis showed TSH < 0.1 µIU/mL, free triiodothyronine (FT3) of 2.70 pg/mL, and free thyroxine (FT4) of 3.6 ng/dL. He was diagnosed with Graves' disease and was treated with 20 mg thiamazole. One year later, he was referred to the department of endocrinology because of SITSH. He was finally diagnosed with RTH due to the finding of a heterozygous missense mutation (methionine 334 threonine) in the thyroid hormone receptor ß gene. Three years after cessation of thiamazole, his hyperthyroxinemia showed marked exacerbation with TSH suppression. We diagnosed him with painless destructive thyroiditis because of low technetium-99 m (Tc-99 m) uptake in the thyroid. Extreme hyperthyroxinemia was ameliorated, with a return to the usual SITSH levels, within 1 month without any treatment. CONCLUSION: The present case demonstrates that diagnosing RTH is difficult when patients show hyperthyroxinemia with complete suppression of TSH to undetectable levels, and the data lead to misdiagnosis of RTH as Graves' disease. The initial diagnosis is important, and Tc-99 m scintigraphy is useful for the differential diagnosis of thyrotoxicosis accompanying RTH.

Analysis of Antithyroid Drug-Induced Severe Liver Injury in 18,558 Newly Diagnosed Patients with Graves' Disease in Japan.

Background: The prevalence of antithyroid drug (ATD)-related drug-induced liver injury (DILI) has been reported to vary among patients in several countries. The purpose of this study was to summarize the prevalence of liver injury induced by ATD and to determine the actual prevalence of severe liver injury. Methods: The medical records of 18,558 patients who were newly diagnosed with Graves' disease between January 2005 and December 2016 were retrospectively reviewed. Severe DILI was defined as alanine aminotransferase (ALT) 8 times higher than the upper limit of normal (ULN) or total bilirubin (T-bil) 3 times higher than the ULN. The most severe DILI was defined as ALT higher than 20 times the ULN or T-bil higher than 10 times the ULN. Results: A total of 461 subjects (470 cases) were analyzed, and they consisted of 10 males and 451 females, with a median age of 37 years (range 10-82 years). Nine of 461 patients had severe DILI with both drugs. The total prevalence of severe DILI in this study was 2.5%, and the prevalence of DILI by drug was 1.4% with metimazole (MMI) (n = 198) and 6.3% with propylthiouracil (PTU) (n = 272) (p < 0.001). The prevalence of the most severe ATD-related DILI was 0.22% (n = 40), and the prevalence for each drug was 0.08% with MMI (n = 11) and 0.68% with PTU (n = 29). The median time to DILI development was 30 days (range 7-314 days), and all patients recovered from DILI, with no fatalities. The prevalence of MMI-related DILI was significantly age dependent (p < 0.001). Conclusions: Though there were no fatalities in this study, the prevalence of PTU-related severe DILI was significantly higher than that of MMI-related severe DILI.

Incidence of Neonatal Hyperthyroidism Among Newborns of Graves' Disease Patients Treated with Radioiodine Therapy.

BACKGROUND: The serum thyrotropin receptor antibody (TRAb) titers of Graves' disease (GD) patients are known to increase after radioiodine (RAI) therapy, and they can remain high for years. The incidence of neonatal hyperthyroidism (NH) among newborns of mothers with GD who conceived after RAI therapy has not been previously reported. The aims of this study were to investigate the incidence of NH among newborns of mothers who conceived within two years after RAI therapy, and to identify predictors of NH. METHODS: GD patients (n = 145) who conceived within two years after RAI therapy were retrospectively reviewed, and information regarding their newborns was collected. RESULTS: Of the 145 pregnant women, 54 (37%) were treated with antithyroid drugs or potassium iodide for maternal hyperthyroidism during the first trimester. There were eight newborns with NH, resulting in an incidence of 5.5%. Seven of the eight mothers whose newborns had NH were treated with antithyroid drugs or potassium iodide during their pregnancy. The incidence of NH among the newborns of mothers who conceived within 6-12 months after RAI therapy was 8.8%, within 12-18 months was 5.5%, and within 18-24 months was 3.6%. Multivariate analysis revealed that the TRAb values in the third trimester were the only risk factor for NH. The cutoff TRAb value in the third trimester for predicting NH was 9.7 IU/L (reference value <2.0 IU/L). CONCLUSIONS: The incidence of NH among newborns of mothers who conceived within two years after RAI therapy was 5.5%. The fetuses of pregnant GD patients whose TRAb value is high in the third trimester should be carefully followed by an obstetrician during pregnancy, and the newborns should be carefully followed by a pediatrician after birth.

Clinical course of thyroid function and thyroid associated-ophthalmopathy in patients with euthyroid Graves' disease.

BACKGROUND: Euthyroid Graves' disease (EGD) is a rare condition defined as the presence of thyroid-associated ophthalmopathy (TAO) in patients with normal thyroid function. Due to the rarity of this disease, only a limited number of studies and case reports are available for further evaluation of the characteristics of the disease. The aim of this study was to examine the changes in the thyroid function, thyrotropin receptor antibodies (TRAb) and eye symptoms, and then determine whether TRAb is related to TAO in EGD patients. TRAb in this study was defined as including both thyrotropin-binding inhibitory immunoglobulin (TBII) and thyroid-stimulating immunoglobulin (TSAb). PATIENTS AND METHODS: Medical records of patients diagnosed with EGD were reviewed. Ophthalmologists specializing in TAO examined the eyes of all subjects. RESULTS: Of the 58 patients diagnosed with EGD, 24.1% developed hyperthyroidism, while 3.4% developed hypothyroidism. A total of 72.4% of the 58 patients remained euthyroid throughout the entire follow-up period. At the initial presentation, TBII and TSAb were positive in 74.5% and 70.5%, respectively. Ophthalmic treatments were administered to 30 (51.7%) out of the 58 patients. A significant spontaneous improvement of the eye symptoms was found in 28 of the EGD patients who did not require eye treatments. EGD patients exhibited positive rates for both TBII and TSAb, with the number of the TRAb-positive patients gradually decreasing while the eye symptoms spontaneously improved over time. There were no correlations found between TRAb at initial presentation and the eye symptoms. CONCLUSION: TBII and TSAb were positive in about 70% of EGD patients at their initial visit. Thyroid functions of EGD patients who have been euthyroid for more than 6.7 years may continue to remain euthyroid in the future.

Seasonal Changes in Serum Thyrotropin Concentrations Observed from Big Data Obtained During Six Consecutive Years from 2010 to 2015 at a Single Hospital in Japan.

BACKGROUND: This study analyzed big data for serum thyrotropin (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) concentrations in patients who had attended the outpatient clinic of Ito Hospital (Tokyo, Japan) during a recent six-year period (between January 1, 2010, and December 31, 2015) in order to investigate for seasonal changes. METHODS: The serum TSH concentrations were reviewed for all 135,417 patients aged >20 years. Patients with any thyroid diseases were included, irrespective of whether they were receiving drug therapy. In total 1,637,721 serum samples were analyzed for TSH, 1,626,269 for fT3, and 1,669,381 for fT4. RESULTS: It was observed that the TSH concentrations showed annual changes during the six-year period. They decreased during the summer, while they increased during the winter. The TSH concentrations were negatively correlated with the daily temperatures (Spearman rank correlation coefficient -0.4486; p < 0.0001). The same applied for the correlation between fT3 concentrations and daily temperatures. CONCLUSIONS: The fact that the TSH concentrations show annual changes in areas where the temperature ranges during the year are rather wide should be borne in mind for interpretation of results.

Sialic Acid-Binding Immunoglobulin-Like Lectin1 as a Novel Predictive Biomarker for Relapse in Graves' Disease: A Multicenter Study.

BACKGROUND: There are currently no reliable biomarkers to predict relapse in Graves' disease (GD). In the present study, we investigated novel diagnostic biomarkers to predict the long-term remission of or relapse in GD. METHODS: A DNA microarray analysis was performed to examine gene expression in the peripheral leukocytes of a frequently relapsing patient with GD and a patient in long-term remission after the discontinuation of antithyroid drugs (ATDs). Based on the DNA microarray analysis, we focused on Sialic acid-binding immunoglobulin-like lectin1 (SIGLEC1) as a candidate novel biomarker to predict GD relapse. Three hundred and fifty-eight patients with GD in the thyroid clinics of four different hospitals in Japan were included in a cross-sectional study to establish whether SIGLEC1 mRNA levels distinguish GD relapse experience from long-term remission. An additional 55 patients with GD were enrolled in a prospective study to clarify whether SIGLEC1 mRNA levels at ATD discontinuation predict GD relapse. RESULTS: SIGLEC1 mRNA levels were significantly higher in patients with GD relapse experience than in those in long-term remission. Based on the receiver operating characteristic analysis, we found that high SIGLEC1 mRNA levels (≥258.9 copies) significantly distinguished GD relapse experience from long-term remission (p < 0.0001; sensitivity 66.7%, specificity 70.1%). In the prospective study, when the optimal cutoff value from the receiver operating characteristic curve analysis was applied to SIGLEC1 mRNA positivity at ATD discontinuation, SIGLEC1-positive patients (≥258.9 copies) showed a significantly higher cumulative risk of relapse than SIGLEC1-negative patients (<258.9 copies) (p = 0.022, the log-rank test). CONCLUSIONS: SIGLEC1 mRNA levels have potential as a novel predictive biomarker for GD relapse.