STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of MIR7-2/MIR1179.

Thyrotropin (TSH) is the master regulator of thyroid gland growth and function. Resistance to TSH (RTSH) describes conditions with reduced sensitivity to TSH. Dominantly inherited RTSH has been linked to a locus on chromosome 15q, but its genetic basis has remained elusive. Here we show that non-coding mutations in a (TTTG)4 short tandem repeat (STR) underlie dominantly inherited RTSH in all 82 affected participants from 12 unrelated families. The STR is contained in a primate-specific Alu retrotransposon with thyroid-specific cis-regulatory chromatin features. Fiber-seq and RNA-seq studies revealed that the mutant STR activates a thyroid-specific enhancer cluster, leading to haplotype-specific upregulation of the bicistronic MIR7-2/MIR1179 locus 35 kb downstream and overexpression of its microRNA products in the participants' thyrocytes. An imbalance in signaling pathways targeted by these micro-RNAs provides a working model for this cause of RTSH. This finding broadens our current knowledge of genetic defects altering pituitary-thyroid feedback regulation.

Selenium supplementation in inactive moderate to severe Graves' orbitopathy patients: a randomized controlled trial.

PURPOSE: This study was designed to evaluate the effect of selenium supplementation in inactive moderate-severe Graves' orbitopathy (GO) patients. METHODS: This study was a single-center, placebo-controlled, double-masked, randomized trial. Inactive moderate-severe GO participants were randomized to receive six months of 200 micrograms/day of selenium supplementation or placebo. Thorough eye exams, clinical activity score (CAS), Graves' Ophthalmopathy quality of life questionnaire (GO-QOL), and serum selenium level were evaluated at baseline and 6 months after the interventions. The chi-squared or Fisher's exact test was used to compare categorical variables. The t-test and the paired t-test were used to compare continuous variables between two independent samples and two dependent samples, respectively. RESULTS: A total of 25 participants were enrolled, 13 in the selenium group and 12 in the placebo group. Both groups had adequate baseline serum selenium levels at 98.96 ± 15.63 mcg/L and 102.55 ± 17.71 mcg/L, respectively. After 6 months of intervention, the selenium group showed a greater improvement in palpebral aperture (mean difference: -1.4 ± 1.7 mm, p = .04) compared to the placebo group (-0.3 ± 2.7 mm). Notably, 5(41.67%) people in the placebo group developed larger palpebral apertures. Proptosis, ocular motility, and soft tissue signs did not change significantly. GO-QOL and CAS score improvement showed no statistically significant difference between both groups. Minor adverse effects were observed. CONCLUSIONS: Selenium supplementation has a positive effect on eyelid aperture even in inactive moderate-to-severe GO patients with a sufficient baseline selenium level.

Clinical characteristics and outcomes of an exogenous thyrotoxicosis epidemic in prison.

Introduction: An outbreak of exogenous thyrotoxicosis is an uncommon cause of thyrotoxicosis. This study aimed to investigate the characteristics and outcomes of exogenous thyrotoxicosis and electrolyte imbalance in a prison during an outbreak of exogenous thyrotoxicosis in the Phitsanulok, Thailand prison. Methods: This study collected cross-sectional data during an outbreak of thyrotoxicosis among inmates at Phitsanulok prison between 29 December 2019 and 17 January 2020. In the first phase, a total of 2815 prisoners were screened for thyroid-stimulating hormone (TSH), potassium levels and pulse rate. In the second phase, samples from 490 male prisoners were collected for test on thyroid function, serum electrolytes and urine electrolytes. Thyroglobulin levels were also measured in patients with thyrotoxicosis. A questionnaire was used to obtain patient information about signs and symptoms of thyrotoxicosis. Results: The prevalence of subclinical thyrotoxicosis was 78.1%. The pulse rate was significantly higher in the subclinical thyrotoxicosis group. Weight loss, palpitation, muscle weakness and fatigue were found predominantly in the subclinical thyrotoxicosis group. The prevalence of hypokalaemia was 38.4%; however, there was no difference between subclinical thyrotoxicosis and normal TSH. The mean magnesium levels were significantly lower in the subclinical thyrotoxicosis group. Patients with hypokalaemia mainly showed potassium loss through the kidneys. Almost all patients with suppressed TSH levels had low to normal thyroglobulin levels. In addition, the mean of calculated total step-up deiodinase activity in patients with subclinical thyrotoxicosis was lower than 30 nmol/s, which was an additional clue to confirm exogenous thyrotoxicosis. The frozen meat during the outbreak had higher levels of thyroid hormone compared with the control group. Conclusions: With an outbreak of thyrotoxicosis, most likely due to exposure to exogenous thyroid hormone in frozen meat, our findings have raised awareness of nutritional problems in prison. The development of surveillance systems to prevent outbreaks is urgently needed.

Concomitant myocarditis and painless thyroiditis after AstraZeneca coronavirus disease 2019 vaccination: a case report.

BACKGROUND: Incidence of myocarditis following messenger RNA coronavirus disease 2019 vaccination has been widely described, but this clinical scenario after adenoviral vector coronavirus disease 2019 vaccination has only been rarely reported. In addition, a few case reports of thyroiditis after adenoviral vector coronavirus disease 2019 vaccination have been published. CASE PRESENTATION: A 55-year-old Thai woman presented with palpitation without neck pain 14 days after receiving AstraZeneca coronavirus disease 2019 vaccination. Electrocardiography revealed sinus tachycardia. Her blood tests showed elevation of cardiac troponin and free triiodothyronine with suppressed serum thyroid stimulating hormone, reflecting a hyperthyroid status. Evidence of myocardial inflammation and necrosis from cardiac magnetic resonance imaging supported the diagnosis of recent myocarditis. Laboratory results and imaging findings were consistent with thyroiditis. After 3 weeks of symptomatic treatment, her symptom and blood tests had returned to normal. CONCLUSIONS: This case demonstrates that the adenoviral vector coronavirus disease 2019 vaccine could possibly cause myocarditis and painless thyroiditis. Clinicians should have a high index of suspicion and promptly evaluate these conditions, despite minimal symptoms.

Clinical phenotypes and prognosis of thyrotoxic heart failure and cardiomyopathy in patients hospitalized for acute heart failure.

BACKGROUND: We sought to examine clinical characteristics and outcomes in patients hospitalized for acute heart failure (HF) and thyrotoxicosis. METHODS: Patients with thyrotoxic HF were compared with age and gender-matched patients hospitalized for acute HF (controls). Thyr-HF was defined by the Framingham criteria for HF and clinical hyperthyroidism. Thyrotoxic cardiomyopathy was defined as left ventricular ejection fraction (LVEF) < 55%. RESULTS: Of 11 109 consecutive patients hospitalized for acute HF between 1 January 2002 and 1 January 2017, 92 patients (0.8%) had thyrotoxic HF. Clinical and echocardiographic data were available in 87 patients (age 51 ± 16 years; 74% female), representing the study population. Compared with controls, patients with Thyr-HF had a smaller body surface area (BSA), a higher LVEF, a lower LV end-diastolic diameter, a higher tricuspid annular plane systolic excursion (TAPSE), higher blood pressure, higher heart rate, and were more likely to have right-sided HF at presentation (P < 0.01 for all). The survival rate among patients with thyrotoxic HF was higher than the control group (HR: 4.3; 95% CI: 2.1-9.5). Fifty-eight percent of patients with thyrotoxic HF had thyrotoxic cardiomyopathy. In multivariate analysis, TAPSE (OR = 46; 95% CI: 1.04-2008.20; P = 0.047) and leukocytosis (OR = 16; 95% CI 1.01-259.39; P = 0.049) correlated with thyrotoxic cardiomyopathy. LV recovery was observed in 69% of these patients. CONCLUSIONS: Thyrotoxic HF was uncommon among patients hospitalized for acute HF. However, after definitive therapy, these patients had a more favourable prognosis than those hospitalized for acute HF without thyrotoxic HF. Clinical phenotypes of thyrotoxic HF include small BSA, middle-aged female, HF-pEF, and right-sided HF. Thyrotoxic cardiomyopathy affected over half of the patients with thyrotoxic HF with a two-third recovery rate.

Pembrolizumab- and ipilimumab-induced diabetic ketoacidosis and isolated adrenocorticotropic hormone deficiency: a case report.

BACKGROUND: Several human monoclonal antibodies directed against immune checkpoints, including T lymphocyte antigen 4 and programmed cell death protein 1, have been implemented for cancer treatment in order to promote effector T cell response to tumors. Despite the antitumor activity of these agents, a significant number of patients demonstrated immune-related adverse events that affected the functions of multiple organs, including the endocrine system. We report the first case of immune checkpoint inhibitor-induced simultaneous diabetic ketoacidosis and isolated adrenocorticotropic hormone deficiency following combination treatment with immune checkpoint inhibitors. CASE PRESENTATION: A 70-year-old Thai man with no previous history of diabetes mellitus was diagnosed with stage IVB non-small cell lung with pleural and liver metastases. After 14 weeks of combination treatment with pembrolizumab and ipilimumab, he presented with fatigue, nausea, and vomiting. Laboratory investigation revealed random plasma glucose 794 mg/dl, serum ketone 6.3 mmol/L, bicarbonate 13 mmol/L, and high anion gap 24 mmol/L. New-onset diabetes mellitus and diabetic ketoacidosis were diagnosed. Insulin therapy was initiated a favorable outcome within 10 hours. Despite improvement of hyperglycemia, the patient had persistent nausea and hyponatremia. Further investigation revealed cortisol 0.8 µg/dl and adrenocorticotropic hormone 21.7 pg/ml. His other pituitary hormone levels were normal, except for mild elevation of gonadotropin hormone. Magnetic resonance imaging of the pituitary showed a normal pituitary gland. Isolated adrenocorticotropic hormone deficiency was diagnosed, and corticosteroid replacement therapy was administered, resulting in an improvement of his symptoms. CONCLUSION: Our patient developed new-onset diabetes mellitus, diabetic ketoacidosis, and isolated adrenocorticotropic hormone deficiency during cancer treatment with pembrolizumab and ipilimumab. The present case highlights the need for physicians to be aware that immune-related adverse events can occur in multiple organs at the same time.

Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism.

Defects in genes mediating thyroid hormone biosynthesis result in dyshormonogenic congenital hypothyroidism (CH). Here, we report homozygous truncating mutations in SLC26A7 in 6 unrelated families with goitrous CH and show that goitrous hypothyroidism also occurs in Slc26a7-null mice. In both species, the gene is expressed predominantly in the thyroid gland, and loss of function is associated with impaired availability of iodine for thyroid hormone synthesis, partially corrected in mice by iodine supplementation. SLC26A7 is a member of the same transporter family as SLC26A4 (pendrin), an anion exchanger with affinity for iodide and chloride (among others), whose gene mutations cause congenital deafness and dyshormonogenic goiter. However, in contrast to pendrin, SLC26A7 does not mediate cellular iodide efflux and hearing in affected individuals is normal. We delineate a hitherto unrecognized role for SLC26A7 in thyroid hormone biosynthesis, for which the mechanism remains unclear.

Fetal Exposure to High Maternal Thyroid Hormone Levels Causes Central Resistance to Thyroid Hormone in Adult Humans and Mice.

Context: Fetuses exposed to the high thyroid hormone (TH) levels of mothers with resistance to thyroid hormone beta (RTH-ß), due to mutations in the THRB gene, have low birth weight and suppressed TSH. Objective: Determine if such exposure to high TH levels in embryonic life has a long-term effect into adulthood. Design: Observations in humans with a parallel design on animals to obtain a preliminary information regarding mechanism. Setting: University research centers. Patients or other participants: Humans and mice with no RTH-ß exposed during intrauterine life to high TH levels from mothers who were euthyroid due to RTH-ß. Controls were humans and mice of the same genotype but born to fathers with RTH-ß and mothers without RTH-ß and thus, with normal serum TH levels. Interventions: TSH responses to stimulation with thyrotropin-releasing hormone (TRH) during adult life in humans and male mice before and after treatment with triiodothyronine (T3). We also measured gene expression in anterior pituitaries, hypothalami, and cerebral cortices of mice. Results: Adult humans and mice without RTH-ß, exposed to high maternal TH in utero, showed persistent central resistance to TH, as evidenced by reduced responses of serum TSH to TRH when treated with T3. In mice, anterior pituitary TSH-ß and deiodinase 3 (D3) mRNAs, but not hypothalamic and cerebral cortex D3, were increased. Conclusions: Adult humans and mice without RTH-ß exposed in utero to high maternal TH levels have persistent central resistance to TH. This is likely mediated by the increased expression of D3 in the anterior pituitary, enhancing local T3 degradation.

Diagnostic Dilemma in Discordant Thyroid Function Tests Due to Thyroid Hormone Autoantibodies.

OBJECTIVE: Assay interference could be the cause of abnormal thyroid function tests. Early recognition prevents inappropriate patient management. The objective of this report is to present a case with discordant thyroid function tests in different thyroid assay platforms due to thyroid autoantibodies. METHODS: We present a case her family, laboratory data and methods that investigate immunoassay interference. RESULTS: A 21-year-old woman with autoimmune thyroid disease was treated for hypothyroidism with levothyroxine and noted to have elevated total and free thyroxine, free triiodothyronine but normal thyroid-stimulating hormone. Repeat thyroid function tests using different platforms revealed discrepant results. Further investigation showed that the patient had positive thyroid hormone autoantibodies (THAAbs). CONCLUSION: We demonstrates abnormal thyroid function tests caused by THAAbs. The latter were the cause of interference with assays resulting in discrepant test results inconsistent with the clinical presentation. Early recognition would prevent inappropriate patient management.

DUOX2 Gene Mutation Manifesting as Resistance to Thyrotropin Phenotype.

Resistance to thyrotropin (TSH) (RTSH; defined by elevated TSH and a normal or hypoplastic thyroid gland) can be caused by mutations in genes encoding the TSH receptor and PAX8, and it has been linked to a locus on chromosome 15. In two nonconsanguineous families with nongoitrous euthyroid hyperthyrotropinemia, typical of the RTSH phenotype, exome analysis identified five rare DUOX2 gene variants (p.A649E, p.P1391A, p.R885L, p.G488R, and p.SF965-6SfsX29) found to be pathogenic. This form of nongoitrous dyshormonogenesis masquerades both clinically and biochemically as RTSH. Accordingly, mutations in DUOX2 should be added to those of SLC26A4 as causes of RTSH.

A Novel Thyroid Hormone Receptor Beta Gene Mutation (G251V) in a Thai Patient with Resistance to Thyroid Hormone Coexisting with Pituitary Incidentaloma.

A patient is reported with resistance to thyroid hormone beta caused by a novel THRB gene mutation and coexisting pituitary microadenoma. A 41-year-old Thai woman presented with elevated serum thyroid hormone levels and non-suppressed thyrotropin (TSH). Magnetic resonance imaging showed a 4 mm × 2 mm pituitary adenoma. Five of her relatives had similar thyroid tests abnormalities, but a sister had Graves' disease. Thyroperoxidase and thyroglobulin antibodies were positive in all affected family members, except for the proband's 4.5-year-old niece. Lack of thyrotoxic symptoms and TSH suppression by triiodothyronine indicated incidentaloma rather than a TSH-secreting pituitary adenoma. Genetic analysis revealed a THRB gene mutation (c.1037G>T), resulting in p.G251V.

A Novel Mutation (S54C) of the PAX8 Gene in a Family with Congenital Hypothyroidism and a High Proportion of Affected Individuals.

BACKGROUND: Congenital hypothyroidism (CH) is a common endocrine disorder in newborns. The cause of CH is thyroid dysgenesis in 80-85% of patients. Paired box gene 8 (PAX8) is a thyroid transcription factor that plays an important role in thyroid organogenesis and development. To date, 22 different PAX8 gene mutations have been reported. METHODS: Four generations of a Hungarian Jewish family were affected, and in the 3 generations studied, 9 males and 4 females were affected and 3 first-degree relatives were unaffected. Six were diagnosed at birth [thyroid-stimulating hormone (TSH) level 59-442 mU/l] and 7 at 2-48 years of age (TSH level 6-223 mU/l). One affected patient had thyroid hemiagenesis on ultrasound. RESULTS: Direct sequencing of the PAX8 gene revealed a novel single nucleotide substitution (c.162 A>T) in exon 2 that resulted in the substitution of the normal serine 54 with a cysteine (S54C), which segregated with elevated serum TSH levels. Other mutations of the same amino acid (S54G and S54R) have also been shown to produce functional impairment. CONCLUSION: We report a large family with a novel mutation in the PAX8 gene presenting with variable phenotype and with a high proportion of affected family members.

Undercarboxylated osteocalcin is associated with insulin resistance, but not adiponectin, during pregnancy.

In mice, undercarboxylated osteocalcin (ucOC) improves beta-cell function and insulin sensitivity through adiponectin. In humans, levels of total osteocalcin (OC) and ucOC were negatively correlated with insulin resistance (IR) indices in patients with type 2 diabetes. Whether ucOC plays a role in glucose homeostasis and whether its effect is mediated through adiponectin during pregnancy is unclear. Serum levels of total OC, ucOC, and adiponectin were measured in 130 pregnant women with varying degrees of IR [gestational diabetes mellitus (GDM), n = 74 and non-GDM, n = 56]. In all participants, total OC and ucOC levels were positively correlated with HOMA-IR and HOMA-%B, and negatively correlated with QUICKI. In contrast, adiponectin levels were negatively correlated with HOMA-IR and positively correlated with QUICKI (P < 0.01, both). However, neither total OC nor ucOC was associated with adiponectin. Although none of these markers could help distinguish women with and without GDM, total OC and ucOC levels were significantly higher in non-GDM women who had 1 abnormal OGTT value than those who had all normal OGTT values. Total OC and ucOC levels were significantly correlated with insulin secretion and IR indices, but not adiponectin levels, in pregnant women. Changes in OC might be a sensitive response to increased IR during pregnancy, which was not mediated through adiponectin.

Evidence of vaccine protection among thai medical students and implications for occupational health.

In a cross-sectional study of Thai medical students, we compared the seroprevalence of antibody to measles virus, rubella virus, varicella zoster virus, hepatitis A virus, and hepatitis B virus with self-reports of prior infection or vaccination. Self-report predicted immunity to varicella zoster virus only. These data contribute to risk assessment and occupational health strategies in this resource-limited setting.