Investigating the connection among thyroid function, sensitivity to thyroid hormones, and metabolic syndrome in euthyroid children and adolescents affected by type 1 diabetes.

OBJECTIVES: A connection between thyroid hormones (THs) and diverse metabolic pathways has been reported. We evaluated thyroid function and tissue sensitivity to THs in children and adolescents with T1D in comparison to euthyroid controls. Additionally, we investigate whether a relationship exists between sensitivity indices and metabolic parameters. METHODS: A retrospective analysis was conducted on 80 pediatric patients diagnosed with T1D. Clinical parameters, TSH, FT3, FT4, and the presence of MS were documented. Additionally, indices of peripheral sensitivity (FT3/FT4 ratio) and central sensitivity (TSH index, TSHI; TSH T4 resistance index, TT4RI; TSH T3 resistance index, TT3RI) were assessed. Thirty healthy subjects were considered as controls. RESULTS: The overall prevalence of MS was 7.27 %, with MS identified in 8 out of 80 (10 %) T1D subjects; none of the controls manifested MS (p<0.01). No significant differences were observed in indexes of tissue sensitivity to THs between subjects with or without MS (all p>0.05). Correlations between THs and indexes of THs tissue sensitivity and metabolic parameters in controls and T1D patients were noted. CONCLUSIONS: This study affirms a heightened prevalence of MS in children with T1D compared to controls and underscores the potential role of THs in maintaining metabolic equilibrium.

Thyroid hormone resistance and large goiter mimicking infiltrative carcinoma in a pediatric patient.

OBJECTIVES: Resistance to thyroid hormone (RTH) is a genetic condition, caused by mutations in the thyroid hormone receptor gene and characterized by impaired end organ responsiveness to thyroid hormone. Here we describe a novel case of THR associated with large goiter mimicking infiltrative c. CASE PRESENTATION: A 13-year-old male with a hyperthyroid phenotype of RTH diagnosed as a toddler, on methimazole and nadolol therapies presented with an increase in goiter size and possible nodule. Thyroid ultrasound was concerning for a diffuse infiltrative process or malignancy. Methimazole was discontinued and he underwent further imaging, fine needle aspiration and core biopsies. Biopsy results were reassuring and imaging findings were subsequently attributed to RTH rather than malignancy. He started every other day liothyronine therapy, which led to a decrease in goiter size, thyroglobulin level, and improvement of hyperthyroid symptoms. CONCLUSIONS: This is the first case to our knowledge describing the above thyroid imaging findings in association with RTH. It also adds important information to the pediatric literature regarding management of the hyperthyroid phenotype of RTH, including the role of liothyronine therapy.

Impaired thyroid hormone sensitivity increases the risk of papillary thyroid cancer and cervical lymph node metastasis.

BACKGROUND: The association of thyroid hormone sensitivity with papillary thyroid carcinoma (PTC) is unclear. This study investigated the relationship between the thyroid hormone sensitivity indices and the risk of PTC and the influence of thyroid hormone sensitivity on the aggressive clinicopathologic features of PTC. METHODS: This retrospective study recruited 1225 PTC patients and 369 patients with benign nodules undergoing surgery in Zhongshan Hospital in 2020. The thyroid hormone sensitivity indices were thyroid feedback quantile-based index (TFQI), TSH index (TSHI) and thyrotropin thyroxine resistance index (TT4RI). We employed logistic regression models to explore the correlation between the thyroid hormone sensitivity indices and the risk of PTC and its cervical lymph node metastasis (LNM). RESULTS: PTC patients had significantly higher levels of TSH, TFQI, TSHI and TT4RI compared to the patients with benign nodules, but thyroid hormone levels did not differ significantly between the two groups. Logistic regression analysis revealed that the higher levels of TFQI, TSHI, and TT4RI were associated with an increased risk of PTC after adjustment for multiple risk factors (TFQI: OR = 1.92, 95% CI: 1.39-2.65, P < 0.001; TSHI: OR = 2.33, 95% CI:1.67-3.26, P < 0.001; TT4RI: OR = 2.41, 95% CI:1.73-3.36, P < 0.001). In addition, patients with decreased thyroid hormone sensitivity had a higher risk of cervical LNM in multiple logistic regression analysis (TFQI: OR = 1.38, 95% CI:1.03-1.86, P = 0.03; TSHI: OR = 1.37, 95% CI:1.02-1.84, P = 0.04; TT4RI: OR = 1.41, 95% CI:1.05-1.89, P = 0.02). CONCLUSION: Impaired sensitivity to thyroid hormone was associated with an increased risk of PTC, and it is also associated with a higher risk of cervical LNM in PTC patients.

Diagnosis of Resistance to Thyroid Hormone due to a Rare Mutation in the Thyroid Hormone Receptor Beta Gene in a Patient Previously Presumed to Have Graves' Disease.

Clinicians may confuse an impaired sensitivity to thyroid hormone with hyperthyroidism and offer an inappropriate treatment. We report a diagnosis of resistance to thyroid hormone (RTH) caused by a rare mutation in the thyroid hormone receptor beta gene in a patient previously presumed to have Graves' disease. We have found only one published case of a novel point mutation, c.749T>C (p.Ile250Thr variant) associated with 50% reduction in thyroid hormone receptor binding affinity for triiodothyronine in the I250T mutant; it was found in this patient. A 66-year-old male veteran, with a history of non-ischemic cardiomyopathy and arrhythmias, was referred by a cardiologist with concerns for a possible thyrotropin (TSH) adenoma on account of elevated TSH and free thyroxine (FT4) levels. Pituitary imaging was negative. He was previously treated with radioiodine for presumptive Graves' disease in the civilian sector. Examination revealed a goiter with no nodules. Repeat TSH and FT4 levels were elevated and also free triiodothyronine (FT3) and reverse triiodothyronine. These findings and other test results were consistent with RTH, which was confirmed by genetic testing. Mutation analysis showed the patient to be heterozygous for the p.Ile250Thr variant. He later developed hypothyroidism. Resistance to thyroid hormone can be misdiagnosed as hyperthyroidism with consequent inappropriate treatment. Treatment is not needed in most RTH-beta patients. Thyroid ablation should generally be avoided. Clinicians must be cautious whenever they encounter concurrent elevation of TSH, FT4, and FT3. This RTH-beta patient has a rare I250T mutant of the thyroid hormone receptor beta gene, the second reported case in the literature.

Impaired Sensitivity to Thyroid Hormones Is Associated With Decreased Vitamin D Levels in the Euthyroid Population.

CONTEXT: The relationship between vitamin D and thyroid profiles lacks consensus despite extensive investigations. Whether vitamin D levels correlate with thyroid hormone sensitivity remains largely unexplored. OBJECTIVE: To explore the relationship between vitamin D levels and thyroid hormone sensitivity among euthyroid individuals. METHODS: This study involved 6452 euthyroid participants. Clinical parameters, including TSH, free thyroxine, 25-hydroxyvitamin D [25(OH)D], and other relevant indicators were extracted from the National Health and Nutrition Examination Survey 2007-2012. To quantify thyroid hormone sensitivity, we calculated the Thyroid Feedback Quantile-based Index (TFQI), the TSH index (TSHI), and the thyrotropin thyroxine resistance index (TT4RI). RESULTS: Subjects with impaired thyroid hormone sensitivity have decreased 25(OH)D levels (TFQI, TT4RI: P < 0.05; TSHI: P = .05574) following adjustment of confounding variables. Age-specific analysis found negative correlations between thyroid hormone sensitivity indices and 25(OH)D within the 20 to 60 years subgroup, turning positive in the 60 to 80 years subgroup. In females, thyroid hormone sensitivity indices and vitamin D levels were negatively linked, while in males, vitamin D's relationships with TFQI, TT4RI, and TSHI shifted from negative to positive when 25(OH)D levels exceeded 63.5 nmol/L, 56.7 nmol/L, and 56.7 nmol/L, respectively. Stratification by race revealed U-shaped curvilinear patterns resembling those found in the males. In body mass index (BMI) subanalysis, vitamin D had differing associations with thyroid hormone sensitivity indices: negative in the <25 kg/m2 and ≥30 kg/m2 subgroups and U-shaped in the 25-30 kg/m2 subgroup. CONCLUSION: Impaired thyroid hormone sensitivity correlates with decreased vitamin D levels among euthyroid subjects, with associations varying by age, sex, race, and BMI.

Can a novel drug dose be used for T3 suppression test?

PURPOSE: This study aimed to investigate whether 25 µg/day dose of triiodothyronine (T3) can also suppress thyroid stimulating hormone (TSH) level, as well as the routine dose of 50-100 µg/day in T3 suppression test, which is used to the distinguish between resistance to thyroid hormone (RTH) and TSH secreting pituitary adenoma. METHODS: In this prospective study, 26 patients with genetically proven RTH were randomly divided into two groups: Group 1 comprised 13 patients who were administered 50-100 µg/day T3 for 3-9 days, while Group 2 also comprised 13 patients who were administered 25 µg/day T3 for 7 days for T3 suppression test. The two groups' responses to T3 suppression tests were compared. RESULTS: The comparison of the mean percentage changes in TSH values by the T3 suppression tests showed no significant differences between the groups, and a ≥80% decrease was detected in all patients. Nine patients in Group 1 and one patient in Group 2 reported that they had to use propranolol due to tachycardia developed during the test. CONCLUSION: As higher doses of T3 can increase the risk of severe tachycardia during T3 suppression test, a low dose with 25 mcg/day for a week appears to be safer and more useful.

Resistance to thyroid hormone induced tachycardia in RTHα syndrome.

Mutations in thyroid hormone receptor α1 (TRα1) cause Resistance to Thyroid Hormone α (RTHα), a disorder characterized by hypothyroidism in TRα1-expressing tissues including the heart. Surprisingly, we report that treatment of RTHα patients with thyroxine to overcome tissue hormone resistance does not elevate their heart rate. Cardiac telemetry in male, TRα1 mutant, mice indicates that such persistent bradycardia is caused by an intrinsic cardiac defect and not due to altered autonomic control. Transcriptomic analyses show preserved, thyroid hormone (T3)-dependent upregulation of pacemaker channels (Hcn2, Hcn4), but irreversibly reduced expression of several ion channel genes controlling heart rate. Exposure of TRα1 mutant male mice to higher maternal T3 concentrations in utero, restores altered expression and DNA methylation of ion channels, including Ryr2. Our findings indicate that target genes other than Hcn2 and Hcn4 mediate T3-induced tachycardia and suggest that treatment of RTHα patients with thyroxine in high dosage without concomitant tachycardia, is possible.

Impaired sensitivity to thyroid hormones is associated with hyperuricemia in a Chinese euthyroid population.

Objective: Impaired sensitivity to thyroid hormones has been reported as a common metabolic disorder, and it remains poorly understood whether it interplays with uric acid (UA) metabolism as an established risk factor for cardiovascular diseases (CVDs). We aimed to investigate the relationship between thyroid hormone sensitivity and elevated UA in a Chinese euthyroid population. Methods: A total of 15,955 euthyroid subjects were included in this study. Thyroid hormone sensitivity indices were calculated, including the thyroid feedback quantile-based index (TFQI), the Chinese-referenced parametric TFQI (PTFQI), the TSH index (TSHI), and the thyrotropin thyroxine resistance index (TT4RI), and the FT3/FT4 ratio. Linear and logistic regression analyses were performed to detect the association between thyroid hormone sensitivity and elevated UA. Results: Subjects with reduced sensitivity to thyroid hormones had increased UA levels in both genders (p for trend < 0.001). Logistic and linear regression analyses showed that higher TFQI, PTFQI, TSHI, and TT4RI were positively associated with elevated UA levels, but negatively associated with the FT3/FT4 ratio. The odds ratio (OR) of the highest versus the first quartile of TFQI was 1.20 (1.05, 1.38) in men and 1.80 (1.46, 2.23) in women (p < 0.001). PTHQI, TSHI, and TT4RI obtained similar results in both genders. Conversely, the highest quartile of the FT3/FT4 ratio was negatively correlated with elevated UA levels [men: OR 0.78 (0.68,0.89), women: OR 0.66 (0.53,0.81)]. Conclusion: Impaired sensitivity to thyroid hormones was associated with elevated UA levels in euthyroid subjects. Our findings shed light on the role of thyroid hormone sensitivity in UA metabolism.

Thyroid hormone resistance resulting from a novel mutation in the THRB gene in a Chinese child: A case report.

INTRODUCTION: Thyroid hormone resistance (RTH) (mim # 188570) is a rare autosomal dominant genetic disorder characterized by reduced thyroid hormone response in target tissues. The clinical manifestations of RTH vary from no symptoms to symptoms of thyroid hormone deficiency to symptoms of thyroid hormone excess. PATIENT CONCERN AND CLINICAL FINDINGS: A 24-month-old girl presented with growth retardation, tachycardia, and persistently elevated thyroid hormones despite antithyroid treatment. DIAGNOSIS/INTERVENTION/OUTCOMES: The patient was diagnosed with RTH, after whole exon gene sequencing, found a de novo missense mutation (c.1375T > G,p.Phe459Val) in a novel locus of the thyroid hormone receptor beta gene. She had only mild growth retardation, so the decision was made to monitor her development without intervention. At her last follow-up at 5 years and 8 months of age, she continued to show growth retardation (-2 standard deviation below age-appropriate levels), in addition to delayed language development. Her comprehension ability and heart rate have remained normal. CONCLUSIONS: We report a mild case of RTH caused by a novel thyroid hormone receptor beta gene mutation. RTH should be considered in the differential diagnosis of abnormal serum thyroxine levels during neonatal screening.

Association of multiple blood metals with thyroid function in general adults: A cross-sectional study.

Introduction: Thyroid function has a large impact on humans' metabolism and is affected by iodine levels, but there is a scarcity of studies that elucidate the association between thyroid function and other elements. Methods: We performed a cross-sectional study on 1,067 adults to evaluate the associations of the common essential metals with thyroid function in adults living in an iodine-adequate area of China. Serum free thyroxine (FT4), free triiodothyronine (FT3), thyroid stimulating hormone (TSH), and blood metals (zinc, iron, copper, magnesium, manganese, and calcium) were measured. Further, the thyroid hormone sensitivity indexes, FT3:FT4 ratio, and thyrotropin T4 resistance index (TT4RI) were calculated. Linear regression, quantile g-computation, and Bayesian kernel machine regression methods were used to explore the association of metals with thyroid function. Results: We found that the TSH levels correlated with copper (negative) and zinc (positive). Iron and copper were positively associated with FT3 and FT4 levels, respectively. Iron (positive) and copper (negative) were correlated with the FT3:FT4 ratio. Furthermore, we found that manganese was inversely correlated with TT4RI, while zinc was positively correlated. Discussion: Our findings suggest that manganese, iron, copper, and zinc levels were strongly correlated with thyroid function, and patients with thyroid disorders are recommended to measure those metals levels.

Impaired sensitivity to thyroid hormone correlates to osteoporosis and fractures in euthyroid individuals.

BACKGROUND: There is growing evidence that thyroid function affects bone metabolism and even fractures risk. However, little is known about the relationship between thyroid sensitivity and osteoporosis and fractures. Therefore, we explored the relationship between thyroid sensitivity-related indices and bone mineral density (BMD) and fractures in euthyroid US adults. METHODS: In this cross-sectional study, 20,686 subjects from National Health and Nutrition Examination Survey (NHANES) data were extracted and analyzed during 2007 to 2010. A total of 3403 men and postmenopausal women aged 50 years or older with available data on diagnosis of osteoporosis and/or fragility fractures, bone mineral density (BMD) and thyroid function, were eligible. TSH index (TSHI), thyrotrophin T4/T3 resistance index (TT4RI/TT3RI), Thyroid feedback quantile-based index (TFQI), Parametric TFQI (PTFQI), free triiodothyronine to free thyroxine ratio (FT3/FT4), the secretory capacity of the thyroid gland (SPINA-GT) and the sum activity of peripheral deiodinases (SPINA-GD) were calculated. RESULTS: FT3/FT4, SPINA-GD, FT4, TSHI, TT4RI, TFQI and PTFQIFT4 were significantly correlated with BMD (P < 0.001). Multiple linear regression analysis showed that FT3/FT4 and SPINA-GD was significantly positively associated with BMD, while FT4, TSHI, TT4RI, TFQI and PTFQIFT4 were negatively associated with BMD (P < 0.05 or P < 0.001). In logistic regression analysis, the odds ratio (OR) for osteoporosis of TSHI, TFQI and PTFQIFT4 were 1.314(1.076, 1.605), 1.743(1.327, 2.288) and 1.827(1.359, 2.455) respectively, and were 0.746(0.620, 0.898) for FT3/FT4 (P < 0.05). CONCLUSIONS: In elderly euthyroid individuals, impaired sensitivity to thyroid hormones correlates to osteoporosis and fractures, independent of other conventional risk factors.

The clinical characteristics and gene mutations associated with thyroid hormone resistance syndrome coexisting with pituitary tumors.

Aims: Resistance to thyroid hormone (RTH) and pituitary tumors are both rare diseases, and the differential diagnosis of these two diseases is difficult in some cases. There are also patients who have both conditions, making diagnosis more difficult. To better understand this aspect, we analyzed the clinical characteristics and gene mutations of RTH coexisting with pituitary tumors. Methods: Database retrieval was conducted in the PubMed, Cochrane Library, and SinoMed databases, and the search contents were case reports or case series of patients with RTH coexisting with pituitary tumors. The demographic, clinical manifestations, and imaging characteristics of pituitary tumors and gene mutations were summarized. Results: Thirteen articles involving 16 patients with RTH coexistent with pituitary tumors, consisting of 13 female patients, one male patient, and two patients with unknown sex, were included. The patients were 10 to 79 years old and most patients were 41-55 years old (43.75%). The 16 patients were from seven different countries and three continents (Asia, the Americas, and Europe). All the patients showed an abnormal secretion of TSH, and five patients underwent transsphenoidal surgery. Finally, four patients were pathologically confirmed to have TSHoma. A total of 11 different mutations occurred at nine amino acid sequence sites (251, 310, 344, 347, 383, 429, 435, 438, and 453). Two different mutations occurred in both the no. 435 and no. 453 amino acid sequences. Fourteen patients provided their treatment histories, and all had undergone different treatment regimens. Conclusions: Patients with both RTH and pituitary tumors had multiple clinical manifestations and different thyroid functions, imaging characteristics of pituitary tumors, genetic mutations of THRß, and treatments. However, due to the limited number of cases, the patients were mainly women. Further studies with more cases that focus on the mechanism are still needed.

Central and peripheral sensitivity to thyroid hormones and glucose metabolism in prepubertal children with obesity: pilot multicenter evaluation.

PURPOSE: An alteration of central and peripheral sensitivity to thyroid hormones (THs) seems to be associated with an increased risk of prediabetes in adulthood. Aims of this study was to evaluate the relationship between the sensitivity to THs, the severity of overweight and the glyco-metabolic alterations in prepubertal euthyroid children with obesity. METHODS: Prepubertal subjects with simple obesity and matched controls were recruited from three Italian pediatric endocrinology centers and underwent clinical and biochemical evaluations. HOMA-IR, HOMA-ß, insulinogenic index, Matsuda index were evaluated in children with obesity. Indexes of peripheral sensitivity (FT3/FT4 ratio) and central sensitivity (TSH index, TSHI; TSH T4 resistance index, TT4RI; Thyroid Feedback Quantile-based Index, TFQI; Parametric TFQI, PTFQI) to thyroid hormones were calculated in both groups. RESULTS: Eighty prepubertal children with obesity (Group 1; mean age 7.60 ± 1.51 years) and 28 healthy normal-weight controls (Group 2) were recruited. BMI and leptin were higher in group 1 than in group 2. The FT3/FT4 ratio correlated negatively with HOMA-ß (r = -0.29; p = 0.01) and was significantly positively associated with BMI (p = 0.03), IR (p = 0.03) and fasting blood glucose (p = 0.04) in group 1. TT4RI, TSHI, PTFQI, TFQI, were significantly negatively associated with Matsuda-index, IGI and BMI in group 1. CONCLUSION: Central and peripheral sensitivity to thyroid hormones is significantly affected by the severity of overweight and the presence of IR. Altered tissue sensitivity to THs in the prepubertal children with obesity could be implicated in the pathogenesis of glucose metabolism impairment.

Mediator subunit MED1 differentially modulates mutant thyroid hormone receptor intracellular dynamics in Resistance to Thyroid Hormone syndrome.

Thyroid hormone receptor (TR) controls the expression of thyroid hormone (T3)-responsive genes, while undergoing rapid nucleocytoplasmic shuttling. In Resistance to Thyroid Hormone syndrome (RTH), mutant TR fails to activate T3-dependent transcription. Previously, we showed that Mediator subunit 1 (MED1) plays a role in TR nuclear retention. Here, we investigated MED1's effect on RTH mutants using nucleocytoplasmic scoring and fluorescence recovery after photobleaching in transfected cells. MED1 overexpression and knockout did not change the nucleocytoplasmic distribution or intranuclear mobility of C392X and P398R TRα1 at physiological T3 levels. At elevated T3 levels, however, overexpression increased P398R's nuclear retention and MED1 knockout decreased P398R's and A263V's intranuclear mobility, while not impacting C392X. Although A263V TRα1-transfected cells had a high percentage of aggregates, MED1 rescued A263V's impaired intranuclear mobility, suggesting that MED1 ameliorates nonfunctional aggregates. Results correlate with clinical severity, suggesting that altered interaction between MED1 and TRα1 mutants contributes to RTH pathology.

Association between sensitivity to thyroid hormones and dyslipidemia in patients with coronary heart disease.

BACKGROUND: Thyroid hormones affect lipid metabolism via central and peripheral regulation. However, there have been few studies on the association between thyroid hormone sensitivity and dyslipidemia. We aimed to investigate the association between thyroid hormone sensitivity and dyslipidemia in patients with coronary heart disease (CHD). METHODS: A total of 31,678 patients with CHD were included in this large multicenter retrospective study. Central thyroid hormone sensitivity was evaluated using the thyroid feedback quantile-based index (TFQI), parametric thyroid feedback quantile-based index (PTFQI), thyroid-stimulating hormone index (TSHI), and thyrotropin thyroxine resistance index (TT4RI); peripheral thyroid hormone sensitivity was assessed by the ratio of free triiodothyronine (FT3)/free thyroxine (FT4). Logistic regression analysis was used to analyze the association between thyroid hormone sensitivity and dyslipidemia. RESULTS: Among 31,678 participants, 21,648 (68.34%) had dyslipidemia. In the multi-adjusted models, the risk of dyslipidemia was positively correlated with TFQI (odds ratio [OR]: 1.04; 95% confidence interval [CI]: 1.03-1.05), PTFQI (OR: 1.09; 95% CI: 1.06-1.12), TSHI (OR: 1.08; 95% CI: 1.06-1.11), and TT4RI (OR: 1.08; 95% CI: 1.05-1.11). Conversely, the risk of dyslipidemia was negatively correlated with FT3/FT4 (OR: 0.94; 95% CI: 0.92-0.97). In stratified analyses, the association between thyroid hormone sensitivity and dyslipidemia was statistically significant for different sexes, glucose levels, and blood pressure states. CONCLUSION: There is a significant association between sensitivity to thyroid hormones and dyslipidemia, regardless of sex, glucose level, or blood pressure. Graphical abstract.

Familial Glucocorticoid Deficiency: the changing landscape of an eponymous syndrome.

Familial Glucocorticoid Deficiency encompasses a broad spectrum of monogenic recessive disorders that theoretically solely abrogate cortisol biosynthesis. In reality, delineating clear genotype-phenotype correlations in this disorder is made complicated by marked phenotypic heterogeneity even within kindreds harbouring identical variants. Phenotypes range from isolated glucocorticoid insufficiency to cortisol deficiency plus a variety of superimposed features including salt-wasting and hypoaldosteronism, primary hypothyroidism, hypogonadism and growth defects. Furthermore, mutation type, domain topology and perceived enzyme activity do not always predict disease severity. Given the high burden of disease and implications of a positive diagnosis, genetic testing is crucial in the management of patients warranting detailed delineation of genomic variants including viable functional studies.

Atrial Fibrillation with Heart Failure in a Case with Resistance to Thyroid Hormone Due to a Rare Thyroid Hormone Receptor ß Gene Mutation.

Resistance to thyroid hormone (RTH) is a rare disease typically associated with elevated levels of thyroid hormones and non-suppressed thyroid stimulating hormones. The most common cause of RTH is thyroid hormone receptor ß (THRß) gene mutation. Most individuals with RTH are considered clinical euthyroid. We report a family with a rare heterozygous point mutation, c.959G>T, (p.R320L) of the THRß gene. The proband developed atrial fibrillation and life-threatening heart failure with pulmonary edema, which was quite different from previously reported THRß gene mutations. Considering the rareness of RTH and the heterogeneity of its phenotypes, our report allows for a better understanding of the manifestation and management of patients with RTH and THRß gene mutation.

Effect of Liraglutide on Serum TSH Levels in Patients with NAFLD and its Underlying Mechanisms.

This study aimed to evaluate the effect of liraglutide on serum thyroid-stimulating hormone (TSH) levels in patients with type 2 diabetes mellitus (T2DM) and explore the underlying mechanisms via bioinformatics analysis. A total of 49 obese/overweight patients with T2DM received liraglutide during outpatient visits or hospitalization in the Department of Endocrinology. Meanwhile, the control group included 49 patients with T2DM but without nonalcoholic fatty liver disease (NAFLD) who were matched for age and sex (baseline from July 2016 to June 2021). Follow-up data on the last use of liraglutide were also retrieved. Age, sex, body mass index (BMI), and duration of diabetes were obtained from the participants' records. All patients were tested for biochemical markers hemoglobin A1c (HbA1c), alanine transaminase, aspartate transaminase, free triiodothyronine, free thyroxine (FT4), and TSH at baseline and follow-up. After adjusting for all factors with a p-value < 0.05, BMI, HbA1c, LDL, FT4, and TSH were identified as significant independent risk factors for NAFLD in the univariate analysis. Following liraglutide therapy (average time 16 months), these patients had significantly lower BMI, HbA1c, and TSH but higher high-density lipoprotein (HDL) levels than those in the baseline data (all p < 0.05), and further subgroup analysis stratified by duration of liraglutide use showed that the test for time trends had statistical differences in BMI and TSH but not in HbA1c and HDL. After the therapy, the NAFLD and NASH groups showed significantly decreased TSH levels after liraglutide therapy compared with the corresponding baseline data. Furthermore, the expression of THRB, which encodes TRß, was significantly decreased in the NAFLD group, which may explain the thyroid hormone resistance-like manifestation in the clinical findings. In conclusion, liraglutide improves hepatic thyroid hormone resistance in T2DM with NAFLD, and restoration of impaired TRß expression in NAFLD is a potential mechanism involved in the process of liraglutide therapy.

Resistance to Thyroid Hormones: A Case-Series Study.

The aim of the study is to describe the clinical features of two unrelated patients with resistance to thyroid hormones (RTH), the first, a total thyroidectomized patient, and the second, a pregnant woman. We report the features found in her newborn who also showed RTH. Patient 1 is a 38-year-old man with total thyroidectomy managed for excessive thyroid stimulating hormone (TSH) production, which poorly responded to the replacement therapy. He was found with a THRß c.1378G>A p.(Glu460Lys) heterozygous mutation, which was also present in other members of his family (son, brother, and father). Interestingly, Patient 1 had hypertension, dyslipidemia, and hepatic steatosis, which have been recently suggested as RTH-related comorbidities. Patient 2 is a 32-year-old pregnant woman with multinodular goiter, and the THRß heterozygous variant c.959G>C, that, to the best of our knowledge, has been reported in literature only once. Her newborn had tachycardia and increased thyroid hormone levels, and showed the same mutation. After delivery, high parathyroid hormone (PTH) and calcium serum levels were found in Patient 2 and the scintigraphy showed the presence of adenoma of a parathyroid gland. This case-series study provides a practical example of the management of RTH in a thyroidectomized patient, a pregnant woman, and a newborn. A novel RTH pathogenic mutation is described for the second time in literature. Furthermore, the importance of metabolic assessment in patients with RTHß has been highlighted and the possible correlation between RTH and primary hyperparathyroidism is discussed.

Thyroid function tests of iodine deficiency goiter can mimic thyroid hormone resistance alpha.

OBJECTIVES: Iodine deficiency goiter can develop in children on a restrictive diet and most have normal thyroid function. We report a 6-year-old girl with iodine deficiency goiter with thyroid function studies mimicking thyroid hormone resistance alpha. Thyroid hormones mediate its effects through thyroid hormone receptors alpha and beta. Biochemical picture of low/low-normal T4 and high/high-normal T3 levels, variably reduced reverse T3 and normal TSH is characteristic of thyroid hormone resistance alpha. CASE PRESENTATION: A 6-year-old girl, born out of non-consanguineous marriage presented with goiter of 1.5 years duration. She was without symptoms of thyroid dysfunction. The patient was evaluated at one year of age for macrocephaly with cranial ultrasound which was normal. She had normal growth and development. Patient was vegan and was not on any medications or supplements. Laboratory work up showed TSH 5.03 uIU/mL (0.34-5.5), FT4 0.3 ng/dL (0.58-1.2), FT3 5.3 pg/mL (2.5-3.9), total T3 258 ng/dL (94-241), reverse T3 <5.0 ng/dL (8.3-22.9) and negative thyroglobulin antibody and thyroid peroxidase antibody. Thyroglobulin level was 1,098.8 ng/mL (<13 ug/L), and urine iodine 15.8 ug/L (<100 ug/L) confirming a diagnosis of iodine deficiency goiter. Patient was started on iodine supplements, 150 ug daily and repeat work up 3 months later were TSH: 2.717 uIU/mL, T3, total 182 ng/dL, T4, total 9.3 ug/dL, FT 4 2.1 ng/dL. CONCLUSIONS: Iodine deficiency goiter may present with low FT 4, elevated T3 and normal TSH mimicking thyroid hormone resistance alpha and should be considered in children on restrictive diet.