Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Institute of Clinical Medicine, Faculty of Health and Clinical Sciences, Copenhagen University, Copenhagen, Denmark
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QualityMetric Inc, Johnston, Lincoln, Rhode Island, USA
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Internal Medicine Research Unit, University Hospital of Southern Jutland, Aabenraa, Denmark
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Institute of Clinical Medicine, Faculty of Health and Clinical Sciences, Copenhagen University, Copenhagen, Denmark
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Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Purpose
We investigated whether selenium supplementation improves quality-of-life (QoL) in patients with autoimmune thyroiditis (ID:NCT02013479).
Methods
We included 412 patients ≥18 years with serum thyroid peroxidase antibody (TPOAb) level ≥100 IU/mL in a multicentre double-blinded randomised clinical trial. The patients were allocated 1:1 to daily supplementation with either 200 μg selenium as selenium-enriched yeast or matching placebo tablets for 12 months, as add-on to levothyroxine (LT4) treatment. QoL, assessed by the Thyroid-related Patient-Reported-Outcome questionnaire (ThyPRO-39), was measured at baseline, after 6 weeks, and after 3, 6, 12, and 18 months.
Results
In total, 332 patients (81%) completed the intervention period, of whom 82% were women. Although QoL improved during the trial, no difference in any of the ThyPRO-39 scales was found between the selenium group and the placebo group after 12 months of intervention. In addition, employing linear mixed model regression no difference between the two groups was observed in the ThyPRO-39 composite score (28.8 (95% CI: 24.5–33.6) and 28.0 (24.5–33.1), respectively; P = 0.602). Stratifying the patients according to duration of the disease at inclusion, ThyPRO-39 composite score, TPOAb level, or selenium status at baseline did not significantly change the results. TPOAb levels after 12 months of intervention were lower in the selenium group than in the placebo group (1995 (95% CI: 1512–2512) vs 2344 kIU/L (1862–2951); P = 0.016) but did not influence LT4 dosage or free triiodothyronine–free thyroxine ratio.
Conclusion
In hypothyroid patients on LT4 therapy due to autoimmune thyroiditis, daily supplementation with 200 μg selenium or placebo for 12 months improved QoL to the same extent.
Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Data and Data Support, Region Zealand, Sorø, Denmark
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Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark
Department of Cardiology, University Hospital Nordsjælland, Hillerød, Denmark
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Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Steno Diabetes Center Copenhagen, Herlev, Denmark
Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
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Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Objective
Some studies suggest that hypothyroidism is associated with increased oxidative stress. Urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) represents whole-body RNA and DNA oxidation, respectively. These biomarkers have only been explored sparsely in patients with thyroid disorders.
Methods
In 45 Danish women with newly diagnosed hypothyroidism, we compared 8-oxoGuo and 8-oxodG before or shortly after initiating levothyroxine with the excretion rates at euthyroidism. We also compared the excretion of 8-oxoGuo and 8-oxodG in the patients after restored euthyroidism with 18 healthy control subjects.
Results
Compared with baseline, none of the biomarkers changed significantly in the patients after becoming euthyroid. The geometric mean of 8-oxoGuo was 1.63 (95% CI: 1.49–1.78) nmol/mmol creatinine at baseline and 1.67 nmol/mmol at euthyroidism (95% CI: 1.53–1.83) (P = 0.39), while that of 8-oxodG was 1.28 nmol/mmol creatinine at baseline (95% CI: 1.14–1.44) and 1.32 nmol/mmol at euthyroidism (95% CI: 1.18–1.48), respectively (P = 0.47). The relative mean differences were 0.97 (95% CI: 0.91–1.04) for 8-oxoGuo and 0.97 (95% CI: 0.88–1.06) for 8-oxodG. At baseline, multiple linear regression revealed a positive association between free thyroxine and both biomarkers (8-oxoGuo, P < 0.001; 8-oxodG, P = 0.04). Furthermore, 8-oxoGuo was positively associated with age (P = 0.04) and negatively associated with thyrotropin (P = 0.02). In the control group, the geometric mean of 8-oxoGuo was 1.23 nmol/mmol creatinine (95% CI: 1.07–1.42), while that of 8-oxodG was 1.04 nmol/mmol creatinine (95% CI: 0.88–1.23). Thus, compared with control subjects, euthyroid patients showed a significantly higher level of both 8-oxoGuo (P < 0.001) and 8-oxodG (P = 0.03).
Conclusion
In hypothyroid women, no significant effect of levothyroxine treatment on the oxidative stress biomarkers 8-oxoGuo and 8-oxodG could be demonstrated. However, the excretion of these biomarkers was significantly higher than in healthy controls.
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Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
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The clinical consequences of primary hypothyroidism include cardiovascular morbidity, increased mortality, and poor quality of life; therefore guidelines endorsed by several Scientific Societies recommend measuring circulating thyroid-stimulating hormone (TSH) in patients at risk. The assessment of serum TSH levels is also deemed to be the most robust and accurate biomarker during the management of replacement therapy in patients with a previous diagnosis of primary hypothyroidism. In line with a reflex TSH laboratory strategy, free thyroxine is measured only if the TSH falls outside specific cutoffs, in order to streamline investigations and save unjustified costs. This serum TSH-based approach to both diagnosis and monitoring has been widely accepted by several national and local health services; nevertheless, false-negative or -positive testing may occur, leading to inappropriate management or treatment. This review aims to describe several infrequent causes of increased circulating TSH, including analytical interferences, resistance to TSH, consumptive hypothyroidism, and refractoriness to levothyroxine replacement treatment. We propose a clinical flowchart to aid correct recognition of these various conditions, which represent important potential pitfalls in the diagnosis and treatment of primary hypothyroidism.
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Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
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Department of Medicine, College of Medicine and King Saud Medical City, King Saud University, Riyadh, Saudi Arabia
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Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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Background
Hypothyroidism is clinically characterized by a decrease in levels of the circulating thyroid hormones namely thyroxine and triiodothyronine. The main treatment for hypothyroidism is thyroid hormone replacement using levothyroxine to normalize serum thyroid hormone levels.
Objectives
In this study, we explored the metabolic changes in the plasma of patients with hypothyroidism after reaching a euthyroid state with levothyroxine treatment.
Methods
Plasma samples from 18 patients diagnosed as overt hypothyroidism were collected before and after levothyroxine treatment upon reaching a euthyroid state and were analyzed by high-resolution mass spectrometry-based metabolomics. Multivariate and univariate analyses evaluated data to highlight potential metabolic biomarkers.
Results
Liquid chromatography-mass spectrometry-based metabolomics revealed a significant decrease in the levels of ceramide, phosphatidylcholine, triglycerides, acylcarnitine, and peptides after levothyroxine treatment; this could indicate a change in the fatty acid transportation system and an enhanced β-oxidation, compared with a hypothyroid state. At the same time, the decrease in the peptides suggested a shift in protein synthesis. In addition, there was a considerable rise in glycocholic acid following therapy, suggesting the involvement of thyroid hormones in stimulating bile acid production and secretion.
Conclusions
A metabolomic analysis of patients with hypothyroidism revealed significant changes in several metabolites and lipids after treatment. This study showed the value of the metabolomics technique in providing a complementary understanding of the pathophysiology of hypothyroidism and as a crucial tool for examining the molecular impact of levothyroxine treatment on hypothyroidism. It was an important tool for investigating the therapeutic effects of levothyroxine on hypothyroidism at the molecular level.
Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands
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Department of Pediatric Endocrinology, Emma Children’s Hospital, Amsterdam UMC, location University of Amsterdam, Amsterdam, The Netherlands
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Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands
Endocrine Laboratory, Department of Laboratory Medicine, Amsterdam UMC, location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Department of Pediatric Endocrinology, Emma Children’s Hospital, Amsterdam UMC, location University of Amsterdam, Amsterdam, The Netherlands
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Thyroid hormone (TH) is indispensable for brain development in utero and during the first 2–3 years of life, and the negative effects of TH deficiency on brain development are irreversible. Detection of TH deficiency early in life by neonatal screening allows early treatment, thereby preventing brain damage.
Inborn shortage of TH, also named congenital hypothyroidism (CH), can be the result of defective thyroid gland development or TH synthesis (primary or thyroidal CH (CH-T)). Primary CH is characterized by low blood TH and elevated thyroid-stimulating hormone (TSH) concentrations. Less frequently, CH is due to insufficient stimulation of the thyroid gland because of disturbed hypothalamic or pituitary function (central CH). Central CH is characterized by low TH concentrations, while TSH is normal, low or slightly elevated.
Most newborn screening (NBS) programs for CH are primarily TSH based and thereby do not detect central CH. Only a few NBS programs worldwide aim to detect both forms of CH by different strategies. In the Netherlands, we have a unique T4–TSH–thyroxine-binding globulin (TBG) NBS algorithm for CH, which enables the detection of primary and central CH.
Although the necessity of central CH detection by NBS is still under debate, it has been shown that most central CH patients have moderate-to-severe hypothyroidism instead of mild and that early detection of central CH by NBS probably improves its clinical outcome and clinical care for central CH patients with multiple pituitary hormone deficiency. We are therefore convinced that detection of central CH by NBS is of utmost importance.
Department of Pediatric Endocrinology, Faculty of Medicine, Istinye University, Istanbul, Turkey
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Department of Medical Genetics, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey
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Department of Medical Genetics, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey
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Objective
Guidelines on congenital hypothyroidism (CH) recommend that genetic testing should aim to improve diagnosis, treatment or prognosis, but it is unclear which patients would benefit most from the genetic investigation. We aimed to investigate the genetic etiology of transient CH (TCH) and permanent CH (PCH) in a well-characterized cohort, and thereby evaluate the impact of genetic testing on the management and prognosis of children with CH.
Methods
A total of 48 CH patients with normal, goitrous (n 5) or hypoplastic thyroid (n 5) were studied by high-throughput sequencing using a custom-designed 23-gene panel. Patients initially categorized as TCH (n 15), PCH (n 26) and persistent hyperthyrotropinemia (PHT, n 7) were re-evaluated after genetic testing.
Results
Re-evaluation based on genetic testing changed the initial diagnoses from PCH to PHT (n 2) or TCH (n 3) and from PHT to TCH (n 5), which resulted in a final distribution of TCH (n 23), PCH (n 21) and PHT (n 4). Genetic analysis also allowed us to discontinue treatment in five patients with monoallelic TSHR or DUOX2, or no pathogenic variants. The main reasons for changes in diagnosis and treatment were the detection of monoallelic TSHR variants and the misdiagnosis of thyroid hypoplasia on neonatal ultrasound in low birthweight infants. A total of 41 (35 different, 15 novel) variants were detected in 65% (n 31) of the cohort. These variants, which most frequently affected TG, TSHR and DUOX2, explained the genetic etiology in 46% (n 22) of the patients. The molecular diagnosis rate was significantly higher in patients with PCH (57%, n 12) than TCH (26%, n 6).
Conclusions
Genetic testing can change diagnosis and treatment decisions in a small proportion of children with CH, but the resulting benefit may outweigh the burden of lifelong follow-up and treatment.
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Department of Internal Medicine & Pediatrics, Ghent University, Ghent, Belgium
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Department of Internal Medicine & Pediatrics, Ghent University, Ghent, Belgium
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Department of Internal Medicine & Pediatrics, Ghent University, Ghent, Belgium
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Introduction
Thyroid hormone replacement in central hypothyroidism (CHT) is more difficult than in primary hypothyroidism (PHT), putting patients at risk for inappropriate substitution. In this study, we compared the dosage of thyroid hormone replacement in patients with CHT with that of patients with PHT. In addition, we explored and compared quality of life (QoL) between both groups, based on two questionnaires, the SF-36 health score and the thyroid-specific ThyPRO score.
Methods
This is a monocentric, cross-sectional study, performed at the Ghent University Hospital (Belgium). We included 82 patients in total, 41 patients with CHT and 41 patients with PHT. At the time of inclusion, all patients had to have a stable dose of levothyroxine over the past 6 months and patients with PHT needed to be euthyroid (defined as having a thyroid-stimulating hormone level within the reference range, 0.2–4.5 mU/L). All data were retrieved from medical files, and questionnaires on QoL were self-administered.
Results
The CHT and PHT groups were comparable regarding age and BMI. There was no significant difference between both groups regarding total daily dose of levothyroxine (100 (93.75–125.00) vs 107.14 (75.00–133.93) μg in CHT and PHT, respectively; P = 0.87) or daily dose of levothyroxine per kg body weight (1.34 (1.16–1.55) vs 1.55 (1.16–1.82) μg/kg, respectively; P = 0.13). Serum levels of fT4 (P = 0.20) and fT3 (P = 0.10) also did not differ between the two groups and both were in the normal (mid)range for the two groups. Regarding QoL, patients with CHT scored worse in terms of depressive and emotional symptoms, impaired daily and social life.
Conclusion
We could demonstrate a difference in QoL between patients with CHT and PHT. Although patients with CHT had a somewhat lower levothyroxine substitution dose than patients with PHT, this difference was also not significant and probably does not explain the difference in QoL.
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Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Introduction
High compared with low educational level increases the odds of starting levothyroxine (L-T4) with a normal thyroid-stimulating hormone – the mechanism is most likely patient request. The use of liothyronine (L-T3) and desiccated thyroid extract (DTE) is also speculated to be initiated at patients’ request. Therefore, the primary aim of this study was to evaluate if educational level influences treatment with L-T3 and DTE.
Material and methods
In this register-based cross-sectional study, we included all Danish citizens ≥30 years with redeemed prescription of L-T4, L-T3, or DTE during 2017–2020. We defined educational levels as short, medium, and long (<10 years, 10–12 years, and above 12 years, respectively). The association between educational level and treatment with LT3 or DTE vs only LT4 was analyzed in logistic regression models adjusted for age and sex.
Results
We included 154,360 individuals using thyroid medication of whom 3829 were treated with L-T3 (2.48%) and 430 with DTE (0.28%). The usage was highest among women (3.15%) and the age group 40–49 (5.6%). Longer education compared with short increased the odds of being treated with DTE or L-T3 (medium education odds ratio (OR) 1.61 (95% CI 1.50–1.8) and long education OR 1.95 (95% CI 1.79–2.13)). Test for trend: OR: 1.37 (95% CI 1.31–1.42). Adjustment for other covariates did not affect the results substantially.
Conclusion
Persons with a longer compared to a shorter education are more often treated with either DTE or L-T3, and the usage of these drugs is limited to less than 3% of thyroid hormone users.
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Regional Center for Newborn Screening, Diagnosis and Treatment of Congenital Metabolic and Endocrinological Diseases, Verona, Italy
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Pediatric Section, Department Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy
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Regional Center for Newborn Screening, Diagnosis and Treatment of Congenital Metabolic and Endocrinological Diseases, Verona, Italy
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Pediatric Section, Department Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy
Regional Center for the Diagnosis and Treatment of Children and Adolescents Rare Skeletal Disorders, Pediatric Clinic, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy
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Introduction
Infants of mothers with autoimmune hypothyroidism (AH) are at risk of developing late-onset hypothyroidism, often escaping at newborn screening. This condition might be caused both by the action of maternal antibodies and/or by maternal treatment.
Objectives
The aim of this study is to evaluate the prevalence of AH in the mothers of children born in Veneto region, Italy, and to define what is the most appropriate management for these newborns.
Methods
Newborns of six different hospitals with a mother suffering from AH and with negative neonatal screening for congenital hypothyroidism (CH) were included in the study. Between 15 and 20 days of life, we collected a serum sample for the evaluation of thyroid function (thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3)) and anti-thyroid antibodies. On the same occasion, a capillary blood sampling was performed for a second screening test.
Results
Maternal AH has a prevalence of 3.5%. A total of 291 newborns were enrolled from November 2019 to May 2021. Whereas the 11.4% of infants had a slight elevated serum TSH (>6 mU/L) and required a follow-up, only 2 children presented an elevated TSH level at the second screening test. One of these, with the gland in situ, showed persistently elevated serum TSH levels and required treatment with levothyroxine.
Conclusions
Maternal AH rarely caused neonatal thyroid dysfunction. We suggest to reassess newborns from mothers with AH 15 days after birth by means of a second neonatal screening test. This procedure avoids false negatives due to maternal thyroid status, is less invasive and cheaper than the serum TSH evaluation, and prevents a long follow-up.
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Introduction
Consumptive hypothyroidism is a rare paraneoplastic condition most commonly associated with infantile hemangiomas. It is caused by overexpression of deiodinase type 3 (D3), which leads to preferential conversion of thyroxine to the metabolically inactive reverse triiodothyronine (rT3), paralleled by a decrease of the biologically active T3.
Case presentation
A 46-year-old male patient with previously normal thyroid function was diagnosed with a renal carcinoma with rhabdoid differentiation. He was treated with sunitinib, followed by the immune checkpoint inhibitors ipilimumab and nivolumab, and he developed primary hypothyroidism secondary to thyroiditis. Substitution with unusually high doses of levothyroxine as high as 4.3 µg/kg/day did not normalize his thyroid function. Poor compliance was refuted because there was no improvement after observed administration. He had no malabsorption. Although tyrosine kinase inhibitors can increase the expression of D3, this effect tends to be modest. Therefore, the suspicion of tumor-related consumptive hypothyroidism was raised and supported by low free T3 and elevated rT3 levels. The therapy could not be further modified because the patient opted for palliative care and passed away 12 days later.
Immunohistochemistry of the tumor from a sample obtained prior to systemic therapy documented abundant expression of D3, corroborating the diagnosis of consumptive hypothyroidism.
Conclusions
This observation extends the spectrum of malignancies overexpressing D3. Although rare, increased awareness of this paraneoplastic syndrome is key, if persistent hypothyroidism cannot be explained by compliance issues or malabsorption. Substitution with high doses of levothyroxine, and combination therapy with liothyronine, can correct hypothyroidism in these patients.
