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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 Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
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Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Wallenberg’s Centre of Molecular and Translational Medicine, Region Västra Götaland, Sweden
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Department of Pedagogical, Curricular and Professional Studies, Faculty of Education, University of Gothenburg, Gothenburg, Sweden
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Wallenberg’s Centre of Molecular and Translational Medicine, Region Västra Götaland, Sweden
Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden
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Objective
Mental fatigue, depression, anxiety, and cognitive complaints are common in Graves’ disease (GD). Our aims were to assess the relationship between these variables in patients with GD during both hyperthyroidism and a long stable euthyroidism.
Methods
A prospective longitudinal case-control study where 65 premenopausal women diagnosed with GD and 65 matched controls were assessed twice with 15 months in between. The first visit for patients was in overt hyperthyroidism and the second after treatment.
Results
During the hyperthyroid phase, mental fatigue, depression, and anxiety were significantly increased for GD patients compared to controls (all P < 0.001). Among GD patients, 89% reported mental fatigue and among controls 14%. No difference in cognitive tests was found. After 15 months, significant improvements for GD patients after treatment were found for the items of mental fatigue, depression, and anxiety (all P < 0.001), but these were unchanged in controls. GD patients reported residual mental fatigue (38%), 23% without depression, and 15% mental fatigue combined with depression. Self-reported cognitive complaints were pronounced while cognitive tests did not reveal any deficiencies.
Conclusion
Mental fatigue and emotional distress are common in the hyperthyroid phase. These improve with treatment but are still more common in GD patients after 15 months of therapy than in controls. The residual mental fatigue is shown to be a phenomenon distinct from depression in this study. This indicates the importance of assessing mental fatigue in GD patients and underlines the need for rehabilitation and healthcare support as fatigue will have consequences for work ability.
Search for other papers by Marta Nascimento Soares in
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Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
Department of Surgery and Physiology, Cardiovascular Research Unit, Faculty of Medicine from the University of Porto, Porto, Portugal
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Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
Institute for Research Innovation in Health, University of Porto, Porto, Portugal
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Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
Department of Surgery and Physiology, Cardiovascular Research Unit, Faculty of Medicine from the University of Porto, Porto, Portugal
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Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
Institute for Research Innovation in Health, University of Porto, Porto, Portugal
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Aim
The prevalence of thyroid nodules and the risk of thyroid cancer in patients with Graves’ disease is uncertain. We aimed to evaluate the prevalence of thyroid nodules and cancer in patients with Graves’ disease.
Methods
Retrospective observational study of adult subjects with Graves' disease (positive autoantibodies thyrotropin receptor antibodies (TRAbs)) between 2017 and 2021 at our center was done. We evaluated the prevalence of thyroid nodules and cancer in this population and characterized the predictive factors for thyroid malignancy using linear and logistic regression models.
Results
We evaluated a total of 539 patients with Graves' disease during a median follow-up of 3.3 years (25th–75th percentiles 1.5–5.2 years). Fifty-three percent had thyroid nodules and 18 (3.3%) were diagnosed with thyroid cancer (12 papillary microcarcinomas). All tumors were classified using TNM classification as T1, and only one had lymph node metastasis; there were no recordings of distant metastasis. Sex, age, body mass index, smoking, TSH, and TRAbs levels were not significantly different between patients with and without thyroid cancer. Patients with multiple nodules on ultrasound (OR 1.61, 95%CI 1.04–2.49) and with larger nodules (OR 2.96, 95%CI 1.08–8.14, for 10 mm increase in size) had a greater risk of thyroid cancer diagnosis.
Conclusion
Patients with Graves’ disease had a high prevalence of thyroid nodules and their nodules had a significant risk of thyroid cancer. The risk was higher in those with multiple and larger nodules. Most had low-grade papillary thyroid cancer. More studies are needed to clarify the clinical relevance of these findings.
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Objective
A decrease in the use of radioactive iodine (RAI) treatment for thyroid cancer has been described in the last decade in the US following subsequent updates of the American Thyroid Association guidelines. By contrast, population-based data from European countries are lacking. The study aims to assess the frequency and long-term trends in the use of RAI in Italy.
Methods
From the Italian national hospital discharge database, the proportion of RAI treatment after total thyroidectomy with thyroid cancer diagnosis has been assessed by sex and age class during 2001–2018.
Results
Throughout the whole study period, RAI was performed after 58% of 149,419 total thyroidectomies. The use of RAI was higher for men and younger patients; it peaked in 2007 (64% in women and 68% in men) and declined thereafter (2018: 46% in women and 53% in men), with a similar pattern observed across all ages and areas.
Conclusion
National data show that in Italy trends in RAI treatment paraleled those observed in the US. Further monitoring of the use of RAI is warranted in Italy, as elsewhere, to assess the impact of international guidelines on real-life clinical management of thyroid cancer.
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
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Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
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Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy
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Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Background
Hypertension (HTN) is the most frequent adverse event during treatment with lenvatinib (LEN), but data on its best management are limited.
Aim
The objective of this study was to assess incidence, features and best management of LEN-related HTN in a consecutive single tertiary-care centre cohort.
Methods
Twenty-nine patients were followed up for a mean time of 29.8 months (6–77 months).
Results
After a mean follow-up of 6.8 months, HTN was recorded in 76% of cases, as a de novo occurrence in half of them. HTN significantly correlated with LEN dose and was of grade 1, grade 2 and grade 3 in 5%, 50% and 45% of patients, respectively. The majority (77%) of patients with HTN developed proteinuria. There was no correlation between HTN and proteinuria or clinical features or best morphological response or any other adverse event (AE), with the exception of diarrhoea. Patients with or without pre-existing HTN or any other cardiovascular disease had a similar incidence of HTN during LEN, thus excluding the impact of this potential predisposing factor. After evaluation by a dedicated cardiologist, medical treatment was introduced in 21/22 patients (polytherapy in 20 of them). The most frequently used drugs were calcium channel blockers (CCBs) due to their effect on vasodilation. In case of poor control, CCBs were associated with one or more anti-hypertensive drug.
Conclusion
HTN is a frequent and early AE in patients on LEN treatment. We suggest a diagnostic and therapeutic algorithm to be applied in clinical practice to allow efficient HTN control and improve patient compliance, reducing LEN discontinuation.
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Objective
Global thyroid cancer (TC) incidence is growing worldwide, but great heterogenicity exists among published studies, and thus, population-specific epidemiological studies are needed to adequate health resources and evaluate the impact of overdiagnosis.
Methods
We conducted a Public Health System database retrospective review of TC incident cases from 2000 to 2020 in the Balearic Islands region and evaluated age-standardized incidence rate (ASIR), age at diagnosis, gender distribution, tumor size and histological subtype, mortality rate (MR), and cause of death. Estimated annual percent changes (EAPCs) were also evaluated and data from the 2000–2009 period were compared to the 2010–2020 period when neck ultrasound (US) was routinely performed by clinicians at Endocrinology Departments.
Results
A total of 1387 incident cases of TC were detected. Overall, ASIR (×105) was 5.01 with a 7.82% increment in EAPC. A significant increase in the 2010–2020 period was seen for ASIR (6.99 vs 2.82, P < 0.001) and age at diagnosis (52.11 vs 47.32, P < 0.001) compared to the 2000–2009 period. A reduction in tumor size (2.00 vs 2.78 cm, P < 0.001) and a 6.31% increase in micropapillary TC (P < 0.05) were also seen. Disease-specific MR remained stable at 0.21 (×105). The mean age at diagnosis for all mortality groups was older than survivors (P < 0.001).
Conclusion
The incidence of TC has grown in the 2000–2020 period in the Balearic Islands, but MR has not changed. Beyond other factors, a significant contribution of overdiagnosis to this increased incidence is likely due to changes in the routine management of thyroid nodular disease and increased availability of neck US.
Search for other papers by Sepehr Torabinejad in
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CEINGE – Biotecnologie Avanzate Scarl, Naples, Italy
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There is increasing evidence that thyroid hormones (THs) work in an integrative fashion with androgen receptors (ARs) to regulate gonadal differentiation and reproductive function. Studies reveal that THs have interactions with the AR promoter region and increase AR expression. THs also have a role in the regulation of enzymes involved in the biosynthesis of androgens, such as 5α-reductase, which is essential in the conversion of testosterone into its active form, 5α-dihydrotestosterone. Additionally, the presence of androgen response elements in the promoter regions of TH-related genes, such as deiodinases and TH receptor isoforms, has been identified in some vertebrates, indicating a mutual interaction between THs and ARs. Since the androgen signaling pathway, mediated by ARs, plays a key role in the formation and progression of prostate cancer (PCa), the existence of crosstalk between THs and ARs supports the epidemiologic and experimental evidence indicating a relationship between the high incidence of PCa and hyperthyroidism. This article aims to review the role of androgen-TH crosstalk in PCa and its implication in clinical management. As life expectancy is growing these days, it can increase the number of patients with PCa and the critical relevance of the disease. In order to gain better knowledge about PCa and to improve clinical management, it is essential to get better insight into the key factors related to the formation and progression of this cancer.
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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Search for other papers by Elif İzci Güllü in
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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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Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
Nova Medical School: Faculdade de Ciências Médicas da Universidade Nova de Lisboa, Lisbon, Portugal
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Background
Treatment of advanced follicular thyroid carcinoma (FTC) is based primarily on indirect evidence obtained with multikinase inhibitors (MKI) in clinical trials in which papillary carcinomas represent the vast majority of cases. However, it should be noted that MKI have a non-negligible toxicity that may decrease the patient’s quality of life. Conventional chemotherapy with GEMOX (gemcitabine plus oxaliplatin) is an off-label therapy, which seems to have some effectiveness in advanced differentiated thyroid carcinomas, with a good safety profile, although further studies are needed.
Case report
We report a case of a metastatic FTC, resistant to several lines of therapy. However, with a durable response to GEMOX, the overall survival of our patient appears to have been extended significantly due to this chemotherapy.
Conclusion
GEMOX may have a role in patients with thyroid cancer unresponsive to MKI.
