Adrian J L Clark and Simon Buckmaster
The term 'hyperthyroidism' refers to a form of thyrotoxicosis due to inappropriate high synthesis and secretion of thyroid hormone(s) by the thyroid. The leading cause of hyperthyroidism in adolescents is Graves’ disease (GD); however, one should also consider other potential causes, such as toxic nodular goitre (single or multinodular), and other rare disorders leading to excessive production and release of thyroid hormones. The term 'thyrotoxicosis' refers to a clinical state resulting from inappropriate high thyroid hormone action in tissues, generally due to inappropriate high tissue thyroid hormone levels. Thyrotoxicosis is a condition with multiple aetiologies, manifestations, and potential modes of therapy. By definition, the extrathyroidal sources of excessive amounts of thyroid hormones, such as iatrogenic thyrotoxicosis, factitious ingestion of thyroid hormone, or struma ovarii, do not include hyperthyroidism. The aetiology of hyperthyroidism/and thyrotoxicosis should be determined. Although the diagnosis is apparent based on the clinical presentation and initial biochemical evaluation, additional diagnostic testing is indicated. This testing should include: (1) measurement of thyroid-stimulating hormone receptor (TSHR) antibodies (TRAb); (2) analysis of thyroidal echogenicity and blood flow on ultrasonography; or (3) determination of radioactive iodine uptake (RAIU). A 123I or 99mTc pertechnetate scan is recommended when the clinical presentation suggests toxic nodular goitre. A question arises regarding whether diagnostic workup and treatment (antithyroid drugs, radioiodine, surgery, and others) should be the same in children and adolescents as in adults, as well as whether there are the same goals of treatment in adolescents as in adults, in female patients vs in male patients, and in reproductive or in postreproductive age. In this aspect, different treatment modalities might be preferred to achieve euthyroidism and to avoid potential risks from the treatment. The vast majority of patients with thyroid disorders require life-long treatment; therefore, the collaboration of different specialists is warranted to achieve these goals and improve patients’ quality of life.
Aditya Dutta, Ganesh Jevalikar, Rutuja Sharma, Khalid J Farooqui, Shama Mahendru, Arun Dewan, Sandeep Bhudiraja, and Ambrish Mithal
To study the prevalence of thyroid dysfunction and its association with disease severity in hospitalized patients of coronavirus disease-19 (COVID-19).
In this retrospective cohort study, thyroid function tests (TFT) of 236 hospitalized patients of COVID-19 along with demographic, comorbid, clinical, biochemical and disease severity records were analysed. Patients were divided into previous euthyroid or hypothyroid status to observe the effect of prior hypothyroidism on the severity of COVID-19.
TFT abnormalities were common. Low free T3 (FT3), high thyroid-stimulating hormone (TSH) and low TSH were seen in 56 (23.7%), 15 (6.4%) and 9 (3.8%) patients, respectively. The median levels of TSH (2.06 vs 1.26 mIU/mL, P = 0.001) and FT3 (2.94 vs 2.47 pg/mL, P < 0.001) were significantly lower in severe disease. Previous hypothyroid status (n = 43) was associated with older age, higher frequency of comorbidities, higher FT4 and lower FT3. TFT did not correlate with markers of inflammation (except lactate dehydrogenase); however, FT3 and TSH negatively correlated with outcome severity score and duration of hospital stay. Cox regression analysis showed that low FT3 was associated with severe COVID-19 (P = 0.032, HR 0.302; CI 0.101–0.904), irrespective of prior hypothyroidism.
Functional thyroid abnormalities (low FT3 and low TSH) are frequently seen in hospitalized patients of COVID-19. Although these abnormalities did not correlate with markers of inflammation, this study shows that low FT3 at admission independently predicts the severity of COVID-19.
Sandeep Kumar, Anurag Ranjan Lila, Saba Samad Memon, Vijaya Sarathi, Virendra A Patil, Santosh Menon, Neha Mittal, Gagan Prakash, Gaurav Malhotra, Nalini S Shah, and Tushar R Bandgar
Risk of metastatic disease in the cluster 2-related pheochromocytoma/paraganglioma (PPGL) is low. In MEN2 patients, identification of origin of metastases from pheochromocytoma (PCC) or medullary thyroid carcinoma (MTC) is challenging as both are of neuroendocrine origin. We aim to describe our experience and perform a systematic review to assess prevalence, demographics, biochemistry, diagnostic evaluation, management, and predictors of cluster 2-related metastatic PPGL. Retrospective analysis of 3 cases from our cohort and 43 cases from world literature was done. For calculation of prevalence, all reported patients (n = 3063) of cluster 2 were included. We found that the risk of metastasis in cluster 2-related PPGL was 2.6% (2% in RET, 5% in NF1, 4.8% in TMEM127 and 16.7% in MAX variation). In metastatic PCC in MEN2, median age was 39 years, bilateral tumors were present in 71% and median tumor size was 9.7 cm (range 4–19) with 43.5% mortality. All patients had a primary tumor size ≥4 cm. Origin of primary tumor was diagnosed by histopathology of metastatic lesion in 11 (57.9%), 131I-MIBG scan in 6 (31.6%), and selective venous sampling and CT in 1 (5.3%) patient each. In subgroup of neurofibromatosis 1 (NF1), median age was 46 years (range 14–59) with median tumor size 6 cm and 57% mortality. To conclude, the risk of metastatic disease in cluster 2-related PPGL is low, being especially high in tumors with size ≥4 cm and associated with high mortality. One-third patients of NF1 with metastatic PPGL had presented in second decade of life. Long-term studies are needed to formulate management recommendations.
Ying Xu, Lei Li, Jihong Zheng, Meng Wang, Bopei Jiang, Yue Zhai, Liumei Lu, Cong Zhang, Zhe Kuang, Xiaomei Yang, Li-Na Jin, Gufa Lin, and Chao Zhang
As a member of the seven-transmembrane rhodopsin-like G protein-coupled receptor superfamily, the melanocortin-3 receptor (MC3R) is vital for the regulation of energy homeostasis and rhythms synchronizing in mammals, and its pharmacological effect could be directly influenced by the presence of melanocortin receptor accessory proteins (MRAPs), MRAP1 and MRAP2. The tetrapod amphibian Xenopus laevis (xl) retains higher duplicated genome than extant teleosts and serves as an ideal model system for embryonic development and physiological studies. However, the melanocortin system of the Xenopus laevis has not yet been thoroughly evaluated. In this work, we performed sequence alignment, phylogenetic tree, and synteny analysis of two xlMC3Rs. Co-immunoprecipitation and immunofluorescence assay further confirmed the co-localization and in vitro interaction of xlMC3Rs with xlMRAPs on the plasma membrane. Our results demonstrated that xlMRAP2.L/S could improve α-MSH-stimulated xlMC3Rs signaling and suppress their surface expression. Moreover, xlMC3R.L showed a similar profile on the ligands and surface expression in the presence of xlMRAP1.L. Overall, the distinct pharmacological modulation of xlMC3R.L and xlMC3R.S by dual MRAP2 proteins elucidated the functional consistency of melanocortin system during genomic duplication of tetrapod vertebrates.
João Castro-Teles, Bernardo Sousa-Pinto, Sandra Rebelo, and Duarte Pignatelli
Pheochromocytomas are a hallmark feature of von Hippel–Lindau disease (vHL). To our knowledge, this is the first systematic review with meta-analysis evaluating the frequency of pheochromocytomas and/or paragangliomas (PPGLs) in patients with vHL, as well as among patients with different vHL subtypes.
Systematic review with meta-analysis.
We searched on MEDLINE, Scopus, and Web of Science. We included primary studies assessing participants with vHL and reporting on the frequency of PPGL. We performed random-effects meta-analysis to quantitatively assess the frequency of PPGL, followed by meta-regression and subgroup analysis. Risk of bias analysis was performed to assess primary studies’ methodological quality.
We included 80 primary studies. In 4263 patients with vHL, the pooled frequency of PPGL was 19.4% (95% CI = 15.9–23.6%, I 2 = 86.1%). The frequency increased to 60.0% in patients with vHL type 2 (95% CI = 53.4–66.3%, I 2 = 54.6%) and was determined to be of 58.2% in patients with vHL type 2A (95% CI = 49.7–66.3%, I 2 = 36.2%), compared to 49.8% in vHL type 2B (95% CI = 39.9–59.7%, I 2 = 42.7%), and 84.1% in vHL type 2C (95% CI = 75.1–93.1%, I 2 = 0%). In meta-regression analysis, more recent studies were associated with a higher frequency of PPGL. All studies had at least one internal validity item classified as 'high risk of bias,' with 13% studies having low risk of bias in all external validity items.
PPGLs are a common manifestation of vHL. Despite methodological limitations and differences across primary studies, our results point to the importance of PPGL screening in patients with vHL.
Qiuyu Huang, Hanshen Chen, Fan Xu, Chao Liu, Yafeng Wang, Weifeng Tang, and Liangwan Chen
Type 2 diabetes mellitus (T2DM) is considered as a metabolic disease with hyperglycemia. Accumulating investigations have explored the important role of hereditary factors for T2DM occurrence. Some functional microRNA (miR) polymorphisms may affect their interactions with target mRNAs and result in an aberrant expression. Thus, miR variants might be considered as a biomarker of the susceptibility of T2DM. In this study, we recruited 502 T2DM cases and 782 healthy subjects. We selected miR-146a rs2910164 C>G, miR-196a2 rs11614913 T>C and miR-499 rs3746444 A>G loci and carried out an investigation to identify whether these miR loci could influence T2DM occurrence. In this investigation, a Bonferroni correction was harnessed. After adjustment, we found that rs2910164 SNP was a protective factor for T2DM (GG vs CC/CG: adjusted P = 0.010), especially in never drinking (GG vs CC/CG: adjusted P = 0.001) and BMI ≥24 kg/m2 (GG vs CC/CG: adjusted P = 0.002) subgroups. We also identified that rs11614913 SNP was a protective factor for T2DM in smoking subjects (CC/TC vs TT: adjusted P = 0.002). When we analyzed an interaction of SNP–SNP with the susceptibility tof T2DM, rs11614913/rs3746444, rs2910164/rs3746444 and rs11614913/rs2910164 combinations were not associated with the risk of T2DM. In summary, this study highlights that rs2910164 SNP decreases the susceptibility of T2DM, especially in BMI ≥24 kg/m2 and never drinking subgroups. In addition, we also identify that rs11614913 C allele decreases the susceptibility of T2DM significantly in smoking subgroup.
Davoud Jafari-Gharabaghlou, Mostafa Vaghari-Tabari, Hajar Oghbaei, Laura Lotz, Reza Zarezadeh, Yeganeh Rastgar Rezaei, Mahnaz Ranjkesh, Mohammad Nouri, Amir Fattahi, Saba Nikanfar, and Ralf Dittrich
Embryo implantation is a complex process in which multiple molecules acting together under strict regulation. Studies showed the production of various adipokines and their receptors in the embryo and uterus, where they can influence the maternal-fetal transmission of metabolites and embryo implantation. Therefore, these cytokines have opened a novel area of study in the field of embryo–maternal crosstalk during early pregnancy. In this respect, the involvement of adipokines has been widely reported in the regulation of both physiological and pathological aspects of the implantation process. However, the information about the role of some recently identified adipokines is limited. This review aims to highlight the role of various adipokines in embryo–maternal interactions, endometrial receptivity, and embryo implantation, as well as the underlying molecular mechanisms.
Daniel Bell, Julia Hale, Cara Go, Ben G Challis, Tilak Das, Brian Fish, and Ruth T Casey
Primary hyperparathyroidism (pHPT) is a common endocrine disorder that can be cured by parathyroidectomy; patients unsuitable for surgery can be treated with cinacalcet. Availability of surgery may be reduced during COVID-19, and cinacalcet can be used as bridging therapy. In this single-centre retrospective analysis, we investigated the utility and safety of cinacalcet in patients with pHPT receiving cinacalcet between March 2019 and July 2020, including pre-parathyroidectomy bridging. We reviewed and summarised the published literature. Cinacalcet dosages were adjusted by endocrinologists to achieve target calcium < 2.70 mmol/L. Eighty-six patients were identified, with the most achieving target calcium (79.1%) with a mean dose of 39.4 mg/day (±17.1 mg/day) for a median duration of 35 weeks (1–178 weeks). Calcium was normalised in a median time of 5 weeks. The majority of patients commenced cinacalcet of 30 mg/day (78 patients) with the remainder at 60 mg/day (8 patients). Forty-seven patients commencing lower dose cinacalcet (30 mg/day) achieved target calcium without requiring 60 mg/day. Baseline PTH was significantly higher in patients requiring higher doses of cinacalcet. 18.6% of patients reported adverse reactions and 4.7% discontinued cinacalcet. Patients treated with cinacalcet pre-parathyroidectomy required a higher dose and fewer achieved target calcium compared to medical treatment with cinacalcet alone. Post-operative calcium was similar to patients who were not given pre-parathyroidectomy cinacalcet. In summary, cinacalcet at an initial dose of 30 mg/day is safe and useful for achieving target calcium in patients with symptomatic or severe hypercalcaemia in pHPT, including those treated for pre-parathyroidectomy. We propose a PTH threshold of >30 pmol/L to initiate at a higher dose of 60 mg/day.
Ren-Lei Ji, Lu Huang, Yin Wang, Ting Liu, Si-Yu Fan, Min Tao, and Ya-Xiong Tao
Melanocortin-3 receptor (MC3R) is a regulator of energy homeostasis, and interaction of MC3R and melanocortin-2 receptor accessory protein 2 (MRAP2) plays a critical role in MC3R signaling of mammals. However, the physiological roles of MC3R in teleosts are not well understood. In this study, qRT-PCR was used to measure gene expression. Radioligand binding assay was used to study the binding properties of topmouth culter MC3R (caMC3R). Intracellular cAMP generation was determined by RIA, and caMC3R expression was quantified with flow cytometry. We showed that culter mc3r had higher expression in the CNS. All agonists could bind and stimulate caMC3R to increase dose dependently intracellular cAMP accumulation. Compared to human MC3R, culter MC3R showed higher constitutive activity, higher efficacies, and R max to alpha-melanocyte-stimulating hormone (α-MSH), des-α-MSH, and adrenocorticotrophic hormone. Both caMRAP2a and caMRAP2b markedly decreased caMC3R basal cAMP production. However, only caMRAP2a significantly decreased cell surface expression, B max, and R max of caMC3R. Expression analysis suggested that MRAP2a and MRAP2b might be more important in regulating MC3R/MC4R signaling during larval period, and reduced mc3r, mc4r, and pomc expression might be primarily involved in modulation of MC3R/MC4R in adults. These data indicated that the cloned caMC3R was a functional receptor. MRAP2a and MRAP2b had different effects on expression and signaling of caMC3R. In addition, expression analysis suggested that MRAP2s, receptors, and hormones might play different roles in regulating culter development and growth.