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Open access

Claire L Wood, Michael Cole, Malcolm Donaldson, David B Dunger, Ruth Wood, Niamh Morrison, John N S Matthews, Simon H S Pearce, Timothy D Cheetham, and the British Society for Paediatric Endocrinology and Diabetes (BSPED)

Objective

First-line treatment of thyrotoxicosis in young people is thionamide anti-thyroid drug (ATD) in a blocking dose with levothyroxine replacement (block and replace, BR) or in a smaller dose tailored to render the patient euthyroid (dose titration, DT). Our objective was to determine which regimen provides more stable biochemical control.

Design

A multi-centre phase III, open-label randomised trial comparing BR with DT in patients aged 2–17 years with newly diagnosed thyrotoxicosis at 15 UK centres.

Methods

Patients were randomised shortly after diagnosis and treated for 3 years. The primary outcome was the percentage of serum thyroid-stimulating hormone (TSH) levels in the reference range between 6 months and 3 years. Secondary outcomes included the proportion of Free thyroxine (FT4) levels in the reference range, adverse event frequency and 4 years outcome (remission/relapse).

Results

Eighty-two patients were randomised, with details on clinical course in 81 (62 Female); 40 were allocated to BR (41 DT). Three withdrew with one ineligible. The mean percentage of serum TSH within reference range was 60.2% in BR and 63.8% in DT patients; adjusted difference 4.3%, 95% CI (−7.8 to 16.4); P = 0.48. Proportions for FT4 were 79.2% in BR and 85.7% in DT patients; adjusted difference 6.8%, (−0.2 to 15.6); P = 0.13. Three patients developed neutropenia – all on BR. 6 BR and 10 DT patients were in remission at 4y.

Conclusion

This randomised trial has shown no evidence to suggest that BR, when managing the young patient with thyrotoxicosis, is associated with improved biochemical stability when compared to DT.

Open access

Chin-Chun Chang, Chih-Jen Cheng, Chih-Chien Sung, Tzong-Shi Chiueh, Chien-Hsing Lee, Tom Chau, and Shih-Hua Lin

Background

A comprehensive analysis has not been performed on patients with thyrotoxic periodic paralysis (TPP) characterized by acute hypokalemia and paralysis in the setting of thyrotoxicosis.

Purpose

The aim of this study was to analyze the detailed symptomatology of thyrotoxicosis and precipitating factors for the attack in a large cohort of TPP patients.

Patients and methods

A prospective observational study enrolled patients with TPP consecutively over 10 years at an academic medical center. Clinical features, including signs/symptoms of thyrotoxicosis and precipitating factors, were analyzed. The Wayne's index was used to assess the severity of thyrotoxicosis at presentation. Patients who agreed to receive an oral glucose-loading test after recovery were evaluated.

Results

Among the 135 TPP patients (male:female, 130:5), 70% of paralytic attacks occurred in the morning, especially during the seasons of summer and fall. Two-thirds of patients did not have a known family or personal history of hyperthyroidism. Only 17% of TPP patients manifested overt signs/symptoms of thyrotoxicosis (Wayne's index >19). A clear precipitating factor, such as high carbohydrate load, acute upper respiratory tract infection, strenuous exercise, high-salt diet, or the use of steroids or bronchodilators, was identified in only 34% of TPP patients. A glucose load to stimulate insulin secretion induced acute hypokalemia (K+2.47±0.6 mmol/l) with reparalysis in only 18% (10/55) of TPP patients.

Conclusions

Most TPP patients have only subtle clinical signs/symptoms of thyrotoxicosis and only a small fraction has clear precipitating factors. In addition to the effects of hyperinsulinemia, other insulin-independent mechanisms may participate in the pathogenesis of TPP.

Open access

Kristien Boelaert, W Edward Visser, Peter Nicholas Taylor, Carla Moran, Juliane Léger, and Luca Persani

This manuscript provides guidance on the management of thyroid dysfunction during the COVID-19 pandemic. Autoimmune thyroid diseases are not linked to increased risks of COVID-19. Uncontrolled thyrotoxicosis may result in more severe complications from SARS-CoV-2 infection, including thyroid storm. The management of patients with a new diagnosis of hyperthyroidism is best undertaken with a block-and-replace regimen due to limited biochemical testing availability. Antithyroid drug (ATD)-induced neutropenia may favour the progression of COVID-19 and symptoms of infection may be confused with SARS-CoV-2 infection. The withdrawal of ATDs and urgent measurement of neutrophils should be considered in case of flu-like manifestations occurring in the initial months of treatment. Urgent surgery or 131-I may be undertaken in selected cases of uncontrolled thyrotoxicosis. Patients with COVID-19 infection may present with conjunctivitis, which could cause diagnostic difficulties in patients with new or existing Graves’ ophthalmopathy. Patients who are on replacement treatment with thyroid hormones should ensure they have sufficient supply of medication. The usual advice to increase dosage of levothyroxine during pregnancy should be adhered to. Many newly presenting and previously diagnosed patients with thyroid dysfunction can be managed through virtual telephone or video clinics supported by a dedicated nurse-led service, depending on available facilities.

Open access

Bridget A Knight, Beverley M Shields, Andrew T Hattersley, and Bijay Vaidya

Objective

Subclinical hypothyroidism and isolated hypothyroxinaemia in pregnancy have been associated with an increased risk of gestational diabetes. We aimed to ascertain if these women have a worse metabolic phenotype than euthyroid pregnant women.

Design, subjects and methods

We recruited 956 healthy Caucasian women with singleton, non-diabetic pregnancies from routine antenatal clinics. Detailed anthropometric measurements (including BMI and skinfold thickness) and fasting blood samples (for TSH, free thyroxine (FT4), free triiodothyronine (FT3), HbA1c, lipid profile, plasma glucose and insulin resistance (HOMA-IR) analysis) were obtained at 28 weeks gestation.

Results

In comparison to euthyroid women (n=741), women with isolated hypothyroxinaemia (n=82) had significantly increased BMI (29.5 vs 27.5 kg/m2, P<0.001), sum of skinfolds (57.5 vs 51.3 mm, P=0.002), fasting plasma glucose (4.5 vs 4.3 mmol/l, P=0.01), triglycerides (2.3 vs 2.0 mmol/l, P<0.001) and HOMA-IR (2.0 vs 1.3, P=0.001). Metabolic parameters in women with subclinical hypothyroidism (n=133) were similar to those in euthyroid women. Maternal FT4 was negatively associated with BMI (r=−0.22), HbA1c (r=−0.14), triglycerides (r=−0.17), HOMA-IR (r=−0.15) but not total/HDL cholesterol ratio (r=−0.03). Maternal FT3:FT4 ratio was positively associated with BMI (r=0.4), HbA1c (r=0.21), triglycerides (r=0.2), HOMA–IR (r=0.33) and total/HDL cholesterol ratio (r=0.07). TSH was not associated with the metabolic parameters assessed.

Conclusions

Isolated hypothyroxinaemia, but not subclinical hypothyroidism, is associated with adverse metabolic phenotype in pregnancy, as is decreasing maternal FT4 and increasing FT3:FT4 ratio. These associations may be a reflection of changes in the thyroid hormone levels secondary to increase in BMI rather than changes in thyroid hormone levels affecting body weight and related metabolic parameters.

Open access

Andrii Dinets, Mykola Hulchiy, Anastasios Sofiadis, Mehran Ghaderi, Anders Höög, Catharina Larsson, and Jan Zedenius

Background

Increased incidence of papillary thyroid carcinoma (PTC) is observed as a consequence of radiation exposure in connection to the Chornobyl nuclear plant accident in 1986. In this study, we report a cohort of adult Ukrainian patients diagnosed with PTC from 2004 to 2008 following exposure at the age of 18 years or younger.

Methods

In total, 70 patients were identified and clinically characterized. The common BRAF 1799T>A mutation was assessed by pyrosequencing, the RET/PTC1 and RET/PTC3 (NCOA4) rearrangements by RT-PCR, and the expression of Ki-67 (MIB-1 index), BCL2, cyclin A, and cyclin D1 by immunohistochemistry.

Results

In total, 46/70 (66%) cases carried a BRAF mutation and/or a RET/PTC rearrangement. A BRAF mutation was detected in 26 tumors, RET/PTC1 in 20 cases, and RET/PTC3 in four cases. In four of these cases, BRAF mutation and RET/PTC rearrangement were coexisting. The BRAF mutation was underrepresented among PTCs with accompanying chronic lymphocytic thyroiditis (CLT) compared with PTCs without this feature (12 vs 44%). MIB-1 proliferation index determined by double staining with leukocyte common antigen was low (mean 0.8%; range 0.05–4.5%). Moreover, increased expression of cyclin A was observed in PTCs with a tumor size >2 cm compared with PTCs ≤2 cm (1.2 vs 0.6%). BCL2 and cyclin D1 showed frequent expression but without associations to clinical characteristics or amplification of the CCND1 locus.

Conclusions

Our results suggest that this cohort has frequent BRAF mutation, RET/PTC1 rearrangement, and low proliferation index. Furthermore, BRAF 1799T>A was underrepresented in PTCs with CLT, and cyclin A expression was associated with increased PTC tumor size.

Open access

Brigitte Delemer, Jean-Pierre Aubert, Pierre Nys, Frédéric Landron, and Stéphane Bouée

Objective

To document the initial management of hypothyroidism in France with respect to diagnostic setting, investigations, and therapeutic approach.

Design

Observational study of the management by primary care practitioners (PCPs) and endocrinologists of patients diagnosed with, and treated for, hypothyroidism during the enrollment period or the previous 6 months.

Methods

A representative sample of PCPs and endocrinologists enrolled up to five consecutive patients and reported sociodemographic, clinical, therapeutic, and laboratory data. Data were submitted at baseline and at the first measurement of TSH after starting the treatment.

Results

The analysis population comprised 1255 patients (mean (s.d.) age 52.8 (16.3) years; 84% female). Hypothyroidism was suspected on clinical grounds in 77% of patients, with goiter in 16%. Autoimmune thyroiditis, supported by positive anti-thyroid antibodies, was the most frequent diagnosis (59%), followed by iatrogenic causes (28%), of which thyroidectomy was the most common. The median baseline TSH was 8.6 mIU/l, suggesting a high incidence of subclinical hypothyroidism. Imaging studies were requested in over 75% of patients, with ultrasound performed in 98% and scintigraphy performed in 19% of these patients. Both groups of physicians treated their patients almost exclusively with levothyroxine. Endocrinologists were more likely than PCPs to provide counseling on how to take medication correctly.

Conclusions

This observational study of a large cohort of patients with newly diagnosed hypothyroidism in France illustrates current practice and indicates some areas where physician education may be required to optimize adherence to guidelines and cost-effectiveness.

Open access

Peter N Taylor, Vijay Panicker, Adrian Sayers, Beverley Shields, Ahmed Iqbal, Alexandra P Bremner, John P Beilby, Peter J Leedman, Andrew T Hattersley, Bijay Vaidya, Timothy Frayling, Jonathan Evans, Jonathan H Tobias, Nicholas J Timpson, John P Walsh, and Colin M Dayan

Objective

Common variants in PDE8B are associated with TSH but apparently without any effect on thyroid hormone levels that is difficult to explain. Furthermore, the stability of the association has not been examined in longitudinal studies or in patients on levothyroxine (l-T4).

Design

Totally, four cohorts were used (n=2557): the Busselton Health Study (thyroid function measured on two occasions), DEPTH, EFSOCH (selective cohorts), and WATTS (individuals on l-T4).

Methods

Meta-analysis to clarify associations between the rs4704397 single nucleotide polymorphism in PDE8B on TSH, tri-iodothyronine (T3), and T4 levels.

Results

Meta-analysis confirmed that genetic variation in PDE8B was associated with TSH (P=1.64×10−10 0.20 s.d./allele, 95% confidence interval (CI) 0.142, 0.267) and identified a possible new association with free T4 (P=0.023, −0.07 s.d./allele, 95% CI −0.137, −0.01), no association was seen with free T3 (P=0.218). The association between PDE8B and TSH was similar in 1981 (0.14 s.d./allele, 95% CI 0.04, 0.238) and 1994 (0.20 s.d./allele, 95% CI 0.102, 0.300) and even more consistent between PDE8B and free T4 in 1981 (−0.068 s.d./allele, 95% CI −0.167, 0.031) and 1994 (−0.07 s.d./allele, 95% CI −0.170, 0.030). No associations were seen between PDE8B and thyroid hormone parameters in individuals on l-T4.

Conclusion

Common genetic variation in PDE8B is associated with reciprocal changes in TSH and free T4 levels that are consistent over time and lost in individuals on l-T4. These findings identify a possible genetic marker reflecting variation in thyroid hormone output that will be of value in epidemiological studies and provides additional evidence that PDE8B is involved in TSH signaling in the thyroid.

Open access

Jeroen M K de Filette, Joeri J Pen, Lore Decoster, Thomas Vissers, Bert Bravenboer, Bart J Van der Auwera, Frans K Gorus, Bart O Roep, Sandrine Aspeslagh, Bart Neyns, Brigitte Velkeniers, and Aan V Kharagjitsingh

Objective

To better define the rare adverse event (AE) of diabetes mellitus associated with immune checkpoint inhibitors (ICIs).

Design and methods

We report the case of a lung cancer patient with diabetic ketoacidosis (DKA) and autoimmune thyroiditis during pembrolizumab treatment. We provide a systematic review of all published cases (PubMed/Web of Science/Cochrane, through November 2018) of autoimmune diabetes mellitus related to blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4)-, programmed cell death 1 (PD-1) receptor or its ligand (PD-L1) or combination (ICI) therapy.

Results

Our literature search identified 90 patient cases (our case excluded). Most patients were treated with anti-PD-1 or anti-PD-L1 as monotherapy (79%) or in combination with CTLA-4 blockade (15%). On average, diabetes mellitus was diagnosed after 4.5 cycles; earlier for combination ICI at 2.7 cycles. Early-onset diabetes mellitus (after one or two cycles) was observed during all treatment regimens. Diabetic ketoacidosis was present in 71%, while elevated lipase levels were detected in 52% (13/25). Islet autoantibodies were positive in 53% of patients with a predominance of glutamic acid decarboxylase antibodies. Susceptible HLA genotypes were present in 65% (mostly DR4). Thyroid dysfunction was the most frequent other endocrine AE at 24% incidence in this patient population.

Conclusion

ICI-related diabetes mellitus is a rare but often life-threatening metabolic urgency of which health-care professionals and patients should be aware. Close monitoring of blood glucose and prompt endocrine investigation in case of hyperglycemia is advisable. Predisposing factors such as HLA genotype might explain why some individuals are at risk.

Open access

Yongze Li, Zhongyan Shan, and Weiping Teng

Objective: Longitudinal studies have investigated the effects of changing iodine status on thyroid disorders, but the effect of a transition from more than adequate iodine to adequate iodine on national changes in prevalence adjusted for changing risk factors remains unclear.

Design: Two repeat nationwide surveys were conducted from 2009-2010 to 2015-2017 to assess changes in thyroid disorder prevalence and iodine status in China.

Methods: A multistage stratified random sampling method was used to obtain a nationally representative sample of urban adults aged 18 and older in mainland China in 2009 (n=14925) and 2015 (n=12553). Changes in thyroid disorder prevalence, urinary iodine concentration (UIC), and thyroid-stimulating hormone (TSH) levels were assessed. Logistic regression models were used to examine changes in prevalence over time.

Results: The median UIC decreased significantly from 219.7 to 175.9 μg/L (P<0.0001). The weighted prevalence of overt hyperthyroidism, subclinical hyperthyroidism, Graves’ disease, and goitre decreased between 2009 and 2015 in the overall population (P<0.05 for all). Despite no significant changes in subclinical hyperthyroidism or hypothyroidism or anti-thyroid peroxidase or anti-thyroglobulin antibody positivity prevalence, a significant increase in thyroid nodule prevalence (P<0.0001) was found in the overall population. The 2.5th TSH percentile increased by 0.15 mIU/L (95%CI, 0.01 to 0.30 mIU/L, P=0.04) from 2009 to 2015.

Conclusions: With the iodine status transition from more than adequate to adequate, thyroid disorder (except for thyroid nodules) prevalence remained stable or even decreased after adjusting for confounding factors among adults in mainland China between 2009 and 2015. Additional studies are needed to explore the reasons for the increased thyroid nodule prevalence.

Open access

Serena Khoo, Greta Lyons, Anne McGowan, Mark Gurnell, Susan Oddy, W Edward Visser, Sjoerd van den Berg, David Halsall, Kevin Taylor, Krishna Chatterjee, and Carla Moran

Objective

Familial dysalbuminaemic hyperthyroxinaemia (FDH), most commonly due to an Arginine to Histidine mutation at residue 218 (R218H) in the albumin gene, causes artefactual elevation of free thyroid hormones in euthyroid individuals. We have evaluated the susceptibility of most current free thyroid hormone immunoassay methods used in the United Kingdom, Europe and Far East to interference by R218H FDH.

Methods

Different, one- and two-step immunoassay methods were tested, measuring free T4 (FT4) and free T3 (FT3) in 37 individuals with genetically proven R218H FDH.

Results

With the exception of Ortho VITROS, FT4 measurements were raised in all assays, with greatest to lowest susceptibility to interference being Beckman ACCESS > Roche ELECSYS > FUJIREBIO Lumipulse > Siemens CENTAUR > Abbott ARCHITECT > Perkin-Elmer DELFIA. Five different assays recorded high FT3 levels, with the Siemens CENTAUR method measuring high FT3 values in up to 30% of cases. However, depending on the assay method, FT4 measurements were unexpectedly normal in some, genetically confirmed, affected relatives of index FDH cases.

Conclusions

All FT4 immunoassays evaluated are prone to interference by R218H FDH, with their varying susceptibility not being related to assay architecture but likely due to differing assay conditions or buffer composition. Added susceptibility of many FT3 assays to measurement interference, resulting in high FT4 and FT3 with non-suppressed TSH levels, raises the possibility of R218H FDH being misdiagnosed as resistance to thyroid hormone beta or TSH-secreting pituitary tumour, potentially leading to unnecessary investigation and inappropriate treatment.