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Herman Verloop, Johannes W A Smit and Olaf M Dekkers

Objective

Thyroid function abnormalities are common during treatment with tyrosine kinase inhibitors such as sorafenib. Suggested causes are direct effects on thyroid tissue and increased extrathyroidal metabolism of serum thyroxine and 3,5,3-triiodothyronine. We postulated that tyrosine kinase inhibitors may affect the peripheral metabolism of TSH as well. The effect of sorafenib on TSH clearance was studied.

Design

In a study of athyreotic patients on TSH suppression therapy, TSH concentrations were measured after recombinant human TSH (rhTSH) injections before and after 26 weeks of sorafenib therapy.

Methods

Before and after the last week of sorafenib therapy, 20 patients with progressive differentiated thyroid carcinoma received a standard dose regimen of two injections 0.9 mg rhTSH on two consecutive days. TSH concentrations were measured 48 h (TSH48 h) and 96 h (TSH96 h) after the first rhTSH injection. The area under the curve (TSH-AUC), reflecting TSH content between 48 and 96 h following rhTSH administration, was calculated.

Results

TSH48 h levels (120.5 mU/l before vs 146.3 mU/l after; P=0.029), TSH96 h levels (22.0 mU/l before vs 35.5 mU/l after; P=0.001), and TSH-AUC (142.7 vs 186.8 mU/l; P=0.001) were significantly higher after sorafenib treatment. Higher sorafenib doses were associated with increased changes in TSH96 h and TSH-AUC. In two patients, TSH levels after sorafenib therapy exceeded 200 mU/l.

Conclusions

Sorafenib therapy is accompanied by higher rhTSH levels, probably due to a decreased TSH clearance. Further studies are recommended to clarify whether a decreased clearance of TSH is sorafenib specific.

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Olaf M Dekkers, Pia Burman and On behalf of the ESE Clinical Committee

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Jacqueline Trouillas, Pia Burman, Ann McCormack, Stephan Petersenn, Vera Popovic, Olaf Dekkers and Gerald Raverot

The European Society of Endocrinology (ESE) survey reported on the largest cohort of 125 aggressive pituitary tumours (APT) and 40 pituitary carcinomas (PC). Whilst the survey focused on treatment effectiveness, all pathological data were not explored in detail. Here, we comment on some interesting pathological findings, notably the difference between APT and PC.

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Natasha M Appelman-Dijkstra, Marnick Rijndorp, Nienke R Biermasz, Olaf M Dekkers and Alberto M Pereira

Background

Recombinant human growth hormone (rhGH) replacement is advocated in adult growth hormone-deficient (GHD) patients to increase bone mass and improve lipid profile, body composition, and quality of life. The long-term effects of discontinuation of rhGh replacement are unknown.

Methods

This cohort study and systematic review aim to evaluate the long-term metabolic effects of discontinuation of rhGh replacement in adult GHD patients, with a subgroup analyses according to age (< or > 60 years). Data on anthropometry, lipids, glucose, and bone mass density (BMD) were assessed for 3 years after discontinuation.

Results

Cohort study included 64 patients who had discontinued rhGh replacement for >12 months. Fat percentage increased from 31.5±9.5% to 33.8±9.0% (mean difference 2.3, P=0.003). BMI decreased only in subjects <60 years (P=0.014). Glucose, total cholesterol, and LDL-cholesterol levels did not change; however, the percentage of patients on statins increased slightly from 39% to 44%. HDL-C concentration increased only in patients <60 years (mean difference 0.2, P=0.043). Lumbar spine BMD did not change; however, femoral neck BMD and bone turnover markers decreased in subjects <60 years (P=0.001). Systematic review included eight studies (n=166 patients) with a follow-up duration of 6–18 months. Of the eight studies, three qualified as low risk of bias and five as having an intermediate risk of bias. None of the studies reported handling of statins, bisphosphonates, and glucose-lowering medication or excluded patients using these medications.

Conclusions

In this study, discontinuation of rhGh replacement resulted in metabolic changes only in patients <60 years after 3 years. Further research warrants to determine the optimal strategies for (dis)continuation of rhGh replacement in adult patients with GHD.

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Herman Verloop, Olaf M Dekkers, Robin P Peeters, Jan W Schoones and Johannes W A Smit

Iodothyronine deiodinases represent a family of selenoproteins involved in peripheral and local homeostasis of thyroid hormone action. Deiodinases are expressed in multiple organs and thyroid hormone affects numerous biological systems, thus genetic variation in deiodinases may affect multiple clinical endpoints. Interest in clinical effects of genetic variation in deiodinases has clearly increased. We aimed to provide an overview for the role of deiodinase polymorphisms in human physiology and morbidity. In this systematic review, studies evaluating the relationship between deiodinase polymorphisms and clinical parameters in humans were eligible. No restrictions on publication date were imposed. The following databases were searched up to August 2013: Pubmed, EMBASE (OVID-version), Web of Science, COCHRANE Library, CINAHL (EbscoHOST-version), Academic Search Premier (EbscoHOST-version), and ScienceDirect. Deiodinase physiology at molecular and tissue level is described, and finally the role of these polymorphisms in pathophysiological conditions is reviewed. Deiodinase type 1 (D1) polymorphisms particularly show moderate-to-strong relationships with thyroid hormone parameters, IGF1 production, and risk for depression. D2 variants correlate with thyroid hormone levels, insulin resistance, bipolar mood disorder, psychological well-being, mental retardation, hypertension, and risk for osteoarthritis. D3 polymorphisms showed no relationship with inter-individual variation in serum thyroid hormone parameters. One D3 polymorphism was associated with risk for osteoarthritis. Genetic deiodinase profiles only explain a small proportion of inter-individual variations in serum thyroid hormone levels. Evidence suggests a role of genetic deiodinase variants in certain pathophysiological conditions. The value for determination of deiodinase polymorphism in clinical practice needs further investigation.

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Charlotte Steffensen, Alberto M Pereira, Olaf M Dekkers and Jens Otto L Jørgensen

Objective

Type 2 diabetes (T2D) and Cushing’s syndrome (CS) share clinical characteristics, and several small studies have recorded a high prevalence of hypercortisolism in T2D, which could have therapeutic implications. We aimed to assess the prevalence of endogenous hypercortisolism in T2D patients.

Design

Systematic review and meta-analysis of the literature.

Methods

A search was performed in SCOPUS, MEDLINE, and EMBASE for original articles assessing the prevalence of endogenous hypercortisolism and CS in T2D. Data were pooled in a random-effect logistic regression model and reported with 95% confidence intervals (95% CI).

Results

Fourteen articles were included, with a total of 2827 T2D patients. The pooled prevalence of hypercortisolism and CS was 3.4% (95% CI: 1.5–5.9) and 1.4% (95 CI: 0.4–2.9) respectively. The prevalence did not differ between studies of unselected patients and patients selected based on the presence of metabolic features such as obesity or poor glycemic control (P = 0.41 from meta-regression). Imaging in patients with hypercortisolism (n = 102) revealed adrenal tumors and pituitary tumors in 52 and 14% respectively.

Conclusions

Endogenous hypercortisolism is a relatively frequent finding in T2D, which may have therapeutic implications.

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Esther Donga, Olaf M Dekkers, Eleonora P M Corssmit and Johannes A Romijn

Objective

The aim of this study was to perform a systematic review and meta-analysis on insulin resistance in adult patients with type 1 diabetes mellitus compared to healthy controls, assessed by hyperinsulinemic euglycemic clamp studies.

Design and methods

We conducted a systematic search of publications using PubMed, EMBASE, Web of Science and COCHRANE Library. Hyperinsulinemic euglycemic clamp studies comparing adult patients with type 1 diabetes mellitus to healthy controls were eligible. Primary outcome measures were pooled mean differences of insulin sensitivity of endogenous glucose production (EGP), of glucose uptake and of lipolysis. We estimated mean (standardized) differences and 95% CIs using random effects meta-analysis.

Results

We included 38 publications in this meta-analysis. The weighed mean differences in EGP during hyperinsulinemia between patients and controls was 0.88 (95% CI: 0.47, 1.29) in the basal state and 0.52 (95% CI: 0.09, 0.95) in insulin stimulated conditions, indicating decreased hepatic insulin sensitivity in patients. Insulin sensitivity of glucose uptake was either reported as M value (M), glucose infusion rate (GIR), glucose disposal rate (GDR) or metabolic clearance rate (MCR). Weighed mean differences were similar for M −3.98 (95% CI: −4.68, −3.29) and GIR −4.61 (95% CI: −5.86, −3.53). Weighed mean difference for GDR was −2.43 (95% CI: −3.03, −1.83) and −3.29 (95% CI: −5.37, −1.22) for MCR, indicating decreased peripheral insulin sensitivity in patients. Insulin mediated inhibition of lipolysis was decreased in patients, reflected by increased non-esterified fatty acid levels.

Conclusions

Insulin resistance is a prominent feature of patients with type 1 diabetes mellitus and involves hepatic, peripheral and adipose tissues.

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Christa Nederstigt, Bas Uitbeijerse, Laura Janssen, E P Corssmit, Eelco de Koning and Olaf Dekkers

Introduction: The association between type 1 diabetes (T1D) and other auto-immune diseases is well-known. However, a quantitative overview of all associated auto-immune diseases and their prevalence in T1D is lacking.

Methods: We searched Pubmed, Web of Science, EMBASE and Cochrane library in September 2018 to identify relevant articles about the prevalence of the following associated auto-immune diseases in T1D cohorts: auto-immune thyroid disease, celiac disease, gastric autoimmunity including pernicious anemia, vitiligo, and adrenal gland insufficiency. A meta-analysis was performed to estimate pooled prevalences using a random effects model. Furthermore, random-effects meta-regression analysis was performed to assess the association between prevalence and mean age or diabetes duration.

Results: 180 articles were eligible including a total of 293,889 type 1 diabetes patients. Hypothyroidism (65 studies) was prevalent in 9.8 percent (95%CI 7.5-12.3) of patients. Meta-regression showed that for every 10 years age-increase, hypothyroidism prevalence increased with 4.6 percent (95% CI 2.6-6.6, P <0.000, 54 studies). Weighted prevalence of celiac disease was 4.5 percent (95%CI 4.0-5.5, 87 studies). Gastric autoimmunity was found in 4.3 percent of patients (95%CI 1.6-8.2, 8 studies), vitiligo in 2.4 percent (95%CI 1.2-3.9, 14 studies) of patients. The prevalence of adrenal insufficiency was 0.2 percent (95%CI 0.0-0.4, 14 studies) and hyperthyroidism was found in 1.3 percent (95%CI 0.9-1.8, 45 studies) of type 1 diabetes patients. For all analyses, statistical heterogeneity between studies was moderate to high.

Conclusions: The prevalence of antibody mediated auto-immune disease is high among type 1 diabetes patients. Especially hypothyroidism and celiac disease are frequently found.

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Olaf M Dekkers, Erzsébet Horváth-Puhó, Suzanne C Cannegieter, Jan P Vandenbroucke, Henrik Toft Sørensen and Jens Otto L Jørgensen

Objective

Several studies have shown an increased risk for cardiovascular disease (CVD) in hyperthyroidism, but most studies have been too small to address the effect of hyperthyroidism on individual cardiovascular endpoints. Our main aim was to assess the association among hyperthyroidism, acute cardiovascular events and mortality.

Design

It is a nationwide population-based cohort study. Data were obtained from the Danish Civil Registration System and the Danish National Patient Registry, which covers all Danish hospitals. We compared the rate of all-cause mortality as well as venous thromboembolism (VTE), acute myocardial infarction (AMI), ischemic and non-ischemic stroke, arterial embolism, atrial fibrillation (AF) and percutaneous coronary intervention (PCI) in the two cohorts. Hazard ratios (HR) with 95% confidence intervals (95% CI) were estimated.

Results

The study included 85 856 hyperthyroid patients and 847 057 matched population-based controls. Mean follow-up time was 9.2 years. The HR for mortality was highest in the first 3 months after diagnosis of hyperthyroidism: 4.62, 95% CI: 4.40–4.85, and remained elevated during long-term follow-up (>3 years) (HR: 1.35, 95% CI: 1.33–1.37). The risk for all examined cardiovascular events was increased, with the highest risk in the first 3 months after hyperthyroidism diagnosis. The 3-month post-diagnosis risk was highest for atrial fibrillation (HR: 7.32, 95% CI: 6.58–8.14) and arterial embolism (HR: 6.08, 95% CI: 4.30–8.61), but the risks of VTE, AMI, ischemic and non-ischemic stroke and PCI were increased also 2- to 3-fold.

Conclusions

We found an increased risk for all-cause mortality and acute cardiovascular events in patients with hyperthyroidism.

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Jens Bollerslev, Lars Rejnmark, Claudio Marcocci, Dolores M Shoback, Antonio Sitges-Serra, Wim van Biesen and Olaf M Dekkers

Hypoparathyroidism (HypoPT) is a rare (orphan) endocrine disease with low calcium and inappropriately low (insufficient) circulating parathyroid hormone levels, most often in adults secondary to thyroid surgery. Standard treatment is activated vitamin D analogues and calcium supplementation and not replacement of the lacking hormone, as in other hormonal deficiency states. The purpose of this guideline is to provide clinicians with guidance on the treatment and monitoring of chronic HypoPT in adults who do not have end-stage renal disease. We intend to draft a practical guideline, focusing on operationalized recommendations deemed to be useful in the daily management of patients. This guideline was developed and solely sponsored by The European Society of Endocrinology, supported by CBO (Dutch Institute for Health Care Improvement) and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles as a methodological base. The clinical question on which the systematic literature search was based and for which available evidence was synthesized was: what is the best treatment for adult patients with chronic HypoPT? This systematic search found 1100 articles, which was reduced to 312 based on title and abstract. The working group assessed these for eligibility in more detail, and 32 full-text articles were assessed. For the final recommendations, other literature was also taken into account. Little evidence is available on how best to treat HypoPT. Data on quality of life and the risk of complications have just started to emerge, and clinical trials on how to optimize therapy are essentially non-existent. Most studies are of limited sample size, hampering firm conclusions. No studies are available relating target calcium levels with clinically relevant endpoints. Hence it is not possible to formulate recommendations based on strict evidence. This guideline is therefore mainly based on how patients are managed in clinical practice, as reported in small case series and based on the experiences of the authors.