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Beomseok Suh, Dong Wook Shin, Youngmin Park, Hyunsun Lim, Jae Moon Yun, Sun Ok Song, Jin Ho Park, BeLong Cho and Eliseo Guallar

Objective

Many thyroid cancer patients are exposed to long-term thyroid-stimulating hormone (TSH) suppression, often as lifetime treatment, and are consequently at risk for cardiovascular disease. We investigated the incidence of coronary heart disease (CHD) and ischemic stroke among thyroid cancer patients compared with matched control subjects.

Design

Retrospective cohort study.

Methods

A total of 182 419 subjects who received thyroidectomy for thyroid cancer during 2004–2012 were selected from the Korean National Health Insurance data, which cover approximately 97% of the entire Korean population. Propensity score matching was used to select non-cancer controls. Cox proportional hazards regression analysis was used to determine relative risk of coronary heart disease and ischemic stroke. Mean follow-up was 4.32 years.

Results

Thyroid cancer patients had elevated risk for CHD and ischemic stroke with hazard ratio (HR) of 1.15 (95% confidence interval (CI): 1.10–1.22) and 1.15 (1.09–1.22), respectively. This risk was increased in those who took a higher dosage of levothyroxine (HR: 1.47, 95% CI: 1.34–1.60 for CHD and HR: 1.56, 95% CI: 1.42–1.72 for ischemic stroke among those who took ≥170 μg/day levothyroxine). Although risk of atrial fibrillation was dose-dependently associated with levothyroxine dosage, it represents only a small proportion of ischemic stroke incidence (4.4%, 128/2914).

Conclusions

The risk for CHD and ischemic stroke was higher in thyroid cancer patients who received thyroidectomy, and the dosage of levothyroxine administered appears to play a major role. Greater caution is suggested for the screening and treatment of thyroid cancer and subsequent TSH suppression therapy, as well as proper management for cardiovascular disease prevention.

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K David, C Moyson, D Vanderschueren and B Decallonne

Objective

Chronic hypoparathyroidism and its treatment may lead to symptoms and complications affecting quality of life. We determined complications in chronic hypoparathyroid patients.

Design

Retrospective cross-sectional study of patients with chronic hypoparathyroidism treated with active vitamin D supplements in a tertiary care centre during the year 2015. Primary outcome parameters were history of kidney stones and seizures and presence of renal and cerebral calcifications on imaging. Secondary outcome parameters were current symptoms of paraesthesia/cramps, hospitalization due to hyper/hypocalcaemia and hypercalciuria.

Subjects

One hundred and seventy patients were included – 143 (84%) with post-surgical hypoparathyroidism (PSHP), 16 (9%) with non-surgical hypoparathyroidism (NSHP) and 11 (7%) with pseudo-hypoparathyroidism (PHP).

Results

History of kidney stones and seizures was present in 15 and 9% of patients, respectively. Renal and cerebral imaging was performed in 51 and 26% of the patients, with 22 and 25% of these patients having renal and cerebral calcifications respectively. Both history of seizures and cerebral calcifications were significantly more in NSHP and PHP than in PSHP patients. No association was observed between seizures and cerebral calcifications. Cramps/paraesthesia were present in 16%, and hospitalization related to hypocalcaemia was reported in 5% of the patients. Calciuria was screened in 47% at the time of consultation, and in 76% of the patients during the past 5 years. In 36% of these patients, calciuria was increased.

Conclusions

Patients with chronic hypoparathyroidism frequently develop ectopic calcifications. Non-surgical patients suffer more from seizures and cerebral calcifications than patients that developed hypoparathyroidism post surgery. There is a need for increased screening of long-term complications, according to the guidelines.

Free access

Valérie Bernard, Bruno Donadille, Tiphaine Le Poulennec, Mariana Nedelcu, Laetitia Martinerie and Sophie Christin-Maitre

Turner syndrome (TS), affecting 1/2000 to 1/2500 live born girls, is a chromosomal aberration with a total or partial loss of one of the X chromosomes. The diagnosis can be established from the intra-uterine life to adulthood. TS is a chronic disease with particular morbidity and mortality. The loss to follow-up rate, during transition, between children and adult units, remains a crucial issue. This review focusses on the adolescent and young adult patients with TS. The different goals of TS transition are presented as well as some of the tools available in order to improve this transition. The involvement of the patient’s family, advocacy groups and therapeutic educational programs are discussed. A specificity concerning TS transition, as compared to other chronic diseases, relies on the fact that patients with TS may present a peculiar neurocognitive profile. They are in general more anxious than the general population. Therefore, psychological support should be offered to optimize transition. Data illustrating the beneficial impact of an organised transition of TS, from paediatric units to multidisciplinary adult care systems, within the same reference centre are presented. Further studies are required to evaluate the mid-to-long-term transition of paediatric patients with TS referred to adult units.

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Bente L Langdahl

Osteoporosis is a common chronic disease and therefore a long-term management plan based on disease severity, comorbidities, other pharmacological treatments, gender, age and patient preferences is necessary. Consideration of treatment breaks may be included in the long-term management plan if the patient has been treated with a bisphosphonate, the disease is less severe, the response to treatment has been satisfactory and the risk of future fracture is estimated to be low. This perspective reviews the current evidence for long-term treatment with bisphosphonates and off treatment effects. Approaches to decision making and monitoring of treatment breaks are discussed.

Open access

René Klinkby Støving

Anorexia nervosa is a syndrome, that is collections of symptoms, which is not defined by its etiology. The severe cases are intractable. The syndrome is associated with multiple, profound endocrine alterations which may be adaptive, reactive or etiologic. Adaptive changes potentially may be inappropriate in clinical settings such as inpatient intensive re-nutrition or in a setting with somatic comorbidity. Electrolyte levels must be closely monitored during the refeeding process, and the need for weight gain must be balanced against potentially fatal refeeding complications. An important focus of clinical research should be to identify biomarkers associated with different stages of weight loss and re-nutrition combined with psychometric data. Besides well-established peripheral endocrine actions, several hormones also are released directly to different brain areas, where they may exert behavioral and psychogenic actions that could offer therapeutic targets. We need reliable biomarkers for predicting outcome and to ensure safe re-nutrition, however, first of all we need them to explore the metabolism in anorexia nervosa to open new avenues with therapeutic targets. A breakthrough in our understanding and treatment of this whimsical disease remains. Considering this, the aim of the present review is to provide an updated overview of the many endocrine changes in a clinical perspective.

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Denise Rockstroh, Heike Pfäffle, Diana Le Duc, Franziska Rößler, Franziska Schlensog-Schuster, John T Heiker, Jürgen Kratzsch, Wieland Kiess, Johannes R Lemke, Rami Abou Jamra and Roland Pfäffle

Objective

The IGF/IGF1R axis is involved in the regulation of human growth. Both IGF1 and IGF2 can bind to the IGF1R in order to promote growth via the downstream PI3K/AKT pathway. Pathogenic mutations in IGF1 and IGF1R determine intrauterine growth restriction and affect postnatal body growth. However, to date, there are only few reports of pathogenic IGF2 mutations causing severe prenatal, as well as postnatal growth retardation.

Results

Here we describe a de novo c.195delC IGF2 variant (NM_000612, p.(Ile66Serfs*93)) in a 4-year-old patient with severe pre- and post-natal growth retardation in combination with dystrophy, facial dimorphism, finger deformities, as well as a patent ductus. Cloning and sequencing of a long-range PCR product harboring the deletion and a SNP informative site chr11:2153634 (rs680, NC_000011.9:g.2153634T>C) demonstrated that the variant resided on the paternal allele. This finding is consistent with the known maternal imprinting of IGF2. 3D protein structure prediction and overexpression studies demonstrated that the p.(Ile66Serfs*93) IGF2 gene variation resulted in an altered protein structure that impaired ligand/receptor binding and thus prevents IGF1R activation.

Conclusion

The severity of the phenotype in combination with the dominant mode of transmission provides further evidence for the involvement of IGF2 in growth disorders.

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Alejandro García-Castaño, Leire Madariaga, Gustavo Pérez de Nanclares, Gema Ariceta, Sonia Gaztambide, Luis Castaño and Spanish Endocrinology Group and Renal Tube Group

Objective

Molecular diagnosis is a useful diagnostic tool in calcium metabolism disorders. The calcium-sensing receptor (CaSR) is known to play a central role in the regulation of extracellular calcium homeostasis. We performed clinical, biochemical and genetic characterization of sequence anomalies in this receptor in a cohort of 130 individuals from 82 families with suspected alterations in the CASR gene, one of the largest series described.

Methods

The CASR gene was screened for mutations by polymerase chain reaction followed by direct Sanger sequencing.

Results

Presumed CaSR-inactivating mutations were found in 65 patients from 26 families. These patients had hypercalcemia (median: 11.3 mg/dL) but normal or abnormally high parathyroid hormone (PTH) levels (median: 52 pg/mL). On the other hand, presumed CaSR-activating mutations were detected in 17 patients from eight families. These patients had a median serum calcium level of 7.4 mg/dL and hypoparathyroidism (median: PTH 13 pg/mL). Further, common polymorphisms previously associated with high blood ionized calcium levels were found in 27 patients (median calcium: 10.6 mg/dL; median PTH: 65 pg/mL) with no other alterations in CASR. Overall, we found 30 different mutations, of which, 14 have not been previously reported (p.Ala26Ser, p.Cys60Arg, p.Lys119Ile, p.Leu123Met, p.Glu133Val, p.Gly222Glu, p.Phe351Ile, p.Cys542Tyr, p.Cys546Gly, p.Cys677Tyr, p.Ile816Val, p.Ala887Asp, p.Glu934*, p.Pro935_Gln945dup).

Conclusions

Patients with CASR mutations may not fit the classic clinical pictures of hypercalcemia with hypocalciuria or hypocalcemia with hypercalciuria. Molecular studies are important for confirming the diagnosis and distinguishing it from other entities. Our genetic analysis confirmed CaSR disorders in 82 patients in the study cohort.

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Carmela Iglesias Felip, Carles Zafon Llopis, Jordi Temprana-Salvador, Amparo García-Burillo, Xavier Serres Créixams, Enric Caubet Busquet, Isabel Roca Bielsa, Jordi Mesa Manteca, Joan Castell Conesa, José Manuel Fort López-Barajas, Ricardo Pujol-Borrell, Santiago Ramon y Cajal Agüeras and Oscar González López

Objective

Lymphadenectomy in papillary thyroid carcinoma (PTC) is controversial. It is indicated whenever metastases have been proven before or during surgery and as a prophylactic treatment in high-risk patients. However, 30–50% of cN0 patients become pN1 postoperatively. In PTC, selective-sentinel-lymph-node-biopsy (SLNB) with conventional intraoperative analysis is 8% false negative. One-step nucleic acid amplification (OSNA) is a molecular technique which allows real-time detection of mRNA encoding for cytokeratin 19. OSNA has been introduced in intraoperative analysis of several tumors to reduce false-negative rates and distinguish micrometastasis from macrometastasis. Our objective was to evaluate the impact of the introduction of OSNA in the intraoperative evaluation of the sentinel node (SN) in PTC.

Design

We analyzed a series of 35 patients subjected to SLNB.

Methods

All the dissected nodes, SN and non-SN, were evaluated with OSNA and cytology.

Results

We obtained a total of 110 SN. SLNB proved positive in 14 patients (40%) with cytology and in 23 (65.7%) with OSNA (P < 0.001). In the 29 patients with subsequent lymphadenectomy we obtained 360 lymph nodes ((52 positive in cytology (14.4%) and 107 in OSNA (29.7%)). Lymphadenectomy proved positive in 16 patients according to cytology (55%) and in 24 according to OSNA (83%) (P = 0002). The majority of patients with micrometastasis in SN showed only micrometastasis in lymphadenectomy.

Conclusions

The present study shows selective-sentinel-lymph-node-biopsy with one-step nucleic acid amplification technique to be feasible in papillary thyroid carcinoma. The quantitative nature of one-step nucleic acid amplification paves the way toward a more personalized surgical approach, limiting lymphadenectomy to patients with intraoperative evidence of macrometastasis in the sentinel node.

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Ashley Grossman

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Mark R Postma, Thalijn L C Wolters, Gerrit van den Berg, Antonius E van Herwaarden, Anneke C Muller Kobold, Wim J Sluiter, Margreet A Wagenmakers, Alfons C M van den Bergh, Bruce H R Wolffenbuttel, Ad R M M Hermus, Romana T Netea-Maier and André P van Beek

Objective

To assess the effect of somatostatin analogs (SSAs) on mortality in relation to disease control of acromegaly after pituitary surgery.

Design

A retrospective study in two large tertiary referral centers in The Netherlands.

Methods

Overall, 319 patients with acromegaly in whom pituitary surgery was performed as primary therapy between January 1980 and July 2017 were included. Postoperative treatment with SSA was prescribed to 174 (55%) patients because of persistent or recurrent disease. Disease control at last visit was assessed by IGF1 standard deviation score (SDS). Adequate disease control was defined as IGF1 SDS ≤2. Univariate determinants of mortality and standardized mortality ratios (SMRs) were calculated for groups with and without SSA at any moment postoperatively and at last visit.

Results

In total, 27 deaths were observed. In univariate analysis, determinants of mortality were inadequate disease control (relative risk (RR): 3.41, P = 0.005), surgery by craniotomy (RR: 3.53, P = 0.013) and glucocorticoid substitution (RR: 2.11, P = 0.047). There was a strong trend toward increased mortality for patients who used SSA (RR: 2.01, P = 0.067) and/or dopamine agonists (RR: 2.54, P = 0.052) at last visit. The SMR of patients with adequate disease control who used SSA at any moment postoperatively (1.07, P = 0.785) and at last visit (1.19; P = 0.600) was not increased. Insufficiently controlled patients had a significantly raised SMR (3.92, P = 0.006).

Conclusions

Postoperative use of SSA is not associated with increased mortality in patients with acromegaly who attain adequate disease control. In contrast, inadequate disease control, primary surgery by craniotomy and glucocorticoid substitution are associated with increased mortality.