Clinical Endocrinology

Wiley Online Library : Clinical Endocrinology
  • Obstructive Sleep Apnoea and Polycystic Ovary Syndrome; a comprehensive review of clinical interactions and underlying pathophysiology
    Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder in women of reproductive age. PCOS is associated with multiple co-morbidities including, obesity, insulin resistance and type 2 diabetes, as well as mood disorders and impaired quality of life (QoL). Obstructive sleep apnoea (OSA) is also a common medical condition that is often undiagnosed, particularly in women. OSA is associated with a similar spectrum of comorbidities to that observed in PCOS, including manifestations of the metabolic syndrome and impaired QoL, whilst obesity frequently constitutes a common denominator in the pathophysiology of both OSA and PCOS. Hence, it is not surprising that OSA and PCOS may co-exist in women of reproductive age, and the current clinical guidelines on the management of PCOS recommend screening for OSA symptoms in overweight/obese women with PCOS. In this review, we examine the relationship between OSA and PCOS and explore the potential underlying mechanisms that link these two conditions. This article is protected by copyright. All rights reserved.
  • Effects of androgen deprivation therapy on telomere length
    Objective Recent evidence suggests that androgens either directly or via aromatisation to oestradiol may regulate telomere length, hence providing a mechanism whereby reproductive steroids are linked to biological ageing in men. Using men with prostate cancer initiating androgen deprivation therapy (ADT), we tested the hypothesis that severe sex steroid deprivation would accelerate telomere shortening. Design We conducted a secondary analysis of a 2-year prospective controlled study among 65 men with nonmetastatic prostate cancer newly commencing adjuvant ADT (n=40) and age- and radiotherapy-matched prostate cancer controls (n=25). Methods We measured leucocyte telomere length (LTL) expressed as telomeric/single copy control gene (T/S) ratio at baseline, 6, 12 and 24 months. Generalized linear models determined the mean adjusted difference (MAD) (95% confidence interval) between groups during follow-up. Results Compared to controls over 24 months, men receiving ADT had no change in LTL, MAD for T/S ratio (0.105 [−0.004; 0.213], P=.235). Conclusions Using men with prostate cancer receiving ADT as a model we found no evidence that prolonged and profound sex steroid deprivation is associated with accelerated telomere shortening. Larger studies will be required to confirm or refute these findings.
  • Prevalence of primary aldosteronism among patients with type 2 diabetes
    Context Diabetes and hypertension coexist in 40%-60% of individuals with type 2 diabetes. The coexistence of these two conditions is associated with increased risk of retinopathy, nephropathy and cardiovascular disease. Objective To investigate the prevalence of primary aldosteronism (PA) in a general cohort of persons with type 2 diabetes. Design Cross-sectional study involving six diabetes outpatient clinics in Sweden. Patients were enrolled individuals with type 2 diabetes between February 2008 and December 2013. Measurements Plasma aldosterone concentrations (PAC pmol/L) and direct renin concentrations (DRC mIU/L) were measured. Patients with increased aldosterone renin ratios (ARR) >65 were further evaluated for PA. Results Of 578 consecutively screened patients with type 2 diabetes, 27 were treated with mineralocorticoid receptor antagonists (MRA) and potassium-sparing diuretics not further evaluated. Among the remaining 551 patients, 38 had increased ARR, including 22 who were clinically indicated for PA tests and 16 who were not further evaluated due to severe comorbidities and old age. There were five (0.93%) patients with confirmed PA after computerized tomography and adrenal venous sampling. Patients with PA had higher systolic blood pressure (P=.032) and lower potassium levels (P=.027) than those without PA. No significant association was found between plasma aldosterone and diabetic complications. Conclusions The prevalence of PA in an unselected cohort of patients with type 2 diabetes is relatively low, and measures of plasma aldosterone are not strong risk factors for micro- and macrovascular diabetic complications.
  • Role of the tumour necrosis factor-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) axis in autoimmune thyroid disease
    Background TNF-like weak inducer of apoptosis (TWEAK), its receptor fibroblast growth factor-inducible 14 (Fn14) and its scavenger receptor CD163 (sCD163) have known associations with many autoimmune diseases. However, the role of the TWEAK axis in autoimmune thyroid disease (AITD) remains unclear. Therefore, the aim of this study was to investigate the role of the TWEAK-Fn14 axis in the pathogenesis of AITD. Methods Serum levels of soluble TWEAK (sTWEAK) and sCD163 were measured in 38 patients with Graves’ disease (GD), 40 patients with Hashimoto's thyroiditis (HT), and 40 healthy controls (HCs). Additionally, the mRNA expression of TWEAK and Fn14 in peripheral blood mononuclear cells (PBMCs) was explored, and the protein expression of TWEAK and Fn14 in thyroid glands surgically removed from 10 patients with GD, 10 patients with HT, and 10 HCs was studied by immunohistochemical staining. Results The results showed that the serum levels of sTWEAK were significantly reduced in HT patients and inversely correlated with anti-thyroid peroxidase antibody (TPOAb) levels. Additionally, high levels of sCD163 and a high sCD163/sTWEAK ratio were positively associated with the TPOAb levels in HT patients and the thyrotropin receptor antibody (TRAb) levels in GD patients. TWEAK mRNA and protein expression were up-regulated in thyroid glands and PBMCs from HT patients. Conclusion Expression of the TWEAK-Fn14 axis was up-regulated in patients with AITD and might play a role in the pathogenesis of AITD. This article is protected by copyright. All rights reserved.
  • Comparison of serum vaspin levels and vaspin expression in adipose tissue and smooth muscle tissue in pregnant women with and without gestational diabetes
    Objective Vaspin is associated with metabolic parameters and insulin resistance. However, the expression of vaspin in visceral adipose tissue (VAT) in pregnant women with gestational diabetes mellitus (GDM) has not been fully explored, and the contribution of vaspin to the biological mechanisms underlying GDM remains unclear. This study aimed to compare circulating vaspin levels and its expression in different insulin target tissues including subcutaneous adipose tissue (SAT), VAT, and smooth muscle tissue (SMT) in pregnant women with and without GDM. Design A total of 37 women with GDM (GDM group) and 37 normal pregnant women (control group) were selected. Fasting plasma glucose (FPG), fasting insulin (FINS), and serum vaspin levels were quantified at term, and homeostasis model of assessment2-insulin resistance (HOMA2-IR) values were calculated. RT-qPCR and western blotting were used to measure mRNA and protein levels of vaspin in VAT, SAT, and SMT of 15 GDM women and normal pregnant women. Results In the GDM group, serum vaspin concentrations were significantly higher than in the control group. Serum vaspin levels were positively correlated with HOMA2-IR in the GDM group but not in the control group. In the GDM group, vaspin mRNA and protein expression levels in SAT and VAT were both significantly higher than in controls but no difference was found in SMT. Moreover, relative mRNA but not protein expression levels of vaspin in SAT were highest among the three tissues in both groups. Conclusions Circulating vaspin levels and expression of vaspin in SAT and VAT were higher in GDM women than in normal pregnant women. However, the specific role of vaspin from SAT and VAT in the pathogenesis of GDM needs further study. This article is protected by copyright. All rights reserved.
  • Temporal trends in thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (ATPO) testing across two phases of iodine fortification in Tasmania (1995-2013)
    Context Tasmania is an island state of the Australian Commonwealth with a well-documented history of mild iodine deficiency. Between 2001 and 2009, Tasmania experienced two incremental phases of iodine fortification. Objective To examine trends in thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (ATPO) testing and their relationship to different phases of iodine nutrition in the Tasmanian population between 1995 and 2013. Design Retrospective longitudinal study. Setting and participants The major primary care and largest public hospital pathology providers in Tasmania submitted data for all TSH and ATPO tests performed between 1995 and 2013. Data linkage methodology was used to determine trends in TSH and ATPO testing. Results A total of 1.66 million TSH assessments, involving 389,910 individual patients, were performed in Tasmania between 1995 and 2013. There was approximately a fourfold increase in the overall rate of TSH testing during this period with the rate of incident TSH assessment remaining relatively stable over the study period. The incidence of overt suppression and elevation of TSH (TSH≤0.1 mIU/L and ≥10 mIU/L) declined 62.3% and 59.7%, respectively, with a trend for increased incidence of borderline TSH elevation ≥4.0 mIU/L. The incidence of thyroid autoimmunity as determined by the proportion of abnormal ATPO results remained stable, with the absolute number of positive test results increasing during the study period. Conclusion Iodine supplementation of this mildly iodine-deficient population was not associated with an obvious increase in incidence of overt thyroid dysfunction or autoimmunity. Whilst the volume of TSH testing increased over the study period, the increase was driven by patients undergoing follow-up TSH assessments.
  • Polycystic ovary morphology is associated with insulin resistance in women with polycystic ovary syndrome
    Background/Objectives Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by chronic anovulation, hyperandrogenism, polycystic ovary morphology (PCOM) and metabolic disturbances including insulin resistance and type 2 diabetes mellitus. Although insulin resistance could be associated with PCOM, recent studies have shown controversial results. The aim of this study was to determine the relationship between PCOM and insulin resistance. Subjects/Methods This was a cross-sectional clinical study. A total of 679 women with PCOS who were diagnosed using the National Institute of Child Health and Human Disease (NICHD) criteria and 272 control women were analysed. We measured fasting glucose and insulin levels, 75 g oral glucose tolerance test-derived glucose and insulin levels, testosterone levels, ovarian volume and follicle number. Results Polycystic ovary morphology was described in 543 women (80.0%) with PCOS. Women with PCOS had significantly higher 2 hours postload glucose, fasting and 2 hours postload insulin levels, ovarian volume, ovarian follicle numbers and lower insulin sensitivity compared with those of the controls (all P<.01). In women with PCOS, ovarian volume and ovarian follicle number were negatively associated with the quantitative insulin sensitivity check index after adjusting for age, body mass index and total testosterone; however, this association was not observed in the controls. In the logistic regression analysis, increased ovarian follicle number was associated with decreased insulin sensitivity in women with PCOS. Conclusions In PCOS, enlarged ovarian volume and follicle excess were associated with insulin resistance, and the number of ovarian follicles could be a predictor of insulin resistance.
  • The incidence of anterior pituitary hormone deficiencies in patients with microprolactinoma and idiopathic hyperprolactinaemia
    Introduction Patients with microprolactinoma and idiopathic hyperprolactinaemia are not generally considered to be at risk of hypopituitarism and are therefore not routinely screened for this abnormality. In our clinical practice, we have observed a number of patients with nonmacroadenomatous hyperprolactinaemia to have anterior pituitary hormone deficits. Aims We aimed to establish the frequency and clinical significance of anterior pituitary hormone deficiencies, comparing patients with radiologically proven microprolactinomas and patients with idiopathic hyperprolactinaemia. Study Design We retrospectively examined the casenotes of 206 patients with hyperprolactinaemia from our centre. Patients who did not fit the profile of surgically naïve microprolactinoma or idiopathic hyperprolactinaemia or who had incomplete data were excluded, resulting in a study group of 56 patients. Results A total of 35 patients with MRI evidence of microprolactinoma were identified, three (8.57%) of whom had one or more anterior pituitary hormone deficiencies. A total of 21 patients with MRI-negative idiopathic hyperprolactinaemia were identified, nine (42%) of whom had one or more anterior pituitary hormone deficiencies (P<.01). Only one patient in the MRI-positive group had deficiency that required hormone replacement, in contrast six patients in the MRI-negative group had deficiencies that were of clinical significance and which required hormone replacement. Summary This study shows a clinically significant incidence of anterior pituitary hormone deficiency in patients with idiopathic hyperprolactinaemia. The authors recommend that dynamic pituitary assessment should be considered routinely in this patient group. A prospective study would be required to assess the underlying cause for these abnormalities, as they suggest a nontumour pan-pituitary process.
  • Prolactinomas diagnosed in the postmenopausal period: clinical phenotype and outcomes
    Objective Most prolactinomas in females are diagnosed during the reproductive age and the majority are microadenomas. Prolactinomas detected in the postmenopausal period are less common with limited published data on their presentation and prognosis. Our objective was to assess the presenting clinical, biochemical and imaging findings, as well as the outcomes of women diagnosed with a prolactinoma in the postmenopausal period. Design and Methods We undertook a retrospective cohort study of women diagnosed with prolactinoma after menopause and followed-up in a large UK pituitary center. Information on presentation, management and outcomes were collected. Results Seventeen women with a median age at diagnosis of 63 years (range 52-78) were identified. Headaches and/or visual deterioration were the most commonly reported complaints at detection of the adenoma (47%). Acute pituitary apoplexy was diagnosed at presentation or during follow-up in 18% of the cases. The median serum prolactin was 12364 mU/L (range 2533-238479). Macroprolactinomas comprised 94% of the tumours, and 88% of them had supra/parasellar extension. All patients with macroprolactinoma were offered dopamine agonist and normal prolactin was achieved in 94% of them (median follow-up 91.5 months). Adenoma shrinkage was observed in all women. Improvement or resolution of visual disturbances documented at presentation was observed in 86% of cases. Conclusions The clinical phenotype of prolactinomas diagnosed in the postmenopausal period is characterized by dominance of macroadenomas, with frequent supra/parasellar extension and a relative high rate of acute pituitary apoplexy. In this group of patients, the response of the macroadenomas to dopamine agonists is good. This article is protected by copyright. All rights reserved.
  • Prolactin correction for adequacy of petrosal sinus cannulation may diminish diagnostic accuracy in Cushing's disease
    Objective Petrosal venous prolactin concentrations have been promoted to improve the diagnostic accuracy of inferior petrosal sinus sampling (IPSS), beyond that achieved with ACTH measurement alone, in diagnosing a pituitary ACTH source, and determining corticotrophinoma side (L/R). Our objective was to assess the effect of using prolactin to confirm adequacy of petrosal cannulation in a cohort of patients with ACTH-dependent Cushing's syndrome. Design Retrospective cohort study. Patients Thirteen patients with clinical and biochemical Cushing's syndrome who underwent IPSS. Measurements Serum prolactin and ACTH in peripheral and inferior petrosal sinus blood before and after corticotrophin-releasing hormone (CRH) injection. Results Thirteen consecutive patients were diagnosed with Cushing's disease using uncorrected ACTH ratios. The side of PRL excess was the same as the side of ACTH excess in all cases. Use of various published prolactin-related equations suggested that the ACTH non-dominant side was not cannulated in four, six or seven patients depending on the equation used. The equations generally decreased the central-to-peripheral gradient on the uncorrected ACTH dominant side, increased the central-to-peripheral gradient on the contralateral side, and diminished or even reversed the ACTH intersinus gradient. Conclusions Consistent co-lateralisation of prolactin and ACTH in IPSS strongly suggests that prolactin cannot act as an independent guide to the diagnosis and lateralisation of Cushing's disease. All patients with Cushing's disease had a prolactin intersinus gradient towards the tumourous side of the pituitary, for likely biological reasons. PRL-corrected ACTH concentrations may threaten the sensitivity and specificity of IPSS in diagnosing Cushing's disease and conceal lateralisation. This article is protected by copyright. All rights reserved.
  • Predictors for Secondary Therapy After Surgical Resection of Non-Functioning Pituitary Adenomas
    Context Factors determining recurrence of non-functioning pituitary adenomas (NFAs) that require further therapy are unclear as are post-operative follow-up imaging guidelines Objective To identify predictors for secondary therapy after surgical resection of NFAs and use this knowledge to inform post-operative management Design and Patients A single-centre retrospective study of surgically resected NFAs in 108 patients followed for up to 15 years. Measurements Serial tumour images were analysed for size, location and growth rate (GR) and tissue analysed for hormone cell type and proliferation indices with secondary treatment as outcome measure. Results 24 of 66 (36%) patients harboring a post-operative remnant required secondary treatment, all occurring within 10 years. No secondary treatment was required in any of 42 patients with complete tumour resection. Age, gender, remnant volume and tumour histology were not different between patients requiring and not requiring secondary therapy. Remnant GRs in those requiring secondary therapy was more than 10 fold higher (p<0.01). Tumours with a GR ≥80 mm3/year (Hazard Ratio HR: 8.1, Confidence Interval CI: 2.4 to 27.3, p<0.01) and those located in the suprasellar region (HR: 6.1, CI: 1.1 to 32, p=0.03) had a higher risk for secondary therapy. Tumour GR in the first 3 post-operative years correlated significantly (r2 = 0.6, p<0.01) with GR during the period of follow up. Conclusion In surgically-resected NFAs further treatment is dependent on the presence of residual tumour, growth rate and location but not tumour histology. Post-operative growth rate of NFAs in the first 3 years of imaging can be used to tailor long-term follow-up to optimize use of health resources. This article is protected by copyright. All rights reserved.
  • Graves’ disease with severe neutropenia: any clues?
    In volume 85, issue 6 of “Clinical Endocrinology”, Aggarwal, et al. published a study titled “Treatment of Hyperthyroidism With Antithyroid Drugs Corrects Mild Neutropenia in Graves’ Disease”. The authors treated Graves’ disease (GD) with mild neutropenia using a thionamide anti-thyroid drug (ATD). From that study we conclude that neutropenia is not uncommon in association with GD and accounts for 14% of cases, and that mild neutropenia does not preclude the use of ATDs. This article is protected by copyright. All rights reserved.
  • Isolated Growth Hormone Deficiency due to the R183H Mutation in GH1: Clinical Analysis of a Four-Generation Family
    The R183H mutation in the growth hormone gene (GH1) is a well-described genetic variant that causes autosomal dominant isolated growth hormone deficiency (IGHD) type II. Previous studies have demonstrated that individuals with this mutation have releasable growth hormone (GH) stores, but such release is severely impaired. Hess et al. reported variable height deficits (-4.5 to -1.0 SDS), variable IGF-I concentrations (-2.9 to -0.8 SDS), and low but detectable, or even normal stimulated peak GH in several patients with the R183H mutation. This article is protected by copyright. All rights reserved.
  • Identification of somatic TERT promoter mutations in familial nonmedullary thyroid carcinomas
    Objective The genes causing familial nonmedullary thyroid carcinoma (FNMTC) identified to date are only involved in a small fraction of the families. Recently, somatic mutations in TERT promoter region and in EIF1AX gene were reported in thyroid tumours of undefined familial status. The aim of this study was to investigate the role of TERT and EIF1AX mutations in familial thyroid tumours. Design The promoter region of TERT was sequenced in leucocyte DNA of the probands from 75 FNMTC families. In thyroid tumours from 54 familial cases, we assessed somatic TERT promoter, RAS and BRAF hotspot mutations, and the whole EIF1AX gene. Results No potentially pathogenic germline variants were identified in TERT in the 75 FNMTC families’ probands. In the 54 carcinomas, we identified five cases (9%) with hotspot somatic TERT promoter mutations. BRAF mutations were found in 41% of the tumours. All TERT-positive samples were also positive for BRAF p.Val600Glu, and this co-occurrence was found to be statistically significant (P=.008). RAS mutations were detected in four tumours wild-type for TERT (7%). Evaluation of tumour mutation data together with the patients’ clinicopathological features revealed a significant correlation between TERT plus BRAF mutations and advanced tumour stage (T4) (P=.020). No mutations were identified in EIF1AX. Conclusions The results of this study suggest that TERT promoter and EIF1AX mutations are not frequently involved in FNMTC aetiology. However, we show for the first time that TERT alterations are associated with familial thyroid tumour progression. Our data also suggest that TERT mutations are more often found in concomitance with BRAF mutations in advanced stages of FNMTC.
  • Microstructure alterations in the hypothalamus in cranially radiated childhood leukaemia survivors but not in craniopharyngioma patients unaffected by hypothalamic damage
    Objective Metabolic complications are frequent in childhood leukaemia (ALL) survivors treated with cranial radiotherapy (CRT). These complications are potentially mediated by damage to the hypothalamus (HT), as childhood onset (CO) craniopharyngioma (CP) survivors without HT involvement are spared overt obesity. Diffusion tensor imaging (DTI) shows brain tissue microstructure alterations, by fractional anisotrophy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). We used DTI to determine the integrity of the microstructure of the HT in ALL survivors. Design Case-control study. Patients Three groups were included: (i) 27 CRT treated ALL survivors on hormone supplementation, (ii) 17 CO-CP survivors on hormone supplementation but without HT involvement and (iii) 27 matched controls. Measurements DTI parameters of the HT were measured and body composition. Results Microstructural alterations in the HT were more severe in ALL survivors with a BMI ≥25 than with BMI <25. Compared to controls, ALL survivors had reduced FA (P=.04), increased MD (P<.001), AD (P<.001) and RD (P<.001) in the right and left HT. In the right HT, ALL survivors with a BMI ≥25 showed elevated MD (P=.03) and AD (P=.02) compared to ALL survivors with BMI <25. In contrast, DTI parameters did not differ between CP survivors and controls. Conclusions Long-term follow-up after CRT for ALL DTI measures were affected in the HT despite complete hormone replacement. The present data suggest that ALL survivors have demyelination and axonal loss in the HT.
  • Incidence of Parathyroid Disorders in an Indian Adult Male Population: A 25 year follow up study
    Context and Objective Detailed information on the epidemiology of parathyroid disorders in India is lacking. Most of the available data pertain to primary hyperparathyroidism (PHPT) rather than the overall burden of parathyroid disorders. We studied the incidence of parathyroid disorders in a cohort of service personnel followed for a long duration. Design, setting and patients The data for this retrospective, descriptive epidemiological study were derived from the electronic medical records (EMR) of health care personnel enrolled between 1990 and 2015. Subjects were recruited between the ages of 17 and 20 years in good health and the data pertaining to parathyroid disorders were derived from the EMR. Main outcomes measures We calculated the incidence rates per person-years of parathyroid disorders using appropriate statistical methods. Results Our analysis includes 51,217 participants (median age 33, range 17 – 54 years) with a mean follow up of 12.5 years. Yearly evaluation of the data gave a cumulative follow up duration of 613,925 person-years. PHPT was diagnosed in 37 and hypoparathyroidism in 16 patients, giving incidence rates of 6 and 2.6 per 100,000 person-years respectively. Only one patient was diagnosed with pseudohypoparathyroidism (0.16 per 100,000 person-years). Out of the 37 patients with PHPT, 16 (43%) developed post-surgical hypoparathyroidism. Conclusion Our cohort had a low incidence of PHPT when compared to western populations. Long term epidemiological studies are essential to identify the demographic trends of metabolic bone disorders in India. This article is protected by copyright. All rights reserved.
  • A Novel HSD17B3 Gene Mutation in a 46,XY Female Phenotype Newborn Identified by Whole Exome Sequencing
    Deficiency of 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) enzyme encoded by HSD17B3 is a rare cause of disorders of sexual development (DSD). Mutations in this gene in 46,XY individuals present at birth with external female phenotype or ambiguous genitalia. The diagnosis of 46,XY DSD is very challenging and not rarely is confirmed only at older ages. This article is protected by copyright. All rights reserved.
  • Utility of a Formatted Pathologic Reporting System in Thyroid Core Needle Biopsy: a Validation Study of 1998 Consecutive Cases
    Objective Thyroid core needle biopsy (CNB) is increasingly being used as a tool for evaluating thyroid nodules; thus, standardization of its diagnostic terminology is called for. We aimed to analyze the pathologic reporting system of thyroid CNB based on the recently proposed protocol by the Korean Endocrine Pathology Thyroid Core Needle Biopsy Study Group and evaluate its usefulness. Design/Methods 1998 consecutive cases of thyroid CNBs were reviewed and divided into 6 categories according to the protocol. Malignancy rate in each category as well as the diagnostic performance of thyroid CNB were calculated using 705 resected cases. Results Thyroid CNB yielded 132 nondiagnostic (6.6%), 791 benign (39.6%), 328 indeterminate (16.4%), 227 follicular neoplasm (11.4%), 69 suspicious for malignancy (3.5%), and 451 malignant lesions (22.6%). In resected specimens, all of the cases designated as suspicious for malignancy and malignant categories in CNB were proven to be true malignant lesions. Lesions diagnosed with follicular neoplasm in CNB were identified as malignant lesions in 57.0%. Malignancy rate was significantly higher in indeterminate lesions with nuclear atypia compared to those with architectural atypia (80.0% vs. 28.2%). When CNB diagnoses of indeterminate lesions or higher categories were considered positive, the sensitivity and positive predictive value for final malignant diagnoses were 99.2% and 81.3%, respectively. Conclusions CNB is an accurate method of evaluating thyroid nodules and can serve as an alternative to fine needle aspiration when it is used and reported according to standardized diagnostic categories. This article is protected by copyright. All rights reserved.
  • The Turner Syndrome Life Course Project: Karyotype-phenotype analyses across the lifespan
    Introduction Turner Syndrome is associated with a variety of morbidities affecting nearly every body system, some of which increase in prevalence in adult life. The severity of clinical features in TS is roughly in parallel with the magnitude of the deficit of X chromosome material. The aim of this study was to extend the established karyotype phenotype relationships using data from a large adult cohort. Materials & Methods Karyotypes were available in 656 (78.1%), 611 of whom could be classified into five major groups within the cohort: 45,X; 45,X mosaicism (45,X/46,XX); isochromosome X (isochromosome Xq); mosaicism 45,X/46,XY and ring X. Continuous variables such as blood pressure and biochemical markers from clinic data were binarised allocating those in the upper quartile to represent at- risk individuals. With the exception of bone mineral density T- score for which the lower quartile was allocated as at risk. For co-morbidities, initiation of formal treatment was recorded. Results 45,X/46,XX had considerably lower incidences of co-morbidities compared to 45,X. The isochromosome group experienced similar outcomes to 45,X. Novel associations were found between the XY mosaic karyotype group and a decreased prevalence of thyroid disease and severe hearing loss. A previously unreported increased incidence of metabolic syndrome was noted within the ring chromosome subgroup. Conclusions Karyotype may play an important factor against stratifying risk of co-morbidity in TS and should be taken into consideration when managing adults with TS. Further investigations of the isochromosome (Xq) and ring groups are necessary to further clarify their associations with co-morbidities. This article is protected by copyright. All rights reserved.
  • Characterization of four Latin American families confirms previous findings and reveals novel features of acid-labile subunit deficiency
    Objective Acid-labile subunit deficiency (ACLSD), caused by inactivating mutations in both IGFALS gene alleles, is characterized by marked reduction in IGF-I and IGFBP-3 levels associated with mild growth retardation. The aim of this study was to expand the known phenotype and genetic characteristics of ACLSD by reporting data from four index cases and their families. Design Auxological data, biochemical and genetic studies were performed in four children diagnosed with ACLSD and all available relatives. Methods Serum levels of IGF-I, IGFBP-3, acid-labile subunit (ALS), and in vitro ternary complex formation (ivTCF) were determined. After sequencing the IGFALS gene, pathogenicity of novel identified variants was evaluated by in vitro expression in transfected Chinese hamster ovarian (CHO) cells. ALS protein was detected in patients′ sera and CHO cells conditioned media and lysates by Western immunoblot (WIB). Results Four index cases and four relatives were diagnosed with ACLSD. The following variants were found: p.Glu35Glyfs*17, p.Glu35Lysfs*87, p.Leu213Phe, p.Asn276Ser, p.Leu409Phe, p.Ala475Val and p.Ser490Trp. ACLSD patients presented low IGF-I and low or undetectable levels of IGFBP-3 and ALS. Seven out of 8 patients did not form ivTCF. Conclusions This study confirms previous findings in ACLSD, such as the low IGF-I and a more severe reduction in IGFBP-3 levels, and a gene dosage effect observed in heterozygous carriers (HC). In addition, father-to-son transmission (father compound heterozygous and mother HC), preservation of male fertility, and marginal ALS expression with potential involvement in preserved responsiveness to rhGH treatment, are all novel aspects, not previously reported in this condition.
  • Longitudinal changes in serum 25-hydroxyvitamin D in the Dallas Heart Study
    Context While the prevalence of vitamin D deficiency is well described in various populations, limited data are available regarding longitudinal variation in serum 25-hydroxyvitamin D concentrations. Objectives To evaluate the temporal trends in serum 25(OH)D, prevalence of vitamin D deficiency and factors influencing these trends. Participants, Design and Setting: Adults enrolled in the Dallas Heart Study, a longitudinal, probability-based, multiethnic, population study in Dallas, Texas, USA. Main Outcome Measures Prevalence of vitamin D deficiency and predictors of change in serum 25(OH)D. Results A total of 2045 participants had serum 25(OH)D measured on two occasions (2000-2002 and 2007-2009) at a median interval of 7 years. Serum 25(OH)D decreased (42.7-39.4 nmol/L, P<.001) and the prevalence of vitamin D deficiency [25(OH)D <50 nmol/L] increased significantly (60.6%-66.4%, P<.0001) despite vitamin D supplementation increasing over the interval (7.2%-23.0%; P<.0001). In a multivariable model adjusting for sex, race, BMI, age, season of blood draw, smoking and exercise, a greater decline in serum 25(OH)D was noted in men compared with women (−8.0 vs −3.5 nmol/L, P<.0001), in participants of Hispanic ethnicity vs White and Black ethnicity (P<.0001), in nonobese vs obese participants (−7.2 vs −4.0 nmol/L, P=.005) and in nonusers vs users of vitamin D supplements (−5.7 vs −1.7 nmol/L, P=.032). Conclusions Despite increased vitamin D supplementation, serum 25(OH)D decreased in an ethnically diverse cohort of Dallas County residents between 2000-2002 and 2007-2009. Features most predictive of a decline in serum 25(OH)D include male sex, Hispanic ethnicity and weight gain.
  • Volumetric magnetic resonance imaging analysis in patients with short-term remission of Cushing's disease
    Objective The data on patients with short-term remission of Cushing's disease (CD) might provide information that is not available from previous long-term remission studies. We aimed to investigate structural changes in the brain in these patients and to examine whether these changes were associated with clinical characteristics. Design A cross-sectional study was performed. Methods Thirty-four patients with CD (14 with CD in short-term remission and 20 with active CD) and 34 controls matched for age, sex and education underwent clinical evaluation and magnetic resonance imaging brain scans. Biometric measurements, disease duration and remission duration data were collected. Grey matter volumes in the whole brain were examined using voxel-based morphometry (VBM). Results No differences were observed in the grey matter volumes of the medial frontal gyrus (MFG) and cerebellum between the patients with remitted CD and healthy controls, whereas patients with active CD had smaller grey matter volumes in these two regions compared with controls and patients with remitted CD. Furthermore, significant correlations were found between remission time and grey matter values in these regions in short-term remission patients with CD. Additionally, greater grey matter volumes in the bilateral caudate of short-term remission patients with CD were observed. Conclusions Trends for structural restoration were found in CD patients with short-term remission. This finding was associated with the number of days elapsed since curative surgery and the current age of the patients. This study enhances our understanding of potential reversibility after the resolution of hypercortisolism in CD patients.
  • Thyroid function after TSH suppression for thyroid cancer: When is optimal time to check?
  • Management and outcome of clinically evident neck recurrence in patients with papillary thyroid cancer
    Background The aim of this study was to report our incidence of clinically evident neck recurrence, salvage neck management and subsequent outcomes in patients with papillary thyroid cancer. This is important to know so that patients with thyroid cancer can be properly counselled about the implications of recurrent disease and subsequent outcome. Methods An institutional database of 3664 patients with thyroid cancer operated between 1986 and 2010 was reviewed. Patients with nonpapillary histology and gross residual disease and those with distant metastases at presentation or distant metastases prior to nodal recurrence were excluded from the study. Of these, 99 (3.0%) patients developed clinically evident nodal recurrence. Details of recurrence and subsequent therapy were recorded for each patient. Subsequent disease-specific survival (sDSS), distant recurrence-free survival (sDRFS) and nodal recurrence-free survival (sNRFS) were determined from the date of first nodal recurrence using the Kaplan-Meier method. Results Of the 99 patients, 59% were female and 41% male. The median age was 41 years (range 5-91). The majority of patients had pT3/4 primary tumours (63%) and were pN+ (78%) at initial presentation. The median time to clinically evident nodal recurrence was 28 months (range: 3-264). Nodal recurrence occurred in the central neck in 15 (15%) patients, lateral neck in 74 (75%) patients and both in 10 (10%) patients. After salvage treatment, the 5-year sDSS was 97.4% from time of nodal recurrence. The 5-year sDRFS and sNRFS were 89.2% and 93.7%, respectively. Conclusion In our series, isolated clinically evident nodal recurrence occurred in 3.0% of patients. Such patients are successfully salvaged with surgery and adjuvant therapy with sDSS of 97.4% at 5 years.
  • Thyrotropin levels and coronary artery calcification: cross-sectional results of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)
    Background There is little information about the association between thyrotropin (TSH) levels and coronary artery calcification (CAC). Objective Our aim was to analyze the association between TSH quintiles and subclinical atherosclerosis measured by CAC, using baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Design Cross-sectional study. Patients and Measurements We excluded individuals using medications that affect thyroid function and who self-reported cardiovascular disease. We included euthyroid subjects, and individuals with subclinical hypothyroidism (SCHypo) and subclinical hyperthyroidism (SCHyper). Logistic regression models evaluated CAC >100 Agatston units as the dependent variable, and increasing quintiles of TSH as the independent variable, adjusted for demographic and cardiovascular risk factors. Results Our sample included 3,836 subjects, mean age 49 years (interquartile range 44–56); 1,999 (52.1%) were female, 3,551 (92.6%) were euthyroid, 239 (6.2%) had SCHypo and 46 (1.2%) had SCHyper. The frequency of women, whites, and never smokers as well as body mass index and insulin resistance increased according to quintiles. The 1st quintile for TSH (0–0.99mIU/l) was associated with CAC >100, using the 3rd quintile (1.39–1.85mIU/l) as reference (adjusted OR=1.57, 95% CI 1.05–2.35, P=0.027), but no association was shown for the 5th quintile (2.68–35.5mIU/l) compared to the 3rd. Restricting the analysis to euthyroid subjects did not change the results. For women, but not for men, we observed a U-shaped curve with 1st and 5th TSH quintiles associated with CAC>100. Conclusion Low and low-normal (1st quintile) TSH levels were associated with CAC >100 Agatston units in a sample with subclinical thyroid disorders and euthyroid subjects. This article is protected by copyright. All rights reserved.

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