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Journal of Clinical Endocrinology & Metabolism
Journal Prestige (SJR): 2.941
Citation Impact (citeScore): 5
Number of Followers: 172  
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ISSN (Print) 0021-972X - ISSN (Online) 1945-7197
Published by Endocrine Society, The Homepage  [4 journals]
  • Hypercalcemia in Glucagon Cell Hyperplasia and Neoplasia (Mahvash
           Syndrome): A New Association
    • Authors: Gild M; Tsang V, Samra J, et al.
      Pages: 3119 - 3123
      Abstract: AbstractContextHyperglucagonemia in the absence of glucagonomas is rare. Biallelic-inactivating mutations in the glucagon receptor gene (GCGR) cause glucagon cell hyperplasia and neoplasia (GCHN), also termed Mahvash syndrome. Here, we report the first case to our knowledge of GCHN presenting with hypercalcemia and demonstrate a unique relationship between calcium and α-cell hyperplasia.Case DescriptionA 47-year-old man presented with severe PTH-independent hypercalcemia, 13.95 mg/dL (3.48 mmol/L). Imaging and extensive pathology tests yielded no conclusive cause. Glucagon levels >300 times the upper limit of normal were discovered. Subtotal pancreatectomy identified α-cell hyperplasia and neoplasia with metastatic disease in lymph nodes. Genomic analysis confirmed a homozygous missense variant in GCGR (Asp63Asn). This is a previously described pathologic variant and has a known association with GCHN.ConclusionsInactivating mutations of the glucagon receptor gene lead to nonfunctional hyperglucagonemia and are associated with GCHN. Homozygous or compound heterozygous GCGR mutations are associated with α-cell hyperplasia, a known precursor to pancreatic neuroendocrine tumors that can metastasize. Hypercalcemia is an unreported consequence of GCHN with an unclear mechanism.
      PubDate: Wed, 18 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-01074
      Issue No: Vol. 103, No. 9 (2018)
  • Gestational Gigantomastia Complicated by PTHrP-Mediated Hypercalcemia
    • Authors: Modarressi T; Levine M, Tchou J, et al.
      Pages: 3124 - 3130
      Abstract: AbstractContextGestational gigantomastia is an uncommon condition characterized by abnormal and excessive growth of breast tissue during an otherwise uncomplicated pregnancy. Gestational gigantomastia may be accompanied by hypercalcemia, which in some cases has been associated with elevated serum levels of PTHrP. The source of the PTHrP in these cases has been suggested to be the enlarged breasts.ObjectiveTo describe the rapid resolution of hypercalcemia and normalization of serum PTHrP after elective termination of pregnancy, indicating that the placenta was the source of the PTHrP.DesignA retrospective analysis of clinical and biochemical data over a 2-year interval and review of literature.SettingAn academic medical center.PatientA 33-year-old G8P4 female who presented at week 8 of pregnancy with gestational gigantomastia and subsequently developed marked hypercalcemia at week 13. Serum levels of PTH were suppressed but circulating PTHrP was elevated. There was no history of hypercalcemia or significant breast growth during previous pregnancies.InterventionHypercalcemia was poorly responsive to IV saline, prednisone, calcitonin, and cinacalcet. She requested termination of pregnancy at week 20.ResultsSerum levels of calcium, PTH, and PTHrP normalized within 48 hours of termination of pregnancy.ConclusionThe rapid resolution of hypercalcemia after termination of pregnancy, despite persistent gigantomastia, provides evidence for a pathologic role of the placenta in the excess production of PTHrP, possibly through an as yet uncharacterized placenta-breast hormonal axis.
      PubDate: Wed, 18 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-01181
      Issue No: Vol. 103, No. 9 (2018)
  • One-Hour Postload Hyperglycemia: Implications for Prediction and
           Prevention of Type 2 Diabetes
    • Authors: Fiorentino T; Marini M, Succurro E, et al.
      Pages: 3131 - 3143
      Abstract: AbstractContextRecently, a value of 1-hour postload glucose concentration (1-h-PG) ≥155 mg/dL (8.6 mmol/L) in individuals with normal glucose tolerance (NGT) has been found to be associated with an increased risk for future type 2 diabetes mellitus (T2DM). In this review, we analyze the implication of 1-h-PG determination in prediction of T2DM and cardiovascular disease.DesignA literature search was performed using MEDLINE. We included all English studies published up to February 2018 in peer-reviewed journals that examined the relationship between 1-h-PG and diabetes, cardiometabolic alterations, organ damage, and cardiovascular disease.ResultsSeveral longitudinal studies have consistently shown that 1-h-PG ≥155 mg/dL can recognize individuals at increased risk for future T2DM among subjects with NGT. Additionally, we describe the pathophysiological abnormalities associated with 1-h-PG ≥155 mg/dL including impaired insulin sensitivity, β-cell dysfunction, and increased glucose intestinal absorption, which are known to be involved in T2DM pathogenesis. Importantly, numerous studies have demonstrated that a value of 1-h-PG ≥155 mg/dL in individuals with NGT is not only linked to an increased risk for future T2DM, but also able to identify those having a worse cardiovascular phenotype and an increased risk of adverse cardiovascular outcomes.ConclusionsAlthough 1-h-PG determination is not currently recommended by the American Diabetes Association for identifying high-risk individuals, the available evidence indicates that a value of 1-h-PG ≥155 mg/dL may be a useful tool to recognize, among subjects with NGT, those at increased risk of T2DM and cardiovascular disease.
      PubDate: Tue, 17 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00468
      Issue No: Vol. 103, No. 9 (2018)
  • Programmed Cell Death-1 Inhibitor–Induced Type 1 Diabetes Mellitus
    • Authors: Clotman K; Janssens K, Specenier P, et al.
      Pages: 3144 - 3154
      Abstract: AbstractContextPembrolizumab (Keytruda; Merck Sharp & Dohme) is a humanized IgG4 monoclonal antibody used in cancer immunotherapy. It targets the programmed cell death-1 (PD-1) receptor, which is important in maintaining self-tolerance. However, immune checkpoint blockade is associated with a risk for immune-related adverse events (irAEs) potentially affecting the endocrine organs. Type 1 diabetes mellitus is a rare irAE of PD-1 inhibitors, occurring in 0.2% of cases.Evidence AcquisitionSystematic search of four databases (MEDLINE, Embase, Web of Science, and Cochrane Library) using the search terms “diabetes” or “ketoacidosis” and “pembrolizumab,” “nivolumab,” “PD-1 inhibitor,” or “immunotherapy.” Included were articles published in English between 1 January 2012 and 1 January 2018. The search was supplemented by bibliographic searches of the complete reference lists of all included papers.Evidence SynthesisWe provide an overview of all published cases (n = 42) of PD-1 inhibitor–induced type 1 diabetes mellitus to date, including a well-characterized case of islet cell antibody and glutamic acid decarboxylase antibody–positive diabetes mellitus, in a patient with a diabetes-prone HLA genotype. She presented with diabetic ketoacidosis during pembrolizumab therapy for a metastatic uveal melanoma. Furthermore, we discuss potential pathogenic mechanisms, clinical presentation, prognostic markers (β-cell antibodies and HLA type), treatment, and a screening protocol.ConclusionsBecause the use of immunotherapy will increase, it is essential that all clinicians are aware of diabetic ketoacidosis as a rare and life-threatening side effect of immunotherapy. Blood glucose monitoring during anti–PD-1 therapy is necessary.
      PubDate: Wed, 27 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00728
      Issue No: Vol. 103, No. 9 (2018)
  • Insights and Implications of Genome-Wide Association Studies of Height
    • Authors: Guo M; Hirschhorn J, Dauber A.
      Pages: 3155 - 3168
      Abstract: AbstractContextIn the last decade, genome-wide association studies (GWASs) have catalyzed our understanding of the genetics of height and have identified hundreds of regions of the genome associated with adult height and other height-related body measurements.Evidence AcquisitionGWASs related to height were identified via PubMed search and a review of the GWAS catalog.Evidence SynthesisThe GWAS results demonstrate that height is highly polygenic: that is, many thousands of genetic variants distributed across the genome each contribute to an individual’s height. These height-associated regions of the genome are enriched for genes in known biological pathways involved in growth, such as fibroblast growth factor signaling, as well as for genes expressed in relevant tissues, such as the growth plate. GWASs can also uncover previously unappreciated biological pathways, such as the STC2/PAPPA/IGFBP4 pathway. The genes implicated by GWASs are often the same genes that are the genetic causes of Mendelian growth disorders or skeletal dysplasias, and GWAS results can provide complementary information about these disorders.ConclusionsHere, we review the rationale behind GWASs and what we have learned from GWASs for height, including how it has enhanced our understanding of the underlying biology of human growth. We also highlight the implications of GWASs in terms of prediction of adult height and our understanding of Mendelian growth disorders.
      PubDate: Mon, 02 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-01126
      Issue No: Vol. 103, No. 9 (2018)
  • Methodology, Criteria, and Characterization of Patient-Matched Thyroid
           Cell Lines and Patient-Derived Tumor Xenografts
    • Authors: Marlow L; Rohl S, Miller J, et al.
      Pages: 3169 - 3182
      Abstract: AbstractObjectiveTo investigate the molecular underpinnings of thyroid cancer, preclinical cell line models are crucial; however, ∼40% of these have been proven to be either duplicates of existing thyroid lines or even nonthyroid-derived lines or are not derived from humans at all. Therefore, we set out to establish procedures and guidelines that should proactively avoid these problems, which facilitated the creation of criteria to make valid preclinical models for thyroid cancer research.DesignBased on our recommendations, we systematically characterized all new cell lines that we generated by a standardized approach that included (1) determination of human origin, (2) exclusion of lymphoma, (3) DNA fingerprinting and histological comparisons to establish linkage to presumed tissue of origin, (4) examining thyroid differentiation by screening two to three thyroid markers, (5) examination of biological behavior (growth rate, tumorigenicity), and (6) presence of common thyroid cancer genetic changes (TP53, BRAF, PTEN, PIK3CA, RAS, TERT promoter, RET/PTC, PAX8/PPARγ, NF1, and EIF1AX).ResultsWe established seven new thyroid cell lines (LAM136, EAM306, SDAR1, SDAR2, JEM493, THJ529, and THJ560) out of 294 primary culture attempts, and 10 patient-derived tumor xenografts (PDTXs; MC-Th-95, MC-Th-374, MC-Th-467, MC-Th-491, MC-Th-493, MC-Th-504, MC-Th-524, MC-Th-529, MC-Th-560, and MC-Th-562) out of 67 attempts. All were successfully validated by our protocols.ConclusionsThis standardized approach for cell line and PDTX characterization should prevent (or detect) future cross-contamination and ensure that only valid preclinical models are used for thyroid cancer research.
      PubDate: Fri, 25 May 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-01845
      Issue No: Vol. 103, No. 9 (2018)
  • A Phase III Randomized Placebo-Controlled Trial to Evaluate Efficacy and
           Safety of Romosozumab in Men With Osteoporosis
    • Authors: Lewiecki E; Blicharski T, Goemaere S, et al.
      Pages: 3183 - 3193
      Abstract: AbstractContextGlobally, one in five men aged >50 years is predicted to experience an osteoporotic fracture. Because of the treatment gap in osteoporosis and the paucity of bone-forming agents for men, new osteoporosis treatments are needed.ObjectiveTo evaluate the safety and efficacy of romosozumab in men with osteoporosis.DesignPhase III randomized BRIDGE study (placebo-controlled double-blind study evaluating the efficacy and safety of romosozumab in treating men with osteoporosis; identifier, NCT02186171) for 12 months.SettingThirty-one centers in Europe, Latin America, Japan, and North America.PatientsMen aged 55 to 90 years with a baseline bone mineral density (BMD) T-score at the lumbar spine (LS), total hip (TH), or femoral neck of ≤−2.5 or ≤−1.5 with a history of a fragility nonvertebral or vertebral fracture.InterventionsThe subjects were randomized 2:1 to receive romosozumab 210 mg subcutaneously monthly or placebo for 12 months.Main Outcome MeasuresThe primary efficacy endpoint was percentage change from baseline in LS BMD at month 12.ResultsIn 245 subjects (163 romosozumab, 82 placebo), at month 12, the mean percentage change from baseline in the LS and TH BMD was significantly greater for the romosozumab group than for the placebo group (LS, 12.1% vs 1.2%; TH, 2.5% vs −0.5%; P < 0.001). Adverse events and serious adverse events were balanced between the two groups, with a numerical imbalance in the positively adjudicated cardiovascular serious adverse events [romosozumab, 8 (4.9%) vs placebo, 2 (2.5%)].ConclusionsTreatment with romosozumab for 12 months increased the spine and hip BMD compared with placebo and was well tolerated in men with osteoporosis.
      PubDate: Wed, 20 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02163
      Issue No: Vol. 103, No. 9 (2018)
  • Subcutaneous Fat Fibrosis Links Obesity to Insulin Resistance in Chinese
    • Authors: Alba D; Farooq J, Lin M, et al.
      Pages: 3194 - 3204
      Abstract: AbstractObjectiveType 2 diabetes presents at a lower body mass index (BMI) in Chinese individuals than in white individuals. We sought to determine the role of subcutaneous adipose tissue (SCAT)–intrinsic factors, vs BMI or adiposity per se, in the vulnerability of Chinese individuals to obesity-associated impairment of insulin sensitivity.Research Design and MethodsThirty-two Chinese and 30 white men and women from a cohort in the San Francisco Bay Area underwent anthropometric measurements, body composition (dual-energy X-ray absorptiometry) analyses, and measurement of fasting plasma glucose and insulin. Forty-eight also provided abdominal SCAT samples for transcriptional and biochemical analyses of tissue fibrosis.ResultsBMI correlated with total body fat in white (r = 0.74, P < 0.001) but not Chinese individuals, whereas BMI correlated with visceral adipose tissue (VAT) accrual in both ethnicities (r = 0.88 and 0.81, respectively; P < 0.01). Insulin resistance (homeostatic model assessment of insulin resistance) worsened with VAT mass, but not total body fat, in Chinese subjects (r = 0.63, P < 0.01), whereas it worsened with both in white individuals. By contrast, SCAT mRNA levels of genes encoding profibrotic proteins rose remarkably along with both BMI and VAT mass in Chinese but not white subjects. Similarly, SCAT levels of hydroxyproline, an indicator of tissue collagen content that correlated with increasing VAT mass, were higher in Chinese vs white subjects, particularly in the setting of relative insulin resistance.ConclusionsOur findings dissociate BMI from adiposity in Chinese individuals and instead highlight SCAT fibrosis as a process linked to visceral adiposity and insulin resistance in this group.
      PubDate: Mon, 28 May 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02301
      Issue No: Vol. 103, No. 9 (2018)
  • Persistence of Excess Mortality Following Individual Nonhip Fractures: A
           Relative Survival Analysis
    • Authors: Tran T; Bliuc D, Hansen L, et al.
      Pages: 3205 - 3214
      Abstract: AbstractContextLittle is known about long-term excess mortality following fragility nonhip fractures.ObjectiveThe study aimed to determine which fracture was associated with excess mortality and for how long the postfracture excess mortality persisted.Design, Setting, and PatientsThis nationwide registry-based follow-up study included all individuals in Denmark aged 50+ years who first experienced fragility fractures in 2001 and were followed up for up to 10 years for their mortality risk.Main Outcome MeasureThe contribution of fracture to mortality at precise postfracture time intervals was examined using relative survival analysis, accounting for time-related mortality changes in the background population.ResultsThere were 21,123 women (aged 72 ± 13 years) and 9481 men (aged 67 ± 12 years) with an incident fragility fracture in 2001, followed by 10,668 and 4745 deaths, respectively. Excess mortality was observed following all proximal and lower leg fractures. The majority of deaths occurred within the first year after fracture, and thereafter excess mortality gradually declined. Hip fractures were associated with the highest excess mortality (33% and 20% at 1 year after fracture in men and women, respectively). One-year excess mortality after fracture of a femur or pelvis was 20% to 25%; vertebrae, 10%; humerus, rib, or clavicle, 5% to 10%; and lower leg, 3%. A significant although smaller excess mortality was still observed until 10 years for hip fractures and ~5 years after femur, other proximal, and lower leg fractures.ConclusionThis study highlights the important contribution of a wide variety of fragility fractures to long-term excess mortality and thus the potential for benefit from early intervention.
      PubDate: Thu, 19 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02656
      Issue No: Vol. 103, No. 9 (2018)
  • GSK2881078, a SARM, Produces Dose-Dependent Increases in Lean Mass in
           Healthy Older Men and Women
    • Authors: Neil D; Clark R, Magee M, et al.
      Pages: 3215 - 3224
      Abstract: AbstractContextGlaxoSmithKline (GSK) 2881078 is a nonsteroidal, selective androgen receptor modulator (SARM) under investigation by GSK for treatment of reduced mobility and other functional limitation in men and women with muscle weakness associated with chronic and acute illnesses.ObjectiveThis was a phase 1b study intended to explore across a dose range the pharmacokinetics (PK)–pharmacodynamics relationship and further safety and tolerability data for GSK2881078. This study also evaluated effects of CYP3A4 inhibition on PK of GSK2881078.MethodsThis was a randomized, placebo-controlled, parallel-group, repeat-dose, dose-escalation study in healthy older males and postmenopausal females. A total of three cohorts of males and three cohorts of females were studied. Dosing at each dose level was twice daily for the first 3 days followed by once daily for up to 53 days. Repeated dual-energy X-ray absorptiometry and MRI cross-sectional thigh scans were performed. The effect of CYP3A4 inhibition on GSK2881078 PK was evaluated in a separate cohort.ResultsGSK2881078 was generally well tolerated and no serious adverse events were reported. Compared with placebo, there was greater lean mass accrual with all dose levels of GSK2881078. Females exhibited a greater response at lower doses than did males. Transient elevations of alanine aminotransferase were observed. The effect of CYP3A4 inhibition on GKS2881078 PK was unlikely to be of clinical significance.ConclusionsGSK2881078 yielded dose-dependent increases in lean mass with evidence of enhanced sensitivity in women. The compound was well tolerated.
      PubDate: Mon, 02 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02644
      Issue No: Vol. 103, No. 9 (2018)
  • PLIN1 Haploinsufficiency Is Not Associated With Lipodystrophy
    • Authors: Laver T; Patel K, Colclough K, et al.
      Pages: 3225 - 3230
      Abstract: AbstractContextMonogenic partial lipodystrophy is a genetically heterogeneous disease where only variants with specific genetic mechanisms are causative. Three heterozygous protein extending frameshift variants in PLIN1 have been reported to cause a phenotype of partial lipodystrophy and insulin resistance.ObjectiveWe investigated if null variants in PLIN1 cause lipodystrophy.MethodsAs part of a targeted sequencing panel test, we sequenced PLIN1 in 2208 individuals. We also investigated the frequency of PLIN1 variants in the gnomAD database, and the type 2 diabetes knowledge portal.ResultsWe identified 6/2208 (1 in 368) individuals with a PLIN1 null variant. None of these individuals had clinical or biochemical evidence of overt lipodystrophy. Additionally, 14/17,000 (1 in 1214) individuals with PLIN1 null variants in the type 2 diabetes knowledge portal showed no association with biomarkers of lipodystrophy. PLIN1 null variants occur too frequently in gnomAD (126/138,632; 1 in 1100) to be a cause of rare overt monogenic partial lipodystrophy.ConclusionsOur study suggests that heterozygous variants that are predicted to result in PLIN1 haploinsufficiency are not a cause of familial partial lipodystrophy and should not be reported as disease-causing variants by diagnostic genetic testing laboratories. This finding is in keeping with other known monogenic causes of lipodystrophy, such as PPARG and LMNA, where only variants with specific genetic mechanisms cause lipodystrophy.
      PubDate: Tue, 17 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02662
      Issue No: Vol. 103, No. 9 (2018)
  • Association Between Diabetic Retinopathy and Parkinson Disease: The Korean
           National Health Insurance Service Database
    • Authors: Lee S; Han K, Baek J, et al.
      Pages: 3231 - 3238
      Abstract: AbstractContextStudies have shown an association between diabetes and Parkinson disease (PD). The retina is a part of the central nervous system; it was proposed that diabetic retinopathy (DR) and PD share common pathophysiology of dopamine deficiency. However, no epidemiologic studies have investigated the relationship between these two diseases.ObjectiveWe assessed the association between DR and incident PD using a population-based database.Design/Setting/ParticipantsUsing the Korean National Health Insurance Service database, 14,912,368 participants who underwent regular health checkup from 2005 to 2008 were included. Subjects were classified into non-diabetes, diabetes without DR, and diabetes with DR groups at baseline and followed up until the date of PD incidence, death, or 31 December 2013. Cox proportional hazards regression analysis was used to evaluate the association between DR and incident PD.ResultsDuring the period, 34,834 subjects were newly diagnosed with PD. The incidence of PD was 2.74, 8.39, and 15.51 per 10,000 person-years for the non-diabetes, diabetes without DR, and diabetes with DR groups, respectively. In multivariate Cox proportional hazard models, DR groups were associated with significantly higher risk of PD than non-diabetes or diabetes without DR groups even after adjusting for age, sex, fasting plasma glucose level, insulin usage, and other possible risk factors.ConclusionConcurrent DR was associated with an increased risk of incident PD. Future studies are necessary to investigate the mechanism of increased risk of PD in DR including dopamine deficiency in the central nervous system and long-lasting poor glycemic control.
      PubDate: Mon, 02 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2017-02774
      Issue No: Vol. 103, No. 9 (2018)
  • A Dose-Escalating Study With the Fetal Estrogen Estetrol in Healthy Men
    • Authors: Coelingh Bennink H; Zimmerman Y, Verhoeven C, et al.
      Pages: 3239 - 3249
      Abstract: AbstractContextLuteinizing hormone–releasing hormone (LHRH) agonists have replaced estrogens for endocrine treatment of advanced prostate cancer (PC) because of cardiovascular side effects. The fetal estrogen estetrol (E4) may be safer for PC treatment and is expected to decrease testosterone (T) and prevent estrogen deficiency.ObjectiveTo investigate the safety and T-suppressive effect of E4 in healthy men.DesignDouble-blind, randomized, placebo-controlled, dose-escalating study.SettingThe study was conducted at a phase I clinical unit (QPS, Netherlands).ParticipantsHealthy male volunteers aged 40 to 70 years.Intervention(s)Three treatment cohorts of 15 volunteers with placebo (n = 5) and E4 (n = 10). Estetrol doses tested were 20, 40, and 60 mg/d. Subjects were treated for 4 weeks.Main Outcome MeasuresSubjective side effects, pharmacodynamic effects on hemostatic variables, lipids, glucose, bone parameters, and endocrine parameters related to T metabolism.ResultsTotal and free T decreased dose-dependently and significantly. Nipple tenderness occurred in 40% and decrease of libido occurred in 30% of E4-treated men. The unwanted estrogenic effects on hemostasis were small, dose dependent, and in some cases significant. Lipid and bone parameters showed a favorable trend.ConclusionThe effect of E4 on testosterone levels is insufficient for standalone PC treatment. Taking all clinical and pharmacodynamic variables into consideration, a daily dose of 40 mg E4 seems safe for further evaluation of endocrine PC treatment in combination with LHRH analogs.
      PubDate: Wed, 20 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00147
      Issue No: Vol. 103, No. 9 (2018)
  • Comparison of 68Ga PET/CT to Other Imaging Studies in Medullary Thyroid
           Cancer: Superiority in Detecting Bone Metastases
    • Authors: Castroneves L; Coura Filho G, de Freitas R, et al.
      Pages: 3250 - 3259
      Abstract: AbstractContextPersistent disease after surgery is common in medullary thyroid cancer (MTC), requiring lifelong radiological surveillance. Staging workup includes imaging of neck, chest, abdomen, and bones. A study integrating all sites would be ideal. Despite the established use of gallium-68 (68Ga) positron emission tomography (PET)/CT with somatostatin analogues in most neuroendocrine tumors, its efficacy is controversial in MTC.ObjectiveEvaluate the efficacy of 68Ga PET/CT in detecting MTC lesions and evaluate tumor expression of somatostatin receptors (SSTRs) associated with 68Ga PET/CT findings.MethodsProspective study evaluating 30 patients with MTC [group 1 (n = 16), biochemical disease; group 2 (n = 14), metastatic disease]. Patients underwent 68Ga PET/CT, bone scan, CT and ultrasound of the neck, CT of the chest, CT/MRI of the abdomen, and MRI of the spine. 68Ga PET/CT findings were analyzed by disease site as positive or negative and as concordant or discordant with conventional studies. Sensitivity and specificity were calculated using pathological or cytological analysis or unequivocal identification by standard imaging studies. Immunohistochemical analysis of SSTRs was compared with 68Ga PET/CT findings.ResultsIn both groups, 68Ga PET/CT was inferior to currently used imaging studies except for bone scan. In group 2, 68Ga PET/CT sensitivities were 56%, 57%, and 9% for detecting neck lymph nodes, lung metastases, and liver metastases, respectively, and 100% for bone metastases, superior to the bone scan (44%). Expression of SSTRs, observed in 44% of tumors, was not associated with 68Ga-DOTATATE uptake.Conclusions68Ga PET/CT does not provide optimal whole-body imaging as a single procedure in patients with MTC. However, it is highly sensitive in detecting bone lesions and could be a substitute for a bone scan and MRI.
      PubDate: Mon, 28 May 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00193
      Issue No: Vol. 103, No. 9 (2018)
  • No Correlation of Pancreatic Fat and β-Cell Function in Young Women With
           and Without a History of Gestational Diabetes
    • Authors: Popp D; Aertsen S, Luetke-Daldrup C, et al.
      Pages: 3260 - 3266
      Abstract: AbstractContextPancreatic steatosis may contribute to β-cell dysfunction in type 2 diabetes (T2D), but data are controversial. Women who had gestational diabetes mellitus (GDM) are at high risk for developing T2D.ObjectiveTo examine the association of pancreatic fat content with early/first-phase insulin secretion (as markers of β-cell function).DesignCross-sectional analysis of a subcohort of the monocentric, prospective cohort study titled Prediction, Prevention, and Subclassification of Type 2 Diabetes.SettingLudwig Maximilians University Hospital, Munich, Germany.ParticipantsNinety-seven women, 3 to 16 months after pregnancy [41 normoglycemic women post-GDM, 19 women post-GDM with pathological glucose metabolism, and 37 normoglycemic women after a normoglycemic pregnancy (controls)].Main Outcome MeasuresCorrelation of MRI-measured pancreatic fat content with early insulin release in an oral glucose tolerance test (OGGT) [insulin increment within the first 30 minutes of the OGTT (IR30)] and first-phase insulin response (FPIR) in an intravenous glucose tolerance test (n = 65), both adjusted for insulin sensitivity index (ISI).ResultsPancreatic fat content did not correlate with IR30 and FPIR adjusted for ISI. It correlated positively with body mass index, waist circumference, liver fat, and intraabdominal fat volume.ConclusionPancreatic fat content does not correlate with β-cell function in a cohort of young women with different degrees of T2D risk.
      PubDate: Tue, 26 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00187
      Issue No: Vol. 103, No. 9 (2018)
  • Vitamin D and Inflammatory Bowel Disease: Mendelian Randomization Analyses
           in the Copenhagen Studies and UK Biobank
    • Authors: Lund-Nielsen J; Vedel-Krogh S, Kobylecki C, et al.
      Pages: 3267 - 3277
      Abstract: AbstractContextVitamin D may be a modifiable risk factor for inflammatory bowel disease (IBD).ObjectivesWe tested the hypothesis that plasma 25-hydroxyvitamin D levels are causally associated with risk of Crohn disease (CD) and ulcerative colitis (UC).Design, Setting, Patients, and InterventionsWe used a Mendelian randomization design to study 120,013 individuals from the Copenhagen City Heart Study, the Copenhagen General Population Study, and a Copenhagen-based cohort of patients with IBD. Of these, 35,558 individuals had plasma 25-hydroxyvitamin D measurements available, and 115,110 were genotyped for rs7944926 and rs11234027 in DHCR7 and rs10741657 and rs12794714 in CYP2R1, all variants associated with plasma 25-hydroxyvitamin D levels. We identified 653 cases of CD and 1265 cases of UC, of which 58 and 113, respectively, had 25-hydroxyvitamin D measurements available. We also included genetic data from 408,455 individuals from the UK Biobank, including 1707 CD cases and 3147 UC cases.Main Outcome MeasureHazard ratios for higher plasma 25-hydroxyvitamin D levels.ResultsThe multivariable-adjusted hazard ratios for 10 nmol/L higher 25-hydroxyvitamin D level were 1.04 (95% CI: 0.93 to 1.16) for CD and 1.13 (95% CI: 1.06 to 1.21) for UC. A combined 25-hydroxyvitamin D allele score was associated with a 1.4-nmol/L increase in plasma 25-hydroxyvitamin D level and hazard ratios of 0.98 (95% CI: 0.94 to 1.03) for CD and 1.01 (95% CI: 0.97 to 1.05) for UC. Combining genetic data from the Copenhagen studies and the UK Biobank, genetically determined vitamin D did not appear to influence the risk of CD or UC.ConclusionsOur results do not support a major role for vitamin D deficiency in the development of IBD.
      PubDate: Tue, 26 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00250
      Issue No: Vol. 103, No. 9 (2018)
  • Determination of Free 25(OH)D Concentrations and Their Relationships to
           Total 25(OH)D in Multiple Clinical Populations
    • Authors: Schwartz J; Gallagher J, Jorde R, et al.
      Pages: 3278 - 3288
      Abstract: AbstractContextThe optimal measure of vitamin D status is unknown.ObjectiveTo directly measure circulating free 25-hydroxyvitamin D [25(OH)D] concentrations and relationships to total 25(OH)D in a clinically diverse sample of humans.DesignCross-sectional analysis.SettingSeven academic sites.PatientsA total of 1661 adults: healthy (n = 279), prediabetic (n = 479), outpatients (n = 714), cirrhotic (n = 90), pregnant (n = 20), nursing home resident (n = 79).InterventionsMerge research data on circulating free 25(OH)D (directly-measured immunoassay), total 25(OH)D (liquid chromatography/tandem mass spectrometry), D-binding protein [DBP; by radial (polyclonal) immunodiffusion assay], albumin, creatinine, intact parathyroid hormone, and DBP haplotype.Main outcome measuresDistribution of free 25(OH)D (ANOVA with Bonferroni correction for post hoc comparisons) and relationships between free and total 25(OH)D (mixed-effects modeling incorporating clinical condition, DBP haplotype with sex, race, estimated glomerular filtration rate (eGFR), body mass index (BMI), and other covariates).ResultsFree 25(OH)D was 4.7 ± 1.8 pg/mL (mean ± SD) in healthy persons and 4.3 ± 1.9 pg/mL in outpatients, with levels of 0.5 to 8.1 pg/mL and 0.9 to 8.1 pg/mL encompassing 95% of healthy persons and outpatients, respectively. Free 25(OH)D was higher in patients with cirrhosis (7.1 ± 3.0 pg/mL; P < 0.0033) and nursing home residents (7.9 ± 2.1 pg/mL; P < 0.0033) than in other groups and differed between whites and blacks (P < 0.0033) and between DBP haplotypes (P < 0.0001). Mixed-effects modeling of relationships between free and total 25(OH)D identified clinical conditions (patients with cirrhosis > nursing home residents > patients with prediabetes > outpatients > pregnant women) and BMI (lesser effect) as covariates affecting relationships but not eGFR, sex, race, or DBP haplotype.ConclusionsTotal 25(OH)D, health condition, race, and DBP haplotype affected free 25(OH)D, but only health conditions and BMI affected relationships between total and free 25(OH)D. Clinical importance of free 25(OH)D needs to be established in studies assessing outcomes.
      PubDate: Wed, 27 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00295
      Issue No: Vol. 103, No. 9 (2018)
  • Objectively Measured Sedentary Behavior, Physical Activity, and
           Cardiometabolic Risk in Hispanic Youth: Hispanic Community Health
           Study/Study of Latino Youth
    • Authors: Strizich G; Kaplan R, Sotres-Alvarez D, et al.
      Pages: 3289 - 3298
      Abstract: AbstractContextTime spent in moderate-to-vigorous physical activity (MVPA), but not in sedentary behavior (SB), is related to cardiometabolic risk among non-Hispanic white youth.ObjectiveExamine associations of SB and MVPA with cardiometabolic risk factors among Hispanic/Latino youth.DesignCross-sectional analysis.SettingFour US communities.ParticipantsHispanic/Latino youth (N = 1,426) ages 8 to 16 years.MeasurementsAssociations of MVPA and SB, measured using 7-day accelerometer data (independent variables), with markers of glucose and lipid metabolism, inflammation, and endothelial function (dependent variables), were assessed in multivariable linear regression models while adjusting for sociodemographic characteristics and accelerometer wear time. Additional models controlled for obesity measures.ResultsSB comprised a mean (SD) of 75% (13%) of accelerometer wear time; mean (SD) time of MVPA was 35 min/d (22 min/d). Deleterious levels of high-density lipoprotein–cholesterol (HDL-C), triglycerides, insulin resistance, C-reactive protein, and plasminogen activator inhibitor-1 were associated with lower levels of MVPA and higher levels of SB (all P < 0.05). Associations of MVPA with log-transformed triglyceride concentrations (β per 15-min/d increment, −0.039; SE, 0.018; P = 0.037) and SB with HDL-C (β per 30-min/d increment, −0.63; SE, 0.26; P = 0.018), but not those with other markers, remained significant after adjusting for MVPA or SB and further adjustment for body mass index and waist circumference. Higher SB tertiles were associated with lower soluble receptor for advanced glycation end products in fully adjusted models (P for trend = 0.037).ConclusionsPhysiological precursors of diabetes and cardiovascular disease were associated with MVPA and SB among US Hispanic/Latino youth, a group that bears a disproportionate burden of metabolic disorders.
      PubDate: Tue, 26 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00356
      Issue No: Vol. 103, No. 9 (2018)
  • BMI-Independent Effects of Gestational Diabetes on Human Placenta
    • Authors: Stirm L; Kovářová M, Perschbacher S, et al.
      Pages: 3299 - 3309
      Abstract: AbstractPurposeRecently, alterations in maternal lipid metabolism were associated with gestational diabetes mellitus (GDM). However, detailed plasma lipid profiles and their relevance for placental and fetal metabolism are currently not understood.MethodsMaternal and placental lipid profiles were characterized in women with GDM and women with normal glucose tolerance (NGT). Inflammatory gene expression was compared in placentas and primary term trophoblasts between the groups. In addition, trophoblasts were stimulated with nonesterified fatty acids (NEFAs), and effects on gene expression were quantified. Finally, placental macrophage content and cord blood concentrations of inflammatory parameters and NEFAs were compared between women with GDM and women with NGT with similar body mass index (BMI).ResultsPalmitate and stearate levels were elevated in both maternal plasma and placental tissue of women with GDM. Placental GDM-associated elevations of IL6, IL8, and TLR2 expression were reflected in trophoblasts derived from women with GDM. Stimulation of primary trophoblasts with palmitate led to increased mRNA expression and protein release of the cytokine IL6 and the chemokine IL8. In line with this, elevated amounts of CD68-positive cells were quantified in the placental tissue of women with GDM. No GDM-associated elevations in a range of inflammatory parameters and NEFAs in cord blood of NGT vs GDM neonates was found.ConclusionsGDM, independently of BMI, altered maternal plasma NEFAs and the placental lipid profile. GDM was associated with trophoblast and whole-placenta lipoinflammation; however, this was not accompanied by elevated concentrations of inflammatory cytokines or NEFAs in neonatal cord blood.
      PubDate: Wed, 20 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00397
      Issue No: Vol. 103, No. 9 (2018)
  • Association of Hypothyroidism With All-Cause Mortality: A Cohort Study in
           an Older Adult Population
    • Authors: Huang H; Wang J, Kao S.
      Pages: 3310 - 3318
      Abstract: AbstractContextAlthough hypothyroidism is associated with many comorbidities, the evidence for its association with all-cause mortality in older adults is limited.ObjectiveTo evaluate the association between hypothyroidism and all-cause mortality in older adults.DesignPopulation-based retrospective cohort study.SettingNational Health Insurance Research Database in Taiwan.PatientsAfter 1:10 age/sex/index year matching, 2029 patients aged ≥65 years who received a new diagnosis of hypothyroidism between 2001 and 2011 and 20,290 patients without hypothyroidism or other thyroid diseases were included in the hypothyroidism and nonhypothyroidism cohorts, respectively.Main Outcome MeasuresAll-cause mortality was defined as the primary outcome. Cox proportional hazards regression models were used to calculate the hazard ratios of mortality. To further evaluate the effect of thyroxine replacement therapy (TRT) on mortality, we divided patients with hypothyroidism into two groups: patients who received TRT and those who did not.ResultsHypothyroidism was associated with an increased risk of all-cause mortality [adjusted hazard ratio (aHR), 1.82; 95% CI, 1.68 to 1.98; P < 0.001]. Patients with hypothyroidism who received TRT had a lower risk of mortality than patients who did not receive TRT (aHR, 0.57; 95% CI, 0.49 to 0.66; P < 0.001). Similar results were obtained after further propensity score matching in age-, sex-, and comorbidity-stratified analyses.ConclusionsHypothyroidism was independently associated with increased all-cause mortality in older adults. In patients with hypothyroidism, TRT was associated with a lower risk of all-cause mortality.
      PubDate: Tue, 26 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00408
      Issue No: Vol. 103, No. 9 (2018)
  • Regional Differences in the Prevalence of Coronary Heart Disease and
           Stroke in Patients With Type 2 Diabetes in China
    • Authors: Lyu Y; Luo Y, Li C, et al.
      Pages: 3319 - 3330
      Abstract: AbstractBackgroundThere are large regional variations in the prevalence and mortality of cardiovascular disease in general populations in China. It remains uncertain whether the prevalence in type 2 diabetes mellitus (T2DM) varies by region in China.MethodsWe analyzed data of 219,522 Chinese patients with T2DM retrieved from the China National HbA1c Surveillance System in 2012. We used the Chinese population distribution in 2010 to standardize prevalence of coronary heart disease (CHD), stroke, and composite of both in 30 provinces and seven geological regions. Multivariable logistic regression was performed to obtain ORs and CIs of provinces/geological regions for CHD, stroke, and composite of both.ResultsAge and sex standardized prevalence of CHD, stroke, and composite of both was, respectively, 4.59% (95% CI, 4.58 to 4.60), 1.79% (1.79 to 1.80), and 5.85% (5.84 to 5.86), in contrast to 0.60% of CHD, 0.80% of stroke, and 1.37% of composite of both in the general population in China. After adjustment for traditional risk factors, Northeast had the highest risks of CHD, stroke, and composite of both, and North had the second highest risks of CHD, stroke, and composite of both among the seven regions, both being higher than any other regions (all P values < 0.05). The ORs of Northeast vs Southwest were up to 2.60 (2.35 to 2.88) for CHD, 2.49 (2.15 to 2.88) for stroke, and 2.61 (2.38 to 2.86) for composite of both.ConclusionsThere were large variations in risks of CHD, stroke, and composite of both in T2DM in China with Northeast and North having the highest risks.
      PubDate: Tue, 03 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00422
      Issue No: Vol. 103, No. 9 (2018)
  • Altered Plasma Amino Acids and Lipids Associated With Abnormal Glucose
           Metabolism and Insulin Resistance in Older Adults
    • Authors: Semba R; Gonzalez-Freire M, Moaddel R, et al.
      Pages: 3331 - 3339
      Abstract: AbstractContext and ObjectivesGlucose metabolism becomes progressively impaired with older age. Fasting glucose and insulin resistance are risk factors for premature death and other adverse outcomes. We aimed to identifying plasma metabolites associated with altered glucose metabolism and insulin resistance in older community-dwelling adults.Participants and MethodsA targeted metabolomics approach was used to identify plasma metabolites associated with impaired fasting plasma glucose, 2-hour plasma glucose on oral glucose tolerance testing, and homeostatic model assessment insulin resistance (HOMA-IR) in 472 participants who participated in the Baltimore Longitudinal Study of Aging, with a mean (SD) age of 70.7 (9.9) years.ResultsWe measured 143 plasma metabolites. In ordinal logistic regression analyses, using a false discovery rate of 5% and adjusting for potential confounders, we found that alanine, glutamic acid, and proline were significantly associated with increased odds of abnormal fasting plasma glucose. Phosphatidylcholine (diacyl C34:4, alkyl-acyl C32:1, C32:2, C34:2, C34:3, and C36:3) was associated with decreased odds of abnormal fasting plasma glucose. Glutamic and acid phosphatidylcholine alkyl-acyl C34:2 were associated with increased and decreased odds of 2-hour plasma glucose, respectively. Glutamic acid was associated with increased odds of higher tertiles of HOMA-IR. Glycine; phosphatidylcholine (diacyl C32:0, alkyl-acyl C32:1, C32:2, C34:1, C34:2, C34:3, C36:2, C36:3, C40:5, C40:6, C42:3, C42:4, and C42:5); sphingomyelin C16:0, C24:1, and C26:1; and lysophosphatidylcholine C18:1 were associated with decreased odds of abnormal HOMA-IR.ConclusionsTargeted metabolomics identified four plasma amino acids and 16 plasma lipid species, primarily containing polyunsaturated fatty acids, that were associated with abnormal glucose metabolism and insulin resistance in older adults.
      PubDate: Tue, 26 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00480
      Issue No: Vol. 103, No. 9 (2018)
  • Bone Mass, Microstructure, and Strength Can Discriminate Vertebral
           Fracture in Patients on Long-Term Steroid Treatment
    • Authors: Shen J; Griffith J, Zhu T, et al.
      Pages: 3340 - 3349
      Abstract: AbstractContextMeasurement of areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry (DXA) was able to predict fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) yields additional information about volumetric bone mineral density (vBMD), microarchitecture, and strength that may increase our understanding of fracture susceptibility.ObjectiveTo ascertain whether vBMD, microarchitecture, and estimated bone strength derived from HR-pQCT can discriminate vertebral fractures in patients with glucocorticoid-induced osteoporosis (GIOP) independent of aBMD.DesignA cross-sectional case-control study.SettingSeven regional hospitals in Hong Kong.PatientsA total of 110 patients on long-term glucocorticoids with vertebral fracture, determined radiographically, and 110 patients on long-term glucocorticoids without fracture.Main Outcome MeasuresWe assessed vBMD, microarchitecture, and bone strength; aBMD; and fracture risk assessment tool (FRAX).ResultsPatients with vertebral fracture had lower total vBMD and a thinner cortex at the distal tibia after adjustment for age, sex, and aBMD or FRAX. In the antiresorptive treatment–naive subgroup, patients with vertebral fracture also had lower total vBMD at both the distal radius and the tibia after adjustment for covariates. Lower total vBMD and a thinner cortex were also noticed in the nonosteoporotic or FRAX score of <10% subgroups with vertebral fracture and were also associated with increasing prevalence of vertebral fracture.ConclusionPatients with GIOP and vertebral fracture have a significant reduction in total vBMD and cortical thinning independent of aBMD and FRAX. These changes may help identify high-risk patients in the subgroups currently considered to have low fracture risk as assessed by DXA or FRAX.
      PubDate: Mon, 02 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00490
      Issue No: Vol. 103, No. 9 (2018)
  • Frequent Monitoring of C-Peptide Levels in Newly Diagnosed Type 1 Subjects
           Using Dried Blood Spots Collected at Home
    • Authors: Willemsen R; Burling K, Barker P, et al.
      Pages: 3350 - 3358
      Abstract: AbstractObjectiveTo evaluate an approach to measure β-cell function by frequent testing of C-peptide concentrations in dried blood spots (DBSs).PatientsThirty-two children, aged 7 to 17 years, with a recent diagnosis of type 1 diabetes.DesignMixed-meal tolerance test (MMTT) within 6 and again at 12 months after diagnosis, with paired venous and DBS C-peptide sampling at 0 and 90 minutes. Weekly DBS C-peptide before and after standardized breakfasts collected at home.ResultsDBS and plasma C-peptide levels (n = 115) correlated strongly (r = 0·91; P < 0.001). The Bland-Altman plot indicated good agreement. The median number of home-collected DBS cards per participant was 24 over a median of 6.9 months. Repeated DBS C-peptide levels varied considerably within and between subjects. Adjustment for corresponding home glucose measurements reduced the variance, permitting accurate description of changes over time. The correlation of the C-peptide slope over time (assessed by repeated home DBS) vs area under the curve during the two MMTTs was r = 0.73 (P < 0.001). Mixed models showed that a 1-month increase in diabetes duration was associated with 17-pmol/L decline in fasting DBS C-peptide, whereas increases of 1 mmol/L in glucose, 1 year older age at diagnosis, and 100 pmol/L higher baseline plasma C-peptide were associated with 18, 17, and 61 pmol/L higher fasting DBS C-peptide levels, respectively. In addition, glucose responsiveness decreased with longer diabetes duration.ConclusionOur approach permitted frequent assessment of C-peptide, making it feasible to monitor β-cell function at home. Evaluation of changes in the slope of C-peptide through this method may permit short-term evaluation of promising interventions.
      PubDate: Thu, 31 May 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00500
      Issue No: Vol. 103, No. 9 (2018)
  • Patients With Autoimmune Thyroiditis Show Diminished Levels and Defective
           Suppressive Function of Tr1 Regulatory Lymphocytes
    • Authors: Vitales-Noyola M; Serrano-Somavilla A, Martínez-Hernández R, et al.
      Pages: 3359 - 3367
      Abstract: AbstractContextT regulatory type 1 (Tr1) cells are a subpopulation of T lymphocytes (CD4+CD49+LAG-3+IL-10+) that exert a considerable immunosuppressive effect. However, their possible role in autoimmune thyroid disease (AITD) has not been explored so far.PurposeTo analyze the levels and function of Tr1 cells in peripheral blood and thyroid tissue of patients with AITD.DesignCases and controls, observational study.SettingDepartment of Endocrinology, Hospital Universitario de la Princesa, Madrid, Spain.PatientsThirty-eight patients with AITD (23 with Graves disease and 15 with Hashimoto thyroiditis) and 26 controls.InterventionMultiparametric flow cytometry and immunofluorescence techniques were used to analyze the levels in peripheral blood (n = 38) and thyroid mononuclear cells (n = 5). An in vitro assay of suppression of cellular activation and cytokine release was performed to study the function of Tr1 cells.Main Outcome MeasureLevels and function of Tr1 cells in patients with AITD and controls.ResultsLevels of Tr1 cells were significantly diminished in peripheral blood from patients with AITD. Functional studies showed that Tr1 cells from patients with AITD exhibit a diminished suppressive function compared with healthy controls. Tr1 levels were associated with disease severity, including longer duration of the disease and ophthalmopathy activity, and with autoantibody titers.ConclusionsThe low levels of Tr1 cells and their diminished function may have a relevant role in the defective immune-regulatory function characteristic of patients with AITD.
      PubDate: Mon, 02 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00498
      Issue No: Vol. 103, No. 9 (2018)
  • Associations Between Change in Total and Free 25-Hydroxyvitamin D With
           24,25-Dihydroxyvitamin D and Parathyroid Hormone
    • Authors: Shieh A; Ma C, Chun R, et al.
      Pages: 3368 - 3375
      Abstract: AbstractContextThe physiologic role of free 25-hydroxyvitamin D [25(OH)D] in humans is unclear.ObjectiveTo assess whether rise in total vs free 25(OH)D is associated with change in downstream biomarkers of 25(OH)D entry into target cells in kidney and parathyroid: 24,25-dihyroxyvitamin D [24,25(OH)2D] and PTH, respectively.Design16-week randomized controlled trial.Intervention60 μg (2400 IU)/d of D3 or 20 μg/d of 25(OH)D3.SettingAcademic medical center.Participants35 adults age ≥18 years with 25(OH)D levels < 20 ng/mL.Main Outcome Measures24,25(OH)2D, 1,25-dihyroxyvitamin D [1,25(OH)2D] and PTH.ResultsAt baseline, participants [D3 and 25(OH)D3 groups combined] were 35.1 ± 10.6 years. Mean total 25(OH)D, free 25(OH)D, 24,25(OH)2D, and PTH were 16.6 ng/mL, 4.6 pg/mL, 1.3 ng/mL, and 37.2 pg/mL, respectively. From 0 to 4 weeks, rise in only free 25(OH)D was associated with a concurrent 24,25(OH)2D increase [P = 0.03, adjusted for change in 1,25(OH)2D and supplementation regimen] and PTH decrease (P = 0.01, adjusted for change in calcium and supplementation regimen). Between 4 and 8 weeks, and again from 8 to 16 weeks, rises in free and total 25(OH)D were associated with 24,25(OH)2D increase; in contrast, rise in neither total nor free 25(OH)D was associated with PTH decrease during these time periods.ConclusionsEarly rise in free 25(OH)D during treatment of vitamin D deficiency was more strongly associated with changes in biomarkers of 25(OH)D entry into target kidney and parathyroid cells, suggesting a physiologic role of free 25(OH)D in humans.
      PubDate: Wed, 20 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00515
      Issue No: Vol. 103, No. 9 (2018)
  • Expression of Müllerian-Inhibiting Substance/Anti-Müllerian Hormone Type
           II Receptor in the Human Theca Cells
    • Authors: Cheon K; Chung Y, Cho H, et al.
      Pages: 3376 - 3385
      Abstract: AbstractContextMüllerian-inhibiting substance/anti-Müllerian hormone (MIS/AMH) is produced in the ovarian granulosa cells, and it is believed to inhibit ovarian folliculogenesis and steroidogenesis in women of reproductive age.ObjectiveTo investigate the expression of MIS/AMH type II receptor (MISRII/AMHRII) that binds MIS/AMH in the ovaries of reproductive-age women; to identify the exact targets of MIS/AMH.DesignLaboratory study using human ovarian tissue.SettingUniversity hospital.PatientsTissue samples from 25 patients who had undergone ovarian surgery.InterventionsThe segregation of ovarian granulosa and theca cells by laser microdissection was followed by RT-PCR, analyzing MISRII/AMHRII mRNA expression. Afterward, in situ hybridization and immunohistochemistry were performed to determine the localization of MISRII/AMHRII mRNA and protein expression.Main Outcome MeasuresMISRII/AMHRII mRNA expression by RT-PCR, in situ hybridization, and immunohistochemistry.ResultsMISRII/AMHRII were expressed in granulosa and theca cells of preantral and antral follicles. The granulosa cells showed stronger MISRII/AMHRII expression than theca cells. MISRII/AMHRII mRNA staining of granulosa and theca cells in large antral follicles, early atretic follicles, and corpus luteum waned but were still detected weakly, showing higher expression in theca cells than in granulosa cells. However, MISRII/AMHRII protein in the granulosa layer of the atretic follicle and corpus luteum could not be assessed.ConclusionsAs MISRII/AMHRII is expressed in both granulosa and theca cells, this indicates that MIS/AMH, produced in the granulosa cells, is active in the theca cells as well. MIS/AMH is most likely actively involved not only in the autocrine and endocrine processes but also in the paracrine processes involving theca cells.
      PubDate: Tue, 26 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00549
      Issue No: Vol. 103, No. 9 (2018)
  • Diurnal Cortisol Concentrations and Growth Indexes of 12- to 48-Month-Old
           Children From Mexico City
    • Authors: Rosa-Parra J; Tamayo-Ortiz M, Lamadrid-Figueroa H, et al.
      Pages: 3386 - 3393
      Abstract: AbstractContextEarly life cortisol plays an important role in bone, muscle, and fat mobilization processes, which could influence body composition, affecting anthropometric indicators such as weight and height.ObjectiveTo explore the association between diurnal cortisol levels and growth indexes in children from 12 to 48 months of age.DesignThis study includes data from 404 children from the Programming Research in Obesity, Growth, Environment and Social Stressors Mexican birth cohort. Cortisol was measured in eight saliva samples collected at four time points during the day (from wakeup to bedtime), over 2 days, when the child was either 12, 18, or 24 months old. Total daytime cortisol levels were calculated by averaging the area under the curve (AUC) for the 2 days. Height and weight were measured from 12 to 48 months of age. Growth indexes were constructed according to z scores following World Health Organization standards: weight-for-age z score (Z-WFA), height/length-for-age z score, weight-for-height/length z score (Z-WFH), and body mass index–for-age z score (Z-BMIFA). Mixed models were used to analyze the association between cortisol AUC quartiles and growth indexes.ResultsCortisol showed an inverted U-shaped association with the four growth indexes. Compared with the first quartile, all quartiles had a positive association with indexes that include weight, with the second quartile having the strongest association, resulting in an average change of β (95% CI) 0.38 (0.13–0.64) for Z-WFA, 0.36 (0.10–0.62) for Z-WFH, and 0.43 (0.17–0.69) for Z-BMIFA.ConclusionsResults suggest that early life daytime cortisol levels, as a reflection of hypothalamic-pituitary-adrenal axis development, might influence growth in early infancy.
      PubDate: Tue, 17 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00550
      Issue No: Vol. 103, No. 9 (2018)
  • Ectopic Lipid Deposition Is Associated With Insulin Resistance in
           Postmenopausal Women
    • Authors: Abildgaard J; Danielsen E, Dorph E, et al.
      Pages: 3394 - 3404
      Abstract: AbstractContextMenopause is associated with an increased incidence of insulin resistance and diabetes.ObjectiveThe aim of this study was to explore the lipid deposition in liver and skeletal muscle and investigate the association with insulin sensitivity in postmenopausal and premenopausal women.Design and SettingSingle-center cross-sectional study of 55 healthy women between 45 and 60 years of age. We measured lipid deposition in the liver with magnetic resonance spectroscopy, intramuscular and intra-abdominal lipid deposition with MRI, body composition with a dual-energy X-ray absorptiometry scan, and insulin sensitivity with the composite Matsuda Index.Outcome MeasuresWe studied the association between fat distribution, ectopic lipid deposition, and insulin sensitivity in pre- and postmenopausal women.ResultsPostmenopausal women had an increased lipid deposition in the liver [0.68% (0.44 to 0.99) vs 0.49% (0.38 to 0.64), P = 0.01] and skeletal muscle [3% (2 to 4) vs 2% (1 to 3), P = 0.001] and had a 28% lower Matsuda insulin sensitivity index during an oral glucose tolerance test (6.31 ± 3.48 vs 8.78 ± 4.67, P = 0.05) compared with premenopausal women. Total fat mass and leg fat mass were stronger predictors of ectopic lipid deposition, and visceral fat mass was a stronger predictor of both ectopic lipid deposition and insulin resistance in postmenopausal women compared with premenopausal women.ConclusionsFor a given subcutaneous and visceral fat depot size, postmenopausal women show increased ectopic lipid deposition and insulin resistance compared with premenopausal women. It is suggested that lipid deposition in liver and skeletal muscle may represent important mechanistic links between the changes in fat depots and the increased incidence of insulin resistance seen after menopause.
      PubDate: Thu, 07 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00554
      Issue No: Vol. 103, No. 9 (2018)
  • Lower Spine Volumetric Bone Density in Patients With a History of Epidural
           Steroid Injections
    • Authors: Liu Y; Carrino J, Dash A, et al.
      Pages: 3405 - 3410
      Abstract: AbstractContextEpidural steroid injections (ESIs) are a common, effective treatment of lumbar radiculopathy and sciatica. Although the negative skeletal effects of oral glucocorticoids are well established, little is known about the impact of ESI on bone quality.ObjectiveTo investigate the relationship between ESI exposure and volumetric bone mineral density (vBMD) at the lumbar spine (LS) using central quantitative CT.DesignRetrospective study.SettingUniversity hospital outpatient facility.PatientsAll patients had CT scans of the LS between 2011 and 2016. Cases received at least three ESIs prior to the date of CT (n = 121). Controls were matched for age and sex (n = 121).Main Outcome MeasuresCumulative ESI dose was calculated. vBMD was measured at T12 through L5 using QCT Pro phantomless software (MindWays).ResultsMean age of subjects was 65 ± 14 years, and 49% were women. Median number of ESIs was 4 (range: 3 to 16). Median cumulative ESI dosage was 340 mg of triamcinolone or equivalent (range: 150 to 1400 mg). Compared with controls, ESI subjects had lower vBMD at each vertebral level. Higher cumulative dose was associated with lower mean vBMD at T12 to L5 (r = –0.22, P = 0.02).ConclusionsGreater cumulative ESI dose was related to lower vBMD at the LS. To our knowledge, this is the first study to measure vBMD in patients treated with ESIs. Prospective studies are needed to confirm these findings and to help identify the best strategies for preventing bone loss in this population.
      PubDate: Mon, 02 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00558
      Issue No: Vol. 103, No. 9 (2018)
  • Hydrocortisone Affects Fatigue and Physical Functioning Through Metabolism
           of Tryptophan: A Randomized Controlled Trial
    • Authors: Sorgdrager F; Werumeus Buning J, Bos E, et al.
      Pages: 3411 - 3419
      Abstract: AbstractContextHydrocortisone (HC) treatment influences health-related quality of life (HRQOL) in secondary adrenal insufficiency (AI). Glucocorticoids regulate tryptophan metabolism through the kynurenine pathway, which modulates mood and energy homeostasis.ObjectiveThis study investigated whether tryptophan metabolism mediated the effect of HC dose on HRQOL in patients with secondary AI.Design, Setting, and PatientsForty-seven patients with secondary AI participated in this double-blind randomized controlled cross-over trial in the University Medical Center Groningen.InterventionPatients were treated for two 10-week periods with a daily HC dose of 0.2 to 0.3 mg/kg and 0.4 to 0.6 mg/kg body weight, respectively.Main Outcome MeasuresDiary data and questionnaires were used to assess HRQOL. Tryptophan, kynurenine and 3-hydroxykynurenine were measured in serum and dialyzed plasma and the kynurenine-to-tryptophan ratio (Kyn/Trp ratio) ratio was calculated.ResultsA higher dose HC was associated with increased levels of tryptophan (95% CI for mean difference 0.37 to 12.5, P = 0.038), reduced levels of kynurenine (95% CI, −0.49 to −0.10, P = 0.004) and 3-hydroxykynurenine (95% CI, −10.6 to −2.35, P = 0.003), and a reduced Kyn/Trp ratio (95% CI, −0.84 to −0.50, P < 0.001). The Kyn/Trp ratio mediated the effect of a higher dose HC on fatigue (P = 0.041) and physical functioning (P = 0.005).ConclusionMetabolism of tryptophan through the kynurenine pathway is reduced after a 10-week treatment with a higher dose HC and plays a role in the effect of HC on fatigue and physical functioning in patients with secondary AI.
      PubDate: Mon, 02 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00582
      Issue No: Vol. 103, No. 9 (2018)
  • HS6ST1 Insufficiency Causes Self-Limited Delayed Puberty in Contrast With
           Other GnRH Deficiency Genes
    • Authors: Howard S; Oleari R, Poliandri A, et al.
      Pages: 3420 - 3429
      Abstract: AbstractContextSelf-limited delayed puberty (DP) segregates in an autosomal-dominant pattern, but the genetic basis is largely unknown. Although DP is sometimes seen in relatives of patients with hypogonadotropic hypogonadism (HH), mutations in genes known to cause HH that segregate with the trait of familial self-limited DP have not yet been identified.ObjectiveTo assess the contribution of mutations in genes known to cause HH to the phenotype of self-limited DP.Design, Patients, and SettingWe performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited DP, validated the pathogenicity of the identified gene variant in vitro, and examined the tissue expression and functional requirement of the mouse homolog in vivo.ResultsA potentially pathogenic gene variant segregating with DP was identified in 1 of 28 known HH genes examined. This pathogenic variant occurred in HS6ST1 in one pedigree and segregated with the trait in the six affected members with heterozygous transmission (P = 3.01 × 10−5). Biochemical analysis showed that this mutation reduced sulfotransferase activity in vitro. Hs6st1 mRNA was expressed in peripubertal wild-type mouse hypothalamus. GnRH neuron counts were similar in Hs6st1+/− and Hs6st1+/+ mice, but vaginal opening was delayed in Hs6st1+/− mice despite normal postnatal growth.ConclusionsWe have linked a deleterious mutation in HS6ST1 to familial self-limited DP and show that heterozygous Hs6st1 loss causes DP in mice. In this study, the observed overlap in potentially pathogenic mutations contributing to the phenotypes of self-limited DP and HH was limited to this one gene.
      PubDate: Wed, 20 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00646
      Issue No: Vol. 103, No. 9 (2018)
  • Effect of Dietary Carbohydrate Type on Serum Cardiometabolic Risk
           Indicators and Adipose Tissue Inflammatory Markers
    • Authors: Meng H; Matthan N, Fried S, et al.
      Pages: 3430 - 3438
      Abstract: AbstractContext and ObjectiveDirect comparisons between types of dietary carbohydrate in terms of cardiometabolic risk indicators are limited. This study was designed to compare the effects of an isocaloric exchange of simple, refined, and unrefined carbohydrates on serum cardiometabolic risk indicators, adipose tissue inflammatory markers, and peripheral blood mononuclear cell (PBMC) fractional cholesterol efflux.Design, Participants, and MeasuresParticipants [postmenopausal women and men (N = 11), 65 ± 8 years, body mass index 29.8 ± 3.2 kg/m2, low-density lipoprotein (LDL) cholesterol ≥2.6 mmol/L] were provided with diets (60% energy from total carbohydrate, 15% from protein, 25% from fat) for 4.5 weeks in a randomized crossover design, with 2-week washout periods. The variable component was an isocaloric exchange of simple, refined, or unrefined carbohydrate–containing foods. Serum lipoprotein, glucose, insulin, and inflammatory marker concentrations were measured. Abdominal subcutaneous adipose tissue was aspirated to assess macrophage and inflammatory marker gene expression and ex vivo cytokine secretion, and PBMCs were isolated to assess ex vivo fractional cholesterol efflux.ResultsFasting serum LDL and non–high-density lipoprotein (HDL) cholesterol concentrations were higher after the refined compared with simple or unrefined carbohydrate–enriched diets (P < 0.01). Other serum measures, ex vivo fractional cholesterol efflux and adipose tissue gene expression and ex vivo cytokine secretion, were similar between diets.ConclusionsDiets enriched in refined compared with simple or unrefined carbohydrate resulted in higher fasting serum LDL and non-HDL cholesterol concentrations but had little effect on other cardiometabolic risk indicators. This small study raises the intriguing possibility that refined carbohydrate may have unique adverse effects on cardiometabolic risk indicators distinct from simple and unrefined carbohydrate.
      PubDate: Thu, 21 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00667
      Issue No: Vol. 103, No. 9 (2018)
  • Statin Use Is Associated With Decreased Osteoporosis and Fracture Risks in
           Stroke Patients
    • Authors: Lin S; Wang J, Liang C, et al.
      Pages: 3439 - 3448
      Abstract: AbstractContextPoststroke osteoporosis and consequent fractures increase the risk of morbidity and mortality and cause considerable socioeconomic burden.ObjectiveTo evaluate the association between statin use and risks of osteoporosis and fracture in stroke patients.DesignPopulation-based propensity score‒matched cohort study.SettingTaiwan’s National Health Insurance Research Database.PatientsPatients newly diagnosed with a stroke between 2000 and 2012 were identified. After propensity score matching, 5254 patients were included, with 2627 patients in the statin and nonstatin cohorts, respectively.Main Outcome MeasuresHazard ratios (HRs) for poststroke osteoporosis, hip fracture, and vertebral fracture (together, the primary outcome) were calculated using Cox proportional hazards regression models according to statin use status.ResultsPoststroke statin use was associated with a lower overall risk of the primary outcome [adjusted hazard ratio (aHR) = 0.66; P < 0.001]. In subanalyses, statin use was associated with a decreased risk of all individual outcomes, including osteoporosis (aHR = 0.68; P < 0.001), hip fracture (aHR = 0.59; P < 0.001), and vertebral fracture (aHR = 0.73; P = 0.003). A dose-effect relationship was identified. The aHRs for developing the primary outcome were 0.96, 0.86, and 0.34 for patients who used 1 to 90, 91 to 365, and >365 cumulative defined daily doses of statins, respectively. These dose-effect relationships were maintained on subgroup analyses stratified by age, sex, and stroke type and sensitivity analyses conducted without propensity score matching.ConclusionsStatin use is associated with decreased risks of osteoporosis, hip fracture, and vertebral fracture in stroke patients.
      PubDate: Mon, 02 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00652
      Issue No: Vol. 103, No. 9 (2018)
  • Oxandrolone Treatment Results in an Increased Risk of Gonadarche in
           Prepubertal Boys With Klinefelter Syndrome
    • Authors: Davis S; Lahlou N, Cox-Martin M, et al.
      Pages: 3449 - 3455
      Abstract: AbstractContextKlinefelter syndrome (KS) is a common genetic condition in which males have an extra X chromosome. KS is associated with testosterone deficiency, neurodevelopmental delays, and cardiometabolic disorders. There has been recent interest in prepubertal androgen treatment; however, the effects on puberty and gonadal function are unknown.ObjectiveTo compare onset of puberty and testicular function in prepubertal boys treated with 2 years of oxandrolone (Ox) vs placebo (Pl).DesignDouble-blind, randomized, controlled trial.SettingSingle tertiary care referral center.ParticipantsEighty prepubertal boys with KS; mean age: 8.0 ± 2.2 years (range: 4 to 12).InterventionsOx 0.05 mg/kg vs identical-appearing Pl capsule given for 2 years.Outcome MeasuresOnset of gonadarche (testicular volume ≥4 mL) and onset of pubarche (Tanner 2 pubic hair); change in testicular hormone concentrations.ResultsOx-treated group had 20.5 times higher odds of reaching gonadarche (OR 95% CI: 6.5, 77.8) and 28.1 times higher odds of reaching pubarche (OR 95% CI: 8.8, 110.4) during the 2-year study period after adjusting for baseline age. Gonadarche and pubarche both occurred at a younger age in the Ox group (gonadarche: 9.8 ± 1.5 vs 12.1 ± 1.0 years, P < 0.001; pubarche: 10.2 ± 1.1 vs 11.6 ± 1.3 years, P = 0.02). Serum concentrations of testicular hormones and gonadotropins were not different between groups.ConclusionsTwo years of Ox treatment in prepubertal boys with KS results in an increased risk of early gonadarche, on average 2 years earlier than in Pl-treated boys. Ox did not affect serum concentrations of testicular hormones.
      PubDate: Wed, 20 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00682
      Issue No: Vol. 103, No. 9 (2018)
  • Combination GLP-1 and Insulin Treatment Fails to Alter Myocardial Fuel
           Selection vs. Insulin Alone in Type 2 Diabetes
    • Authors: Mather K; Considine R, Hamilton L, et al.
      Pages: 3456 - 3465
      Abstract: AbstractContextIt is unclear if effects of glucagon-like peptide-1 (GLP-1) and clinically available GLP-1 agonists on the heart occur at clinical doses in humans, possibly contributing to reduced cardiovascular disease risk.ObjectiveTo determine whether liraglutide, at clinical dosing, augments myocardial glucose uptake (MGU) alone or combined with insulin compared with insulin alone in metformin-treated type 2 diabetes mellitus (T2D).DesignIn a randomized clinical trial of patients with T2D treated with metformin plus oral agents or basal insulin, myocardial fuel use was compared after 3 months of treatment with insulin detemir, liraglutide, or combination detemir plus liraglutide added to background metformin.Main Outcome MeasuresMyocardial blood flow (MBF), fuel selection, and rates of fuel use were evaluated using positron emission tomography, powered to demonstrate large effects.ResultsMBF was greater in the insulin-treated groups [median (25th, 75th percentile): detemir, 0.64 mL/g/min (0.50, 0.69); liraglutide, 0.52 mL/g/min (0.46, 0.58); detemir plus liraglutide, 0.75 mL/g/min (0.55, 0.77); P = 0.035 comparing three groups, P = 0.01 comparing detemir groups to liraglutide alone]. There were no evident differences among groups in MGU [detemir, 0.040 µmol/g/min (0.013, 0.049); liraglutide, 0.055 µmol/g/min (0.019, 0.105); detemir plus liraglutide, 0.037 µmol/g/min (0.009, 0.046); P = 0.68 comparing three groups]. There were no treatment-group differences in measures of myocardial fatty acid uptake or handling, and no differences in total oxidation rate.ConclusionThese observations argue against large effects of GLP-1 agonists on myocardial fuel metabolism as mediators of beneficial treatment effects on myocardial function and ischemia protection.
      PubDate: Tue, 17 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00712
      Issue No: Vol. 103, No. 9 (2018)
  • IL-1 Antagonism in Men With Metabolic Syndrome and Low Testosterone: A
           Randomized Clinical Trial
    • Authors: Ebrahimi F; Urwyler S, Straumann S, et al.
      Pages: 3466 - 3476
      Abstract: AbstractContextHypogonadism is highly prevalent among obese men with metabolic syndrome. Chronic low-grade inflammation is suspected to be a major cause for low testosterone levels in obese individuals.ObjectivesTo test the inflammatory hypothesis of testosterone deficiency in metabolic syndrome.Design, Setting, Participants, and InterventionIn this randomized, placebo-controlled, double-blind trial involving men with metabolic syndrome, we randomly assigned 33 patients to receive 100 mg of anakinra (recombinant human IL-1 receptor antagonist) subcutaneously twice daily for 4 weeks and 34 patients to receive placebo.Main Outcome MeasuresThe primary endpoint was the change from baseline in total testosterone levels after 4 weeks.ResultsThe mean age was 54 years and baseline total testosterone levels were 9.3 nmol/L (95% CI, 8.7 to 10.0). At 4 weeks, total testosterone levels increased by 1.2 nmol/L (95% CI, 0.3 to 2.0; P = 0.01) in the anakinra group as compared with no change in the placebo group (0.01 nmol/L; 95% CI, −0.5 to 0.5; P = 0.99), resulting in a between-group difference of 0.96 nmol/L (95% CI, 0.3 to 1.9; P = 0.04). The effects were most pronounced with baseline C-reactive protein >2 mg/L (between-group difference 2.14 nmol/L; 95% CI, 0.11 to 4.17; P = 0.04) and body mass index >40 kg/m2 (between-group difference 2.64 nmol/L; 95% CI, 0.19 to 5.09; P = 0.04). Anakinra treatment did not exert benefits on fatigue and sexual dysfunction, but it improved grip strength of nondominant hand by 3.5 kg (95% CI 0.23 to 6.81; P = 0.04) and reduced mean arterial blood pressure by 2.9 mm Hg (95% CI, −5.99 to 0.19; P = 0.07).ConclusionsAnti-inflammatory treatment with an antagonist of IL-1 led to an increase in testosterone levels in obese men with testosterone deficiency.
      PubDate: Fri, 22 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00739
      Issue No: Vol. 103, No. 9 (2018)
  • Aldosterone Suppression by Dexamethasone in Patients With KCNJ5-Mutated
           Aldosterone-Producing Adenoma
    • Authors: Inoue K; Yamazaki Y, Kitamoto T, et al.
      Pages: 3477 - 3485
      Abstract: AbstractContextAldosterone biosynthesis is regulated principally by ACTH and gene mutations as well as by angiotensin II and serum potassium. In addition, previous studies have reported the potential effects of KCNJ5 mutations in aldosterone-producing adenoma (APA) on cardiovascular diseases. However, responsiveness to ACTH in APAs according to potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5) mutations remains unknown.ObjectiveTo investigate KCNJ5 genotype–specific differences in aldosterone biosynthesis in response to ACTH stimulation.Design and SettingA cross-sectional study through retrieval of clinical records.ParticipantsOne hundred forty-one patients aged ≥20 years with APA were examined.Main Outcome MeasuresAssociations between KCNJ5 mutations and clinical parameters reflecting the renin-angiotensin system [saline infusion test (SIT)] and ACTH pathways [dexamethasone suppression test (DST)].ResultsKCNJ5 mutations were detected in 107 cases. In the crude comparison, patients with mutations in KCNJ5 had higher plasma aldosterone concentrations (PACs) both at baseline and after the SIT. PAC after the DST showed a significant inverse association with KCNJ5 genotypes after controlling for age, sex, tumor size, and PAC after the SIT. Immunohistochemical analysis of 101 cases revealed more abundant immunoreactivity of CYP11B1 and CYP17 in the KCNJ5-mutated group than in the KCNJ5 wild-type group.ConclusionThis report of marked suppression of PAC by dexamethasone in patients with KCNJ5-mutated APAs indicates that such APAs respond to endogenous ACTH more readily than APAs in nonmutated cases. Further molecular and epidemiologic studies are required to validate our results and clarify the clinical effectiveness of the DST for predicting KCNJ5 mutations before adrenalectomy.
      PubDate: Tue, 17 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00738
      Issue No: Vol. 103, No. 9 (2018)
  • Associations Between Soluble LDLR and Lipoproteins in a White Cohort and
           the Effect of PCSK9 Loss-of-Function
    • Authors: Mayne J; Ooi T, Tepliakova L, et al.
      Pages: 3486 - 3495
      Abstract: AbstractContextElevated circulating cholesterol-rich low-density lipoprotein (LDL) particles increase coronary artery disease risk. Cell-surface hepatic LDL receptors (LDLRs) clear 70% of these particles from circulation. The ectodomain of LDLR is shed into circulation, preventing it from removing LDL particles. The role that LDLR ectodomain shedding plays as a regulatory mechanism is unknown.ObjectiveWe describe LDLR shedding via the relationships between circulating soluble LDLRs (sLDLRs) and serum lipoproteins, serum proprotein convertase subtilin/kexin type 9 (PCSK9; a negative regulator of LDLR), and clinical parameters in a white Canadian population.DesignPopulation-based, cross-sectional study.SettingsClinical Research Center, The Ottawa Hospital, and Faculty of Medicine, University of Ottawa.ParticipantsTwo hundred seventy-three white Canadians.InterventionNone.Main Outcome MeasuressLDLR measured by ELISA; serum lipids and PCSK9, PCSK9 genotypes, and clinical parameters from previous analyses.ResultssLDLRs correlated strongly with triglycerides (TG; r = 0.624, P < 0.0001) and moderately with LDL cholesterol (r = 0.384, P < 0.0001), and high-density lipoprotein cholesterol (r = −0.307, P = 0.0003). Only TG correlations were unaffected by PCSK9 variations. sLDLR levels were significantly elevated in those with TG >50th or LDL cholesterol >75th percentiles.ConclusionsSerum sLDLR levels correlate with several lipoprotein parameters, especially TG, and the presence of PCSK9 loss-of-function variants alters sLDLR levels and correlations, except for TG. Ectodomain LDLR shedding has a role in LDL metabolism, distinct from PCSK9, with interplay between these two pathways that regulate cell-surface LDLRs. Findings suggest alteration of LDLR shedding could emerge as a target to treat dyslipidemia.
      PubDate: Thu, 21 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00777
      Issue No: Vol. 103, No. 9 (2018)
  • Limitations of the 2015 ATA Guidelines for Prediction of Thyroid Cancer: A
           Review of 1947 Consecutive Aspirations
    • Authors: Pandya A; Caoili E, Jawad-Makki F, et al.
      Pages: 3496 - 3502
      Abstract: AbstractBackgroundThe 2015 American Thyroid Association (ATA) guidelines have been proposed to aid in the management of thyroid nodules by determining whether fine needle aspiration is indicated.ObjectiveTo determine whether the ATA guidelines contribute to the overdiagnosis of thyroid cancer.Patients and MethodsThis was a retrospective cohort study of ultrasound-imaged thyroid nodules (n = 1947) consecutively aspirated at a tertiary care center from 1 October 2009 to 22 February 2016. Nodules were retrospectively reviewed, assigned a 2015 ATA morphology, and placed into one of five 2015 ATA categories of risk (ATA-1, <1% risk of malignancy; ATA-2, <3% risk; ATA-3, 5% to 10% risk, ATA-4: 10% to 20% risk; ATA-5, >70% to 90% risk) by a reader who was blinded to cytology. ATA category was compared with cytopathology. The positive predictive value (PPV) of each ATA category was calculated with respect to cancer. Numbers needed to aspirate and Pearson correlations were calculated. Interrater agreement for ATA category across five readers was assessed.ResultsThe PPV for cancer increased by ATA category [category 1 to 5, respectively: 0% (0/14), 2% (4/249), 5% (36/733), 12% (104/850), 28% (28/101)]. The number needed to sample to detect one papillary cancer was 125 (ATA-2), 49 (ATA-3), 13 (ATA-4), and 5 (ATA-5). The overall interrater agreement for ATA score across all five readers was fair (intraclass correlation coefficient 0.460).ConclusionsThe 2015 ATA guidelines stratify risk for thyroid cancer; however, the stratification system is overly optimistic regarding cancer detection rates for the higher-risk nodules, and there is only fair interrater agreement.
      PubDate: Tue, 03 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00792
      Issue No: Vol. 103, No. 9 (2018)
  • Gastric Emptying and the Personalized Management of Type 1 Diabetes
    • Authors: Marathe C; Rayner C, Wu T, et al.
      Pages: 3503 - 3506
      Abstract: “The retention of stomach contents in a diabetic obviously may cause confusion as far as food intake and utilization are concerned.”—Kassander (1)
      PubDate: Wed, 16 May 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00849
      Issue No: Vol. 103, No. 9 (2018)
  • The Role of Molecular Diagnostics in the Management of Indeterminate
           Thyroid Nodules
    • Authors: Klubo-Gwiezdzinska J; Wartofsky L.
      Pages: 3507 - 3510
      Abstract: This paper is a commentary on the study by Livhits et al. addressing the relative utility of two molecular diagnostic techniques for thyroid nodules indeterminate on FNA cytology.
      PubDate: Wed, 18 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-01081
      Issue No: Vol. 103, No. 9 (2018)
  • Physiological Glucocorticoid Replacement in Adrenal Insufficiency: Does It
           Fix the Broken Clock'
    • Authors: Brown M; Matveyenko A.
      Pages: 3511 - 3513
      Abstract: Chronotherapeutic glucocorticoid replacement modulates clock gene expression.
      PubDate: Mon, 02 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-01245
      Issue No: Vol. 103, No. 9 (2018)
  • A Gain-of-Function CASR Mutation Causing Hypocalcemia in a Recessive
    • Authors: Bastepe M.
      Pages: 3514 - 3515
      Abstract: A new gain-of-function CASR mutation has been described as a cause of hypocalcemia. This mutation, unlike other such mutations, is inherited recessively and has implications in genetic evaluation.
      PubDate: Tue, 17 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-01340
      Issue No: Vol. 103, No. 9 (2018)
  • Letter to the Editor: “p.Val804Met, the Most Frequent Pathogenic
           Mutation in RET, Confers a Very Low Lifetime Risk of Medullary Thyroid
    • Authors: Machens A; Dralle H.
      Pages: 3516 - 3517
      Abstract: It was with great interest that we read the innovative research by Loveday et al. (1) that “p.Val804Met, the most frequent pathogenic mutation in RET, confers a very low lifetime risk of medullary thyroid cancer.” The authors endeavored “to gain estimates of penetrance unbiased by ascertainment through studying a population agnostic to phenotype” based on the logic that “a fully penetrant allele cannot be more common than the disease it causes.” In the authors’ sample of ∼51,000 patients with complex disease “not related to cancer,” most of whom were aged 40 to 70 years at the time of ascertainment, p.Val804Met mutations had a more than fivefold higher frequency than any other pathogenic RET mutation, including other moderate-risk mutations such as p.Leu790Phe/c.2370G>C and p.Val804Leu, whereas p.Glu768Asp and p.Ser891Ala mutations were not represented in the authors’ convenience sample (1).
      PubDate: Tue, 26 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00906
      Issue No: Vol. 103, No. 9 (2018)
  • Response to Letter to the Editor: “p.Val804Met, the Most Frequent
           Pathogenic Mutation in RET, Confers a Very Low Lifetime Risk of Medullary
           Thyroid Cancer”
    • Authors: Turnbull C; Loveday C, Izatt L, et al.
      Pages: 3518 - 3519
      Abstract: We thank Drs Machens and Dralle for their interest in our work on the penetrance of RET p.Val804Met and for highlighting the very recently published German series and French series of RET mutation carriers (1, 2). Of note, both publications report sizeable historic case series from large testing centers that each comprise a combination of index cases and family members. p.Val804Met comprises 9.4% and 17.2%, respectively, of RET mutations detected, with penetrance estimated to be 51% in the German series.
      PubDate: Wed, 18 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-01094
      Issue No: Vol. 103, No. 9 (2018)
  • Letter to the Editor: “Metformin Use in PCOS Pregnancies Increases the
           Risk of Offspring Overweight at 4 Years of Age: Follow-Up of Two RCTs”
    • Authors: Castillo-Castro C; Gonzalez-Velazquez C, Rodriguez-Gutierrez R.
      Pages: 3520 - 3520
      Abstract: We read with interest the Hanem et al. article (1), which is currently the largest follow-up study of children born to mothers with polycystic ovary syndrome and concomitant exposure to metformin in utero. While the results are profoundly noteworthy, we highlight two aspects that decrease the confidence and clinical impact of their results.
      PubDate: Wed, 20 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00884
      Issue No: Vol. 103, No. 9 (2018)
  • Response to Letter to the Editor: “Metformin Use in PCOS Pregnancies
           Increases the Risk of Offspring Overweight at 4 Years of Age: Follow-Up of
           Two RCTs”
    • Authors: Hanem L; Ødegård R, Vanky E.
      Pages: 3521 - 3521
      Abstract: We thank Castillo-Castro et al. for their interest in our follow-up study of children born to mothers with polycystic ovary syndrome, who were randomized to metformin or placebo during pregnancy (1). They question the robustness and the clinical impact of our results, as the mean weight in both treatment groups was under the 85th percentile according to the Centers for Disease Control (CDC) children body mass index (BMI) reference standards.
      PubDate: Wed, 20 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-01114
      Issue No: Vol. 103, No. 9 (2018)
  • MicroRNA Expression Profiling in Adrenal Myelolipoma
    • Authors: Decmann A; Perge P, Nyírő G, et al.
      Pages: 3522 - 3530
      Abstract: AbstractIntroductionAdrenal myelolipoma (AML) is the second most common and invariably benign primary adrenal neoplasm. Due to the variable proportion of fat and hematopoietic elements and its often large size, it can cause differential diagnostic problems. Several reports confirmed the utility of miRNAs in the diagnosis of tumors, but miRNA expression in AML has not yet been investigated.Materials and MethodsNext-generation sequencing (NGS) was performed on 30 formalin-fixed, paraffin-embedded (FFPE) archived tissue samples [10 each of AML, adrenocortical adenoma (ACA), and adrenocortical carcinoma (ACC)]. Validation was performed by real-time quantitative reverse transcription polymerase chain reaction on a cohort containing 41 further FFPE samples (15 AML, 14 ACA, and 12 ACC samples). Circulating miRNA counterparts of significantly differentially expressed tissue miRNAs were studied in 33 plasma samples (11 each of ACA, ACC, and AML).ResultsBy NGS, 256 significantly differentially expressed miRNAs were discovered, and 8 of these were chosen for validation. Significant overexpression of hsa-miR-451a, hsa-miR-486-5p, hsa-miR-363-3p, and hsa-miR-150-5p was confirmed in AML relative to ACA and ACC. hsa-miR-184, hsa-miR-483-5p, and hsa-miR-183-5p were significantly overexpressed in ACC relative to ACA but not to AML. Circulating hsa-miR-451a and hsa-miR-363-3p were significantly overexpressed in AML, whereas circulating hsa-miR-483-5p and hsa-miR-483-3p were only significantly overexpressed in ACC vs ACA.ConclusionsWe have found significantly differentially expressed miRNAs in AML and adrenocortical tumors. Circulating hsa-miR-451a might be a promising minimally invasive biomarker of AML. The lack of significantly different expression of hsa-miR-483-3p and hsa-miR-483-5p between AML and ACC might limit their applicability as diagnostic miRNA markers for ACC.
      PubDate: Thu, 21 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00817
      Issue No: Vol. 103, No. 9 (2018)
  • A 10-Year Prospective Study of Bone Mineral Density and Bone Turnover in
           Males and Females With Type 1 Diabetes
    • Authors: Hamilton E; Drinkwater J, Chubb S, et al.
      Pages: 3531 - 3539
      Abstract: AbstractContextIn a previous community-based, cross-sectional study, males with type 1 diabetes (T1D) had lower bone mineral density (BMD) than did matched people without diabetes but females with T1D had normal BMD.ObjectiveTo determine whether BMD in the males continued to decline, the neutral effect of T1D on BMD in females persisted, and whether temporal BMD changes reflected changes in bone turnover markers.DesignLongitudinal observational study.SettingUrban community.PatientsForty-eight of the original 102 original cross-sectional study participants (20 males, 28 females) of mean age 42.0 years and median diabetes duration 14.6 years at baseline who were restudied a mean of 10.3 years later.Main Outcome MeasuresBMD at total hip, femoral neck, lumbar spine (L1 to L4), and distal forearm. Biochemical bone turnover markers.ResultsAfter adjustment for age, body mass index (BMI), and renal function, there was no temporal change in BMD at the hip or forearm in the males (P ≥ 0.12), but lumbar spine BMD increased (P = 0.009). Females exhibited no statistically significant change in BMD in similar multivariable models that also included postmenopausal status, except a mild increase at the forearm (P = 0.046). Age- and sex-related changes in bone turnover markers paralleled those in general population studies.ConclusionsThere is a reduction in BMD in males with T1D that occurs early in the course of the disease but then stabilizes. BMD in females with T1D remains similar to that expected for age, BMI, and postmenopausal status.
      PubDate: Wed, 18 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00850
      Issue No: Vol. 103, No. 9 (2018)
  • First Trimester Urinary Bisphenol and Phthalate Concentrations and Time to
           Pregnancy: A Population-Based Cohort Analysis
    • Authors: Philips E; Kahn L, Jaddoe V, et al.
      Pages: 3540 - 3547
      Abstract: AbstractBackgroundIncreasing evidence suggests that exposure to synthetic chemicals such as bisphenols and phthalates can influence fecundability. The current study describes associations of first trimester urinary concentrations of bisphenol A (BPA), BPA analogs, and phthalate metabolites with time to pregnancy (TTP).MethodsAmong 877 participants in the population-based Generation R pregnancy cohort, we measured first trimester urinary concentrations of bisphenols and phthalates [median gestational age, 12.9 weeks (interquartile range, 12.1, 14.4)]. We used fitted covariate-adjusted Cox proportional hazard models to examine associations of bisphenol and phthalate concentrations with TTP. Participants who conceived using infertility treatment were censored at 12 months. Biologically plausible effect measure modification by folic acid supplement use was tested.ResultsIn the main models, bisphenol and phthalate compounds were not associated with fecundability. In stratified models, total bisphenols and phthalic acid were associated with longer TTP among women who did not use folic acid supplements preconceptionally [respective fecundability ratios per each natural log increase were 0.90 (95% CI, 0.81 to 1.00) and 0.88 (95% CI, 0.79 to 0.99)]. Using an interaction term for the exposure and folic acid supplement use showed additional effect measure modification by folic acid supplement use for high-molecular-weight phthalate metabolites.ConclusionsWe found no associations of bisphenols and phthalates with fecundability. Preconception folic acid supplementation seems to modify effects of bisphenols and phthalates on fecundability. Folic acid supplements may protect against reduced fecundability among women exposed to these chemicals. Further studies are needed to replicate these findings and investigate potential mechanisms.
      PubDate: Mon, 16 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00855
      Issue No: Vol. 103, No. 9 (2018)
  • Reference Ranges and Determinants of Thyroid Function During Early
           Pregnancy: The SELMA Study
    • Authors: Derakhshan A; Shu H, Broeren M, et al.
      Pages: 3548 - 3556
      Abstract: AbstractContextEstablishing reference ranges as well as identifying and quantifying the determinants of thyroid function during pregnancy is important for proper clinical interpretation and optimizing research efforts. However, such data are sparse, specifically for triiodothyronine measurements, and most studies do not take into account thyroid antibodies or human chorionic gonadotropin.ObjectiveTo determine reference ranges and to identify/quantify determinants of TSH, free T4 (FT4), free triiodothyronine (FT3), total T4 (TT4), and total triiodothyronine (TT3).Design, Setting, and ParticipantsThis study included 2314 participants of the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy study, a population-based prospective pregnancy cohort of mother-child pairs. Reference ranges were calculated by 2.5th to 97.5th percentiles after excluding thyroperoxidase antibody (TPOAb)–positive and/or thyroglobulin antibody (TgAb)–positive women.InterventionNone.Main Outcome MeasuresTSH, FT4, FT3, TT4, and TT3 in prenatal serum.ResultsAfter exclusion of TPOAb-positive women, reference ranges were as follows: TSH, 0.11 to 3.48 mU/L; FT4, 11.6 to 19.4 pmol/L; FT3, 3.72 to 5.92 pg/mL; TT4, 82.4 to 166.2 pmol/L; and TT3, 1.28 to 2.92 nmol/L. Additional exclusion of TgAb-positive women did not change the reference ranges substantially. Exposure to tobacco smoke, as assessed by questionnaires and serum cotinine, was associated with lower TSH and higher FT3 and TT3. Body mass index (BMI) and gestational age were the main determinants of TSH (only for BMI), FT4, FT3, TT4, and TT3.ConclusionsWe show that the exclusion of TgAb-positive women on top of excluding TPOAb-positive women hardly affects clinical reference ranges. We identified various relevant clinical determinants of TSH, FT4, FT3, TT4, and TT3 that could reflect endocrine-disrupting effects and/or effects on thyroid hormone transport or deiodination.
      PubDate: Mon, 02 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00890
      Issue No: Vol. 103, No. 9 (2018)
  • Natural History and Outcomes of Cytologically Benign Thyroid Nodules in
    • Authors: Cherella C; Feldman H, Hollowell M, et al.
      Pages: 3557 - 3565
      Abstract: AbstractContextMost pediatric thyroid nodules are cytologically benign, but few data exist to guide treatment.ObjectiveTo describe the natural history and outcomes of cytologically benign, pediatric thyroid nodules.DesignCohort study.SettingMultidisciplinary thyroid clinic at an academic medical center.PatientsConsecutive pediatric patients (≤18 years old) with cytologically benign thyroid nodules evaluated between 1998 and 2016.ResultsCytologically benign nodules (N = 237) in 181 patients were followed by ultrasound (median follow-up, 3.4 years; range, 0.5 to 13.9 years) or to resection. Thyroid cancer was diagnosed in six nodules (2.5%), and all six patients were disease free after median follow-up of 4.9 years. Malignancy was more common in nodules >4 cm (15.4%; P = 0.037) or that grew during follow-up (6.0%; P = 0.048). The likelihood of nodule growth (±SE) was 15% ± 3%, 24% ± 4%, and 49% ± 10% at 6, 12, and 24 months, respectively. Among nodules >2 cm, those with ≥25% cystic content grew more slowly than nodules <25% cystic; nodules <2 cm grew similarly regardless of cystic content.ConclusionBenign cytology in pediatric thyroid nodules has a low false-negative rate similar to that in adults, and prognosis is excellent in the rare cases of malignancy. Resection of nodules >4 cm, combined with surveillance of smaller nodules and repeated aspiration for growth, detects most false-negative results. Follow-up ultrasound in 12 months is appropriate for most cytologically benign pediatric nodules, but delaying surveillance up to 24 months may be reasonable in large, predominantly cystic nodules.
      PubDate: Mon, 02 Jul 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00895
      Issue No: Vol. 103, No. 9 (2018)
  • Predictors of Survival in Adrenocortical Carcinoma: An Analysis From the
           National Cancer Database
    • Authors: Tella S; Kommalapati A, Yaturu S, et al.
      Pages: 3566 - 3573
      Abstract: AbstractContextAdrenocortical carcinoma (ACC) is rare; knowledge about prognostic factors and survival outcomes is limited.ObjectiveTo describe predictors of survival and overall survival (OS) outcomes.Design and PatientsRetrospective analysis of data from the National Cancer Database (NCDB) from 2004 to 2015 on 3185 patients with pathologically confirmed ACC.Main Outcome MeasuresBaseline description, survival outcomes, and predictors of survival were evaluated in patients with ACC.ResultsMedian age at ACC diagnosis was 55 (range: 18 to 90) years; did not differ significantly by sex or stage of the disease at diagnosis. On multivariate analysis, increasing age, higher Charlson-Deyo comorbidity index score, high tumor grade, and no surgical therapy (all P < 0.0001); and stage IV disease (P = 0.002) and lymphadenectomy during surgery (P = 0.02) were associated with poor prognosis. Patients with stage I-III disease treated with surgical resection had significantly better median OS (63 vs 8 months; P < 0.001). In stage IV disease, better median OS occurred in patients treated with surgery (19 vs 6 months; P < 0.001), and postsurgical radiation (29 vs 10 months; P < 0.001) or chemotherapy (22 vs 13 months; P = 0.004).ConclusionOS varied with increasing age, higher comorbidity index, grade, and stage of ACC at presentation. There was improved survival with surgical resection of primary tumor, irrespective of disease stage; postsurgical chemotherapy or radiation was of benefit only in stage IV disease.
      PubDate: Thu, 21 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00918
      Issue No: Vol. 103, No. 9 (2018)
  • Predictors of Renal Function and Calcifications in Primary
           Hyperparathyroidism: A Nested Case-Control Study
    • Authors: Ejlsmark-Svensson H; Bislev L, Rolighed L, et al.
      Pages: 3574 - 3583
      Abstract: AbstractContextSome patients with primary hyperparathyroidism (PHPT) develop renal calcifications. Investigation of urinary and nonurinary risk factors are essential.ObjectiveWe aimed to study the prevalence and potential biochemical predictors of renal calcifications.DesignNested case-control study.SettingUniversity hospital.ParticipantsWe identified 792 patients with PHPT from 2005 to 2015. We used biochemical data to validate the diagnosis of PHPT.Main Outcome MeasuresThe prevalence of renal calcifications defined as nephrolithiasis or nephrocalcinosis assessed by a routine CT scan at the time of diagnosis.ResultsA total of 792 patients with PHPT were identified among whom 617 patients (78%) had a CT scan preformed. We found a prevalence of renal calcifications of 23%, equally frequent between sexes. A total of 76 patients (12%) had nephrolithiasis and 75 patients (12%) had nephrocalcinosis where 7 patients (1%) had both nephrolithiasis and nephrocalcinosis. Compared with patients without renal calcifications, patients with renal calcifications had significantly higher levels of ionized calcium, parathyroid hormone, and 24-hour calcium excretion (Pall < 0.01). Patients with nephrocalcinosis had higher plasma levels of phosphate and a higher calcium-phosphate product compared with patients with nephrolithiasis (Pall < 0.05). Impaired renal function (estimated glomerular filtration rate <60 mL/min) was observed in 12% of patients. However, no differences in renal function were observed between those with and without renal calcifications.ConclusionRenal calcifications are frequent in patients with PHPT and are associated with the severity of the disease. Impaired renal function is also common in PHPT, but renal function was not associated with renal calcifications.
      PubDate: Wed, 27 Jun 2018 00:00:00 GMT
      DOI: 10.1210/jc.2018-00923
      Issue No: Vol. 103, No. 9 (2018)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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