Few topics have elicited more emotion than the issue of screening for vitamin D status and the discussion on the need for global supplementation with vitamin D metabolites. The importance of the problem is highlighted by the USPSTF posted draft research plan with the aim of making an update recommendations statement, possibly next year. Here, we discuss two different viewpoints on screening for vitamin D status: for and against. In the literature there are scientifically sound opinions supporting pro and cons positions. However, we believe that the best way to definitively elucidate this issue is the implementation of a randomized controlled trial evaluating clinical outcomes or harms in persons screened versus those not screened for vitamin D deficiency. The feasibility of such a trial is probably questionable owing to uncertainties still present concerning threshold for vitamin D sufficiency and end points (that is, for example, improved bone mineral density, reduced risk of falls and so on) to be reached.
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Salvatore Minisola, Luciano Colangelo, Cristiana Cipriani, Jessica Pepe, Dana Paulina Cook and Chantal Mathieu
Aliya A Khan, Christian A Koch, Stan Van Uum, Jean Patrice Baillargeon, Jens Bollerslev, Maria Luisa Brandi, Claudio Marcocci, Lars Rejnmark, Rene Rizzoli, M Zakarea Shrayyef, Rajesh Thakker, Bulent O Yildiz and Bart Clarke
Purpose: To provide practice recommendations for the diagnosis and management of hypoparathyroidism in adults.
Methods: Key questions pertaining to the diagnosis and management of hypoparathyroidism were addressed following a literature review. We searched PubMed, MEDLINE, EMBASE and Cochrane databases from January 2000 to March 2018 using keywords ‘hypoparathyroidism, diagnosis, treatment, calcium, PTH, calcidiol, calcitriol, hydrochlorothiazide and pregnancy’. Only English language papers involving humans were included. We excluded letters, reviews and editorials. The quality of evidence was evaluated based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. These standards of care for hypoparathyroidism have been endorsed by the Canadian Society of Endocrinology and Metabolism.
Results: Hypoparathyroidism is a rare disease characterized by hypocalcemia, hyperphosphatemia and a low or inappropriately normal serum parathyroid hormone level (PTH). The majority of cases are post-surgical (75%) with nonsurgical causes accounting for the remaining 25% of cases. A careful review is required to determine the etiology of the hypoparathyroidism in individuals with nonsurgical disease. Hypoparathyroidism is associated with significant morbidity and poor quality of life. Treatment requires close monitoring as well as patient education. Conventional therapy with calcium supplements and active vitamin D analogs is effective in improving serum calcium as well as in controlling the symptoms of hypocalcemia. PTH replacement is of value in lowering the doses of calcium and active vitamin D analogs required and may be of value in lowering long-term complications of hypoparathyroidism. This manuscript addresses acute and chronic management of hypoparathyroidism in adults.
Main conclusions: Hypoparathyroidism requires careful evaluation and pharmacologic intervention in order to improve serum calcium and control the symptoms of hypocalcemia. Frequent laboratory monitoring of the biochemical profile and patient education is essential to achieving optimal control of serum calcium.
C Nederstigt, B S Uitbeijerse, L G M Janssen, E P M Corssmit, E J P de Koning and O M Dekkers
The association between type 1 diabetes (T1D) and other auto-immune diseases is well known. However, a quantitative overview of all associated auto-immune diseases and their prevalence in T1D is lacking.
We searched PubMed, Web of Science, EMBASE and Cochrane library in September 2018 to identify relevant articles about the prevalence of the following associated auto-immune diseases in T1D cohorts: auto-immune thyroid disease, celiac disease, gastric autoimmunity including pernicious anemia, vitiligo and adrenal gland insufficiency. A meta-analysis was performed to estimate pooled prevalence using a random-effects model. Furthermore, random-effects meta-regression analysis was performed to assess the association between prevalence and mean age or diabetes duration.
One hundred eighty articles were eligible including a total of 293 889 type 1 diabetes patients. Hypothyroidism (65 studies) was prevalent in 9.8% (95% CI: 7.5–12.3) of patients. Meta-regression showed that for every 10-year age increase, hypothyroidism prevalence increased 4.6% (95% CI: 2.6–6.6, P < 0.000, 54 studies). Weighted prevalence of celiac disease was 4.5% (95% CI: 4.0–5.5, 87 studies). Gastric autoimmunity was found in 4.3% of patients (95% CI: 1.6–8.2, 8 studies) and vitiligo in 2.4% (95% CI: 1.2–3.9, 14 studies) of patients. The prevalence of adrenal insufficiency was 0.2% (95% CI: 0.0–0.4, 14 studies) and hyperthyroidism was found in 1.3 percent (95% CI: 0.9–1.8, 45 studies) of type 1 diabetes patients. For all analyses, statistical heterogeneity between studies was moderate to high.
The prevalence of antibody-mediated auto-immune disease is high among type 1 diabetes patients. Especially hypothyroidism and celiac disease are frequently found.
Hongbo Yang, Kemin Yan, Xu Yuping, Qi Zhang, Linjie Wang, Fengying Gong, Huijuan Zhu, Weibo Xia and Hui Pan
Adult growth hormone deficiency (AGHD) is characterized by low bone density and increased risk of fracture. Bone microarchitecture is insufficiently evaluated in patients with childhood-onset AGHD (CO AGHD).
To assess volumetric bone density (vBMD) and bone microarchitecture in CO AGHD in early adulthood after cessation of recombinant growth hormone (rhGH) treatment.
Design and subjects
Case–control study in a major academic medical center in Beijing, including 20 young male adults with CO AGHD and 30 age- and weight-matched non-athletic healthy men. High-resolution peripheral quantitative computerized tomography (HR-pQCT) of distal radius and tibia was performed.
The main outcomes were vBMD and morphometry parameters from HR-pQCT.
Compared with healthy controls, CO AGHD group had significantly decreased insulin-like growth factor 1 (IGF-1) level and IGF-1 SDS (P < 0.001). β-CTX and alkaline phosphatase levels in CO AGHD group were significantly increased (P < 0.001). CO AGHD group had significantly decreased total vBMD, cortical vBMD, trabecular vBMD, cortical area, cortical thickness as well as trabecular thickness and trabecular bone volume fraction of both tibia and radius (P < 0.001). CO AGHD patients had an 8.4 kg decrease in grip strength and a significant decrease in creatinine levels (P = 0.001). At both tibia and radius, by finite element analysis, bone stiffness and failure load of the CO AGHD patients were significantly decreased (P < 0.001). After adjusting for age, BMI and serum levels of testosterone and free thyroxin, serum IGF-1 level was a positive predictor for total vBMD, cortical vBMD, cortical area, trabecular vBMD, bone stiffness and failure load of both tibia and distal radius in all subjects.
Young adult male patients with childhood-onset adult growth hormone deficiency who are no longer receiving growth hormone replacement have prominently impaired volumetric bone density and bone microarchitecture and lower estimated bone strength.
Daniela Esposito, Oskar Ragnarsson, Daniel Granfeldt, Tom Marlow, Gudmundur Johannsson and Daniel S Olsson
Lucie Coppin, Amandine Ferrière, Michel Crépin, Magalie Haissaguerre, Miriam Ladsous, Antoine Tabarin and Marie-Françoise Odou
Aimilia Eirini Papathanasiou, Eric Nolen-Doerr, Olivia M Farr and Christos S Mantzoros
The discovery of leptin, an adipocyte-secreted hormone, set the stage for unraveling the mechanisms dictating energy homeostasis, revealing adipose tissue as an endocrine system that regulates appetite and body weight. Fluctuating leptin levels provide molecular signals to the brain regarding available energy reserves modulating energy homeostasis and neuroendocrine response in states of leptin deficiency and to a lesser extent in hyperleptinemic states. While leptin replacement therapy fails to provide substantial benefit in common obesity, it is an effective treatment for congenital leptin deficiency and states of acquired leptin deficiency such as lipodystrophy. Current evidence suggests that regulation of eating behavior in humans is not limited to homeostatic mechanisms and that the reward, attention, memory and emotion systems are involved, participating in a complex central nervous system network. It is critical to study these systems for the treatment of typical obesity. Although progress has been made, further studies are required to unravel the physiology, pathophysiology and neurobehavioral mechanisms underlying potential treatments for weight-related problems in humans.
Hanneke J B H Beijers, Nike M L Stikkelbroeck, Arjen R Mensenkamp, Rolph Pfundt, Rob B van der Luijt, Henri J L M Timmers, Ad R M M Hermus and Marlies J E Kempers
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the tumor suppressor gene MEN1 and can be diagnosed based on clinical, familial and/or genetic criteria. We present a family in which we found both germline and somatic mosaicism for MEN1.
In our proband, we diagnosed MEN1. The mutation was not detected in her parents (DNA extracted from leucocytes). When her brother was found to harbor the same MEN1 mutation as our proband and, around the same time, their father was diagnosed with a neuroendocrine carcinoma, this tumor was investigated for the MEN1 mutation as well. In the histologic biopsy of this tumor, the same MEN1 mutation was detected as previously found in his children. Re-analysis of his blood using multiplex ligation-dependent probe amplification (MLPA) showed a minimal, but consistently decreased signal for the MEN1-specific MLPA probes. The deletion was confirmed in his son by high-resolution array analysis. Based on the array data, we concluded that the deletion was limited to the MEN1 gene and that the father had both germline and somatic mosaicism for MEN1.
To our knowledge, this is the first reported family with combined germline and somatic mosaicism for MEN1. This study illustrates that germline mosaicism is important to consider in apparently sporadic de novo MEN1 mutations, because of its particular importance for genetic counseling, specifically when evaluating the risk for family members and when considering the possibility of somatic mosaicism in the parent with germline mosaicism.
Annewieke W van den Beld, Olga D Carlson, Maire E Doyle, Dimitris Rizopoulos, Luigi Ferrucci, Aart Jan van der Lely and Josephine M Egan
Insulin-like growth factor-binding protein-2 (IGFBP-2) concentrations are low in subjects with metabolic syndrome and type 2 diabetes. Intriguingly, recent studies have demonstrated an association between high IGFBP-2 concentrations and increased mortality not only in populations with certain types of cancer, but also in relatively healthy populations. We evaluated the role of IGFBP-2 in relation to BMI and mortality.
Design and Participants
BMI, insulin sensitivity, insulin-like growth factor 1 (IGF-I) and IGFBP-2 were assessed repeatedly in 539 participants of the Baltimore Longitudinal Study of Aging around the ages of 55, 65 and 75 years.
IGFBP-2 concentrations positively correlated with insulin sensitivity and inversely with BMI, both at baseline and follow-up. Independent of IGF-I, sex, BMI and insulin sensitivity, circulating IGFBP-2 levels positively correlated with age (P < 0.001). Changes over time in BMI were associated with an inverse correlation in IGFBP-2 concentrations. Furthermore, we found indications of a relationship between low baseline IGFBP-2 levels and mortality. Remarkably, after adjustment for insulin sensitivity, the opposite association was found, as a unit increase of log(IGFBP2) was associated with an increase in the log hazard by 1.43 (95% CI: 0.3–2.6). This accounted for both baseline (P = 0.02) as well as serial (P < 0.001) measurements of IGFBP2. Finally, in this longitudinal study, we found that IGF-I concentrations increased with age (0.82 ± 0.2 (µg/L)/year, P < 0.001).
This is the first study investigating the relationship between IGFBP-2 levels and age in a longitudinal setting. Serum IGFBP-2 levels increase with age after the age of 50 years and evolve in parallel with insulin sensitivity. IGFBP-2 may therefore be a potential marker for insulin sensitivity. We further show that IGFBP-2 levels can predict mortality in this aging population. However, its predictive value for mortality can only be interpreted in relation to insulin sensitivity. After adjustment for insulin sensitivity, high IGFBP-2 levels are predictive of increased mortality.
Kumarendran Balachandran, Dana Sumilo, Michael W O'Reilly, Konstantinos A. Toulis, Krishna Gokhale, Chandrika Wijeyaratne, Arri Coomarasamy, Wiebke Arlt, Abd Tahrani and Krishnarajah Nirantharakumar
Objective: Obesity is very common in patients with obstructive sleep apnoea (OSA) and polycystic ovary syndrome (PCOS). Longitudinal studies assessing OSA risk in PCOS and examining the role of obesity are lacking. Our objective was to assess the risk of OSA in women with vs. without PCOS and to examine the role of obesity in the observed findings.
Design: Population-based retrospective cohort study utilizing The Health Improvement Network (THIN), UK.
Methods: 76,978 women with PCOS and 143,077 age-, BMI- and location-matched women without PCOS between January 2000 and May 2017 were identified. Hazard Ratio (HR) for OSA among women with and without PCOS were calculated after controlling for confounding variables using multivariate Cox models.
Results: Median patient age was 30 (IQR: 25 – 35) years; median follow-up was 3.5 (IQR: 1.4 – 7.1) years. We found 298 OSA cases in PCOS women vs. 222 in controls, with incidence rates for OSA of 8.1 and 3.3 per 10,000 person years, respectively. Women with PCOS were at increased risk of developing OSA (Adjusted HR=2.26, 95% CI: 1.89 – 2.69, p<0.001), with similar HRs for normal weight, overweight and obese PCOS women.
Conclusions: Women with PCOS are at increased risk of developing OSA compared to control women irrespective of obesity. Considering the significant metabolic morbidity associated with OSA, clinicians should have a low threshold to test for OSA in women with PCOS. Whether OSA treatment has an impact on PCOS symptoms and outcomes needs to be examined.