Showing papers in "Journal of Endocrinological Investigation in 2019"

Very-low-calorie ketogenic diet (VLCKD) in the management of metabolic diseases: systematic review and consensus statement from the Italian Society of Endocrinology (SIE)

Abstract: Weight loss is a milestone in the prevention of chronic diseases associated with high morbility and mortality in industrialized countries. Very-low calorie ketogenic diets (VLCKDs) are increasingly used in clinical practice for weight loss and management of obesity-related comorbidities. Despite evidence on the clinical benefits of VLCKDs is rapidly emerging, some concern still exists about their potential risks and their use in the long-term, due to paucity of clinical studies. Notably, there is an important lack of guidelines on this topic, and the use and implementation of VLCKDs occurs vastly in the absence of clear evidence-based indications. We describe here the biochemistry, benefits and risks of VLCKDs, and provide recommendations on the correct use of this therapeutic approach for weight loss and management of metabolic diseases at different stages of life.

Mechanisms underlying the weight loss effects of RYGB and SG: similar, yet different

Abstract: The worldwide obesity epidemic continues unabated, adversely impacting upon global health and economies. People with severe obesity suffer the greatest adverse health consequences with reduced life expectancy. Currently, bariatric surgery is the most effective treatment for people with severe obesity, resulting in marked sustained weight loss, improved obesity-associated comorbidities and reduced mortality. Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), the most common bariatric procedures undertaken globally, engender weight loss and metabolic improvements by mechanisms other than restriction and malabsorption. It is now clear that a plethora of gastrointestinal (GI) tract-derived signals plays a critical role in energy and glucose regulation. SG and RYGB, which alter GI anatomy and nutrient flow, impact upon these GI signals ultimately leading to weight loss and metabolic improvements. However, whilst highly effective overall, at individual level, post-operative outcomes are highly variable, with a proportion of patients experiencing poor long-term weight loss outcome and gaining little health benefit. RYGB and SG are markedly different anatomically and thus differentially impact upon GI signalling and bodyweight regulation. Here, we review the mechanisms proposed to cause weight loss following RYGB and SG. We highlight similarities and differences between these two procedures with a focus on gut hormones, bile acids and gut microbiota. A greater understanding of these procedure-related mechanisms will allow surgical procedure choice to be tailored to the individual to maximise post-surgery health outcomes and will facilitate the discovery of non-surgical treatments for people with obesity.

State of the art in osteoporosis risk assessment and treatment.

Abstract: Osteoporosis constitutes a major public health problem, through its association with age-related fractures, particularly of the hip, vertebrae, distal forearm, and humerus. Over recent decades, it has evolved from being viewed as an inevitable consequence of ageing, to being recognised as a serious and eminently treatable disease. In this article, we review the literature pertaining to the epidemiology of osteoporosis, associated health burden, approaches to risk assessment and treatment. Although there is some evidence that fracture incidence has reached a plateau, or even started to decline, in the developed world, an ageing population and adoption of westernised lifestyles in transitioning populations is leading to an increasing burden of osteoporosis across the world. Whilst the clinical definition of osteoporosis has been based solely on bone mineral density, the prediction of fracture at the individual level has been improved by consideration of clinical risk factors in tools such as FRAX®, derived from a greater understanding of the epidemiology of osteoporosis. Such advances in approaches to primary and secondary prevention of fractures, coupled with elucidation of the underlying biology, and the development of a range of highly effective antiosteoporosis medications, have enabled a step change in our ability to prevent osteoporosis-related fractures. However, there remains a substantial disparity between the number of individuals at high fracture risk and number treated globally. Urgent work is needed at the level of health care systems, national and international policy, and in communication with patients and public, to ensure that all patients who should receive treatment for osteoporosis actually do so.

Diagnosis and treatment of lipodystrophy: a step-by-step approach.

Abstract: Lipodystrophy syndromes are rare heterogeneous disorders characterized by deficiency of adipose tissue, usually a decrease in leptin levels and, frequently, severe metabolic abnormalities including diabetes mellitus and dyslipidemia. To describe the clinical presentation of known types of lipodystrophy, and suggest specific steps to recognize, diagnose and treat lipodystrophy in the clinical setting. Based on literature and in our own experience, we propose a stepwise approach for diagnosis of the different subtypes of rare lipodystrophy syndromes, describing its more frequent co-morbidities and establishing the therapeutical approach. Lipodystrophy is classified as genetic or acquired and by the distribution of fat loss, which can be generalized or partial. Genes associated with many congenital forms of lipodystrophy have been identified that may assist in diagnosis. Because of its rarity and heterogeneity, lipodystrophy may frequently be unrecognized or misdiagnosed, which is concerning because it is progressive and its complications are potentially life threatening. A basic diagnostic algorithm is proposed. Effective management of lipodystrophy includes lifestyle changes and aggressive, evidence-based treatment of comorbidities. Leptin replacement therapy (metreleptin) has been found to improve metabolic parameters in many patients with lipodystrophy. Metreleptin is approved in the United States as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy and has been submitted for approval in Europe. Here, we describe the clinical presentation of known types of lipodystrophy, present an algorithm for differential diagnosis of lipodystrophy, and suggest specific steps to recognize and diagnose lipodystrophy in the clinical setting.

Evaluating the effects of mobile health intervention on weight management, glycemic control and pregnancy outcomes in patients with gestational diabetes mellitus.

Abstract: To explore the effects of mobile health (mHealth) intervention on pregnancy weight management, blood glucose control and pregnancy outcomes. A total of 124 patients with gestational diabetes mellitus (GDM) were selected. Patients were randomly divided into two groups. The 60 patients in the control group received standard outpatient treatment, while the remaining 64 patients received a nurse’s online guidance both through a mobile medical App installed on their phone and through regular offline clinical treatment in the mHealth group. Patients were treated for an average of 13 weeks and general conditions, compliance, blood glucose, glycosylated hemoglobin, weight gain, pregnancy, and neonatal outcomes were monitored in both groups longitudinally. The mHealth group demonstrated higher levels of compliance (83.3 ± 12.5% vs. 70.4 ± 10.1%, t = − 6.293, df = 122, p < 0.001), lower frequency of outpatient service (8.1 ± 1.3 vs. 11.2 ± 1.1, t = 14.285, df = 122, p < 0.001), lower hemoglobin A1C before delivery (4.7 ± 0.2 vs. 5.3 ± 0.3, t = 13.216, df = 122, p < 0.001) as well as the rates of off-target measurements both fasting (4.6 ± 0.4% vs. 8.3 ± 0.6%, t = 40.659, df = 122, p < 0.001) and 2 h post-prandial (7.9 ± 0.7% vs. 14.7 ± 0.8%, t = 50.746, df = 122, p < 0.001). Weight gain in the mHealth group was less than control group (3.2 ± 0.8 vs. 4.8 ± 0.7, t = 11.851, df = 122 p < 0.001). Mobile health intervention management of gestational diabetes mellitus improves patients’ compliance and blood glucose control, and reduces weight gain, thereby reducing the rates of complications in both pregnant women and fetuses during delivery during pregnancy.

Epidemiology, pathogenesis, and diagnosis of Addison's disease in adults.

Abstract: Addison’s disease (AD) is a rare disorder and among adult population in developed countries is most commonly caused by autoimmunity. In contrast, in children genetic causes are responsible for AD in the majority of patients. This review describes epidemiology, pathogenesis, genetics, natural history, clinical manifestations, immunological markers and diagnostic strategies in patients with AD. Standard care treatments including the management of patients during pregnancy and adrenal crises consistent with the recent consensus statement of the European Consortium and the Endocrine Society Clinical Practice Guideline are described. In addition, emerging therapies designed to improve the quality of life and new strategies to modify the natural history of autoimmune AD are discussed. Progress in optimizing replacement therapy for patients with AD has allowed the patients to lead a normal life. However, continuous education of patients and health care professionals of ever-present danger of adrenal crisis is essential to save lives of patients with AD.

Expression of miR-217 and HIF-1α/VEGF pathway in patients with diabetic foot ulcer and its effect on angiogenesis of diabetic foot ulcer rats

Abstract: To investigate the expression of miR-217 and HIF-1α/VEGF pathway in patients with diabetic foot ulcer (DFU) and its effect on angiogenesis in DFU rats. The serum levels of miR-217, HIF-1α and VEGF were detected in DFU and simple diabetes mellitus (DM) patients, and healthy controls. DFU rat models were established and treated with miR-217 inhibitors and/or HIF-1α siRNA. The ulcer healing of DFU rats was observed. Besides, ELISA method was performed to detect the serum level of HIF-1α, VEGF and inflammatory factors, immunohistochemical (IHC) method to test the micro-vessel density (MVD), as well as qRT-PCR and Western blot to determine expressions of miR-217, HIF-1α, VEGF, VEGFR2, eNOS, MMP-2, and MMP-9 in tissues. The serum levels of miR-217 were up-regulated while HIF-1α and VEGF were down-regulated in DFU patients and rats when compared with DM and healthy controls (all P < 0.05). Dual-luciferase reporter gene assay confirmed that HIF-1α was the direct target gene of miR-217. DFU rats treated with miR-217 inhibitors had decreased foot ulcer area and accelerated ulcer healing, with significantly reduced inflammatory factors (IL-1β, TNF-α and IL-6), as well as elevated HIF-1α and VEGF (all P < 0.05); meanwhile, they remarkably increased the MVD in foot dorsum wound tissues and the protein expressions of HIF-1α, VEGF, VEGFR2, eNOS, MMP-2, and MMP-9 (all P < 0.05). Inhibiting miR-217 could up-regulate HIF-1α/VEGF pathway to promote angiogenesis and ameliorate inflammation of DFU rats, thereby effectively advancing the healing of ulcerated area.

A 2019 update on TSH-secreting pituitary adenomas

Abstract: Thyrotropin-secreting pituitary adenomas (TSH-omas) present with signs and symptoms of hyperthyroidism and they are characterized by elevated serum levels of free thyroid hormones with measurable TSH levels. TSH-omas are very infrequent, accounting for less than 1% of all pituitary adenomas, thus representing a very rare cause of hyperthyroidism. For this reason, data collected on these rare disorders are relatively few, but some new researches shed new light on the etiopathogenesis, the diagnosis and the treatment of such a remarkable disease. Since the same biochemical picture is present in the syndromes of thyroid hormone resistance (RTH), in particular in the form of pituitary RTH, failure in distinguishing these clinical entities may lead to improper patient management. Conversely, early diagnosis and correct treatment of TSH-omas may prevent the occurrence of neurological and endocrinological complications, thus leading to a better rate of cure. In the present short review article, the most relevant recent advances in the pathophysiology of TSH-omas are described.

Sick fat: the good and the bad of old and new circulating markers of adipose tissue inflammation.

Abstract: Adipose tissue (AT) is one of the largest endocrine organs contributing to metabolic homeostasis. The functional pleiotropism of AT depends on its ability to secrete a large number of hormones, cytokines, extracellular matrix proteins and growth factors, all influencing many local and systemic physiological and pathophysiological processes. In condition of chronic positive energy balance, adipocyte expansion, hypoxia, apoptosis and stress all lead to AT inflammation and dysfunction, and it has been demonstrated that this sick fat is a main risk factor for many metabolic disorders, such as type 2 diabetes mellitus, fatty liver, cardiovascular disease and cancer. AT dysfunction is tightly associated with aberrant secretion of bioactive peptides, the adipocytokines, and their blood concentrations often reflect the expression in the AT. Despite the existence of an association between AT dysfunction and systemic pro-inflammatory state, most of the circulating molecules detectable in obese and dysmetabolic individuals do not identify specifically the condition of sick fat. Based on this premise, this review provides a concise overview of “classic” and novel promising adipocytokines associated with AT inflammation and discusses possible critical approaches to their interpretation in clinical practice.

Effects of growth hormone on pregnancy rates of patients with thin endometrium

Abstract: To investigate whether growth hormone (GH) could improve pregnancy rates of patients with thin endometrium by clinical study and laboratory experiments. Ninety-three patients were randomized to either the GH-received group (40) or the routine exogenous administration of estrogens control group (53) for clinical study. The human endometrial carcinoma cell line RL95-2 was used for testing the role of GH with Western blot and real-time PCR by exposure to various concentrations of GH (0.1 nM,1 nM,10 nM,100 nM). Patients treated with GH had a significantly (P < 0.05) greater endometrium thickness on day 3 (7.87±0.72 vs 6.34±0.86), higher implantation rates (24.4% vs 10.5%) and greater clinical pregnancy rates (42.5% vs 18.9%) compared with the control group. No adverse events were associated with the use of GH. Administration of GH significantly up-regulated the expression of VEGF, ItgB3 and IGF-I expression in RL95-2 cells at both mRNA and protein levels (P < 0.05). AG490, an inhibitor of JAK2, nearly completely inhibited the up-regulative effect of GH through the JAK2-STAT5 pathway, and GH-induced effects could be mediated through autocrine IGF-I together with its hepatic counterpart. IGF-I mRNA was detected in the RL95-2 cells. GH may improve pregnancy outcomes of patients with thin endometrium who undergo frozen embryo transfer by acting on human endometrial cells to promote proliferation and vascularization and to up-regulate receptivity-related molecular expression.

Endocrine and metabolic adverse effects of immune checkpoint inhibitors: an overview (what endocrinologists should know).

Abstract: Immune checkpoint inhibitors (ICIs) are novel anticancer agents, recently introduced with the aim of boosting the immune response against tumors. ICIs are monoclonal autoantibodies that specifically target inhibitory receptors on T cells: cytotoxic T lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1) and its ligand (PD-1L). ICIs also generate peculiar dysimmune toxicities, called immune-related adverse events (irAEs), that can potentially affect any tissue, and some may be life-threatening if not promptly recognized. The endocrine and metabolic side effects of ICIs are reviewed here, with a particular focus on their clinical presentation and management. They are among the most frequent toxicities (around 10%) and include hypophysitis, thyroid disorders, adrenalitis, and diabetes mellitus. Treatment is based on the replacement of specific hormone deficits, accompanied by immunosuppression (with corticosteroids or other drugs), depending on irAEs grade, often without the need of ICI withdrawal, except in more severe forms. Prompt recognition of endocrine and metabolic irAEs and adequate treatment allow the patients to continue a therapy they are benefiting from. Endocrinologists, as an integral part of the multidisciplinary oncologic team, need to be familiar with the unique toxicity profile of these anticancer agents. Practical recommendations for their management are proposed.

Clinical analysis of cervical lymph node metastasis risk factors in patients with papillary thyroid microcarcinoma.

Abstract: Purpose Lymph node metastasis (LNM) is a vital prognosis factor in patients with papillary thyroid microcarcinoma (PTMC). The study tried to identify clinicopathological factors for LNM of PTMC.

Vitamin D status and cardiovascular outcome

Abstract: Vitamin D is classically involved in maintaining bone and mineral health, but it has been shown to exert many extraskeletal functions, including pleiotropic effects on cardiovascular system. This review aims to summarize evidences in literature about vitamin D and cardiovascular outcome. Calcitriol or 1,25(OH)2D, the active hormone, binds to the specific nuclear receptor VDR, which is expressed in rat and human heart and vasculature and has effects on myocardiocytes, smooth cells, and endothelial cells. 25-Hydroxy-vitamin D (25OHD) represents the biomarker of vitamin D levels and reflects vitamin D status. There is consistent evidence that low serum 25OHD levels are associated with increased risk of cardiovascular diseases, including hypertension, coronary artery disease, ischemic heart disease, heart failure, stroke, and type 2 diabetes. Randomized-controlled trials and Mendelian randomization studies so far have not succeeded in proving a benefit of vitamin D supplementation. However, the latter investigations are affected by some methodological limitations, and therefore, it is still unclear if vitamin D deficiency has a causative role in cardiovascular diseases or is rather a marker of poor health in chronic disease.

Safety of long-term antithyroid drug treatment? A systematic review

Abstract: Continued low-dose MMI treatment for longer than 12–18 months may be considered in patients not in remission. However, ATDs are not free from adverse effects. We undertook a systematic review to clarify safety of long-term ATD treatment. Medline and the Cochrane Library for trials published between 1950 and Nov 2018 were systematically searched. We included original studies containing data for long-term (> 18 months) ATD treatment. Two reviewers independently extracted data from included trials and any disagreement was adjudicated by consensus. Of 615 related articles found, 12 fulfilled the criteria. Six articles had data for adults, five for non-adults and one article had data for both groups. The sample sizes ranged between 20 and 249 individuals, and the mean duration of ATD treatment ranged between 2.1 and 14.2 years. Considering all data from 1660 patients treated with ATD for a mean duration of 5.8 years (around 10,000 patient-years), major complications occurred only in 14 patients: 7 severe agranulocytosis, 5 severe liver damage, one ANCA-associated glomerulonephritis and one vasculitis with small cutaneous ulcerations. Minor complications rates were between 2 and 36%, while more complications were in higher doses and in the children. The most reported AE was cutaneous reaction; the other adverse events were elevated liver enzymes, leukocytopenia, arthritis, arthralgia, myalgia, thrombocytopenia, fever, nausea and oral aphthous. Long-term ATD treatment is safe, especially in low dose and in adults, indicating that it should be considered as an earnest alternative treatment for GD.

Clinical inertia, reverse clinical inertia, and medication non-adherence in type 2 diabetes

Abstract: Clinical inertia and medication non-adherence are thought to contribute largely to the suboptimal glycemic control in many patients with type 2 diabetes. The present review explores the relations between A1C targets, clinical inertia and medication non-adherence in type 2 diabetes. We searched PubMed for English-language studies published from 2001 through June 1, 2018. We also manually searched the references of selected articles, reviews, meta-analyses, and practice guidelines. Selected articles were mutually agreed upon by the authors. Clinical inertia is the failure of clinicians to initiate or intensify therapy when indicated, while medication non-adherence is the failure of patients to start or continue therapy that a clinician has recommended. Although clinical inertia may occur at all stages of diabetes treatment, the longest delays were reported for initiation or intensification of insulin. Medication non-adherence to antidiabetic drugs may range from 53 to 65% at 1 year and may be responsible for uncontrolled A1C in about 23% of cases. Reverse clinical inertia can be acknowledged as the failure to reduce or change therapy when no longer needed or indicated. Clinical inertia and medication non-adherence are difficult to address: clinician-and patient-targeted educational programs, more connected communications between clinicians and patients, the help of other health professional figures (nurse, pharmacist) have been explored with mixed results. Both clinical inertia and medication non-adherence remain significant barriers to optimal glycemic targets in type 2 diabetes. Moreover, part of clinical inertia may be a way through which clinicians face current uncertainty in medicine, including some dissonance among therapeutic guidelines. Scientific associations should find an agreement about how to measure and report clinical inertia in clinical practice and should exhort clinicians to consider reverse clinical inertia as a cause of persisting inappropriate therapy in vulnerable patients.

Low frequency of positive antithyroid antibodies is observed in patients with thyroid dysfunction related to immune check point inhibitors

Abstract: Immune checkpoint inhibitors (ICI), such as programmed death-1 inhibitors (anti-PD1), have become a cornerstone for the treatment of different advanced cancers. These antibodies act as modulators of immune checkpoint proteins. However, ICI can lead to the breaking of immune self-tolerance, inducing autoimmune side effects (irAEs), including endocrinopathies. One of the most frequent endocrine irAE of anti-PD1 is thyroid dysfunction, but the exact mechanism of this disease still remains unknown. We conducted a descriptive retrospective study, analyzing 11 patients who received at least one dose of anti-PD1 (nivolumab or pembrolizumab) and presented thyroid irAEs. Data were collected between September 2015 and May 2018 in our hospital. The aim was to analyze the clinically relevant features of thyroid irAEs and the frequency of antithyroid antibodies (ATA) positivity observed on them. 8 of the 11 patients were treated with nivolumab and the other three patients received pembrolizumab. Six patients presented silent thyroiditis with a thyrotoxicosis phase; three patients developed directly primary/subclinical hypothyroidism and two patients showed primary hyperthyroidism. Thyroid autoantibodies (anti-Thyroglobulin and anti-Thyroid Peroxidase) were assessed in all the 11 patients, and only in two of them (18%) a positive titer was displayed. Anti-TSH receptor antibodies (TRAbs) were examined in five patients, three with painless thyroiditis at the time of thyrotoxicosis and two with primary hyperthyroidism, and they all had undetectable levels. In our sample of 11 Caucasian patients with thyroid dysfunction related with anti-PD1, we found low frequency of ATA positive titers, comparable to other recent reports in others ethnicities, which could suggest that silent thyroiditis due to pembrolizumab or nivolumab has a different pathogenesis from the classical autoimmune spontaneous thyroiditis. Further investigations are required to completely understand the immune mechanisms involved.

Oxysterol species: reliable markers of oxidative stress in diabetes mellitus

Abstract: To assess the plasma oxysterol species 7-ketocholesterol (7-Kchol) and cholestane-3β,5α,6β-triol (chol-triol) as biomarkers of oxidative stress in type 1 and type 2 diabetes mellitus (DM). In total, 26 type 1 and 80 type 2 diabetes patients, along with 205 age- and gender-matched healthy controls, were included in this study. Oxysterols were quantified by liquid chromatography coupled with tandem mass spectrometry and N,N-dimethylglycine derivatization. Correlations between oxysterols and clinical/biochemical characteristics of the diabetes patients, and factors affecting 7-Kchol and chol-triol, were also determined. Plasma 7-Kchol and chol-triol levels were significantly higher in type 1 and type 2 diabetes patients compared to healthy controls (P < 0.001). Significant positive correlations were observed between oxysterol levels and levels of glycated hemoglobin (HbA1c), glucose, serum total cholesterol, low-density lipoprotein, very-low-density lipoprotein, and triglycerides, as well as the number of coronary risk factors. Statins, oral hypoglycemic agents, and antihypertensive agents reduced the levels of oxysterols in type 2 diabetes patients. Statin use, HbA1c levels, and the number of coronary risk factors accounted for 98.8% of the changes in 7-Kchol levels, and total cholesterol, smoking status, and the number of coronary risk factors accounted for 77.3% of the changes in chol-triol levels in type 2 diabetes patients. Plasma oxysterol levels in DM, and particularly type 2 DM, may yield complementary information regarding oxidative stress for the clinical follow-up of diabetes patients, especially those with coronary risk factors.

PETC/CT with 18F-Choline localizes hyperfunctioning parathyroid adenomas equally well in normocalcemic hyperparathyroidism as in overt hyperparathyroidism.

Abstract: Identification of pathologic parathyroid glands in primary hyperparathyroidism, traditionally based on neck ultrasound (US) and/or 99mTc-Sestamibi scintigraphy, can be challenging. PET/CT with 18F-Fluorocholine (18F-FCH) might improve the detection of pathologic parathyroid glands. We aimed at comparing the diagnostic performance of 18F-FCH-PET/CT with that of dual-phase dual-isotope parathyroid scintigraphy and neck US. Thirty-four consecutive patients with primary hyperparathyroidism were prospectively enrolled, 7 had normocalcemic hyperparathyroidism, and 27 had classic hypercalcemic hyperparathyroidism. All patients underwent high-resolution neck US, dual-phase dual-isotope 99mTc-Pertechnetate/99mTc-Sestamibi scintigraphy, and 18F-FCH-PET/CT. In the whole patients’ group, the detection rates of the abnormal parathyroid gland were 68% for neck US, 71% for 18F-FCH-PET/CT, and only 15% for 99mTc-Sestamibi scintigraphy. The corresponding figures in normocalcemic and hypercalcemic hyperparathyroidism were 57 and 70% for neck US, 70 and 71% for 18F-FCH-PET/CT, and 0 and 18% for 99mTc-Sestamibi scintigraphy, respectively. In the 17 patients in whom the abnormal parathyroid gland was identified, either at surgery or at fine needle aspiration cytology/biochemistry, the correct detection rate was 82% for neck US, 89% for 18F-FCH-PET/CT, and only 17% for 99mTc-Sestamibi scintigraphy. 18F-FCH-PET/CT can be considered a first-line imaging technique for the identification of pathologic parathyroid glands in patients with normocalcemic and hypercalcemic hyperparathyroidism, even when the parathyroid volume is small.

Alterations in the intestinal microbiota of patients with severe and active Graves’ orbitopathy: a cross-sectional study

Abstract: The intestinal microbiota was linked to autoimmune diseases. Graves’ orbitopathy (GO) is an autoimmune disease that is usually associated with Graves’ disease. However, information on the microbiome of GO patients is yet lacking. To investigate whether GO patients differ from healthy controls in the fecal microbiota. A cross-sectional study. 33 patients with severe and active GO and 32 healthy controls of Han nationality were enrolled between March 2017 and March 2018. The Gut microbial communities of the fecal samples of GO patients and healthy controls were analyzed and compared by 16S rRNA gene sequencing. Community diversity (Simpson and Shannon) was significantly reduced in fecal samples from patients with GO as compared to controls (p < 0.05). The similarity observed while assessing the community diversity (PCoA) proposed that the microbiota of patients with GO differ significantly from those of controls (p < 0.05). At the phyla levels, the proportion of Bacteroidetes increased significantly in patients with GO (p < 0.05), while at the genus and species levels, significant differences were observed in the bacterial profiles between the two groups (p < 0.05). Single-centered study design and limited fecal samples. The present study indicated distinctive features of the gut microbiota in GO patients. The study provided evidence for further exploration in the field of intestinal microbiota with respect to the diagnosis and treatment of GO patients by modifying the microbiota profile.

Serum antibodies against the insulin-like growth factor-1 receptor (IGF-1R) in Graves’ disease and Graves’ orbitopathy

Abstract: A role of the insulin-like growth factor-1 receptor (IGF-1R) in the pathogenesis of Graves’ orbitopathy (GO) has been proposed, but the existence and function of anti-IGF-1R-antibodies (IGF-1R-Abs) are debated. We designed a cross-sectional investigation to measure serum IGF-1R-Abs by a commercial assay in consecutive patients with Graves’ disease (GD) compared with healthy subjects and patients with autoimmune thyroiditis (AT). A total of 134 subjects were screened including 27 healthy subjects, 80 GD patients (54 of whom with GO), and 27 AT patients. The main outcome measure was the prevalence of positive serum IGF-1R-Abs in GO, compared with GD without GO and with the other study groups. Having established a cut-off value at 55.2 ng/ml for positive tests, positive IGF-1R-Abs were more frequent in GD (25%), than in AT (3.7%, P = 0.003) and healthy subjects (0%, P = 0.006). Within GD, there was no difference between patients with or without GO. Serum levels of IGF-1R-Abs differed across the study population (P < 0.0001), reflecting their higher concentrations in GD (P < 0.0001 vs both AT and healthy subjects), but with no difference between patients with or without GO. In patients with GO, there was an inverse correlation between serum IGF-1R-Abs and CAS (R = − 0.376, 95% CI: from − 0.373 to − 0.631; P = 0.005), the significance of which remains to be investigated. Serum autoantibodies against the IFG-1R are present in one-fourth of GD patients, regardless of the presence of GO. Further functional studies are needed to investigate the significance of their inverse correlation with GO activity.

Classifying pain in transoral endoscopic thyroidectomy.

Abstract: Knowledge of visual analog scale (VAS) pain assessment for transoral endoscopic thyroidectomy vestibular approach (TOETVA) is limited. The purpose of this analysis was to classify the postoperative discomfort scores in patients undergoing TOETVA compared to open thyroidectomy. Observational clinical study of patients who underwent thyroidectomy by VAS pain assessment from September 2016 to March 2017. Patients were stratified into two groups: patients eligible for TOETVA (Group TOETVA) and non-candidates for endoscopic intervention (open thyroidectomy approach—OTA). VAS was recorded in the recovery room, at 24 h, + 2, + 5, + 15, + 30, + 90 days, and 6 months after surgery. Pain assessment was stratified in VAS-lower lip, VAS-chin, VAS-jaw, VAS-anterior neck, VAS-cervical/back, VAS-swallowing, VAS-brushing, VAS-speaking, and VAS-shaving. Secondary outcome assessed were analgesic rescue dose, morbidity, operative notes, hospital stay, and histopathology. 41 TOETVA and 45 OTA constituted the analysis. There were differences between the TOETVA and OTA for age, gland volume, mean nodule diameter, coexistence thyroiditis, bilateral procedures, and use of drain. Operative time was longer in TOETVA. Results indicated that TOETVA was associated with reduced neck, cervical back, and swallowing VAS scores in the 24 h after surgery. Conversely, jaw and brushing teeth resulted in higher VAS score in TOETVA group. OTA patients never experienced lower lip or chin pain. The use of rescue analgesics did not differ between the two groups. VAS was used to measure treatment outcome in TOETVA. VAS scores achieved overall a minimal clinical importance difference from the two procedures. There appears to be both a short- and long-term different range of interpretations of pain between TOETVA and OTA.

Effects of PCSK9 inhibitors on LDL cholesterol, cardiovascular morbidity and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials.

Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors determine a wide reduction of LDL cholesterol, greater than other lipid-lowering agents. The present meta-analysis is aimed at the assessment of PCSK9 inhibitors effect on LDL Cholesterol, cardiovascular morbidity and all-cause mortality. A Medline and Clinicaltrials.gov search for eligible studies until December 1, 2017, was performed. All randomized trials (> 12 weeks) comparing PCSK-9 inhibitors with placebo or active drugs were retrieved. Primary endpoints: (a) LDL cholesterol at endpoint; (b) Major cardiovascular events (MACE); (c) All-cause mortality. Data extraction was performed independently by two of the authors, and conflicts resolved by a third investigator. A total of 38 trials fulfilling the inclusion criteria were identified, with mean duration of 36.4 weeks. The reduction of LDL cholesterol at endpoint, versus placebo, ezetimibe, and high-dose statins was − 65.3 [− 69.6, − 60.9]%, − 57.7 [− 68.3;− 47.0]%, and − 34.5 [− 40.8;− 28.1]%, respectively, with alirocumab possibly showing a smaller effect than the other drugs of the class. Treatment with PCSK9 inhibitors was associated with a reduction in the incidence of MACE (Mantel–Haenszel Odds Ratio [MH-OR] 0.83 [0.78, 0.88]), with significant effects of alirocumab and evolocumab only. The number needed to treat for 2 years for preventing one event was 89. All-cause mortality and cardiovascular mortality were not reduced by treatment with PCSK-9 inhibitors (MH-OR 0.94 [0.84, 1.04] and 0.97[0.86;1.09]). PCSK-9 inhibitors are effective in reducing LDL cholesterol and the incidence of major cardiovascular events in high-risk patients. Bococizumab does not show significant effects on MACE. PROSPERO-CRD42018087640.

The diagnostic accuracy of increased late night salivary cortisol for Cushing’s syndrome: a real-life prospective study

Abstract: A prompt diagnosis of Cushing’s Syndrome (CS) in high-risk populations is mandatory: 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), and urinary-free cortisol (UFC) are recommended, despite thresholds calculated in retrospective studies. Our aim was to study the diagnostic accuracy of LNSC measured with chemiluminescence assay in a prospective study, confirming discrepancies with mass spectrometry (MS). We enrolled 117 controls and 164 suspected CS (CS = 47, non-CS = 117). In case of increased LNSC, high clinical suspicion of CS or adrenal incidentaloma, patients were hospitalized to exclude/confirm CS. LNSC levels were higher in patients with suspected CS, CS, and non-CS than controls. Considering 16 nmol/L as threshold for CS, overall LNSC revealed SE 97% and SP 84% in the whole group of subjects considered, achieving positive/negative likelihood ratio of 5.56/0.045, respectively. 35 out of 81 subjects with increased LNSC were non-CS (15 diabetic and 20 obese): considering only those patients with increased likelihood to have a CS (the non-CS patients) SP decreased to 70%, and further reduced to 60% if we discharged subjects with adrenal incidentaloma. MS analyses reduced partially the number of false-positive LNSC. LNSC measured in automated chemiluminescence is reliable in clinical practice: it present a high diagnostic accuracy to exclude hypercortisolism in patients with normal cortisol levels. MS could be used to reduce the number of false-positive results; nevertheless, some non-CS subjects with functional hypercortisolism could have a mild impairment of cortisol rhythm.

Serum levels of adipokines in gestational diabetes: a systematic review

Abstract: To determine the difference of serum levels of 10 adipokines (apelin, chemerin, fatty acid-binding protein-4, fibroblast growth factor-21, monocyte chemoattractant protein-1, nesfatin-1, omentin-1, resistin, vaspin, and visfatin) among women with gestational diabetes and healthy pregnant controls. Literature search was conducted using the Medline (1966–2018), Scopus (2004–2018), Cochrane Central Register of Controlled Trials (CENTRAL) (1999–2018), Clinicaltrials.gov (2008–2018) and Google Scholar (2004–2018) databases, along with the reference list of the included studies. Ninety-one studies were included in the present review, with a total number of 11,074 pregnant women. A meta-analysis was not conducted due to the high inter-study heterogeneity. Current evidence suggests that fatty acid-binding protein-4 levels are significantly increased in pregnancies complicated with gestational diabetes, while no association of serum apelin and monocyte chemoattractant protein-1 with the disease can be supported. Data regarding the rest adipokines are conflicting, since the available studies did not unanimously indicate a significant change of their levels in gestational diabetes. The findings of the present systematic review suggest the promising role of fatty acid-binding protein-4 in the prediction of gestational diabetes, while inconsistent evidence exists regarding the rest novel adipokines. Future cohorts are needed to assess their predictive efficacy and fully elucidate their contribution in the disease.

Cardiovascular outcome trials and major cardiovascular events: does glucose matter? A systematic review with meta-analysis

Abstract: We did a meta-analysis with meta-regression to evaluate the relationship between hemoglobin A1c (A1C) reduction and the primary CV outcome of cardiovascular outcome trials (CVOTs). We used a random effects meta-analysis of the 12 CVOTs to quantify the effect of A1C reduction on major cardiovascular events (MACE) risk by stratifying the difference in achieved A1C (drug vs placebo) in three strata: A1c < 0.3%, A1c ≥ 0.3% and < 0.5%, and A1c ≥ 0.5%. We found a relation between the reduction in achieved A1C and the hazard ratio reduction for MACE (P = 0.002), explaining almost all (94.1%) the between-study variances: lowering A1C by 0.5% conferred a significant HRR of 20% (95% CI 4–33%) for MACE. Blood glucose reduction may play a more important role than previously thought in reducing the risk of MACE during treatment with the newer glucose-lowering drugs, including peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium–glucose co-transporter-2 inhibitors.

Gut microbiome and microbial metabolites: a new system affecting metabolic disorders.

Abstract: The gut microbiome is emerging as an important player in the field of metabolic disorders. Currently, several studies are ongoing to determine whether the effect of gut microbiome on obesity, type 2 diabetes, non-alcoholic fatty liver disease, and other metabolic diseases is determined by singular species or rather by a functional role of bacterial metabolism at higher taxonomical level. Deciphering if a single or more species are responsible for metabolic traits or rather microbial metabolic pathways are responsible for effects on host metabolism may help to identify appropriate dietary interventions to support microbial functions according to the prevalent host disease. Furthermore, the combination of metagenomics and metabolomics-based signature might be applied in the future to improve the risk prediction in healthy subjects. In this review, I will summarize the current findings regarding the role of gut microbiome and metabolites in metabolic disorders to argue whether the current achievements may be translated into clinical practice.

Lack of association between obesity and aggressiveness of differentiated thyroid cancer.

Abstract: Aim of this study was to evaluate the association between body mass index (BMI) and aggressive features of differentiated thyroid cancer (DTC) in a prospective cohort. Patients with DTC were prospectively enrolled at a tertiary referral center and grouped according to their BMI. Aggressive clinic-pathological features were analyzed following the American Thyroid Association Initial Risk Stratification System score. The cohort was composed of 432 patients: 5 (1.2%) were underweight, 187 (43.3%) normal weight, 154 (35.6%) overweight, 68 (15.7%) grade 1 obese, 11 (2.5%) grade 2 obese and 7 (1.6%) grade 3 obese. No single feature of advanced thyroid cancer was more frequent in obese patients than in others. No significant correlation was found between BMI, primary tumor size (Spearman’s ρ − 0.02; p = 0.71) and ATA Initial Risk Stratification System score (ρ 0.03; p = 0.49), after adjustment for age. According to the multivariate logistic regression analysis, male gender and pre-surgical diagnosis of cancer were significant predictors of cancer with high or intermediate–high recurrence risk according to the ATA system (OR 2.06 and 2.51, respectively), while older age at diagnosis was a protective factor (OR 0.98), and BMI was not a predictor. BMI was a predictor of microscopic extrathyroidal extension only (OR 1.06). Obesity was not associated with aggressive features in this prospective, European cohort of patients with DTC.

Tumor suppressor miR-145-5p sensitizes prolactinoma to bromocriptine by downregulating TPT1.

Abstract: Prolactinoma is the most commonly seen secretory tumor of pituitary glands, which accounts for approximately up to 40% of total pituitary adenomas. Due to its high drug resistance, dopamine agonist, such as bromocriptine, has limited effect on the treatment of patients with prolactinoma. Recent discoveries have revealed that multiple miRNAs were involved in regulating drug resistance. In this research, we explored the relationship between miR-145-5p expression as well as bromocriptine sensitivity both in vitro and in vivo. To study the role of miR-145-5p in drug resistance of prolactinoma, the expression levels of miR-145-5p in bromocriptine-resistant prolactinoma cell line MMQ/BRC and its parental cell line MMQ cells, 24 bromocriptine-resistant as well as eight sensitive clinical samples were measured by qRT-PCR. Moreover, CCK8, flow cytometry and immunofluorescence were performed to identify the biological characteristics of MMQ/BRC and MMQ. TPT1 was predicted as a direct target gene of miR-145-5p by bioinformatic methods. In addition, qRT-PCR, western blot and immunohistochemistry were used to detect the expression level of TPT1 in clinical specimens and cell lines. Xenograft mouse model was constructed to analyze whether miR-145-5p could reverse bromocriptine resistance in prolactinoma in vivo. In our study, bromocriptine-resistant prolactinoma clinical samples and cell line had decreased miR-145-5p levels and expressed high levels of TPT1 compared with their sensitive counterparts. Bioinformatic methods and our preliminary dual luciferase reporter assay were utilized to elucidate that TPT1 was a direct target gene of miR-145-5p. Furthermore, introducing miR-145-5p mimic into MMQ cells led to a decrease of IC50 along with upregulation of TPT1; nevertheless, transfecting the corresponding inhibitor into MMQ cells resulted in an upregulation of IC50 as well as reduction of TPT1. Collectively, our findings elucidated the role of miR-145-5p as an important regulator of drug resistance in prolactinoma by controlling TPT1, and implicated the potential application of miR-145-5p in cancer therapy as well.

Effects of selenium and vitamin C on the serum level of antithyroid peroxidase antibody in patients with autoimmune thyroiditis

Abstract: Selenium (Se), an essential trace element, has been implicated in pathogenesis of autoimmune thyroiditis (AIT). Most studies attributed the immune modulating effects of Se to its antioxidant properties. However, there is insufficient evidence to support the use of selenium supplementation or other antioxidants in patients with AIT. This clinical trial was designed to investigate the impact of Se and vitamin C supplementation on antithyroid peroxidase antibody (TPO-Ab) level in patients with AIT. One hundred and two subjects aged 15–78 years were randomized into three groups. Group one (GI) (n = 38) was treated with 200 μg/day sodium selenite, group two (GII) (n = 36) received 500 mg vitamin C/day, and group three (GIII) (n = 28) received placebo over a 3-month period. Thyroid stimulating hormone (TSH), TPO-Ab, antithyroglobulin antibody (Tg-Ab) and Se concentrations were once measured before treatment and at the end of the study. After 3 months, TPO-Ab concentrations decreased within Se and vitamin C-treated groups, but did not change in the placebo subjects. In this regard, there was no significant difference between the groups. We also did not find any statistically significant difference in TSH and Tg-Ab levels within and between the groups. At the end of the study, Se level was significantly higher in GI compared with GII and GIII. Our findings supported the hypothesis of antioxidant beneficial effects of Se in AIT. However, it was not superior to vitamin C, regarding its effects on thyroid-specific antibodies.

Cadmium exposure alters steroid receptors and proinflammatory cytokine levels in endothelial cells in vitro: a potential mechanism of endocrine disruptor atherogenic effect

Abstract: Unfortunately, the figure captions 4 and 6 were incorrectly published in the original publication. The complete correct captions are given below.