The value of SPECT/CT imaging of lacrimal glands as a means of assessing the activity of Graves’ orbitopathy

Background: Graves’ orbitopathy (GO) is an autoimmune disease with mechanical impairment of orbital muscles and lacrimal gland dysfunction. The frequently used methods of assessing GO activity include: Clinical Activity Score (CAS), computed tomography (CT), and magnetic resonance imaging (MRI). These approaches are mainly associated with orbital muscles, however, there are not many studies that focus on the lacrimal gland inflammation of GO patients. Objective: The aim of this study is to assess the usefulness of 99mTc-DTPA SPECT/CT in evaluating the lacrimal gland inflammation in Graves orbitopathy, as compared with other methods. Methods: A retrospective analysis of 48 patients with active GO compared with 33 controls was conducted. All subjects underwent clinical-endocrinological analyses, CAS evaluation, CT scans, and SPECT/CT examination. Lacrimal gland dimensions were determined and analyzed. Results: The lacrimal glands in patients with GO were significantly larger in all measured dimensions (p < 0.001) on CT scans relative to those in controls. Increased lacrimal gland DTPA uptake ratios (p < 0.001) were displayed in active GO patients compared to controls and were also correlated with TRAb levels. The cut-off value for discriminating active and inactive disease was calculated to be 1.735, with specificity of 82.6% and sensitivity of 74.2%. SPECT/CT uptake ratios and CAS values were positively correlated in all GO patients. SPECT/CT uptake ratios were also positively correlated with CT measurements including lacrimal gland volume and coronal width in GO patients. Conclusions: These data indicated that lacrimal gland SPECT/CT images can serve as a good tool for assessing the inflammation and disease activity of GO.

GIPR rs10423928 and bone-mineral density in postmenopausal women in Shanghai

Our previous studies have demonstrated that there is a correlation between GLP-1R SNP and the BMD in postmenopausal women. GLP-1 and GIP are both incretins. Whether the mutation of GIPR gene affects bone metabolism. SNP rs10423928 is a GIPR gene polymorphism that has been studied more frequently. The aim of this study was to investigate the association between GIPR SNP rs10423928 and bone-mineral density (BMD) in postmenopausal women in Shanghai. The GIPR SNP rs10423928 was detected in 884 postmenopausal women in Shanghai, the correlation between the GIPR SNP and BMD was further assessed. The dominant T/T genotype of the GIPR SNP rs10423928 was significantly related to BMD of the femoral neck (P = 0.035) and Ward’s triangle area (P = 0.033). Our research found that the dominant T/T genotype of GIPR SNP rs10423928 in postmenopausal women is significantly associated with higher BMD. The T/T genotype seems to have bone protection.

Immune checkpoint inhibitors, endocrine adverse events, and outcomes of melanoma

Objective: Immune checkpoint inhibitors (ICI) can cause endocrine adverse events. However, endocrine AEs could be related to better treatment outcomes. Our aim was to investigate whether this holds true in a real-world setting of metastatic melanoma patients. Design: A retrospective single-institution study. Methods: We included 140 consecutive metastatic melanoma patients treated with ICI between January 2012 and May 2019. We assessed endocrine toxicity and best possible treatment outcomes from electronic patient records, including laboratory parameters, and radiological images. Results: Of the treated patients, 21 patients (15%) were treated with ipilimumab, 46 (33%) with nivolumab, 67 (48%) with pembrolizumab, and six (4%) with combination therapy (ipilimumab + nivolumab). Endocrine AEs appeared in 29% (41/140) patients. Three patients had two different endocrine AEs. Thyroid disorders were the most common: 26% (36/140), followed by hypophysitis: 4% (5/140). Three subjects (2%, 3/140) were diagnosed with autoimmune diabetes. Three patients had to terminate treatment due to endocrine toxicity. Radiological manifestations of endocrine AEs were found in 16 patients (39%, 16/41). Endocrine toxicity was associated with significantly better treatment outcomes. Median progression-free survival (8.1 months, range 5.1 – 11.1 months vs. 2.7 months, range 2.4 – 3.0 months, P < 0.001), and median overall survival (47.5 months, range 15.5 – 79.5 months vs. 23.7 months, range 15.3 – 32.1 months, P = 0.035) were longer for patients experiencing endocrine AEs. Conclusions: The higher number of endocrine AEs suggest regular laboratory monitoring aids in AE detection. Endocrine AEs in metastatic melanoma may correlate with better treatment outcomes.

Cardio-psycho-metabolic outcomes of bariatric surgery: design and baseline of the WAS trial

Obesity is a rapidly emerging health problem and an established risk factor for cardiovascular diseases. Bariatric surgery profoundly reduces body weight and mitigates sequelae of obesity. The open, randomized controlled WAS trial compares the effects of Roux-en-Y gastric bypass (RYGB) versus psychotherapy-supported lifestyle modification in morbidly obese patients. The co-primary endpoint addresses 1-year changes in cardiovascular function (peak VO2 during cardiopulmonary exercise testing) and quality of life (Short-Form-36 physical functioning scale). Prior to randomization, all included patients underwent a multimodal anti-obesity treatment for 6-12 months. Thereafter, patients were randomized and followed through month 12 to collect primary endpoints. Afterwards, patients in the lifestyle group could opt for surgery, and final visit was scheduled for all patients 24 months after randomization. Sample size calculation suggested to enroll 90 patients in order to arrive at minimally 22 patients per group evaluable for the primary endpoint. Secondary objectives were to quantify changes in body weight, left ventricular hypertrophy, systolic and diastolic function (by echocardiography and cardiac magnet resonance imaging [MRI]), functional brain MRI, psychometric scales, endothelial and metabolic function. WAS enrolled 93 patients (72 women, median age 38 years, BMI 47.5 kg/m2) exhibiting a relevantly compromised exercise capacity (median peakVO2 18.3 ml/min/kg) and quality of life (median physical functioning scale 50). WAS is the first randomized controlled trial focusing on the effects of RYGB on cardiovascular function beyond hypertension. In addition, it will provide a wealth of high-quality data on cerebral, psychiatric, hepatic, and metabolic function in obese patients after RYGB. The trial is registered at ClinicalTrials.gov (NCT01352403).

Oral estrogen leads to falsely low concentrations of estradiol in a common immunoassay

Objectives: Recently, an estradiol immunoassay manufacturer (Beckman Coulter, USA) issued an “Important Product Notice” alerting clinical laboratories their assay (Access Sensitive Estradiol) was not indicated for patients undergoing exogenous estradiol treatment. The objective of this analysis was to evaluate immunoassay bias relative to liquid chromatography tandem mass spectrometry (LC-MS/MS) in transgender women and to examine the influence of unconjugated estrone on measurements. Design: Cross sectional secondary analysis. Methods: Estradiol concentrations from 89 transgender women were determined by three immunoassays (Access Sensitive Estradiol [‘New BC’] and Access Estradiol assays [‘Old BC’], Beckman Coulter; Estradiol III assay [‘Roche’], Roche Diagnostics) and LC-MS/MS. Bias was evaluated with and without adjustment for estrone concentrations. The number of participants who shifted between three estradiol concentration ranges for each immunoassay versus LC-MS/MS (>300 pg/mL, 70-300 pg/mL, and <70 pg/mL) was calculated. Results: The New BC assay had the largest magnitude overall bias (median: -34%) and was -40%, -22%, and -10%, among participants receiving tablet, patch, or injection preparations, respectively. Overall bias was -12% and +17% for the Roche and Old BC assays, respectively. When measured with the New BC assay, 18 participants shifted to a lower estradiol concentration range (versus 9 and 10 participants based on Roche or Old BC assays, respectively). Adjustment for estrone did not minimize bias. Conclusions: Immunoassay measurement of estradiol in transgender women may lead to falsely decreased concentrations that have the potential to affect management. A multi-disciplinary health care approach is needed to ensure appropriate analytical methods are available.

Non-thyroidal illness syndrome predicts outcome in adult critically ill patients: a systematic review and meta-analysis

We performed a systematic review and meta-analysis to comprehensively determine the prevalence and the prognostic role of nonthyroidal illness syndrome (NTIS) in critically ill patients. We included studies that assessed thyroid function by measuring the serum thyroid hormone level and in-hospital mortality in adult septic patients. Reviews, case reports, editorials, letters, animal studies, duplicate studies, and studies with irrelevant populations and inappropriate controls were excluded. A total of 6869 patients in 25 studies were included. The median prevalence rate of NTIS was 58% (IQR 33.2-63.7). In univariate analysis, triiodothyronine (T3) and free T3 (FT3) levels in non-survivors were relatively lower than that of survivors (8 studies for T3; standardized mean difference (SMD) 1.16; 95% confidence interval (CI), 0.41–1.92; I2 = 97%; P < 0.01). Free thyroxine (FT4) levels in non-survivors were also lower than that of survivors (12 studies; SMD 0.54; 95% CI, 0.31–0.78; I2 = 83%; P < 0.01). There were no statistically significant differences in TSH levels between non-survivors and survivors. NTIS was independently associated with increased risk of mortality in critically ill patients (OR = 2.21, 95% CI 1.64.- 2.97, I2 = 65% p < 0.01) The results favor the concept that decreased thyroid function might be associated with a worse outcome in critically ill patients. Hence, the measurement of TH could provide prognostic information on mortality in adult patients admitted to ICU.

Phenotypic spectrum of patients with mutations in CHD7: clinical implications of endocrinological findings

Objective: Heterozygous CHD7 mutations cause a broad spectrum of clinical phenotypes ranging from typical CHARGE syndrome to self-limited delayed puberty. This study aimed to investigate the clinical characteristics of endocrine dysfunction in patients with CHD7 mutations. Methods: The clinical features and endocrine findings from 30 patients with CHD7 variants were retrospectively reviewed. A diagnosis of CHARGE syndrome was based on the Verloes diagnostic criteria. Results: Seventeen patients fulfilled the criteria for typical CHARGE syndrome, one patient for partial/incomplete CHARGE, and the remaining 11 patients had atypical CHARGE syndrome. One patient was diagnosed with Kallmann syndrome and unilateral deafness. The most frequently observed features were inner ear anomalies (80.0%), intellectual disability (76.7%), and external ear anomalies (73.3%). The mean height and weight SDSs at diagnosis were -2.6 ± 1.3 and -2.2 ± 1.8, respectively. Short stature was apparent in 18 patients (60%), and one patient was diagnosed with growth hormone deficiency. Seventeen males showed genital hypoplasia, including micropenis, cryptorchidism, or both. Seven patients after pubertal age had hypogonadotropic hypogonadism with hyposmia/anosmia and olfactory bulb hypoplasia. Truncating CHD7 mutations were the most common (n = 22), followed by missense variants (n = 3), splice-site variants (n = 2), and large deletion (n = 2). Conclusions: A diverse phenotypic spectrum was observed in patients with CHD7 variants, and endocrine defects such as short stature and delayed puberty occurred in most patients. Endocrine evaluation, especially for growth and pubertal impairment, should be performed during diagnosis and follow-up to improve the patient’s quality of life.

Hsa_circ_0005729 enhances the accuracy in diagnosing parathyroid carcinoma

Background: Parathyroid carcinoma (PC), often misdiagnosed as parathyroid adenoma (PA), is prone to local relapse due to the initial surgery being restricted to parathyroid lesions instead of en bloc resection of parathyroid lesions with negative incision margins. However, it is very challenging to distinguish PC from PA preoperatively; hence, this study investigated an effective biomarker for increasing accuracy in PC diagnosis. Method: First, differentially expressed the circular RNAs between three PC tissues and three PA tissues were screened by high-throughput circular RNA sequencing, and the expression of hsa_circ_0005729 was verified by qRT-PCR in 14 patients with PC and 40 patients with PA. Second, the receiver operating characteristic (ROC) curve and the area under the curve (AUC) were used to analyze the diagnostic efficiency of hsa_circ_0005729 in PC by combining with laboratory data. Third, RNF138 mRNA, the corresponding linear transcript of hsa_circ_0005729 was measured, and the relationship between hsa_circ_0005729 and RNF138 mRNA was analyzed in patients with PA and patients with PC. Results: Hsa_circ_0005729 expression was significantly higher in patients with PC than in patients with PA. Serum calcium (p = 0.045), alkaline phosphatase (ALP) (p = 0.048), and creatinine levels (p = 0.036) were significantly higher in patients with PC than in patients with PA. The AUC increased to 0.86 when hsa_circ_0005729 combined with serum calcium, creatinine, and ALP. In addition, hsa_circ_0005729 was positively correlated with RNF138 mRNA in patients with PA but not in patients with PC. Conclusion: The novel circular RNA hsa_circ_0005729 was found to have a higher expression in patients with PC, and indicating its usefulness for distinguishing PC from PA.

Update on dyslipidemia in hypothyroidism

Hypothyroidism is often associated with elevated serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglycerides. Thyroid hormone (TH) affects the production, clearance and transformation of cholesterol, but current research shows that thyroid-stimulating hormone (TSH) also participates in lipid metabolism independently of TH. Therefore, the mechanism of hypothyroidism-related dyslipidemia is associated with the decrease of TH and the increase of TSH levels. Some newly identified regulatory factors, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), angiogenin-like proteins (ANGPTL), and fibroblast growth factors (FGF) are the underlying causes of dyslipidemia in hypothyroidism. High-density lipoprotein (HDL) serum concentration changes were not consistent, and its function was reportedly impaired. The current review focuses on the updated understanding of the mechanism of hypothyroidism-related dyslipidemia.

Individual and joint effects of trehalose and glutamate on diabetic retinopathy: a propensity score-matched case-control study

Although previous studies demonstrate that trehalose can help maintain glucose homeostasis in healthy humans, its role and joint effect with glutamate on diabetic retinopathy (DR) remain unclear. We aimed to comprehensively quantify the associations of trehalose and glutamate with DR. This study included 69 pairs of DR and matched type 2 diabetic (T2D) patients. Serum trehalose and glutamate were determined via ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry system. Covariates were collected by a standardized questionnaire, clinical examinations and laboratory assessments. Individual and joint association of trehalose and glutamate with DR were quantified by multiple conditional logistic regression models. The adjusted odds of DR averagely decreased by 86% [odds ratio (OR): 0.14; 95% confidence interval (CI): 0.06,0.33] with per interquartile range increase of trehalose. Comparing with the lowest quartile, adjusted OR (95% CI) were 0.20 (0.05,0.83), 0.14 (0.03,0.63) and 0.01 (<0.01,0.05) for participants in the 2nd, 3rd and 4th quartiles of trehalose, respectively. In addition, as compared to their counterparts, T2D patients with lower trehalose (<median) and higher glutamate (≥ median) had the highest odds of DR (OR: 36.81; 95% CI: 6.75, 200.61). Apparent super-multiplicative effect of trehalose and glutamate on DR was observed, whereas relative excess risk due to interaction (RERI) was not significant. The study suggests that trehalose is beneficial to inhibit the occurrence of DR and synergistically decreases the risk of DR with reduced glutamate. Our findings also provide new insights into the mechanisms of DR and further longitudinal studies are required to confirm these findings.