The associations of thyroid function parameters with non-alcoholic fatty liver disease (NAFLD) and hepatic iron overload are not entirely clear. We have cross-sectionally investigated these associations among 2734 participants of two population-based cross-sectional studies of the Study of Health in Pomerania. Serum levels of thyroid-stimulating hormone (TSH), free tri-iodothyronine (fT3), and free thyroxine (fT4) levels were measured. Liver fat content (by proton-density fat fraction) as well as hepatic iron content (by transverse relaxation rate; R2*) were assessed by quantitative MRI. Thyroid function parameters were associated with hepatic fat and iron contents by median and logistic regression models adjusted for confounding. There were no associations between serum TSH levels and liver fat content, NAFLD, or hepatic iron overload. Serum fT4 levels were inversely associated with liver fat content, NAFLD, hepatic iron contents, and hepatic iron overload. Serum fT3 levels as well as the fT3 to fT4 ratio were positively associated with hepatic fat, NAFLD, hepatic iron contents, but not with hepatic iron overload. Associations between fT3 levels and liver fat content were strongest in obese individuals, in which we also observed an inverse association between TSH levels and NAFLD. These findings might be the result of a higher conversion of fT4 to the biologically active form fT3. Our results suggest that a subclinical hyperthyroid state may be associated with NAFLD, particularly in obese individuals. Furthermore, thyroid hormone levels seem to be more strongly associated with increased liver fat content compared to hepatic iron content.
Till Ittermann, Rehman Mehmood Khattak, Marcello R P Markus, Jens-Peter Kühn, Marie-Luise Kromrey, Giovanni Targher, Antje Steveling, Matthias Nauck, and Henry Völzke
Ann-Cathrin Koschker, Bodo Warrings, Caroline Morbach, Florian Seyfried, Nicole Rickert, Pius Jung, Andreas Geier, Ulrich Dischinger, Maike Krauthausen, Martin J Herrmann, Christine Stier, Stefan Frantz, Uwe Malzahn, Stefan Störk, Martin Fassnacht, and the WAS Study Group
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 Würzburg Adipositas Studie (WAS) trial compares the effects of Roux-en-Y gastric bypass (RYGB) vs 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 the quality of life (QoL) (Short-Form-36 physical functioning scale). Prior to randomization, all included patients underwent a multimodal anti-obesity treatment for 6–12 months. Thereafter, the patients were randomized and followed through month 12 to collect the 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 MRI), functional brain MRI, psychometric scales, and 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 the QoL (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 the cerebral, psychiatric, hepatic, and metabolic function in obese patients after RYGB.
Fei Wu, Chaoming Mao, Xiao Mou, Chengcheng Xu, Tingting Zheng, Ling Bu, Xuan Luo, Qingyan Lu, and Xuefeng Wang
Hashimoto’s thyroiditis (HT) is a very common organ-speciﬁc autoimmune disease characterized by lymphocyte infiltration and the destruction of thyroid follicular cells (TFCs), in which IFN-γ and chemokines play pivotal roles. Moreover, β-catenin has been implicated in the regulation of T cell infiltration. However, whether β-catenin is involved in Hashimoto’s thyroiditis is unknown. Here, we examined β-catenin expression in thyroid tissues and investigated its role in the pathogenesis of HT. The results showed that β-catenin expression was markedly reduced in the thyroid tissues of HT patients; more importantly, IFN-γ treatment markedly reduced the expression of β-catenin and was accompanied by the secretion of chemokines such as CCL5, CXCL16, GRO-β, and GRO-γ in TFCs in vitro, which was attributed to GSK-3β/β-catenin signaling pathway activation. Collectively, the decreased expression of β-catenin might contribute to IFNγ-induced chemokine secretion and lymphocyte infiltration in the development of HT.
Yukari Maki, Kiyomi Horiuchi, and Takahiro Okamoto
Cancer-related fatigue is one of the most important issues for patients, but research on this topic is sparse. This study aimed to determine the prevalence of fatigue in postoperative patients with papillary thyroid carcinoma (PTC) and to identify the clinical features associated with fatigue.
We conducted a cross-sectional study on 292 thyroid cancer survivors. Fatigue and quality of life were the study outcomes, measured using the Cancer Fatigue Scale (CFS) and the SF-36 version 2.0. Furthermore, correlations of demographic characteristics and hormonal data with the CFS scores were assessed by univariable and multivariable analyses.
The prevalence of fatigue was 41.8% (95% CI: 36.1, 47.5). The CFS score was significantly correlated with the free T3 level (Pearson’s r = −0.123, 95% CI: −0.234, −0.008). Multiple regression analysis revealed that the free T3 level and having a job were significant predictors of the CFS score, with unstandardized regression coefficients of −2.52 (95% CI: −4.94, −0.09) and 2.85 (95% CI: 0.49, 5.20), respectively. The median Z-scores were negative for General Health (−0.28) and Vitality (−0.15) subscales of the SF-36. The CFS score was a significant predictor of summary scores of the SF-36. The free T3 level was significantly associated with the physical component summary score with an unstandardized coefficient of 3.20 (95% CI: 0.77, 5.63).
Fatigue was prevalent and associated with poor quality of life among PTC survivors. Thyroid functional status, particularly the level of free T3, may be worth to be considered in alleviating the burden.
Michelle J Galvan, Michael J Sanchez, Andrew J McAinch, Jeffrey D Covington, Jason B Boyle, and Sudip Bajpeyi
Most US adults (54%) do not meet the minimum exercise recommendations by the American College of Sports Medicine. Neuromuscular electrical stimulation (NMES) is a novel alternate strategy to induce muscle contraction. However, the effectiveness of NMES to improve insulin sensitivity and energy expenditure is unclear. The purpose of this study was to investigate the effects of 4 weeks of NMES on glucose tolerance in a sedentary overweight or obese population.
Participants (n = 10; age: 36.8 ± 3.8 years; BMI = 32 ± 1.3 kg/m2) were randomized into either control or NMES group. All participants received bilateral quadriceps stimulation (12 sessions; 30 min/session; three times/week at 50 Hz and 300 µs pulse width) altering pulse amplitude to either provide low-intensity sensory level (control; tingling sensation) or at high-intensity neuromuscular level (NMES; maximum tolerable levels with visible muscle contraction). Glucose tolerance was assessed by a 3-h oral glucose tolerance test (OGTT), and substrate utilization was measured by indirect calorimetry and body composition via dual X-ray absorptiometry at baseline and after 4 weeks of NMES intervention.
Control and NMES groups had comparable fasting blood glucose, glucose tolerance, substrate utilization, and muscle mass at baseline. Four weeks of NMES resulted in a significant improvement in glucose tolerance measured by OGTT, whereas no change was observed in the control group. There was no change in substrate utilization and muscle mass in both control and NMES groups.
NMES is a novel and effective strategy to improve glucose tolerance in an at-risk overweight or obese sedentary population.
Lizhi Zhang, Jinwei He, Xiang Sun, Dongyue Pang, Jingjing Hu, and Bo Feng
We demonstrated previously that there is a correlation between glucagon-like peptide-1 (GLP-1) single-nucleotide polymorphism (SNP) and bone mineral density in postmenopausal women. Both GLP-1 and glucose-dependent insulinotropic peptide are incretins. The glucose-dependent insulinotropic peptide receptor (GIPR) SNP rs10423928 has been extensively studied. However, it is not clear whether GIPR gene mutations affect bone metabolism. The aim of this study was to investigate the association between rs10423928 and bone mineral density in postmenopausal women in Shanghai. rs10423928 was detected in 884 postmenopausal women in Shanghai, and the correlation between the GIPR SNP and bone mineral density was assessed. The dominant T/T genotype of rs10423928 was found to be related to the bone mineral density of the femoral neck (P = 0.035). Overall, our findings indicate that the dominant T/T genotype of rs10423928 in postmenopausal women is significantly associated with a higher bone mineral density and that the T/T genotype exerts a bone-protective effect.
Qian Wang, Jiacheng Wang, Yunhui Xin, Ziyang He, Xiang Zhou, Xing Liu, Teng Zhao, Lihan He, Hong Shen, Mulan Jin, and Bojun Wei
Parathyroid carcinoma (PC), often misdiagnosed as a 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.
First, the differentially expressed 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. Secondly, the receiver operating characteristic 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. Thirdly, RNF138mRNA, 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.
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.
The novel circular RNA hsa_circ_0005729 was found to have a higher expression in patients with PC, indicating its usefulness for distinguishing PC from PA.
Hanna Karhapää, Siru Mäkelä, Hanna Laurén, Marjut Jaakkola, Camilla Schalin-Jäntti, and Micaela Hernberg
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.
A retrospective single-institution study.
We included 140 consecutive metastatic melanoma patients treated with ICI between January 2012 and May 2019. We assessed the endocrine toxicity and the best possible treatment outcomes from electronic patient records, including laboratory parameters and radiological images.
Of the treated patients, 21 patients (15%) were treated with ipilimumab, 46 (33%) with nivolumab, 67 (48%) with pembrolizumab, and 6 (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.
The higher number of endocrine AEs suggest that regular laboratory monitoring aids in AE detection. Endocrine AEs in metastatic melanoma may correlate with better treatment outcomes.
Chengnan Guo, Yixi Xu, Yange Ma, Xin Xu, Fang Peng, Hui-hui Li, Dongzhen Jin, Shu-zhen Zhao, Zhezheng Xia, Mengyuan Lai, Mingzhu Che, Ruogu Huang, Yanan Wang, Depeng Jiang, Chao Zheng, and Guangyun Mao
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% 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 second, third and fourth 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). An apparent super-multiplicative effect of trehalose and glutamate on DR was observed, whereas relative excess risk due to interaction 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.
Sandeep Kumar Parvathareddy, Abdul K Siraj, Zeeshan Qadri, Saeeda O Ahmed, Felisa DeVera, Saif Al-Sobhi, Fouad Al-Dayel, and Khawla S Al-Kuraya
Recently, lymph node ratio (LNR) has emerged as an alternative to American Joint Committee on Cancer (AJCC) N stage, with superior prognostic value. The utility of LNR in Middle Eastern papillary thyroid carcinoma (PTC) remains unknown. Therefore, we retrospectively analyzed a large cohort of 1407 PTC patients for clinicopathological associations of LNR.
Receiver operating characteristics (ROC) curve was used to determine the cut-off for LNR. We also performed multivariate logistic regression analysis to determine whether LNR or AJCC N stage was superior in predicting recurrence in PTC.
Based on ROC curve analysis, a cut-off of 0.15 was chosen for LNR. High LNR was significantly associated with adverse clinicopathological characteristics such as male sex, extrathyroidal extension, lymphovascular invasion, multifocality, bilateral tumors, T4 tumors, lateral lymph node (N1b) involvement, distant metastasis, advanced tumor stage, American Thyroid Association (ATA) high-risk category and tumor recurrence. On multivariate analysis, we found that LNR was a better predictor of tumor recurrence than AJCC N stage (odds ratio: 1.96 vs 1.30; P value: 0.0184 vs 0.3831). We also found that LNR combined with TNM stage and ATA risk category improved the prediction of recurrence-free survival, compared to TNM stage or ATA risk category alone.
The present study suggests LNR is an independent predictor of recurrence in Middle Eastern PTC. Integration of LNR with 8th edition AJCC TNM staging system and ATA risk stratification will improve the accuracy to predict recurrence in Middle Eastern PTC and help in tailoring treatment and surveillance strategies in these patients.