Subacute thyroiditis after the third dose of the COVID-19 mRNA vaccine. Case report.

Subacute thyroiditis (SAT) is a thyroid inflammatory disease, whose pathogenesis is still unclear. We report a 52-year-old female with SAT after the third dose of COVID-19 mRNA vaccine BNT162b2 (Pfizer-BioNTech). This case was documented with laboratory tests and ultrasound examination. She needed therapy during the acute phase and subsequently thyroxine supplementation.

Thyroid Nodules and Obesity.

A widely discussed topic in the pathophysiology of thyroid nodules is the role of obesity, a state that leads to increased systemic inflammatory markers. Leptin plays a vital role in forming thyroid nodules and cancer through several mechanisms. Together with chronic inflammation, there is an augmentation in the secretion of tumor necrosis factor (TNF) and the cytokine interleukin 6 (IL-6), which contributed to cancer development, progression and metastasis. In addition, leptin exerts a modulatory action in the growth, proliferation and invasion of thyroid carcinoma cell lines via activating various signal pathways, such as Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase (MAPK) and/or phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt). Through several proposed mechanisms, aberrant endogenous estrogen levels have been suggested to play a vital role in the development of both benign and malignant nodules. Metabolic syndrome triggers the development of thyroid nodules by stimulating thyroid proliferation and angiogenesis due to hyperinsulinemia, hyperglycemia and dyslipidemia. Insulin resistance influences the distribution and structure of the thyroid blood vessels. Insulin growth factor 1 (IGF-1) and insulin affect the regulation of the expression of thyroid genes and the proliferation and differentiation of thyroid cells. TSH can promote the differentiation of pre-adipocytes to mature adipocytes but also, in the presence of insulin, TSH possesses mitogenic properties. This review aims to summarize the underlying mechanisms explaining the role of obesity in the pathophysiology of thyroid nodules and discuss potential clinical implications.

Association Between Aggressive Clinicopathologic Features of Papillary Thyroid Carcinoma and Body Mass Index: A Systematic Review and Meta-Analysis.

Background: The association between adiposity and papillary thyroid carcinoma (PTC) has been reported in several studies, but its association with aggressive clinicopathologic features is not well-recognized. Our aim is to systematically review the literature to identify whether adiposity, expressed through Body Mass Index (BMI), is related to aggressive clinicopathologic features such as tumor-node-metastasis (TNM) stage, extrathyroidal extension (ETE), lymph node (LN) metastasis and multifocality in patients with PTC. Methods: A systematic search for articles was performed using the PubMed, EBSCO, and Cochrane Library for all articles published in English until December 2020. Specific keywords such as "papillary thyroid carcinoma", "Body Mass Index", "clinicopathologic features" were used in the search strategy. Two independent reviewers screened all retrieved articles based on predefined inclusion and exclusion criteria. Meta-analysis was performed in the studies that reported crude and adjusted odds ratios (OR). The methodological quality was assessed using the Newcastle-Ottawa Scale. Results: A total of 11 retrospective cohort studies involving 26,196 participants included. Our findings showed that elevated BMI was significantly associated with ETE in both overweight (OR 1.26, 95% CI: 1.09-1.44) and obesity group (OR 1.45, 95% CI:1.26-1.64). Elevated BMI was also significantly associated with multifocality in overweight patients (OR 1.17, 95% CI:1.10-1.24) and obese patients (OR 1.45, 95% CI:1.29-1.62). Also, obesity was significantly associated with increased tumor size (OR 1.77, 95% CI:1.52-2.03) and with LN metastasis (OR 1.28, 95% CI: 1.12-1.44), whereas being overweight was significantly associated with advanced TNM stage (OR 1.55, 95% CI:1.27-1.83). Conclusion: Our results provide strong evidence for the association between higher BMI and ETE, multifocality, and tumor size. Further studies with a larger number of participants are required to elucidate further the association of increased BMI with advanced TNM stage and LN metastasis.

Prevalence of thyroid carcinoma in nodules with thy 3 cytology: the role of preoperative ultrasonography and strain elastography.

BACKGROUND: Fine needle aspiration (FNA) cytology, the gold standard in assessing thyroid nodules, is limited by its inability to determine the true risk of malignancy in Thy 3 nodules. Most patients with Thy3 cytology undergo surgery to establish a histologic diagnosis. The aims of this study were to evaluate the prevalence of malignancy in Thy3 nodules, to examine the ultrasound (US) characteristics that are associated with a high cancer risk and to assess the role of real-time strain elastography. METHODS: Retrospective cohort study of 99 nodules with Thy3 cytology in 99 patients who underwent thyroidectomy over a three-year period. Grayscale US, Doppler and real-time strain elastography data were evaluated. RESULTS: Eighty-one nodules (81.82%) were benign, 18 (18.18%) were malignant, and almost all were papillary thyroid carcinoma (PTC). Univariable analysis revealed irregular margins (p = 0.02), ill-defined borders (p ≤ 0.001), a taller than wide shape (p ≤ 0.001) and the elasticity score (p = 0.02) as significant predictors of malignancy. Multivariable analysis showed that ill-defined borders and the elasticity score were significant and independent factors associated with malignancy. All soft nodules (elasticity scores 1-2) were benign (sensitivity 100%, specificity 33%, NPV 100%, and PPV 23%). There was a higher rate of malignancy in Thy3a nodules than in Thy3f nodules (42.86% versus 11.54%) (p ≤ 0.001). CONCLUSIONS: Irregular margins, ill-defined borders, a taller than wide shape and low elasticity were associated with malignancy. Elastography should be performed when evaluating Thy3 nodules.

Lymph Node Metastasis and Extrathyroidal Extension in Papillary Thyroid Microcarcinoma in Cyprus: Suspicious Subcentimeter Nodules Should Undergo FNA When Multifocality is Suspected.

OBJECTIVE: To determine the prevalence of lymph node (LN) metastasis and extrathyroidal extension (ETE) in patients with papillary thyroid microcarcinoma (PTMC) in Cyprus and to evaluate the role of preoperative ultrasound (U/S) examination. METHODS: A retrospective study of 102 patients who underwent thyroidectomy for PTMC in a 2-year period. Preoperatively, all patients had a thyroid and neck U/S examination with LN mapping. Tumor size according to the largest diameter, number of foci, LN metastasis, and ETE data was collected from the histopathological report and was compared to the preoperative U/S reports. RESULTS: LN metastasis was present in 23.5% of patients. 15.7% had central, 3.9% had lateral, and 3.9% had both central and lateral LN metastasis. ETE was present in 27.5% of patients. 21.6% had multifocal disease, and in this group, 40.9% had LN metastasis and 36.4% had ETE. Multifocality (p = 0.03), size of tumor (p = 0.05), and ETE (p ≤ 0.001) were significantly associated with LN metastasis. The prevalence of LN metastasis in multifocal PTMC ≤5 mm was the same with multifocal PTMC >5 mm. The preoperative U/S sensitivity for the suspicious lateral neck and central LN was 100%, and the specificity was 100%. The preoperative U/S sensitivity for nodules suspicious for ETE was 53.6%, and the specificity was 100%. CONCLUSION: The presence of LN metastasis and ETE in our PTMC patients in Cyprus is frequent. Neck U/S mapping is a highly reliable and accurate tool in identifying metastatic nodes. LN metastasis is associated with ETE and multifocality. Suspicious subcentimeter nodules should undergo FNA irrespective of size when multifocality is suspected.

Diabetes enhances vulnerability to particulate air pollution-associated impairment in vascular reactivity and endothelial function.

BACKGROUND: Epidemiological studies suggest that people with diabetes are vulnerable to cardiovascular health effects associated with exposure to particle air pollution. Endothelial and vascular function is impaired in diabetes and may be related to increased cardiovascular risk. We examined whether endothelium-dependent and -independent vascular reactivity was associated with particle exposure in individuals with and without diabetes. METHODS AND RESULTS: Study subjects were 270 greater-Boston residents. We measured 24-hour average ambient levels of air pollution (fine particles [PM2.5], particle number, black carbon, and sulfates [SO4(2-)]) approximately 500 m from the patient examination site. Pollutant concentrations were evaluated for associations with vascular reactivity. Linear regressions were fit to the percent change in brachial artery diameter (flow mediated and nitroglycerin mediated), with the particulate pollutant index, apparent temperature, season, age, race, sex, smoking history, and body mass index as predictors. Models were fit to all subjects and then stratified by diagnosed diabetes versus at risk for diabetes. Six-day moving averages of all 4 particle metrics were associated with decreased vascular reactivity among patients with diabetes but not those at risk. Interquartile range increases in SO4(2-) were associated with decreased flow-mediated (-10.7%; 95% CI, -17.3 to -3.5) and nitroglycerin-mediated (-5.4%; 95% CI, -10.5 to -0.1) vascular reactivity among those with diabetes. Black carbon increases were associated with decreased flow-mediated vascular reactivity (-12.6%; 95% CI, -21.7 to -2.4), and PM2.5 was associated with nitroglycerin-mediated reactivity (-7.6%; 95% CI, -12.8 to -2.1). Effects were stronger in type II than type I diabetes. CONCLUSIONS: Diabetes confers vulnerability to particles associated with coal-burning power plants and traffic.

The effect of vitamin E on endothelial function of micro- and macrocirculation and left ventricular function in type 1 and type 2 diabetic patients.

We examined the effects of high-dosage vitamin E treatment over a 12-month period on the vascular reactivity of micro- and macrocirculation and left ventricular function in diabetic patients. Subjects (n = 89) were randomized to vitamin E (1,800 IU daily) or placebo and were followed for 12 months. High-resolution ultrasound images were used to measure the flow-mediated dilation (FMD; endothelium dependent) and nitroglycerin-induced dilation (NID; endothelium independent) of the brachial artery. Laser Doppler perfusion imaging was used to measure vascular reactivity in the forearm skin. Left ventricular function was evaluated using transthoracic echocardiogram. At the end of the 6-month period, a worsening in endothelium-dependent skin vasodilation (P = 0.02) and rise in endothelin levels (P = 0.01) were found in the vitamin E compared with the placebo group. At the end of the 12-month period, a worsening was observed in NID (P = 0.02) and a marginal worsening was seen in systolic blood pressure (P = 0.04) and FMD (P = 0.04) in the vitamin E compared with the placebo group. In addition C-reactive protein levels decreased marginally in the vitamin E compared with the placebo group (P = 0.05). No changes were observed in left ventricular function. We concluded that long-term treatment with 1,800 IU of vitamin E has no beneficial effects on endothelial or left ventricular function in diabetic patients. Because vitamin E-treated patients had a worsening in some vascular reactivity measurements when compared with control subjects, the use of high dosages of vitamin E cannot be recommended.

Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes.

OBJECTIVE: Adiponectin and resistin, two recently discovered adipocyte-secreted hormones, may link obesity with insulin resistance and/or metabolic and cardiovascular risk factors. We performed a cross-sectional study to investigate the association of adiponectin and resistin with inflammatory markers, hyperlipidemia, and vascular reactivity and an interventional study to investigate whether atorvastatin mediates its beneficial effects by altering adiponectin or resistin levels. RESEARCH DESIGN AND METHODS: Associations among vascular reactivity, inflammatory markers, resistin, and adiponectin were assessed cross-sectionally using fasting blood samples obtained from 77 subjects who had diabetes or were at high risk to develop diabetes. The effect of atorvastatin on adiponectin and resistin levels was investigated in a 12-week-long randomized, double-blind, placebo-controlled study. RESULTS: In the cross-sectional study, we confirm prior positive correlations of adiponectin with HDL and negative correlations with BMI, triglycerides, C-reactive protein (CRP), and plasma activator inhibitor (PAI)-1 and report a negative correlation with tissue plasminogen activator. The positive association with HDL and the negative association with PAI-1 remained significant after adjusting for sex and BMI. We also confirm prior findings of a negative correlation of resistin with HDL and report for the first time a positive correlation with CRP. All of these associations remained significant after adjusting for sex and BMI. No associations of adiponectin or resistin with any aspects of vascular reactivity were detected. In the interventional study, atorvastatin decreased lipid and CRP levels, but adiponectin and resistin were not specifically altered. CONCLUSIONS: We conclude that adiponectin is significantly associated with inflammatory markers, in part, through an underlying association with obesity, whereas resistin's associations with inflammatory markers appear to be independent of BMI. Lipid profile and inflammatory marker changes produced by atorvastatin cannot be attributed to changes of either adiponectin or resistin.

Lifestyle modification improves endothelial function in obese subjects with the insulin resistance syndrome.

OBJECTIVE: Endothelial dysfunction has been reported in type 2 diabetic patients and in obese subjects with insulin resistance syndrome (IRS). This study evaluates the effects of weight reduction and exercise on vascular reactivity of the macro- and the microcirculation in obese subjects with IRS. RESEARCH DESIGN AND METHODS; We studied 24 obese subjects (9 men and 15 women, age 49.3 +/- 1.9 years, BMI 36.7 +/- 0.94 kg/m(2), mean +/- SEM) with IRS at baseline and after 6 months of weight reduction and exercise. Brachial artery flow-mediated dilation (FMD) and response to sublingual glyceryltrinitrate (GTN) were assessed by high-resolution ultrasound. Microvascular reactivity was evaluated by the laser-Doppler perfusion imaging after iontophoresis of acetylcholine and sodium nitroprusside. We also measured plasma levels of soluble intercellular adhesion molecule (sICAM), vascular adhesion molecule, von Willebrand factor, plasminogen activator inhibitor-1 (PAI-1) antigen, and tissue plasminogen activator antigen. RESULTS: This intervention resulted in 6.6 +/- 1% reduction in body weight (P < 0.001) and significant improvement of insulin sensitivity index (2.9 +/- 0.36 vs. 1.9 +/- 0.33 [10(-4) x min(-1) x ( microU ml(-1))], P < 0.001). FMD significantly improved (12.9 +/- 1.2% vs. 7.9 +/- 1.0%, P < 0.001), whereas response to GTN and microvascular reactivity did not change. Similar observations were seen when the subjects were subclassified according to their glucose tolerance to normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes. sICAM and PAI-1 significantly decreased (251.3 +/- 7.7 vs. 265.6 +/- 9.3 ng/ml, P = 0.018 and 36.2 +/- 3.6 vs. 48.6 +/- 3.9 ng/ml, P = 0.001, respectively). The relationship between percentage weight reduction and improved FMD was linear (R(2) = 0.47, P = 0.001). CONCLUSIONS: We conclude that 6 months of weight reduction and exercise improve macrovascular endothelial function and reduces selective markers of endothelial activation and coagulation in obese subjects with IRS regardless of the degree of glucose tolerance.

Prevalence of Cancer in Patients with Thyroid Nodules in the Island of Cyprus: Predictive Value of Ultrasound Features and Thyroid Autoimmune Status.

BACKGROUND: The purpose of this study was to determine the prevalence of thyroid carcinoma in patients who underwent ultrasound-guided fine needle aspiration biopsy (USgFNA) of thyroid nodules in the island of Cyprus. Ultrasound features as well as the presence of autoimmune thyroid disease were evaluated as risk factors for malignancy. METHODS: 322 consecutively examined patients (272 females/50 males, age 13-81) underwent USgFNA of thyroid nodules in a referral endocrine clinic between July 2007 and July 2009. The ultrasonographic characteristics examined were: echogenicity, margin irregularity, composition, calcifications, presence of increased vasculature and nodule size. The presence or absence of autoimmune thyroid disease was recorded. RESULTS: From the 548 nodules examined, 74 (13.6%) were classified as THY3, 4 or 5. 75 patients (123 nodules) underwent surgical resection. 46 patients (64 nodules) proved to have thyroid carcinoma by histology. There was a significant correlation of suspicious/malignant cytology with solid composition, hypoechogenicity, irregular margins and the presence of calcifications. A significant association was also noted between the presence of positive antithyroglobulin antibodies (p < 0.05) and Graves' disease (p = 0.01) with suspicious/malignant cytology. CONCLUSION: The overall prevalence of thyroid cancer was 14.3%. Ultrasound characteristics were highly predictive of thyroid malignancy. Thyroid autoimmunity should be considered as a risk factor.

The effects of atorvastatin on endothelial function in diabetic patients and subjects at risk for type 2 diabetes.

We have investigated the effect of atorvastatin on the endothelial function of patients with diabetes and subjects at risk for type 2 diabetes in a 12-wk, prospective, randomized, placebo-controlled, double-blind clinical trial. The flow- mediated dilation (FMD; endothelium dependent) and nitroglycerin-induced dilation (endothelium independent) in the brachial artery and the vascular reactivity at the forearm skin were measured. FMD improved in the atorvastatin-treated, at-risk subjects [median (25-75 percentile), 7.2% (2.9-9.6%) at exit visit vs. 6.6% (2.9-9.5%) at baseline; P < 0.05]. A similar improvement of FMD was found in atorvastatin-treated diabetic patients [median (25-75 percentile), 5.6 (3.9-7.9) at exit visit vs. 4.2 (3.2-7.2) at baseline; P = 0.07]. No changes were observed in nitroglycerin-induced dilation and the microcirculation reactivity measurements in either group. In the at-risk group, there was a decrease in the C-reactive protein [median (25-75 percentile), 0.12 mg/dl (0.07-0.27 mg/dl) at exit visit vs. 0.24 mg/dl (0.07-0.35 mg/dl) at baseline; P < 0.05] and TNF alpha [median (25-75 percentile), 2.6 pg/ml (1.8-4.1 pg/ml) at exit visit vs. 4.4 pg/ml (3.6-6.0 pg/ml) at baseline; P < 0.05] in the atorvastatin-treated patients, whereas in the diabetes group, a decrease in endothelin-1 (mean +/- SD, 0.97 +/- 0.29 pg/ml at exit visit vs. 1.19 +/- 0.42 pg/ml at baseline; P < 0.05) and plasminogen activator inhibitor-1 [median (25-75 percentile), 18 ng/ml (9-24 ng/ml) at exit visit vs. 27 ng/ml (7-41 ng/ml) at baseline; P < 0.05] were observed. We conclude that atorvastatin improves endothelial function and decreases levels of markers of endothelial activation and inflammation.

Kidney oxygenation during water diuresis and endothelial function in patients with type 2 diabetes and subjects at risk to develop diabetes.

The aim of the present study was to examine the relationship among water diuresis-induced changes in renal oxygenation, endothelial function, and various metabolic parameters in type 2 diabetic patients and healthy subjects at risk of type 2 diabetes. Thirty-eight subjects with type 2 diabetes (D: age, 54 +/- 10 years, mean +/- SD, 24 men) and 7 healthy subjects with parental history of type 2 diabetes or with impaired glucose tolerance (IGT) (relatives [R]: age 46 +/- 11 years, 4 men) were included. Laser Doppler imaging scanning was used to measure vasodilatation in the forearm skin in response to iontophoresis of 1% acetylcholine (Ach) and 1% sodium nitroprusside (SNP), and ultrasound was used to measure the flow-mediated dilation (FMD) and nitroglycerin-induced dilation (NID) in the brachial artery. Renal oxygenation was assessed by magnetic resonance imaging (MRI) before and during water diuresis. A decrease in the magnetic parameter R2* implies an increase in oxygenation. Renal medullary oxygenation did not improve with diuresis in either group (D: -0.5 +/- 1.9, R: -0.4 +/- 2.1, P = not significant [NS]). The renal cortical oxygenation showed a small, but statistically significant, improvement after diuresis in the 2 groups (D: -0.6 +/- 1.1, R: -0.5 +/- 0.5, P <.05). There were no correlations between the change in cortical R2* (R2* post-minus R2* prewater diuresis) and the micro- and macrovascular reactivity. The postdiuresis renal cortical R2* was negatively correlated with both the Ach- and SNP-induced skin vasodilation (% change over baseline)(r = -.40, P <.01 and r = -.39, P <.05, respectively), while no correlation existed with the FMD and NID. The baseline renal cortical oxygenation was also negatively correlated with the SNP-induced skin vasodilation (r = -.36, P <.05) and positively correlated with the fasting plasma glucose, total cholesterol, and vascular cell adhesion molecule (VCAM) concentrations (r =.34, P <.05, r =.31, P <.05 and r =.37, P <.05, respectively). These preliminary findings suggest an association between the kidney cortical oxygenation and the skin microvascular reactivity, glycemia, and lipidemia. Water diuresis failed to produce an improvement in renal medullary oxygenation in both patients with diabetes and subjects at risk for diabetes.

The effect of aspirin and various iontophoresis solution vehicles on skin microvascular reactivity.

The two main objectives of this study were: (1) to examine the effect of aspirin on the endothelial function in healthy subjects and (2) to examine the effect of deionized water and 5% NaCl as iontophoresis solution vehicles. The skin microcirculation was evaluated at the forearm level of healthy subjects. A laser Doppler scanner was employed to measure vasodilation in response to the iontophoresis of 1% acetylcholine (endothelium-dependent) and 1% sodium nitroprusside (endothelium-independent). In the first experiment, nine healthy subjects were given 500 mg aspirin daily for 3 days. The microvascular reactivity was measured at the beginning and the end of the study. In the second experiment, the response to iontophoresis of acetylcholine and sodium nitroprusside as 1% solutions of deionized water was compared to the responses that were achieved after the iontophoresis of deionized water or 5% NaCl solution. After 3 days of aspirin intake, there were no changes in the vasodilatory response to acetylcholine (endothelium-dependent vasodilation) [81 +/- 11 vs 77 +/- 10 (% of increase over baseline at the beginning vs the end of the study, mean +/- SE), P = NS] or sodium nitroprusside (endothelium-independent vasodilation) (69 +/- 8 vs 64 +/- 12, P = NS). There was also a negligible response after the iontophoresis of 5% NaCl (3 +/- 4) and deionized water (6 +/- 4) in anodal mode (the mode employed for the iontophoresis of acetylcholine). In cathodal mode, employed for the iontophoresis of sodium nitroprusside, the response to 5% NaCl was still negligible but a considerable response was found after the iontophoresis of deionized water. In normal healthy subjects, aspirin administration has no effect on forearm skin microvascular reactivity, including both endothelium-dependent and endothelium-independent vasodilation. In addition, a NaCl solution would be preferable to deionized water as the iontophoresis solution vehicle.