Glucagon-Like Peptide-1 Receptor Agonists and Thyroid Cancer: A Narrative Review.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are highly effective medications for the treatment of type 2 diabetes and obesity. Pharmacological studies in rodents support an association between the use of GLP-1 RAs and the development of medullary thyroid cancer (MTC) resulting in a black box warning for these agents in patients at risk for this condition. Yet, the association between GLP-1 RAs and non-MTC remains controversial. Excessive worry about unproven thyroid cancer risk might lead to underutilizing GLP-1 RAs in patients who could otherwise experience substantial benefits. Unwarranted concerns about thyroid cancer could lead to unnecessary thyroid cancer screening and harms from overdiagnosis. Summary: The body of evidence assessing the association between GLP-1 RA use and thyroid cancer spans a wide range of methodologies, including basic and translational research investigating biological plausibility; randomized trials assessing clinical efficacy and providing the strongest evidence for causality; observational studies providing real-life outcome evaluation in larger populations but with limited evaluation of covariates or dependable outcome definitions; and pharmacovigilance studies that provide postmarketing assessments of a safety signal but do not address causality. There is biological plausibility supporting an association between GLP-1 RA and MTC in rodents, which is less clear for non-MTC in humans. Clinical evidence from randomized trials and associated meta-analysis suggest thyroid cancer as a rare event making effect estimates imprecise but without conclusive and consistent evidence of increase risk in those receiving GLP-1 RA. Observational studies at higher risk of bias also show low event rates for thyroid cancer, with effect estimates that are inconsistent among different studies. Pharmacovigilance studies consistently show a signal of increased reporting of thyroid cancer in patients treated with GLP-1 RA. Conclusions: Evidence from randomized controlled trials indicates occurrence of thyroid cancer is infrequent in individuals exposed to GLP-1 RA. Observational studies at higher risk of bias yield inconsistent results. Overall there is no conclusive evidence of elevated thyroid cancer risk. These findings can help clinicians when addressing patient's concerns about a potential yet unproven link between GLP-1 RA therapy and thyroid cancer.

IMAGE-GUIDED THERMAL ABLATION OF ADRENAL METASTASES: HEMODYNAMIC AND ENDOCRINE OUTCOMES.

OBJECTIVE: Image-guided thermal ablation of adrenal metastases has been increasingly used for local tumor control. This procedure has been associated with hypertensive urgency; however, endocrine complications have not been clearly described. Our objective was to assess the hemodynamic behavior and risk for adrenal insufficiency related to adrenal ablation. Additionally, we sought to understand the utility of preprocedural α-blockade to prevent periprocedural hemodynamic complications. METHODS: This was a retrospective study of patients undergoing image-guided ablation of adrenal metastases between 2003 and 2015 at our institution. We reviewed electronic medical records to obtain clinical information, including α-blockade preparation, periprocedural hemodynamic parameters, interventions, and postablation adrenal function. RESULTS: Thermal ablation was performed in 58 patients (46 men [79%]; median age, 66 years) with 60 adrenal metastases ablated in 62 sessions. Alpha-blockade was used pre-ablation in 49 (79%) sessions; it was associated with less hypertensive urgency (23 [47%] for α-blockade vs. 10 [77%] for no α-blockade; P = .048) but higher need for vasopressors (22 [45%] for α-blockade vs. 1 [8%] for no α-blockade; P = .02) during ablation. Adrenal insufficiency occurred in 13 (22%) patients, of whom 10 had history of contralateral adrenalectomy or metastases, and only 3 of 13 had a normal-appearing contralateral adrenal gland. CONCLUSION: Hemodynamic changes during ablation of adrenal metastases are common. Pre-ablation α-blockade decreases the severity of the hypertensive episode, at the expense of higher need for vasopressors periprocedurally. Adrenal function should be assessed after adrenal metastasis ablation, as adrenal insufficiency may occur after such treatment. ABBREVIATIONS: ACTH = adrenocorticotropic hormone BP = blood pressure CT = computed tomography DBP = diastolic blood pressure HR = heart rate IQR = interquartile range IV = intravenous MAP = mean arterial pressure MWA = microwave ablation RFA = radiofrequency ablation SBP = systolic blood pressure.

Effects of increasing levothyroxine on pregnancy outcomes in women with uncontrolled hypothyroidism.

OBJECTIVE: Uncontrolled hypothyroidism has been associated with an increased risk of adverse pregnancy outcomes. We aimed to assess the effectiveness of increasing levothyroxine (LT4) dose on reducing the risk of adverse outcomes for pregnant women with TSH level greater than the recommended 1st trimester limit. DESIGN, PATIENTS, MEASUREMENTS: We reviewed the electronic medical records of pregnant women evaluated from January 2011 to December 2013, who had history of LT4-treated hypothyroidism and were found to have TSH > 2·5 mIU/l in 1st trimester. Women were divided into two groups: group A - LT4 dose was increased within two weeks from the TSH test, group B - LT4 dose remained stable. We compared the frequency of pregnancy loss (primary outcome) and other prespecified pregnancy-related adverse outcomes between groups. RESULTS: There were 85 women in group A (median TSH: 5·0, interquartile range 3·8-6·8 mIU/l) and 11 women in group B (median TSH: 4·5, interquartile range 3·2-4·9 mIU/l). The groups were not different in baseline clinical and socioeconomic characteristics. The mean interval between TSH test and LT4 dose increase was 4·5 (SD 4·6) days. Pregnancy loss was significantly lower in group A (2/85, 2·4%) vs group B (4/11, 36·4%) (P = 0·001). Other pregnancy-related adverse outcomes were similar between groups. CONCLUSIONS: Increasing LT4 dose for women with uncontrolled hypothyroidism in the 1st trimester of pregnancy was associated with a decreased risk of pregnancy loss. Given the limitations of our study, this association awaits further confirmation from larger studies.

Risk of Malignancy in Thyroid Nodules with Non-Diagnostic Fine-Needle Aspiration: A Retrospective Cohort Study.

BACKGROUND: Fine-needle aspiration (FNA) of thyroid nodules is commonly performed, and despite the use of ultrasound (US) guidance, the rate of non-diagnostic FNAs is still significant. The risk of malignancy of thyroid nodules with a non-diagnostic FNA is not clearly defined. However, most studies exclude the majority of patients without a repeat biopsy or surgery, thus increasing the likelihood of selection bias. The aims of this study were to determine the malignancy risk in nodules with an initial non-diagnostic FNA, and to identify the factors associated with malignancy. METHODS: This was a retrospective cohort study of patients with thyroid nodules who underwent US-guided FNA between 2004 and 2010 and had a non-diagnostic result. Patients were followed until confirmatory diagnosis of the nature of the nodule was made. The outcome of malignant or benign disease was based on one of the following: (i) final surgical pathology following thyroidectomy; (ii) repeat biopsy; (iii) clinically, based on repeat ultrasound performed at least three years following biopsy; or (iv) report of thyroid status for patients without follow-up visits contacted by mail. RESULTS: There were 699 nodules from 665 patients included. The mean age was 59 ± 15 years, and 71.7% were women. There was complete follow-up of 495 nodules. After a median follow-up of 2.7 years, thyroid cancer was found in 15 nodules. The prevalence of malignancy was 3% (15/495). The presence of nodular calcifications was the strongest predictor of thyroid malignancy (odds ratio 5.03 [confidence interval 1.8-14.7]). Initial nodule size was inversely associated with malignancy (odds ratio 0.55 [confidence interval 0.28-0.93]). However, the 193 patients without follow-up had smaller nodules compared with those included in the analysis. None of the patients with repeatedly non-diagnostic results were diagnosed with thyroid cancer at follow-up. CONCLUSION: The prevalence of thyroid cancer in nodules with non-diagnostic results is lower than the malignancy rate in thyroid nodules in general, but not negligible. They should be followed as per guidelines with heightened suspicion for nodules containing calcifications. Nodules with repeatedly non-diagnostic FNA results especially in the absence of calcifications have a low risk of malignancy and may be observed.

Physical exam in asymptomatic people drivers the detection of thyroid nodules undergoing ultrasound guided fine needle aspiration biopsy.

Understanding epidemiology and the factors leading to thyroid nodule diagnosis might help alter the course of the thyroid cancer epidemic. Population-based study using the Rochester Epidemiology Project database between 2003 and 2006. Patients with thyroid nodules who underwent ultrasound guided fine needle aspiration biopsy were included. We identified 453 patients with 520 thyroid nodules undergoing ultrasound guided fine needle aspiration. Patients were mostly women (n: 349, 77 %) with a mean age of 52 (standard deviation 17) years. The age-adjusted and sex-adjusted incidence of ultrasound guided fine needle aspiration-thyroid nodules between 2003 and 2006 was 89 (95 % confidence interval, 80-97) per 100,000 person-years; the incidence in women was 130 (95 % confidence interval, 117-144), and for men 43 (95 % confidence interval, 35-52) per 100,000 person-years. The incidence of ultrasound guided fine needle aspiration-thyroid nodules increased by 42 %, from 68 (95 % confidence interval, 54-82) in 2003 to 97 (95 % confidence interval, 80-113) per 100,000 person-years in 2006. The group with the highest incidence was patients between 70 and 79 years of age, 258 per 100,000 person-years. Most ultrasound guided fine needle aspiration-thyroid nodules were found in asymptomatic patients (n: 371, 82 %) by physical examination (n: 197, 43 %) or on imaging studies performed for non-thyroid issues (n: 108, 24 %). Women were more likely to have nodules detected by palpation (45 %), whereas imaging and physical examination contributed similarly in men (39 and 38 %). There is a large and rapid increase in the ultrasound guided fine needle aspiration-thyroid nodules, particularly among women and elderly patients which mirrors the trends observed in thyroid cancer. Most thyroid nodules were found in asymptomatic patients as a result of routine physical examination or imaging.

Diagnostic accuracy of ultrasound-guided fine needle aspiration biopsy for thyroid malignancy: systematic review and meta-analysis.

PURPOSE: To systematically appraise and summarize the available evidence about the diagnostic accuracy of ultrasound-guided fine needle aspiration biopsy (USFNA) for thyroid malignancy, and to explore the integration of these estimates with the probability of thyroid malignancy before USFNA. METHODS: A comprehensive search of multiple databases from each database's inception to August 2014 was performed. Eligible studies included those that evaluated patients with thyroid nodules who underwent USFNA and subsequent evaluation by histopathology or long-term follow-up. RESULTS: We identified 32 studies at moderate risk of bias evaluating the USFNA diagnostic characteristics for the diagnosis of thyroid malignancy. Results were imprecise and inconsistent across trials. The pooled likelihood ratio (LR) of thyroid malignancy for a benign USFNA result was 0.09 (95 % CI 0.06, 0.14; I (2) = 33 %), whereas the pooled LR for a malignant result was 197 (95 % CI, 68, 569; I (2) = 77 %). In the case of a suspicious for follicular neoplasm result, the pooled LR for malignancy was 0.6 (95 % CI, 0.4, 1.0; I (2) = 84 %) and 8.3 (95 % CI, 3.6, 19.2; I (2) = 89) for a result of suspicious for malignancy. CONCLUSION: The available evidence regarding the diagnostic accuracy of USFNA warrants only limited confidence due to risk of bias, imprecision, and inconsistency. However, some USFNA results (benign, malignant) are likely very helpful, by significantly changing the pre-test probability of thyroid cancer.

Effects of Levothyroxine Therapy on Pregnancy Outcomes in Women with Subclinical Hypothyroidism.

BACKGROUND: Subclinical hypothyroidism (SCH) has been associated with increased risk of adverse pregnancy outcomes in some, but not all, studies. Uncertainty remains regarding the impact of levothyroxine (LT4) therapy on improving health outcomes in pregnant women with SCH. The objective of this study was to assess the potential benefits of LT4 therapy in pregnant women with SCH. METHODS: The medical records were reviewed of pregnant women with SCH, defined as an elevated serum thyrotropin (TSH) of >2.5 mIU/L for the 1st trimester or >3 mIU/L for the 2nd and 3rd trimesters, but ≤10 mIU/L. Pregnant women were divided into two groups depending on whether they received LT4 (group A) or not (group B). Pregnancy loss and other pre-specified adverse outcomes were evaluated during follow-up. RESULTS: There were 82 women in group A and 284 in group B. Group A had a higher body mass index (p = 0.04) and a higher serum TSH level (p < 0.0001) compared with group B. Group A had fewer pregnancies lost (n = 5 [6.1%] vs. n = 25 [8.8%]; p = 0.12), low birth weight (LBW) offspring (1.3% vs. 10%; p < 0.001), and no neonates with a five-minute Apgar score ≤7 (0% vs. 7%; p < 0.001) compared with group B. Other pregnancy-related adverse outcomes were similar between the two groups. Inferences remained unchanged after considering different models to adjust for potential predictors of outcome. CONCLUSIONS: LT4 therapy is associated with a decreased risk of LBW and a low Apgar score among women with SCH. This association awaits confirmation in randomized trials before the widespread use of LT4 therapy in pregnant women with SCH.

Outcomes of Parathyroidectomy in Patients with Primary Hyperparathyroidism: A Systematic Review and Meta-analysis.

BACKGROUND: Parathyroidectomy is a definitive treatment for primary hyperparathyroidism. Patients contemplating this intervention will benefit from knowledge regarding the expected outcomes and potential risks of the currently available surgical options. PURPOSE: To appraise and summarize the available evidence regarding benefits and harms of minimally invasive parathyroidectomy (MIP) and bilateral neck exploration (BNE). DATA SOURCES: A comprehensive search of multiple databases (MEDLINE, EMBASE, and Scopus) from each database's inception to September 2014 was performed. STUDY SELECTION: Eligible studies evaluated patients with primary hyperparathyroidism undergoing MIP or BNE. DATA EXTRACTION: Reviewers working independently and in duplicate extracted data and assessed the risk of bias. DATA SYNTHESIS: We identified 82 observational studies and 6 randomized trials at moderate risk of bias. Most of them reported outcomes after MIP (n = 71). Using random-effects models to pool results across studies, the cure rate was 98 % (95 % CI 97-98 %, I (2) = 10 %) with BNE and 97 % (95 % CI 96-98 %, I (2) = 86 %) with MIP. Hypocalcemia occurred in 14 % (95 % CI 10-17 % I (2) = 93 %) of the BNE cases and in 2.3 % (95 % CI 1.6-3.1 %, I (2) = 87 %) with MIP (P < 0.001). There was a statistically significant lower risk of laryngeal nerve injury with MIP (0.3 %) than with BNE (0.9 %), but similar risk of infection (0.5 vs. 0.5 %) and mortality (0.1 vs. 0.5 %). LIMITATIONS: The available evidence, mostly observational, is at moderate risk of bias, and limited by indirect comparisons and inconsistency for some outcomes (cure rate, hypocalcemia). CONCLUSION: MIP and BNE are both effective surgical techniques for the treatment of primary hyperparathyroidism. The safety profile of MIP appears superior to BNE (lower rate of hypocalcemia and recurrent laryngeal nerve injury).

Subclinical Hypothyroidism in Pregnancy: A Systematic Review and Meta-Analysis.

BACKGROUND: The impact of subclinical hypothyroidism (SCH) and of levothyroxine replacement in pregnant women with SCH is unclear. The aims of this study were to assess (i) the impact of SCH during pregnancy on maternal and neonatal outcomes, and (ii) the effect of levothyroxine replacement therapy in these patients. METHODS: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, the Cochrane Controlled Trials Register, Ovid EMBASE, Web of Science, and Scopus were searched from inception to January 2015. Randomized trials and cohort studies of pregnant women with SCH that examined adverse pregnancy and neonatal outcomes were included. Reviewers extracted data and assessed methodological quality in duplicate. Eighteen cohort studies at low-to-moderate risk of bias were included. Compared with euthyroid pregnant women, pregnant women with SCH were at higher risk for pregnancy loss (relative risk [RR] 2.01 [confidence interval (CI) 1.66-2.44]), placental abruption (RR 2.14 [CI 1.23-3.70]), premature rupture of membranes (RR 1.43 [CI 1.04-1.95]), and neonatal death (RR 2.58 [CI 1.41-4.73]). One study at high risk of bias compared pregnant women with SCH who received levothyroxine to those who did not and found no significant decrease in the rate of pregnancy loss, preterm delivery, gestational hypertension, low birth weight, or low Apgar score. CONCLUSIONS: SCH during pregnancy is associated with multiple adverse maternal and neonatal outcomes. The value of levothyroxine therapy in preventing these adverse outcomes remains uncertain.

Effect of Dehydroepiandrosterone and Testosterone Supplementation on Systemic Lipolysis.

CONTEXT: Dehydroepiandrosterone (DHEA) and T hormones are advertised as antiaging, antiobesity products. However, the evidence that these hormones have beneficial effects on adipose tissue metabolism is limited. OBJECTIVE: The objective of the study was to determine the effect of DHEA and T supplementation on systemic lipolysis during a mixed-meal tolerance test (MMTT) and an iv glucose tolerance test (IVGTT). DESIGN: This was a 2-year randomized, double-blind, placebo-controlled trial. SETTING: The study was conducted at a general clinical research center. PARTICIPANTS: Sixty elderly women with low DHEA concentrations and 92 elderly men with low DHEA and bioavailable T concentrations participated in the study. INTERVENTIONS: Elderly women received 50 mg DHEA (n = 30) or placebo (n = 30). Elderly men received 75 mg DHEA (n = 30), 5 mg T (n = 30), or placebo (n = 32). MAIN OUTCOME MEASURES: In vivo measures of systemic lipolysis (palmitate rate of appearance) during a MMTT or IVGTT. RESULTS: At baseline there was no difference in insulin suppression of lipolysis measured during MMTT and IVGTT between the treatment groups and placebo. For both sexes, a univariate analysis showed no difference in changes in systemic lipolysis during the MMTT or IVGTT in the DHEA group and T group when compared with placebo. There was no change in the results after adjusting for the resting energy expenditure, except for a small, but significant (P = .03) lowering of MMTT nadir palmitate rate of appearance in women who received DHEA. CONCLUSION: In elderly individuals with concentrations of DHEA (men and women) or T (men) below the normal range for young adults, supplementation of these hormones has no effect on insulin suppression of systemic lipolysis.