Diagnosis and Management of Nodular Thyroid Disease.

Thyroid nodules are common and often asymptomatic. However, patients may seek treatment for nonfunctional benign nodules that cause compressive symptoms or cosmetic problems. Additionally, many patients with autonomously functioning nodules also seek treatment. As minimally invasive thermal ablation techniques become more wide spread, providers offering these treatments should be familiar with the pathophysiology of thyroid nodules, and with how to work up a patient with nodular thyroid disease.

Lipoic acid supplementation associated with neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy.

Lipoic acid (alpha lipoic acid, thioctic acid) is a popular over-the-counter antioxidant and insulin-mimetic supplement under investigation in a variety of conditions including multiple sclerosis, diabetes, and schizophrenia. Unfortunately, high-grade proteinuria was an unexpected adverse event specific to the treatment arm of our clinical trial investigating lipoic acid supplementation in patients with multiple sclerosis. This observation led to detection of similar patients in our nephrology practice. Here, we describe four biopsy-proven cases of neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy following lipoic acid supplementation and a fifth suspected case. Discontinuation of lipoic acid and supportive therapy resulted in remission.

A Survey of American Thyroid Association Members Regarding the 2015 Adult Thyroid Nodule and Differentiated Thyroid Cancer Clinical Practice Guidelines.

Background: The 2015 American Thyroid Association (ATA) clinical practice guidelines (CPGs) on management of thyroid nodules (TNs) and differentiated thyroid cancer (DTC) in adults were developed to inform clinicians, patients, researchers, and health policy makers about the best available evidence, and its limitations, relating to management of these conditions. Methods: We conducted a cross-sectional electronic survey of ATA members' perspectives of these CPGs, using a standardized survey (Clinician Guidelines Determinant Questionnaire) developed by the Guidelines International Network. A survey link was electronically mailed to members in February of 2019, with reminders sent to nonrespondents 2 and 5 weeks later. Data were descriptively summarized, after excluding missing responses. Results: The overall response rate was 19.8% (348/1761). The effective response rate was 20.2% (348/1720), after excluding a recently deceased member and individuals who had either invalid e-mail addresses or whose e-mails were returned. Of the respondents, 37.9% (132/348) were female, 60.4% (209/346) were endocrinologists, 27.5% (95/346) were surgeons, and 3.5% (12/346) were nuclear medicine specialists. The majority of respondents (71.9%; 250/348) were at a mid- or advanced-career level, and more than half were in academia (57.5%; 195/339). The majority (69.8%; 243/348) practiced in North America. The vast majority of respondents indicated that the CPGs explained the underlying evidence (92.3%; 298/323) and 92.9% (300/323) agreed or strongly agreed with the content. Most respondents stated that they regularly used the CPGs in their practice (83.0%; 268/323). Most respondents (83.0%; 268/323) also agreed or strongly agreed that the recommendations were easy to incorporate in their practice. The most popular CPG format was an electronic desktop file (78.8%; 252/320). Shorter more frequent CPGs were favored by 55.0% (176/320) of respondents, and longer traditional CPGs were favored by 39.7% (127/320). Conclusions: The clinical content and evidence explanations in the adult TN and DTC CPGs are widely accepted and applied among ATA survey respondents. Future ATA CPG updates need to be optimized to best meet users' preferences regarding format, frequency, and length.

Cognitive functioning in thyroid cancer survivors: a systematic review and meta-analysis.

BACKGROUND: Some thyroid cancer (TC) survivors experience cognitive symptoms. PURPOSE: The purpose of this study is to perform a systematic literature review and meta-analysis comparing cognitive performance in TC survivors to controls. METHODS: We performed a seven-database electronic search and hand-search. We performed duplicate independent reviews and data abstraction. Random effects meta-analyses reported standardized mean differences (SMDs) with 95% confidence intervals (CIs), where a negative value implies worse performance in the TC group. RESULTS: We reviewed 1174 unique citations and 10 full-text papers. We included seven studies of 241 treated TC survivors and 273 controls. Cognitive function was statistically significantly worse in TC survivors in the following domains: Attention and Concentration (Digit Span Forwards) SMD - 0.37 (95% CI - 0.62, - 0.13, p = 0.003, four studies), Speed of Processing (Trail Making A) SMD - 0.36 (95% CI - 0.66, - 0.05, p = 0.022, four studies), and Language (Controlled Oral Word Association [COWAT]-Categories) SMD - 0.97 (95% - 1.31, - 0.64, p < 0.001, two studies). Executive Function results varied: COWAT-Letters SMD - 0.60 (95% CI - 0.94, - 0.27, p < 0.001, two studies), Digit Span Backwards SMD - 0.40 (95% CI - 0.64, - 0.15, p = 0.002, four studies), and Trail Making B test SMD - 0.20 (95% CI - 0.51, 0.10, p = 0.191, four studies). Statistical heterogeneity limited the COWAT-Categories and Digit Span Backwards meta-analyses. CONCLUSIONS: Cognitive function was worse in TC survivors in multiple domains. Limitations included few studies, potential confounding, and lack of prospective data. IMPLICATIONS FOR CANCER SURVIVORS: TC survivors may experience impairments in cognitive function and should report cognitive concerns to healthcare practitioners.

Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline.

OBJECTIVE: To formulate clinical practice guidelines for hormonal replacement in hypopituitarism in adults. PARTICIPANTS: The participants include an Endocrine Society-appointed Task Force of six experts, a methodologist, and a medical writer. The American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology co-sponsored this guideline. EVIDENCE: The Task Force developed this evidence-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, the American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. CONCLUSIONS: Using an evidence-based approach, this guideline addresses important clinical issues regarding the evaluation and management of hypopituitarism in adults, including appropriate biochemical assessments, specific therapeutic decisions to decrease the risk of co-morbidities due to hormonal over-replacement or under-replacement, and managing hypopituitarism during pregnancy, pituitary surgery, and other types of surgeries.

2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis.

BACKGROUND: Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This document describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspecialty physicians and others providing care for patients with this condition. METHODS: The American Thyroid Association (ATA) previously cosponsored guidelines for the management of thyrotoxicosis that were published in 2011. Considerable new literature has been published since then, and the ATA felt updated evidence-based guidelines were needed. The association assembled a task force of expert clinicians who authored this report. They examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to update the 2011 text and recommendations. The strength of the recommendations and the quality of evidence supporting them were rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group. RESULTS: Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' orbitopathy; and management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011 guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves' hyperthyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded. CONCLUSIONS: One hundred twenty-four evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.

A prospective study of thyroid function, bone loss, and fractures in older men: The MrOS study.

Excess thyroid hormone is associated with increased bone loss and fracture risk in older women, but few data exist for men. We sought to determine if thyroid function is independently associated with bone loss and fracture risk in older men. Data were analyzed from the Osteoporotic Fractures in Men (MrOS) study, a cohort of community-dwelling U.S. men aged 65 years and older. Using a case-cohort design, fasting baseline serum archived at -80°C was assayed for thyroid-stimulating hormone (thyrotropin) (TSH) and free thyroxine (FT4) in 397 men with confirmed nonspine fracture, including 157 hip fractures, and 1420 randomly selected men without fracture. TSH and FT4 were analyzed as continuous variables and as thyroid function categories (subclinical hyperthyroid, euthyroid, and subclinical hypothyroid). Hip dual-energy X-ray absorptiometry (DXA) (Hologic QDR4500) was measured at baseline and after a mean follow-up of 4.6 years. Incident nonspine fractures were centrally adjudicated. Bone loss was evaluated with multivariate regression methods and fractures risk was evaluated using hazard models that accounted for the case-cohort sampling, adjusted for age, clinic-site, body mass index (BMI), race, physical activity, corticosteroid use, smoking, alcohol intake, and thyroid medication use. In fully adjusted analyses, TSH was not associated with risk of nonspine fracture (relative hazard [RH] 0.92 per SD decrease in TSH; 95% confidence interval [CI], 0.74-1.14), but was significantly associated with risk of hip fracture (RH 1.31; 95% CI, 1.01-1.71), which persisted among normal range TSH values (RH 1.21; 95% CI, 1.00-1.47). There was no association between TSH or FT4 and bone loss, and fracture risk did not differ significantly by thyroid function category. We conclude that although neither TSH nor FT4 are associated with bone loss, lower serum TSH may be associated with an increased risk of hip fractures in older men.

Subacute, silent, and postpartum thyroiditis.

Subacute, silent, and postpartum thyroiditis are temporary forms of thyroid dysfunction caused by thyroid gland inflammation. They classically present with a triphasic course: a brief period of thyrotoxicosis due to release of preformed thyroid hormone that lasts for 1 to 3 months, followed by a more prolonged hypothyroid phase lasting up to 6 months, and eventual return to a euthyroid state. However, the types and degree of thyroid dysfunction are variable in these disorders, and individual patients may present with mild or more severe cases of thyrotoxicosis alone, hypothyroidism alone, or both types of thyroid dysfunction.

Thyroid function and mortality in older men: a prospective study.

CONTEXT: Mild abnormalities of thyroid function have been associated with both beneficial and detrimental effects on mortality. OBJECTIVE: Our objective was to determine the association between continuous TSH as well as categories of thyroid function with total and cause-specific mortality in a cohort of older men. DESIGN, SETTING, AND PARTICIPANTS: Data were analyzed from the Osteoporotic Fractures in Men (MrOS) study, a cohort of community-dwelling U.S. men aged 65 yr and older. A total of 1587 participants randomly selected for thyroid function testing were included in this analysis. TSH and free T4 were measured at baseline, and four categories of thyroid function were defined. (subclinical hyperthyroid; euthyroid; subclinical hypothyroid TSH<10 mIU/liter; and subclinical hypothyroid, TSH≥10 mIU/liter.) MAIN OUTCOME MEASURE: Total mortality, cardiovascular (CV) and cancer deaths were confirmed by review of death certificates. RESULTS: There were 432 deaths over a mean follow-up of 8.3 yr. In fully adjusted models, there was no association between baseline TSH and any death [relative hazard (RH)=1.01 per mIU/liter, 95% confidence interval (CI)=0.95-1.06], CV death (RH=1.05 per mIU/liter, 95% CI 0.96-1.15), or cancer death (RH=0.96 per mIU/liter, 95% CI=0.85-1.07). There was also no statistically significant association between thyroid function category and total or cause-specific mortality, but few men (n=8) had subclinical hypothyroidism with TSH levels of 10 mIU/liter or higher. CONCLUSIONS: A single measurement of thyroid function did not predict total or cause-specific mortality in this cohort. These data support neither a beneficial nor a detrimental effect of subclinical thyroid dysfunction in older men. SUMMARY: Subclinical thyroid dysfunction is not associated with an increased risk of all-cause or CV mortality in older men.

Cognition is not modified by large but temporary changes in sex hormones in men.

CONTEXT: Little is known about the role of testosterone and estradiol on cognition in healthy older men. OBJECTIVE: The cognitive effects of increasing or lowering testosterone or estradiol were examined. DESIGN: Cognition was assessed before and after 6 wk of double-blind placebo-controlled hormone modification. SETTING: The study was conducted at an academic medical center. PARTICIPANTS: Healthy older (ages 60-80 yr) and younger men (ages 25-35 yr) were recruited from the community. INTERVENTION: Men were randomized to one of four treatments: 1) maintain testosterone and estradiol at eugonadal levels for young men (GnRH agonist + testosterone gel); 2) block testosterone's conversion to estradiol (GnRH agonist + testosterone gel + aromatase inhibitor); 3) induce hypogonadism (GnRH agonist alone); and 4) all placebo. MAIN OUTCOME MEASURES: Measures of executive function, memory, and spatial cognition were obtained before and after treatment. Hormone levels were obtained 10 times over the course of the study. RESULTS: Counter to expectations, hormone treatment did not affect cognition (P > 0.10). Free testosterone was positively related to spatial cognition in older men after treatment and controlling for age and estradiol level or exclusion of the hypogonadal men (P = 0.02). Estradiol was negatively associated with working memory controlling for the same variables (P = 0.01). Blinding to treatment assignment was maintained, with the exception of the hypogonadal group. CONCLUSIONS: A significant change in sex hormone status, including complete hypogonadism, does not modify cognition in men. These findings, along with studies that show a risk for neurodegenerative disease in those with low testosterone, suggest that sex hormone status may be important for neuroprotection in aging but not modulation of normal day-to-day cognitive function.

Estrogen, testosterone, and sequential movement in men.

Behavioral and physiological data suggest that the striatal dopaminergic system is important in the production and execution of sequential movements. Striatal function is also modulated by sex hormones, and previous studies show that estradiol is related to sequential movement in women. The authors examined whether sex hormones are involved in the production of sequential movement in healthy older and younger men. Testosterone was modified for a 6-week period such that levels in older men matched those of younger men, the conversion of testosterone to estradiol was blocked, the production of testosterone was blocked, or the men received no treatment (placebo). Sequential movement was measured before and after hormone treatment. Older men were slower and more accurate than younger men on the sequential movement task pre- and posttreatment. Hormone manipulation had no effect on movement speed. Hormone levels were not correlated with sequential movement performance in either older or younger men, suggesting that sex hormones do not modulate sequential movement in men, and hormone replacement may not restore a loss of sequential movement ability in elderly men or men with Parkinson's disease.

Utility of computed tomography in the detection of subclinical nodal disease in papillary thyroid carcinoma.

OBJECTIVE: To characterize the ability of computed tomography (CT) to identify subclinical cervical metastatic disease in papillary thyroid carcinoma (PTC). DESIGN: Retrospective review. SETTING: Tertiary academic center. PATIENTS: Consecutive patients undergoing neck dissection for PTC between July 1, 2004, and July 1, 2006. INTERVENTION: Preoperative CT scans were reevaluated in a blinded fashion by a single head and neck radiologist. Positive criteria included node with size larger than 10 mm, round shape, calcification, cystic character, or abnormal enhancement. MAIN OUTCOME MEASURE: Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated separately for central compartment (level VI) and lateral compartment (levels III and IV) dissections. RESULTS: One hundred four patients underwent selective neck dissection for PTC during the study period. Forty-three patients had disease that involved primary lymphadenectomy at the time of thyroidectomy, and 61 had persistent or recurrent disease. There were 111 lateral compartment dissections and 145 central compartment dissections. The overall sensitivity was 59% for both the central and lateral compartments, and the specificity was 76% and 71%, respectively. The PPV and NPV were 84% and 47% for the central compartment and 73% and 57% for the lateral compartment, respectively. CONCLUSIONS: Computed tomography has a limited capability to identify subclinical metastatic cervical disease in PTC, with a sensitivity near 60% and an NPV near 50%. Sole reliance on CT findings will miss a significant portion of disease likely because of the high incidence of microscopic foci. However, using strict criteria, a positive finding on a CT scan provides useful information because it predicts with a fairly high assurance that disease will in fact be found in a specific compartment during surgical dissection.

Efficacy of nodal dissection for treatment of persistent/recurrent papillary thyroid cancer.

CONTEXT: Although commonly performed, data are lacking regarding efficacy and safety of lymph node dissection (LND) for recurrent/persistent papillary thyroid cancer (PTC). OBJECTIVE: Evaluate the efficacy and morbidity of LND in recurrent/persistent PTC. DESIGN: Retrospective review of central or lateral LND performed for persistent/recurrent PTC between January 2004 and March 2006. SETTING: Multidisciplinary thyroid cancer clinic with a single surgeon at an academic medical center. PARTICIPANTS: Seventy-five patients who underwent 79 LND for persistent/residual PTC. Safety analysis included all 79 resections. Exclusion criteria for the efficacy analysis were factors prohibiting evaluation of thyroglobulin (Tg) response. Forty-one resections were included in the efficacy analysis. INTERVENTION: Selective LND per standard of care. MAIN OUTCOME MEASURE: Primary outcome was the Tg response to LND. Secondary outcomes were surgical complications. RESULTS: Thirty-nine of the 41 evaluable resections also had Tg data allowing classification of Tg response. Of 39 classifiable resections, 16 (41%) resulted in undetectable postoperative stimulated Tg levels. An additional 12 resections resulted in significant (> or =50%) reductions in suppressed or stimulated Tg levels for an overall improvement rate of 72%. Of all 79 resections, 25 (32%) resulted in minor and 7 (9%) resulted in major complications. CONCLUSIONS: LND for persistent/recurrent PTC is a relatively safe procedure in experienced hands. It can lead to an undetectable Tg in 41% of cases and produce a major Tg reduction in an additional 31%. Its efficacy in short-term follow-up is comparable with that reported for I-131, and it should be considered in the management of persistent/recurrent PTC.

Hot flashes and estrogen therapy do not influence cognition in early menopausal women.

OBJECTIVE: To examine how menopausal symptoms and estrogen therapy (ET)-induced symptom relief affect cognition in early menopause. DESIGN: There were two components. Part 1 was a cross-sectional study of 37 healthy, recently postmenopausal women with diverse menopausal symptoms. Women were categorized as having low (n=20) or high symptoms (n=17) based on a validated symptom questionnaire. Women completed mood and sleep questionnaires and underwent cognitive testing, which included verbal memory, visual memory, emotional memory, and verbal fluency. Thirty-two of these women went on to part 2 of the study. Fourteen were randomly assigned to receive ET and 18 to receive placebo for 8 weeks. Before treatment and at 4 and 8 weeks, women completed the same measures as in part 1 of the study. RESULTS: High symptom women had more negative mood (P=0.01) and lower quality sleep (P<0.001) than low symptom women. Despite suffering from more menopausal symptoms, worse mood, and poorer sleep, women in the high symptom group performed the same on cognitive testing as women in the low symptom group. Women receiving ET had greater improvements in menopausal symptoms and sleep compared with those receiving the placebo (P

Perioperative parathyroid hormone levels in thyroid surgery.

OBJECTIVE: Perioperative hypocalcemia from temporary parathyroid gland dysfunction is common after thyroid surgery. No reliable cutoff values for parathyroid hormone (PTH) and the subsequent possibility of developing hypocalcemia exist. The purpose of this study is to determine a criterion for predicting hypocalcemia based on different PTH levels as cutoff values. STUDY DESIGN: Retrospective chart review. METHODS: A centralized database of intraoperative PTH levels was analyzed. PTH values approximately 10 minutes after excision of the thyroid gland and in the recovery room were obtained; serial ionized calcium levels were also analyzed. PTH values were then compared using chi-square analysis with significance defined as P < .05. A receiver operator characteristic (ROC) curve was also constructed to define sensitivities and specificities of different PTH levels as potential cutoff values. RESULTS: Eighty patients were identified meeting the study criteria between January 1999 and February 2005. Fourteen of the 80 (17.5%) patients became hypocalcemic during the hospital stay; none experienced permanent hypocalcemia. Patients who became hypocalcemic during their hospitalization were more likely to have a PTH level below 15 pg/mL (P < .01). Patients with a PTH level less than 15 pg/mL were more likely to develop hypocalcemia (P < .01). Finally, an ROC curve was constructed, allowing the surgeon to determine acceptable sensitivities and specificities and various PTH cutoff values. CONCLUSION: Low perioperative PTH levels significantly correlate with the presence of postoperative hypocalcemia but cannot be used to predict it. Using the ROC curve allows different chosen cutoff values to predict hypocalcemia with varying sensitivity and specificity.

A comparison of short-term changes in health-related quality of life in thyroid carcinoma patients undergoing diagnostic evaluation with recombinant human thyrotropin compared with thyroid hormone withdrawal.

CONTEXT: Thyroid carcinoma requires lifelong monitoring with serum thyroglobulin, radioactive iodine whole body scanning, and other imaging modalities. Levothyroxine (L-T4) withdrawal for thyroglobulin measurement and whole body scanning increases these tests' sensitivities but causes hypothyroidism. Recombinant human TSH (rhTSH) enables testing without L-T4 withdrawal. OBJECTIVE: Our objective was to examine the impact of short-term hypothyroidism on the health-related quality of life (HRQOL) of patients after rhTSH vs. L-T4 withdrawal. DESIGN, SETTING, AND PATIENTS: In this multicenter study, the SF-36 Health Survey was administered to 228 patients at three time points: on L-T4, after rhTSH, and after L-T4 withdrawal. INTERVENTIONS: INTERVENTIONS included administration of rhTSH on L-T4 and withdrawal from thyroid hormone. MAIN OUTCOME MEASURES: Mean SF-36 scores were compared during the two interventions and with the U.S. general population and patients with heart failure, depression, and migraine headache. RESULTS: Patients had SF-36 scores at or above the norm for the general U.S. population in six of eight domains at baseline on L-T4 and in seven of eight domains after rhTSH. Patients' scores declined significantly in all eight domains after L-T4 withdrawal when compared with the other two periods (P < 0.0001). Patients' HRQOL scores while on L-T4 and after rhTSH were at or above those for patients with heart failure, depression, and migraine in all eight domains. After L-T4 withdrawal, patients' HRQOL scores were significantly below congestive heart failure, depression, and migraine headache norms in six, three, and six of the eight domains, respectively. CONCLUSIONS: Short-term hypothyroidism after L-T4 withdrawal is associated with a significant decline in quality of life that is abrogated by rhTSH use.