Impact of the COVID-19 pandemic on CTSA Clinical Research Centers over 2 years.

Introduction: The COVID-19 pandemic had an abrupt impact on patient-oriented research early in the pandemic. CTSA Clinical Research Centers (CRCs) rapidly adapted to this challenge, but the continued impact of later phases of the pandemic on CRC operations is not clear. Methods: An online REDCap survey of CTSA CRCs was developed that covered the first 2 years of the pandemic. The survey focused on impact on CRC functions, mitigation strategies, recovery of CRC activities, CRC contributions to COVID-related research, and potential lessons for future public health emergencies. The survey was sent to CRC directors at 61 CTSA Hubs in May 2022. Results: Twenty-seven Hubs (44%) responded to the survey. Most CRCs reported greater than 50% declines in inpatient census in the first year of the pandemic, with less severe impacts on outpatient census. CRCs pivoted to support COVID-related research and adopted innovative technology-driven approaches to support clinical research. Census improved in the second year of the pandemic in most CRCs but often remained below pre-pandemic levels, and greater than half of CRCs reported decreased revenue. Conclusions: CTSA-supported CRCs faced unprecedented challenges at the onset of the COVID-19 pandemic and responded rapidly to support COVID-related research and implement innovative approaches that allowed patient-oriented research activities to resume. However, many CRCs continued to report decreased research activities in the second year of the pandemic, and the long-term effects on CRC operations on finances are not clear. CRCs will likely need to evolve to provide support in nontraditional ways.

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.

Brain Fog in Hypothyroidism: What Is It, How Is It Measured, and What Can Be Done About It.

Background: Some levothyroxine (LT4)-treated hypothyroid patients report a constellation of persistent and distressing cognitive symptoms that has been termed brain fog. This narrative review focuses on attempts to define and measure hypothyroid-associated brain fog, summarize possible etiologies and contributing factors, present treatment options, and propose avenues for future research. Methods: Published literature was reviewed to summarize available information on patient-reported symptoms associated with brain fog in hypothyroidism, as well as objective evidence of impairment based on neurocognitive testing and functional imaging studies. Given the limited information specific for hypothyroid-associated brain fog, relevant data from other medical conditions associated with brain fog were also reviewed and incorporated into recommendations for clinical care and future research areas. Results: Hypothyroid-associated brain fog has not been well defined or quantitated, and the underlying pathophysiology is unclear. Symptoms vary among patients but commonly include fatigue, depressed mood, and cognitive difficulties in the areas of memory and executive function. Symptoms often predate the diagnosis of hypothyroidism, and the magnitude of cognitive impairment can range from mild to severe. Regardless of severity, these symptoms are associated with impaired quality of life and cause dissatisfaction with treatment, so often lead to requests for alternate therapies. Disease-specific and psychological factors impact the experience of brain fog in complex ways, including potential limitations in LT4 monotherapy, self-knowledge of a disease state, and expectations for therapeutic effects. Conclusions: Brain fog is a variable symptom complex in people with hypothyroidism, causing significant distress and diminished quality of life. In the absence of proven therapies, individualized treatment plans are recommended, which incorporate thyroid-specific, general medical, and psychosocial approaches. In particular, cognitive rehabilitation is an underutilized technique that is beneficial in other medical conditions associated with brain fog and could improve symptoms in hypothyroid people. The limitations in our current knowledge and questions presented throughout this review highlight a major need for clinical research in this understudied area. Future research should include attention to standardization of survey instruments to quantitate brain fog in hypothyroid people, as well as rigorously designed intervention studies.

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.

Association of Thyroid Dysfunction With Cognitive Function: An Individual Participant Data Analysis.

Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings. Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia. Design, Setting, and Participants: This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021. Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values. Main Outcomes and Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated. Results: Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia. Conclusions and Relevance: In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.

Phase I randomized trial of liothyronine for remyelination in multiple sclerosis: A dose-ranging study with assessment of reliability of visual outcomes.

BACKGROUND: Thyroid hormone promotes remyelination in multiple sclerosis (MS) animal models through a variety of mechanisms. Liothyronine (L-T3) is a short-acting thyroid hormone with demonstrated safety and tolerability for short-term and chronic use in euthyroid adults with other health conditions, but has not been studied in people with MS. The objectives of this single-center, phase I, placebo-controlled, clinical trial were to determine the safety, tolerability, and optimal dosing of L-T3 in people with MS in preparation for a phase 2 remyelination clinical trial. Secondary goals included exploration of the reliability of functional and clinical measurements of myelination in the anterior visual pathway over one week. METHODS: Groups of six clinically stable people with MS were randomized in a 4:2 ratio to receive L-T3 or placebo. The first group received 50 mcg total daily dose (TDD) of L-T3, with escalating doses of L-T3 in subsequent groups, up to potentially 150 mcg TDD in the final group. Prior to enrollment for the next dose-escalated group, all safety measures for the prior dose were reviewed. The maximum tolerated dose (MTD) was considered to be the dose below which two or more participants experienced dose limiting symptoms or one participant experienced a serious adverse event. After the MTD was reached, no further patients were enrolled. Visual evoked potentials (VEP) P100 latency with two different check sizes (17' and 34') and Sloan low contrast letter acuity (LCLA) were measured pre- and post-treatment. To determine whether there was a treatment effect, the placebo and L-T3 groups were compared using a clustered bootstrap regression estimation. A linear mixed effects model was used to determine test-retest reliability of VEP and LCLA in all eyes. RESULTS: Between May 2016 and November 2016, 15 people with MS were randomized to L-T3 (n = 10) or placebo (n = 5). Subjects were adherent to the study drug and the MTD was 75 mcg TDD. No serious adverse events were observed and the most common adverse events were poor sleep and loose stools. No treatment effect of L-T3 was observed over one week. Therefore, data from patients on L-T3 and placebo were pooled to explore VEP and LCLA reliability. The intraclass correlations of VEP 17', VEP 34' and LCLA were 0.836, 0.860, and 0.932, respectively. The mean differences in values between visits 1 and 2 for VEP 17' and 34' and LCLA were 1.9 ms/eye (SD 6.5), 0.4 ms/eye (6.3), and 0.8/eye (3.6), respectively. CONCLUSIONS: This study confirms the short-term safety and tolerability of L-T3 in people with MS, with 75 mcg TDD as the MTD. Our results also support that, despite small variations over one week, VEP with various check sizes and Sloan LCLA are reliable functional and clinical outcome measures that could be used in remyelination clinical trials in MS. A future phase 2 clinical trial to investigate the efficacy of L-T3 as a remyelination therapy may be warranted. This trial was registered on clinicaltrials.gov (NCT02760056).

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.

Effects of Altering Levothyroxine Dose on Energy Expenditure and Body Composition in Subjects Treated With LT4.

Background: It is unclear whether variations in thyroid status within or near the reference range affect energy expenditure, body mass, or body composition. Methods: 138 subjects treated with levothyroxine (LT4) for hypothyroidism with normal TSH levels underwent measurement of total, resting, and physical activity energy expenditure; thermic effect of food; substrate oxidation; dietary intake; and body composition. They were assigned to receive an unchanged, higher, or lower LT4 dose in randomized, double-blind fashion, targeting one of three TSH ranges (0.34 to 2.50, 2.51 to 5.60, or 5.61 to 12.0 mU/L). The doses were adjusted every 6 weeks to achieve target TSH levels. Baseline measures were reassessed at 6 months. Results: At study end, the mean LT4 doses and TSH levels were 1.50 ± 0.07, 1.32 ± 0.07, and 0.78 ± 0.08 µg/kg (P < 0.001) and 1.85 ± 0.25, 3.93 ± 0.38, and 9.49 ± 0.80 mU/L (P < 0.001), respectively, in the three arms. No substantial metabolic differences in outcome were found among the three arms, although direct correlations were observed between decreases in thyroid status and decreases in resting energy expenditure for all subjects. The subjects could not ascertain how their LT4 dose had been adjusted but the preferred LT4 dose they perceived to be higher (P < 0.001). Conclusions: Altering LT4 doses in subjects with hypothyroidism to vary TSH levels in and near the reference range did not have major effects on energy expenditure or body composition. Subjects treated with LT4 preferred the perceived higher LT4 doses despite a lack of objective effect. Our data do not support adjusting LT4 doses in patients with hypothyroidism to achieve potential improvements in weight or body composition.

An Online Survey of Hypothyroid Patients Demonstrates Prominent Dissatisfaction.

BACKGROUND: Approximately 15% more patients taking levothyroxine (LT4) report impaired quality of life compared to controls. This could be explained by additional diagnoses independently affecting quality of life and complicating assignment of causation. This study sought to investigate the underpinnings of reduced quality of life in hypothyroid patients and to provide data for discussion at a symposium addressing hypothyroidism. METHODS: An online survey for hypothyroid patients was posted on the American Thyroid Association Web site and forwarded to multiple groups. Respondents were asked to rank satisfaction with their treatment for hypothyroidism and their treating physician. They also ranked their perception regarding physician knowledge about hypothyroidism treatments, need for new treatments, and life impact of hypothyroidism on a scale of 1-10. Respondents reported the therapy they were taking, categorized as LT4, LT4 and liothyronine (LT4 + LT3), or desiccated thyroid extract (DTE). They also reported sex, age, cause of hypothyroidism, duration of treatment, additional diagnoses, and prevalence of symptoms. RESULTS: A total of 12,146 individuals completed the survey. The overall degree of satisfaction was 5 (interquartile range [IQR] = 3-8). Among respondents without self-reported depression, stressors, or medical conditions (n = 3670), individuals taking DTE reported a higher median treatment satisfaction of 7 (IQR = 5-9) compared to other treatments. At the same time, the LT4 treatment group exhibited the lowest satisfaction of 5 (IQR = 3-7), and for the LT4 + LT3 treatment group, satisfaction was 6 (IQR = 3-8). Respondents taking DTE were also less likely to report problems with weight management, fatigue/energy levels, mood, and memory compared to those taking LT4 or LT4 + LT3. CONCLUSIONS: A subset of patients with hypothyroidism are not satisfied with their current therapy or their physicians. Higher satisfaction with both treatment and physicians is reported by those patients on DTE. While the study design does not provide a mechanistic explanation for this observation, future studies should investigate whether preference for DTE is related to triiodothyronine levels or other unidentified causes.

Effects of Altering Levothyroxine (L-T4) Doses on Quality of Life, Mood, and Cognition in L-T4 Treated Subjects.

Background: The brain is a critical target organ for thyroid hormone, but it is unclear whether variations in thyroid function within and near the reference range affect quality of life, mood, or cognition. Methods: A total of 138 subjects with levothyroxine (L-T4)-treated hypothyroidism and normal thyrotropin (TSH) levels underwent measures of quality of life (36-Item Short Form Health Survey, Underactive Thyroid-Dependent Quality of Life Questionnaire), mood (Profile of Mood States, Affective Lability Scale), and cognition (executive function, memory). They were then randomly assigned to receive an unchanged, higher, or lower L-T4 dose in double-blind fashion, targeting one of three TSH ranges (0.34 to 2.50, 2.51 to 5.60, or 5.61 to 12.0 mU/L). Doses were adjusted every 6 weeks based on TSH levels. Baseline measures were reassessed at 6 months. Results: At the end of the study, by intention to treat, mean L-T4 doses were 1.50 ± 0.07, 1.32 ± 0.07, and 0.78 ± 0.08 µg/kg (P < 0.001), and mean TSH levels were 1.85 ± 0.25, 3.93 ± 0.38, and 9.49 ± 0.80 mU/L (P < 0.001), respectively, in the three arms. There were minor differences in a few outcomes between the three arms, which were no longer significant after correction for multiple comparisons. Subjects could not ascertain how their L-T4 doses had been adjusted (P = 0.55) but preferred L-T4 doses they perceived to be higher (P < 0.001). Conclusions: Altering L-T4 doses in hypothyroid subjects to vary TSH levels in and near the reference range does not affect quality of life, mood, or cognition. L-T4-treated subjects prefer perceived higher L-T4 doses despite a lack of objective benefit. Adjusting L-T4 doses in hypothyroid patients based on symptoms in these areas may not result in significant clinical improvement.

Thyroid Function Variation in the Normal Range, Energy Expenditure, and Body Composition in L-T4-Treated Subjects.

Purpose: It is not clear whether upper limits of the thyrotropin (TSH) reference range should be lowered. This debate can be better informed by investigation of whether variations in thyroid function within the reference range have clinical effects. Thyroid hormone plays a critical role in determining energy expenditure, body mass, and body composition, and therefore clinically relevant variations in these parameters may occur across the normal range of thyroid function. Methods: This was a cross-sectional study of 140 otherwise healthy hypothyroid subjects receiving chronic replacement therapy with levothyroxine (L-T4) who had TSH levels across the full span of the laboratory reference range (0.34 to 5.6 mU/L). Subjects underwent detailed tests of energy expenditure (total and resting energy expenditure, thermic effect of food, physical activity energy expenditure), substrate oxidation, diet intake, and body composition. Results: Subjects with low-normal (≤2.5 mU/L) and high-normal (>2.5 mU/L) TSH levels did not differ in any of the outcome measures. However, across the entire group, serum free triiodothyronine (fT3) levels were directly correlated with resting energy expenditure, body mass index (BMI), body fat mass, and visceral fat mass, with clinically relevant variations in these outcomes. Conclusions: Variations in thyroid function within the laboratory reference range have clinically relevant correlations with resting energy expenditure, BMI, and body composition in L-T4-treated subjects. However, salutary effects of higher fT3 levels on energy expenditure may be counteracted by deleterious effects on body weight and composition. Further studies are needed before these outcomes should be used as a basis for altering L-T4 doses in L-T4-treated subjects.

Effectiveness and cost of recruiting healthy volunteers for clinical research studies using an electronic patient portal: A randomized study.

INTRODUCTION: It is not clear how to effectively recruit healthy research volunteers. METHODS: We developed an electronic health record (EHR)-based algorithm to identify healthy subjects, who were randomly assigned to receive an invitation to join a research registry via the EHR's patient portal, letters, or phone calls. A follow-up survey assessed contact preferences. RESULTS: The EHR algorithm accurately identified 858 healthy subjects. Recruitment rates were low, but occurred more quickly via the EHR patient portal than letters or phone calls (2.7 vs. 19.3 or 10.4 d). Effort and costs per enrolled subject were lower for the EHR patient portal (3.0 vs. 17.3 or 13.6 h, $113 vs. $559 or $435). Most healthy subjects indicated a preference for contact via electronic methods. CONCLUSIONS: Healthy subjects can be accurately identified from EHR data, and it is faster and more cost-effective to recruit healthy research volunteers using an EHR patient portal.

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.

Thyroid Function Variations Within the Reference Range Do Not Affect Quality of Life, Mood, or Cognitive Function in Community-Dwelling Older Men.

BACKGROUND: Variations in thyroid function within the laboratory reference range have been associated with a number of clinical outcomes. However, quality of life, mood, and cognitive function have not been extensively studied, and it is not clear whether mild variations in thyroid function have major effects on these neurocognitive outcomes. METHODS: Data were analyzed from the Osteoporotic Fractures in Men (MrOS) Study, a cohort of community-dwelling men aged 65 years and older in the United States. A total of 539 participants who were not taking thyroid medications and had age-adjusted TSH levels within the reference range underwent detailed testing of quality of life, mood, and cognitive function at baseline. The same quality of life, mood, and cognitive outcomes were measured again in 193 of the men after a mean follow-up of 6 years. Outcomes were analyzed using thyrotropin (TSH) and free thyroxine (FT4) levels as continuous independent variables, adjusting for relevant covariates. RESULTS: At baseline, there were no associations between TSH or FT4 levels and measures of quality of life, mood, or cognition in the 539 euthyroid men. Baseline thyroid function did not predict changes in these outcomes over a mean of 6 years in the 193 men in the longitudinal analysis. CONCLUSIONS: Variations in thyroid function within the age-adjusted laboratory reference range are not associated with variations in quality of life, mood, or cognitive function in community-dwelling older men.

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.

Effect of Thyroid Function Variations Within the Laboratory Reference Range on Health Status, Mood, and Cognition in Levothyroxine-Treated Subjects.

BACKGROUND: There has been recent debate within the thyroid field regarding whether current upper limits of the thyrotropin (TSH) reference range should be lowered. This debate can be better informed by investigation of whether variations in thyroid function within the reference range have clinical effects. One important target organ for thyroid hormone is the brain, but little is known about variations in neurocognitive measures within the reference range for thyroid function. METHODS: This was a cross-sectional study of 132 otherwise healthy hypothyroid subjects receiving chronic replacement therapy with levothyroxine (LT4) who had TSH levels across the full span of the laboratory reference range (0.34-5.6 mU/L). Subjects underwent detailed tests of health status, mood, and cognitive function, with an emphasis on memory and executive functions. RESULTS: Subjects with low-normal (≤2.5 mU/L) and high-normal (>2.5 mU/L) TSH levels did not differ on most tests of health status, mood, or cognitive function, and there were no correlations between TSH, free T4, or free T3 levels and most outcomes. There was, however, a suggestion that thyroid function affected performance on the Iowa Gambling Task, which mimics real life decision-making. Subjects with low-normal TSH levels made more advantageous decisions than those with high-normal TSH levels. CONCLUSIONS: Variations in thyroid function within the laboratory reference range do not appear to have clinically relevant effects on health status, mood, or memory in LT4 treated subjects. However, decision making, which encompasses many executive functions, may be affected. Unless further studies strengthen this finding, these data do not support narrowing the TSH reference range.

Effects of Levothyroxine Replacement or Suppressive Therapy on Energy Expenditure and Body Composition.

BACKGROUND: Thyrotropin (TSH)-suppressive doses of levothyroxine (LT4) have adverse effects on bone and cardiac function, but it is unclear whether metabolic function is also affected. The objective of this study was to determine whether women receiving TSH-suppressive LT4 doses have alterations in energy expenditure or body composition. METHODS: This study was a cross-sectional comparison between three groups of women: 26 women receiving chronic TSH-suppressive LT4 doses, 80 women receiving chronic replacement LT4 doses, and 16 untreated euthyroid control women. Subjects underwent measurements of resting energy expenditure (REE), substrate oxidation, and thermic effect of food by indirect calorimetry; physical activity energy expenditure by accelerometer; caloric intake by 24-hour diet recall; and body composition by dual X-ray absorptiometry. RESULTS: REE per kilogram lean body mass in the LT4 euthyroid women was 6% lower than that of the LT4-suppressed group, and 4% lower than that of the healthy control group (p = 0.04). Free triiodothyronine (fT3) levels were directly correlated with REE, and were 10% lower in the LT4 euthyroid women compared with the other two groups (p = 0.007). The groups of subjects did not differ in other measures of energy expenditure, caloric intake, or body composition. CONCLUSIONS: LT4 suppression therapy does not adversely affect energy expenditure or body composition in women. However, LT4 replacement therapy is associated with a lower REE, despite TSH levels within the reference range. This may be due to lower fT3 levels, suggesting relative tissue hypothyroidism may contribute to impaired energy expenditure in LT4 therapy.