- Internal Medicine
- Thyroid Diseases
Clinical Associate Professor, Medicine - Endocrinology, Gerontology, & Metabolism
Medical Education, University of Miami Miller School of Medicine, MD (2009)
Residency, University of Miami/Jackson Memorial Hospital Internal Med Residency, Internal Medicine (2011)
Fellowship, University of Miami/Jackson Memorial Hospital Endocrinology Fellowship, Endocrinology (2014)
Board Certification: American Board of Internal Medicine, Endocrinology, Diabetes and Metabolism (2014)
Board Certification: American Board of Internal Medicine, Internal Medicine (2013)
Examination of Neurofilament Light Chain Serum Concentrations, Physical Activity, and Cognitive Decline in Older Adults.
JAMA network open
2022; 5 (3): e223596
Little is known about the association of serum neurofilament light chain (NfL) concentrations and physical activity with the rate of cognitive decline in older adults.To examine the association of physical activity and NfL concentrations with cognitive decline in older adults over time.This cohort study used data from the Chicago Health and Aging Project (CHAP), a population-based cohort study that recruited participants through door-to-door census in 4 Chicago-area communities and collected data between 1993 and 2012 in cycles of 3 years. Participants in CHAP who had 2 or more cognitive function assessments and at least 1 blood sample collected for NfL measurement were selected for inclusion in the current study. Data were analyzed from January to December 2021.Self-reported physical activity (minutes per week) and serum NfL concentration (pg/mL).Associations of baseline physical activity and NfL concentrations with changes in global cognitive function over time as evaluated using the East Boston Memory Test for episodic memory, the Symbol Digit Modalities Test for perceptual speed, and the Mini-Mental State Examination. Mixed-effects regression analyses were conducted to examine associations at baseline and longitudinally.The study sample included 1158 participants (695 [60%] African American; 728 [63%] female), with a mean (SD) age of 77.4 (6.0) years and a mean educational level of 12.6 (3.5) years. Among participants with high NfL concentrations (>25 pg/mL), those who engaged in medium physical activity (<150 minutes per week) had a 12% slower rate of global cognitive decline (SD units, or β, -0.065; 95% CI, -0.099 to -0.032) and participants who engaged in high physical activity (≥150 minutes per week) had a 36% slower rate of decline (β, -0.048; 95% CI, -0.080 to -0.016) than did participants with low physical activity (no reported participation) (β, -0.075; 95% CI, -0.108 to -0.041). For participants with low NfL concentrations (≤25 pg/mL), those who took part in medium physical activity had 43% slower global cognitive decline (β, -0.025; 95% CI, -0.043 to -0.007) and individuals who participated in high physical activity had 30% slower decline (β, -0.031; 95% CI, -0.048 to -0.014) than did those who participated in low physical activity (β, -0.046; 95% CI, -0.066 to -0.025).The findings suggest that physical activity is associated with diminished cognitive decline among older adults with increased serum NfL concentrations. The results support the potential use of blood biomarkers in measuring the benefits of health behaviors, such as physical activity, and early intervention for older adults at risk for cognitive decline.
View details for DOI 10.1001/jamanetworkopen.2022.3596
View details for PubMedID 35315915
Brain Fog in Hypothyroidism: Understanding the Patient's Perspective.
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists
OBJECTIVES: Patient-centered studies have shown that many patients on thyroid hormone replacement therapy for hypothyroidism exhibit persistent symptoms, including "brain fog." Here we wished to determine which of these specific symptoms are associated with brain fog, to identify patient-reported factors that modify these symptoms, and to identify patient concerns related to brain fog not included in thyroid-specific questionnaires.METHODS: A survey on brain fog symptoms adapted from ThyPRO was distributed online. Textual data analysis was performed to identify common areas of concern from open-ended survey responses.RESULTS: A total of 5170 participants reporting brain fog while being treated for hypothyroidism were included in the analysis. 2409 (46.6%) participants reported symptom onset prior to the diagnosis of hypothyroidism, and 4096 (79.2%) participants experienced brain fog symptoms frequently. Of the symptoms listed, participants associated fatigue and forgetfulness most frequently with brain fog. More rest was the most common factor provided for improving symptoms. The textual data analysis identified areas of concern that are not often included in thyroid-specific quality of life questionnaires, including a focus on the diagnosis of hypothyroidism, the types and doses of medications, and the patient-doctor relationship.CONCLUSIONS: Brain fog in patients treated for hypothyroidism was associated most frequently with fatigue and cognitive symptoms. Several additional areas of patient concern were found to be associated with brain fog, which are not typically addressed in thyroid-specific questionnaires.
View details for DOI 10.1016/j.eprac.2021.12.003
View details for PubMedID 34890786
Longitudinal Association of Total Tau Concentrations and Physical Activity With Cognitive Decline in a Population Sample.
JAMA network open
2021; 4 (8): e2120398
Tau is a brain protein located in neurons and develops abnormally in individuals with Alzheimer disease. New technology is convenient for measuring blood total tau concentrations and provides a unique and increased opportunity for early intervention to slow cognitive decline.To evaluate the association of physical activity and total tau concentrations with cognitive decline at baseline and over time.The Chicago Health and Aging Project is a population-based cohort study conducted in 4 Chicago communities. Data collection occurred in 3-year cycles between 1993 and 2012. Participants completed in-home interviews. Clinical evaluations, which included blood samples, were performed with a stratified random sample of 1159 participants. Statistical analyses were conducted from October 30, 2020, to May 25, 2021.Physical activity and total serum tau concentrations. Data on physical activity were obtained through self-report items, and a sum of minutes per week was calculated. Little physical activity was defined as no participation in a minimum of 4 of the items on the physical activity measure. Medium activity was defined as participating in less than 150 minutes of physical activity per week, and high activity was defined as participating in 150 minutes or more of physical activity per week.The main outcome for this study is global cognitive function, measured through a battery of cognitive tests. The study hypothesis was developed after data were collected.Of the 1159 participants in the study, 728 were women (63%), and 696 were African American (60%); the mean (SD) age was 77.4 (6.0) years, and the mean (SD) educational level was 12.6 (3.5) years. Participants with high total tau concentrations with medium physical activity had a 58% slower rate of cognitive decline (estimate, -0.028 standard deviation unit [SDU] per year [95% CI, -0.057 to 0.002 SDU per year]; difference, 0.038 SDU per year [95% CI, 0.011-0.065 SDU per year]), and those with high physical activity had a 41% slower rate of cognitive decline (estimate, -0.038 SDU per year [95% CI, -0.068 to -0.009 SDU per year]; difference, 0.027 SDU per year [95% CI, -0.002 to 0.056 SDU per year]), compared with those with little physical activity. Among participants with low total tau concentrations, medium physical activity was associated with a 2% slower rate of cognitive decline (estimate, -0.050 SDU per year [95% CI, -0.069 to -0.031 SDU per year]; difference, 0.001 SDU per year [95% CI, -0.019 to 0.021 SDU per year]), and high physical activity was associated with a 27% slower rate of cognitive decline (estimate, -0.037 SDU per year [95% CI, -0.055 to -0.019 SDU per year]; difference, 0.014 SDU per year [95% CI, -0.007 to 0.034 SDU per year]), compared with little physical activity. Individual tests of cognitive function showed similar results.This study suggests that, among participants with both high and low total tau concentrations, physical activity was associated with slower cognitive decline. Results support the potential utility of blood biomarkers in measuring the benefits associated with health behaviors and may contribute to specifying target populations or informing interventions for trials that focus on improving physical activity behavior. Future work should examine the association of total tau concentrations with other health behaviors and physical activity types.
View details for DOI 10.1001/jamanetworkopen.2021.20398
View details for PubMedID 34379124
View details for PubMedCentralID PMC8358733
- Response to Letter to the Editor from Steen Joop Bonnema: (Comparative Effectiveness of Levothyroxine, Desiccated Thyroid Extract, and Levothyroxine+Liothyronine in Hypothyroidism)". The Journal of clinical endocrinology and metabolism 2021
Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document.
Thyroid : official journal of the American Thyroid Association
2021; 31 (2): 156-182
Background: Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3). Despite the publication of these trials, combination therapy is widely used and patients reporting benefit continue to generate patient and physician interest in this area. Recent scientific developments may provide insight into this inconsistency and guide future studies. Methods: The American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA) held a joint conference on November 3, 2019 (live-streamed between Chicago and London) to review new basic science and clinical evidence regarding combination therapy with presentations and input from 12 content experts. After the presentations, the material was synthesized and used to develop Summary Statements of the current state of knowledge. After review and revision of the material and Summary Statements, there was agreement that there was equipoise for a new clinical trial of combination therapy. Consensus Statements encapsulating the implications of the material discussed with respect to the design of future clinical trials of LT4/LT3 combination therapy were generated. Authors voted upon the Consensus Statements. Iterative changes were made in several rounds of voting and after comments from ATA/BTA/ETA members. Results: Of 34 Consensus Statements available for voting, 28 received at least 75% agreement, with 13 receiving 100% agreement. Those with 100% agreement included studies being powered to study the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes, inclusion of patients dissatisfied with their current therapy and requiring at least 1.2 μg/kg of LT4 daily, use of twice daily LT3 or preferably a slow-release preparation if available, use of patient-reported outcomes as a primary outcome (measured by a tool with both relevant content validity and responsiveness) and patient preference as a secondary outcome, and utilization of a randomized placebo-controlled adequately powered double-blinded parallel design. The remaining statements are presented as potential additional considerations. Discussion: This article summarizes the areas discussed and presents Consensus Statements to guide development of future clinical trials of LT4/LT3 combination therapy. The results of such redesigned trials are expected to be of benefit to patients and of value to inform future thyroid hormone replacement clinical practice guidelines treatment recommendations.
View details for DOI 10.1089/thy.2020.0720
View details for PubMedID 33276704
View details for PubMedCentralID PMC8035928
Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document.
European thyroid journal
2021; 10 (1): 10-38
Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3). Despite the publication of these trials, combination therapy is widely used and patients reporting benefit continue to generate patient and physician interest in this area. Recent scientific developments may provide insight into this inconsistency and guide future studies.The American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA) held a joint conference on November 3, 2019 (live-streamed between Chicago and London) to review new basic science and clinical evidence regarding combination therapy with presentations and input from 12 content experts. After the presentations, the material was synthesized and used to develop Summary Statements of the current state of knowledge. After review and revision of the material and Summary Statements, there was agreement that there was equipoise for a new clinical trial of combination therapy. Consensus Statements encapsulating the implications of the material discussed with respect to the design of future clinical trials of LT4/LT3 combination therapy were generated. Authors voted upon the Consensus Statements. Iterative changes were made in several rounds of voting and after comments from ATA/BTA/ETA members.Of 34 Consensus Statements available for voting, 28 received at least 75% agreement, with 13 receiving 100% agreement. Those with 100% agreement included studies being powered to study the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes, inclusion of patients dissatisfied with their current therapy and requiring at least 1.2 µg/kg of LT4 daily, use of twice daily LT3 or preferably a slow-release preparation if available, use of patient-reported outcomes as a primary outcome (measured by a tool with both relevant content validity and responsiveness) and patient preference as a secondary outcome, and utilization of a randomized placebo-controlled adequately powered double-blinded parallel design. The remaining statements are presented as potential additional considerations.This article summarizes the areas discussed and presents Consensus Statements to guide development of future clinical trials of LT4/LT3 combination therapy. The results of such redesigned trials are expected to be of benefit to patients and of value to inform future thyroid hormone replacement clinical practice guidelines treatment recommendations.
View details for DOI 10.1159/000512970
View details for PubMedID 33777817
View details for PubMedCentralID PMC7983670
Accelerating functional gene discovery in osteoarthritis.
2021; 12 (1): 467
Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease.
View details for DOI 10.1038/s41467-020-20761-5
View details for PubMedID 33473114
View details for PubMedCentralID PMC7817695
Population estimate of people with clinical Alzheimer's disease and mild cognitive impairment in the United States (2020-2060).
Alzheimer's & dementia : the journal of the Alzheimer's Association
The estimate of people with clinical Alzheimer's disease (AD) and mild cognitive impairment provides an understanding of the disease burden.We estimated people with cognitive impairment using a quasibinomial regression model in 10,342 participants with cognitive test scores.The 2020 US Census-adjusted prevalence of clinical AD was 11.3% (95% confidence interval [CI] = 10.7-11.9): 10.0% among non-Hispanic Whites, 14.0% among Hispanics, and 18.6% among non-Hispanic Blacks. We estimate that in 2020, 6.07 (95% CI = 5.75-6.38) million people were living with clinical AD, which increases to 13.85 (95% CI = 12.98-14.74) million in 2060, 423% higher among Hispanics, 192% higher among Blacks, and 63% higher among Whites. However, there are predicted to be more significant increases in later years among those over 85 and women compared to men.The number of people with clinical AD will increase as the "baby boom" generation reaches older ages, exerting a strong upward influence on disease burden.
View details for DOI 10.1002/alz.12362
View details for PubMedID 34043283
- Publisher Correction: Accelerating functional gene discovery in osteoarthritis. Nature communications 2021; 12 (1): 3302
Comparative effectiveness of levothyroxine, desiccated thyroid extract, and levothyroxine+Liothyronine in hypothyroidism.
The Journal of clinical endocrinology and metabolism
Studies comparing LT4 therapy with LT4+LT3 or desiccated thyroid extract (DTE) did not detect consistent superiority of either treatment. Here we investigated these therapies, focusing on the whole group of LT4-treated hypothyroid patients, while also exploring the most symptomatic patients.Prospective, randomized, double-blind, crossover study of 75 hypothyroid patients randomly allocated to one of three treatment arms, LT4, LT4+LT3 and DTE, for 22 weeks. The primary outcomes were post-treatment scores on the 36-point thyroid symptom questionnaire (TSQ-36), 12-point quality of life general health questionnaire (GHQ-12), the Wechsler memory scale-Version IV (VMS-IV), and the Beck Depression Inventory (BDI). Secondary endpoints included treatment preference, biochemical and metabolic parameters, etiology of hypothyroidism, and Thr92Ala-DIO2 gene polymorphism. Analyses were performed with a linear mixed model using subject as a random factor and group as a fixed effect.Serum TSH remained within reference range across all treatment arms. There were no differences for primary and secondary outcomes, except for a minor increase in heart rate caused by DTE. Treatment preference was not different and there were no interferences of the etiology of hypothyroidism or Thr92Ala-DIO2 gene polymorphism in the outcomes. Subgroup analyses of the 1/3 most symptomatic patients on LT4 revealed strong preference for treatment containing T3, which improved performance on TSQ-36, GHQ-12, BDI and visual memory index (VMS-IV component).As a group, outcomes were similar among hypothyroid patients taking DTE vs. LT4+T3 vs. LT4. However, those patients that were most symptomatic on LT4 preferred and responded positively to therapy with LT4+LT3 or DTE.
View details for DOI 10.1210/clinem/dgab478
View details for PubMedID 34185829
Temporal Pole Responds to Subtle Changes in Local Thyroid Hormone Signaling.
Journal of the Endocrine Society
2020; 4 (11): bvaa136
To study thyroid hormone (TH) signaling in the human brain, we analyzed published microarray data sets of the temporal pole (Brodmann area 38) of 19 deceased donors. An index of TH signaling built on the expression of 19 well known TH-responsive genes in mouse brains (T3S+) varied from 0.92 to 1.1. After Factor analysis, T3S+ correlated independently with the expression of TH transporters (MCT8, LAT2), TH receptor (TR) beta and TR coregulators (CARM1, MED1, KAT2B, SRC2, SRC3, NCOR2a). Unexpectedly, no correlation was found between T3S+ vs DIO2, DIO3, SRC1, or TRα. An unbiased systematic analysis of the entire transcriptome identified a set of 1649 genes (set #1) with strong positive correlation with T3S+ (r > 0.75). Factor analysis of set #1 identified 2 sets of genes that correlated independently with T3S+, sets #2 (329 genes) and #3 (191 genes). When processed through the Molecular Signatures Data Base (MSigDB), both sets #2 and #3 were enriched with Gene Ontology (GO)-sets related to synaptic transmission and metabolic processes. Ranking individual human brain donors according to their T3S+ led us to identify 1262 genes (set #4) with >1.3-fold higher expression in the top half. The analysis of the overlapped genes between sets #1 and #4 resulted in 769 genes (set #5), which have a very similar MSigDB signature as sets #2 and #3. In conclusion, gene expression in the human temporal pole can be assessed through T3S+ and fluctuates with subtle variations in local TH signaling.
View details for DOI 10.1210/jendso/bvaa136
View details for PubMedID 33123655
View details for PubMedCentralID PMC7575126
Temporal changes in the likelihood of dementia and MCI over 18 years in a population sample.
2020; 94 (3): e292-e298
To examine the temporal changes in the likelihood of dementia and mild cognitive impairment (MCI) between 1993 and 2012 using a short battery of cognitive tests.A cohort of 10,342 participants underwent a short battery of cognitive tests collected during triennial in-home interviews with 2,794 of those evaluated for the clinical diagnosis of dementia and MCI. We used a generalized logit regression model to estimate the likelihood of dementia and MCI, and a quasibinomial regression model to examine the temporal changes in those likelihood scores.A short battery of cognitive tests-delayed story recall test, Symbol Digit Modalities Test, and the Mini-Mental State Examination-were associated with the clinical diagnosis of dementia and MCI. The classification accuracy of likelihood scores was 0.92 for dementia and 0.85 for MCI. After adjusting for age, race/ethnicity, and education, the likelihood of dementia in the population decreased from 21.6% (95% confidence interval [CI] 20.9%-22.3%) to 18.9% (95% CI 18.1%-19.7%) between 1993-1996 and 2000-2002 and showed no significant decline between 2000-2002 and 2009-2012 (-0.2%, 95% CI -1.1% to 0.7%). The estimated likelihood of MCI remained similar between 1993-1996 and 2009-2012 (29.0%, 95% CI 27.9%-30.1%), but showed a nonsignificant decrease in 2000-2002.The likelihood scores based on a short battery of cognitive tests can serve as a measure of dementia and MCI in epidemiologic studies. The decline in the likelihood of dementia and MCI over earlier years was not sustained in later years.
View details for DOI 10.1212/WNL.0000000000008731
View details for PubMedID 31806693
View details for PubMedCentralID PMC7108808
Remote Blood Biomarkers of Longitudinal Cognitive Outcomes in a Population Study.
Annals of neurology
2020; 88 (6): 1065-1076
The longitudinal association of the blood biomarkers total tau (t-tau), neurofilament light (Nf-L), and glial fibrillary acidic protein (GFAP) with common sporadic Alzheimer disease (AD) and cognitive decline is not established.Using a single molecule array technology, ultrasensitive immunoassays for serum concentrations of t-tau, Nf-L, and GFAP were measured in a population sample of 1,327 participants (60% African Americans and women) who had a clinical evaluation for AD, had completed in-home cognitive assessments, and had undergone 1.5T structural magnetic resonance imaging.Higher concentrations of serum biomarkers were associated with the development of clinical AD; especially, the time-specific associations were notable: t-tau 8 to 16 years, and Nf-L and GFAP 4 to 8 years prior to clinical AD. Serum biomarkers were associated with faster cognitive decline over 16 years; baseline t-tau > 0.40pg/ml had 30% faster decline, Nf-L > 25.5pg/ml had 110% faster decline, and GFAP > 232pg/ml had 130% faster decline compared to those in the lowest quartile. Participants with baseline GFAP > 232pg/ml showed 160% faster decline in hippocampal volume compared to those with values < 160pg/ml. Additionally, higher baseline t-tau was associated with faster increase in 3rd ventricular volume, and baseline Nf-L and GFAP were associated with faster decline in cortical thickness.Serum t-tau, Nf-L, and GFAP predict the development of sporadic AD and cognitive decline, and changes in structural brain characteristics, suggesting their usefulness not only as screening and predictive biomarkers, but also in capturing the pathogenesis of Alzheimer dementia. ANN NEUROL 2020;88:1065-1076.
View details for DOI 10.1002/ana.25874
View details for PubMedID 32799383
Race, APOEɛ4, and Long-Term Cognitive Trajectories in a Biracial Population Sample.
Journal of Alzheimer's disease : JAD
2019; 72 (1): 45-53
The association of the APOEɛ4 allele with incident Alzheimer's dementia is higher among European Americans (EAs) than African Americans (AAs), but similar for the rate of cognitive decline.To examine the racial differences in the association of the APOEɛ4 allele with incident Alzheimer's dementia and cognitive decline.Using a population-based sample of 5,117 older adults (66% AAs and 63% females), we identified cognitive trajectory groups from a latent class mixed model and examined the association of the APOEɛ4 allele with these groups.The frequency of the APOEɛ4 allele was higher among AAs than EAs (37% versus 26%). Four cognitive trajectories were identified: slow, mild, moderate, and rapid. Overall, AAs had a lower baseline global cognition than EAs, and a higher proportion had rapid (7% versus 5%) and moderate (20% versus 15%) decline, but similar mild (44% versus 46%), and lesser slow (29% versus 34%) decline compared to EAs. Additionally, 25% of AAs (13% of EAs) with mild and 5% (<1% of EAs) with slow decline were diagnosed with incident Alzheimer's dementia. The APOEɛ4 allele was associated with higher odds of rapid and moderate decline compared to slow decline among AAs and EAs, but not with mild decline.AAs had lower cognitive levels and were more likely to meet the cognitive threshold for Alzheimer's dementia among mild and slow decliners, explaining the attenuated association of the ɛ4 allele with incident Alzheimer's dementia among AAs.
View details for DOI 10.3233/JAD-190538
View details for PubMedID 31561363
View details for PubMedCentralID PMC6914259
Amiodarone and thyroid physiology, pathophysiology, diagnosis and management.
Trends in cardiovascular medicine
2019; 29 (5): 285-295
Although amiodarone is considered the most effective antiarrhythmic agent, its use is limited by a wide variety of potential toxicities. The purpose of this review is to provide a comprehensive "bench to bedside" overview of the ways amiodarone influences thyroid function. We performed a systematic search of MEDLINE to identify peer-reviewed clinical trials, randomized controlled trials, meta-analyses, and other clinically relevant studies. The search was limited to English-language reports published between 1950 and 2017. Amiodarone was searched using the terms adverse effects, hypothyroidism, myxedema, hyperthyroidism, thyroid storm, atrial fibrillation, ventricular arrhythmia, and electrical storm. Google and Google scholar as well as bibliographies of identified articles were reviewed for additional references. We included 163 germane references in this review. Because amiodarone is one of the most frequently prescribed antiarrhythmic drugs in the United States, the mechanistic, diagnostic and therapeutic information provided is relevant for practicing clinicians in a wide range of medical specialties.
View details for DOI 10.1016/j.tcm.2018.09.005
View details for PubMedID 30309693
View details for PubMedCentralID PMC6661016
Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain.
The Journal of clinical investigation
2019; 129 (1): 230-245
Levothyroxine (LT4) is a form of thyroid hormone used to treat hypothyroidism. In the brain, T4 is converted to the active form T3 by type 2 deiodinase (D2). Thus, it is intriguing that carriers of the Thr92Ala polymorphism in the D2 gene (DIO2) exhibit clinical improvement when liothyronine (LT3) is added to LT4 therapy. Here, we report that D2 is a cargo protein in ER Golgi intermediary compartment (ERGIC) vesicles, recycling between ER and Golgi. The Thr92-to-Ala substitution (Ala92-D2) caused ER stress and activated the unfolded protein response (UPR). Ala92-D2 accumulated in the trans-Golgi and generated less T3, which was restored by eliminating ER stress with the chemical chaperone 4-phenyl butyric acid (4-PBA). An Ala92-Dio2 polymorphism-carrying mouse exhibited UPR and hypothyroidism in distinct brain areas. The mouse refrained from physical activity, slept more, and required additional time to memorize objects. Enhancing T3 signaling in the brain with LT3 improved cognition, whereas restoring proteostasis with 4-PBA eliminated the Ala92-Dio2 phenotype. In contrast, primary hypothyroidism intensified the Ala92-Dio2 phenotype, with only partial response to LT4 therapy. Disruption of cellular proteostasis and reduced Ala92-D2 activity may explain the failure of LT4 therapy in carriers of Thr92Ala-DIO2.
View details for DOI 10.1172/JCI123176
View details for PubMedID 30352046
View details for PubMedCentralID PMC6307951
Apolipoprotein E Genotypes, Age, Race, and Cognitive Decline in a Population Sample.
Journal of the American Geriatrics Society
2019; 67 (4): 734-740
To examine the effects of age and race on the association of apolipoprotein E (APOE) genotypes with cognitive decline in a population sample.Longitudinal study of 18 years' duration.Biracial urban US population sample.There were a total of 5807 participants, 60% African American (AA) and 40% European American (EA).A composite cognitive function based on individual tests of episodic memory, perceptual speed, and the Mini-Mental State Examination.The frequencies of APOE ε2/ε3 (14% vs 12%), ε2/ε4 (4% vs 2%), ε3/ε4 (29% vs 22%), and ε4/ε4 (4% vs 2%) genotypes were higher among AAs than EAs. After adjusting for demographic factors, the rate of decline in global cognition was twice as high among participants with the APOE ε4/ε4 genotype compared to participants with the APOE ε3/ε3 genotype (0.097 vs 0.048 SD units [SDUs] per year; P < .0001). This doubling was not different between AAs (0.091 vs 0.045 SDUs per year) and EAs (0.118 vs 0.059 SDUs per year) (Pinteraction = .63). The APOE ε3/ε4 genotype was associated with a higher rate of decline with age (Pinteraction = .021), while the APOE ε2/ε4 genotype (Pinteraction = .016) and the APOE ε2/ε3 genotype (Pinteraction = .043) were associated with a lower rate of decline with higher age. The APOE ε2/ε2 genotype was associated with a lower rate of decline in episodic memory, while the APOE ε2/ε4 was associated with a higher rate of decline in episodic memory and perceptual speed.The association of the APOE genotypes with cognitive decline was not different between AAs and EAs. However, individuals with different APOE genotypes showed a lower or a higher rate of decline with age. J Am Geriatr Soc 67:734-740, 2019.
View details for DOI 10.1111/jgs.15727
View details for PubMedID 30584655
View details for PubMedCentralID PMC6813761
Disagreement Between Hospital Rating Systems: Measuring the Correlation of Multiple Benchmarks and Developing a Quality Composite Rank.
American journal of medical quality : the official journal of the American College of Medical Quality
2019; 35 (3): 222-230
In the United States, hospital rating system usefulness is limited by heterogeneity and conflicting results. US News Best Hospitals, Vizient Quality and Accountability Study, Centers for Medicare & Medicaid Services (CMS) Star Rating, Leapfrog Hospital Safety Grade, and the Truven Top 100 Hospitals ratings were compared using Spearman correlations. Rank aggregation was used to combine the scores generating a Quality Composite Rank (QCR). The highest correlation between rating systems was shown between the Leapfrog Safety Grade and the CMS Star Rating. In a proportional odds logistic regression, a greater discordance between the CMS Star Rating, Vizient rank, US News, and Leapfrog was associated with a lower overall rank in the QCR. Lack of transparency and understanding about the differences and similarities for these hospital ranking systems complicates use of the measures. By combining the results of these ranking systems into a composite, the measurement of hospital quality can be simplified.
View details for DOI 10.1177/1062860619860250
View details for PubMedID 31253048
The Swinging Pendulum in Treatment for Hypothyroidism: From (and Toward?) Combination Therapy.
Frontiers in endocrinology
2019; 10: 446
Thyroid hormone replacement for hypothyroidism can be achieved via several approaches utilizing different preparations of thyroid hormones, T3, and/or T4. "Combination therapy" involves administration of both T3 and T4, and was technically the first treatment for hypothyroidism. It was lauded as a cure for the morbidity and mortality associated with myxedema, the most severe presentation of overt hypothyroidism. In the late nineteenth and the early Twentieth centuries, combination therapy per se could consist of thyroid gland transplant, or more commonly, consumption of desiccated animal thyroid, thyroid extract, or thyroglobulin. Combination therapy remained the mainstay of therapy for decades despite development of synthetic formulations of T4 and T3, because it was efficacious and cost effective. However, concerns emerged about the consistency and potency of desiccated thyroid hormone after cases were reported detailing either continued hypothyroidism or iatrogenic thyrotoxicosis. Development of the TSH radioimmunoassay and discovery of conversion of T4-to-T3 in humans led to a major transition in clinical practices away from combination therapy, to adoption of levothyroxine "monotherapy" as the standard of care. Levothyroxine monotherapy has a favorable safety profile and can effectively normalize the serum TSH, the most sensitive marker of hypothyroidism. Whether levothyroxine monotherapy restores thyroid hormone signaling within all tissues remains controversial. Evidence of persistent signs and symptoms of hypothyroidism during levothyroxine monotherapy at doses that normalize serum TSH is mounting. Hence, in the last decade there has been acknowledgment by all thyroid professional societies that there may be a role for the use of combination therapy; this represents a significant shift in the clinical practice guidelines. Further bolstering this trend are the recent findings that the Thr92AlaD2 polymorphism may reduce thyroid hormone signaling, resulting in localized and systemic hypothyroidism. This strengthens the hypothesis that treatment options could be personalized, taking into consideration genotypes and comorbidities. The development of long-acting formulations of liothyronine and continued advancements in development of thyroid regenerative therapy, may propel the field closer to adoption of a physiologic thyroid hormone replacement regimen with combination therapy.
View details for DOI 10.3389/fendo.2019.00446
View details for PubMedID 31354624
View details for PubMedCentralID PMC6629976
A Common DIO2 Polymorphism and Alzheimer Disease Dementia in African and European Americans
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
2018; 103 (5): 1818-1826
A common single nucleotide polymorphism in DIO2, Thr92AlaD2, has been associated with a transcriptome typically found in neurodegenerative diseases in postmortem human brain tissue.To determine whether Thr92AlaD2 is associated with incident Alzheimer disease (AD).Population-based study; human brain tissue microarray.Community-based cohorts from Chicago and northeastern Illinois and religious clergymen from across the United States constituted the primary population. A representative sample of the U.S. population was used for secondary analyses.3054 African Americans (AAs) and 9304 European Americans (EAs).Incident AD.In the primary population, AAs with Thr92AlaD2 had 1.3 times [95% confidence interval (CI), 1.02 to 1.68; P = 0.048] greater odds of developing AD. AAs from a second population with Thr92AlaD2 showed a trend toward increased odds of dementia (odds ratio, 1.33; 95% CI, 0.99 to 1.78; P = 0.06) and 1.35 times greater odds of developing cognitive impairment not demented (CIND; 95% CI, 1.09 to 1.67; P = 0.006). Meta-analysis showed that AAs with Thr92AlaD2 had 1.3 times increased odds of developing AD/dementia (95% CI, 1.07 to 1.58; P = 0.008). In EAs, no association was found between Thr92AlaD2 and AD, dementia, or CIND. Microarray of AA brain tissue identified transcriptional patterns linked to AD pathogenesis.Thr92AlaD2 was associated with molecular markers known to underlie AD pathogenesis in AAs, translating to an observed phenotype of increased odds of developing AD/dementia in AAs in these populations. Thr92AlaD2 might represent one factor contributing to racial discrepancies in incident AD.
View details for DOI 10.1210/jc.2017-01196
View details for Web of Science ID 000432309500009
View details for PubMedID 29481662
View details for PubMedCentralID PMC6276710
Systemic Thyroid Hormone Status During Levothyroxine Therapy In Hypothyroidism: A Systematic Review and Meta-Analysis.
The Journal of clinical endocrinology and metabolism
The standard of care for overt hypothyroidism is levothyroxine at doses that normalize serum TSH levels. Whether this approach universally restores thyroid hormone signaling is unknown.To review studies of overt hypothyroidism in which participants were treated with levothyroxine to normalize serum TSH levels and measured other objective markers of thyroid hormone signaling.Databases were searched for studies that reported objective markers of thyroid hormone signaling (serum low-density lipoprotein (LDL), total cholesterol (TC), sex hormone-binding globulin (SHBG), creatine kinase and/or ferritin levels; cognition, energy expenditure, and/or renal function) in levothyroxine monotherapy for overt, primary hypothyroidism among nonpregnant adults with normal serum TSH levels. For studies with LDL, TC and SHBG outcomes, data were pooled using random effects meta-analysis.A total of 99 studies met inclusion criteria, including 65 that reported serum cholesterol data. Meta-analysis showed that levothyroxine-treated hypothyroid participants with normal serum TSH levels had 3.31 ± 1.64 mg/dL higher serum LDL levels (p=0.044) and 9.60 ± 3.55 mg/dL higher serum TC levels (p=0.007) compared to controls. In studies that did not concomitantly assess healthy controls, serum LDL levels were 138.3 ± 4.6 mg/dL (p<0.001) and serum TC levels were 209.6 ± 3.4 mg/dL (p<0.001). Meta-analysis of 2 studies showed no significant difference between SHBG levels of levothyroxine-treated participants and controls.In studies that utilized levothyroxine monotherapy at doses that normalized the serum TSH for overt, primary hypothyroidism, not all systemic biological markers of thyroid hormone signaling were normalized, including serum LDL and TC levels.
View details for DOI 10.1210/jc.2018-01361
View details for PubMedID 30124904
View details for PubMedCentralID PMC6226605
The Foxo1-Inducible Transcriptional Repressor Zfp125 Causes Hepatic Steatosis and Hypercholesterolemia.
2018; 22 (2): 523-534
Liver-specific disruption of the type 2 deiodinase gene (Alb-D2KO) results in resistance to both diet-induced obesity and liver steatosis in mice. Here, we report that this is explained by an ∼60% reduction in liver zinc-finger protein-125 (Zfp125) expression. Zfp125 is a Foxo1-inducible transcriptional repressor that causes lipid accumulation in the AML12 mouse hepatic cell line and liver steatosis in mice by reducing liver secretion of triglycerides and hepatocyte efflux of cholesterol. Zfp125 acts by repressing 18 genes involved in lipoprotein structure, lipid binding, and transport. The ApoE promoter contains a functional Zfp125-binding element that is also present in 17 other lipid-related genes repressed by Zfp125. While liver-specific knockdown of Zfp125 causes an "Alb-D2KO-like" metabolic phenotype, liver-specific normalization of Zfp125 expression in Alb-D2KO mice rescues the phenotype, restoring normal susceptibility to diet-induced obesity, liver steatosis, and hypercholesterolemia.
View details for DOI 10.1016/j.celrep.2017.12.053
View details for PubMedID 29320745
View details for PubMedCentralID PMC6474669
Blood pressure and risk of incident Alzheimer's disease dementia by antihypertensive medications and APOE ε4 allele.
Annals of neurology
2018; 83 (5): 935-944
To examine the association of blood pressure (BP) with incident Alzheimer's disease (AD) dementia.This work is based on a longitudinal, cohort study of 18 years, the Chicago Health and Aging Project (CHAP) performed in 2,137 participants (55% black) with systolic BP measured around 8.1 years before incident AD dementia.The association of BP with risk of AD dementia was U-shaped, with the lowest risks of AD dementia near the center of the systolic BP (SBP) and diastolic BP (DBP) distributions, and modestly elevated risk at lower BPs, and greater risk at higher BPs. The degree of U-shape and the range of lowest risk (threshold ranges) varied with antihypertensive medication use and presence of the APOE ε4 allele. The U-shape was most prominent for the subgroup not taking antihypertensive medications and having an APOE ε4 allele. At higher BPs, those having the APOE ε4 allele and not receiving antihypertensive medication were at greater risk of AD dementia than other groups: The risk of incident AD dementia increased by 100% (relative risk [RR] = 2.00; 95% confidence interval [CI] = 1.70, 2.31) for every 10 mm Hg increase in SBP above 140 mm Hg. For DBP, the risk of incident of AD dementia increased by 57% (RR = 1.57; 95% CI = 1.33, 1.86) for every 5 mm Hg increase in DBP above 76 mm Hg.The BP risk of AD dementia association is U-shaped, with elevated risk at lower and higher BPs. People having the APOE ε4 allele and not receiving antihypertensive medication with higher BPs have notably elevated risk of AD dementia. Ann Neurol 2018;83:935-944.
View details for DOI 10.1002/ana.25228
View details for PubMedID 29637601
View details for PubMedCentralID PMC6149540
Induction of Type 2 Iodothyronine Deiodinase After Status Epilepticus Modifies Hippocampal Gene Expression in Male Mice.
2018; 159 (8): 3090-3104
Status epilepticus (SE) is an abnormally prolonged seizure that results from either a failure of mechanisms that terminate seizures or from initiating mechanisms that inherently lead to prolonged seizures. Here we report that mice experiencing a 3 hours of SE caused by pilocarpine exhibit a rapid increase in expression of type 2 iodothyronine deiodinase gene (Dio2) and a decrease in the expression of type 3 iodothyronine deiodinase gene in hippocampus, amygdala and prefrontal cortex. Type 3 iodothyronine deiodinase in hippocampal sections was seen concentrated in the neuronal nuclei, typical of ischemic injury of the brain. An unbiased analysis of the hippocampal transcriptome of mice undergoing 3 hours of SE revealed a number of genes, including those involved with response to oxidative stress, cellular homeostasis, cell signaling, and mitochondrial structure. In contrast, in mice with targeted disruption of Dio2 in astrocytes (Astro D2KO mouse), the highly induced genes in the hippocampus were related to inflammation, apoptosis, and cell death. We propose that Dio2 induction caused by SE accelerates production of T3 in different areas of the central nervous system and modifies the hippocampal gene expression profile, affecting the balance between adaptive and maladaptive mechanisms.
View details for DOI 10.1210/en.2018-00146
View details for PubMedID 29905787
View details for PubMedCentralID PMC6669821
Does Sex Bias Play a Role for Dissatisfied Patients With Hypothyroidism?
Journal of the Endocrine Society
2018; 2 (8): 970-973
The current state of the diagnosis and management of thyroid disease cannot be separated from the larger context of women's health for the following reasons: (1) the disproportionate incidence and prevalence of functional and structural thyroid diseases among women vs men; (2) the role of thyroid health on fertility, pregnancy, and postpartum; and (3) the challenge posed in managing the nonspecific symptoms of functional thyroid disease in the context of menopause. Here, we explore the hypothesis that sex bias has played a role in the management of thyroid diseases historically and has extended into the modern medical era. Once knowledge gaps that may have resulted from sex bias are recognized, we can strive to overcome this bias and develop better treatments to improve patient outcomes universally.
View details for DOI 10.1210/js.2018-00169
View details for PubMedID 30094410
View details for PubMedCentralID PMC6077803
Racial Differences in the Association Between Apolipoprotein E Risk Alleles and Overall and Total Cardiovascular Mortality Over 18 Years.
Journal of the American Geriatrics Society
2017; 65 (11): 2425-2430
To examine the difference in the association between apolipoprotein (APO)E allele and overall and cardiovascular mortality between African Americans (AAs) and European Americans (EAs).Longitudinal, cohort study of 18 years.Biracial urban US population sample.4,917, 68% AA and 32% EA.APOE genotype and mortality based on National Death Index.A higher proportion of AAs than of EAs had an APOE ε2 allele (ε2ε2/ε2ε3/ε2ε4; 22% vs 13%) and an APOE ε4 allele (ε3ε4/ε4ε4; 33% vs 24%). After adjusting for known risk factors, the risk of mortality was 19% less with the APOE ε2 allele (hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.76-0.87), and the risk of cardiovascular mortality was 35% less (HR = 0.65, 95% CI = 0.58-0.76) than with the ε3ε3 allele. The risk of mortality was 10% greater with the APOE ε4 allele (HR = 1.10, 95% CI = 1.04-1.16), and the risk of cardiovascular mortality was 20% greater (HR = 1.20, 95% CI = 1.07-1.29) than with the ε3ε3 allele. No difference in the association between APOE allele and mortality was observed between AAs and EAs.The APOE ε4 allele increased the risk of overall and cardiovascular mortality, whereas the APOE ε2 allele decreased the risk of overall and cardiovascular mortality. There was no racial difference in the association between these alleles and mortality.
View details for DOI 10.1111/jgs.15059
View details for PubMedID 28898389
View details for PubMedCentralID PMC6201232
Bendamustine-induced nephrogenic diabetes insipidus.
2017; 87 (2017) (1): 47-50
A 59-year-old man presented with polyuria and polydipsia immediately following his sixth cycle of rituximab and bendamustine for chronic lymphocytic leukemia. He initially compensated by increasing his oral fluid intake at home, but later developed septic shock and was admitted with orders to be kept nil per os (NPO). This prompted an episode of acute hypernatremia during which he exhibited continued polyuria with inappropriately dilute urine. Desmopressin challenge yielded no response in the urine osmolality, indicating a nephrogenic source of his diabetes insipidus (DI). He had no known exposure to other causative agents and had demonstrated a robust response to chemotherapy. The patient became eunatremic once oral intake was resumed and his infection was treated. Two months after presentation, he remained symptomatic. A trial with hydrochlorothiazide resulted in a significant increase in urine osmolality and subsequent decrease in urine output. To our knowledge, this is the first case of nephrogenic diabetes insipidus after rituximab and bendamustine exposure. We propose that bendamustine, similar to the alkylating agent ifosfamide, is toxic to the glomerulus and proximal tubule cells and is the most likely cause of the patient's nephrogenic DI..
View details for DOI 10.5414/CN108908
View details for PubMedID 27719738
Cognitive decline following incident and preexisting diabetes mellitus in a population sample.
2016; 87 (16): 1681-1687
To examine if incident and preexisting diabetes mellitus (DM) were associated with cognitive decline among African Americans (AAs) and European Americans (EAs).Based on a prospective study of 7,740 older adults (mean age 72.3 years, 64% AA, 63% female), DM was ascertained by hypoglycemic medication use and Medicare claims during physician or hospital visits, and cognition by performance on a brief battery for executive functioning, episodic memory, and Mini-Mental State Examination (MMSE). Decline in composite and individual tests among those with incident DM, with preexisting DM, and without DM was studied using a linear mixed effects model with and without change point.At baseline, 737 (15%) AAs and 269 (10%) EAs had preexisting DM. Another 721 (17%) AAs and 289 (12%) EAs had incident DM in old age. Following incident DM, cognitive decline increased by 36% among AAs and by 40% among EAs compared to those without DM. No significant difference was observed between AAs and EAs (p = 0.64). However, cognitive decline increased by 17% among AAs with preexisting DM compared to those without DM, but no increased decline was observed among EAs with preexisting DM. In secondary analyses, faster decline in executive functioning and episodic memory was observed following incident DM.In old age, faster cognitive decline was present among AAs and EAs following incident DM, compared to cognitive decline prior to DM, and among those without DM. This underscores the need for stronger prevention and control of DM in old age.
View details for DOI 10.1212/WNL.0000000000003226
View details for PubMedID 27655734
View details for PubMedCentralID PMC5085078
- An active life is a sweet life. The lancet. Diabetes & endocrinology 2016; 4 (6): 548
The History and Future of Treatment of Hypothyroidism.
Annals of internal medicine
2016; 164 (1): 50-6
Thyroid hormone replacement has been used for more than a century to treat hypothyroidism. Natural thyroid preparations (thyroid extract, desiccated thyroid, or thyroglobulin), which contain both thyroxine (T4) and triiodothyronine (T3), were the first pharmacologic treatments available and dominated the market for the better part of the 20th century. Dosages were adjusted to resolve symptoms and to normalize the basal metabolic rate and/or serum protein-bound iodine level, but thyrotoxic adverse effects were not uncommon. Two major developments in the 1970s led to a transition in clinical practice: 1) The development of the serum thyroid-stimulating hormone (TSH) radioimmunoassay led to the discovery that many patients were overtreated, resulting in a dramatic reduction in thyroid hormone replacement dosage, and 2) the identification of peripheral deiodinase-mediated T4-to-T3 conversion provided a physiologic means to justify l-thyroxine monotherapy, obviating concerns about inconsistencies with desiccated thyroid. Thereafter, l-thyroxine monotherapy at doses to normalize the serum TSH became the standard of care. Since then, a subgroup of thyroid hormone-treated patients with residual symptoms of hypothyroidism despite normalization of the serum TSH has been identified. This has brought into question the inability of l-thyroxine monotherapy to universally normalize serum T3 levels. New research suggests mechanisms for the inadequacies of l-thyroxine monotherapy and highlights the possible role for personalized medicine based on deiodinase polymorphisms. Understanding the historical events that affected clinical practice trends provides invaluable insight into formulation of an approach to help all patients achieve clinical and biochemical euthyroidism.
View details for DOI 10.7326/M15-1799
View details for PubMedID 26747302
View details for PubMedCentralID PMC4980994
Less is More: Comparing the 2015 and 2009 American Thyroid Association Guidelines for Thyroid Nodules and Cancer.
Thyroid : official journal of the American Thyroid Association
2016; 26 (6): 759-64
The American Thyroid Association (ATA) has recently revised its guidance pertaining to thyroid nodules and follicular cell-derived thyroid cancer. The 2015 guidelines are massive in both scope and scale, with changes in the organizational approach to risk stratification of nodules and cancer, as well as multiple sections covering new material. This review highlights the major structural and organizational changes, focusing attention on the most dramatically changed recommendations, that is, those recommendations that clinicians will find striking because they call for significant divergence from prior clinical practice.The revised approach to thyroid nodule risk stratification is based on sonographic pattern, with an emphasis on pattern rather than growth in the long-term surveillance of nodules. Accumulating data have also been incorporated into an updated risk stratification scheme for thyroid cancer that increases the size of the low-risk pool, in part because low-volume lymph nodal metastases are now considered low risk. The most fundamentally altered recommendation is that lobectomy might be considered as the initial surgical approach for follicular cell-derived thyroid cancers from 1 to 4 cm in size.The underlying theme of the 2015 ATA guidelines is that "less is more." As these new recommendations are adopted, fewer fine-needle aspiration biopsies will need to be done, less extensive surgeries will become more common, less radioactive iodine will be used either for treatment or for diagnostics, and less stimulated thyroglobulin testing will be done. Mastery of these guidelines will help clinicians know when it is reasonable to do less, thus providing responsibly individualized therapy for their patients.
View details for DOI 10.1089/thy.2016.0068
View details for PubMedID 27141822
Type 2 Deiodinase Disruption in Astrocytes Results in Anxiety-Depressive-Like Behavior in Male Mice.
2016; 157 (9): 3682-95
Millions of levothyroxine-treated hypothyroid patients complain of impaired cognition despite normal TSH serum levels. This could reflect abnormalities in the type 2 deiodinase (D2)-mediated T4-to-T3 conversion, given their much greater dependence on the D2 pathway for T3 production. T3 normally reaches the brain directly from the circulation or is produced locally by D2 in astrocytes. Here we report that mice with astrocyte-specific Dio2 inactivation (Astro-D2KO) have normal serum T3 but exhibit anxiety-depression-like behavior as found in open field and elevated plus maze studies and when tested for depression using the tail-suspension and the forced-swimming tests. Remarkably, 4 weeks of daily treadmill exercise sessions eliminated this phenotype. Microarray gene expression profiling of the Astro-D2KO hippocampi identified an enrichment of three gene sets related to inflammation and impoverishment of three gene sets related to mitochondrial function and response to oxidative stress. Despite normal neurogenesis, the Astro-D2KO hippocampi exhibited decreased expression of four of six known to be positively regulated genes by T3, ie, Mbp (∼43%), Mag (∼34%), Hr (∼49%), and Aldh1a1 (∼61%) and increased expression of 3 of 12 genes negatively regulated by T3, ie, Dgkg (∼17%), Syce2 (∼26%), and Col6a1 (∼3-fold) by quantitative real-time PCR. Notably, in Astro-D2KO animals, there was also a reduction in mRNA levels of genes known to be affected in classical animal models of depression, ie, Bdnf (∼18%), Ntf3 (∼43%), Nmdar (∼26%), and GR (∼20%), which were also normalized by daily exercise sessions. These findings suggest that defects in Dio2 expression in the brain could result in mood and behavioral disorders.
View details for DOI 10.1210/en.2016-1272
View details for PubMedID 27501182
View details for PubMedCentralID PMC5007895
Is a Normal TSH Synonymous With "Euthyroidism" in Levothyroxine Monotherapy?
The Journal of clinical endocrinology and metabolism
2016; 101 (12): 4964-4973
Levothyroxine (LT4) monotherapy is the standard of care for hypothyroidism.To determine whether LT4 at doses that normalize the serum TSH is associated with normal markers of thyroid status.Cross-sectional data from the US National Health and Nutrition Examination Survey (2001-2012) was used to evaluate 52 clinical parameters. LT4 users were compared to healthy controls and controls matched for age, sex, race, and serum TSH. Regression was used to evaluate for correlation with T4 and T3 levels.A total of 9981 participants with normal serum TSH were identified; 469 were LT4-treated.Participants using LT4 had higher serum total and free T4 and lower serum total and free T3 than healthy or matched controls. This translated to approximately 15-20% lower serum T3:T4 ratios in LT4 treatment, as has been shown in other cohorts. In comparison to matched controls, LT4-treated participants had higher body mass index despite report of consuming fewer calories/day/kg; were more likely to be taking beta-blockers, statins, and antidepressants; and reported lower total metabolic equivalents. A serum TSH level below the mean in LT4-treated participants was associated with a higher serum free T4 but similar free and total T3; yet those with lower serum TSH levels exhibited higher serum high-density lipoprotein and lower serum low-density lipoprotein, triglycerides, and C-reactive protein. Age was negatively associated with serum free T3:free T4 ratio in all participants; caloric intake was positively associated in LT4-treated individuals.In a large population study, participants using LT4 exhibited lower serum T3:T4 ratios and differed in 12/52 objective and subjective measures.
View details for DOI 10.1210/jc.2016-2660
View details for PubMedID 27700539
View details for PubMedCentralID PMC6287526
Perinatal deiodinase 2 expression in hepatocytes defines epigenetic susceptibility to liver steatosis and obesity
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2015; 112 (45): 14018-14023
Thyroid hormone binds to nuclear receptors and regulates gene transcription. Here we report that in mice, at around the first day of life, there is a transient surge in hepatocyte type 2 deiodinase (D2) that activates the prohormone thyroxine to the active hormone triiodothyronine, modifying the expression of ∼165 genes involved in broad aspects of hepatocyte function, including lipid metabolism. Hepatocyte-specific D2 inactivation (ALB-D2KO) is followed by a delay in neonatal expression of key lipid-related genes and a persistent reduction in peroxisome proliferator-activated receptor-γ expression. Notably, the absence of a neonatal D2 peak significantly modifies the baseline and long-term hepatic transcriptional response to a high-fat diet (HFD). Overall, changes in the expression of approximately 400 genes represent the HFD response in control animals toward the synthesis of fatty acids and triglycerides, whereas in ALB-D2KO animals, the response is limited to a very different set of only approximately 200 genes associated with reverse cholesterol transport and lipase activity. A whole genome methylation profile coupled to multiple analytical platforms indicate that 10-20% of these differences can be related to the presence of differentially methylated local regions mapped to sites of active/suppressed chromatin, thus qualifying as epigenetic modifications occurring as a result of neonatal D2 inactivation. The resulting phenotype of the adult ALB-D2KO mouse is dramatic, with greatly reduced susceptibility to diet-induced steatosis, hypertriglyceridemia, and obesity.
View details for DOI 10.1073/pnas.1508943112
View details for Web of Science ID 000364470300078
View details for PubMedID 26508642
View details for PubMedCentralID PMC4653175
Epicardial adipose tissue has a unique transcriptome modified in severe coronary artery disease
2015; 23 (6): 1267-1278
To explore the transcriptome of epicardial adipose tissue (EAT) as compared to subcutaneous adipose tissue (SAT) and its modifications in a small number of patients with coronary artery disease (CAD) versus valvulopathy.SAT and EAT samples were obtained during elective cardiothoracic surgeries. The transcriptome of EAT was evaluated, as compared to SAT, using an unbiased, whole-genome approach in subjects with CAD (n = 6) and without CAD (n = 5), where the patients without CAD had cardiac valvulopathy.Relative to SAT, EAT is a highly inflammatory tissue enriched with genes involved in endothelial function, coagulation, immune signaling, potassium transport, and apoptosis. EAT is lacking in expression of genes involved in protein metabolism, tranforming growth factor-beta (TGF-beta) signaling, and oxidative stress. Although underpowered, in subjects with severe CAD, there is an expression trend suggesting widespread downregulation of EAT encompassing a diverse group of gene sets related to intracellular trafficking, proliferation/transcription regulation, protein catabolism, innate immunity/lectin pathway, and ER stress.The EAT transcriptome is unique when compared to SAT. In the setting of CAD versus valvulopathy, there is possible alteration of the EAT transcriptome with gene suppression. This pilot study explores the transcriptome of EAT in CAD and valvulopathy, providing new insight into its physiologic and pathophysiologic roles.
View details for DOI 10.1002/oby.21059
View details for Web of Science ID 000355150300020
View details for PubMedID 25959145
View details for PubMedCentralID PMC5003780
Prevalent Polymorphism in Thyroid Hormone-Activating Enzyme Leaves a Genetic Fingerprint That Underlies Associated Clinical Syndromes
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
2015; 100 (3): 920-933
A common polymorphism in the gene encoding the activating deiodinase (Thr92Ala-D2) is known to be associated with quality of life in millions of patients with hypothyroidism and with several organ-specific conditions. This polymorphism results in a single amino acid change within the D2 molecule where its susceptibility to ubiquitination and proteasomal degradation is regulated.To define the molecular mechanisms underlying associated conditions in carriers of the Thr92Ala-D2 polymorphism.Microarray analyses of 19 postmortem human cerebral cortex samples were performed to establish a foundation for molecular studies via a cell model of HEK-293 cells stably expressing Thr92 or Ala92 D2.The cerebral cortex of Thr92Ala-D2 carriers exhibits a transcriptional fingerprint that includes sets of genes involved in CNS diseases, ubiquitin, mitochondrial dysfunction (chromosomal genes encoding mitochondrial proteins), inflammation, apoptosis, DNA repair, and growth factor signaling. Similar findings were made in Ala92-D2-expressing HEK-293 cells and in both cases there was no evidence that thyroid hormone signaling was affected ie, the expression level of T3-responsive genes was unchanged, but that several other genes were differentially regulated. The combined microarray analyses (brain/cells) led to the development of an 81-gene classifier that correctly predicts the genotype of homozygous brain samples. In contrast to Thr92-D2, Ala92-D2 exhibits longer half-life and was consistently found in the Golgi. A number of Golgi-related genes were down-regulated in Ala92-D2-expressing cells, but were normalized after 24-h-treatment with the antioxidant N-acetylecysteine.Ala92-D2 accumulates in the Golgi, where its presence and/or ensuing oxidative stress disrupts basic cellular functions and increases pre-apoptosis. These findings are reminiscent to disease mechanisms observed in other neurodegenerative disorders such as Huntington's disease, and could contribute to the unresolved neurocognitive symptoms of affected carriers.
View details for DOI 10.1210/jc.2014-4092
View details for Web of Science ID 000353358900040
View details for PubMedID 25569702
View details for PubMedCentralID PMC4333048
Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine
JOURNAL OF CLINICAL INVESTIGATION
2015; 125 (2): 769-781
The current treatment for patients with hypothyroidism is levothyroxine (L-T4) along with normalization of serum thyroid-stimulating hormone (TSH). However, normalization of serum TSH with L-T4 monotherapy results in relatively low serum 3,5,3'-triiodothyronine (T3) and high serum thyroxine/T3 (T4/T3) ratio. In the hypothalamus-pituitary dyad as well as the rest of the brain, the majority of T3 present is generated locally by T4 deiodination via the type 2 deiodinase (D2); this pathway is self-limited by ubiquitination of D2 by the ubiquitin ligase WSB-1. Here, we determined that tissue-specific differences in D2 ubiquitination account for the high T4/T3 serum ratio in adult thyroidectomized (Tx) rats chronically implanted with subcutaneous L-T4 pellets. While L-T4 administration decreased whole-body D2-dependent T4 conversion to T3, D2 activity in the hypothalamus was only minimally affected by L-T4. In vivo studies in mice harboring an astrocyte-specific Wsb1 deletion as well as in vitro analysis of D2 ubiquitination driven by different tissue extracts indicated that D2 ubiquitination in the hypothalamus is relatively less. As a result, in contrast to other D2-expressing tissues, the hypothalamus is wired to have increased sensitivity to T4. These studies reveal that tissue-specific differences in D2 ubiquitination are an inherent property of the TRH/TSH feedback mechanism and indicate that only constant delivery of L-T4 and L-T3 fully normalizes T3-dependent metabolic markers and gene expression profiles in Tx rats.
View details for DOI 10.1172/JCI77588
View details for Web of Science ID 000348962700031
View details for PubMedID 25555216
View details for PubMedCentralID PMC4319436
Acute-on-Chronic Kidney Injury in Thyroid Hormone Withdrawal: A Case with Possible Implications for Radioactive Iodine Planning
CASE REPORTS IN ENDOCRINOLOGY
2015; 2015: 932372
The association between renal dysfunction and hypothyroidism is of increasing clinical importance as thyroid hormone replacement may attenuate decline in renal function and improve cardiovascular outcomes in patients with chronic kidney disease (CKD). Although multiple mechanisms for the induction of renal insufficiency in hypothyroidism have been described, the renal impact of short-term, acute hypothyroidism is unknown, which has possible implications for thyroid cancer patients preparing to receive radioactive iodine (RAI). A 56-year-old gentleman with history of unilateral renal agenesis and CKD stage III presented with intermediate-risk papillary thyroid cancer. In preparation for RAI, he underwent thyroid hormone withdrawal (THW) associated with acute kidney injury (AKI), as marked by a decrease in his estimated GFR from 53 to 32 mL/min/1.73 m(2). Upon resumption of thyroid hormone, renal function returned to baseline within months. Although AKI in this case was not otherwise associated with adverse outcome and reversed upon resumption of thyroid hormone, it is possible that this phenomenon could result in potential harm, particularly in the patient with baseline renal insufficiency. In CKD patients, preparation for RAI therapy may require special consideration; future studies should address the role of recombinant TSH to mitigate deleterious renal effects of acute hypothyroidism in this setting.
View details for DOI 10.1155/2015/932372
View details for Web of Science ID 000369667400001
View details for PubMedID 26351591
View details for PubMedCentralID PMC4553173
Thyroid Hormone at Near Physiologic Concentrations Acutely Increases Oxygen Consumption and Extracellular Acidification in LH86 Hepatoma Cells.
2015; 156 (11): 4325-35
Thyroid hormone (T3) has been known to regulate the basal metabolic rate for more than a century, but mechanistic understanding is lacking both at the level of the intact organism and in terms of how T3 alters energy expenditure in individual tissues. The current studies investigate the question of which metabolically relevant genes respond acutely as T3 concentrations increase through the physiologic range in liver cells. Because this has been technically unfeasible historically, we developed a modified protocol for extracellular flux analysis using a 96-well Extracellular Flux Analyzer (Seahorse Bioscience). Using a modified extracellular flux protocol and LH86 human hepatoma cells, we established an experimental system where small but significant changes in O2 consumption could be reproducibly quantified as hypothyroid cells were exposed to near-physiologic final concentrations of T3 approximately 2 orders of magnitude lower than most studies (0.04 nM free T3), in only 6-7 hours. Taking advantage of the nondestructive nature of 96-well Extracellular Flux Analyzer measurements, the acute, direct, transcriptional changes that occur were measured in the exact same cells demonstrating increased O2 consumption. An unbiased, genome-wide microarray analysis identified potential candidate genes related to fatty acid oxidation, angiogenesis, nucleotide metabolism, immune signaling, mitochondrial respiration, and cell proliferation. The identified transcriptome is likely enriched in the genes most important for mediating the energetic effects of T3 in hepatoma cells.
View details for DOI 10.1210/en.2015-1221
View details for PubMedID 26287403
- New insights into the variable effectiveness of levothyroxine monotherapy for hypothyroidism. The lancet. Diabetes & endocrinology 2015; 3 (10): 756-8
Scope and limitations of iodothyronine deiodinases in hypothyroidism.
Nature reviews. Endocrinology
2015; 11 (11): 642-652
The coordinated expression and activity of the iodothyronine deiodinases regulate thyroid hormone levels in hypothyroidism. Once heralded as the pathway underpinning adequate thyroid-hormone replacement therapy with levothyroxine, the role of these enzymes has come into question as they have been implicated in both an inability to normalize serum levels of tri-iodothyronine (T3) and the incomplete resolution of hypothyroid symptoms. These observations, some of which were validated in animal models of levothyroxine monotherapy, challenge the paradigm that tissue levels of T3 and thyroid-hormone signalling can be fully restored by administration of levothyroxine alone. The low serum levels of T3 observed among patients receiving levothyroxine monotherapy occur as a consequence of type 2 iodothyronine deiodinase (DIO2) in the hypothalamus being fairly insensitive to ubiquitination. In addition, residual symptoms of hypothyroidism have been linked to a prevalent polymorphism in the DIO2 gene that might be a risk factor for neurodegenerative disease. Here, we discuss how these novel findings underscore the clinical importance of iodothyronine deiodinases in hypothyroidism and how an improved understanding of these enzymes might translate to therapeutic advances in the care of millions of patients with this condition.
View details for DOI 10.1038/nrendo.2015.155
View details for PubMedID 26416219
View details for PubMedCentralID PMC5003781
- Of rats and men: thyroid homeostasis in rodents and human beings - Authors' reply. The lancet. Diabetes & endocrinology 2015; 3 (12): 933
Considerations regarding adherence of anti-osteoporosis therapy
2015; 127 (1): 92-98
Osteoporosis remains a challenging disease to treat due to a number of barriers including patient adherence to therapies. One of the most recent advances has been the development of the Fracture Risk Assessment Tool, which is helpful in conveying fracture risk to patients and providing treatment guidance to clinicians. The decision to use an anti-osteoporosis therapy must be tailored to the patient's specific clinical scenario. The bisphosphonates are first-line agents in the treatment of osteoporosis and are efficacious in substantially reducing fracture risk between 25% and 70% on average depending on fracture site. Compliance with oral bisphosphonate pills can be poor, resulting in a significant deterrent to the proper management of osteoporosis. Non-pill forms of bisphosphonate and nonbisphosphonate therapy are available for the treatment of osteoporosis and may increase compliance. Among these is Binosto, a new formulation of weekly effervescent alendronate, as well as intravenous bisphosphonates, teriparatide, and subcutaneously administered denosumab, which are all costly medications and are unlikely to become the mainstay of treatment over the oral bisphosphonate pills. Having a detailed conversation between the patient and physician is essential to the development of a tailored treatment plan that will decrease fracture risk.
View details for DOI 10.1080/00325481.2015.993278
View details for Web of Science ID 000353451700014
View details for PubMedID 25526234
- Tissue-Specific Inactivation of Type 2 Deiodinase Reveals Multilevel Control of Fatty Acid Oxidation by Thyroid Hormone in the Mouse (vol 63, pg 1594, 2014) DIABETES 2014; 63 (8): 2895
Heterozygosis for Inactive Type-3 Deiodinase Gene in Mice Results in Delayed Puberty in Males and Precocious Puberty with Low Fertility in Females
ENDOCRINE SOC. 2014
View details for Web of Science ID 000209805104124
Coccidiomycosis Thyroiditis in an Immunocompromised Host Post-Transplant: Case Report and Literature Review
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
2014; 99 (5): 1537-1542
Acute infectious thyroiditis, particularly fungal thyroiditis, is rare and typically presents in immunocompromised individuals. Here we report the first case of coccidiomycosis thyroiditis occurring in an organ recipient as a consequence of likely allograft contamination and discuss the management strategies for thyroid masses in the setting of disseminated infection.In this clinical case seminar, we summarize the previously published cases of coccidiomycosis thyroiditis based on a MEDLINE search of all peer-reviewed publications (original articles and reviews) on this topic. We identified six other cases, five of which also occurred in immunocompromised hosts, although none occurred in organ recipients.A case of coccidiomycosis thyroiditis occurring in a post-liver transplant immunocompromised host is reported. Analysis of donor serum revealed the liver allograft as the likely infectious source, resulting in hematological spread to the thyroid. Although our patient's thyroid gland was lacking gross structural abnormalities at presentation, new-onset thyroid masses developed after relative immune restoration and initiation of antifungal therapies. The differential diagnosis of new-onset thyroid masses in immunocompromised hosts is discussed, with a focus on immune reconstitution inflammatory syndrome. The role of thyroidectomy in the management of fungal thyroiditis is also discussed.
View details for DOI 10.1210/jc.2013-4373
View details for Web of Science ID 000342339800033
View details for PubMedID 24606101
Tissue-Specific Inactivation of Type 2 Deiodinase Reveals Multilevel Control of Fatty Acid Oxidation by Thyroid Hormone in the Mouse
2014; 63 (5): 1594-1604
Type 2 deiodinase (D2) converts the prohormone thyroxine (T4) to the metabolically active molecule 3,5,3'-triiodothyronine (T3), but its global inactivation unexpectedly lowers the respiratory exchange rate (respiratory quotient [RQ]) and decreases food intake. Here we used FloxD2 mice to generate systemically euthyroid fat-specific (FAT), astrocyte-specific (ASTRO), or skeletal-muscle-specific (SKM) D2 knockout (D2KO) mice that were monitored continuously. The ASTRO-D2KO mice also exhibited lower diurnal RQ and greater contribution of fatty acid oxidation to energy expenditure, but no differences in food intake were observed. In contrast, the FAT-D2KO mouse exhibited sustained (24 h) increase in RQ values, increased food intake, tolerance to glucose, and sensitivity to insulin, all supporting greater contribution of carbohydrate oxidation to energy expenditure. Furthermore, FAT-D2KO animals that were kept on a high-fat diet for 8 weeks gained more body weight and fat, indicating impaired brown adipose tissue (BAT) thermogenesis and/or inability to oxidize the fat excess. Acclimatization of FAT-D2KO mice at thermoneutrality dissipated both features of this phenotype. Muscle D2 does not seem to play a significant metabolic role given that SKM-D2KO animals exhibited no phenotype. The present findings are unique in that they were obtained in systemically euthyroid animals, revealing that brain D2 plays a dominant albeit indirect role in fatty acid oxidation via its sympathetic control of BAT activity. D2-generated T3 in BAT accelerates fatty acid oxidation and protects against diet-induced obesity.
View details for DOI 10.2337/db13-1768
View details for Web of Science ID 000334796600023
View details for PubMedID 24487027
View details for PubMedCentralID PMC3994955
Thyroid hormone signaling in energy homeostasis and energy metabolism
YEAR IN DIABETES AND OBESITY
2014; 1311: 77-87
The thyroid hormone (TH) plays a significant role in diverse processes related to growth, development, differentiation, and metabolism. TH signaling modulates energy expenditure through both central and peripheral pathways. At the cellular level, the TH exerts its effects after concerted mechanisms facilitate binding to the TH receptor. In the hypothalamus, signals from a range of metabolic pathways, including appetite, temperature, afferent stimuli via the autonomic nervous system, availability of energy substrates, hormones, and other biologically active molecules, converge to maintain plasma TH at the appropriate level to preserve energy homeostasis. At the tissue level, TH actions on metabolism are controlled by transmembrane transporters, deiodinases, and TH receptors. In the modern environment, humans are susceptible to an energy surplus, which has resulted in an obesity epidemic and, thus, understanding the contribution of the TH to cellular and organism metabolism is increasingly relevant.
View details for DOI 10.1111/nyas.12374
View details for Web of Science ID 000336210700006
View details for PubMedID 24697152
View details for PubMedCentralID PMC4451242
The role of thyroid hormone and brown adipose tissue in energy homoeostasis
LANCET DIABETES & ENDOCRINOLOGY
2013; 1 (3): 250-258
The presence of brown adipose tissue (BAT) in adults has become increasingly well defined as a result of functional imaging studies of thermogenically active BAT. Findings from these studies have created a surge of scientific interest in BAT, because it represents a potential therapeutic target for obesity--a condition with profound health consequences and few successful therapies. BAT contributes to overall energy expenditure in small mammals and neonates through adaptive thermogenesis. Thyroid-hormone signalling, particularly through induction of type II deiodinase, has a central role in brown adipogenesis in vitro and BAT development in mouse embryos. Additionally, because of high intracellular expression of type II deiodinase, adult BAT has enhanced thyroid-hormone signalling with several thyroid-hormone-dependent thermogenic pathways, including expression of the genes Ppargc1a and Ucp1. BAT thermogenesis explains the essential part played by thyroid hormone in energy homoeostasis and adaptation to cold. Stimulation of BAT in adults, specifically through thyroid-hormone-mediated pathways, is a promising therapeutic target for obesity.
View details for DOI 10.1016/S2213-8587(13)70069-X
View details for Web of Science ID 000341799600026
View details for PubMedID 24622373
View details for PubMedCentralID PMC4976626
Efficacy of a Hospital-Based Fracture Liaison Service in the Secondary Prevention of Osteoporotic Fractures
View details for Web of Science ID 000332035803212