Scope and limitations of iodothyronine deiodinases in hypothyroidism.

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

Accelerating functional gene discovery in osteoarthritis.

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

Accelerating functional gene discovery in osteoarthritis.

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

Acute-on-Chronic Kidney Injury in Thyroid Hormone Withdrawal: A Case with Possible Implications for Radioactive Iodine Planning

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 m2. 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

A Cutaneous False Positive in Radioiodine Scintigraphy for Metastatic Thyroid Cancer

Contamination of external sites with secretions or excretory products can mimic metastases and yield false positives in radioiodine whole-body scintigraphy for thyroid cancer. We present a case of a 26-year-old woman with differentiated papillary thyroid carcinoma who received radioiodine 131 (I-131) for treatment of persistent upper mediastinal metastasis. Her post-treatment whole-body scintigraphy revealed an unexpected focus of increased uptake near the scalp in addition to the mediastinal lesion. Although the scalp is the most common site of cutaneous thyroid cancer metastasis, differentiated thyroid cancers rarely manifest with cutaneous thyroid cancer metastasis and thus it is prudent to consider etiologies of false positive I-131 uptake in such cases. Contamination of our patient’s hair from salivary secretions was confirmed on history and with coiffure repositioning during whole-body scintigraphy

Supplemental Tables--McAninch et al 2018

Supplemental Tables--McAninch et al 201

Data from: Systemic thyroid hormone status during levothyroxine therapy in hypothyroidism: a systematic review and meta-analysis

CONTEXT: 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. OBJECTIVE: 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. DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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

Statin initiation and risk of incident Alzheimer disease and cognitive decline in genetically susceptible older adults

BACKGROUND AND OBJECTIVES: The association of statin initiation with incident Alzheimer disease (AD) dementia and cognitive decline by the APOE ε4 allele is unknown. Our objective was to examine whether the association of statin initiation with incident AD dementia and cognitive decline differs by the APOE ε4 allele. METHODS: This population-based longitudinal cohort study was conducted in 4 urban communities in Chicago, IL, United States, consisting of 4,807 participants. Statin initiation is based on the inspection of medications during home assessments. Clinical diagnosis for incident AD used the NINCDS-ADRDA criteria, and longitudinal measurements of global cognition consisted of episodic memory, perceptual speed, and the Mini-Mental State Examination tests. RESULTS: The study participants had a mean age of 72 years, consisting of 63% female individuals and 61% non-Hispanic Black individuals. During the study period, 1,470 (31%) participants reported statin initiation. In a covariate-adjusted competing risk model, statin initiation was associated with a reduced risk of incident clinical AD [hazard ratio (HR) 0.81 (95% CI 0.70-0.94)] compared with nonusers. This association was statistically significantly lower (p interaction = 0.015) among participants with the APOE ε4 allele [HR 0.60 (95% CI 0.49-0.74)] compared with those without the APOE ε4 allele [HR 0.96 (95% CI 0.82-1.12)]. The annual decline in global cognition (β = 0.021, 95% CI 0.007-0.034) and episodic memory (β = 0.020, 95% CI 0.007-0.033) was also substantially slower among participants with the APOE ε4 allele after statin initiation compared with nonusers. However, the association of statin initiation with cognitive decline was not significant among those without the APOE ε4 allele. DISCUSSION: Our findings suggest that statins might be associated with a lower risk of incident AD among individuals with the APOE ε4 allele. The benefits of statin therapy need further consideration in randomized clinical trials, especially among those with the APOE ε4 allele. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among those aged 65 years or older, statin initiation was associated with a reduced risk of Alzheimer disease, especially in the presence of an APOE-e4 allele

Temporal changes in the likelihood of dementia and MCI over 18 years in a population sample.

OBJECTIVE: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. METHODS: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. RESULTS: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. CONCLUSION: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