Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas.

Insulinomas are pancreatic islet tumors that inappropriately secrete insulin, producing hypoglycemia. Exome and targeted sequencing revealed that 14 of 43 insulinomas harbored the identical somatic mutation in the DNA-binding zinc finger of the transcription factor Yin Yang 1 (YY1). Chromatin immunoprecipitation sequencing (ChIP-Seq) showed that this T372R substitution changes the DNA motif bound by YY1. Global analysis of gene expression demonstrated distinct clustering of tumors with and without YY1(T372R) mutations. Genes showing large increases in expression in YY1(T372R) tumors included ADCY1 (an adenylyl cyclase) and CACNA2D2 (a Ca(2+) channel); both are expressed at very low levels in normal ß-cells and show mutation-specific YY1 binding sites. Both gene products are involved in key pathways regulating insulin secretion. Expression of these genes in rat INS-1 cells demonstrated markedly increased insulin secretion. These findings indicate that YY1(T372R) mutations are neomorphic, resulting in constitutive activation of cAMP and Ca(2+) signaling pathways involved in insulin secretion.

AN INDIVIDUALIZED APPROACH TO THE EVALUATION AND MANAGEMENT OF PRIMARY ALDOSTERONISM.

OBJECTIVE: With the increased emphasis on personalized and individualized medicine, the American Association of Clinical Endocrinologists Adrenal Scientific Committee has developed a series of articles to update members on personalized medicine as it applies to adrenal diseases. METHODS: We synthesized literature reviews, guidelines from professional societies, and personal experience. RESULTS: Since Conn described primary aldosteronism (PA) over 60 years ago, debate has raged about the prevalence of PA in the hypertensive population, the wisdom of broadly screening for PA, and prudent approaches to evaluate and manage these patients. Accumulated data from multiple centers around the globe have begun to crystallize the clinical characteristics about these patients, which allows for an individualized approach before the diagnosis of PA is even established. Evidence-based criteria for screening, improved and widely available clinical assays, and validated algorithms for evaluation empower all endocrinologists to address this complex disease in an effective manner. CONCLUSION: Breakthroughs in the pathogenesis and evolution of PA illustrate why our thinking about this disease must remain flexible: PA is not a rare and uniform condition, but rather a common syndrome with protean manifestations. ABBREVIATIONS: A/C = cortisol-corrected aldosterone concentration; ACE = angiotensin-converting enzyme; APA = aldosterone-producing adenoma; APCC = aldosterone-producing cell cluster; ARB = angiotensin receptor blocker; ARR = aldosterone-to-renin ratio; AVS = adrenal venous sampling; CT = computed tomography; ENaC = epithelial sodium channel; GRA = glucocorticoid remediable aldosteronism; IHA = idiopathic hyperaldosteronism; LI = lateralization ratio; MR = mineralocorticoid receptor; MRI = magnetic resonance imaging; PA = primary aldosteronism; PRA = plasma renin activity; SRA = surgical remediable aldosteronism.

Daily Glucocorticoid Replacement Dose in Adrenal Insufficiency, a Mini Review.

The Endocrine Society Guidelines and recent reviews of adrenal insufficiency (AI) recommend a daily glucocorticoid replacement dose of 15 to 25 mg with a midpoint of 20 mg of hydrocortisone (HC) (alternatively 3 to 5 mg prednisolone) in divided doses in otherwise healthy individuals with AI. In contrast, a daily glucocorticoid replacement dose of 4.3 to 26 mg/d HC with a midpoint of 15 mg/d is predicted from current measurements of daily cortisol production rates and oral HC bioavailability. The higher HC doses recommended in the current guidelines may result in glucocorticoid overtreatment of some AI patients and associated long-term adverse outcomes. A titration method for determination of the individual patient's daily glucocorticoid replacement dose and the impact of lower doses are reviewed. Future related research questions are identified.

Metformin Decreases Serum Thyroglobulin Concentration in Nonmedullary Thyroid Carcinoma.

Context: The conventional treatment of nonmedullary thyroid carcinoma (NMTC) includes surgical resection, thyrotropin (TSH) suppression, and 131-iodine. Some patients develop persistent/recurrent metastatic disease requiring expensive alternative therapies, such as external radiation and multikinase inhibitors, which may have clinically significant side effects. Recent in vitro studies, in vivo studies in animals, and association studies in humans suggest that metformin, an inexpensive medication with a modest side effect profile, may help prevent or treat NMTC. No interventional trials analyzing the effect of metformin have been performed in humans. Objective: We hypothesize that metformin administration will decrease serum thyroglobulin concentration (Tg), a surrogate marker for NMTC burden. Methods: This retrospective institutional review board-approved study included 10 patients with persistent/recurrent NMTC who had exhausted conventional therapies including total thyroidectomy and 131-iodine. Five had detectable disease on computed tomography imaging. All had biochemical evidence of NMTC with Tg > 2.0 ng/mL with nondetectable serum thyroglobulin antibody concentrations. Five elected to have metformin treatment at doses varying from 500 to 2000 mg/day for 2 to 5 months. The remaining 5 served as untreated controls. Statistical significance was determined by the Mann-Whitney test. Results: Tg decreased (mean decrease = 21.7 ± 8.4%) in all 5 patients receiving metformin and increased (mean increase = 16.6 ± 12.1%) in all 5 controls (P < .01). TSH did not change significantly in either group. Conclusion: In summary, metformin caused a TSH-independent Tg decrease in patients with persistent/recurrent NMTC. More extensive studies are required to determine if metformin slows NMTC progression.

Resolution of manic symptoms following unilateral adrenalectomy in patient with primary bilateral macronodular adrenal hyperplasia.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is often associated with symptoms of cortisol excess, which may include neuropsychological symptoms. We report a patient with PBMAH who presented with manic symptoms that resolved following unilateral adrenalectomy.

Analytical and clinical validation of pairwise microRNA expression analysis to identify medullary thyroid cancer in thyroid fine-needle aspiration samples.

BACKGROUND: Medullary thyroid carcinoma (MTC) is an aggressive malignancy originating from the parafollicular C cells. Preoperatively, thyroid nodule fine-needle aspiration cytology (FNAC) and pathogenic gene mutations are definitive in approximately one-half of cases. MicroRNAs (miRNAs) are endogenous, noncoding, single-stranded RNAs that regulate gene expression, a characteristic that confers the potential for identifying malignancy. In the current study, the authors hypothesized that differential pairwise (diff-pair) analysis of miRNA expression levels would reliably identify MTC in FNA samples. METHODS: The relative abundance of 10 different miRNAs in total nucleic acids was obtained from ThyraMIR test results. Diff-pair analysis was performed by subtracting the critical threshold value of one miRNA from the critical threshold values of other miRNAs. Next-generation sequencing with the ThyGeNEXT panel identified oncogenic gene alterations. The discovery cohort consisted of 30 formalin-fixed, paraffin-embedded benign and malignant thyroid neoplasms, including 4 cases of MTC. After analytical validation, clinical validation was performed using 3 distinct cohorts (total of 7557 specimens). RESULTS: In the discovery cohort, 9 diff-pairs were identified as having significant power using the Kruskal-Wallis test (P < .0001) to distinguish MTC samples from non-MTC samples. The assay correctly classified all MTC and non-MTC samples in the analytical validation study and in the 3 clinical validation cohorts. The overall test accuracy was 100% (95% confidence interval, 99%-100%). In indeterminate FNAC samples, the sensitivity of the diff-pair analysis was greater than that of the MTC-specific mutation analysis (100% vs 25%; P = .03). CONCLUSIONS: Pairwise miRNA expression analysis of ThyraMIR results were found to accurately predict MTC in thyroid FNA samples, including those with indeterminate FNAC findings.

Empiric Determination of the Daily Glucocorticoid Replacement Dose in Adrenal Insufficiency.

BACKGROUND: For the treatment of adrenal insufficiency (AI) in adults, the Endocrine Society's recommended daily glucocorticoid replacement dose (DGRD) is 15 to 25 mg hydrocortisone (HC), which is approximately 1.7 times the reported mean daily cortisol production rate. Prolonged glucocorticoid overtreatment causes multiple morbidities. HYPOTHESIS: We tested the hypotheses that the DGRD, empirically determined by individual patient titration, is lower than that of the Endocrine Society guidelines and tolerated without evidence of glucocorticoid under-replacement. METHODS: We empirically determined the DGRD in 25 otherwise healthy adults with AI by titrating the DGRD to the lowest dose tolerated as judged by body mass index, blood pressure, serum sodium concentration and AI symptoms. Patients received either HC or prednisone (PRED). The HC equivalent of PRED was assumed to be 4:1. RESULTS: The mean empirically determined DGRD, expressed as HC equivalent, was significantly less than the midpoint of the Endocrine Society's recommended DGRD (7.6 ± 3.5 mg/m2 vs 11.8 mg/m2; P < 0.001). The DGRD in the adrenalectomy group was not significantly different than the DGRD of those with other AI causes (7.9 ± 4.0 mg/m2 vs 7.3 ± 3.1 mg/m2; P = ns), demonstrating that the empirically determined DGRD was not biased by residual cortisol secretion. There was no evidence of glucocorticoid under-replacement as determined by measured biometrics and AI symptoms. CONCLUSIONS: We conclude that an empirically determined DGRD is significantly lower than that of the Endocrine Society guidelines and tolerated without evidence of glucocorticoid under-replacement.

Isolated DHEAS production by an adrenal neoplasm: Clinical, biochemical and pathologic characteristics.

Androgen-secreting adrenal neoplasms have a low incidence, usually secrete multiple hormones, and may present with hirsutism, acne, and alopecia. We report an exceedingly rare case of a purely dehydroepiandrosterone-sulfate (DHEA-S) secreting adrenal neoplasm found incidentally on cross sectional imaging. The clinical, biochemical, and pathologic findings of this neoplasm are described.

Number of aberrant crypt foci associated with adiposity and IGF1 bioavailability.

BACKGROUND: Dysregulation of the insulin-like growth factor (IGF) system, a common consequence of adiposity-induced insulin resistance, may be a key underlying mechanism linking excess body weight with colon cancer. Evidence has been derived from studies of cancer and polyps. Supporting data about aberrant crypt foci (ACF), putative pre-polyp changes, have been generated only from animal studies to date. METHODS: We randomly selected 26 patients with sex-specific elevated waist-hip-ratio (WHR) and 26 with normal values from a series of 150 patients seeking routine colonoscopy at the University of Connecticut Health Center. Cross-sectional analyses were performed of ACF number (<5, > or = 5) in relation to total IGF1, IGF-binding protein-3 (IGFBP3), insulin, body mass index (BMI), WHR and waist circumference (WC). Visualized ACF in the 20 cm of the distal colon were counted using advanced endoscopic imaging. RESULTS: Patients with > or = 5 ACF had higher BMI, WHR, and WC compared with patients with >5 ACF (p = 0.04, p = 0.03, and p = 0.01, respectively). IGFBP3 was reduced (p = 0.02) and IGF1:IGFBP3 molar ratio was greater (p = 0.03) in patients with > or = 5 ACF. We did not observe significant associations between ACF number and insulin or total IGF1. CONCLUSIONS: Our study provides the first report in humans of a possible association of ACF prevalence and IGF1 bioavailability as characterized by IGF1:IGFBP3 molar ratio and IGFBP3 level. More research is needed to determine whether this relationship is varied by ACF features (e.g., size, dysplasia, molecular changes), synchronous cancer and polyps, and is modified by colon cancer risk factors.

Adrenal vein sampling with and without cosyntropin stimulation for detection of surgically remediable aldosteronism.

CONTEXT AND OBJECTIVE: Bilateral adrenal vein sampling (AVS), the diagnostic standard for identifying surgically remediable aldosteronism (SRA), is commonly performed after cosyntropin stimulation (post-ACTHstim). The role of AVS without cosyntropin stimulation (pre-ACTHstim) has not been established. The selectivity index (SI), the adrenal vein (av) serum cortisol concentration divided by that in a peripheral vein, confirms av sampling. The minimally acceptable SI is controversial. The objectives of this study were to determine the role of pre-ACTHstim AVS and a predetermined SI. DESIGN: Using biochemical cure as the endpoint, we performed a retrospective head-to-head comparison of pre-ACTHstim AVS to post-ACTHstim AVS. The specificity of a predetermined minimum SI of 1.5 in pre-ACTHstim AVS was determined. PATIENTS: At a regional AVS referral centre, we analysed 32 patients who had undergone simultaneous bilateral AVS both pre- and post-ACTHstim and had returned for postadrenalectomy evaluation. MEASUREMENTS: Simultaneous bilateral AVS was performed with measurements of venous concentrations of aldosterone and cortisol. End points were postadrenalectomy plasma renin activity, serum aldosterone concentration, and number of antihypertensive medications. RESULTS: All 32 patients achieved a biochemical cure following adrenalectomy. The two AVS protocols were complementary. Notably, seven patients (22%; CI = 11-38) were found to have SRA by a lateralization index (LI) > 4 on the pre-ACTHstim AVS, but not on the post-ACTHstim AVS. SI pre-ACTHstim was divided into tertiles. Specificity was 100% in all. CONCLUSIONS: Simultaneous bilateral AVS performed both pre-ACTHstim and post-ACTHstim maximizes SRA identification. A SI of 1.5 pre-ACTHstim does not reduce specificity.

Shear wave elastography and Afirma™ gene expression classifier in thyroid nodules with indeterminate cytology: a comparison study.

PURPOSE: To compare shear wave elastography (SWE) and Afirma™ gene expression classifier (GEC) for diagnosis of malignancy in thyroid nodules (TNs) with Bethesda Classification (BC) III or IV indeterminate cytology. METHODS: This preliminary single-center prospective study was approved by the Institutional Review Board. We evaluated 151 consented patients with 151 indeterminate TNs (123 BC III, 28 BC IV) on fine-needle aspiration biopsy (FNAB). B-mode ultrasound, vascularity, and SWE were performed prior to FNAB. TN stiffness was measured as shear wave velocity (SWV) in meters per second (m/s). The stiffest area of the TN was selected for SWV measurement. GEC testing was performed with a second FNAB. Surgery was recommended for GEC-suspicious TNs, or GEC-benign TNs with two or more worrisome B-mode US features. RESULTS: Surgical pathology confirmed 31 malignant TNs. Among the GEC-suspicious group, 28 of 59 TNs were malignant. The SWV value of ≥3.59 m/s was the best cut-off for malignancy risk based on the receiver operating curve (ROC). Twenty-six malignant TNs had SWV ≥ 3.59 m/s. The sensitivity and specificity for SWV ≥ 3.59 m/s were 83.9 and 79.2%, respectively. Positive predictive value (PPV) was 51.0% and negative predictive value (NPV) was 95.0%. For the GEC-suspicious group, sensitivity, specificity, PPV, and NPV were 90.3, 74.2, 47.5, and 96.7%, respectively. In multivariate analysis, SWV and GEC-suspicious were significant predictors of malignancy, but B-mode features and vascularity were not. CONCLUSION: This preliminary study indicates that SWE and GEC are independent predictors of malignancy in TNs with BC III or IV.

A PRKAR1A mutation associated with primary pigmented nodular adrenocortical disease in 12 kindreds.

CONTEXT: Primary pigmented nodular adrenocortical disease (PPNAD), a rare cause of corticotropin-independent Cushing syndrome, can be part of Carney complex (CNC), an autosomal dominant multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac myxomas, and endocrine tumors or be isolated (i). Germline PRKAR1A-inactivating mutations have been observed in both CNC and iPPNAD, but with no apparent genotype-phenotype correlation. OBJECTIVE: The objectives of the study were a detailed phenotyping for CNC manifestations in 12 kindreds bearing the same PRKAR1A mutation and a study of the consequences of the mutation and a potential founder effect. DESIGN: The study consisted of descriptive case reports. SETTING: The study was conducted at two referral centers. PATIENTS: The patients described in this study were referred for PRKAR1A gene mutation analysis because of a diagnosis of apparently iPPNAD. RESULTS: We describe a 6-bp polypyrimidine tract deletion [exon 7 IVS del (-7-->-2)] in 12 unrelated kindreds that were referred for Cushing syndrome due to PPNAD. Nine of the patients had no family history; in two, there was a family history of iPPNAD. Only one patient met the criteria for CNC. Relatives carrying the same mutation had no manifestations of CNC or PPNAD, suggesting a low penetrance of this PRKAR1A defect. A founder effect was excluded by extensive genotyping of chromosome 17 markers. CONCLUSIONS: In conclusion, a small intronic deletion of the PRKAR1A gene is a low-penetrance cause of mainly iPPNAD; it is the first PRKAR1A genetic defect to have an association with a specific phenotype.

Shear Wave Elastography and Cervical Lymph Nodes: Predicting Malignancy.

This prospective study evaluates the accuracy of virtual touch imaging quantification (VTIQ), a non-invasive shear wave elastography method for measuring cervical lymph nodes (LN) stiffness in differentiating benign from malignant LN. The study evaluated 270 LN in 236 patients with both conventional B-mode ultrasound and VTIQ shear wave elastography before fine-needle aspiration biopsy (FNAB). LN stiffness was measured as shear wave velocity (SWV) in m/s. Surgical resection was advised for FNAB results that were not clearly benign. Surgical pathology confirmed 54 malignant LN. The receiver operating curve (ROC) identified a single cut-off value of 2.93 m/s as the maximum SWV for predicting a malignant cervical LN. The sensitivity and specificity were 92.59% and 75.46%, respectively. Positive predictive value (PPV) was 48.54% and negative predictive value (NPV) was 97.60%. LN stiffness measured by VTIQ-generated shear wave elastography is an independent predictor of malignancy.

Shear wave elastography and parathyroid adenoma: A new tool for diagnosing parathyroid adenomas.

OBJECTIVES: This study prospectively determines the shear wave elastography characteristics of parathyroid adenomas using virtual touch imaging quantification, a non-invasive ultrasound based shear wave elastography method. METHODS: This prospective study examined 57 consecutive patients with biochemically proven primary hyperparathyroidism and solitary parathyroid adenoma identified by ultrasound and confirmed by at least one of the following: surgical resection, positive Technetium-99m Sestamibi Scintigraphy (MIBI) scan, or fine needle aspiration biopsy with positive PTH washout (performed only in MIBI negative patients). Vascularity and shear wave elastography were performed for all patients. Parathyroid adenoma stiffness was measured as shear wave velocity in meters per second. RESULTS: The median (range) pre-surgical value for PTH and calcium were 58pg/mL (19, 427) and 10.8mg/dL (9.5, 12.1), respectively. 37 patients had positive MIBI scan. 20 patients had negative MIBI scan but diagnosis was confirmed with positive PTH washout. 42 patients underwent parathyroidectomy, and an adenoma was confirmed in all. The median (range) shear wave velocity for all parathyroid adenomas enrolled in this study was 2.02m/s (1.53, 2.50). The median (range) shear wave velocity for thyroid tissue was 2.77m/s (1.89, 3.70). The shear wave velocity of the adenomas was independent of adenoma size, serum parathyroid hormone concentration, or plasma parathyroid hormone concentration. CONCLUSIONS: Tissue elasticity of parathyroid adenoma is significantly lower than thyroid tissue. B-mode features and distinct vascularity pattern are helpful tools in diagnosing parathyroid adenoma with ultrasound. Shear wave elastography may provide valuable information in diagnosing parathyroid adenoma.

Glucocorticoid resistance and hypersensitivity.

This article emphasizes the disorders caused by mutations and polymorphisms of the alpha form of the glucocorticoid receptor. These disorders usually present with increased circulating cortisol concentrations and must be distinguished from Cushing's syndrome, because the therapies are markedly different. The other disorders present with clinical features limited to a specific organ system. Although they illustrate important physiologic and pathophysiologic principles, they usually are not confused with Cushing's syndrome.

Impaired desensitization of a mutant adrenocorticotropin receptor associated with apparent constitutive activity.

A naturally occurring ACTH receptor [melanocortin 2 receptor (MC2R)] mutation (F278C) has been identified in a subject with ACTH-independent Cushing's syndrome. Functional characterization of this mutant receptor reveals that it is associated with elevated basal cAMP accumulation when compared with wild-type receptor-expressing cell lines. Dose responsiveness is similar between wild-type and mutant receptors in cell lines expressing similar numbers of binding sites. In view of the location of this mutation in the C-terminal tail of the MC2R, desensitization and internalization were investigated and found to be impaired. Inhibition of protein kinase A by H89 blocks wild-type MC2R desensitization and also results in increased basal activity, as does alanine substitution of Ser 280 in the C-terminal tail. Alanine substitution of Ser 208, the consensus protein kinase A phosphorylation target in the third cytoplasmic loop also results in a reduction in desensitization without significant change in basal activity or internalization. These findings suggest a novel mechanism is involved in the apparently constitutive activation of the MC2R in which failure of desensitization appears to be associated with enhanced basal receptor activity.

A novel noninvasive blood glucose monitor.

OBJECTIVE: To evaluate the precision and accuracy of a new advanced prototype of a noninvasive blood glucose monitor across a wide range of serum glucose concentrations. RESEARCH DESIGN AND METHODS: An advanced handheld noninvasive glucose monitor prototype was calibrated and tested using patients recruited by the General Research Center of the University of Connecticut Health Center. The monitor, developed by Infratec, uses principles of thermal emission spectroscopy. The noninvasive measurement of tympanic membrane glucose concentration was calibrated to the serum glucose concentration using 432 paired measurements from 20 subjects with insulin-requiring diabetes. This calibration was subsequently tested (results of power analyses) in a blind fashion with 126 paired measurements from six diabetic subjects who require insulin. RESULTS: In vivo measurements demonstrated the reproducibility of the methodology of the noninvasive glucose monitor. Based on the calibration model, predicted glucose concentrations for six subjects were as follows (for 126 data points): SD = 32 mg/dl, mean absolute relative error (%MARE) = 11.6, with a correlation coefficient of r = 0.87. Noninvasive glucose results were also compared with laboratory reference measurements using an error-in-variables method. Clark error grid analysis showed that 100% of the measurements fell within zones A and B (90% in zone A and 10% in zone B). The SD for all noninvasive measured concentrations was 27 mg/dl, %MARE was 8.6, and the correlation coefficient was r = 0.94. CONCLUSIONS: This first independent clinical study of an advanced noninvasive blood glucose prototype based on thermal emission in the mid-infrared spectral region has demonstrated glucose measurements with clinically acceptable accuracy but without the necessity of individual daily calibration.

Thyroid Nodules and Shear Wave Elastography: A New Tool in Thyroid Cancer Detection.

This study determines the performance of virtual touch imaging quantification (VTIQ), a non-invasive shear wave elastography method for measuring thyroid nodule (TN) stiffness, in distinguishing benign from malignant TNs. This prospective study evaluates 707 TNs in 676 patients with fine-needle aspiration biopsy (FNAB). Before FNAB, both conventional B-mode ultrasound and shear wave elastography were performed. Surgical resection was recommended for FNAB results that were not clearly benign. Surgical pathology confirmed 82 malignant TNs. The receiver operating curve identified a single cut-off of 3.54 m/s as the maximum shear wave velocity (SWV) for predicting thyroid cancer (TC). The sensitivity and specificity were 79.27% and 71.52%, respectively. Positive predictive value (PPV) was 26.75% and negative predictive value (NPV) was 96.34%. Compared with B-mode US features for predicting malignancy, SWV ≥3.54 m/s has a higher sensitivity, specificity, PPV and NPV. TN stiffness measured by VTIQ-generated shear wave elastography is an independent predictor of TC.

Thyroid hormones and functional outcomes after ischemic stroke.

BACKGROUND: Stroke is the fifth leading cause of death and the primary cause of long-term adult disability in the United States. Increasing evidence suggests that low T3 levels immediately following acute ischemic stroke are associated with greater stroke severity, higher mortality rates, and poorer functional outcomes. Prognosis is also poor in critically ill hospitalized patients who have non-thyroidal illness syndrome (NTIS), where T3 levels are low, but TSH is normal. However, data regarding the association between TSH levels and functional outcomes are contradictory. Thus, this study investigated the role of TSH on stroke outcomes, concomitantly with T3 and T4. FINDINGS: In this work, blood was collected from patients with radiologically confirmed acute ischemic stroke at 24±6 hours post-symptom onset and serum levels of TSH, free T3, and free T4 were measured. Stroke outcomes were measured at discharge, 3 and 12 months using the modified Rankin scale and modified Barthel Index as markers of disability. Though we found that lower levels of free T3 were associated with worse prognosis at hospital discharge, and at 3 and 12 months post-stroke, none of these outcomes held after multivariate analysis. Thus, it is likely that thyroid hormones are associated with other factors that impact stroke outcomes, such as sex, age and stroke etiology. CONCLUSIONS: This study found that lower levels of free T3 were associated with poorer outcomes at hospital discharge, and at 3 and 12 months post stroke, however, these associations diminished after correction for other known predictors of stroke outcome. Thyroid hormones have a complex relationship with ischemic stroke and stroke recovery, which merits further larger investigations.