Unexplained Cachexia as a Presenting Symptom of Pheochromocytoma in a Geriatric Patient.

Pheochromocytomas are rare neuroendocrine tumors that may secrete catecholamines, resulting in a wide array of clinical symptoms. While patients classically present with hypertension, headache, diaphoresis, and flushing, these symptoms are present in only 40% of cases. Here, we describe a 70-year-old woman whose predominant symptom was unexplained severe weight loss over a 12-month period associated with fatigue, anxiety, and palpitations at her endocrinologist and geriatrician visits. Diagnostic imaging was performed to assess for malignancy and demonstrated a 2.0 cm × 2.0 cm left adrenal mass. The diagnosis of pheochromocytoma was confirmed by elevated plasma normetanephrine levels. After a 2-week alpha blockade with doxazosin, the patient underwent robotic left adrenalectomy. Following surgery, the patient regained weight, and her hypertension also improved significantly. We hope this uncommon clinical presentation in an older adult characterized by weight loss and frailty will increase the awareness of atypical pheochromocytoma symptomatology, particularly in older individuals.

Thyroid hormone action and liver disease, a complex interplay.

Thyroid hormone action is involved in virtually all physiological processes. It is well known that the liver and thyroid are intimately linked, with thyroid hormone playing important roles in de novo lipogenesis, beta-oxidation (fatty acid oxidation), cholesterol metabolism, and carbohydrate metabolism. Clinical and mechanistic research studies have shown that thyroid hormone can be involved in chronic liver diseases, including alcohol-associated or NAFLD and HCC. Thyroid hormone action and synthetic thyroid hormone analogs can exert beneficial actions in terms of lowering lipids, preventing chronic liver disease and as liver anticancer agents. More recently, preclinical and clinical studies have indicated that some analogs of thyroid hormone could also play a role in the treatment of liver disease. These synthetic molecules, thyromimetics, can modulate lipid metabolism, particularly in NAFLD/NASH. In this review, we first summarize the thyroid hormone signaling axis in the context of liver biology, then we describe the changes in thyroid hormone signaling in liver disease and how liver diseases affect the thyroid hormone homeostasis, and finally we discuss the use of thyroid hormone-analog for the treatment of liver disease.

Selective adipocyte loss of Angiopoietin-2 prompts female-specific obesity and metabolic syndrome.

Thermogenic fat differentiation and function can be promoted through multiple pathways, resulting in a common cell phenotype characterized by the expression of Uncoupling Protein-1 and the ability to dissipate energy, but local and systemic stimuli are necessary to promote adequate thermogenic fat vascularization, which is a precondition for the transport of substrate and the dissipation of heat. Angiopoietin-2 is an important driver of vascularization, and its transcription is in part promoted by estrogen signaling. In this study we demonstrate that adipose tissue-specific knock out of Angiopoietin-2 causes a female-specific reduced thermogenic fat differentiation and function, resulting in obesity and impaired glucose tolerance with end-organ features consistent with metabolic syndrome. In humans, angiopoietin-2 levels are higher in females than in males, and are inversely correlated with adiposity and age more strongly in pre-menopause when compared to post-menopause. Collectively, these data indicate a novel and important role for estrogen-mediated Angiopoietin-2 adipose tissue production in the protection against calorie overload in females, and potentially in the development of postmenopausal weight gain.

Metabolic Phenotyping in Mice with NASH Using Indirect Calorimetry.

Obesity caused by caloric overload has assumed epidemic proportions. Obesity is frequently associated with metabolic dysfunctions, such as type 2 diabetes, non-alcoholic steatohepatitis (NASH), cardiovascular diseases, and cancer. Metabolic phenotyping is a set of techniques for studying metabolic dysfunction and behavior information including energy expenditure, body weight gain, glucose homeostasis, and lipid profile. Among different metabolic phenotyping methods, indirect calorimetry is an indispensable tool for quantifying the energy balance/imbalance in various mouse models, which enables researchers to probe the development of disease and to evaluate the therapeutic benefit from different interventions. In this chapter, we will describe the procedures of metabolic phenotyping using indirect calorimetry in db/db mouse, a metabolic disorder mouse model which develops NASH.

Weight Gain After Thyroidectomy: A Systematic Review and Meta-Analysis.

CONTEXT: Weight gain is a major driver of dissatisfaction and decreased quality of life in patients with hypothyroidism. Data on the changes in body weight following thyroidectomy are conflicting. OBJECTIVE: To perform a systematic review of the literature and a meta-analysis of weight changes following total thyroidectomy. DATA SOURCES: Literature search on PubMed. STUDY SELECTION: Studies in English published between September 1998 and May 2018 reporting post-thyroidectomy weight changes. DATA EXTRACTION: Data were reviewed and compared by 3 investigators; discrepancies were resolved by consensus. Meta-analyses were performed using fixed and random effect models. Univariable and multivariable meta-regression models for weight change were implemented against study follow-up, gender, and age. Exploratory subgroup analyses were performed for indication for surgery. DATA SYNTHESIS: Seventeen studies (3164 patients) with 23.8 ± 23.6 months follow-up were included. Severe heterogeneity across studies was observed. Using a random effect model, the estimated overall weight change was a gain of 2.13 kg, 95% confidence interval (CI; 0.95, 3.30). Age was negatively associated with weight change (ß = -0.238, P < 0.001). In subgroup analyses, weight gain was more evident in patients undergoing thyroidectomy for hyperthyroidism: 5.19 kg, 95% CI (3.21, 7.17) vs goiter or malignancy 1.55 kg, 95% CI (0.82, 2.27) and 1.30 kg, 95% CI (0.45, 2.15), respectively. CONCLUSIONS: Patients undergoing thyroidectomy experience possible mild weight gain, particularly younger individuals and those with hyperthyroidism as the indication for surgery. Prospective studies directed to assess the pathophysiology of weight gain post-thyroidectomy, and to test novel treatment modalities, are needed to better characterize post-thyroidectomy weight changes.

Adipocyte ADAM17 plays a limited role in metabolic inflammation.

The role of ADAM17, its substrates, and its natural inhibitor has been well studied in the context of inflammation, including metabolic inflammation, with mixed results. Previous studies examining global Adam17 knockdown models and ADAM17 inhibition using overexpression of endogenous ADAM17 inhibitors have shown improved metabolic health and decreased metabolic inflammation. However, there have been no studies examining the role of adipocyte ADAM17 using in vivo models. In this study, we developed an adipocyte-specific Adam17 knockout model using Adipoq-Cre-expressing mice crossed with Adam17-floxed mice. Using this model, we show that loss of adipocyte ADAM17 plays no evident role in baseline metabolic responses. Surprisingly, in a state of metabolic stress using high-fat diet (HFD), we observed that adipocyte ADAM17 had little effect overall on the metabolic phenotype as well as inflammatory cell populations. Using whole-body metabolic phenotyping, we show that loss of ADAM17 has no effect on energy utilization both at a baseline state as well as following HFD. However, lastly, using high-parameter flow cytometry, we show that loss of adipocyte ADAM17 alters macrophage and eosinophil populations following HFD. Overall, the studies presented here give more insight into the role of ADAM17 in metabolic responses and metabolic inflammation, specifically in adipocytes.

Pharmacokinetics of L-Triiodothyronine in Patients Undergoing Thyroid Hormone Therapy Withdrawal.

Background: L-triiodothyronine (LT3) is a substitute for levothyroxine (LT4) for thyroid cancer (TC) patients during the preparation for nuclear medicine procedures, and it is used in combination with LT4 in patients who do not respond to the standard treatment for hypothyroidism. This therapy is commonly done by using fixed doses, potentially resulting in supraphysiologic levels of triiodothyronine (T3). A good understanding of the LT3 pharmacokinetics (PK) is necessary to design combination treatment schemes that are able to maintain serum T3 levels within the reference range, but data on the PK of LT3 are conflicting. Here, we present a study designed to characterize the PK of LT3 in patients devoid of endogenous thyroid hormone production, and not receiving LT4 therapy. Methods: We performed an open-label, PK study in patients undergoing thyroid hormone withdrawal in preparation for nuclear medicine procedures for the evaluation and treatment of follicular-derived TC. LT3 was substituted for LT4 at a 1:3 mcg/mcg dosage ratio thrice daily for at least 30 days. PK of the last LT3 dose while at steady state and terminal elimination was assessed over 11 days. Thereafter, a PK study was performed following the nuclear medicine procedure in patients who volunteered for a second study. Results: Fourteen patients age 48.5 ± 16.0 years completed the last dose study and five completed the second PK study. PK analysis indicates a time to maximum serum concentration of 1.8 ± 0.32 hours and two distinct phases of linear elimination, with a fast distribution phase and slow elimination phases with half-lives of 2.3 ± 0.11 hours and 22.9 ± 7.7 hours, supporting a two-compartment model. PK modeling predicts that a twice-daily administration of low-dose LT3 (0.07 mcg/kg twice daily) in combination with LT4 can predictably increase the serum T3 concentration without significant peaks above the reference range. Conclusions: The PK of LT3 is well described by a two-compartment model that assumes elimination only from the sampling compartment, with a rapid distribution phase and a slow elimination phase. This information will contribute to design therapeutic strategies for LT3/LT4 combination therapies directed to maintain stable T3 serum levels.

E0771 and 4T1 murine breast cancer cells and interleukin 6 alter gene expression patterns but do not induce browning in cultured white adipocytes.

Breast cancer remains a substantial clinical problem worldwide, and cancer-associated cachexia is a condition associated with poor prognosis in this and other malignancies. Adipose tissue is involved in the development and progression of cancer-associated cachexia, but its various roles and mechanisms of action are not completely defined, especially as it relates to breast cancer. Interleukin 6 has been implicated in several mechanisms contributing to increased breast cancer tumorigenesis, as well as a net-negative energy balance and cancer-associated cachexia via adipose tissue remodeling in other models of cancer; however, its potential role in breast cancer-associated white adipose browning has not been explored. In this study, we demonstrate localized white adipose tissue browning in a spontaneous model of murine mammary cancer. We then used an in vitro murine adipocyte culture system with the E0771 and 4T1 cell lines as models of breast cancer. We demonstrate that while the E0771 and 4T1 secretomes and cross-talk with white adipocytes alter white adipocyte mRNA expression, they do not directly induce white adipocyte browning. Additionally, we show that neither exogenous administration of interleukin 6 alone or with its soluble receptor directly induce white adipocyte browning. Together, these results demonstrate that neither the E0771 or 4T1 murine breast cancer cell lines, nor interleukin 6, directly cause browning of cultured white adipocytes. This suggests that their roles in adipose tissue remodeling are more complex and indirect in nature.

Prevalence and Severity of Nonalcoholic Fatty Liver Disease Among Caregivers of Patients With Nonalcoholic Fatty Liver Disease Cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, affecting nearly 1 in 3 Americans.1 Nonalcoholic steatohepatitis (NASH), the clinically aggressive variant of NAFLD, has a propensity of fibrosis progression and increased risk of cirrhosis and hepatocellular carcinoma. NASH-related cirrhosis is now the most rapidly growing indication for liver transplantation (LT).2 Disease recurrence and progression to advanced fibrosis after LT are high3; however, the key contributors of these are unknown. We hypothesized that patients with NASH cirrhosis reside in a microenvironment conducive to not only development of NASH but also fibrosis progression, which likely persist after LT and contribute to disease recurrence. The hypothesis was tested by performing vibration-controlled transient elastography (VCTE) in primary caregivers and cohabitants of patients with decompensated cirrhosis awaiting LT.

Dexamethasone and postoperative hyperglycemia in diabetics undergoing elective hip or knee arthroplasty: a case control study in 238 patients.

BACKGROUND: Dexamethasone has been routinely used in the pre-operative setting to enhance analgesia and decrease the incidence of nausea and vomiting in patients undergoing primary arthroplasty. However, dexamethasone has the potential to increase blood glucose levels postoperatively, which is a known risk factor for complications after total joint arthroplasty. The aim of this study was to analyze the effect of dexamethasone administration on post-operative blood glucose levels in diabetic patients after primary hip and knee arthroplasty. METHODS: This study was a retrospective review of 238 diabetic patients who underwent primary hip and knee arthroplasty between May 1, 2014 and September 30, 2016 at a single urban academic medical center. A total of 77 patients (32.4%) received dexamethasone and 161 (67.7%) did not. Oral hyperglycemic agents were held during the inpatient stay and blood glucose was controlled either with sliding scale insulin or home insulin regimens were continued. All analyses were adjusted for age, BMI, gender, type of diabetes, pre-operative diabetic medication, type of surgical procedure, and pre-operative HgbA1c level. The primary outcome was post-operative hyperglycemia within 72 h of surgery defined as any blood glucose level greater than or equal to 200 mg/dL. RESULTS: Post-operative hyperglycemia was observed in 17.1 and 20.6% of the measurements during the first 24 and 72 h respectively. After controlling for confounding variables, patients who received dexamethasone had 4.07 (95% CI: 2.46, 6.72) and 3.08 (95% CI: 2.34, 4.04) higher odds of post-operative hyperglycemia in the first 24 and 72 h respectively. CONCLUSIONS: Dexamethasone administration in diabetic patients undergoing primary arthroplasty increases post-operative hyperglycemia during the first 24 and 72 h. While our data did not investigate causation, dexamethasone use in this patient population should be thoughtfully considered, as post-operative hyperglycemia is a known risk factor for complications.

The role of adipose tissue in cancer-associated cachexia.

Adipose tissue (fat) is a heterogeneous organ, both in function and histology, distributed throughout the body. White adipose tissue, responsible for energy storage and more recently found to have endocrine and inflammation-modulatory activities, was historically thought to be the only type of fat present in adult humans. The recent demonstration of functional brown adipose tissue in adults, which is highly metabolic, shifted this paradigm. Additionally, recent studies demonstrate the ability of white adipose tissue to be induced toward the brown adipose phenotype - "beige" or "brite" adipose tissue - in a process referred to as "browning." While these adipose tissue depots are under investigation in the context of obesity, new evidence suggests a maladaptive role in other metabolic disturbances including cancer-associated cachexia, which is the topic of this review. This syndrome is multifactorial in nature and is an independent factor associated with poor prognosis. Here, we review the contributions of all three adipose depots - white, brown, and beige - to the development and progression of cancer-associated cachexia. Specifically, we focus on the local and systemic processes involving these adipose tissues that lead to increased energy expenditure and sustained negative energy balance. We highlight key findings from both animal and human studies and discuss areas within the field that need further exploration. Impact statement Cancer-associated cachexia (CAC) is a complex, multifactorial syndrome that negatively impacts patient quality of live and prognosis. This work reviews a component of CAC that lacks prior discussion: adipose tissue contributions. Uniquely, it discusses all three types of adipose tissue, white, beige, and brown, their interactions, and their contributions to the development and progression of CAC. Summarizing key bench and clinical studies, it provides information that will be useful to both basic and clinical researchers in designing experiments, studies, and clinical trials.

False-Positive Radioactive Iodine Uptake Mimicking Miliary Lung Metastases in a Patient Affected by Papillary Thyroid Cancer and IgA Deficiency.

A 42-year-old female with immunoglobulin A deficiency and recurrent sinopulmonary infections underwent thyroidectomy for papillary thyroid cancer (PTC). Follow-up (123)I scintigraphy demonstrated diffuse pulmonary uptake, suggesting metastatic disease. However, subsequent pathologic, biochemical and radiographic testing proved that she was in fact disease free, and the initial (123)I pulmonary uptake was identified as a false positive. Inflammatory conditions may rarely cause iodine uptake in non-thyroidal tissues due to local retention, organification, and/or immunologic utilization. To avoid exposing patients to unnecessary treatments, it is critical for clinicians to recognize that comorbid pulmonary conditions may mimic metastatic PTC on radioiodine scintigraphy.

Increased Pleiotrophin Concentrations in Papillary Thyroid Cancer.

BACKGROUND: Thyroid nodules are common, and approximately 5% of these nodules are malignant. Pleiotrophin (PTN) is a heparin-binding growth factor which is overexpressed in many cancers. The expression of PTN in papillary thyroid cancer (PTC) is unknown. METHOD AND FINDINGS: 74 subjects (age 47 ± 12 y, 15 males) who had thyroidectomy with a histological diagnosis: 79 benign nodules and 23 PTCs (10 classic, 6 tall cell, 6 follicular variant and 1 undetermined). Fine-needle aspiration (FNA) samples were obtained ex vivo from surgically excised tissue and assayed for PTN and thyroglobulin (Tg). Immunohistochemistry (IHC) was performed on tissue sections. In FNA samples, PTN concentration normalized to Tg was significantly higher in PTC than in benign nodules (16 ± 6 vs 0.3 ± 0.1 ng/mg, p < 0.001). In follicular variant of PTC (n = 6), the PTN/Tg ratio was also higher than in benign nodules (1.3 ± 0.6 vs 0.3 ± 0.1 ng/mg, P < 0.001, respectively). IHC showed cytoplasmic localization of PTN in PTC cells. CONCLUSION: In ex vivo FNA samples, the PTN to thyroglobulin ratio was higher in PTCs, including follicular variant PTC, than in benign thyroid nodules. The findings raise the possibility that measurement of the PTN to Tg ratio may provide useful diagnostic and/or prognostic information in the evaluation of thyroid nodules.

Midkine concentrations in fine-needle aspiration of benign and malignant thyroid nodules.

CONTEXT: The primary preoperative method for distinguishing malignant from benign thyroid nodules is fine-needle aspiration (FNA) cytology, but it is frequently inconclusive. Midkine (MDK) is a heparin-binding growth factor, which is overexpressed in papillary thyroid carcinoma (PTC). OBJECTIVE: We measured MDK concentrations in FNA samples from benign and malignant thyroid nodules to explore the possibility that MDK measurement might aid in the evaluation of thyroid nodules. DESIGN: 35 subjects underwent preoperative FNA of 45 thyroid nodules, followed by thyroidectomy, providing a histological diagnosis. FNA needle contents were first expressed for cytology, and then, the needle was washed with buffer for immunoassay. In 46 subjects without preoperative FNA samples, FNA was performed ex vivo on 62 nodules within surgically excised thyroid tissue. MEASUREMENTS: MDK was measured using a high-sensitivity sandwich ELISA and normalized to thyroglobulin (Tg) concentration in the sample to adjust for tissue content in the aspirate. RESULTS: The MDK/Tg ratio was higher in 18 PTCs than in 87 benign nodules (204 ± 106 vs 1·2 ± 0·3 ng/mg, mean ± SEM, P < 0·001). Using a threshold of 10 ng/mg, the sensitivity and specificity of the MDK/Tg ratio for diagnosis of PTC were 67% and 99%, respectively. All follicular variant PTCs had a MDK/Tg ratio <10 ng/mg. CONCLUSIONS: The findings indicate that, in FNA samples, the MDK/Tg ratio in PTC is greater than in benign thyroid nodules, raising the possibility that this approach might provide adjunctive diagnostic or prognostic information to complement existing approaches.

Cabozantinib-induced thyroid dysfunction: a review of two ongoing trials for metastatic bladder cancer and sarcoma.

BACKGROUND: Thyroid dysfunction is a common adverse event associated with tyrosine kinase inhibitors (TKI), but its underlying pathophysiology is unclear. Cabozantinib is a novel TKI currently Food and Drug Administration approved for advanced medullary thyroid cancer and tested in clinical trials on solid tumors including prostate, liver, bladder, breast, and ovarian cancer. METHODS: We analyzed the thyroid function of patients enrolled in two phase 2 clinical trials using cabozantinib at the National Institutes of Health Clinical Center. Two cases of thyroiditis associated with cabozantinib therapy are presented in detail, and a systematic review of the literature on TKI-associated thyroid dysfunction is also discussed. RESULTS: Between September 2012 and September 2013, 33 patients were treated with cabozantinib, and follow-up thyroid function tests were available for 31 (20 males, 11 females; age 59±1 years). Thyroid dysfunction was recorded in the majority of patients (93.1%), with a predominance of subclinical hypothyroidism. Two cases showed a biphasic pattern of thyroid dysfunction characterized by a transient thyrotoxicosis followed by hypothyroidism. Color Doppler demonstrated an increase in vascularization during the thyrotoxic phase, but no uptake was visualized on nuclear medicine imaging. A systematic review of the literature resulted in the identification of 40 original manuscripts, of which 13 were case series and 6 were case reports describing TKI-associated thyroid dysfunction. CONCLUSION: TKI therapy often results in clinically significant thyroid dysfunction. Cabozantinib treatment commonly results in thyroid dysfunction varying from subclinical hypothyroidism to symptomatic thyrotoxicosis. Early detection and characterization of cabozantinib-associated thyroid dysfunction and close follow-up are essential to provide adequate management of this common adverse event.

Moderate weight loss is sufficient to affect thyroid hormone homeostasis and inhibit its peripheral conversion.

BACKGROUND: Thyroid hormones are important determinants of energy expenditure, and in rodents, adipose tissue affects thyroid hormone homeostasis via leptin signaling. The relationship between thyroid hormones and nutritional status in humans has been assessed primarily in drastic dietary or bariatric surgery interventions, while limited information is available on serial assessment of this axis during moderate, prolonged dietary restriction. METHODS: To evaluate the effects of moderate dietary restriction on thyroid hormone homeostasis, 47 subjects with a body mass index (BMI) of 25-45 kg/m(2) were enrolled in a longitudinal intervention study; 30 nonoverweight volunteers were also enrolled as controls. Overweight and obese subjects underwent a 12-month individualized dietary intervention aimed at achieving a 5-10% weight loss. RESULTS: The intervention resulted in a 6.3±0.9 kg (6.5±1.0%) weight loss. At baseline, thyrotropin (TSH) and T3 concentrations correlated significantly with fat mass (R=0.257, p=0.024 and R=0.318, p=0.005, respectively). After weight loss, T3 decreased significantly (from 112.7±3.1 to 101.8±2.6 ng/dL, p<0.001) in the absence of significant changes in TSH or free T4 (fT4). The decrease in serum T3 correlated with the decrease in weight (R=0.294, p<0.001). The T3:fT4 ratio decreased significantly (p=0.02) in individuals who lost >5% body weight. CONCLUSIONS: T3 concentration closely correlates with individual nutritional status, and moderate weight loss results in a decrease in T3 with minimal changes in other thyroid hormone homeostasis parameters. The data suggest that a decrease in peripheral conversion of the prohormone T4 into its hormonally active metabolite T3 is at least in part responsible for the observed changes in thyroid hormone homeostasis.

Increased oxidative metabolism in the Li-Fraumeni syndrome.

There is growing evidence that alterations in metabolism may contribute to tumorigenesis. Here, we report on members of families with the Li-Fraumeni syndrome who carry germline mutations in TP53, the gene encoding the tumor-suppressor protein p53. As compared with family members who are not carriers and with healthy volunteers, family members with these mutations have increased oxidative phosphorylation of skeletal muscle. Basic experimental studies of tissue samples from patients with the Li-Fraumeni syndrome and a mouse model of the syndrome support this in vivo finding of increased mitochondrial function. These results suggest that p53 regulates bioenergetic homeostasis in humans. (Funded by the National Heart, Lung, and Blood Institute and the National Institutes of Health; ClinicalTrials.gov number, NCT00406445.).

Oxidized low-density lipoproteins impair endothelial function by inhibiting non-genomic action of thyroid hormone-mediated nitric oxide production in human endothelial cells.

BACKGROUND: Thyroid hormone (TH) plays an important role in the modulation of cardiac function, including contractility and systemic vascular resistance (SVR). 3,5,3'-triiodothyronine (T(3)), the active form of TH, induces the activation of endothelial nitric oxide synthase via PI3K/AKT non-genomic signaling. Hypothyroidism is associated with an increase in SVR and serum low-density lipoproteins (LDL) levels, and accumulation of oxidized LDL (oxLDL) may impair endothelial-dependent vascular relaxation. The aim of this study was to investigate the effects of both native LDL (nLDL) and oxLDL on T(3)-mediated AKT phosphorylation, nitric oxide (NO), and cyclic guanosine monophosphate (cGMP) production in human endothelial cells. METHODS: Human umbilical vein endothelial cells were exposed to either nLDL or oxLDL for 3 hours and then stimulated with T(3) (10(-7) M) or pretreated with an antioxidant mixture of vitamins E and C for 12 hours before treatment with LDL. An analysis of AKT phosphorylation was performed by Western blot, and NO production was evaluated by using 4,5-diaminofluorescein diacetate. Intracellular production of cGMP was measured by enzymatic immunoassay. LDL oxidation was carried out by incubating LDL with CuSO(4), and α-tocopherol content of LDL was evaluated by high-performance liquid chromatography. RESULTS: OxLDL impaired T(3)-mediated AKT phosphorylation at serine 473 and significantly decreased the production of both NO (oxLDL+T(3) vs. T(3), 9.79±0.5 AU vs. 80.75±2.8 AU, mean±standard deviation, p<0.0001) and cGMP. Furthermore, pretreatment with the antioxidant mixture obviated the inhibitory effect of LDL on T(3) action. CONCLUSIONS: The results of this study demonstrate that oxLDL may contribute to a blunting of the non-genomic action of T(3) and impair the effect of T(3) on NO and cGMP production in endothelial cells. These data suggest that oxLDL, apart from inducing the atherosclerotic process, may also promote a mechanism of peripheral resistance to T(3,) further amplifying the impact of hypothyroidism on endothelial function by increasing SVR.

The -258A/G (SNP rs12885300) polymorphism of the human type 2 deiodinase gene is associated with a shift in the pattern of secretion of thyroid hormones following a TRH-induced acute rise in TSH.

OBJECTIVE: Type 2 deiodinase gene (DIO2) polymorphisms have been associated with changes in pituitary-thyroid axis homeostasis. The -258A/G (SNP rs12885300) polymorphism has been associated with increased enzymatic activity, but data are conflicting. To characterize the effects of -258A/G polymorphism on intrathyroidal thyroxine (T(4)) to triiodothyronine (T(3)) conversion and thyroid hormone (TH) secretion pattern, we studied the effects of acute, TRH-mediated, TSH stimulation of the thyroid gland. DESIGN: Retrospective analysis. METHODS: The TH secretion in response to 500  µg i.v. TRH injection was studied in 45 healthy volunteers. RESULTS: Twenty-six subjects (16 females and ten males, 32.8 ± 10.4 years) were homozygous for the ancestral (-258A/A) allele and 19 (11 females and eight males, 31.1 ± 10.9 years) were carriers of the (-258G/x) variant. While no differences in the peak TSH and T(3) levels were observed, carriers of the -258G/x allele showed a blunted rise in free T(4) (FT(4); P<0.01). The -258G/x92Thr/Thr haplotype, compared with the other groups, had lower TSH values at 60  min (P<0.03). No differences were observed between genotypes in baseline TH levels. CONCLUSIONS: The -258G/x DIO2 polymorphism variant is associated with a decreased rate of acute TSH-stimulated FT(4) secretion with a normal T(3) release from the thyroid gland consistent with a shift in the reaction equilibrium toward the product. These data indicate that the -258G DIO2 polymorphism causes changes in the pattern of hormone secretion. These findings are a proof of concept that common polymorphisms in DIO2 can subtly affect the circulating levels of TH and might modulate the TH homeostasis.

Wnt/ß-catenin signaling is differentially regulated by Gα proteins and contributes to fibrous dysplasia.

Skeletal dysplasias are common disabling disorders characterized by aberrant growth of bone and cartilage leading to abnormal skeletal structures and functions, often attributable to defects in skeletal progenitor cells. The underlying molecular and cellular mechanisms of most skeletal dysplasias remain elusive. Although the Wnt/ß-catenin signaling pathway is required for skeletal progenitor cells to differentiate along the osteoblastic lineage, inappropriately elevated levels of signaling can also inhibit bone formation by suppressing osteoblast maturation. Here, we investigate interactions of the four major Gα protein families (Gα(s), Gα(i/o), Gα(q/11), and Gα(12/13)) with the Wnt/ß-catenin signaling pathway and identify a causative role of Wnt/ß-catenin signaling in fibrous dysplasia (FD) of bone, a disease that exhibits abnormal differentiation of skeletal progenitor cells. The activating Gα(s) mutations that cause FD potentiated Wnt/ß-catenin signaling, and removal of Gα(s) led to reduced Wnt/ß-catenin signaling and decreased bone formation. We further show that activation of Wnt/ß-catenin signaling in osteoblast progenitors results in an FD-like phenotype and reduction of ß-catenin levels rescued differentiation defects of FD patient-derived stromal cells. Gα proteins may act at the level of ß-catenin destruction complex assembly by binding Axin. Our results indicate that activated Gα proteins differentially regulate Wnt/ß-catenin signaling but, importantly, are not required core components of Wnt/ß-catenin signaling. Our data suggest that activated Gα proteins are playing physiologically significant roles during both skeletal development and disease by modulating Wnt/ß-catenin signaling strength.