Optimal Free Thyroxine Levels for Thyroid Hormone Replacement in Hypothyroidism

ObjectiveTo determine whether a difference exists in the free thyroxine level required to achieve a normal thyrotropin (thyroid-stimulating hormone or TSH) level between patients with primary hypothyroidism and euthyroid control subjects and compare the free thyroxine levels in patients with primary and secondary hypothyroidism receiving thyroid hormone replacement.MethodsWe retrospectively assessed TSH and free thyroxine values in 58 patients with primary hypothyroidism and 78 euthyroid control subjects for whom screening thyroid function tests had been performed. From the medical records, we also obtained free thyroxine values for 23 patients with central hypothyroidism receiving stable levothyroxine replacement therapy.ResultsThe mean free thyroxine level was significantly higher in patients with primary hypothyroidism than in euthyroid control subjects (1.36 ± 0.201 ng/dL versus 1.10 ± 0.155 ng/dL, respectively, P < .0001), whereas the corresponding mean TSH concentrations did not differ significantly (1.60 ± 1.183 mlU/L versus 1.73 ± 0.792 mlU/L, P = .46). The mean free thyroxine value was also significantly higher in the patients with central hypothyroidism in comparison with that in the euthyroid control subjects (1.31 ± 0.278 ng/dL versus 1.10 ± 0.155 ng/dL, respectively, P < .0001), and no significant difference was noted between the patients with primary and central hypothyroidism (1.36 ng/dL versus 1.31 ng/dL, P = .60).ConclusionPatients with hypothyroidism require a higher level of serum free thyroxine to achieve a normal TSH value in comparison with euthyroid control subjects. This finding suggests that patients with central hypothy-roidism should be treated to achieve free thyroxine levels in the upper part of the reference range. (Endocr Pract. 2008;14:550-555)     

Hypocortisolemia in Graves Hyperthyroidism

ObjectiveTo assess the risk of concomitant adrenal sufficiency in 2 patients with Graves thyrotoxicosis.MethodsWe present the clinical course and laboratory findings of 2 patients with hyperthyroidism associated with low basal serum cortisol and briefly review the literature with regard to possible mechanisms of hypocortisolemia in thyrotoxic states.ResultsTwo women aged 37 and 43 years with longstanding Graves disease presented with hyperthyroidism secondary to nonadherence to prescribed antithyroid medications. Both women also had symptoms suggestive of adrenal insufficiency including nausea, vomiting, and diffuse abdominal pain in Patient 1 and fatigue and hypotension in Patient 2. In both patients, physical examination findings were consistent with hyperthyroidism. Laboratory results of Patient 1 included the following: thyrotropin, < 0.002 mIU/L; free thyroxine, > 6 μg/dL; and total triiodothyronine, 539 ng/dL. Laboratory results of Patient 2 included the following: thyrotropin, < 0.002 mIU/L; free thyroxine, > 6 μg/dL; and total triiodothyronine, 539 ng/dL. Morning basal cortisol levels were 0.9 μg/dL in Patient 1 and 0.6 pg/dL in Patient 2. Because of the low basal serum cortisol levels, the patients underwent a high-dose (250 mcg) cosyntropin-stimulation test; however, both patients had adequate cortisol response. At 60 minutes, serum cortisol concentration was 31.4 μg/dL in Patient 1 and 25.5 pg/dL in Patient 2. After adequately treating the hyperthyroidism, basal cortisol levels in both patients returned to the reference range.ConclusionSymptomatic hypocortisolemia may be present in severe hyperthyroidism, and it resolves with adequate treatment of the hyperthyroidism. (Endocr Pract. 2009;15:220-224)     

Reduction of Insulin Resistance and Plasma Glucose Level by Salsalate Treatment in Persons With Prediabetes

ObjectiveTo evaluate the effect of salsalate as an antiinflammatory agent on insulin resistance and glycemic control in persons with prediabetes.MethodsIn this double-blind, placebo-controlled clinical trial, 66 persons who had prediabetes on the basis of the American Diabetes Association criteria were enrolled. They were randomly assigned to receive salsalate (3 g daily) or placebo for 12 weeks. Fasting plasma glucose (FPG) and insulin, glucose 2 hours after oral administration of 75 g of glucose, hemoglobin A_1c, lipid profile, homeo stasis model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of beta-cell function were determined before and after treatment.ResultsSalsalate treatment reduced the FPG level from 5.86 ± 0.07 mmol/L to 5.20 ± 0.11 mmol/L and HOMA-IR from 4.2 ± 0.9 to 3.8 ± 0.3 (P = .01 for both changes). Homeostasis model assessment of beta-cell func tion increased in the salsalate-treatment group from 139.8 ± 11.0 to 189.4 ± 24.6 (P = .01). At the end of the study, FPG, HOMA-IR, and insulin levels were significantly different between salsalate and placebo groups (5.20 ± 0.11 mmol/L versus 5.53 ± 0.10 mmol/L, 3.8 ± 0.3 versus 4.4 ± 0.9, and 16.1 ± 1.9 μIU/mL versus 18.2 ± 2 μIU/mL, respectively; P < .05 for all). There were no persistent complications after salsalate therapy.ConclusionTreatment with salsalate can reduce insu lin resistance and the FPG level in subjects with predia betes. Determination of the long-term safety and efficacy of the use of salsalate necessitates further investigation. (Endocr Pract. 2012;18:826-833)     

Reduced Parathyroid Hormone-Stimulated 1,25-Dihydroxyvitamin D Production in Vitamin D Sufficient Postmenoposual Women with Low Bone Mass and Idiopathic Secondary Hyperparathyroidism

ObjectiveDistinguishing secondary hyperparathyroidism (sHPT) from eucalcemic primary hyperparathyroidism (EC-pHPT) is important. The objective of this study was to measure parathyroid hormone (PTH)-stimulated production of 1α,25-dihydroxyvitamin D (1,25[OH]₂D) in early postmenopausal patients with idiopathic sHPT, who also fit the criteria for EC-pHPT, compared to age-matched controls.MethodsIn this pilot case-control study, postmenopausal women aged 44 to 55 years with normal serum calcium (Ca), glomerular filtration rate (GFR) ≥65 mL/min, and 25-hydroxyvitamin D (25[OH]D) ≥75 nmol/L (30 ng/mL) were given an 8 hour infusion of PTH(1-34), 12 pmol/kg/h. Patients (n = 5) had elevated PTH, normal 1,25(OH)₂D, and no hypercalciuria. Controls (n = 5) had normal PTH. At baseline, 4, and 8 hours, serum Ca, creatinine (Cr), phosphorus (P), 1,25(OH)₂D, fibroblast growth factor (FGF23), and 24,25(OH)₂D as well as urine Ca, P, Cr, and cAMP/GFR were measured. The fractional excretion of calcium (FeCa) and tubular reabsorption of phosphorus (TMP)/GFR were calculated.ResultsPatients had lower 1,25(OH)₂D levels (± SD) than controls at 4 (39.8 ± 6.9 versus 58.8 ± 6.7; P = .002) and 8 hours (56.4 ± 9.2 versus 105 ± 2.3; P = .003) of PTH infusion, attenuated after adjusting for higher body mass index (BMI) in patients (P = .05, .04), respectively. The 24,25(OH)2D levels were lower in patients than controls (1.9 ± 0.6 versus 3.4 ± 0.6, respectively; P = .007). No differences were seen in serum Ca or P, urine cAMP/GFR, TRP/GFR, FeCa, or PTH suppression at 8 hours (patients 50%, controls 64%).ConclusionVitamin D sufficient patients who fit the criteria for EC-pHPT had reduced PTH-stimulated 1,25(OH)₂D compared to controls, partially attributable to their higher BMI. Other causes of reduced 1,25(OH)₂D production ruled out were excessive catabolism of vitamin D metabolites, elevated FGF23, and CYP27B1 mutation. Elevated BMI and idiopathic reduced PTH-stimulated 1,25(OH)₂D production should be considered in the differential of sHPT. (Endocr Pract. 2013;19:91-99)     

Value of Baseline Serum Thyrotropin as a Predictor of Hypothyroidism in Patients With Diabetes Mellitus

ObjectiveTo determine whether serum thyrotropin measurement performed at diagnosis of diabetes mellitus or at initial patient contact predicts subsequent development of hypothyroidism.MethodsWe retrospectively reviewed the computerized records of patients attending annual visits between January 2008 and December 2008 at a hospital diabetes mellitus clinic. Serum free thyroxine and thyrotropin at current and baseline annual visits were documented. A Cox regression model was used to analyze the relationship between development of thyroid dysfunction and patient characteristics including age, sex, type of diabetes, and baseline serum thyrotropin concentration. KaplanMeier survival curves were generated for predictors of hypothyroidism.ResultsClinical records of 1101 patients were reviewed (595 men [54%] and 506 women [46%]). Mean age was 60.0 ± 17 years. Two hundred twenty-three patients (20.3%) had type 1 DM and 878 (79.7%) had type 2 diabetes. Thyroid dysfunction was present in 136 patients (12.4%) at baseline and developed in 71 patients (6.4%) at follow-up (median duration, 37 months). Overt and subclinical hypothyroidism developed in 28 (2.5%) and 38 (3.5%) patients, respectively. Incident hypothyroidism was associated with baseline thyrotropin concentration greater than 2.2 mIU/L (relative risk, 10.4; confidence interval, 5.6-19.6; P < .001) and female sex (relative risk, 1.8; confidence interval, 1.1-2.9; P = .007). The predictive influence of sex was abolished in patients with a thyrotropin value greater than 2.2 mIU/L. This TSH threshold yielded an optimal sensitivity and specificity of 83% and 72%, respectively, for predicting hypothyroidism.ConclusionsBaseline serum thyrotropin predicted hypothyroidism in patients with diabetes mellitus even at thyrotropin concentrations within the reference range. Selective annual thyroid screening in diabetic patients with baseline thyrotropin concentrations greater than 2.2 mIU/L may be more cost-effective than universal screening. (Endocr Pract. 2011;17:26-32)     

Increased Atherogenic Low-Density Lipoprotein Cholesterol in Untreated Subclinical Hypothyroidism

ObjectiveTo evaluate the effects of physiologic doses of levothyroxine replacement on the lipoprotein profile in patients with subclinical hypothyroidism (SCH).MethodsIn a prospective, double-blind, placebo- controlled study, we enrolled 120 patients—mostly, but not exclusively, premenopausal women—with SCH. Patients were randomly assigned to either a levothyroxine- treated group (n = 60) or a placebo (control) group (n = 60). Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were measured before and 52 weeks after assignment to either group.ResultsIn the levothyroxine-treated group, the lipoprotein mean values before and after the 52-week study were as follows: TC, 5.05 ± 0.98 mmol/L versus 4.74 ± 0.87 mmol/L (P < .0001); LDL-C, 3.30 ± 0.90 mmol/L versus 2.89 ± 0.59 mmol/L (P < .01); TG, 1.18 ± 0.71 mmol/L versus 0.95 ± 0.53 mmol/L (P < .002); and HDL-C, 1.20 ± 0.33 mmol/L versus 1.19 ± 0.32 mmol/L (P = .29). In the control group, TC, HDL-C, and TG values remained unchanged after 52 weeks in comparison with baseline, but LDL-C mean values increased from 2.79 ± 0.60 mmol/L to 3.11 ± 0.77 mmol/L, a change that was statistically significant (P < .001). At the end of the study, the lipid profile changes between levothyroxine- treated and control groups were compared. Total cholesterol and LDL-C were significantly lower in the levothyroxine-receiving group (P < .029 and P < .0001, respectively) in comparison with the control group. The difference did not reach statistical significance for TG and HDL-C values.ConclusionIn premenopausal women, SCH has a negative effect on the lipoprotein profile and may translate into a sizable cardiovascular risk if left untreated. (Endocr Pract. 2008;14:570-575)     

Positive Thyrotropin Receptor Antibodies in Patients with Transient Thyrotoxicosis

Objective: Thyrotropin (TSH) receptor antibody (TRAb) testing is considered accurate for the diagnosis of Graves disease (GD) and has been identified rarely in thyrotoxic patients without GD. We describe 4 patients with transient thyrotoxicosis and positive TRAb to highlight this clinical possibility.Methods: Patient demographics, symptoms, laboratory findings, and time to resolution of thyrotoxicosis are summarized. TRAb testing was performed by either a third-generation thyrotropin-binding inhibitory immunoglobulin (TBII) competitive-binding assay or a thyroid-stimulating immunoglobulin (TSI) bioassay from either Mayo Clinic Laboratory or Quest Diagnostics.Results: Four patients with transient thyrotoxicosis and positive TRAb testing were identified. Of these, three were female, and the median age was 44 years (range, 25 to 49 years). Median symptom duration at evaluation was 6.5 weeks (range, 3 to 12 weeks). No patient had any clinical manifestations unique to GD or exposure to biotin, thyroid hormone, supplements, iodine, or relevant medications. The TSH was <0.1 mIU/L in all patients. Three patients had a positive TSI, which was elevated less than twice the upper limit of the reference range in all cases, and 1 patient had a strongly positive TBII. None of the patients were treated with thionamides or radioactive iodine. Spontaneous resolution occurred in all patients at a median of 5.5 weeks (range, 2 to 14.4 weeks).Conclusion: These cases demonstrate that TSI or TBII may be present in thyrotoxic patients with transient thyrotoxicosis. For clinically stable patients presenting without pathognomonic evidence of GD, mildly elevated TRAb results may require cautious interpretation, and alterative diagnostic testing or close monitoring should be considered.Abbreviations: cAMP = cyclic adenosine monophosphate; FT4 = free thyroxine; GD = Graves disease; TBII = thyrotropin-binding inhibitory immunoglobulin (also known as TBI); TRAb = thyrotropin receptor antibody; TSH = thyrotropin; TSHR = thyrotropin receptor; TSI = thyroid-stimulating immunoglobulin; TT3 = total triiodothyronine; TT4 = total thyroxine     

Color-Flow Doppler Sonography in Patients with Subclinical Thyroid Dysfunction

ObjectiveTo assess the value of color-flow Doppler sonography (CFDS) in evaluating intrathyroidal blood flow and velocity in patients with subclinical thyroid dysfunction.MethodsIn this prospective study, patients with subclinical hypothyroidism, patients with subclinical hyperthyroidism, and euthyroid patients without known thyroid autoimmune disease who served as controls were included. Subclinical thyroid dysfunction was defined as normal serum free thyroxine (FT₄) and free triiodothyronine (FT₃) in the presence of high (subclinical hypothyroidism), or lowsuppressed (subclinical hyperthyroidism) serum thyrotropin (TSH) levels. Serum FT₄, FT₃, TSH, and antibodies to thyroid peroxidase and thyroglobulin were measured in all participants. In addition, TSH receptor antibody levels were determined in patients with subclinical hyperthyroidism. All participants underwent conventional sonography and CFDS. Mean peak systolic velocity (PSV) and resistive index were obtained from multiple extranodular thyroid parenchyma samplings and inferior thyroid artery measurements.ResultsThe study population included 27 patients with subclinical hypothyroidism, 15 patients with subclinical hyperthyroidism, and 20 euthyroid patients. Patients with subclinical hypothyroidism had significantly higher mean intrathyroidal PSV values than control patients (19.9 ± 5.6 cm/s vs 15.7 ± 4.4 cm/s; P = .008), whereas patients with subclinical hyperthyroidism had significantly higher mean PSV values than control patients at the inferior thyroid artery level (29.7 ± 10.7 cm/s vs 21.9 ± 6.8 cm/s; P = .014). Compared with control patients, a greater proportion of patients with subclinical hypothyroidism and patients with subclinical hyperthyroidism had marked CFDS patterns (78% vs 15% [P <.001] and 53% vs 15%; [P <.001], respectively). A significant association was found between positivity for thyroid autoantibodies and intense CFDS patterns. No correlation was found between TSH or thyroid hormone levels and CFDS pattern or blood flow velocity.ConclusionWe have demonstrated that significantly increased thyroid blood flow velocity and vascularity are already present in patients with mild thyroid dysfunction.(Endocr Pract. 2010;16:376-381)     

Seasonal Variation Of Vitamin D And Serum Thyrotropin Levels And Its Relationship In A Euthyroid Caucasian Population

Objective: It is unclear whether seasonal variations in vitamin D concentrations affect the hypothalamo-pituitary-thyroid axis. We investigated the seasonal variability of vitamin D and serum thyrotropin (TSH) levels and their interrelationship.Methods: Analysis of 401 patients referred with nonspecific symptoms of tiredness who had simultaneous measurements of 25-hydroxyvitamin D3 (25&lsqb;OH]D3) and thyroid function. Patients were categorized according to the season of blood sampling and their vitamin D status.Results: 25(OH)D3 levels were higher in spring-summer season compared to autumn-winter (47.9 ± 22.2 nmol/L vs. 42.8 ± 21.8 nmol/L; P = .02). Higher median (interquartile range) TSH levels were found in autumn-winter (1.9 &lsqb;1.2] mU/L vs. 1.8 &lsqb;1.1] mU/L; P = .10). Across different seasons, 25(OH)D3 levels were observed to be higher in lower quartiles of TSH, and the inverse relationship was maintained uniformly in the higher quartiles of TSH. An independent inverse relationship could be established between 25(OH)D3 levels and TSH by regression analysis across both season groups (autumn-winter: r = -0.0248; P<.00001 and spring-summer: r = -0.0209; P<.00001). We also observed that TSH varied according to 25(OH)D3 status, with higher TSH found in patients with vitamin D insufficiency or deficiency in comparison to patients who had sufficient or optimal levels across different seasons.Conclusion: Our study shows seasonal variability in 25(OH)D3 production and TSH secretion in euthyroid subjects and that an inverse relationship exists between them. Further studies are needed to see if vitamin D replacement would be beneficial in patients with borderline thyroid function abnormalities.Abbreviations: 25(OH)D2 = 25-hydroxyvitamin D2; 25(OH)D3 = 25-hydroxyvitamin D3; AITD = autoimmune thyroid disease; FT4 = free thyroxine; TFT = thyroid function test; TSH = thyrotropin; UVB = ultraviolet B     

Assessing the Relationship Between Serum Ghrelin Levels and Metabolic Parameters and Autoimmunity in Patients with Euthyroid Hashimoto's Thyroiditis

ObjectivesHashimoto’s thyroiditis (HT) may affect metabolic parameters and increase predisposition to obesity. In this study, we aimed to assess the relationships among serum ghrelin concentrations, metabolic parameters, and thyroid autoimmunity in euthyroid HT patients.MethodsThe study included 48 euthyroid HT patients and 41 age- and sex-matched healthy controls. We assessed serum ghrelin, free triiodothyronine (T3), free thyroxine (T4), thyroid-stimulating hormone (TSH), thyroid peroxidase antibody (anti-TPO), thyroglobulin antibody (anti-Tg), fasting blood glucose (FBG), insulin, lipid levels, and homeostasis model assessment insulin resistance (HOMA-IR) in all subjects.ResultsSex distribution, mean age, and body mass index (BMI) were similar in HT patients and controls (female/male, 42/6 vs. 33/8, 46.8 ± 14.7 vs. 45 ± 12.5 years,28.5 ± 6.1 vs. 28.4 ± 4.9 kg/m², respectively; P>.05 for all). The mean waist circumference (WC) of the HT group was significantly higher than that of the control group (100.6 ± 14.6 vs. 93.2 ± 13.2 cm, P = .015). While FBG, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels in the HT group were significantly higher than in the control group, insulin levels and HOMA-IR were similar. Ghrelin levels were lower in HT patients compared to controls (416.9 ± 224.4 and 689.9 ± 191.6 pg/mL, respectively; P<.001). Ghrelin levels were similar in patients with low and high anti-TPO titers. Negative correlations were observed between ghrelin levels and BMI, WC, and anti-TPO levels. Regression analysis revealed that HT was the most important predictor of ghrelin levels.ConclusionEuthyroid HT is associated with a decrease in plasma ghrelin levels. Altered body fat distribution and increased anti-TPO levels do not seem to be directly involved in lower ghrelin levels in euthyroid HT patients.     

顺铂对HepG2细胞增殖、细胞周期及肝癌干细胞标志物的影响

目的:研究顺铂对HepG2细胞增、细胞周期及肝癌干细胞标志物(CD133、ICAM-1和ABCG2)的影响。方法:选取HepG2作为研究对象,分别采用MMT比色法、PI染色法及免疫荧光法检测不同浓度顺铂对其增殖、细胞周期、CD133、ICAM-1和ABCG2表达的影响。结果:每个浓度顺铂作用后均可以显著抑制HepG2细胞增殖力(F=12.23,P=0.004);顺铂对HepG2细胞增殖力的抑制作用和浓度可能与时间成正比。0 mg/L组静息期(G0/G1期)细胞比例为(50.25±0.79)%、2 mg/L组G0/G1期细胞比例为(89.24±0.41)%、4 mg/L组G0/G1期细胞比例为(29.54±3.02)%,2 mg/L组和4 mg/L组分别比0 mg/L组显著上升和下降,差异明显有统计学意义(t=6.53、-3.65,均P0.05)。0 mg/L组DNA合成期(S期)细胞比例为(47.13±0.74)%、2 mg/L组S期细胞比例为(5.65±0.42)%、4 mg/L组S期细胞比例为(67.46±3.24)%,2 mg/L组和4 mg/L组分别比0 mg/L组显著下降和上升,差异明显有统计学意义(t=-7.35、3.79,均P0.05)。结果提示2 mg/L组和4 mg/L组顺铂可让HepG2在G0/G1期与S期显著阻滞,差异有统计学意义(P0.01);顺铂处理后,剩余的HepG2细胞的CD133、ICAM-1和ABCG2呈现高表达水平。结论:HepG2细胞系中会有很少部分肝癌干细胞避开了顺铂的杀灭作用,是造成临床上肝癌反复发作的重要因素之一,临床上应予以重视。     

Cardiac Complications as Initial Manifestation of Pheochromocytoma: Frequency,Outcome, and Predictors

ObjectiveTo examine the frequency, outcome, and clinical predictors of cardiac complications as the initial manifestation of pheochromocytoma.MethodsThe medical records of all 76 patients with pheochromocytoma or functional paraganglioma treated at Cedars-Sinai Medical Center, Los Angeles, California, from 1995 to 2011 were reviewed. The patients initially presenting with cardiac complications were identified, and their clinical, laboratory, and imaging characteristics were compared with those of the patients presenting with other complaints, especially hypertension and adrenal mass.ResultsOf the 76 patients, 9 (12%) presented with the following: 2 with acute heart failure, 1 with left ventricular thrombus, 3 with myocardial infarction, and 3 with severe arrhythmia. Failure to diagnose pheochromocytoma resulted in unnecessary invasive interventions in 2 patients. Recovery of cardiac function was excellent after resection of the tumor in all patients. In comparison with the 67 patients presenting with other complaints, the 9 with cardiac complications had similar demographics and cardiac risk factors but harbored larger tumors (6.7 ± 0.8 cm versus 4.4 ± 0.3 cm; P = .015) and exhibited higher biochemical marker levels (23.9 ± 9.0-fold versus 11.3 ± 2.4fold; P = .082), longer corrected QT interval (473 ± 8 ms versus 443 ± 6 ms; P = .015), and lower ejection fraction (43% ± 8% versus 66% ± 2%; P = .002).ConclusionIn this study, 12% of patients with pheochromocytoma initially presented with cardiac complications. Patients with large tumors and high levels of biochemical markers were more likely to develop cardiac injury. Our results confirm that the presence of pheochromocytoma should be ruled out in patients with cardiac diseases and features suggesting pheochromocytoma so that unnecessary interventions can be avoided and cardiac recovery can be achieved. (Endocr Pract. 2012;18:483-492)     

Platelet-Lymphocyte Ratio as a Novel Surrogate Marker to Differentiate Thyrotoxic Patients with Graves Disease from Subacute Thyroiditis: a Cross-Sectional Study from South India

Objective: Graves disease (GD) and the toxic phase of subacute thyroiditis (SAT) have similar clinical and biochemical presentations, and differentiating them requires sophisticated investigations. Since thyroid hormones have been noted to affect all hematologic cell lines, we have used the platelet lymphocyte ratio (PLR)—an index usually utilized in inflammatory or malignant disorders—to compare patients with and without thyrotoxicosis and to analyze its use in distinguishing between patients with GD and SAT prior to therapy.Methods: This was a cross-sectional study conducted in the Department of Endocrinology, Christian Medical College, Vellore, India. During the study period, 800 patients with features of thyrotoxicosis visited the outpatient clinic. Those who had thyroid radioiodine (¹³¹I) uptake (RAIU) study and complete blood count (CBC) at diagnosis were included (N = 500). Based on the RAIU values, these were divided as GD (n = 354) and SAT (n = 146). Baseline characteristics, thyroid function tests, and components of the CBC and PLR were obtained. The data were compared with a group of 250 matched euthyroid controls. Analyses were performed using SPSS version 21.0 software.Results: PLR showed significant reductions in both GD and SAT patients when compared to euthyroid controls (P = .01), with greater reductions seen in GD than SAT (74.5 ± 19 vs. 84.4 ± 26; P = .01). Using receiver operating characteristic analysis of PLR, an optimal PLR cut-off of 70.4 was found to differentiate GD from SAT with a sensitivity of 86% and specificity of 74%.Conclusion: PLR can be used as a novel surrogate marker to differentiate between patients with GD and SAT prior to therapy, especially in resource-limited settings.     

Effect of Proton Pump Inhibitors on Serum Thyroid-Stimulating Hormone Level in Euthyroid Patients Treated with Levothyroxine for Hypothyroidism

ObjectiveTo examine retrospectively the effect of proton pump inhibitors (PPIs) on thyrotropin (thyroid-stimulating hormone or TSH) values in patients with hypothyroidism and normal TSH levels receiving levothyroxine (LT₄) replacement therapy.MethodsThe data collection was done by retrospective review of electronic medical records from the period of December 2002 to August 2005 from patients with hypothyroidism who were receiving at least 25 μg of LT₄ replacement daily at Queens Hospital Center. The first 92 patients meeting all inclusion and exclusion criteria were included in the study. The study group (N = 37) patient data were collected by selecting euthyroid patients who had received stable LT₄ replacement for at least 6 months and in whom PPI therapy (lansoprazole) was later initiated. TSH levels were collected before and at least 2 months after the PPI treatment was started. The control group (N = 55) patient data were collected by reviewing TSH levels among euthyroid patients with a history of hypothyroidism receiving stable LT₄ therapy and not receiving a PPI during the period of data collection. The statistical analysis was done by comparing the mean change in TSH level in each group with use of the Student t test.ResultsIn the study group, the mean change in the TSH level from before to at least 2 months after initiation of PPI therapy, 0.69 ± 1.9 μIU/mL, was statistically significant (P = 0.035). In the control group, the mean change in the TSH level during the study period, 0.11 ± 1.06 μIU/mL, was not statistically significant (P = 0.45).ConclusionTo our best knowledge, this is the first study in humans with hypothyroidism demonstrating the effect of PPIs on serum TSH levels. PPIs should be added to the list of medications affecting the level of thyroid hormone in patients with hypothyroidism treated with LT₄ replacement. Patients with hypothyroidism and normal TSH values during LT₄ replacement therapy may need additional thyroid function testing after treatment with PPIs and may need adjustment of their LT₄ dose. (Endocr Pract. 2007;13:345-349)     

Higher Growth Hormone Levels are Associated with Erectile Dysfunction in Male Patients With Acromegaly

Objective: To investigate in vivo correlates of erectile dysfunction (ED) in male patients with acromegaly.Methods: Fifty-one male patients with acromegaly were assessed by the International Index of Erectile Function-5 and Acromegaly Quality of Life (Acro-QoL) questionnaires. The measurement of serum nitric oxide (NO) were performed in patients and age-matched nonacromegalic controls.Results: Among 51 patients analyzed, 32 (62.7%) had ED. Patients with ED showed lower Acro-QoL scores regarding global (69.8 ± 17.7 versus 79.4 ± 11.2; P = .035) and personal relationship dimensions (59.6 ± 22.1 versus 76.8 ± 17.6; P = .012) than non-ED patients. ED patients were older (44.5 ± 11.2 years versus 33.2 ± 8.5 years; P = .04) and showed higher growth hormone (GH) levels (15.5 μg/L &lsqb;interquartile range of 9.5 to 34.5 μg/L] versus 5.9 μg/L &lsqb;interquartile range of 3.4 to 13.9 μg/L]; P = .001) compared to non-ED patients. The cutoff values for identifying ED were 7.9 μg/L for random GH and 5.3 μg/L for GH nadir after oral administration of 75 g of glucose. There was no significant difference in total testosterone levels between the two groups (6.36 ± 4.24 nmol/L versus 9.54 ± 5.50 nmol/L; P = .299). The NO levels in patients with acromegaly were significantly lower than those in nonacromegalic controls (8.77 ± 1.78 μmol/L versus 19.19 ± 5.02 μmol/L, respectively; P = .049). Furthermore, the NO levels were even lower in ED patients than those in non-ED patients (5.14 ± 0.98 μmol/L versus 12.09 ± 3.44 μmol/L; P = .027).Conclusion: Our study showed that ED is prevalent in male acromegalic patients and may be associated with systemic endothelial dysfunction induced by excessive GH. Further studies investigating the mechanism of GH and ED are required.Abbreviations: Acro-QoL = Acromegaly Quality of Life; ED = erectile dysfunction; FSH = follicle-stimulating hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1; IIEF-5 = international index of erection function-5; LH = luteinizing hormone; MRI = magnetic resonance imaging; NO = nitric oxide; OGTT = oral glucose tolerance test; QoL = quality of life; ROC = receiver operating characteristic     

TRPV4 plays an important role in rat prefrontal cortex changes induced by acute hypoxic exercise

ObjectiveThis study aims to investigate the effects of TRPV4 on acute hypoxic exercise-induced central fatigue, in order to explore the mechanism in central for exercise capacity decline of athletes in the early stage of altitude training.Methods120 male Wistar rats were randomly divided into 12 groups: 4 normoxia groups (quiet group, 5-level group, 8-level group, exhausted group), 4 groups at simulated 2500 m altitude (grouping as before), 4 groups at simulated 4500 m altitude (grouping as before), 10 in each group. With incremental load movement, materials were drawn corresponding to the load. Intracellular calcium ion concentration was measured by HE staining, enzyme-linked immunosorbent assay, immunohistochemistry, RT-qPCR, Fluo-4/AM and Fura-2/AM fluorescence staining.Results(1) Hypoxic 2–5 groups showed obvious venous congestion, with symptoms similar to normoxia-8 group; Hypoxic 2–8 groups showed meningeal loosening edema, infra-meningeal venous congestion, with symptoms similar to normoxia-exhausted group and hypoxic 1-exhaused group. (2) For 5,6-EET, regardless of normoxic or hypoxic environment, significant or very significant differences existed between each exercise load group (normoxic ? 5 level 20.58 ± 0.66 pg/mL, normoxic ? 8 level 23.15 ± 0.46 pg/mL, normoxic - exhausted 26.66 ± 0.71 pg/mL; hypoxic1-5 level 21.72 ± 0.43 pg/mL, hypoxic1-8 level 24.73 ± 0.69 pg/mL, hypoxic 1-exhausted 28.68 ± 0.48 pg/mL; hypoxic2-5 level 22.75 ± 0.20 pg/mL, hypoxic2-8 level 25.62 ± 0.39 pg/mL, hypoxic 2-exhausted 31.03 ± 0.41 pg/mL) and quiet group in the same environment(normoxic-quiet 18.12 ± 0.65 pg/mL, hypoxic 1-quiet 19.94 ± 0.43 pg/mL, hypoxic 2-quiet 21.72 ± 0.50 pg/mL). The 5,6-EET level was significantly or extremely significantly increased in hypoxic 1 environment and hypoxic 2 environment compared with normoxic environment under the same load. (3) With the increase of exercise load, expression of TRPV4 in the rat prefrontal cortex was significantly increased; hypoxic exercise groups showed significantly higher TRPV4 expression than the normoxic group. (4) Calcium ion concentration results showed that in the three environments, 8 level group (normoxic-8 190.93 ± 6.11 nmol/L, hypoxic1-8 208.92 ± 6.20 nmol/L, hypoxic2-8 219.13 ± 4.57 nmol/L) showed very significant higher concentration compared to quiet state in the same environment (normoxic-quiet 107.11 ± 0.49 nmol/L, hypoxic 1-quiet 128.48 ± 1.51 nmol/L, hypoxic 2-quiet 171.71 ± 0.84 nmol/L), and the exhausted group in the same environment (normoxic-exhausted 172.51 ± 3.30 nmol/L, hypoxic 1-exhausted 164.54 ± 6.01 nmol/L, hypoxic 2-exhausted 154.52 ± 1.80 nmol/L) had significant lower concentration than 8-level group; hypoxic2-8 had significant higher concentration than normoxic-8.ConclusionAcute hypoxic exercise increases the expression of TRPV4 channel in the prefrontal cortex of the brain. For a lower ambient oxygen concentration, expression of TRPV4 channel is higher, suggesting that TRPV4 channel may be one important mechanism involved in calcium overload in acute hypoxic exercise.     

Enhanced effects of 1,25(OH)(2)D(3) plus genistein on adipogenesis and apoptosis in 3T3-L1 adipocytes

Objective: To investigate the ability of 1,25(OH)₂D₃ (D) and genistein (G), alone and in combination, to inhibit adipogenesis and induce apoptosis in 3T3‐L1 adipocytes. Methods and Procedures: 3T3‐L1 preadipocytes and mature adipocytes were incubated with various concentrations of D and G, alone and in combination, for 48 h. Viability was determined using the Cell Titer 96 Aqueous One Solution Cell Proliferation Assay. Post‐confluent preadipocytes were incubated with D and G for up to 6 days during adipogenesis and lipid content was quantified by Nile Red dye; apoptosis was quantified by measurement of single‐stranded DNA. Expression of adipocyte‐specific proteins and VDR was analyzed by western blotting. Results: Combining D and G did not cause an enhanced effect on cell viability in either preadipocytes or mature adipocytes. In maturing preadipocytes, D at 0.5 nmol/l (D0.5) increased apoptosis by 47 ± 10.25% (P < 0.05) and inhibited lipid accumulation by 28 ± 10% (P < 0.001), while G at 25 μmol/l (G25) had no significant effect. However, D+G caused an enhanced apoptosis by 136 ± 12.6% (P < 0.001) and enhanced inhibition of lipid accumulation by 82.46 ± 2.95% (P < 0.001). Similarly, D0.5 alone decreased adipose‐specific gene 422 (aP2) expression to 34.2 ± 2.3% and increased VDR expression levels by 41.8 ± 11% (P < 0.001), but G25 showed no effect. However, D0.5+G25 decreased aP2 expression to 52 ± 4.2% (P < 0.05) and increased VDR expression levels by 131 ± 14.5% (P < 0.0001). Discussion: These findings suggest that combining 1,25(OH)₂D₃ with genistein results in an enhanced inhibition of lipid accumulation and induction of apoptosis in maturing 3T3‐L1 preadipocytes.     

Effect of An Educational Inpatient Diabetes Management Program on Medical Resident Knowledge and Measures of Glycemic Control: A Randomized Controlled Trial

ObjectiveTo investigate the effectiveness of an Inpatient Diabetes Management Program (IDMP) on physician knowledge and inpatient glycemic control.MethodsResidents assigned to General Internal Medicine inpatient services were randomized to receive the IDMP (IDMP group) or usual education only (nonIDMP group). Both groups received an overview of inpatient diabetes management in conjunction with reminders of existing order sets on the hospital Web site. The IDMP group received print copies of the program and access to an electronic version for a personal digital assistant (PDA). A Diabetes Knowledge Test (DKT) was administered at baseline and at the end of the 1-month rotation. The frequency of hyperglycemia among patients under surveillance by each group was compared by using capillary blood glucose values and a dispersion index of glycemic variability. IDMP users completed a questionnaire related to the program.ResultsTwenty-two residents participated (11 in the IDMP group and 11 in the non-IDMP group). Overall Diabetes Knowledge Test scores improved in both groups (IDMP: 69% ± 1.7% versus 83% ± 2.1%, P = .003; nonIDMP: 76% ± 1.2% versus 84% ± 1.4%, P = .02). The percentage of correct responses for management of corticosteroid-associated hyperglycemia (P = .004) and preoperative glycemic management (P = .006) improved in only the IDMP group. The frequency of hyperglycemia (blood glucose level > 180 mg/dL) and the dispersion index (5.3 ± 7.6 versus 3.7 ± 5.6; P = .2) were similar between the 2 groups.ConclusionAn IDMP was effective at improving physician knowledge for managing hyperglycemia in hospitalized patients treated with corticosteroids or in preparation for surgical procedures. Educational programs directed at improving overall health care provider knowledge for inpatient glycemic management may be beneficial; however, improvements in knowledge do not necessarily result in improved glycemic outcomes. (Endocr Pract. 2012;18:238-249)     

Effects of N-ethylmaleimide on the ATPase activities of cardiac myosin from thyrotoxic rabbits.

The ATPase activities of cardiac myosin from thyrotoxic and euthyroid rabbits have been compared. The Ca²⁺-ATPase activity of myosin from thyrotoxic animals was elevated by 200%, while the K⁺(EDTA)-ATPase activity was the same as in euthyroid animals. Modification by N-ethyl-maleimide of the most rapidly reacting class of sulfhydryls (SH₁) in myosin from euthyroid animals increased Ca²⁺-ATPase activity about 177% over the unreacted value. Modification of the SH₁ groups in myosin from thyrotoxic animals had no effect on CA²⁺-ATPase activity. We conclude that thyroxin may increase cardiac myosin ATPase activity by a conformational change in the same region as the SH₁ thiols.     

A Novel Monoclonal Antibody Degrades the Thyrotropin Receptor Autoantibodies in Graves' Disease

ObjectiveAutoantibodies against the thyrotropin receptor (TSH-R-Ab) are key mediators for the pathogenesis of Graves' disease (GD). TSH-R-Ab degradation was evaluated using several immunoassays within an exploratory, controlled trial in patients with GD receiving a monoclonal antibody (mAb) targeting the neonatal crystallizable fragment receptor (FcRn).MethodsSerial measurements of TSH-R-Ab serum levels were performed using 3 different binding and cell-based assays in patients with GD either on medication or on placebo.ResultsIn contrast to the placebo group, in which no changes were observed, a 12-week mAb therapy led to an early and significant decrease (>60%) in the serum TSH-R-Ab levels in patients with thyroidal and extrathyroidal GD, as unanimously shown in all 3 assays. These marked changes were noted already at week 7 post baseline (P <.0001 for the binding immunoassay and for the luciferase (readout) bioassay). The 3 TSH-R-Ab binding and bioassays were highly correlated in the samples of both study groups (binding immunoassay vs luciferase bioassay, r =.91, P <.001, binding vs cyclic adenosine monophosphate (cAMP) bioassay, r = 0.86, P <.001, and luciferase vs cAMP bioassay, r = 0.71, P =.006). The serological results correlated with the course of the extrathyroidal clinical parameters of GD, that is, clinical activity score and proptosis.ConclusionTargeting the FcRn markedly reduces the disease-specific TSH-R-Ab in patients with GD. The novel and rapid TSH-R-Ab bioassay improves diagnosis and management of patients with GD.