Is GH nadir during OGTT a reliable test for diagnosis of acromegaly in patients with abnormal glucose metabolism?

PURPOSE: The growth hormone (GH) nadir during oral glucose tolerance test (OGTT) is the gold standard diagnostic test for acromegaly. The utility of OGTT-GH suppression test in patients with abnormal glucose metabolism (AGM) has not been well established. In this study, we compared the GH nadir during OGTT in patients evaluated for acromegaly in the presence and absence of AGM. METHODS: This is a retrospective cohort study of patients with acromegaly (G1, n = 40) and a group in whom acromegaly was not confirmed (G2, n = 53) who had OGTT-GH suppression test during 2000-2012, using a monoclonal GH immunoenzymatic assay. The patients were categorized as having normal glucose metabolism (NGM) or AGM. GH nadir during OGTT in each group were compared. RESULTS: In G1 and G2, 17 and 19 patients had AGM, respectively. Among 17 patients with diabetes, median HbA1C was 7% (range 5.7-9.6%). All except one patient had HbA1C< 8%. There was no difference in the GH nadir in patients with or without AGM within G1 (p = 0.15) and G2 (p = 0.43). All G1 patients with AGM had GH nadir > 0.4 µg/L. Four G1 patients with NGM had GH nadir<0.4 µg/L. All G2 patients had GH nadir < 0.4 µg/L, except one with NGM and GH nadir of 0.4 µg/L. CONCLUSION: Using highly sensitive GH assay, a GH nadir ≥ 0.4 µg/L during the OGTT-GH suppression test may be used for diagnosis of acromegaly in patients with AGM in the absence of poorly controlled diabetes.

Effect of surgery on ovarian reserve in women with endometriomas, endometriosis and controls.

BACKGROUND: Many women who experience endometriosis and endometriomas also encounter problems with fertility. OBJECTIVE: The purpose of this study was to determine the impact of surgical excision of endometriosis and endometriomas compared with control subjects on ovarian reserve. STUDY DESIGN: This was a prospective cohort study of 116 women aged 18-43 years with pelvic pain and/or infertility who underwent surgical treatment of suspected endometriosis (n=58) or endometriomas (n=58). Based on surgical findings, the suspected endometriosis group was further separated into those with evidence of peritoneal disease (n=29) and those with no evidence of endometriosis (n=29). Ovarian reserve was measured by anti-Müllerian hormone and compared before surgery and at 1 month and 6 months after surgery. RESULTS: Baseline anti-Müllerian hormone values were significantly lower in the endometrioma vs negative laparoscopy group (1.8 ng/mL [95% confidence interval, 1.2-2.4 ng/mL] vs 3.2 ng/mL [95% confidence interval, 2.0-4.4 ng/mL]; P<.02), but the peritoneal endometriosis group was not significantly different than either of these groups. Only patients with endometriomas had a significant decline in ovarian reserve at 1 month (-48%; 95% confidence interval, -54 to -18%; P<.01; mean anti-Müllerian hormone baseline value, 1.77-1.12 ng/mL at 1 month). Six months after surgery, anti-Müllerian hormone values continued to be depressed from baseline but were no longer significantly different. The rate of anti-Müllerian hormone decline was correlated positively with baseline preoperative anti-Müllerian hormone values and the size of endometrioma that was removed. Those with bilateral endometriomas (n=19) had a significantly greater rate of decline (53.0% [95% confidence interval, 35.4-70.5%] vs 17.5% [95% confidence interval, 3.2-31.8%]; P=.002). CONCLUSION: At baseline, patients with endometriomas had significantly lower anti-Müllerian hormone values compared with women without endometriosis. Surgical excision of endometriomas appears to have temporary detrimental effects on ovarian reserve.

Islet cell-associated autoantibodies in Ethiopians with diabetes mellitus.

BACKGROUND & AIMS: Our understanding of the role of autoimmunity in the pathogenesis of diabetes in African populations is limited. This study aims to evaluate the prevalence of 4 different islet cell-associated antibodies in Ethiopian patients with diabetes and non-diabetic controls. METHODS: A total of 187 subjects from a diabetic clinic at an Ethiopian hospital were evaluated in a cross-sectional study. Fifty-five patients had type 1 diabetes mellitus (T1DM), 86 had type 2 diabetes mellitus (T2DM) and 46 were non-diabetic controls. Islet cell-associated antibodies were measured using 4 different assays for antibodies against islet cells (ICA), glutamic acid decarboxylase (GADA), insulin (IAA) and the protein tyrosine phosphatase-like IA-2 (IA-2A). RESULTS: Comparing the antibody positivity in subjects with T1DM versus T2DM, the results were as follows: 29% versus 3.5% for GADA; 21% versus 2.7% for ICA; 27% versus 16% for IAA. In the control group, the only positive result was for IAA at 2%. IA-2A was absent in all groups. The combi-assay for GADA and IA-2A detected all GADA-positive subjects. T2DM patients who were GADA positive had lower BMI, lower C-peptide levels and all of them were on insulin therapy. CONCLUSIONS: Compared to Caucasians, Ethiopians with T1DM have less prevalence of islet cell-associated antibodies, but the rates are higher than in T2DM. GADA is present in Ethiopians, whereas IA-2A seems to be absent. GADA positivity in T2DM correlates with clinical features of T1DM, indicating the existence in Ethiopia of the subgroup, latent autoimmune diabetes in adults.

Diagnostic accuracy of circulating thyrotropin receptor messenger RNA combined with neck ultrasonography in patients with Bethesda III-V thyroid cytology.

BACKGROUND: The aim of this study was to analyze the usefulness of thyrotropin receptor messenger RNA (TSHR-mRNA) combined with neck ultrasonography (US) in the management of thyroid nodules with Bethesda III-V cytology. METHODS: Cytology slides of patients with a preoperative fine needle aspiration (FNA) and TSHR-mRNA who underwent thyroidectomy between 2002 and 2011 were recategorized based on the Bethesda classification. Results of thyroid FNA, TSHR-mRNA, and US were compared with the final pathology. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: There were 12 patients with Bethesda III, 112 with Bethesda IV, and 58 with Bethesda V cytology. The sensitivity of TSHR-mRNA in predicting cancer was 33%, 65%, and 79 %, and specificity was 67%, 66%, and 71%, for Bethesda III, IV, and V categories, respectively. For the same categories, the PPV of TSHR-mRNA was 25%, 33%, and 79%, respectively; whereas the NPV was 75%, 88%, and 71%, respectively. The addition of neck US to TSHR-mRNA increased the NPV to 100% for Bethesda III, and 86%, for Bethesda IV, and 82% for Bethesda V disease. CONCLUSION: This study documents the potential usefulness of TSHR-mRNA for thyroid nodules with Bethesda III-V FNA categories. TSHR-mRNA may be used to exclude Bethesda IV disease. A large sample analysis is needed to determine its accuracy for Bethesda category III nodules.

The utility of peripheral thyrotropin receptor mRNA in the management of differentiated thyroid cancer.

BACKGROUND: Our aim was to analyze the utility of peripheral thyrotropin receptor (TSHR) messenger RNA (mRNA) in predicting and detecting the recurrence of differentiated thyroid cancer. METHODS: Peripheral blood TSHR-mRNA was obtained in 103 patients before and after total thyroidectomy. An analysis was performed to correlate peripheral blood TSHR-mRNA concentration with oncologic outcomes. RESULTS: Tumor types were papillary (n = 92), follicular (n = 9) and Hürthle cell (n = 2) cancer. Preoperative TSHR-mRNA was ≥1.02 ng/µg in 85% (88/103). On follow-up (median 48 months), 10 patients (10 %) developed recurrence. Recurrence rate in patients with a preoperative TSHR-mRNA ≥ 1.02 ng/µg was 11% versus 0% in those with a lesser concentration. TSHR-mRNA correctly diagnosed 7 (70%) of 10 recurrences. Of 19 patients with positive thyroglobulin (Tg) antibodies, TSHR-mRNA confirmed disease-free status in 12 (63%) and recurrence in 1 (5%). For Tg, TSHR-mRNA and whole-body radioactive iodine scan, sensitivity was 70%, 70%, and 75%; specificity 94%, 76%, 97%; PPV 54%, 24%, and 67%; and NPV 97%, 96%, and 98%, respectively, in detecting recurrent disease. CONCLUSION: This study shows that patients with preoperative TSHR-mRNA ≥1.02 ng/µg may be at a greater risk for recurrence compared with those with a lesser concentration. In the presence of Tg antibodies, TSHR-mRNA accurately predicted disease status in 68% of patients. Its overall performance in detecting recurrence was similar to Tg and whole-body radioactive iodine scan, albeit with lower specificity and PPV.

CIRCULATING THYROID-STIMULATING HORMONE RECEPTOR MESSENGER RNA AS A MARKER OF TUMOR AGGRESSIVENESS IN PATIENTS WITH PAPILLARY THYROID MICROCARCINOMA.

BACKGROUND: We have previously shown that thyroid-stimulating hormone receptor messenger RNA (TSHR mRNA) is detectable in the peripheral blood of patients with papillary thyroid microcarcinoma (PTmC). The aim of this study was to analyze the utility of TSHR mRNA status as a marker of tumor aggressiveness in patients with PTmC. METHODS: Preoperative TSHR mRNA values were obtained in 152 patients who underwent thyroidectomy and were found to have PTmC on final pathology. Clinical parameters were analyzed from an institutional review board-approved database using χ(2) and t tests. RESULTS: Preoperatively, TSHR mRNA was detected in the peripheral blood in 46% of patients, which was less than that for macroscopic papillary thyroid carcinoma (PTC) (80%) but higher than for benign thyroid disease (18%) (P<.001). The focus of cancer was larger in the TSHR mRNA-positive group compared to the negative group (0.41 vs. 0.30 cm, respectively, P = .015). The prevalence of tall-cell variant was higher in the TSHR mRNA positive group. The rates of lymph node (LN) metastasis (16% vs. 10%), multifocality (46% vs. 49%), and extra-thyroidal extension (10% vs. 5%) were similar between the TSHR mRNA-positive and-negative groups, respectively. In patients 45 years or older, rate of LN metastasis was higher in those who were TSHR mRNA positive (10%) versus negative (2%) (P = .039). TSHR mRNA positivity predicted a higher likelihood of radioactive iodine treatment (36% vs. 17%, P = .009) postoperatively. CONCLUSION: This study shows that TSHR mRNA, which is a marker of circulating thyroid cancer cells, is detectable in about half of patients with PTmC. The positivity of this marker predicts a higher likelihood of LN involvement in patients with PTmC who are 45 years or older.

Measurement of Serum Free Thyroxine Index May Provide Additional Case Detection Compared to Free Thyroxine in the Diagnosis of Central Hypothyroidism.

The diagnosis of central hypothyroidism is often suspected in patients with hypothalamic/pituitary pathology, in the setting of low, normal, or even slightly elevated serum TSH and low free thyroxine (FT4). We present four cases of central hypothyroidism (three had known pituitary pathology) in whom central hypothyroidism was diagnosed after the serum free thyroxine index (FTI) was found to be low. All had normal range serum TSH and free thyroxine levels. This report illustrates that the assessment of the serum FTI may be helpful in making the diagnosis of central hypothyroidism in the appropriate clinical setting and when free T4 is in the low-normal range, particularly in patients with multiple anterior pituitary hormone deficiencies and/or with symptoms suggestive of hypothyroidism.

The clinical utility of free thyroxine in oral levothyroxine absorption testing.

OBJECTIVE: Original absorption studies for levothyroxine (LT4) were validated using total thyroxine (TT4) measurements. Free thyroxine (FT4) has largely supplanted TT4 in clinical practice. The objective of our study was to assess the clinical utility of FT4 in oral LT4 absorption testing. METHODS: In this retrospective electronic health record analysis, we recorded data of patients who underwent LT4 oral absorption testing between November 2010 and January 2012 because of persistent hypothyroidism despite a greater than anticipated weight-based dose of LT4. Patients included had primary hypothyroidism and an absorption test with assessment of both TT4 and FT4 measured at times 0, 30, 60, 90, 120, 180, 240, 300, and 360 minutes. The test was conducted with 1 mg (five 200-µg tablets) of Synthroid® after an overnight fast by a standard nonisotopic method. RESULTS: A total of 10 patients (3 men/7 women) underwent absorption testing. Prior to testing, the median daily LT4 dose was 250 µg (range, 150 to 350 µg). Three patients were also on liothyronine (10, 20, or 50 µg daily). Based on the calculated amount absorbed, 1 patient demonstrated subnormal absorption, and 9 patients were normal. Median body mass index was 33 kg/m2 (range, 21 to 50 kg/m2). Median calculated absorption was 105% (range, 3.7 to 195.6%). The correlation comparing FT4 and TT4 was 0.88 (95% confidence interval, 0.56 to 0.97; P<.001), a significant correlation. CONCLUSION: FT4 and TT4 correlated highly, even in patients who were severely hypothyroid; FT4 may be used interchangeably with TT4 as a qualitative assessment of suspected malabsorption using an oral LT4 absorption test.

Metabolic effects of bariatric surgery in patients with moderate obesity and type 2 diabetes: analysis of a randomized control trial comparing surgery with intensive medical treatment.

OBJECTIVE: To evaluate the effects of two bariatric procedures versus intensive medical therapy (IMT) on ß-cell function and body composition. RESEARCH DESIGN AND METHODS: This was a prospective, randomized, controlled trial of 60 subjects with uncontrolled type 2 diabetes (HbA1c 9.7 ± 1%) and moderate obesity (BMI 36 ± 2 kg/m(2)) randomized to IMT alone, IMT plus Roux-en-Y gastric bypass, or IMT plus sleeve gastrectomy. Assessment of ß-cell function (mixed-meal tolerance testing) and body composition was performed at baseline and 12 and 24 months. RESULTS: Glycemic control improved in all three groups at 24 months (N = 54), with a mean HbA1c of 6.7 ± 1.2% for gastric bypass, 7.1 ± 0.8% for sleeve gastrectomy, and 8.4 ± 2.3% for IMT (P < 0.05 for each surgical group versus IMT). Reduction in body fat was similar for both surgery groups, with greater absolute reduction in truncal fat in gastric bypass versus sleeve gastrectomy (-16 vs. -10%; P = 0.04). Insulin sensitivity increased significantly from baseline in gastric bypass (2.7-fold; P = 0.004) and did not change in sleeve gastrectomy or IMT. ß-Cell function (oral disposition index) increased 5.8-fold in gastric bypass from baseline, was markedly greater than IMT (P = 0.001), and was not different between sleeve gastrectomy versus IMT (P = 0.30). At 24 months, ß-cell function inversely correlated with truncal fat and prandial free fatty acid levels. CONCLUSIONS: Bariatric surgery provides durable glycemic control compared with intensive medical therapy at 2 years. Despite similar weight loss as sleeve gastrectomy, gastric bypass uniquely restores pancreatic ß-cell function and reduces truncal fat, thus reversing the core defects in diabetes.

Is chronic nipple piercing associated with hyperprolactinemia?

Literature on hyperprolactinemia in the setting of a nipple piercing is limited to individuals with concomitant breast/chest wall infection. It is unclear if chronic nipple stimulation from a piercing alone can cause sustained elevations of serum prolactin. Nipple piercing is emerging as a more mainstream societal form of body art, and the answer to this clinical question would potentially alter patient management. Our aim was to assess serum prolactin levels in subjects with nipple piercing. Inclusion criteria were as follows: men and women ≥ 18 years old with nipple piercing(s) present > 6 months. Exclusion criteria included: women who are pregnant, lactating or < 6 months postpartum; subjects on medications known to increase prolactin levels; chest wall/breast infection at the time of phlebotomy or conditions known to be associated with hyperprolactinemia. Three men and eight women were enrolled. Median (range) ages for men and women were 33 (24-42) and 27 years (23-42), respectively. All except one subject had bilateral piercings. The median interval from nipple piercing to blood draw was 4.0 (2.0-12.0) years. None of the subjects had hyperprolactinemia. Median (range) prolactin levels for men and women were 5.6 ng/mL (3.8-7.4) and 8.0 ng/mL (2.8-10.9), respectively. Our results suggest that in the absence of any concomitant infection, chronic nipple piercing is not associated with hyperprolactinemia.

Evaluation of two automated immunoassays for 25-OH vitamin D: comparison against LC-MS/MS.

BACKGROUND/METHODS: A total of 95 human serum specimens, and a 12 specimen precision panel, were measured by 2 automated immunoassays (investigation use only DiaSorin LIAISON(®) 25 OH Vitamin D TOTAL Assay [LSN], and Siemens ADVIA Centaur(®) Vitamin D Total (VitD) assay [Centaur]) and the results compared against LC-MS/MS [LCMS] used as the reference method (Esoterix Inc.). For functional sensitivity and precision, 12 serum specimens [range 1.2-148ng/mL] were run in six replicates [N=30] or four replicates [N=20], respectively, for 5 consecutive days. RESULTS: Passing-Bablok fit and Difference plot analysis [N=92] showed that although both immunoassays had comparable correlation coefficient [r] values to LCMS (0.936 and 0.933), the LSN assay results were statistically equivalent to those given by LCMS (slope 0.93, intercept -2.5), whereas the results of the Centaur assay showed overall significant assay bias compared to LCMS (slope 1.30, intercept -15.8) and this bias was more significant for doses <30ng/mL by LCMS [bias -30.4%; 95% limits of agreement -72.4% to 11.7%]. For specificity, based on 25-OHD2 and 25-OHD3 levels assessed by LCMS, we divided the specimens into 2 groups, one with detectable 25-OHD2 [Group 1, N=41] and the other with no detectible 25OHD2 [Group 2, N=51]. The 2 groups showed comparable correlation coefficient [r] values between the methods, but showed significant differences in slope: Centaur [1.48 with group 1 and 1.18 with group 2] compared to LSN [0.91 with Group 1 and 0.96 with Group 2]. LSN demonstrated better precision [total CV range 5.5-10.0%] compared to Centaur [total CV range 11.0-16.3%]. Functional sensitivity was calculated per EP-17A: 2.15ng/mL by LSN and 4.57ng/mL by Centaur. CONCLUSIONS: Though there was good overall correlation, substantial bias was present in Centaur. Although LSN had a slope and intercept that was not significantly different than LCMS, Centaur had a significantly higher slope in specimens containing measurable 25-OHD2 levels, a large negative intercept and a significant negative dose bias for doses <30ng/mL by LCMS, suggesting the Centaur assay would report a higher frequency of patients with apparent vitamin D insufficiency/deficiency at the low end and apparent vitamin D toxicity at the high end compared against LCMS. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Clinically significant variability of serum IgE concentrations in patients with severe asthma.

OBJECTIVE: To determine the magnitude of immunoglobulin E (IgE) variability in a cohort of patients with severe asthma considered for omalizumab therapy. METHODS: Retrospective chart review identified 65 patients with two or more IgE determinations out of the 124 patients referred to the Cleveland Clinic Respiratory Institute for treatment with omalizumab from 2003 to 2011. Patients with conditions known to affect IgE concentrations were excluded. Demographic data, pulmonary function testing, medications, smoking status, and atopy were recorded. The range of variability and percent variability in relation to baseline serum IgE were calculated. RESULTS: The median difference of serum IgE between the minimal and maximal values was 94.9 IU/ml (IQR 26.3-324.1 IU/ml). Percent variability from minimum value had a median of 75.5% (IQR 23.3-152.6%). There was no correlation between age, body mass index, lung function, and IgE variability. Greater variability was associated with female gender (p = .06). There was no association with peripheral eosinophilia, systemic corticosteroid use, and leukotriene modifier use at presentation. The observed variability would have affected omalizumab dosing in 20 out of 42 patients. Six patients who may have qualified at different time points would not have been deemed candidates based on an IgE concentration <30 IU/ml or >700 IU/ml. CONCLUSION: Serum IgE concentration may have clinically significant variability over time, affecting candidacy and dosing of omalizumab. Our findings imply that repeating serum IgE determinations merits consideration for patients whose initial concentrations are <30 or >700 IU/ml. Prospective studies are warranted to delineate the factors that contribute to IgE variability.

Circulating thyrotropin receptor messenger RNA for evaluation of thyroid nodules and surveillance of thyroid cancer in children.

PURPOSE: The aim of this study was to determine the role of thyrotropin receptor messenger RNA as a novel blood test for evaluation of thyroid nodules and cancer in children. METHODS: We reviewed thyroid disease management of patients younger than 18 years with thyrotropin receptor messenger RNA measurements identified from a prospective, institutional review board-approved registry during 2008 to 2010. RESULTS: Thirty-nine thyrotropin receptor messenger RNA measurements were made in 21 female patients (12-17 years old; median, 16 years). Four patients with fine-needle aspiration only had benign thyroid cytology, and 3 of 4 had undetectable thyrotropin receptor messenger RNA. Seventeen patients underwent 22 thyroid operations. Preoperative thyrotropin receptor messenger RNA was measured in 9 patients: 3 of 4 with thyroid cancer had elevated levels and 3 of 5 with goiters undetectable. Postthyroidectomy surveillance (median, 16 months; range, 6-24) of 11 thyroid cancer patients (8 papillary, 3 follicular) showed that thyrotropin receptor messenger RNA was concordant with thyroglobulin in 14 (73%) of 19 measurements. In 3 (16%) of 19 measurements, thyrotropin receptor messenger RNA was the only blood test useful for disease assessment because of elevated antithyroglobulin antibodies. Overall, to predict thyroid cancer, thyrotropin receptor messenger RNA demonstrated 73% sensitivity, 82% specificity, 62% positive predictive value, 88% negative predictive value, and 79% accuracy. CONCLUSION: Thyrotropin receptor messenger RNA provides complementary evaluation to thyroglobulin and fine-needle aspiration for pediatric thyroid nodule management.

Prolactin measurement during inferior petrosal sinus sampling improves the localization of pituitary adenomas in Cushing's disease.

OBJECTIVE: Inferior petrosal sinus sampling (IPSS) distinguishes pituitary-dependent Cushing's disease (CD) from ectopic ACTH syndrome with a high degree of certainty, but has not been reliable in predicting the location of an adenoma within the pituitary gland. We investigated whether prolactin measurements during IPSS would improve pituitary tumour localization. METHODS: Fifty-four patients with suspected ACTH-dependent Cushing's syndrome who underwent IPSS between 1997 and 2009 were studied retrospectively. Twenty-eight patients who had an identifiable tumour that stained for ACTH on histopathology are the subject of this study. Intersinus ACTH gradients before and after adjustment for prolactin were compared with surgical findings and pathology. RESULTS: Magnetic resonance imaging localized a pituitary adenoma in 17/28 (61%) patients. Using a maximum intersinus ACTH gradient of ≥1·4 before or after CRH stimulation, we could diagnose the tumour location correctly in 15/28 (54%) patients. By comparison, tumour lateralization by means of a dominant (≥1·4) prolactin-adjusted ACTH intersinus gradient was correct in 21/28 (75%) patients (P = 0·041). Tumour localization was correct in 23/28 (82%) patients when MRI and prolactin-adjusted ratio data were combined. Fourteen patients with proper bilateral IPS venous sampling (as determined by concurrent IPS to peripheral prolactin ratio ≥1·8) either had correct localization of the tumour (n = 12) or had a central lesion (n = 2). In none of these 14 patients was the dominant prolactin-adjusted ACTH ratio associated with a tumour on the opposite side of the gland. CONCLUSION: Prolactin measurement, during IPSS, improves our ability to correctly localize the pituitary adenoma site in CD.

A new, vitamin D-based, multidimensional nomogram for the diagnosis of primary hyperparathyroidism.

OBJECTIVE: To refine the diagnostic criteria for primary hyperparathyroidism (1°HPT) to identify atypical patients, in whom serum calcium, parathyroid hormone (PTH), or both are within the "normal" range. METHODS: Total serum calcium, intact PTH, and 25-hydroxyvitamin D [25(OH)D] levels were measured in patients with 1°HPT and healthy patient groups. Multivariate analysis of healthy patient data first identified factors that significantly affected PTH levels and defined a new PTH reference range with a mathematical model. That nomogram was then validated for prediction of atypical 1°HPT in patients with surgically confirmed disease. RESULTS: On multivariate analysis, calcium (P = .0002), 25(OH)D (P<.0001), and age (P = .015) independently affected PTH. With these variables, we created a 4-dimensional nomogram that distinguished normal patients from those with hyperparathyroid states. Mathematically, this nomogram predicts 1°HPT when the measured serum PTH value is higher than PTH calculated by the following formula: PTH (pg/mL) = 120 - [6 × calcium (mg/dL)] - [0.52 × 25(OH)D (ng/mL)] + [0.26 × patient age (years)]. When applied to our surgical group of patients, this nomogram successfully identified 100% of patients (238 of 238) with classic 1°HPT, 84% (64 of 76) with normocalcemic 1°HPT, and 54% (20 of 37) with 1°HPT and normal PTH. CONCLUSION: This study uniquely defines a patient-specific upper limit of normal for PTH based on the readily available variables of serum calcium, 25(OH)D, and patient age. Our nomogram may allow for more rapid definitive diagnosis and treatment of 1°HPT in patients with atypical presentations.

Reduced cardiovascular risk following bariatric surgeries is related to a partial recovery from "adiposopathy".

BACKGROUND: Altered cytokine secretion from dysfunctional adipose tissue or "adiposopathy" is implicated in obesity related inflammation and may mediate reduced cardiovascular disease (CVD) risk in response to weight loss after bariatric surgery. We hypothesized that bariatric surgery reduces CVD risk by favorably altering the pro-inflammatory profile of adipose tissue as a result of weight loss. METHODS: In this observational study with repeated measures, 142 patients underwent bariatric surgery of which 45 returned for follow-up at ∼6 months. At both time-points, lipid profiles and levels of plasma adiponectin, leptin, and TNF-α were obtained. Ratios of various adipokine parameters were related to pre- and post- surgical (gastric bypass vs. other restrictive bariatric procedures) lipid ratios. RESULTS: Prior to surgery, circulating adiponectin and the adiponectin/TNF-α ratio was strongly associated with CVD risk characterized by levels of triglycerides, HDL, and the TC/HDL, LDL/HDL, and TG/HDL ratios (all P < 0.05). Following bariatric surgery, BMI was decreased by 22%, adiponectin was increased by 93%, and leptin decreased by 50% as compared to baseline (all P < 0.01). TNF-α levels increased by 120% (P < 0.01) following surgery. Post-surgical changes in adiponectin and the leptin/adiponectin ratio were strongly associated with incremental improvements in triglycerides, HDL, and TC/HDL, LDL/HDL and TG/HDL ratios (all P < 0.05). Roux-en-y gastric bypass surgery (RYGB) as compared to other bariatric procedures was associated with more robust improvements in BMI, HDL, and leptin/adiponectin ratio than other gastric restrictive procedures (P < 0.05). CONCLUSIONS: Thus, bariatric surgery, especially RYGB, ameliorates CVD risk through a partial recovery from "adiposopathy", distinctively characterized by improved adiponectin and the leptin/adiponectin ratio.

Reduction of false-negative results in inferior petrosal sinus sampling with simultaneous prolactin and corticotropin measurement.

OBJECTIVE: To investigate the value of prolactin as an independent marker of catheter placement to improve the diagnostic accuracy of inferior petrosal sinus sampling (IPSS) in patients with corticotropin-dependent Cushing syndrome. METHODS: In this retrospective cohort study, we reviewed hospital records of patients who underwent IPSS procedures at the Cleveland Clinic between 1997 and 2009. Serum prolactin and plasma corticotropin levels were measured prospectively in peripheral and inferior petrosal sinus (IPS) samples. RESULTS: Forty-one patients underwent 42 IPSS procedures at our institution during the study period. Among 35 patients with Cushing disease, 1 patient had erroneous IPSS results: all pre-corticotropin-releasing hormone (CRH) and post-CRH IPS to peripheral (IPS:P) ACTH ratios were less than 2 and less than 3, respectively. Despite radiologic evidence of appropriate IPS catheter placement, concurrent IPS:P prolactin ratios indicated that successful IPS venous sampling was not achieved. A second case with equivocal IPSS results could also be explained by corresponding IPS:P prolactin ratios. During IPSS, all patients with an identifiable ACTH-staining adenoma localizing to 1 side of the pituitary gland (n = 22) who demonstrated absent IPS:P ACTH gradients (<2 before or <3 after CRH administration) on the ipsilateral side of the corticotroph adenoma had corresponding IPS:P prolactin ratios less than 1.3. CONCLUSIONS: Measurement of prolactin during IPSS testing may reduce false-negative results in patients with Cushing disease who do not demonstrate an appropriate central-to-peripheral ACTH gradient. In our series, all false-negative IPS:P ACTH ratios had a corresponding IPS:P prolactin ratio less than 1.3.

Circulating thyrotropin receptor mRNA as a novel marker of thyroid cancer: clinical applications learned from 1758 samples.

OBJECTIVES: Since thyroglobulin, no new blood tests for differentiated thyroid cancer (DTC) have been introduced into routine clinical practice. In initial studies, the detection of circulating DTC cells by thyrotropin receptor (TSHR) mRNA measurement distinguished benign from malignant thyroid diseases. This prospective validation study tests the ability of TSHR mRNA to diagnose DTC preoperatively and to detect cancer recurrence. METHODS: TSHR mRNA was measured by quantitative RT-PCR from blood drawn perioperatively in patients undergoing thyroid surgery (n = 526), postoperatively in patients undergoing DTC follow-up (n = 418) and in patients monitored for known benign disease (n = 151). The reference range and applications for TSHR mRNA were previously defined from 663 samples from patients with normal, benign, and malignant thyroid disease. RESULTS: In patients with follicular neoplasms or suspicious cytology, preoperative TSHR mRNA >1 ng/µg had 96% predictive value for DTC, whereas 95% of patients with undetectable mRNA and benign thyroid sonography had benign disease. In patients with DTC, elevated TSHR mRNA levels became undetectable in all patients (n = 64) on the first postoperative day, except in 5 who manifested persistent or recurrent cervical disease within the year. In long-term follow-up of DTC patients with thyroglobulin antibodies, 96% with undetectable TSHR mRNA also had no evidence of cancer recurrence. CONCLUSIONS: TSHR mRNA provides an additional clinical tool for the evaluation of patients with thyroid nodules. It is particularly useful in guiding appropriate initial surgery for follicular neoplasms. TSHR mRNA also represents a new blood test to aid assessment of disease status in thyroid cancer follow-up.

Detection of circulating thyroid cancer cells in patients with thyroid microcarcinomas.

BACKGROUND: Circulating thyroid cancer cells detected by peripheral blood thyroid-stimulating hormone receptor (TSHR) mRNA have demonstrated usefulness for thyroid cancer diagnosis and long-term surveillance. The aim of this study was to determine detectability and clinical importance of TSHR mRNA in patients with microcarcinomas. METHODS: We compared clinical characteristics of 37 patients with papillary thyroid microcarcinomas (PTMC; tumor size 1 cm (72%; P = NS) and distinctly higher than false (+) rates in benign goiters (15%; P < .001). All patients with (-)TSHR mRNA had classical PTMC, whereas variants (32%) occurred with (+)mRNA (P = .001). Mean tumor size (5 mm) and multifocality rates (45%) were similar in both mRNA groups. Of the PTMC patients, 35% had concurrent cervical nodal metastases, which occurred more frequently with tumors >/=5 mm (P = .04) and with (+)TSHR mRNA in pre-operatively known PTMC (P < .05). No patients with incidentally detected PTMC and (-)TSHR mRNA had metastases. CONCLUSION: This study is the first to demonstrate that TSHR mRNA, reflecting circulating thyroid cancer cells, is detectable even with thyroid microcarcinomas. PTMC with (+)TSHR mRNA may characterize patients with potentially more aggressive histology at initial operation.