CiteULike: omalbam's diagnosis

High Prevalence of Central Adrenal Insufficiency in Patients with Prader-Willi Syndrome

de Lind — 2008-05-11T23:51:05-00:00

J Clin Endocrinol Metab, Vol. 93, No. 5. (1 May 2008), pp. 1649-1654.

Context: The annual death rate of Prader-Willi syndrome (PWS) patients is very high (3%). Many of these deaths are sudden and unexplained. Objective: Because most deaths occur during moderate infections and PWS patients suffer from various hypothalamic insufficiencies, we investigated whether PWS patients suffer from central adrenal insufficiency (CAI) during stressful conditions. Design: Overnight single-dose metyrapone tests were performed. Metyrapone (30 mg/kg) was administered at 2330 h. At 0400, 0600, and 0730 h, ACTH, 11-deoxycortisol, cortisol, and glucose levels were measured. Diurnal salivary cortisol profiles were assessed on a different day at wake-up, 30 min after wake-up, at 1400 h, and at 2000 h. Setting: The study was conducted in a pediatric intensive care unit. Patients: Patients included 25 randomly selected PWS patients. Main Outcome Measure: Patients were considered as having CAI when ACTH levels remained below 33 pmol/liter at 0730 h. Results: Median (interquartile range) age was 9.7 (6.8-13.6) yr. Fifteen patients (60%) had an insufficient ACTH response (CAI, P < 0.001). There was no significant difference in age, gender, genotype, and body mass index SD score between patients with CAI and those without. Morning salivary cortisol levels and diurnal profiles were normal in all children, suggesting that CAI becomes apparent only during stressful conditions. Conclusions: Strikingly, 60% of our PWS patients had CAI. The high percentage of CAI in PWS patients might explain the high rate of sudden death in these patients, particularly during infection-related stress. Based on our data, one should consider treatment with hydrocortisone during acute illness in PWS patients unless CAI has recently been ruled out with a metyrapone test. 10.1210/jc.2007-2294

A Prospective Study of Gastric Carcinoids and Enterochromaffin-Like Cell Changes in Multiple Endocrine Neoplasia Type 1 and Zollinger-Ellison Syndrome: Identification of Risk Factors

Marc Berna — 2008-05-11T23:45:51-00:00

J Clin Endocrinol Metab, Vol. 93, No. 5. (1 May 2008), pp. 1582-1591.

Context: Multiple endocrine neoplasia type 1 (MEN1) patients frequently develop Zollinger-Ellison syndrome (ZES). These patients can develop proliferative changes of gastric enterochromaffin-like (ECL) cells and gastric carcinoids (ECL-cell tumors). ECL-cell changes have been extensively studied in sporadic ZES patients and can be precursor lesions of gastric carcinoids, but little is known about factors influencing their severity or development of carcinoids in MEN1/ZES patients. Objectives: Our objective was to prospectively analyze ECL-cell changes and gastric carcinoids (ECL-cell tumors) in a large series of MEN1/ZES patients to detect risk factors and deduct clinical guidelines. Setting and Patients: Fifty-seven consecutive MEN1/ZES patients participated in this prospective study at two tertiary-care research centers. Interventions and Outcome Measures: Assessment of MEN1, gastric hypersecretion, and gastroscopy with multiple biopsies was done according to a fixed protocol and tumor status. ECL-cell changes and alpha-human chorionic gonadotropin staining were assessed in each biopsy and correlated with clinical, laboratory, and MEN1 features. Results: ECL-cell proliferative changes were universally present, advanced changes in 53% and carcinoids in 23%. Gastric nodules are common and are frequently associated with carcinoids. Patients with high fasting serum gastrin levels, long disease duration, or a strong alpha-human chorionic gonadotropin staining in a biopsy are at higher risk for an advanced ECL-cell lesion and/or gastric carcinoid. Conclusions: Gastric carcinoids and/or advanced ECL-cell changes are frequent in MEN1/ZES patients, and therefore, regular surveillance gastroscopy with multiple routine biopsies and biopsies of all mucosal lesions are essential. Clinical/laboratory data and biopsy results can be used to identify a subgroup of MEN1/ZES patients with a significantly increased risk for developing gastric carcinoids, allowing development of better surveillance strategies. 10.1210/jc.2007-2279

Approach to the Patient with a Positive Serum Thyroglobulin and a Negative Radioiodine Scan after Initial Therapy for Differentiated Thyroid Cancer

Richard Kloos — 2008-05-09T19:55:08-00:00

J Clin Endocrinol Metab, Vol. 93, No. 5. (1 May 2008), pp. 1519-1525.

The 10-yr survival of differentiated thyroid cancer is about 76-93%, and at least 10% of patients manifest tumor persistence or recurrence, depending on their disease stage, after initial therapy, which typically includes total thyroidectomy and 131I ablation. Previously the realization of their residual/recurrent cancer often presented simultaneously with the additional surprise that they lacked pathological uptake on their diagnostic whole-body radioiodine image despite their elevated stimulated serum thyroglobulin (Tg) level, a scenario referred to as the scan-negative, Tg-positive patient. Now that serum Tg and neck ultrasonography have supplanted the diagnostic whole-body scan because of its inferior sensitivity, patients are often recognized to harbor residual disease without radioiodine imaging, and a new challenging scenario has emerged: the ultrasonography-negative, Tg-positive patient. Similarities and differences of these two patient populations aside, these Tg-positive patients are frequently encountered, and some are considered for additional 131I therapy, although now typically after negative anatomic +/- 18F-fluorodeoxyglucose positron emission tomography imaging or in the setting of known or suspected distant metastases already localized by anatomic imaging. Thus, the scan-negative, Tg-positive patient of today differs from those of the past, but the term still has relevance to current practice. The optimal evaluation and treatment of these patients remain controversial, partly because many of these patients will not die from thyroid cancer, and there are no randomized trials to demonstrate that intervention could have prevented the deaths that do occur. Here a case is presented that adds the complexity of advanced age, and one approach to these challenging patients is offered. 10.1210/jc.2007-2357

Variations in the uncoupling protein-3 gene are associated with specific obesity phenotypes

Annet van Abeelen — 2008-04-21T19:09:45-00:00

Eur J Endocrinol, Vol. 158, No. 5. (1 May 2008), pp. 669-676.

ObjectiveUncoupling protein 3 (UCP-3) uncouples oxidative metabolism from ATP synthesis, resulting in the production of heat instead of energy storage. Single nucleotide polymorphisms (SNPs) in UCP-3 might result in a reduced function or expression of UCP-3 and therefore lead to an increased capacity to store energy as fat. DesignWe conducted a population-based, cross-sectional single-center study among 400 Dutch men between 40 and 80 years. MethodsSeven SNPs in the UCP-3 gene were genotyped by means of an allele-specific real-time TaqMan PCR. Linear regression analyses were performed to examine the independent effects of these SNPs on obesity phenotypes. ResultsWe found a significant association between homozygosity for the minor allele of rs647126, rs1685356, and rs2075577 and an increase in body mass index (BMI; P=0.033, P=0.016, and P=0.019 respectively). Heterozygosity for rs1685354 was associated with a significant decrease in visceral fat mass (P=0.030). ConclusionsOur results suggest that genetic variations in the UCP-3 gene are associated with an increase in BMI. A plausible mechanism by which these SNPs lead to an increase in BMI is that due to these SNPs, the UCP-3 activity might be decreased. As a result, uncoupling activity may also decrease, which will lead to an increase in body weight and BMI. 10.1530/EJE-07-0834

Evaluation of Gene Expression Profiles in Thyroid Nodule Biopsy Material to Diagnose Thyroid Cancer

Stephanie Durand — 2008-04-21T17:03:02-00:00

J Clin Endocrinol Metab, Vol. 93, No. 4. (1 April 2008), pp. 1195-1202.

Context: Detection of thyroid cancer among benign nodules on fine-needle aspiration biopsies (FNAB), which presently relies on cytological examination, is expected to be improved by new diagnostic tests set up from genomic data. Objective: The aim of the study was to use a set of genes discriminating benign from malignant tumors, on the basis of their expression levels, to build tumor classifiers and evaluate their capacity to predict malignancy on FNAB. Design: We analyzed the level of expression of 200 potentially informative genes in 56 thyroid tissue samples (benign or malignant tumors and paired normal tissue) using nylon macroarrays. Gene expression data were subjected to a weighted voting algorithm to generate tumor classifiers. The performances of the classifiers were evaluated on a series of 26 sham FNAB, i.e. FNAB carried out on thyroid nodules after surgical resection. Results: A series of 19 genes with a similar expression in follicular adenomas and normal tissue and discriminating follicular adenomas+normal tissue from the following: 1) follicular thyroid carcinomas (FTCs), 2) papillary thyroid carcinomas (PTCs), or 3) both FTCs and PTCs. These were used to generate four classifiers, the FTCs, PTCs, common (FTC+PTCs), and global classifiers. In 23 of the 26 sham FNAB, the four classifiers yielded a diagnosis in agreement with the diagnosis of the pathologist used as reference; in the three other cases, the correct diagnosis was given by three of four classifiers. Conclusions: We developed a procedure of molecular diagnosis of benign vs. malignant tumors applicable to the material collected by FNAB. The molecular test complied with a preclinical validation stage; it must be now evaluated on ultrasound-guided FNAB in a large-scale prospective study. 10.1210/jc.2007-1571

Measurement of basal growth hormone (GH) is a useful test of disease activity in treated acromegalic patients

Jayasena — 2007-12-14T09:35:44-00:00

Clinical Endocrinology, Vol. 68, No. 1. (January 2008), pp. 36-41.

Does thoracic or lumbar spine bone architecture predict vertebral failure strength more accurately than density?

EM Lochmüller — 2008-03-24T21:21:13-00:00

Osteoporosis International, Vol. 19, No. 4. (14 April 2008), pp. 537-545.

Abstract Summary Trabecular bone microstructure was studied in 6 mm bone biopsies taken from the 10th thoracic and 2nd lumbar vertebra of 165 human donors and shown to not differ significantly between these sites. Microstructural parameters at the locations examined provided only marginal additional information to quantitative computed tomography in predicting experimental failure strength. Introduction It is unknown whether trabecular microstructure differs between thoracic and lumbar vertebrae and whether it adds significant information in predicting the mechanical strength of vertebrae in combination with QCT-based bone density. Methods Six mm cylindrical biopsies taken at mid-vertebral level, anterior to the center of the thoracic vertebra (T) 10 and the lumbar vertebra (L) 2 were studied with micro-computed tomography (μCT) in 165 donors (age 52 to 99 years). The segment T11-L1 was examined with QCT and tested to failure using a testing machine. Results The correlation of microstructural properties was moderate between T10 and L2 (r ≤ 0.5). No significant differences were observed in the microstructural properties between the thoracic and lumbar spine, nor were sex differences at T10 or L2 observed. Cortical/subcortical density of T12 (r 2 = 48%) was more strongly correlated with vertebral failure stress than trabecular density (r 2 = 32%). BV/TV (of T10) improved the prediction by 52% (adjusted r 2) in a multiple regression model. Conclusion Microstructural properties of trabecular bone biopsies displayed a high degree of heterogeneity between vertebrae but did not differ significantly between the thoracic and lumbar spine. At the locations examined, bone microstructure only marginally improved the prediction of structural vertebral strength beyond QCT-based bone density.

Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels.

Richa Saxena — 2007-05-07T08:53:58-00:00

Science (26 April 2007)

New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single nucleotide polymorphisms (SNPs) in 1,464 patients with T2D and 1,467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D) we identify and confirm three loci associated with T2D -- in a non-coding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 -- and replicate associations near HHEX and in SLC30A8 found by a recent whole genome association study. We identify and confirm association of a SNP in an intron of glucokinase regulatory protein with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues into the pathogenesis of common diseases.

Studies of Association of Variants Near the HHEX, CDKN2A/B, and IGF2BP2 Genes With Type 2 Diabetes and Impaired Insulin Release in 10,705 Danish Subjects: Validation and Extension of Genome-Wide Association Studies

Niels Grarup — 2008-03-14T19:12:33-00:00

Diabetes, Vol. 56, No. 12. (1 December 2007), pp. 3105-3111.

OBJECTIVE In the present study, we aimed to validate the type 2 diabetes susceptibility alleles identified in six recent genome-wide association studies in the HHEX/KIF11/IDE (rs1111875), CDKN2A/B (rs10811661), and IGF2BP2 (rs4402960) loci, as well as the intergenic rs9300039 variant. Furthermore, we aimed to characterize quantitative metabolic risk phenotypes of the four variants. RESEARCH DESIGN AND METHODS The variants were genotyped in the population-based Inter99 cohort (n = 5,970), the ADDITION Study (n = 1,626), a population-based sample of young healthy subjects (n = 377), and in additional type 2 diabetic case (n = 2,111) and glucose-tolerant (n = 521) subjects. The case-control studies involved a total of 4,089 type 2 diabetic patients and 5,043 glucose-tolerant control subjects. RESULTS We validated association of variants near HHEX/KIF11/IDE, CDKN2A/B, and IGF2BP2 with type 2 diabetes. Interestingly, in middle-aged people, the rs1111875 C-allele of HHEX/KIF11/IDE strongly associated with lower acute insulin response during an oral glucose tolerance test (P = 6 x 107). In addition, decreased insulin release following intravenous tolbutamide injection was observed in young healthy subjects (P = 0.02). Also, a reduced insulin release was observed for the CDKN2A/B rs10811661 T-allele after both oral and intravenous glucose challenges (P = 0.001 and P = 0.009, respectively). CONCLUSIONS We validate that variants in the proximity of the HHEX/KIF11/IDE, CDKN2A/B, and IFG2BP2 loci associate with type 2 diabetes. Importantly, variations within the HHEX/KIF11/IDE and CDKN2A/B loci confer impaired glucose- and tolbutamide-induced insulin release in middle-aged and young healthy subjects, suggesting a role for these variants in the pathogenesis of pancreatic beta-cell dysfunction. 10.2337/db07-0856

Polymorphism Interaction Analysis (PIA): a method for investigating complex gene-gene interactions

Leah Mechanic — 2008-03-07T09:32:16-00:00

BMC Bioinformatics, Vol. 9, No. 1. (2008)

BACKGROUND:The risk of common diseases is likely determined by the complex interplay between environmental and genetic factors, including single nucleotide polymorphisms (SNPs). Traditional methods of data analysis are poorly suited for detecting complex interactions due to sparseness of data in high dimensions, which often occurs when data are available for a large number of SNPs for a relatively small number of samples. Validation of associations observed using multiple methods should be implemented to minimize likelihood of false-positive associations. Moreover, high-throughput genotyping methods allow investigators to genotype thousands of SNPs at one time. Investigating associations for each individual SNP or interactions between SNPs using traditional approaches is inefficient and prone to false positives. RESULTS:We developed the Polymorphism Interaction Analysis tool (PIA version 2.0) to include different approaches for ranking and scoring SNP combinations, to account for imbalances between case and control ratios, stratify on particular factors, and examine associations of user-defined pathways (based on SNP or gene) with case status. PIA v. 2.0 detected 2-SNP interactions as the highest ranking model 77% of the time, using simulated data sets of genetic models of interaction (minor allele frequency=0.2; heritability=0.01; N=1600) generated previously [Velez DR, White BC, Motsinger AA, Bush WS, Ritchie MD, Williams SM, Moore JH: A balanced accuracy function for epistasis modeling in imbalanced datasets using multifactor dimensionality reduction. Genet Epidemiol 2007, 31:306-315.]. Interacting SNPs were detected in both balanced (20 SNPs) and imbalanced data (case:control 1:2 and 1:4, 10 SNPs) in the context of non-interacting SNPs.CONCLUSIONS:PIA v. 2.0 is a useful tool for exploring gene*gene or gene*environment interactions and identifying a small number of putative associations which may be investigated further using other statistical methods and in replication study populations.

Insulin gene mutations as a cause of permanent neonatal diabetes.

J Støy — 2008-03-05T17:02:50-00:00

Proc Natl Acad Sci U S A, Vol. 104, No. 38. (18 September 2007), pp. 15040-15044.

We report 10 heterozygous mutations in the human insulin gene in 16 probands with neonatal diabetes. A combination of linkage and a candidate gene approach in a family with four diabetic members led to the identification of the initial INS gene mutation. The mutations are inherited in an autosomal dominant manner in this and two other small families whereas the mutations in the other 13 patients are de novo. Diabetes presented in probands at a median age of 9 weeks, usually with diabetic ketoacidosis or marked hyperglycemia, was not associated with beta cell autoantibodies, and was treated from diagnosis with insulin. The mutations are in critical regions of the preproinsulin molecule, and we predict that they prevent normal folding and progression of proinsulin in the insulin secretory pathway. The abnormally folded proinsulin molecule may induce the unfolded protein response and undergo degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum stress and potentially beta cell death by apoptosis. This process has been described in both the Akita and Munich mouse models that have dominant-acting missense mutations in the Ins2 gene, leading to loss of beta cell function and mass. One of the human mutations we report here is identical to that in the Akita mouse. The identification of insulin mutations as a cause of neonatal diabetes will facilitate the diagnosis and possibly, in time, treatment of this disorder.

Combined immunostaining with galectin-3, fibronectin-1, CITED-1, Hector Battifora mesothelial-1, cytokeratin-19, peroxisome proliferator-activated receptor-gamma, and sodium/iodide symporter antibodies for the differential diagnosis of non-medullary thyroid carcinoma

Ying Liu — 2008-02-26T16:58:44-00:00

Eur J Endocrinol, Vol. 158, No. 3. (1 March 2008), pp. 375-384.

ObjectivesThe microscopic distinction between benign and malignant thyroid lesions in clinical practice is still largely based on conventional histology. This study was performed to evaluate the diagnostic value of galectin-3 (Gal-3), Hector Battifora mesothelial-1 (HBME-1), cytokeratin (CK)-19, CBP P300-interacting transactivator with glutamic acid E- and aspartic acid D-rich C-terminal domain (CITED-1), fibronectin (FN)-1, peroxisome proliferator-activated receptor (PPAR)-gamma, and intracellular sodium/iodide symporter (iNIS) immunostaining in a large panel of thyroid neoplasms. Our study differed from earlier ones with regard to the identification of optimal semiquantitative cut-off levels using receiver operator curve (ROC) analysis and hierarchical cluster analysis. MethodsWe used tissue arrays containing 177 thyroid tissues: 100 benign tissues (including normal thyroid, Graves disease, multinodular goiter, and follicular adenoma (FA)) and 77 thyroid carcinomas (including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, and follicular variant of PTC (FVPTC)). Antibody staining was scored semiquantitatively based on the ROC analyses and with hierarchical cluster analysis. ResultsIn general, we found overexpression of FN-1, CITED-1, Gal-3, CK-19, HBME-1, and iNIS in malignant thyroid lesions. Gal-3, FN-1, and iNIS had the highest accuracy in the differential diagnosis of follicular lesions. A panel of Gal-3, FN-1, and iNIS, identified by hierarchical cluster analysis, had a 98% accuracy to differentiate between FA and malignant thyroid lesions. In addition, HBME-1 was found to be useful in the differentiation between FA and FVPTC (accuracy 88%). ConclusionWe conclude that identifying optimal antibody panels with cluster analysis increases the diagnostic value in the differential diagnosis of thyroid neoplasms, the combination of FN-1, Gal-3, and iNIS having the best accuracy (98%). 10.1530/EJE-07-0492

The Clinical Significance of Subclinical Thyroid Dysfunction

Bernadette Biondi — 2008-02-09T17:41:26-00:00

Endocr Rev, Vol. 29, No. 1. (1 February 2008), pp. 76-131.

Subclinical thyroid disease (SCTD) is defined as serum free T4 and free T3 levels within their respective reference ranges in the presence of abnormal serum TSH levels. SCTD is being diagnosed more frequently in clinical practice in young and middle-aged people as well as in the elderly. However, the clinical significance of subclinical thyroid dysfunction is much debated. Subclinical hyper- and hypothyroidism can have repercussions on the cardiovascular system and bone, as well as on other organs and systems. However, the treatment and management of SCTD and population screening are controversial despite the potential risk of progression to overt disease, and there is no consensus on the thyroid hormone and thyrotropin cutoff values at which treatment should be contemplated. Opinions differ regarding tissue effects, symptoms, signs, and cardiovascular risk. Here, we critically review the data on the prevalence and progression of SCTD, its tissue effects, and its prognostic implications. We also examine the mechanisms underlying tissue alterations in SCTD and the effects of replacement therapy on progression and tissue parameters. Lastly, we address the issue of the need to treat slight thyroid hormone deficiency or excess in relation to the patient's age. 10.1210/er.2006-0043

Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy.

M Braga-Basaria — 2008-02-02T15:59:21-00:00

J Clin Oncol, Vol. 24, No. 24. (20 August 2006), pp. 3979-3983.

PURPOSE: Prostate cancer (PCa) is one of the most common cancers in men. Men with recurrent or metastatic PCa are treated with androgen-deprivation therapy (ADT), resulting in profound hypogonadism. Because male hypogonadism is a risk factor for metabolic syndrome and men with PCa have high cardiovascular mortality, we evaluated the prevalence of metabolic syndrome in men undergoing long-term ADT. PATIENTS AND METHODS: This was a cross-sectional study. We evaluated 58 men, including 20 with PCa undergoing ADT for at least 12 months (ADT group), 18 age-matched men with nonmetastatic PCa who had received local treatment and were recently found to have an increasing prostate-specific antigen (non-ADT group), and 20 age-matched controls (control group). Men in the non-ADT and control groups were eugonadal. Metabolic syndrome was defined according to the Adult Treatment Panel III criteria. RESULTS: Mean age was similar among the groups. Men on ADT had significantly higher body mass index and lower total and free testosterone levels. The prevalence of metabolic syndrome was higher in the ADT group compared with the non-ADT (P < .01) and control (P = .03) groups. Among the components of metabolic syndrome, men on ADT had a higher prevalence of abdominal obesity and hyperglycemia. Androgen-deprived men also had elevated triglycerides compared with controls (P = .02). The prevalence of hypertension and low high-density lipoprotein levels were similar. CONCLUSION: These data suggest that metabolic syndrome was present in more than 50% of the men undergoing long-term ADT, predisposing them to higher cardiovascular risk. Abdominal obesity and hyperglycemia were responsible for this higher prevalence. We recommend prospective studies to further delineate this association.

Perception of males' aging symptoms, health and well-being in elderly community-dwelling men is not related to circulating androgen levels.

G T'Sjoen — 2007-07-20T10:00:22-00:00

Psychoneuroendocrinology, Vol. 29, No. 2. (February 2004), pp. 201-214.

Aging in men is associated with a progressive but variable decline in androgen production. In aging men there is also an increased occurrence of symptoms such as lack of concentration, nervousness, impaired memory, depressive mood, insomnia, lack of energy and general sense of well-being, decreased libido and erectile dysfunction, periodic sweating, bone and joint complaints, reduction of strength and increased adiposity. This ill-defined male climacterium syndrome is often referred to as "andropause", with the underlying implication that it is at least in part related to (relative) androgen deficiency. Recently an "aging males" symptoms' (AMS) rating scale was developed aimed at a more systematic description of severity of symptoms related to a clinically defined "male climacteric". We studied the relationship of male climacteric symptoms as assessed by the AMS with androgen levels and other questionnaires assessing the perception of health and well-being. Serum levels of sex steroids, sex hormone binding globulin and gonadotropins were measured in blood samples of 161 healthy, ambulatory, elderly men, aged 74-89 years who also completed the AMS scale. Mean value of total, free and bioavailable testosterone in this group was 401.6, 6.8 and 151.4 ng/dl, respectively, with 24.7, 32.4 and 52.2% of the values under the normal range for young men. The results of the AMS scores mostly suggested mild psychological and mild to moderate somatovegetative symptoms. However, clear sexual symptoms were reported in 88% of cases. None of the three AMS domain scale scores significantly correlated with testosterone, free testosterone or bioavailable testosterone. Significant correlations were observed between results for the AMS scores and those for other health questionnaires, but none of the subscores for the latter questionnaires correlated with androgen serum levels. In conclusion, the results of this study have shown that, as assessed by the AMS, healthy ambulatory elderly males over 70 had a high perception of sexual symptoms with mild psychological and mild to moderate somatovegetative symptoms. These data failed to support the view that in healthy elderly men, "climacteric symptoms" can predict androgen levels.

The CAG repeat polymorphism in the androgen receptor gene is associated with HDL-cholesterol but not with coronary atherosclerosis or myocardial infarction.

M Hersberger — 2008-01-29T20:04:58-00:00

Clin Chem, Vol. 51, No. 7. (July 2005), pp. 1110-1115.

BACKGROUND: Age-adjusted morbidity and mortality rates from coronary heart disease (CHD) are higher in men than in women. Androgens are suspected to be responsible for the male disadvantage. The genomic effect of androgens is mediated by the androgen receptor (AR), which has a polymorphic CAG repeat in exon 1. The number of repeats is inversely related to the transcriptional activity of the AR on target genes. METHODS: We investigated the association of this CAG repeat polymorphism with CHD and myocardial infarction (MI) in 2 independent case-control studies involving 544 Caucasian men. RESULTS: The number of CAG repeats in the AR gene correlated significantly with HDL-cholesterol (HDL-C) in controls (r = 0.21; P = 0.015). This effect was independent of triglycerides, body mass index, alcohol intake, smoking, and age in a multiple regression model (R(2) = 50%). Despite decreased HDL-C, lower CAG repeat numbers were not associated with increased risk for CHD (odds ratio = 0.82; 95% confidence interval, 0.50-1.36; P = 0.44) or MI in carriers of AR genes with lower CAG repeat numbers (odds ratio = 0.72; 95% confidence interval, 0.37-1.39; P = 0.33). CONCLUSIONS: Shorter, more androgenic AR alleles with fewer CAG repeats are associated with lower HDL-C, but not with an increased risk for CHD or MI, which argues against a detrimental androgen effect on cardiovascular risk under physiologic conditions.

Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis.

EL Ding — 2007-05-27T10:15:42-00:00

JAMA, Vol. 295, No. 11. (15 March 2006), pp. 1288-1299.

CONTEXT: Inconsistent data suggest that endogenous sex hormones may have a role in sex-dependent etiologies of type 2 diabetes, such that hyperandrogenism may increase risk in women while decreasing risk in men. OBJECTIVE: To systematically assess studies evaluating the association of plasma levels of testosterone, sex hormone-binding globulin (SHBG), and estradiol with risk of type 2 diabetes. DATA SOURCES: Systematic search of EMBASE and MEDLINE (1966-June 2005) for English-language articles using the keywords diabetes, testosterone, sex-hormone-binding-globulin, and estradiol; references of retrieved articles; and direct author contact. STUDY SELECTION: From 80 retrieved articles, 43 prospective and cross-sectional studies were identified, comprising 6974 women and 6427 men and presenting relative risks (RRs) or hormone levels for cases and controls. DATA EXTRACTION: Information on study design, participant characteristics, hormone levels, and risk estimates were independently extracted by 2 investigators using a standardized protocol. DATA SYNTHESIS: Results were pooled using random effects and meta-regressions. Cross-sectional studies indicated that testosterone level was significantly lower in men with type 2 diabetes (mean difference, -76.6 ng/dL; 95% confidence interval [CI], -99.4 to -53.6) and higher in women with type 2 diabetes compared with controls (mean difference, 6.1 ng/dL; 95% CI, 2.3 to 10.1) (P<.001 for sex difference). Similarly, prospective studies showed that men with higher testosterone levels (range, 449.6-605.2 ng/dL) had a 42% lower risk of type 2 diabetes (RR, 0.58; 95% CI, 0.39 to 0.87), while there was suggestion that testosterone increased risk in women (P = .06 for sex difference). Cross-sectional and prospective studies both found that SHBG was more protective in women than in men (P< or =.01 for sex difference for both), with prospective studies indicating that women with higher SHBG levels (>60 vs < or =60 nmol/L) had an 80% lower risk of type 2 diabetes (RR, 0.20; 95% CI, 0.12 to 0.30), while men with higher SHBG levels (>28.3 vs < or =28.3 nmol/L) had a 52% lower risk (RR, 0.48; 95% CI, 0.33 to 0.69). Estradiol levels were elevated among men and postmenopausal women with diabetes compared with controls (P = .007). CONCLUSIONS: This systematic review indicates that endogenous sex hormones may differentially modulate glycemic status and risk of type 2 diabetes in men and women. High testosterone levels are associated with higher risk of type 2 diabetes in women but with lower risk in men; the inverse association of SHBG with risk was stronger in women than in men.

Prevalence of symptomatic androgen deficiency in men.

AB Araujo — 2008-01-25T20:09:48-00:00

J Clin Endocrinol Metab, Vol. 92, No. 11. (November 2007), pp. 4241-4247.

CONTEXT: Despite recognition that androgen deficiency in men should be defined according to biochemical and clinical criteria, most prevalence estimates are based on low testosterone levels alone. OBJECTIVE: The objective of this study was to examine the association between symptoms of androgen deficiency and low total and calculated free testosterone levels and estimate the prevalence of symptomatic androgen deficiency in men. DESIGN: This study was a population-based, observational survey. PARTICIPANTS: A total of 1,475 Black, Hispanic, and white men, between the ages of 30-79 yr, with complete data on testosterone, SHBG, and symptoms of androgen deficiency, and who are not taking medications that impact sex steroid levels were randomly selected from the Boston Area Community Health Survey. OUTCOME: Outcomes were measured as symptomatic androgen deficiency, defined as low total (<300 ng/dl) and free (<5 ng/dl) testosterone plus presence of low libido, erectile dysfunction, osteoporosis or fracture, or two or more of following symptoms: sleep disturbance, depressed mood, lethargy, or diminished physical performance. RESULTS: Mean age of the sample was 47.3 +/- 12.5 yr. Approximately 24% of subjects had total testosterone less than 300 ng/dl, and 11% of subjects had free testosterone less than 5 ng/dl. Prevalence of symptoms were as follows: low libido (12%), erectile dysfunction (16%), osteoporosis/fracture (1%), and two or more of the nonspecific symptoms (20%). Low testosterone levels were associated with symptoms, but many men with low testosterone levels were asymptomatic (e.g. in men 50+ yr, 47.6%). Crude prevalence of symptomatic androgen deficiency was 5.6% (95% confidence interval: 3.6%, 8.6%), and was not significantly related to race and ethnic group. Prevalence was low in men less than 70 yr (3.1-7.0%) and increased markedly with age to 18.4% among 70 yr olds. Projection of these estimates to the year 2025 suggests that there will be as many as 6.5 million American men ages 30-79 yr with symptomatic androgen deficiency, an increase of 38% from 2000 population estimates. CONCLUSIONS: Prevalence of symptomatic androgen deficiency in men 30 and 79 yr of age is 5.6% and increases substantially with age. The aging of the U.S. male population will cause a large increase in the burden of symptomatic androgen deficiency. Future work should address the clinical significance of low testosterone levels in asymptomatic men.

The validity of androgen assays.

M Carruthers — 2008-01-25T20:06:37-00:00

Aging Male, Vol. 10, No. 3. (September 2007), pp. 165-172.

Problems in the measurement of androgens and in interpreting results have been reviewed and classified as follows: PREANALYTICAL FACTORS: The exact sampling conditions in relation to circadian and seasonal variations, diet, alcohol, physical activity and posture. PHYSIOLOGICAL AND MEDICAL FACTORS: Androgen levels vary according to the patient's general health, stress, sexual activity and smoking habits. Analytical variables. Sample preservation and storage variables are often unknown. The different androgen assays used have widely differing accuracy and precision and are subject to large inter-laboratory variation, which especially in women and children can render the results of routinely available direct immunoassays meaningless. INTERPRETATION OF RESULTS: Laboratory reference ranges vary widely, largely independent of methodology, and fail to take into account the log-normal distribution of androgen values, causing errors in clinical diagnosis and treatment. Other unknowns are antagonists such as SHBG, estrogens, catecholamines, cortisol, and anti-androgens. As well as age, androgen receptor polymorphisms play a major role in regulating androgen levels and resistance to their action. CONCLUSIONS: Though laboratory assays can support a diagnosis of androgen deficiency in men, they should not be used to exclude it. It is suggested that there needs to be greater reliance on the history and clinical features, together with careful evaluation of the symptomatology, and where necessary a therapeutic trial of androgen treatment given.

Assessing the probability that a positive report is false: an approach for molecular epidemiology studies.

S Wacholder — 2007-03-10T13:50:49-00:00

J Natl Cancer Inst, Vol. 96, No. 6. (17 March 2004), pp. 434-442.

Too many reports of associations between genetic variants and common cancer sites and other complex diseases are false positives. A major reason for this unfortunate situation is the strategy of declaring statistical significance based on a P value alone, particularly, any P value below.05. The false positive report probability (FPRP), the probability of no true association between a genetic variant and disease given a statistically significant finding, depends not only on the observed P value but also on both the prior probability that the association between the genetic variant and the disease is real and the statistical power of the test. In this commentary, we show how to assess the FPRP and how to use it to decide whether a finding is deserving of attention or "noteworthy." We show how this approach can lead to improvements in the design, analysis, and interpretation of molecular epidemiology studies. Our proposal can help investigators, editors, and readers of research articles to protect themselves from overinterpreting statistically significant findings that are not likely to signify a true association. An FPRP-based criterion for deciding whether to call a finding noteworthy formalizes the process already used informally by investigators--that is, tempering enthusiasm for remarkable study findings with considerations of plausibility.

In vivo 3D reconstruction of human vertebrae with the three-dimensional X-ray absorptiometry (3D-XA) method

S Kolta — 2008-01-22T20:50:02-00:00

Osteoporosis International, Vol. 19, No. 2. (4 February 2008), pp. 185-192.

Abstract Summary We used a standard DXA device equipped with a C-arm to do in vivo reconstruction of human vertebrae from two orthogonal scans. This new technique, called 3D-XA (three-dimensional X-ray absorptiometry), allows the direct measurement of geometric parameters of the vertebrae with a good accuracy and precision. Introduction Geometric parameters are predictors of bone strength. A technique called three-dimensional X-ray absorptiometry (3D-XA) allows 3D reconstruction of bones from DXA scans. We used the 3D-XA method to reconstruct human vertebrae and to evaluate the method’s in vitro accuracy and in vivo precision. Methods A standard DXA device equipped with a C-arm was used. Calibration of its environment and identification of different anatomical landmarks of the vertebrae allows personalized 3D geometric reconstruction of vertebrae. Accuracy was calculated by reconstructing 16 dry human vertebrae by 3D-XA and CT scanner. In vivo inter-observer precision was calculated using 20 human spines. Results The mean difference between 3D reconstruction by CT and 3D-XA was −0.2 ± 1.3 mm. The in vivo mean difference of the 3D-XA method between the two rheumatologists was −0.1 ± 0.8 mm. For geometric parameters, mean difference ranged from 0.4 to 0.9 mm. For cross-sectional area and vertebral body volume, it was 2.9% and 3.2%, respectively. Conclusion This study shows the good accuracy and precision of 3D-XA using a standard DXA device. It yields complementary information on bone geometry. Further studies are needed to evaluate if, coupled with bone density, it improves vertebral fracture risk prediction.

Underdeveloped trabecular bone microarchitecture is detected in children with cerebral palsy using high-resolution magnetic resonance imaging

C Modlesky — 2008-01-22T20:45:18-00:00

Osteoporosis International, Vol. 19, No. 2. (4 February 2008), pp. 169-176.

Abstract Summary Using high resolution magnetic resonance imaging, we detected severely underdeveloped trabecular bone microarchitecture in the distal femur of children with cerebral palsy who can not ambulate independently vs. typically developing controls. Furthermore, very good short-term reliability of trabecular bone microarchitecture measurements was observed in both groups of children. Introduction Severe forms of cerebral palsy (CP) are associated with very low areal bone mineral density and a very high incidence of fracture in the distal femur; however, the state of trabecular bone microarchitecture has not been evaluated. Furthermore, the short-term reliability of trabecular bone microarchitecture assessment in children using high-resolution magnetic resonance imaging (MRI) has not been determined. Methods Apparent bone volume to total volume (appBV/TV), trabecular number, (appTb.N), trabecular thickness (appTb.Th) and trabecular separation (appTb.Sp) were determined in the distal femur of non-ambulatory children with CP and typically developing children using MRI. Results Children with CP had a 30% lower appBV/TV, a 21% lower appTb.N, a 12% lower appTb.Th and a 48% higher appTb.Sp in the distal femur than controls (n = 10/group; P < 0.001). The short-term reliability of the trabecular bone microarchitecture measures was very good, with coefficients of variation ranging from 2.0 to 3.0% in children with CP (n = 6) and 1.8 to 3.5% in control children (n = 6). Conclusions Underdeveloped trabecular bone microarchitecture can be detected in the distal femur of children with CP who can not ambulate independently using high-resolution MRI. Furthermore, MRI can be used to assess trabecular bone microarchitecture in children with a high degree of reliability.

RET Genetic Screening in Patients with Medullary Thyroid Cancer and Their Relatives: Experience with 807 Individuals at One Center

Rossella Elisei — 2008-01-12T18:59:34-00:00

J Clin Endocrinol Metab, Vol. 92, No. 12. (1 December 2007), pp. 4725-4729.

Background: Germline RET gene mutations are causative of multiple endocrine neoplasia (MEN) 2 and may be identified by genetic screening. Three different syndromes are distinguished: MEN 2A, when medullary thyroid carcinoma (MTC) is associated with pheochromocytoma and/or parathyroid adenomas; MEN 2B, when accompanied by a marfanoid habitus and/or pheochromocytoma; and familial medullary thyroid carcinoma (FMTC), when only MTC is present. Patients and Methods: During the last 13 yr, we performed RET genetic screening in 807 subjects: 481 with apparently sporadic MTC, 37 with clinical evidence of MEN 2, and 289 relatives. Genomic DNA was extracted from the blood of all subjects, and exons 10, 11, 13, 14, 15, and 16 were analyzed by direct sequencing after PCR. Results: We unexpectedly discovered a germline RET mutation in 35 of 481 (7.3%) apparently sporadic MTC patients. A germline RET mutation was also found in 36 of 37 patients with clinical evidence of hereditary MTC. The distribution of RET mutations in cysteine and noncysteine encoding codons was significantly different in the two groups of patients, with the prevalence of RET mutations in noncysteine codons being higher in MTC that presented as apparently sporadic (P < 0.0001). A total of 34 FMTCs (75.5% of all FMTC) arrived with apparent sporadic MTC, with no familial history of other MTC cases. According to genetic screening and clinical data, our 72 families were classified as follows: 45 FMTC (62.5%), 22 MEN 2A (30.5%), and five MEN 2B (7%). Conclusions: In this large series of MTC, hereditary forms, mainly FMTC, were clinically unsuspected in 7.3% of apparently sporadic cases. As a consequence, the prevalence of FMTC in our series is higher than that previously reported (60 vs. 10%). In these cases, RET mutations were more prevalently located in noncysteine codons. Data derived from our series helped elucidate the role of RET genetic screening for the identification of all forms of MEN 2, and especially for FMTC, which are frequently clinically misdiagnosed as nonheritable, sporadic cases. 10.1210/jc.2007-1005

A Pulmonary Adrenocorticotropin-Secreting Carcinoid Tumor Localized by 6-Fluoro-[18F]L-Dihydroxyphenylalanine Positron Emission/Computed Tomography Imaging in a Patient with Cushing's Syndrome

S Dubois — 2008-01-12T18:39:31-00:00

J Clin Endocrinol Metab, Vol. 92, No. 12. (1 December 2007), pp. 4512-4513.

10.1210/jc.2007-1337

Accuracy of [18F]Fluorodopa Positron Emission Tomography for Diagnosing and Localizing Focal Congenital Hyperinsulinism

Olga Hardy — 2008-01-12T18:37:49-00:00

J Clin Endocrinol Metab, Vol. 92, No. 12. (1 December 2007), pp. 4706-4711.

Objectives: Focal lesions in infants with congenital hyperinsulinism (HI) represent areas of adenomatosis that express a paternally derived ATP-sensitive potassium channel mutation due to embryonic loss of heterozygosity for the maternal 11p region. This study evaluated the accuracy of 18F-fluoro-L-dihydroxyphenylalanine ([18F]DOPA) positron emission tomography (PET) scans in diagnosing focal vs. diffuse disease and identifying the location of focal lesions. Design: A total of 50 infants with HI unresponsive to medical therapy were studied. Patients were injected iv with [18F]DOPA, and PET scans were obtained for 5060 min. Images were coregistered with abdominal computed tomography scans. PET scan interpretations were compared with histological diagnoses. Results: The diagnosis of focal or diffuse HI was correct in 44 of the 50 cases (88%). [18F]DOPA PET identified focal areas of high uptake of radiopharmaceutical in 18 of 24 patients with focal disease. The locations of these lesions matched the areas of increased [18F]DOPA uptake on the PET scans in all of the cases. PET scan correctly located five lesions that could not be visualized at surgery. The positive predictive value of [18F]DOPA in diagnosing focal adenomatosis was 100%, and the negative predictive value was 81%. Conclusions: [18F]DOPA PET scans correctly diagnosed 75% of focal cases and were 100% accurate in identifying the location of the lesion. These results suggest that [18F]DOPA PET imaging provides a useful guide to surgical resection of focal adenomatosis and should be considered as a guide to surgery in all infants with congenital HI who have medically uncontrollable disease. 10.1210/jc.2007-1637

Phaeochromocytoma with normal urinary catecholamines: the potential value of urinary free metadrenalines

DF Davidson — 2008-01-12T18:21:06-00:00

pp. 557-566.

Background: Normal urine catecholamine values in patients with phaeochromocytoma is an occasional finding and may lead to a missed diagnosis. Additional urinary free metadrenaline analysis may be of value in this situation. Methods: In addition to vanillylmandelic acid, homovanillic acid and the catecholamines, urinary free normetadrenaline (fNMA) and free metadrenaline (fMA) were measured. This report describes six confirmed cases of phaeochromocytoma showing normal urinary catecholamine output and compares fMA results and tumour size with other confirmed cases where the urine catecholamines were increased. Results: Urine catecholamines in these patients with, on average, smaller tumours, were all normal. Urinary fNMA and fMA were available on five patients, and were increased in three. The data suggest that, unlike the catecholamines, urinary fNMA and fMA could be a useful predictor of tumour size. Conclusion: The inclusion of fNMA and fMA in the test profile is likely to be of additional benefit in tumour detection, particularly when catecholamines or other metabolites are normal.

Comparison of Diagnostic Accuracy of Urinary Free Metanephrines, Vanillyl Mandelic Acid, and Catecholamines and Plasma Catecholamines for Diagnosis of Pheochromocytoma

James Boyle — 2008-01-12T18:10:51-00:00

J Clin Endocrinol Metab, Vol. 92, No. 12. (1 December 2007), pp. 4602-4608.

Context: Recent evidence suggests that plasma-free metanephrines provide a highly sensitive test in patients requiring exclusion of pheochromocytoma. The diagnostic efficacy of urinary free metanephrines, however, has not been evaluated. Objective, Design, Setting, Patients, and Outcome Measures: We compared retrospectively the diagnostic efficacy of 24-h urinary free metanephrines with our currently available measurements of 24-h urinary vanillyl mandelic acid (VMA), urinary catecholamines, and plasma catecholamines in 159 outpatients tested in a tertiary referral center for pheochromocytoma over a 4-yr period. Results: The sensitivity of urinary free metanephrines was 100% [25 of 25 patients; 95% confidence interval (CI) 86100%)] compared with the sensitivity of 84% (21 of 25; 95% CI 6495%) for urinary catecholamines; 72% (18 of 25; 95% CI 5188%) for urinary VMA; and 76% (16 of 21; 95% CI 5392%) for plasma catecholamines. The specificity of urinary free metanephrines was 94% (116 of 123; 95% CI 8998%), compared with the specificity of 99% (127 of 129; 95% CI 96100%) for urinary catecholamines; 96% (130 of 134; 95% CI 9198%) for urinary VMA; and 88% (66 of 75; 95% CI 7894%) for plasma catecholamines. Receiver operating characteristic curves for all test groups were generated. Pairwise comparisons of the area under the receiver operating characteristic curve for urinary free metanephrines with that of each of the other three test groups individually were: 0.993 (95% CI 0.9620.999) vs. 0.919 (95% CI 0.8620.957, P = 0.032) for urine catecholamines; 0.993 (95% CI 0.9620.999) vs. 0.846 (95% CI 0.7780.900, P = 0.002) for urine VMA; and 0.992 (95% CI 0.9450.998) vs. 0.852 (95% CI 0.7620.918, P = 0.009) for plasma catecholamines. Testing with urinary free metanephrines failed to misidentify a single case of pheochromocytoma, compared with four missed cases for urinary catecholamines, seven missed cases for urinary VMA, and five missed cases for plasma catecholamines. Conclusion: Urinary free metanephrines were superior to urinary VMA, urinary catecholamines, and plasma catecholamines and can provide a valuable test for diagnosis of pheochromocytoma in adults. 10.1210/jc.2005-2668

Contribution of impaired glucose tolerance in subjects with the metabolic syndrome: Baltimore Longitudinal Study of Aging.

A Rodriguez — 2008-01-11T15:10:15-00:00

Metabolism, Vol. 54, No. 4. (April 2005), pp. 542-547.

BACKGROUND: In addition to fasting plasma glucose (FPG), we examined the contribution of the oral glucose tolerance test (OGTT) in the prevalence of subjects with the metabolic syndrome (MS). METHODS AND RESULTS: Study participants were white adults in the Baltimore Longitudinal Study of Aging who underwent a fasting 2-hour OGTT. In men between the ages of 20 to 39, 40 to 59, 60 to 79, and 80 to 95 years, the prevalence of the MS by Adult Treatment Panel (ATP) III criteria (which excludes OGTT) was 11%, 28%, 32%, and 15%, respectively; whereas in women the prevalence was 5%, 12%, 24%, and 16%, respectively. If the current ATPIII dysglycemia criteria also included a 2-hour postchallenge glucose (2hPG) of 7.8 mmol/L or higher, the prevalence of the MS increased from 25% to 33% in men and from 15% to 21% in women (P<.0001). In study participants with FPG less than 5.6 mmol/L, the prevalence of the MS increased from 16% to 23% in men and from 9% to 13% in women. In men between the ages of 20 to 39, 40 to 59, 60 to 79, and 80 to 95 years and FPG less than 5.6 mmol/L, the prevalence of the MS increased to 15%, 32%, 40%, and 29%, respectively (P<.005 for men between 40 and 95 years of age), with inclusion of an abnormal 2hPG. In women between the ages of 20 to 39, 40 to 59, 60 to 79, and 80 to 95 years and FPG less than 5.6 mmol/L, the prevalence of the MS increased to 7%, 14%, 33%, and 31%, respectively, with inclusion of an abnormal 2hPG (P<.001 for women between 60 and 95 years of age). CONCLUSION: The prevalence of the MS is significantly underestimated when the current ATPIII criteria of FPG 6.1 mmol/L or higher is the only determinant of dysglycemia.

Plasma Chromogranin A or Urine Fractionated Metanephrines Follow-Up Testing Improves the Diagnostic Accuracy of Plasma Fractionated Metanephrines for Pheochromocytoma

Alicia Algeciras-Schimnich — 2008-01-10T23:57:34-00:00

J Clin Endocrinol Metab, Vol. 93, No. 1. (1 January 2008), pp. 91-95.

Context: The initial diagnosis of pheochromocytoma relies on plasma fractionated metanephrines levels. Normal levels exclude pheochromocytoma, but positive tests have a low positive predictive value due to the disease's rarity. Objectives: The objective of the study was to evaluate three approaches to distinguish between true-positive and false-positive tests: 1) increased cutoff for plasma fractionated metanephrines, 2) measurement of serum/plasma chromogranin A (CGA), and 3) urine fractionated metanephrine testing. Design: We studied retrospectively all Mayo Clinic patients with positive plasma fractionated metanephrine tests over a 15-month period and determined their final diagnosis based on histology, imaging, additional biochemical tests, and more than 1 yr follow-up. For a subgroup, urine fractionated metanephrine results were available. All original plasma samples were retested for CGA. Results: Of 140 patients, 40 had a chromaffin tumor confirmed and 100 excluded, indicating a positive predictive value of plasma fractionated metanephrines of 28.6%. Increasing the threshold for a positive test improved specificity to 98% but missed eight cases (20%). Incorporation of urine fractionated metanephrine testing as follow-up test achieved 80% specificity and 91% sensitivity. The corresponding figures for CGA were 71 and 87% for all patients and 89 and 87% when patients taking proton pump inhibitors were excluded. Conclusions: Unless plasma fractionated metanephrines levels are elevated more than 4-fold above the upper limit of normal, patients with a positive plasma fractionated metanephrines test should be evaluated with urine fractionated metanephrines and serum/plasma CGA assays before being subjected to imaging or invasive diagnostic tests. 10.1210/jc.2007-1354