What is the best criterion for the interpretation of adrenal vein sample results in patients with primary hyperaldosteronism?

BACKGROUND: In patients with primary hyperaldosteronism, adrenal vein sampling (AVS) has emerged as a gold standard for distinguishing between unilateral and bilateral disease, but multiple criteria have been used and no consensus exists as to the most accurate criterion. The objective of this study was to determine which AVS criteria most accurately identify patients with unilateral surgical disease and are associated with significant clinical improvement after adrenalectomy. METHODS: This is a retrospective analysis of AVS results in 108 patients with primary hyperaldosteronism treated at a single institution. Literature review of AVS criteria was used to distinguish between unilateral and bilateral disease. RESULTS: Of the 10 AVS criteria identified in the literature, one criterion (ACTH stimulation, positioning: cortisol [adrenal]/cortisol [periphery] [Ca/Cp] > 5.0 and lateralization: aldosterone/cortisol [A/C] [dominant {D}]: A/C [nondominant {ND}] > 4:1) was the most accurate in identifying and correctly predicting lateralization of disease (P value range: < 0.001-0.0369). For this criterion, the true positive rate was 88%. The second most accurate criterion was no ACTH stimulation, positioning Ca/Cp > 1.1 and lateralization: A/C (D): A/C (ND) > 2:1. For this criterion, the overall true positive was 85%. However, we found no significant difference in clinical outcome based on individual criteria fulfillment. CONCLUSIONS: Of the multiple criteria used for AVS evaluation, one criterion has the best accuracy. With the increasing use of AVS, there should be a consensus by which these results are evaluated and surgeons recommend adrenalectomy.

Consequences of adrenal venous sampling in primary hyperaldosteronism and predictors of unilateral adrenal disease.

BACKGROUND: In patients with primary hyperaldosteronism, distinguishing between unilateral and bilateral adrenal hypersecretion is critical in assessing treatment options. Adrenal venous sampling (AVS) has been advocated by some to be the gold standard for localization of the responsible lesion, but there remains a lack of consensus for the criteria and the standardization of technique. STUDY DESIGN: We performed a retrospective study of 114 patients with a biochemical diagnosis of primary hyperaldosteronism who all underwent CT scan and AVS before and after corticotropin (ACTH) stimulation. Univariate and multivariate analyses were performed to determine what factors were associated with AVS lateralization, and which AVS values were the most accurate criteria for lateralization. RESULTS: Eighty-five patients underwent surgery at our institution for unilateral hyperaldosteronism. Of the 57 patients who demonstrated unilateral abnormalities on CT, AVS localized to the contralateral side in 5 patients and revealed bilateral hyperplasia in 6 patients. Of the 52 patients who showed bilateral disease on CT scan, 43 lateralized with AVS. The most accurate criterion on AVS for lateralization was the post-ACTH stimulation value. Factors associated with AVS lateralization included a low renin value, high plasma aldosterone-to plasma-renin ratio, and adrenal mass > or = 3 cm on CT scan. CONCLUSIONS: Because 50% of patients would have been inappropriately managed based on CT scan findings, patients with biochemical evidence of primary hyperaldosteronism and considering adrenalectomy should have AVS. The most accurate measurement for AVS lateralization was the post-ACTH stimulation value. Although several factors predict successful AVS lateralization, none are accurate enough to perform AVS selectively.

Technical details influence the diagnostic accuracy of the 1 microg ACTH stimulation test.

OBJECTIVE: To examine the factors causing inadequate cortisol responses to the 1 microg ACTH stimulation test. DESIGN: Random test assignment (by age and gender) at 0800 or 1600 h. METHODS: We recruited 20 healthy adults to each of the three age groups (<40 years, 40-55 years, and >55 years; half females in each group). ACTH stimulation tests were performed in an outpatient clinic at the NIH Clinical Research Center. Plasma cortisol was measured just before, and 30 and 60 min after the administration of 1 microg ACTH (1-24). The ACTH concentration in diluted and administered solutions was measured. RESULTS: Twenty-five volunteers (19 at 1600 h) had a subnormal cortisol response (peak cortisol 10.4-17.5 microg/dl), using a criterion <18 microg/dl (497 nmol/l), for a specificity of 58% (confidence interval (CI) 45-71%). Afternoon testing had a significant impact on failure rates (odds ratio 6.98, CI 2.17-22.43), while gender and age did not. The stock solution contained 1 microg ACTH, but after administration through tubing it contained only 0.5-0.8 microg. CONCLUSIONS: The high rate of abnormal results, especially in the afternoon, and loss of ACTH through tubing suggest that morning testing and minimal tubing should be adopted to avoid an inappropriate diagnosis of adrenal insufficiency. Earlier time points and standardized protocols would facilitate comparison of studies.

Specificity of screening tests for Cushing's syndrome in an overweight and obese population.

CONTEXT: Recent reports suggest a higher prevalence (1-5%) of Cushing's syndrome in certain patient populations with features of the disorder (e.g., diabetes), but the prevalence in the overweight and obese population is not known. OBJECTIVE: The aim of the study was to evaluate the diagnostic performance of screening tests for Cushing's syndrome in overweight and obese subjects with at least two other features of the disorder. DESIGN AND SETTING: We conducted a cross-sectional prospective study. SUBJECTS AND METHODS: A total of 369 subjects (73% female) completed two or three tests: a 24-h urine cortisol, and/or late-night salivary cortisol, and/or 1 mg dexamethasone suppression test (DST). If any result was abnormal [based on laboratory reference range or cortisol after DST > or = 1.8 microg/dl (50 nmol/liter)], tests were repeated and/or a dexamethasone-CRH test was performed. Subjects with abnormal DST results and a low dexamethasone level were asked to repeat the test with 2 mg of dexamethasone. RESULTS: In addition to obesity, subjects had a mean of five to six features of Cushing's syndrome. None was found to have Cushing's syndrome. Test specificities to exclude Cushing's syndrome for subjects who completed three tests were: urine cortisol, 96% [95% confidence interval (CI), 93-98%]; DST, 90% (95% CI, 87-93%); salivary cortisol, 84% by RIA (95% CI, 79-89%) and 92% by liquid chromatography-tandem mass spectrometry (95% CI, 88-95%). The combined specificity (both tests normal) for all combinations of two tests was 84 to 90%, with overlapping CIs. CONCLUSION: These data do not support widespread screening of overweight and obese subjects for Cushing's syndrome; test results for such patients may be falsely abnormal.

Brief communication: radiographic contrast infusion and catecholamine release in patients with pheochromocytoma.

BACKGROUND: Contrast-enhanced computed tomography (CT) is useful for localizing pheochromocytoma. However, in patients with suspected pheochromocytoma, CT is often canceled or not performed because of the strong belief that intravenous contrast may induce hypertensive crisis. OBJECTIVE: To examine whether intravenous low-osmolar contrast administration during CT induces catecholamine release that increases blood pressure or heart rate. DESIGN: Prospective study. SETTING: Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: 22 patients with pheochromocytoma (15 nonadrenal and 7 adrenal) and 8 unmatched control participants without pheochromocytoma. MEASUREMENTS: Plasma catecholamine levels, blood pressure, and heart rate. RESULTS: Plasma catecholamine levels within and between groups did not significantly differ before and after intravenous administration of low-osmolar CT contrast. Patients with pheochromocytoma experienced a clinically and statistically significant increase in diastolic blood pressure that was not accompanied by corresponding increases in plasma catecholamine levels. The difference became non-statistically significant after adjustment for use of alpha- and beta-blockers. LIMITATION: The study lacked a placebo group, and the sample was relatively small. CONCLUSION: Intravenous low-osmolar contrast-enhanced CT can safely be used in patients with pheochromocytoma who are not receiving alpha- or beta-blockers. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health.

A novel point mutation in the amino terminal domain of the human glucocorticoid receptor (hGR) gene enhancing hGR-mediated gene expression.

CONTEXT: Interindividual variations in glucocorticoid sensitivity have been associated with manifestations of cortisol excess or deficiency and may be partly explained by polymorphisms in the human glucocorticoid receptor (hGR) gene. We studied a 43-yr-old female, who presented with manifestations consistent with tissue-selective glucocorticoid hypersensitivity. We detected a novel, single, heterozygous nucleotide (G --> C) substitution at position 1201 (exon 2) of the hGR gene, which resulted in aspartic acid to histidine substitution at amino acid position 401 in the amino-terminal domain of the hGRalpha. We investigated the molecular mechanisms of action of the natural mutant receptor hGRalphaD401H. METHODS-RESULTS: Compared with the wild-type hGRalpha, the mutant receptor hGRalphaD401H demonstrated a 2.4-fold increase in its ability to transactivate the glucocorticoid-inducible mouse mammary tumor virus promoter in response to dexamethasone but had similar affinity for the ligand (dissociation constant = 6.2 +/- 0.6 vs. 6.1 +/- 0.6 nm) and time to nuclear translocation (14.75 +/- 0.25 vs. 14.25 +/- 1.13 min). The mutant receptor hGRalphaD401H did not exert a dominant positive or negative effect upon the wild-type receptor, it preserved its ability to bind to glucocorticoid response elements, and displayed a normal interaction with the glucocorticoid receptor-interacting protein 1 coactivator. CONCLUSIONS: The mutant receptor hGRalphaD401H enhances the transcriptional activity of glucocorticoid-responsive genes. The presence of the D401H mutation may predispose subjects to obesity, hypertension, and other manifestations of the metabolic syndrome.

Radioimmunoassay and tandem mass spectrometry measurement of bedtime salivary cortisol levels: a comparison of assays to establish hypercortisolism.

CONTEXT: Although bedtime salivary cortisol measurement has been proposed as the optimal screening test for the diagnosis of Cushing's syndrome, its performance using commercially available assays has not been widely evaluated. OBJECTIVE: Our objective was to compare RIA and tandem mass spectrometry (LC-MS/MS) measurement of salivary cortisol in obese subjects and healthy volunteers. DESIGN AND SETTING: We conducted a cross-sectional prospective study of outpatients. SUBJECTS AND METHODS: We studied 261 obese subjects (186 female) with at least two additional features of Cushing's syndrome and 60 healthy volunteers (30 female). Subjects provided split bedtime salivary samples for cortisol measurement by commercially available RIA and LC-MS/MS. Results were considered normal or abnormal based on the laboratory reference range. Subjects with abnormal results underwent evaluation for Cushing's syndrome. RESULTS: In paired samples, RIA gave a lower specificity than LC-MS/MS in obese subjects (86 vs. 94%, P = 0.008) but not healthy volunteers (86 vs. 82%, P = 0.71). Among subjects with at least one abnormal result, both values were abnormal in 44% (confidence interval 26-62%) of obese and 75% (confidence interval 33-96%) of healthy volunteers. In obese subjects, salivary cortisol concentrations were less than 4.0 to 643 ng/dl (<0.11-17.7 nmol/liter; normal, < or =100 ng/dl, 2.80 nmol/liter) by LC-MS/MS and less than 50 to 2800 ng/dl (1.4-77.3 nmol/liter; normal, < or =170 ng/dl, 4.7 nmol/liter) by RIA. Cushing's syndrome was not diagnosed in any subject. CONCLUSION: Salivary cortisol levels should not be used as the sole test to diagnose Cushing's syndrome if laboratory-provided reference ranges are used for diagnostic interpretation.

Long-term impaired quality of life in Cushing's syndrome despite initial improvement after surgical remission.

CONTEXT: Cushing's syndrome (CS) is associated with symptoms that may impair health-related quality of life (HRQL). METHODS: We used the short-form 36 survey to evaluate HRQL in 23 patients with Cushing's disease before and after transsphenoidal surgery (age, 42.7 +/- 12.0 yr; 19 women and four men) and in a cross-section of 343 CS patients (age, 48.2 +/- 14.1 yr; 265 women and 78 men) in remission for up to 25.8 yr after surgery (adrenal, 5%; ectopic, 6%). The z-scores were calculated for short-form 36 domains, and physical (PCS) and mental (MCS) summary scores were compared with those of age- and sex-matched controls (n = 6742). RESULTS: Active Cushing's disease was associated with low PCS and MCS scores (P < 0.05). Despite residual postoperative impairment, primarily of physical domains, all HRQL parameters improved after treatment with transsphenoidal surgery (3.2 +/- 1.5 yr; P < 0.05). In the cross-section in remission at follow-up, there was a small, but significant (P < 0.05), impairment of both PCS and MCS. A longitudinal postoperative analysis confirmed stable, but impaired, HRQL over time. Logistic regression demonstrated that previous pituitary radiation and current glucocorticoid use had little effect on HRQL outcomes. CONCLUSION: CS is associated with impaired HRQL, which partially resolves after treatment. At longer-term follow-up, however, there is residual impairment of HRQL. Determination of modifiable factors that contribute to impaired HRQL may help reduce the physical and psychosocial burden of this disease.

Glucocorticoid excess and hypertension.

Cushing's syndrome is a rare disorder characterized by chronic, excess glucocorticoid exposure. Hypertension is one of the most discriminating features of the disease, as it is present in 80% of patients. Patients with Cushing's syndrome have a mortality rate four times that of the general population, most likely secondary to an increased number of cardiovascular risk factors, including hypertension. In this article, we review several pathogenetic mechanisms of glucocorticoid-induced hypertension, including the role of sodium/water and mineralocorticoid excess, as well as involvement of the vasculature and kidney. Although treatment of hypertension with available antihypertensive medications is only moderately successful, after cure of Cushing's syndrome, approximately 30% of patients have persistent hypertension.