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We performed selective venous catheterization and sampling for ACTH in six patients with ACTH-secreting pituitary adenomas (Cushing's disease) and four patients with occult ectopic ACTH-secreting neoplasms. In five patients with Cushing's disease in whom the inferior petrosal sinus could be catheterized, ACTH levels were unequivocally higher than simultaneous peripheral values: The ratio was greater than 2.0, with a range of 2.2 to 16.7. In contrast, the inferior petrosal sinus-to-peripheral ACTH ratio in three patients with ectopic ACTH secretion was less than 1.5. In the fourth patient, an arteriovenous gradient of 6.8 was shown 2 years before a bronchial carcinoid tumor was clinically apparent. Central-to-peripheral ACTH ratios at the level of the jugular bulb and jugular vein were not diagnostic. We conclude that selective venous ACTH sampling from the inferior petrosal sinus is a reliable and useful aid in the differential diagnosis of Cushing's syndrome when standard clinical and biochemical studies are inconclusive. [ABSTRACT FROM AUTHOR]

Patients with endogenous hypercortisolism, Cushing's syndrome, have significant morbidity and increased mortality when inadequately treated. When surgical therapy has been unsuccessful other treatment modalities are necessary. Previously available therapies have limited effectiveness or significant toxicity. Mifepristone, a glucocorticoid receptor antagonist, provides a novel approach to the treatment of hypercortisolism. It is rapidly absorbed, highly protein bound and has a long plasma half-life. Since it also serves as a progesterone receptor antagonist, mifepristone has been used in several other medical conditions. A recently published prospective trial of mifepristone therapy for Cushing's syndrome resulted in its recent approval by the U.S. Food and Drug Administration for use in Cushing's syndrome., (Copyright 2012 Prous Science, S.A.U. or its licensors. All rights reserved.)

The clinical recognition of Cushing's syndrome and its biochemical confirmation is a challenging problem. The best diagnostic approach to patients with suspected Cushing's syndrome is still evolving. The traditional diagnostic approach of urine free cortisol and low-dose dexamethasone suppression testing may be inadequate when the degree of hypercortisolism is mild. Late-night salivary cortisol determinations may evolve as the simplest means of screening patients for suspected hypercortisolism. Repeated measurements of cortisol secretion (urine free cortisol or late-night salivary cortisol) over an extended period of time may be necessary to provide diagnostic certainty. The dexamethasone-CRH test is a reasonable approach in patients with equivocal data. The introduction of reliable, sensitive, and specific plasma ACTH measurements, the use of IPSS for ACTH with CRH stimulation, and the improved techniques of pituitary and adrenal imaging have made the differential diagnosis of Cushing's syndrome relatively straightforward (see Fig. 2). Clinicians who have never missed the diagnosis of Cushing's syndrome or have never been fooled by attempting to establish its cause should refer their patients with suspected hypercortisolism to someone who has.

Determination of the etiology of primary aldosteronism remains a diagnostic challenge. The most common types of primary aldosteronism are bilateral adrenal hyperplasia (BAH), aldosterone-producing adenomas (APA), and primary adrenal hyperplasia. Computed tomography (CT) and adrenal vein sampling (AVS) are the primary modalities used to differentiate these subtypes. The purpose of this study was to compare AVS and CT imaging of the adrenal glands in patients with hyperaldosteronism in whom CT imaging was normal or in whom focal unilateral or bilateral adrenal abnormalities were detected. The diagnosis of primary aldosteronism was made in 62 patients based on an elevated plasma aldosterone to PRA ratio and an elevated urinary aldosterone excretion rate. Thirty-eight patients had CT imaging and successful bilateral adrenal vein sampling and were included in the final analysis. AVS was considered the gold standard in determining the specific subtype of primary aldosteronism. There were 15 patients with APA, 21 patients with BAH, and 2 patients with primary adrenal hyperplasia. Plasma aldosterone was significantly higher in patients with APA (46.3 +/- 8.5 ng/dL; 1284 +/- 235 pmol/L) than in those with BAH (29.3 +/- 2.4 ng/dL; 813 +/- 11 pmol/L; P < 0.05). Plasma potassium was significantly lower in patients with APA (3.1 +/- 0.1 mmol/L) than in patients with BAH (3.5 +/- 0.1 mmol/L; P < 0.02). There was considerable overlap in the other biochemical indices (e.g. PRA and urinary aldosterone) in patients with the different subtypes. In patients with APA proven by AVS, eight had concordant findings with CT imaging, four had discordant findings, and three had normal CT imaging. In patients with BAH proven by AVS, four had concordant findings with CT imaging, eight had discordant findings, and nine had normal CT imaging. Compared with AVS, CT imaging was either inaccurate or provided no additional information in 68% of the patients with primary aldosteronism. We conclude that adrenal CT imaging is not a reliable method to differentiate primary aldosteronism. Adrenal vein sampling is essential to establish the correct diagnosis of primary aldosteronism.

Study Objective: To analyze the effects of hydrocortisone (40 mg. p.o.) administered to emergency physicians on their first night shift following a series of day shifts., Design: Prospective, double-blinded internal crossover study on objective and subjective parameters. Each participant was studied for a minimum of 10 nights., Type of Participants: Four healthy male emergency physicians in their mid to late thirties., Interventions: After baseline endocrine assessment, the subjects ingested a capsule containing either 40 mg of hydrocortisone or placebo (lactose) at the start of a first nightshift (starting at 10 pm or 11 pm) after day duty. Subjects self-administered psychological testing one hour after taking an oral capsule by listening to a self-guided audio tape (between 11 and 12 p.m), and again between 4 and 5 am. Blood samples were obtained during the first 4 nights of each subject at 11 pm, 2, 5 and 8 am., Measurements and Main Results: Four emergency physicians entered 42 nights of data. No differences in testing were detected. Plasma cortisol levels were measured and demonstrated cortisol levels consistent with oral replacement therapy. Physicians could subjectively differentiate the difference between hydrocortisone treatment and placebo: of 21 hydrocortisone nights, 17 were identified as "a good night" in reference to fatigue. Of 21 nights without hydrocortisone, 15 were identified as "bad" nights, (p < .001)., Conclusion: Hydrocortisone, administered before a nightshift to day-accommodated workers, recreated the rise of plasma cortisol seen on awakening and was shown to be an effective means of decreasing subjective fatigue of a first nightshift.

The best diagnostic approach to patients with suspected Cushing's disease continues to evolve. The introduction of transsphenoidal pituitary surgery as the treatment of choice for Cushing's disease as well as the absence of any pituitary imaging abnormalities in many patients with Cushing's disease has made accurate diagnosis and differential diagnosis essential. In the authors' opinion, two or three late night (11 PM) salivary cortisol determinations and the measurement of 24-hour UFC are the best and simplest means to evaluate patients with suspected hypercortisolism. L-DST can no longer be recommended to exclude the diagnosis of Cushing's disease, particularly if the hypercortisolism is mild. The combination of L-DST and CRH stimulation is a new and apparently sensitive means to establish the presence or absence of pathologic hypercortisolism in equivocal cases. In the absence of an overt pituitary tumor on MR imaging, inferior petrosal sinus sampling with CRH stimulation should be performed to secure the diagnosis of Cushing's disease as well as identify the probable location of the corticotroph adenoma.

The clinical features of Cushing's syndrome (such as obesity, hypertension, and diabetes) are commonly encountered in clinical practice. Patients with Cushing's syndrome have been identified by an abnormal low-dose dexamethasone suppression test, elevated urine free cortisol (UFC), an absence of diurnal rhythm of plasma cortisol, or an elevated late-night plasma cortisol. Because the concentration of cortisol in the saliva is in equilibrium with the free (active) cortisol in the plasma, measurement of salivary cortisol in the evening (nadir) and morning (peak) may be a simple and convenient screening test for Cushing's syndrome. The purpose of this study was to evaluate the usefulness of the measurement of late-night and morning salivary cortisol in the diagnosis of Cushing's syndrome. We studied 73 normal subjects and 78 patients referred for the diagnosis of Cushing's syndrome. Salivary cortisol was measured at 2300 h and 0700 h using a simple, commercially-available saliva collection device and a modification of a standard cortisol RIA. In addition, 24-h UFC was measured within 1 month of saliva sampling. Patients with proven Cushing's syndrome (N = 39) had significantly elevated 2300-h salivary cortisol (24.0 +/- 4.5 nmol/L), as compared with normal subjects (1.2 +/- 0.1 nmol/L) or with patients referred with the clinical features of hypercortisolism in whom the diagnosis was excluded or not firmly established (1.6 +/- 0.2 nmol/L; N = 39). Three of 39 patients with proven Cushing's had 2300-h salivary cortisol less than the calculated upper limit of the reference range (3.6 nmol/L), yielding a sensitivity of 92%; one of these 3 patients had intermittent hypercortisolism, and one had an abnormal diurnal rhythm (salivary cortisol 0700-h to 2300-h ratio <2). An elevated 2300-h salivary cortisol and/or an elevated UFC identified all 39 patients with proven Cushing's syndrome (100% sensitivity). Salivary cortisol measured at 0700 h demonstrated significant overlap between groups, even though it was significantly elevated in patients with proven Cushing's syndrome (23.0 +/- 4.2 nmol/L), as compared with normal subjects (14.5 +/- 0.8 nmol/L) or with patients in whom Cushing's was excluded or not firmly established (15.3 +/- 1.5 nmol/L). Late-night salivary cortisol measurement is a simple and reliable screening test for spontaneous Cushing's syndrome. In addition, late-night salivary cortisol measurements may simplify the evaluation of suspected intermittent hypercortisolism, and they may facilitate the screening of large high-risk populations (e.g. patients with diabetes mellitus).

High dose dexamethasone suppression testing has been widely employed in the differentiation between pituitary ACTH-dependent hypercortisolism [Cushing's disease (CD)] and the ectopic ACTH syndrome. We hypothesized that the high dose dexamethasone suppression test as it is performed in practice does not improve the ability to differentiate between these two types of ACTH-dependent Cushing's syndrome. Cases were drawn from 112 consecutive patients with ACTH-dependent Cushing's syndrome, who were then classified based upon results of inferior petrosal sinus sampling for ACTH levels. Analysis of test characteristics of high dose dexamethasone suppression testing was performed in the 73 patients for whom results are available. Statistical modeling was performed using the 68 cases with complete data on all assessed variables. Logistic regression models were used to predict the probability of pituitary-dependent Cushing's syndrome (CD) given the results of high dose dexamethasone suppression testing before and after adjustment for the contribution of a series of potential covariates. Of the 112 patients with ACTH-dependent Cushing's syndrome, 15.2% had the ectopic ACTH syndrome, and the remainder had pituitary-dependent Cushing's syndrome (CD). Patients with the ectopic ACTH syndrome were significantly older (mean, 51.9 vs. 40.2), were more likely to be male (58.8% vs. 27.4%), had shorter duration of clinical findings (mean, 11.6 vs. 39.9 months), were more likely to have hypokalemia (50% vs. 8.6%), had higher baseline 24-h urinary free cortisol [mean, 8317 vs. 1164 nmol/day (3015 vs. 422 microg)] and plasma ACTH levels [mean, 47 vs. 17 pmol/L (210 vs. 78 pg/mL)] and were less likely to suppress urinary free cortisol or plasma cortisol with high dose dexamethasone using the standard criterion of 50% or more suppression compared with patients with pituitary-dependent Cushing's syndrome. Based upon the standard criterion, the sensitivity and specificity of the high dose dexamethasone suppression test for the diagnosis of pituitary-dependent Cushing's syndrome were 81.0% and 66.7%, respectively. Although the mean percent suppression was significantly greater for patients with CD than for those with the ectopic ACTH syndrome (72.2% vs. 41.3%), the range of suppression was 0-99% for each diagnosis. The area under the receiver operating characteristic curve was 0.710 (95% confidence interval, 0.541-0.879). Logistic regression models were used to evaluate the probability of CD given the responsiveness to high dose dexamethasone suppression testing before and after adjustment for the potential contributions of other factors. A model including all of the variables (age, sex, duration, presence of hypokalemia, urinary free cortisol, and plasma ACTH) had a diagnostic accuracy of 92.7%. A model including all of these variables plus a binary variable indicating whether the patient met the criterion of suppression by 50% or more resulted in 95.6% accuracy, whereas substitution of this binary variable by percent suppression resulted in a model with 94.1% accuracy. There were no statistically significant differences among these models; their values for the c statistic, which is equivalent to the area under the curve in a receiver operating characteristic analysis, were all greater than 0.9. Logistic regression models indicate that the results of the dexamethasone suppression test add little to the differential diagnosis of ACTH-dependent Cushing's syndrome, especially after taking other clinical information into account. In our patient population, the sensitivity and specificity of the dexamethasone suppression test were less than those reported by others. However, because 20-33% of cases of ectopic ACTH syndrome are misdiagnosed with these logistic regression models, other techniques are necessary to achieve greater diagnostic accuracy.

Objective: To describe 15 patients examined for hypocalcemia, skeletal disease, or both in whom the diagnosis of celiac disease was subsequently made., Design: Observational case series., Patients: Fifteen patients (7 women and 8 men) were examined for hypocalcemia (n = 11), skeletal disease (n = 3), or both (n = 1). The diagnosis of celiac disease was subsequently made. The mean age of the patients was 62 years, and 11 patients were 60 years of age or older., Results: Four patients had no gastrointestinal symptoms, 7 patients had mild or intermittent gastrointestinal symptoms, and 4 patients had persistent diarrhea. Ten patients had experienced weight loss. The serum total alkaline phosphatase level was elevated in 10 of 15 patients, the parathyroid hormone level was elevated in all patients, and the urinary calcium level was low in all 6 of the patients tested. The level of 25-hydroxyvitamin D was frankly low in 4 patients, marginal in 8 patients, and normal in 3 patients. Bone mineral density was reduced in all 8 patients in whom it was measured., Conclusions: Celiac disease should be considered in patients with unexplained metabolic bone disease or hypocalcemia, especially because gastrointestinal symptoms may be absent or mild. Advanced age does not exclude the diagnosis of celiac disease.

Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a familial form of diabetes insipidus due to progressive vasopressin deficiency with onset typically at 1-6 yr of age. Affected individuals demonstrate specific degeneration of the vasopressinergic magnocellular neurons in the hypothalamic supraoptic and paraventricular nuclei and loss of the posterior pituitary bright spot on magnetic resonance imaging. The genetic locus of ADNDI is the arginine vasopressin-neurophysin II (AVP-NPII) gene. Mutations that cause ADNDI have been found to occur both within the signal peptide of the prepro-AVP-NPII precursor and within the coding sequence for neurophysin II, but not within the coding sequence for AVP itself. We evaluated the AVP-NPII genes in two independent families with ADNDI and identified a mutation (C280-->T) in the coding sequence for the signal peptide of the prepro-AVP-NPII precursor in both families. This mutation encodes an Ala-->Val substitution at the C-terminus of the signal peptide (-1 amino acid). This mutation predicts the complete inability of signal peptidase to cleave the signal peptide from the preproprecursor and supports the hypothesis that the progressive neural degeneration that underlies ADNDI is caused by accumulation of malprocessed precursor. However, considerable heterogeneity in the age of onset (1-28 yr of age) and the severity of diabetes insipidus among affected members of these two families suggests that additional factors modulate the rate and extent of progression of the neurodegeneration that results from this one specific ADNDI mutation.

Objective: To describe the results of a community-based thyroid screening program., Methods: We review the recruitment process, the screening questionnaire, the laboratory procedure, and the data analysis., Results: News media advertisements and facility-sponsored communications were used to recruit 1,176 participants, each of whom completed a health questionnaire and had blood withdrawn for a thyroid-stimulating hormone (TSH) assay. Most participants were female (78%), Caucasian (92%), and age 50 years or older (61%). Data from 1,139 participants were analyzed. Abnormal TSH values were found in 107 participants: TSH was low in 21 (2%) and elevated in 86 (8%). Elevated TSH values occurred in 8% of females, 7% of males, 8% of Caucasians, and 7% of Hispanics. Although the percentage of elevated TSH values tended to increase with advancing age, primarily in females, 5% of participants younger than 50 years of age had an elevated TSH. No associations were apparent between abnormal TSH values and health maintenance organization membership, self-rating of overall health, or presence of thyroid-related symptoms. Participants who rated their overall health as "excellent" or "very good" accounted for 48% of the TSH values >12 microIU/mL., Conclusion: Experience gained from the conduct of this screening program may help shape the expectations of future screening programs that use disease awareness and self-motivation and provide insights into program design that may maximize participation by the desired target audiences.

Factitious Cushing's syndrome is an unusual problem that may be clinically and biochemically indistinguishable from endogenous hypercortisolism. Results of biochemical studies may be misleading because of cross-reactivity of synthetic corticosteroids or their metabolites with plasma or urine cortisol. Because of its lack of specificity, radioimmunoassay (RIA) for corticotropin (adrenocorticotropic hormone or ACTH) may not show completely suppressed results in patients with surreptitious use of glucocorticoids. A new sensitive and specific immunoradiometric assay (IRMA) for ACTH demonstrates reliably suppressed levels after administration of glucocorticoids. In this report, we describe a 37-year-old woman with typical clinical and biochemical features of ACTH-dependent hypercortisolism. Metabolic evaluation had shown urinary free cortisol excretion of 7,499 nmol/day and plasma ACTH-RIA levels of 13.2 and 33.0 pmol/L on two separate occasions. The use of IRMA for the measurement of ACTH during inferior petrosal sinus sampling revealed a very low peripheral ACTH concentration (=0.4 pmol/L) and a considerably blunted response to ovine corticotropin-releasing hormone, findings that suggested ACTH-independent Cushing's syndrome. Plasma samples obtained during inferior petrosal sinus sampling were assayed for prednisolone and showed a concentration of 360 nmol/L; thus, the presence of factitious Cushing's syndrome was confirmed. Some commercial ACTH-RIA measurements may be unreliable in distinguishing ACTH-dependent from ACTH-independent hypercortisolism. ACTH-IRMA levels are low in patients with ACTH-independent Cushing's syndrome and will be helpful in identifying factitious Cushing's syndrome.

Renal phosphate wasting related to a tumor (oncogenous osteomalacia) is a rare disorder usually associated with benign mesenchymal tumors. In this article, the authors describe a man with renal phosphate wasting and the syndrome of inappropriate antidiuretic hormone associated with small cell carcinoma. Chemotherapy markedly reduced tumor burden and was associated with normalization of renal phosphate handling and serum sodium. With recurrence, renal phosphate wasting and the syndrome of inappropriate antidiuretic hormone developed again, with the additional complication of hypercortisolism secondary to ectopic corticotropin production. The authors report the rare occurrence of renal phosphate wasting with small cell carcinoma (5 previously reported cases) and the unique co-existence of this paraneoplastic syndrome with the syndrome of inappropriate antidiuretic hormone and ectopic corticotropin production.

Autoimmune thyroiditis with hypothyroidism is a well-known complication of immunotherapy with interleukin-2 (IL-2) with or without lymphokine-activated killer (LAK) cells. To date, however, no cases of IL-2/LAK-induced autoimmune adrenalitis with adrenal insufficiency have been reported. We describe a patient who developed primary adrenal insufficiency following IL-2/tumor-infiltrating lymphocytes (TIL) immunotherapy for renal cell carcinoma. A 64-year-old male with renal cell carcinoma metastatic to bone, skin, lung, and the central nervous system presented for IL-2/TIL treatment. Nine months earlier, he had undergone a right nephrectomy and adrenalectomy. He had already received two courses of IL-2 and one course of IL-4 following surgery. Dynamic studies of adrenal function performed prior to IL-2/TIL immunotherapy demonstrated intact cortisol and aldosterone responses to ACTH as well as negative adrenal antibodies. One week after IL-2/TIL therapy, the patient developed a nonanion gap metabolic acidosis, hypotension and hypoglycemia. Adrenocortical function was re-evaluated demonstrating blunted cortisol and aldosterone responses to ACTH with an elevated plasma ACTH confirming the presence of primary adrenal insufficiency. Adrenal antibodies were now positive. Hydrocortisone and fludrocortisone were given with a good clinical response. We suggest immunotherapy with IL-2/TIL may cause adrenal insufficiency by activating autoimmune adrenalitis.

Liddle's syndrome (pseudoaldosteronism) is an autosomal dominant form of human hypertension characterized by a constellation of findings suggesting constitutive activation of the amiloride-sensitive distal renal epithelial sodium channel. We demonstrate complete linkage of the gene encoding the beta subunit of the epithelial sodium channel to Liddle's syndrome in Liddle's original kindred. Analysis of this gene reveals a premature stop codon that truncates the cytoplasmic carboxyl terminus of the encoded protein in affected subjects. Analysis of subjects with Liddle's syndrome from four additional kindreds demonstrates either premature termination or frameshift mutations in this same carboxy-terminal domain in all four. These findings demonstrate that Liddle's syndrome is caused by mutations in the beta subunit of the epithelial sodium channel and have implications for the regulation of this epithelial ion channel as well as blood pressure homeostasis.

Epidural steroids (ESI) are often used for the treatment of low back pain but their effects on the endocrine system have not been determined. We studied the hypothalamic-pituitary adrenal (HPA) axis in 14 patients by measuring plasma adrenocorticotropin (ACTH) by sensitive two-site immunoradiometric assay and by evaluating the acute cortisol response to cosyntropin. We also evaluated the additional impact of sedation with midazolam before ESI on the degree of suppression of the HPA axis. Plasma ACTH and cortisol were significantly suppressed 7 days after the first ESI; the group receiving midazolam was more suppressed. By 14 days after the first ESI (7 days after the second ESI), plasma ACTH was more suppressed in the group receiving midazolam and plasma cortisol was markedly suppressed in both groups. At 48 days after the first ESI (34 days after the third ESI), plasma ACTH and cortisol were significantly suppressed only in the group that had received midazolam before each ESI. At 48 days, the plasma cortisol response to cosyntropin was blunted (< 500 nmol/L) in 5 of 14 patients. All patients had a normal cortisol response to cosyntropin by 3 mo after the last ESI. Weekly ESI over 3 wk caused a dramatic acute and chronic suppression of the HPA axis. Median suppression was less than 1 mo, and all patients had recovered by 3 mo. Sedation with midazolam accentuated the suppression of the HPA axis. Exogenous steroid coverage during this potentially vulnerable period should be considered in patients undergoing major stress especially if the adrenocortical response to ACTH is subnormal.

In summary, the technological advances in the past decade have greatly improved the biochemical and radiological diagnosis of Cushing's syndrome. Figure 13 illustrates an algorithm for the differential diagnosis of Cushing's syndrome that focuses on the importance of ACTH-IRMA and provides two potential diagnostic approaches for the evaluation of ACTH-dependent hypercortisolism. The first approach directly proceeds to IPSS as the most rapid and possibly most cost effective method to establish an accurate diagnosis. A more traditional approach employs high dose dexamethasone suppression testing followed by MR studies of the pituitary. If the biochemical or radiological studies are the least bit equivocal, IPSS should be performed before definitive therapy is recommended.

Hypercalcemia associated with the extrarenal production of 1,25-dihydroxyvitamin D (1,25(OH)2D) has been reported in several disorders, most notably granulomatous diseases such as sarcoidosis. The authors describe a woman with hypercalcemia, renal insufficiency, microscopic hematuria, and anemia. The circulating 1,25(OH)2D level was higher than appropriate for the ambient conditions (renal insufficiency, suppressed intact parathyroid hormone, and hypercalcemia). A kidney biopsy was consistent with Wegener's granulomatosis, and treatment with prednisone and cyclophosphamide was associated with normalization of serum calcium levels, improved renal function, a marked decrease in serum 1,25(OH)2D levels, and increased serum intact parathyroid hormone levels. These findings are consistent with the unregulated production of 1,25(OH)2D by inflammatory cells associated with Wegener's granulomatosis.

The clinical, biochemical, and radiographic features of ectopic ACTH-dependent Cushing's syndrome are often indistinguishable from those of pituitary ACTH-dependent hypercortisolism (Cushing's disease). We prospectively evaluated 29 patients with ACTH-dependent hypercortisolism by means of bilateral inferior petrosal sinus ACTH sampling with ovine CRH (oCRH) stimulation. Patients with Cushing's disease (n = 20), had a maximal basal inferior petrosal sinus to peripheral ACTH ratio (IPS:P-ACTH) of 11.7 +/- 4.4 (+/- SE) from the dominant IPS, which increased to 50.8 +/- 18.3 after oCRH administration. Bilateral IPS sampling was necessary to correctly identify patients with Cushing's disease, since the maximal basal nondominant IPS:P-ACTH was less than 2.0 in over 50% of the patients and remained less than 2.0 after oCRH administration in one third. In contrast, patients with occult ectopic ACTH-secreting neoplasms (n = 9) had maximal basal IPS:P-ACTH of 1.2 +/- 0.1 that did not change after oCRH administration. Occult ectopic ACTH-secreting neoplasms were found in 7 of 9 patients from 0.4-14 yr after the recognition of Cushing's syndrome, and 4 of these patients had intermittent hypercortisolism with prolonged periods of remission. Selective endobronchial lavage for ACTH correctly localized a radiologically occult ACTH-secreting bronchial carcinoid in 1 patient, and magnetic resonance imaging identified a similar neoplasm in a patient with a normal chest computed tomographic scan. Basal ACTH and urinary free cortisol excretion were significantly higher in patients with ectopic ACTH than in those with Cushing's disease, but overlap existed between groups. High dose dexamethasone suppression testing inaccurately classified 24% of patients, and radiological imaging of the pituitary and adrenal glands was misleading. The occult ectopic ACTH syndrome is a common form of ACTH-dependent hypercortisolism that cannot be distinguished from Cushing's disease with routine clinical studies. The accurate differential diagnosis of ACTH-dependent Cushing's syndrome requires bilateral inferior petrosal sinus ACTH sampling with oCRH stimulation.

Adrenocorticotrophic hormone (ACTH)-producing bronchial carcinoid tumors tend to occur in the middle third of the lung adjacent to pulmonary vessels. Because they cause signs and symptoms when quite small (by virtue of their ACTH production), they may not be detected by CT. MR imaging was performed in 10 consecutive patients with surgically proved ACTH-producing bronchial carcinoid tumors in order to test the ability of MR to clarify equivocal or indeterminate findings on CT examinations. All bronchial carcinoid tumors had high signal intensity on T2-weighted and short-inversion-time inversion-recovery images, facilitating their distinction from pulmonary vasculature. In eight patients, the CT and MR images were equivalent in the detection of bronchial carcinoid tumors. In two patients, MR showed tumors in the middle third of the lung that were equivocal on CT. MR imaging may distinguish small bronchial carcinoid tumors from adjacent pulmonary vessels in the central third of the lung at a time when the CT study is nondiagnostic or equivocal.

Acute mitral obstruction may lead to an increase in atrial natriuretic peptide (ANP) due to increased atrial pressure and a large increase in arginine vasopressin (AVP) due to simultaneous arterial and ventricular baroreceptor unloading. We measured ANP and AVP concentration after transseptal puncture and during percutaneous retrograde mitral balloon valvuloplasty (PRMV) in 11 patients (mean age 57 +/- 12 years; nine women) with mitral stenosis and congestive heart failure. Atrial septal puncture per se resulted in a significant increase in ANP and AVP without a significant change in aortic pressure. Subsequent PRMV led to a further increase in ANP, a transient decrease in aortic pressure from 89 +/- 7 to 45 +/- 4 mm Hg, and a large (fivefold) increase in AVP. ANP and AVP were no longer different from baseline values 18 to 24 after the procedure. This study suggests that transseptal puncture and acute mitral obstruction are major stimuli to ANP release and that combined unloading of arterial and left ventricular mechanoreceptors is a very potent vasopressinergic stimulus.

We report a postmenopausal woman with primary hyperparathyroidism (PHPT) and severe hypercalcemia while her total calcium intake was more than 2 g daily. Despite a markedly elevated intact PTH level, her serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] level was low (17 pmol/L; 7 pg/mL). With reduced calcium intake, her serum calcium normalized, and 1,25-(OH)2D increased to 122 pmol/L (51 pg/mL). At the same time, intact PTH decreased to 32% of the initial value. PHPT may be associated with low circulating 1,25-(OH)2D levels. Furthermore, low 1,25-(OH)2D levels in PHPT may be due to a direct effect of severe hypercalcemia and be reversible with correction of hypercalcemia.

A subset of critically ill patients has been described with low plasma aldosterone (Aldo) despite elevated plasma renin activity (PRA). In order to investigate possible mechanisms for these findings, the present study evaluated the Aldo response to exogenous ACTH or metoclopramide (MCP) in normal subjects and in patients admitted to the medical ICU. In addition, measurements of clinical status (Acute Physiology and Chronic Health Evaluation [APACHE II]) and atrial natriuretic peptide (ANP) were correlated with adrenal status. Critically ill patients were subdivided into normal (greater than 2) and subnormal (less than 2) Aldo-to-PRA ratio (Aldo/PRA). Patients with basal Aldo less than 70 ng/dl exhibited subnormal Aldo responses to ACTH, regardless of basal Aldo/PRA. However, normal responses to MCP were noted regardless of basal Aldo/PRA. No correlation between Aldo/PRA and APACHE II score or ANP levels was found. We conclude that critically ill patients with dissociated Aldo and renin can generate a normal Aldo response to MCP. This suggests that this syndrome is due to functional and potentially reversible dysfunction of the zona glomerulosa of the adrenal cortex.

Bioassay and immunoassay techniques for the measurement of ACTH in human plasma have provided sensitive and specific results but have also met with some skepticism as to their reliability in some clinical circumstances. The recent development of a supersensitive two-site immunoradiometric assay for ACTH may resolve sole of the limitations of previous assays and greatly facilitate the evaluation of pituitary-adrenal disorders.