Lower extremity insufficiency fractures: an underappreciated manifestation of endogenous Cushing's syndrome.

This report describes the presence of lower extremity insufficiency fractures in 10 women prior to the clinical and biochemical diagnosis of endogenous Cushing's syndrome (CS). Osteoporosis is a well-recognized complication of overt CS resulting in a high rate of vertebral and other fractures. After institutional review board (IRB) approval, we did a retrospective chart review of patients with lower extremity (LE) insufficiency fractures (IF) and CS. This chart review found 10 women in whom LE-IF preceded the diagnosis of endogenous CS. Low bone density was found in all but one patient. The CS was considered to be mild (or subclinical) in five patients. LE-IF should be considered part of the skeletal spectrum of CS. Physicians caring for patients with LE-IF should have a low threshold for the consideration of CS even in patients without overt physical evidence of cortisol excess.

Treatment of cushing's syndrome: an Endocrine Society Clinical Practice Guideline

OBJECTIVE: The objective is to formulate clinical practice guidelines for treating Cushing's syndrome. PARTICIPANTS: Participants include an Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. The European Society for Endocrinology co-sponsored the guideline. EVIDENCE: The Task Force used the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews and used the best available evidence from other published systematic reviews and individual studies. CONSENSUS PROCESS: The Task Force achieved consensus through one group meeting, several conference calls, and numerous e-mail communications. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. CONCLUSIONS: Treatment of Cushing's syndrome is essential to reduce mortality and associated comorbidities. Effective treatment includes the normalization of cortisol levels or action. It also includes the normalization of comorbidities via directly treating the cause of Cushing's syndrome and by adjunctive treatments (eg, antihypertensives). Surgical resection of the causal lesion(s) is generally the first-line approach. The choice of second-line treatments, including medication, bilateral adrenalectomy, and radiation therapy (for corticotrope tumors), must be individualized to each patient.(AU)

High variability in baseline urinary free cortisol values in patients with Cushing's disease.

OBJECTIVE: Twenty-four-hour urinary free cortisol (UFC) sampling is commonly used to evaluate Cushing's syndrome. Because there are few data on UFC variability in patients with active Cushing's disease, we analysed baseline UFC in a large patient cohort with moderate-to-severe Cushing's disease and assessed whether variability correlates with hypercortisolism severity. These data will help clinicians establish the minimum number of UFC samples required to obtain reliable data. DESIGN: Observational study (enrolment phase of Phase III study). METHODS: Patients (n = 152) with persistent/recurrent or de novo Cushing's disease and mean UFC (mUFC) ≥1·5×ULN (normal: 30-145 nmol/24 h) were included. Mean UFC level was calculated from four 24-h urine samples collected over 2 weeks. RESULTS: Over 600 24-h UFC samples were analysed. The mUFC levels of samples 1 and 2 and samples 3 and 4 were 1000 nmol/24 h (SD 1872) and 940 nmol/24 h (SD 2148), respectively; intrapatient coefficient of variation (CV) was 38% for mUFC. The intrapatient CV using all four samples was 52% (95% CI: 48-56). The intrapatient CV was 51% (95% CI: 44-58) for samples 1 and 2, 49% (95% CI: 43-56) for samples 3 and 4 and 54% (95% CI: 49-59) for samples 1, 2 and 3. Variability in mUFC increased as UFC levels increased. There were no correlations between UFC and clinical features of hypercortisolism. CONCLUSIONS: There is intrapatient variability of approximately 50% in 24-h UFC measurements, which is relevant to targets set to estimate any treatment effect. Analysing more than two 24-h collection periods in individual patients does not result in a relevant decrease in variability. Interestingly, UFC levels did not correlate with hypercortisolism severity.

The use of mifepristone in the treatment of Cushing's syndrome.

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.

Diagnosis and complications of Cushing's syndrome: a consensus statement.

In October 2002, a workshop was held in Ancona, Italy, to reach a Consensus on the management of Cushing's syndrome. The workshop was organized by the University of Ancona and sponsored by the Pituitary Society, the European Neuroendocrine Association, and the Italian Society of Endocrinology. Invited international participants included almost 50 leading endocrinologists with specific expertise in the management of Cushing's syndrome. The consensus statement on diagnostic criteria and the diagnosis and treatment of complications of this syndrome reached at the workshop is hereby summarized.

Diagnosis and differential diagnosis of Cushing's syndrome.

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.

Comparison of adrenal vein sampling and computed tomography in the differentiation of primary aldosteronism.

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.

Randomized trial of oral hydrocortisone and its effect on emergency physicians during night duty.

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.

Newer diagnostic techniques and problems in Cushing's disease.

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.

Late-night salivary cortisol as a screening test for Cushing's syndrome.

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).

Effectiveness versus efficacy: the limited value in clinical practice of high dose dexamethasone suppression testing in the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome.

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.

Hypocalcemia and skeletal disease as presenting features of celiac disease.

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.

Liddle's syndrome: prospective genetic screening and suppressed aldosterone secretion in an extended kindred.

Liddle's syndrome is an autosomal dominant form of hypertension that resembles primary hyperaldosteronism, is characterized by the early onset of hypertension with hypokalemia and suppression of both PRA and aldosterone, and is caused by mutations in the carboxyl-terminus of the beta- or gamma-subunits of the renal epithelial sodium channel. We describe a kindred (K176) whose distinguishing clinical features were mild hypertension and decreased aldosterone secretion. The index case was a 16-yr-old girl with intermittent mild hypertension and hypokalemia and subnormal PRA, aldosterone, 18-hydroxy-corticosterone, and deoxycortisol levels, but normal cortisol/cortisone metabolite ratio and cortisol half-life. A frameshift mutation in the carboxyl-terminus of the beta-subunit of the epithelial sodium channel was identified in the index case, establishing the diagnosis of Liddle's syndrome. Sixteen at-risk relatives of the index case were tested. Seven new subjects were heterozygous for the mutation found in the index case, and two deceased obligate carriers were identified. All genetically affected adult subjects had a history of mild hypertension, and four had a history of hypokalemia. Basal and postcosyntropin plasma aldosterone and urinary aldosterone levels were significantly suppressed in those positive for the mutation. The family demonstrates variability in the severity of hypertension and hypokalemia in this disease, raising the possibility that this disease may be underdiagnosed among patients with essential hypertension.

Heterogeneity in clinical manifestation of autosomal dominant neurohypophyseal diabetes insipidus caused by a mutation encoding Ala-1-->Val in the signal peptide of the arginine vasopressin/neurophysin II/copeptin precursor.

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.

Results of a community thyroid screening program: who will benefit?

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: discovery with use of a sensitive immunoradiometric assay for corticotropin.

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.

Case report: renal phosphate wasting, syndrome of inappropriate antidiuretic hormone, and ectopic corticotropin production in small cell carcinoma.

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.

Intraoperative measurement of adrenocorticotropin (ACTH) during removal of ACTH-secreting bronchial carcinoid tumors.

The optimal treatment for ectopic ACTH syndrome is the complete removal of the tumor secreting ACTH. These tumors are often occult, with their location suggested but not proven with imaging techniques. The intraoperative measurement of ACTH by immunoradiometric assay in five patients with the occult ectopic ACTH syndrome during removal of suspicious intrapulmonary lesions is reported. A significant ACTH gradient was detected in the pulmonary veins of the affected lobes in two patients. ACTH had decreased significantly in all five patients by 10 and 15 min after tumor removal. All five patients had histologically proven ACTH-secreting bronchial carcinoid tumors, suppressed plasma ACTH by 24 h after tumor removal, and subsequent secondary adrenal insufficiency indicating successful surgical therapy (five of five true-positive). In one patient, previous surgery was not curative and did not result in a decrease in intraoperative measurement of ACTH (one of one true-negative). It was demonstrated that a rapid ACTH immunochemiluminescence assay with a 15-min incubation time has sufficient sensitivity and precision to detect decreases in ACTH described above. These results demonstrate that complete removal of ACTH-secreting bronchial carcinoid tumors can be detected intraoperatively by a decrease in arterial ACTH by 15 min. The modification of the ACTH immunochemiluminescence assay to 15 min incubation allows the documentation of a successful tumor removal in the operating room. It may also be used to locate the tumor intraoperatively by selective pulmonary vein sampling. This protocol may be applicable to the intraoperative measurement of ACTH during pituitary microadenomectomy for Cushing's disease.

Autoimmune Addison's disease after treatment with interleukin-2 and tumor-infiltrating lymphocytes.

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.