Diagnosis and treatment of primary aldosteronism: practical clinical perspectives.

Primary aldosteronism (PA), the most common form of secondary hypertension, can be either surgically cured or treated with targeted pharmacotherapy. PA is frequently undiagnosed and untreated, leading to aldosterone-specific cardiovascular morbidity and nephrotoxicity. Thus, clinicians should perform case detection testing for PA at least once in all patients with hypertension. Confirmatory testing is indicated in most patients with positive case detection testing results. The next step is to determine whether patients with confirmed PA have a disease that can be cured with surgery or whether it should be treated medically; this step is guided by computed tomography scan of the adrenal glands and adrenal venous sampling. With appropriate surgical expertise, laparoscopic unilateral adrenalectomy is safe, efficient and curative in patients with unilateral adrenal disease. In patients who have bilateral aldosterone hypersecretion, the optimal management is a low-sodium diet and lifelong treatment with a mineralocorticoid receptor antagonist administered at a dosage to maintain a high-normal serum potassium concentration without the aid of oral potassium supplements.

Long-term outcomes in patients with multiple endocrine neoplasia type 1 and pancreaticoduodenal neuroendocrine tumours.

BACKGROUND: In patients with multiple endocrine neoplasia type 1 (MEN-1), pancreaticoduodenal (PD) neuroendocrine tumours (NETs) are associated with early mortality, yet the best treatment strategy remains uncertain. AIM: To assess patient important outcomes (mortality and metastasis) of PD-NETs and predictors of outcomes in patients with MEN-1. METHODS: Retrospective cohort of patients with MEN-1 who attended the Mayo Clinic, Rochester, MN from 1997 to 2014. RESULTS: We identified 287 patients with MEN-1; 199 (69%) patients had 217 PD-NETs. Among those with a PD-NETs, 129 (65%) had surgery of which 90 (70%) had their primary surgery performed at Mayo Clinic. The median postoperative follow-up was 8 years during which 13 (14%) patients died. The mean (±standard deviation) age of death was 51 (±9) years. Tumour size, metastasis at surgery or tumour type were not predictive of mortality, but for every year older at surgery, the odds of metastasis increased by 6%. Surgery was not performed in 70 (35%) patients. Among those who were observed/medically managed without known metastatic disease, mean tumour growth was 0·02 cm/year (range, -0·13-0·4 cm/year). Four patients (7%) died at a median age of 77 (range, 51-89) years. CONCLUSION: PD-NETs are common in patients with MEN-1 and are associated with early mortality even after surgical intervention. Active surveillance is a viable option in nonaggressive PD-NETs, although definitive factors identifying such patients are lacking. Therefore, counselling regarding risks and benefits of current treatment options remains integral to the care of patients with MEN-1.

Silent subtype 3 pituitary adenoma: a clinicopathologic analysis of the Mayo Clinic experience.

BACKGROUND: Macroadenomas represent 50% of pituitary tumours and are often (30%) nonfunctioning. Their immunophenotype suggests differentiation toward a specific pituitary cell line. A substantial proportion of tumours with particularly aggressive behaviour are so called 'silent subtype 3 adenoma'. Its diagnosis requires ultrastructural confirmation. Although once included among silent corticotroph adenomas, this aggressive, morphologically distinctive tumour is now recognized as a major form of plurihormonal adenoma and, in fact, some patients might present with clinical hormonal excess. The cytogenesis and pathobiology of silent subtype 3 adenomas is unsettled. OBJECTIVE: We undertook a systematic clinicopathologic examination of the Mayo Clinic experience with this poorly understood tumour. DESIGN: This retrospective, single institution study found 27 confirmed examples of silent subtype 3 adenoma, a frequency of 0.9% of adenomas. Despite histologic and immunophenotypic variation, their ultrastructural features were diagnostic and the sole basis for case inclusion. RESULTS: The study group was comprised of 16 men (59%) and 11 women (41%); two patients (7%) had definitive diagnosis of multiple endocrine neoplasia type 1 (MEN1). Three tumours (11%) were discovered incidentally. Nine patients each (38%) presented with headaches or visual field loss. Endocrine hyperfunction was noted in eight cases (30%), including GH excess in five (19%) and clinically significant PRL elevation in three (11%). Hypogonadism was noted in 17 cases (63%) and growth arrest in one (4%). All tumours were macroadenomas; 16 (60%) showed radiographic evidence of invasion. Most tumours were plurihormonal, featuring immunoreactivity for PRL (17), GH (15), TSH (16) or ACTH (3); only one lesion was immunonegative. Although a gross total resection was achieved in 19 cases (70%), re-operation for recurrence(s) was required in seven of these (37%). Follow-up (mean, 69 months) showed a high (59%) rate of persistent or recurrent of tumour. Overall, 14 patients (54%) underwent radiotherapy after surgical treatment: three patients (12%) for substantial residual tumour, eight (31%) as adjuvant therapy and three (12%) for tumour regrowth. CONCLUSION: Silent subtype 3 adenoma, a plurihormonal tumour, is rare and aggressive in nature. This adenoma must be considered in the differential of often clinically nonfunctioning but plurihormonal adenomas featuring variable cytologic atypia. Electron microscopy is required for confirmation of the diagnosis. The cytogenesis of silent subtype 3 adenoma remains unsettled.

Corticotropin hormone assay interference: A case series.

Measuring the plasma corticotropin (ACTH) concentration is an important step in determining the underlying cause in patients with hypercortisolemia. Interfering substances in immunoassays can lead to erroneous results impacting clinical management. We describe a case series of 12 patients, the majority of whom were being investigated for possible Cushing's syndrome and in whom inconsistencies between the clinical picture and biochemical testing raised concerns of assay interference. ACTH assay interference resulted in falsely elevated ACTH concentrations using the Siemens Immulite assay and consequently led to additional unnecessary testing. Communication between physician and laboratory as well as appropriate investigation (including sample dilution, use of blocking antibodies and testing on an alternate platform) resulted in assay interference identification. Recognition of biochemical results which are clinically discrepant remains an essential step in patient assessment.

Human monoamine oxidase. Lack of brain and platelet correlation.

Monoamine oxidase (MAO) exists in two forms, MAO A and MAO B. Both are present in human brain, but the human platelet contains only MAO B. We studied whether individual variations in the activity of human platelet MAO B reflect individual variations in cerebral cortical MAO activities. Optimal conditions were determined for the measurement of MAO activities in both the platelet and cerebral cortex, obtained from 14 patients with epilepsy during clinically indicated neurosurgery. There was no significant correlation between the activities of MAO B in the cerebral cortex and platelets of these patients. Platelet MAO B activities also failed to correlate significantly with cerebral cortical MAO A activities. However, there was a significant positive correlation between cerebral cortical MAO A and MAO B activities. Individual variations in platelet MAO B activities do not reflect individual variations in either cerebral cortical MAO B or MAO A activities in patients with epilepsy who undergo neurosurgery.

Pheochromocytoma: 1926-1993.

Pheochromocytoma is a tumor frequently sought and rarely found. It is associated with spectacular cardiovascular disturbances and, when correctly diagnosed and properly treated, it is curable; when undiagnosed or improperly treated, it can be fatal. Catecholamine-producing tumors that arise from chromaffin cells of the adrenal medulla and sympathetic ganglia are termed pheochromocytomas and paragangliomas, respectively. However, the term pheochromocytoma has become the generic name for all catecholamine-producing tumors. The biochemical diagnosis is straightforward. The localization of pheochromocytoma has been greatly facilitated by advances in computerized imaging and meta-iodobenzylguanidine scanning. Treatment with preoperative alpha- and beta-adrenergic blockade followed by surgical excision of the pheochromocytoma are associated with very low morbidity and mortality.

Renin-Independent hypermineralocorticoidism.

Although renin-independent hypermineralocorticoidism is an uncommon form of hypertension, its diagnosis provides the clinician with a unique opportunity in the field of hypertension, that is, to render a surgical cure or to achieve a dramatic pharmacologic response in the treatment of hypertension. Primary aldosteronism is the most common form of renin-independent hypermineralocorticoidism. The plasma aldosterone concentration to plasma renin ratio is an excellent screening test for primary aldosteronism, the diagnosis of which should be confirmed by demonstrating unsuppressible urine or plasma levels of aldosterone. The subtype of primary aldosteronism dictates the most appropriate therapy. Computerized imaging of the adrenal glands and adrenal venous sampling assist in distinguishing unilateral (requiring surgical treatment) from bilateral (requiring pharmacologic treatment) adrenal disease. The forms of mineralocorticoid excess considered in the hypokalemic hypertensive patient with low aldosterone values include congenital adrenal hyperplasia (11 beta-hydroxylase and 17alpha-hydroxylase deficiencies), deoxycorticosterone-producing tumor, Cushing's syndrome, primary cortisol resistance, and 11 beta-hydroxysteroid dehydrogenase deficiency (apparent mineralocorticoid excess syndrome). The I1 beta-hydroxysteroid dehydrogenase deficiency may be congenital or acquired (for example, ingestion of licorice or carbenoxolone).

Growth hormone therapy for hypopituitary adults: time for re-appraisal.

The advent of the production of large quantities of recombinant growth hormone (GH) has made it possible to have sufficient material to assess its efficacy in adult growth hormone deficiency (GHD). Although some studies have shown that patients who are severely deficient benefit from GH therapy, the spectrum of GHD is broad, and the degree of deficiency at times is very difficult to define. In some cases, benefit is not easily quantified, and some studies have claimed benefits that, although statistically significant, are either not clinically important or are so marginal as to be questionable in terms of cost, difficulty of administration and potential risks. The purpose here is to identify the current problems in the diagnosis of GHD, to discuss the rationale for GH therapy and to assess the potential effects of GHD as well as the benefits of GH therapy in GHD adults. We will include a commentary as to which effects appear more robust than others and which are likely to result in the greatest patient benefit. Finally, some attention will be paid to long-term safety issues that should be monitored to ensure that this medication is safe even for the patients with the greatest need.

The pituitary in Turner syndrome.

Although Turner syndrome is not uncommon, studies of the pituitary in this condition are few. We undertook a histochemical and immunohistochemical study of four cases. As expected, "gonadal failure cells" were seen, but without recognizable gonadotroph hyperplasia. No gonadotroph adenomas were encountered. Instead, three silent corticotroph microadenomas were seen; their etiology remains unexplained. The question of whether the simultaneous occurrence of Turner syndrome and silent corticotroph adenoma is causal or incidental cannot be answered on the basis of the study of our material. Because these two diseases are rare, an etiologic association has to be considered. For example, it is possible that (a) protracted stimulation of gonadotrophs leads to transdifferentiation to corticotrophs, a hypothesis supported by the fact that normal and neoplastic gonadotrophs can contain ACTH and that some corticotroph adenomas produce LH and/or alpha subunit, (b) corticotrophs develop gonadotropin-releasing hormone (GnRH) receptors and undergo neoplastic transformation when exposed to continuous elevation of GnRH, FSH, and/or LH levels, and (c) the genetic defect in Turner syndrome promotes the formation of corticotroph adenomas.

Medical care patterns at the onset of insulin-dependent diabetes mellitus: association with severity and subsequent complications.

The hospitalization of a child at the onset of insulin-dependent diabetes mellitus (IDDM) has become routine in many parts of the world, although controversy exists about its necessity. We examined the patterns of medical care use and the prognosis for acute complications after diagnosis for children with newly diagnosed IDDM in Colorado from 1978 to 1982. We reasoned that if children cared for entirely in outpatient settings at diagnosis had no more frequent acute complications after diagnosis than hospitalized children, we would be encouraged to further explore other potential benefits of outpatient care at onset. Twelve percent of 305 children studied statewide received only outpatient care during the first 2 wk after diagnosis, and, prognostically, their subsequent hospitalization and ketoacidosis rates were 2-3.7 times lower than those of children who received any inpatient care. No differences were noted for severe insulin reaction rates. Children classified as "severe" at onset, or with parents of lower education and income, or aged 10-14 yr at onset, regardless of care setting, had 2-4 times higher subsequent acute complication rates after onset than children without these characteristics. These findings, together with data on nights hospitalized and average length of stay in hospital at onset, suggest that a 42% reduction in total nights hospitalized could occur if children with "mild" or "normal" severity at onset were treated largely in the outpatient setting.

Preventive care in diabetes mellitus. Current practice in urban health-care system.

Early identification and treatment of complications of diabetes mellitus may reduce the severity of the complications. As part of a program to reduce these complications in the Denver Department of Health and Hospitals patient population, our study determined how frequently preventive care, e.g., fundoscopic examinations, referral to an ophthalmologist, foot examinations, and assessment of cardiovascular risk factors, was provided to diabetic patients. With the use of billing records to identify a large sample of diabetic patients, a chart review of 544 patients was conducted. During the study year, the mean +/- SE number of visits to primary-care clinics was 5.7 +/- 0.22, with 86.4% having at least one visit. Most diabetic patients were seen by primary-care physicians; only 9% received care in a specialized diabetes clinic. Despite frequent primary-care visits, most diabetic patients in this county health-care system did not have documentation of care to detect complications of diabetes mellitus, and referral services for detection and treatment of these complications were infrequently used. Moreover, among patients seen on greater than or equal to 10 occasions in a primary-care setting, preventive care was not provided to 30% of the patients. Preventive care does not appear to be a regular part of a primary-care visit for most of the diabetic patients in this study.

Triiodothyronine: a substrate for the thermostable and thermolabile forms of human phenol sulfotransferase.

The enzyme(s) responsible for the sulfate conjugation of L-T3 in man has not been characterized. T3 sulfotransferase (T3-ST) activity was characterized in normal human liver tissue obtained during clinically indicated surgical resection. Subcellular distribution studies showed that the T3-ST activity was localized to the cytoplasmic fraction. This finding raised the possibility that T3-ST activity might be similar to the 2 previously identified forms of cytoplasmic phenol sulfotransferase (PST) found in human tissue. A thermostable (TS) form of PST catalyzes the sulfate conjugation of micromolar concentrations of p-nitrophenol, and a thermolabile (TL) form catalyzes the sulfate conjugation of dopamine and other monoamines. Thermal stability and enzyme inhibitor experiments showed that T3-ST activity in pooled liver homogenates was very similar to the TS form of PST. The apparent similarity of T3-ST to TS PST was studied further by measuring T3-ST, TS PST, and TL PST activities in 20 individual liver samples. T3-ST activities correlated significantly with TS PST activities (r = 0.939; P less than 0.001) measured with p-nitrophenol, but not with TL PST activities (r = -0.118; P greater than 0.6) measured with dopamine. However, sulfation of T3 by the TL form of the enzyme might have been masked by the 18-fold higher specific activity of TS than TL PST in human liver homogenates. When the two forms of PST were separated by ion exchange chromatography, T3 was found to be a substrate for both the TS and TL forms of PST. "True" Km values for T3 were similar for TS and TL PST (81 and 127 microM, respectively).

C-peptide suppression test: effects of gender, age, and body mass index; implications for the diagnosis of insulinoma.

To assess the effects of gender, age, and body mass index (BMI) on suppression of plasma C-peptide during insulin-induced hypoglycemia, 101 lean and obese, healthy men and women ages 20 to 80 yr underwent infusion of human regular insulin, 0.125 U/kg over 60 min after an overnight fast. Plasma glucose, insulin, and C-peptide were measured every 30 min for 120 min. C-peptide concentrations were influenced by gender at 30 min, by BMI at baseline and both BMI and age at all subsequent time points. Because of variations in baseline plasma C-peptide concentrations, percent decrease in C-peptide was evaluated. Significantly less percent decrease of C-peptide with increased age at 30, 60, and 90 min and with increased BMI at 30 and 60 min were noted with no effect of gender. From stepwise regression analysis using multiple, additional variables only the plasma glucose concentration at 30 min made a significant, albeit small (8%), contribution to the variability in percent decrease in C-peptide at 60 min. When C-peptide responses from eight histologically confirmed insulinoma patients were contrasted to values adjusted for age, gender, and BMI of normal subjects, all insulinoma patients had abnormal responses when percent decrease in C-peptide was used, whereas only four insulinoma patients had abnormal response when actual C-peptide concentrations were used.

Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore.

Recent studies using the ratio of plasma aldosterone concentration (PAC) to PRA as the screening test for primary aldosteronism in hypertensive populations suggested that the prevalence may be as high as 5-15%, with well over half of the subjects having normal serum potassium concentrations. Despite an increasing clinical awareness of this entity, many clinicians are reluctant to consider routine screening for primary aldosteronism in essential hypertensive patients because there are few community-based prevalence studies of primary aldosteronism in different populations. Furthermore, genetic and environmental differences may affect the prevalence and presentation of primary aldosteronism in distinct populations. This study was designed to determine the prevalence of primary aldosteronism in the predominantly Chinese population in Singapore. Three hundred and fifty unselected adult hypertensive patients attending two primary care clinics had random ambulatory measurements for PAC (nanograms per dL) and PRA (nanograms per mL/h). Serum urea, creatinine, and electrolyte measurements were obtained simultaneously. Subjects with renal insufficiency (serum creatinine, >140 micromol/L) and those treated with glucocorticoids or spironolactone were excluded. Screening was considered positive if the PAC: PRA ratio was more than 20 and the PAC was more than 15 ng/dL (>416 pmol/L). Primary aldosteronism was confirmed with the determination of PAC after 2 L saline administered iv over 4 h. Adrenal computed tomographic (CT) scans were performed in biochemically confirmed cases of primary aldosteronism. Further localization with adrenal vein sampling was carried out in selected patients with equivocal findings on adrenal CT scan. Sixty-three (18%) of the 350 hypertensive patients (215 women and 135 men; age range, 23-75 yr) were screened positive for primary aldosteronism. Only 13 of these 63 subjects (21%) were hypokalemic (serum potassium, <3.5 mmol/L). Confirmatory studies were carried out in 56 (89%) of the subjects with a positive PAC:PRA ratio. Using a PAC above 10 ng/dL (>277 pmol/L) after saline infusion as the diagnostic cut-off, 16 of the 56 patients had biochemically confirmed primary aldosteronism. Hypokalemia was found in 6 of the 16 patients (37.5%) with primary aldosteronism. Subtype evaluation with adrenal CT scan and adrenal vein sampling indicated that half of the patients with primary aldosteronism may have had potentially curable unilateral adrenal adenoma. Our data suggest that primary aldosteronism occurs in at least 5% of the adult Asian hypertensive population, and approximately half of these individuals may have potentially curable, unilateral, aldosterone-producing adrenal adenoma. Our findings also confirm the poor predictive value of hypokalemia in both the diagnosis and the exclusion of primary aldosteronism.

Erythrocyte catechol-O-methyltransferase, platelet monoamine oxidase, and platelet phenol sulfotransferase activities in patients with prolactin-secreting pituitary adenomas.

Dopamine is metabolized by oxidative deamination catalyzed by monoamine oxidase, O-methylation catalyzed by catechol-O-methyltransferase, and sulfate conjugation catalyzed by phenol sulfotransferase. This study was performed to determine whether platelet monoamine oxidase, red blood cell catechol-O-methyltransferase and platelet phenol sulfotransferase enzymatic activities in patients with prolactinomas were quantitatively different from the same enzyme activities in blood samples from normal subjects. The mean enzyme activities in blood samples from 22 women with histologically proven prolactinomas were compared to the mean enzyme activities in blood samples from 32 normal women. The blood levels of these 3 enzymatic activities were not significantly different between the two groups (P greater than 0.4). If the regulation of these catecholamine-metabolizing enzyme activities in blood elements reflects the regulation of the enzymes in the hypothalamic-hypophyseal region, these results suggest that a defect in the regulation of dopamine-metabolizing enzymes is not associated with the pathogenesis of prolactinomas.

Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients.

Paragangliomas are rare tumors that arise from extraadrenal chromaffin cells. We examined the clinical characteristics, location, treatment, and outcome of 236 patients (141 females, 60%) with 297 benign paragangliomas evaluated at the Mayo Clinic during 1978-1998. The mean age (+/-SD) at diagnosis was 47 +/- 16 yr. Of the 297 paragangliomas, 205 were in the head and neck region, and 92 were below the neck. Paragangliomas were discovered and diagnosed incidentally on imaging studies in 9% of patients. Biochemical screening was performed in 128 patients; 40 patients (17% of the total and 31% of those screened) had hyperfunctional tumors. Of the 40 patients with tumoral catecholamine excess, 38 had documented hypertension. In patients identified with catecholamine-secreting paragangliomas, the sensitivities achieved by measurements in the 24-h urine collection were 74% for total metanephrines, 84% for norepinephrine, 18% for dopamine, and 14% for epinephrine. Multiple imaging modalities were used for tumor localization. The false negative rates were 0% for magnetic resonance imaging, 5.8% for computed tomography, 3.4% for angiography, 10.7% for ultrasonography, and 39% for radioactive iodine-labeled metaiodobenzylguanidine scintigraphy. Of 192 patients (81.4%) with follow-up data (mean, 43.9 months; range, 0.5-240), operative cure was achieved in 133 (69%). Of the 59 patients without cure, 23 had persistent disease, 5 had recurrent disease, 16 had multiple persistent synchronous tumors, and 15 subsequently developed metachronous tumors. In conclusion, most paragangliomas are nonhypersecretory and located in the head and neck region. Magnetic resonance imaging was associated with the lowest false negative rate, and metaiodobenzylguanidine was the least sensitive imaging study. A significant proportion of patients (31%) has persistent or recurrent disease, and long-term follow-up is important.

Laparoscopic adrenalectomy for adrenocorticotropin-dependent Cushing's syndrome.

Bilateral adrenalectomy is indicated for the treatment of ACTH-dependent Cushing's syndrome when the tumorous source of ACTH hypersecretion cannot be identified or removed. Potential advantages of laparoscopic over open adrenalectomy include shorter hospitalization, decreased requirement for postoperative analgesia, and decreased postoperative morbidity due to incisional complications. Bilateral laparoscopic adrenalectomy performed for the treatment of ACTH-dependent Cushing's syndrome was attempted in 19 patients at our institution between 1995 and 1998. Conversion to an open procedure was required in three patients. All patients who underwent bilateral laparoscopic adrenalectomy were subsequently followed to assess the outcome of this intervention. Twelve patients with pituitary-dependent Cushing's syndrome and four with ectopic ACTH syndrome underwent successful bilateral laparoscopic adrenalectomy. All patients experienced resolution of the signs and symptoms (e.g. proximal myopathy, hirsutism, and emotional lability) of Cushing's syndrome as well as weight loss, improved glucose tolerance, and improved control of blood pressure. No residual cortisol secretion was detected in the patients. Bilateral laparoscopic adrenalectomy is a safe and effective treatment for Cushing's syndrome when the ACTH-secreting neoplasm cannot be removed.

Cushing's syndrome due to medullary thyroid carcinoma: diagnosis by proopiomelanocortin messenger ribonucleic acid in situ hybridization.

Medullary thyroid carcinoma (MTC) rarely causes ectopic ACTH syndrome. We describe a 38-yr-old man with renal stones who had a 5-cm MTC removed in 1992. He was RET-protooncogene positive (codon 618). Serum calcitonin was 1597 pg/ml postoperatively. In 1996 he had rib fractures, bruising, weakness, and three to four stools per day. Laboratory studies revealed an elevated 24-h urine-free cortisol (780 micro g/d), epinephrine (66 micro g/d), and calcium (558 mg/d). Baseline serum cortisol was 23.9 micro g/dl and decreased to 12.9 and 4.5 micro g/dl after 2 mg and 8 mg dexamethasone suppression, respectively. Plasma ACTH was 170 pg/ml and decreased to 75 and 24 pg/ml after dexamethasone. Bone density t-score was -4.3 (trochanter). Computed tomography scans showed multiple cervical nodes and 2-cm right adrenal nodule. Magnetic resonance imaging (MRI) scan showed a prominent, homogeneous pituitary; the adrenal MRI scan was not typical for a pheochromocytoma. Serum CRH was less than 6.6 pg/ml. Bilateral adrenalectomy revealed two adjacent right adrenal pheochromocytomas and corrected the elevated urine cortisol (30 micro g/d), epinephrine (0 micro g/d), and calcium (281 mg/d) but not plasma ACTH (125 pg/ml). Neck dissection reduced calcitonin by 96% (5300 to 120 pg/ml) and ACTH by 91% (125 to 11 pg/ml). Carcinoembryonic antigen was reduced from 32.0 to 2.3 ng/ml. Immunohistochemical stain was negative for ACTH in the MTC-positive lymph nodes and the pheochromocytoma. Proopiomelanocortin mRNA by in situ hybridization was positive in the MTC but not in the pheochromocytoma. A repeat pituitary MRI scan was normal. The differential diagnosis of ACTH-dependent Cushing's syndrome in this case included pituitary disease or ectopic ACTH, either from medullary thyroid carcinoma or pheochromocytoma. ACTH stains were unrevealing, but proopiomelanocortin mRNA in situ hybridization in MTC tissue and plasma ACTH response to neck dissection confirmed MTC as the source of ectopic ACTH.

Tension pneumocranium, a rare complication of transsphenoidal pituitary surgery: Mayo Clinic experience 1976-1998.

We describe four cases of symptomatic pneumocranium, a rare, potentially life-threatening complication of transsphenoidal pituitary surgery. Symptomatic pneumocranium manifested as impaired mental status, headaches, and grand mal seizures, early in the postoperative course after transsphenoidal pituitary surgery. Furthermore, a Cushing response, including systemic hypertension and bradycardia (secondary to intracranial hypertension) was seen, which has not been previously described in association with symptomatic pneumocranium. We describe a previously unreported risk factor for tension pneumocranium, untreated obstructive sleep apnea. Other factors predisposing to tension pneumocranium in our patients included: cerebrospinal fluid leaks, postoperative positive-pressure mask ventilation, large pituitary tumors, and intraoperative lumbar drainage catheters. Surgical drainage of the pneumocranium and repair of any coexistent cerebrospinal fluid leak markedly improved neurologic status. Symptomatic pneumocranium occurring early in the postoperative course after transsphenoidal pituitary surgery is rare, but prompt recognition and treatment of this condition can be life-saving.

Safety and efficacy of long-term octreotide therapy of acromegaly: results of a multicenter trial in 103 patients--a clinical research center study.

One hundred and three acromegalic patients from 14 medical centers were enrolled in this study to determine the efficacy and safety of the somatostatin analog, octreotide acetate, during long term treatment. Seventy percent of the patients had undergone previous surgery or radiation treatment. Octreotide was initiated at a dose of 100 micrograms, sc, every 8 h and gradually increased to a maximum of 1500 micrograms daily depending upon the individual patient's clinical and biochemical response [GH and insulin-like growth factor I (IGF-I) reduction]. The mean duration of treatment was 24 months (range, 3-30 months). However, most patients were treated for a mean of 30 months, because this study took place after an initial 6-month study previously reported. Mean serum GH fell from 30.9 micrograms/L (range, 2.7-350) to 5.7 micrograms/L (range, 0.6-59) at the 3 months visit and remained suppressed (P < 0.001). Plasma IGF-I concentrations were also significantly reduced and remained in the normal range for at least half of the treatment visits in 56 of 87 patients (64%) treated for 12-30 months. Patients with higher initial GH concentrations were less likely to normalize IGF-I concentrations during treatment (P < 0.001). There was no evidence of drug tachyphylaxis in those patients who continued taking stable doses of medication. With some exceptions, dose increments above 800 micrograms daily in 31 patients did not provide additional benefit in terms of GH and IGF-I reduction. Headache, excessive perspiration, fatigue, and joint pain were ameliorated in 83-95% of patients. Mean finger circumference was decreased significantly at the 12 month visit (P < 0.05). The most common adverse events reported were diarrhea, abdominal discomfort, loose stools, and nausea; these symptoms usually disappeared within 3 months of treatment. Five patients discontinued octreotide because of adverse events. Of 102 patients with normal baseline ultrasound examinations of the gallbladder, 24 patients (23.5%) developed gallstones (usually during the first year of treatment), and 21 patients developed sludge alone. Gallstone formation was not related to the dose of octreotide. Most patients with cholelithiasis were asymptomatic, and none developed cholecystitis. These observations suggest that octreotide is a valuable long term medical treatment for acromegaly.