Cortisol and adrenocorticotropin response to desmopressin in women with Cushing's disease compared with depressive illness

The pituitary-adrenal responsiveness to desmopressin of women with depressive illness was compared with that of patients with Cushing's disease, who are known to be highly responsive, and to that of normal controls, who are known to be poorly responsive to the peptide. Although 100% of the patients in the group with Cushing's disease met the response criterion with cortisol increases of 632 +/- 80 nmol/L above baseline (mean +/- SE), the prevalence of responders was 36% in the depressive group and 10% in normal controls, with cortisol changes from baseline of 154 +/- 28 and 79 +/- 15 nmol/L, respectively. All response parameters were significantly higher in the patients with Cushing's disease and did not differ between depressive patients and normal controls, who exhibited the same general pattern of cortisol and ACTH responses. It is concluded that the desmopressin test can be used in the differentiation between depression and Cushing's disease, and that the hypothalamic-pituitary-adrenal regulation is distinct in these two conditions.     

11 beta-Hydroxysteroid dehydrogenase activity in Cushing's syndrome: explaining the mineralocorticoid excess state of the ectopic adrenocorticotropin syndrome

A characteristic feature of the ectopic ACTH syndrome is a state of mineralocorticoid excess, although the etiology remains obscure. Some forms of endocrine hypertension, such as licorice ingestion, have been explained by cortisol acting as a mineralocorticoid in the setting of inhibition or deficiency of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). This enzyme is responsible for the conversion of cortisol (F) to hormonally inactive cortisone, and its activity in vivo can be inferred from the ratio of the urinary excretion of tetrahydrocortisol (THF) and its isomer (5 alpha THF) to tetrahydrocortisone. Twenty-two patients with Cushing's syndrome (11 pituitary dependent, 9 ectopic, and 2 adrenal adenomas) and 13 controls were studied. Compared to controls. Cushing's patients had a significant increase (P < 0.001) in the excretion of all principal metabolites of F, secondary to a 5- to 6-fold increase in the cortisol secretion rate [median, 34.0 (range, 13.3-327) mg/day in Cushing's vs. 6.1 (range, 2.5-10.3) mg/day in controls]. The THF plus 5 alpha THF/tetrahydrocortisone ratio was significantly increased in Cushing's syndrome regardless of etiology [mean, 1.81 (range, 1.09-9.99) in Cushing's vs. 0.81 (range, 0.51-1.47) in controls; P < 0.001), indicative of defective 11 beta HSD activity. Furthermore, compared to patients with pituitary-dependent Cushing's, this ratio was significantly higher in patients with the ectopic ACTH syndrome (4.12 vs. 1.49; P < 0.01) and was inversely correlated with serum potassium levels (r = -0.57; P = 0.01; n = 22). One explanation for the mineralocorticoid excess state of the ectopic ACTH syndrome appears to be that cortisol gains inappropriate access to the mineralocorticoid receptor through failure of its normal metabolism by 11 beta HSD. The reason for the defective 11 beta HSD activity is unclear, but it may be secondary to substrate saturation, inhibition by other adrenal steroids, or product inhibition.     

Diagnosis of Cushing's disease in pregnancy

The Cushing syndrome during pregnancy is very infrequent, being even more so that of hypophysary etiology despite corticotropic adenomas being more prevalent in fertile-aged women. Its diagnosis is difficult since it may be confused with the physiologic alterations of the cortisol and the ACTH which occur during pregnancy. The treatment is controversial. In the cases reported to date, pregnancy represented a worsening of the picture. The case of a patient diagnosed with Cushing disease during the first trimester of pregnancy is presented. The hypercorticism improved clinically and biochemically during the pregnancy with no maternofetal complications observed. The disease activity continued following delivery.     

Early diagnosis of bronchial cancer: its usefulness

Incidence of and mortality from bronchial carcinoma are reviewed. The advantages of early recognition of the disease and the favourable role of early recognition as a factor in the therapeutic outcome are stressed. Etiologic factors and diagnostic procedures are summarized. The need for a public education program is emphasized.     

Anal canal cancer diagnosis: usefulness of serum tumor markers

Many paper based chart recorders still suffer from paper uptake systems for the collection of chart record that operate inefficiently or haphazardly. An efficient low cost paper minder using 1.2 mm diameter stainless steel wire for the Siemens-Elema AB Mingograph 7, has been developed. This wire pivots from the end of the chart viewing table and provides an effective force to redirect paper into the standard collecting basket over the entire range of paper speeds.     

An assessment of the clinical usefulness of plasma ribonuclease assays

The usefulness of plasma ribonuclease assays was studied in (i) patients with possible protein deficiency, (ii) patients with myelomatosis, (iii) patients with carcinoma of the breast. In each group, the major factor associated with elevation of plasma ribonuclease was impairment of renal function. The assay was therefore of little value in the assessment of patients with myelomatosis or carcinoma of the breast. However, in the patients with possible protein deficiency and normal renal function, an elevation of plasma ribonuclease is, in general, associated with a decrease in serum albumin, transferrin and cholinesterase. Plasma ribonuclease may therefore be a useful parameter in the assessment of protein nutritional status.     

Overnight urinary 11-hydroxycorticosteroid estimations in diagnosis of Cushing's syndrome

Overnight specimens of urine were collected from control, obese, and hirsute women and from 11 women with Cushing's syndrome. Urinary 11-hydroxycorticosteroid levels in the group with Cushing's syndrome were significantly higher than in the other three groups. This simple test has proved invaluable when screening for Cushing's syndrome in a busy outpatient clinic.     

The usefulness of transesophageal echocardiography in the diagnosis of atypical aortic coarctation

We report the case of a 20-year-old woman with severe hypertension diagnosed two months previously. The symptoms and physical examination suggested the diagnosis of coarctation of the aorta, but a transthoracic echocardiogram and a thoracic CT scan were normal. Nevertheless, a severe stenosis of the thoracoabdominal aorta was demonstrated by transesophageal echocardiography. The usefulness of transesophageal echocardiography for the diagnosis of atypical coarctation of the aorta is discussed.     

The usefulness of clinical pulmonary examination in the diagnosis of bronchial obstruction

In order to evaluate the usefulness of physical examination of the chest in diagnosing bronchial obstruction, 11 doctors recorded their findings in 692 adult chest patients. Spirometry was carried out after the physical examination. Two categories of patients were selected; patients with known or suspected pulmonary disease (n = 209) and patients who had consulted their doctors for other reasons (n = 483). Bronchial obstruction defined as either FEV1 < 70% predicted or FEV1 < 70% of FVC, was found in 74 of the "pulmonary patients" and 55 of the "non-pulmonary" patients. In the group of patients with bronchial obstruction, a pathological or less certain sign of chest disorder was found in 91% of the "pulmonary" patients, and in 42% of the "non-pulmonary" patients (p < 0.000001). Strenuous respiration was registered in 41% of the "pulmonary" patients with bronchial obstruction, whereas sensitivity was only 2% in the other group. Where there were two or more pathological chest findings, the risk of bronchial obstruction occurring was 66% among the "pulmonary" patients, as opposed to 37% in the "non-pulmonary" group. Physical examination of the chest appeared to be very useful in the detection of bronchial obstruction in patients with pulmonary symptoms, but of limited value in screening for bronchial obstruction.     

Visual evoked potential characteristics and early diagnosis of Pelizaeus-Merzbacher disease

OBJECTIVE: Early diagnosis of Pelizaeus-Merzbacher disease; assessment of disease progression. DESIGN: Pediatric neuro-ophthalmology evaluation of visual function with pattern and luminance visual evoked potentials; behavioral state assessment; electrophysiological diagnostic test; baseline estimates at the age of 11 weeks; 1-year follow-up. SETTING: University hospital electrodiagnostic vision research laboratory. PATIENTS: Case study: X-linked Pelizaeus-Merzbacher disease; leukodystrophy; patient tested at the age of 11 weeks and at the age of 58 weeks for follow-up; five age-matched normal controls. INTERVENTIONS: Physical therapy, medication, evaluation. MAIN OUTCOME: Early diagnosis; diagnostic confirmation; objective monitor of disease progression. RESULTS: Abnormal spatial and temporal vision and abnormal visual pathway maturation; visual evoked potentials of proband with Pelizaeus-Merzbacher disease were grossly abnormal, reflecting myelination disorder. CONCLUSIONS: Visual evoked potential pediatric electrodiagnosis yields reliable measures of visual function and visual system maturation in leukodystrophy.     

Validation of an assay to measure adrenocorticotropin in plasma and from chicken leukocytes

A RIA for mammalian adrenocorticotropic hormone (ACTH) was modified and validated to measure chicken ACTH. The assay was capable of detecting an increase in chicken plasma ACTH following treatments known to increase plasma ACTH. Both splenic and peripheral blood leukocytes stimulated with corticotropin-releasing factor (CRF) showed a significant increase in ACTH production compared with unstimulated leukocytes. This finding supports the conclusion that the substance produced by leukocytes previously shown in our laboratory to stimulate adrenal cells to secrete corticosterone is immunoreactive ACTH.     

Simultaneous analysis of hydrocortisone and hydrocortisone phosphate by high-pressure liquid chromatography: reversed-phase, ion-pairing approach

The reversed-phase, ion-pairing approach to high-pressure liquid chromatography was applied to the simultaneous analysis of hydrocortisone and its phosphate ester in laboratory-prepared samples and injectable solutions. Results of this technique were evaluated and compared with results of the official procedure.     

Overnight dexamethasone pre-treatment improves the performance of the lysine-vasopressin test in the diagnosis of Cushing's syndrome

OBJECTIVE: There is no endocrine test which is completely reliable for the confirmation of Cushing's syndrome and in separation of the various aetiologies. We have tested the hypothesis that overnight dexamethasone pre-treatment should result in a better performance of the lysine-vasopressin (LVP) test in the diagnosis of Cushing's syndrome. STUDY DESIGN AND PATIENTS: We studied 61 subjects, including 25 pituitary-dependent and 9 pituitary independent Cushing's (7 adrenal tumour and 2 ectopic ACTH syndromes), 18 euadrenal controls, 4 depressed subjects, and 5 cushingoid patients. The subjects received 1 mg of dexamethasone orally at 2300 h and the following morning they were given 10 IU of lysine-vasopressin im. MEASUREMENTS: Plasma cortisol (RIA) was measured at times -15, 0, 15, 30, 45, 60, 75, 90 and 120 minutes. RESULTS: The dexamethasone-modified LVP (Dx/LVP) test resulted in four patterns of cortisol response. The dexa sensitive pattern (positive suppression and negative response to LVP) was found in euadrenal subjects; the dexa insensitive pattern (negative suppression and positive response to LVP) was seen in Cushing's disease; a non-responsive pattern (negative suppression and negative response to LVP) was observed only in pituitary independent Cushing's; and an indeterminate pattern (positive suppression and positive response to LVP) was equivocal, being observed in 2 control subjects, 1 patient with Cushing's disease and 1 depressed patient. In separating control subjects from Cushing's syndromes the Dx/LVP test had 88.9% sensitivity, 100% specificity and 96.2% diagnostic accuracy; when the test was used to segregate Cushing's disease from control subjects we found 96.0% sensitivity, 100% specificity and 97.7% diagnostic accuracy. The performance variables for the Dx/LVP test in separating pituitary dependent from pituitary independent Cushing's were uniformly 100%. Depressed and cushingoid subjects did not differ from control subjects in their cortisol patterns during the test. Successful removal of the pituitary microadenoma in Cushing's disease was invariably followed by a reversal of the abnormal cortisol pattern (dexa insensitive) during the test to a dexa sensitive pattern indistinguishable from that of control subjects. CONCLUSION: These results confirm our hypothesis and suggest that an improved performance of any corticotroph stimulus (oCRH, LVP, AVP or desmopressin) in the diagnosis of Cushing's syndrome should result from pre-treatment with dexamethasone.     

Glucocorticoid regulation of leptin synthesis and secretion in humans: elevated plasma leptin levels in Cushing's syndrome

Leptin, the obese (ob) gene product, is an adipocyte-derived satiety factor that is involved in the regulation of food ingestion and body weight. To investigate glucocorticoid regulation of leptin synthesis and secretion in humans, we measured plasma leptin levels in patients with Cushing's syndrome with adrenal or pituitary adenoma and in patients with iatrogenic Cushing's syndrome. Plasma leptin levels in patients with Cushing's syndrome were significantly elevated compared to those in nonobese healthy subjects and obese subjects without any metabolic or endocrine diseases at a given percentage of body fat by analysis of covariance. In patients with adrenal or pituitary adenoma, after the tumor resection, plasma leptin levels were reduced, with a concurrent decrease in plasma cortisol levels. With no significant changes in body weight, plasma leptin levels were also elevated significantly in lean healthy volunteers 24 h after the administration of 1 mg dexamethasone. Dexamethasone potently induced ob gene expression and leptin secretion in the organ culture of human adipose tissue. The data demonstrate that glucocorticoids act, at least in part, directly on the adipose tissue and increase leptin synthesis and secretion in humans.     

Resistance to vasopressin action on the kidney in patients with Cushing's disease

OBJECTIVE: To assess the plasma levels and action of arginine vasopressin (AVP) in patients with Cushing's disease. There are many reports that patients with Addison's disease have increased AVP levels associated with hyponatraemia and hypoosmolality, but none on the dynamics of secretion of this neurohormone during osmolality-based stimulation in patients with chronic hypercortisolism. DESIGN AND SUBJECTS: The plasma AVP concentration and the urinary and plasma osmolality after a 7.5-h water deprivation test (WDT) were evaluated in 13 patients with Cushing's disease and 15 normal (control) individuals. In patients with Cushing's disease we also assessed the urinary osmolality in response to 10 micrograms i.v. desmopressin (DDAVP) administered at the end of the WDT. RESULTS: At the end of the WDT, urinary osmolality was significantly lower in patients with Cushing's disease (511.5 +/- 148.5 mOsm/l) than in the normal subjects (981.1 +/- 107.1 mOsm/l, P < 0.001), whereas plasma osmolality did not differ between the two groups. Consequently, the urine/plasma osmolality ratio (Uosm/Posm) was lower in patients with Cushing's disease than in normal individuals (1.8 +/- 0.5 compared with 3.4 +/- 0.4, P < 0.001). The AVP concentration also was greater (7.3 +/- 3.1 pmol/l) in those with Cushing's disease than in the controls (3.9 +/- 2.3 pmol/l, P < 0.005). After administration of DDAVP to the hypercortisolaemic patients, the urinary osmolality attained (718.0 +/- 200.0 mOsm/l) was still lower than that in the normal group at the end of WDT (P < 0.005). CONCLUSIONS: Patients with Cushing's disease presented higher AVP levels and smaller Uosm/Posm ratios than normal subjects. After DDAVP, the patients with Cushing's disease were unable to concentrate the urine adequately. These data suggest that the kidney shows resistance to the action of both endogenous and exogenous AVP in patients with Cushing's disease.     

Antenatal diagnosis of congenital heart disease and Down's syndrome: the potential effect on the practice of paediatric cardiology

OBJECTIVE: To predict the effect of antenatal ultrasound screening for congenital heart disease and maternal serum screening of Down's syndrome on the practice of paediatric cardiology and paediatric cardiac surgery. DESIGN: A retrospective and prospective ascertainment of all congenital heart disease diagnosed in infancy in 1985-1991. SETTING: One English health region. PATIENTS: All congenital heart disease diagnosed in infancy by echocardiography, cardiac catheterisation, surgery, or necropsy was classified as "complex", "significant", or "minor" and as "detectable" or "not detectable" on a routine antenatal ultrasound scan. RESULTS: 1347 infants had congenital heart disease which was "complex" in 13%, "significant" in 55%, and "minor" in 32%. 15% of cases were "detectable" on routine antenatal ultrasound. Assuming 20% detection and termination of 67% of affected pregnancies, liveborn congenital heart disease would be reduced by 2%, infant mortality from congenital heart disease by 5%, and paediatric cardiac surgical activity by 3%. Maternal screening for Down's syndrome, assuming 75% uptake, 60% detection, and termination of all affected pregnancies, would reduce liveborn cases of Down's syndrome by 45%, liveborn cases of congenital heart disease by 3.5%, and cardiac surgery by 2.6%. CONCLUSIONS: Screening for congenital heart disease using the four chamber view in routine obstetric examinations and maternal serum screening for Down's syndrome is likely to have only a small effect on the requirements for paediatric cardiology services and paediatric cardiac surgery.     

The usefulness of determining des-gamma-carboxy prothrombin by sensitive enzyme immunoassay in the early diagnosis of patients with hepatocellular carcinoma

BACKGROUND: Measurements of serum concentrations of des-gamma-carboxy prothrombin (DCP) are widely used for diagnosing hepatocellular carcinoma (HCC). However, the DCP is not always sensitive enough to detect small HCCs. In the current study, the authors investigated the usefulness of DCP in the early diagnosis of HCC, using a more sensitive enzyme immunoassay than is conventionally employed. METHODS: The authors examined 148 serum samples with DCP concentrations from a conventional assay of less than 100 mAU (arbitrary unit)/mL from 91 patients with HCC and 57 with cirrhosis. DCP concentrations were determined by a more sensitive enzyme immunoassay (ED-036 kit, Eisai Laboratory, Tokyo, Japan) with a minimal detection level of 10 mAU/mL. Ninety-one HCC patients had 43 solitary small HCCs (with a greatest dimension of less than 2 cm). Of these 43 HCCs, 12 were well differentiated. RESULTS: The mean serum concentration of DCP in HCC (48.3 +/- 24.3, mean +/- standard deviation [SD]) was higher than in cirrhosis (20.3 +/- 10.3); this difference was statistically significant. When the tentative cutoff level of 40 mAU/mL (almost corresponding to the mean value + 2SD in patients with cirrhosis) was used as the level of discriminating HCC from cirrhosis, 62% of patients (56 of 91) with HCC had DCP values above this level (sensitivity). However, only three patients with cirrhosis had higher DCP levels. Thus, the specificity of this test was 95% (54 of 57 patients). The total accuracy was 74% (56 + 54/91 + 57). Twenty-three of 43 solitary small HCCs (53%) had DCP values above the cutoff level. Furthermore, 7 of 12 (58%) small, well-differentiated HCCs less than 2 cm in greatest dimension had higher DCP values. CONCLUSIONS: The results of this study indicate that DCP determination by sensitive enzyme immunoassay is useful in the early diagnosis of HCC because a high specificity is maintained.