Intestinal Perforation in ACTH-Dependent Cushing's Syndrome.

Previous studies have linked systemic glucocorticoid use with intestinal perforation. However, the association between intestinal perforation and endogenous hypercortisolism has not been well described, with only 14 previously published case reports. In this study, we investigated if intestinal perforation occurred more frequently in patients with ectopic ACTH syndrome and in those with a greater than 10-fold elevation of 24-hour urinary free cortisol level. Of 110 patients with ACTH-dependent Cushing's syndrome followed in two clinics in Canada, six cases with intestinal perforation were identified over 15 years. Age of patients ranged from 52 to 72, five females and one male, four with Cushing's disease and two with ectopic ACTH production, one from a pancreatic neuroendocrine tumor and one from medullary carcinoma of the thyroid. Five had diverticular perforation and one had intestinal perforation from a stercoral ulcer. All cases had their lower intestinal perforation when the cortisol production was high, and one patient had diverticular perforation 15 months prior to the diagnosis of Cushing's disease. As in previously reported cases, most had hypokalemia and abdominal pain with minimal or no peritoneal symptoms and this occurred during the active phase of Cushing's syndrome. Whereas all previously reported cases occurred in patients with 24-hour urinary free cortisol levels greater than 10-fold the upper limit of normal when measured and 11 of 14 patients had ectopic ACTH production, only one of our patients had this degree of hypercortisolism and four of our six patients had Cushing's disease. Similar to exogenous steroid use, patients with endogenous hypercortisolism also have a higher risk of intestinal, in particular diverticular, perforation and should be monitored closely for its occurrence with a low threshold for investigation and surgical intervention. Elective colonoscopy probably should be deferred until Cushing's syndrome is under control.

Ectopic ACTH syndrome complicated by multiple opportunistic infections treated with percutaneous ablation of the adrenal glands.

Ectopic adrenocorticotropic hormone (ACTH)-related Cushing's syndrome can lead to multiple complications including severe immunosuppression. If the ACTH-secreting tumour cannot be found, definitive treatment is surgical adrenalectomy, typically followed by glucocorticoid replacement. Here, we present a case of fulminant respiratory failure secondary to coinfection with Pneumocystis jirovecii and cytomegalovirus in a patient with ectopic ACTH-dependent Cushing's syndrome with occult primary. Due to significant deconditioning, she was unable to undergo definitive adrenalectomy and instead underwent percutaneous microwave ablation of the adrenal glands.

Effect of hypercortisolism and ACTH on the metabolism of cortisol.

The effects of hypercortisolemia and ACTH on the metabolism of cortisol in congenital adrenal hyperplasia, Cushing's syndrome, and exogenous ACTH and cortisol administration were investigated by analysis of the respective urinary tetrahydro-metabolites of cortisol (THF and aTHF) and cortisone (THE) by capillary gas chromatography. The results for the patients with congenital adrenal hyperplasia establish that ACTH hypersecretion in the absence of an associated marked elevation of plasma cortisol does not cause inhibition of the 11beta-OHSD enzyme. In contrast elevated plasma cortisol levels (adrenal adenoma or intravenous cortisol administration) in the presence of suppressed ACTH secretion leads to significant inhibition of the peripheral conversion of cortisol to cortisone. The latter results are equivalent to the mode of cortisol metabolism noted during clinical states of ACTH hypersecretion and hypercortisolemia (Cushing's disease, ectopic ACTH syndrome and ACTH administration). The overall findings provide convincing evidence that ACTH hypersecretion is not associated with specific in vivo inhibition of 11beta-OHSD enzyme activity.

A very high dose dexamethasone suppression test for differential diagnosis of Cushing's syndrome.

OBJECTIVE: The high-dose dexamethasone (dex) suppression test of cortisol secretion (8 x 2 mg dex over two days or 8 mg overnight) is a mainstay in the differential diagnosis of Cushing's syndrome (CS). In some patients with pituitary Cushing's disease (CD), however, plasma cortisol is not suppressed to < 50% of control by 8 mg of dex. We therefore hypothesized that a higher dose of dex might produce more effective suppression of cortisol secretion in CD. DESIGN AND SUBJECTS: We routinely tested the diagnostic efficacy of a very high dose of dex (32 mg, i.e. 4 x 8 mg in 24 hours) in comparison with the 8 mg overnight dex test in a population of patients with CD, in which an unusually high percentage was refractory to 8 mg dex. End points were the suppression of plasma cortisol, plasma ACTH and urinary free cortisol (UFC) to < 50% of control. Corticotrophin releasing hormone (human CRH) tests were also performed. RESULTS: Eleven out of 26 (11/26) patients with CD (42%), among them six with pituitary macro-adenomas, failed to show suppression of plasma cortisol after 8 mg dex. Five out of 19 patients (26%) with CD failed to suppress after 32 mg dex. Only 3/19 (16%) failed to suppress UFC after 32 mg dex. In nonpituitary CS (n = 11), only one patient with macro-nodular adrenal hyperplasia showed significant suppression of plasma cortisol, but not UFC, after 32 mg dex. ACTH suppression after 8 or 32 mg dex was often less pronounced than that of cortisol and was of no diagnostic value. Cortisol stimulation by > or = 23% after hCRH injection differentiated 100% of patients with CD from other forms of CS. CONCLUSION: In this series, the hCRH test was the most reliable test for the differential diagnosis of Cushing's syndrome. The 32 mg dexamethasone test with measurement of urinary free cortisol was clearly superior to the 8 mg test and to other aspects of the very high dose dexamethasone test. It can be recommended for 'non-suppressible' patients with ACTH-dependent Cushing's syndrome and can be performed on outpatients.

Urinary free cortisol and cortisone determined by high performance liquid chromatography in the diagnosis of Cushing's syndrome.

To determine the efficacy of cortisol and its metabolite, cortisone, measured simultaneously by high performance liquid chromatography (HPLC) in the diagnosis of Cushing's syndrome, we retrospectively reviewed the histories of 29 surgically proven Cushing's syndrome patients (20 Cushing's disease, 5 ectopic ACTH syndrome, and 4 adrenal Cushing's syndrome) and 6 patients with exogenous Cushing's syndrome. These 35 patients had urinary free cortisol determined by both HPLC and competitive binding methods. The efficacy of the HPLC assay using cortisol alone was equivalent to that of the competitive binding assay; 22 of 29 (76%) patients had increased cortisol. Cortisone also aided in the diagnosis; 25 of 29 (86%) had increased cortisone. Twenty-seven of the 29 (93%) patients had either both cortisone and cortisol (n = 19) or at least 1 of the 2 (n = 8) increased. All 6 patients with exogenous Cushing's syndrome had suppressed urinary free cortisol, cortisone, and the presence of prednisone and prednisolone. In the competitive binding assay, all exogenous Cushing's patients had falsely increased cortisol results. In conclusion, urinary free cortisol plus cortisone determined simultaneously by HPLC added a new dimension to the diagnosis of Cushing's syndrome. It should be considered when exogenous Cushing's syndrome is suspected or when only one urinary cortisol test is allowed to be ordered.

Ouabainlike compound in hypertension associated with ectopic corticotropin syndrome.

Molecular mechanisms related to sodium retention have been implicated in the pathogenesis of hypertension. It is unclear how sodium retention leads to a rise in blood pressure, but ouabainlike compound may act as a final common pathway in sodium-induced hypertension. In ectopic corticotropin syndrome, hypertension has been attributed to cortisol inactivation overload, giving rise to mineralocorticoid-type hypertension. We sequentially measured plasma and urinary levels of ouabainlike compound over 2 months to evaluate its role in the hypertensive mechanisms in a 64-year-old man with this syndrome caused by lung cancer. His data included hypokalemia and increased cortisol concentrations, corticotropin levels, and urinary 17-hydroxycorticosteroid excretion. Plasma renin activity was suppressed. Plasma and urinary levels of ouabainlike compound were markedly increased concomitantly with high blood pressure. The maximum plasma level was 40-fold the normal range of the subject. After chemotherapy, ouabainlike compound levels gradually decreased in parallel with the decline in blood pressure and rise in potassium concentration. A correlation was observed between plasma and urinary levels of ouabainlike compound (P < .05). Plasma and urinary levels of ouabainlike compound correlated with systolic (P < .01) and diastolic (P < .05) pressures, respectively. The peak of ouabainlike compound in plasma and urine coincided with that of authentic ouabain on high-performance liquid chromatography. Ouabainlike compound derived from urine inhibited [3H]ouabain binding to human erythrocytes. These findings suggest that ouabainlike compound with biological activity could partly account for hypertension in ectopic corticotropin syndrome.

Successful treatment of ectopic Cushing's syndrome with the long-acting somatostatin analog octreotide.

We report on the efficacy of the long-acting somatostatin analog octreotide in a 43-yr old woman with ectopic ACTH syndrome. Plasma cortisol, ACTH, beta-endorphin (beta-END) and urinary free cortisol (UFC) were elevated (range 743-920 nmol/l, 29.2-49.7 pmol/l, 71.0-84.1 pmol/l, 2117-3119 nmol/day respectively). Ovine CRH (oCRH) and high dose dexamethasone did not affect cortisol and ACTH levels, while UFC significantly decreased after dexamethasone. Initially radiological investigation failed to localize the ACTH secreting tumor. Ketoconazole was not tolerated. Plasma cortisol significantly decreased both after single (100 micrograms sc) (baseline 531 nmol/l, nadir 218 nmol/l) and 3-day octreotide administration (from 810 to 448 nmol/l); plasma ACTH decreased slightly (from 30.4 to 21.3 pmol/l and from 32.4 to 22.5 pmol/l respectively); UFC decreased from 2616 to 711 nmol/day after the 3-day test. Long-term octreotide treatment (100 micrograms/8h per 54 weeks) led to clinical and biochemical improvement and recurrence followed drug withdrawal; no side effects were observed. Six months after octreotide administration a 2 cm lung mass was detected with CT and MR. Surgery was performed and a bronchial carcinoid was removed. Immunoreactive ACTH in the tumor has been demonstrated by histochemistry. Postoperatively a lasting remission of Cushing's syndrome was observed without further therapy.

Ectopic ACTH syndrome due to Grawitz tumor.

An extremely unusual case of adrenocorticotropin (ACTH)-producing Grawitz tumor is reported in a 56-year-old female. The clinical feature of the patient was compatible with Cushing's syndrome. The plasma levels of ACTH and cortisol were markedly elevated. At autopsy, a left renal tumor was demonstrated and its histopathological diagnosis was renal cell carcinoma (Grawitz tumor). The adrenal gland was bilaterally enlarged with diffuse hyperplasia of the fasciculate zone. The adenohypophyseal cells were atrophic and showed Crooke's degeneration. The tumor contained extremely high levels of ACTH, beta-lipotropin and beta-endorphin. The presence of large molecular weight forms of ACTH has also been demonstrated by a Sephadex G-50 gel filtration of the tumor extract. We authors believe that this is the first documented case of ACTH-producing Grawitz tumor in the literature.

Urinary excretion rates of 15 free steroids: potential utility in differential diagnosis of Cushing's syndrome.

To evaluate their potential usefulness in the differential diagnosis of Cushing's syndrome, we estimated the urinary excretion rates of the following non-metabolized, unbound steroid hormones: pregnenolone, progesterone, 17-OH-pregnenolone, 17-OH-progesterone, dehydroepiandrosterone (DHEA), androstenedione, testosterone, dihydrotestosterone, 11-deoxycorticosterone, 11-deoxycortisol, corticosterone, cortisol, 18-OH-11-deoxycorticosterone, 18-OH-corticosterone, and aldosterone. These were measured in normal subjects and in patients with Cushing's disease, adrenal adenoma, or ectopic corticotropin syndrome. We used "high-performance" liquid chromatography and subsequent radioimmunoassay. Our results indicate that simultaneous estimation of urinary free cortisol and DHEA may be useful in differential diagnosis of hypercorticoid states due to adrenal adenoma and Cushing's disease.

Urinary molecular forms of human N-terminal of proopiomelanocortin: possible deglycosylation and degradation by the kidney.

The NH2-terminal fragment (hNT) of proopiomelanocortin is found predominantly as one molecular form of apparent mol wt of 12K in the circulation. Since the kidney may play an important role in the elimination and degradation of proopiomelanocortin-related peptides, we analyzed the urinary forms of immunoreactive hNT (IR-hNT) by molecular sieving and carbohydrate affinity (Concanavalin A-agarose) chromatography. RIA specific for the amino terminal portion and for the gamma 3-MSH (carboxy-terminal portion of hNT) were used in these studies. Molecular sieve chromatography revealed several forms of IR-hNT in the urine from normal subjects, patients with Nelson's syndrome, and patients with ectopic ACTH-secreting tumors. A considerable decrease in IR-hNT and IR-gamma 3-MSH was found in the urine of a patient with ACTH deficiency and normal subjects during glucocorticoid suppression. In urine from normal subjects and a patient with lung cancer not causing Cushing's syndrome, the majority of amino-terminal IR-hNT (66-83%) had apparent mol wts of 3-4K, 6-7K, and 8-10K, and did not cross-react with the gamma 3-MSH antiserum. Ten to nineteen percent of the total IR-hNT was eluted in the position of authentic hNT and reacted with the gamma 3-MSH RIA. In patients with Nelson's syndrome and those with ectopic ACTH syndrome, almost no intact hNT (less than 7% of the total) was present in urine; most of the IR-hNT appeared in the elution volumes with an apparent mol wt of 8-10K. In addition, smaller forms (6-7K and 3-4K) of hNT were also detected in the urine of these patients. The major form of urinary IR-gamma 3-MSH exhibited an apparent mol wt of 7-8K and did not correspond to any of the peaks of IR-hNT. Carbohydrate affinity chromatography (Concanavalin A-agarose) of smaller forms of IR-hNT revealed weak affinity to the lectin, which suggests loss of the carbohydrate moiety during renal excretion. We conclude that hNT in urine is present in extensively cleaved forms and that deglycosylation may be an important step in hNT degradation. These results support a role for the kidney in the catabolism of hNT.

Small cell lung carcinoma with ectopic adrenocorticotropic hormone and antidiuretic hormone syndromes: a case report.

This report describes a 63-yr-old man with lung cancer accompanying hypertension, hyperpigmentation, muscle weakness, psychosis, hypokalemia, hyperglycemia, hyponatremia, massive natriuresis and lower serum osmolality than urine osmolality. Elevated levels of plasma and urine corticosteroids and of plasma immunoreactive adrenocorticotropic hormone (ACTH) were not altered by the administration of large amounts of dexamethasone. Elevated plasma antidiuretic hormone (ADH) values were also demonstrated. Postmortem examinations revealed small cell lung carcinoma with extensive metastasis, bilateral adrenocortical hyperplasia and Crooke's degeneration of the pituitary gland. Immunoradiological and immunohistochemical studies demonstrated the presence of immunoreactive ACTH, ADH and gastrin-releasing peptide in the tumor tissue. Beta-melanocyte-stimulating hormone, calcitonin and carcinoembryonic antigen were also detected by one of the methods. Hence, this is a rare case of lung cancer with multiple hormone production and clinical and laboratory evidence of both the ectopic ACTH and ADH syndromes.