title: Association of hypertension and hypokalemia with Cushing's syndrome caused by ectopic ACTH secretion: a series of 58 cases.
abstract: Cushing's syndrome is associated with hypertension in approximately 80% of cases. Hypertension contributes to the marked increased mortality risk of past or current Cushing's syndrome, largely because of increased cardiovascular risk. Observation of the pathophysiological effect of chronically elevated ACTH and cortisol values in patients with ectopic ACTH secretion complements the available data from acute studies of the effects of ACTH and glucocorticoid infusions in normal volunteers. In a retrospective case review, we identified 58 patients with Cushing's syndrome caused by ectopic ACTH secretion, who were treated at the National Institutes of Health between 1983-1997. The diagnosis of an ectopic ACTH cause was confirmed by inferior petrosal sinus sampling and/or pathologic examination of tumor. The commonest causes were bronchial carcinoid (40%) and thymic carcinoid (10%), but 18 of 58 (31%) patients had an unknown source of ectopic ACTH. Hypertension (systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg in adults) was noted in 45 of 58 (78%) ectopic Cushing's patients, a prevalence similar to that noted in other endogenous Cushing's syndrome etiologies. Hypertension was severe, deemed to require 3 or more drugs by the treating physicians, in 26 of 58 (45%) patients. Hypokalemia was much more prevalent than in patients with other causes of Cushing's syndrome, affecting 33 of 58 (57%) patients. The range of plasma ACTH (17-1557 pg/mL, normal <60) and 24-hour urine cortisol (UC) excretion (192-1600 mcg/24 hr, normal <90) allowed analysis of the influence of these hormones on blood pressure and plasma potassium. There was a significant relationship between 24-hour UC excretion and the presence of hypokalemia (P = 0.003). Eight of nine patients with a UC >6000 mcg/24 hr had hypokalemia. There was no relation between ACTH level and hypokalemia. In addition, we did not find blood pressure severity to be related to UC excretion or ACTH levels. Urine and plasma cortisol and cortisol metabolite measurements suggest that cortisol may act as a mineralocorticoid when in excess, perhaps by saturating the 11beta-hydroxysteroid-dehydrogenase (11beta-HSD2 enzyme) that inactivates cortisol at the renal tubule. The current data suggest that high cortisol levels may be the principal cause of hypokalemic alkalosis in Cushing's syndrome, rather than inhibition of the 11betaHSD2 enzyme by ACTH or the effects of adrenal steroid biosynthetic intermediaries with mineralococorticoid activity.
authors.affiliation: University of Queensland, Department of Medicine, Greenslopes Hospital, Newdegate Street, Brisbane, Queensland 4120, Australia. dtorpy@mailbox.uq.edu.au
authors.forename: David J
authors.initials: DJ
authors.lastname: Torpy
authors.forename: Nancy
authors.initials: N
authors.lastname: Mullen
authors.forename: Ioannis
authors.initials: I
authors.lastname: Ilias
authors.forename: Lynnette K
authors.initials: LK
authors.lastname: Nieman
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D003480:Cushing Syndrome / Q000150:complications* / Q000175:diagnosis / Q000503:physiopathology*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000652:urine; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D006973:Hypertension / Q000209:etiology*; D007008:Hypokalemia / Q000209:etiology*; D008297:Male; D012189:Retrospective Studies
chemical_list: D000324:Adrenocorticotropic Hormone; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human; D006854:Hydrocortisone