Association of Hypertension and Hypokalemia with Cushing's Syndrome Caused by Ectopic ACTH Secretion

Although Cushing's disease is a well documented clinical entity, there is no epidemiological information about it. The present study tries to obtain this information. Forty-nine patients affected by Cushing's disease living in Vizcaya (Spain) between 1975 and 1992 were considered for an epidemiological study. The prevalence of known cases at the end of 1992 was 39.1 per million inhabitants. The average incidence of newly diagnosed cases was 2.4 cases per million people per year. Cushing's disease was more frequent in women (n = 46) than in men (n = 3), with a ratio of 15:1. Diabetes mellitus and hypertension were observed in 38.7 and 55.1% of patients, respectively. Remission of Cushing's disease was achieved in 36 out of 41 patients (87.5%). In general, the mortality was higher than that expected for the control population (standardized mortality ratio, SMR 3.8, 95% confidence interval, CI 2.5-17.9, P < 0.03). Concerning the cause of death, the SMR of vascular disease was 5 (95% CI 3.4-48.6, P < 0.05). Higher age, persistence of hypertension and abnormalities of glucose metabolism after treatment, were independent predictors of mortality (multivariate analyses, P < 0.01). Prevalence of Cushing's disease was 39.1 cases/million inhabitants and average incidence was 2.4 cases/million per year. Mortality was elevated, due to vascular disease, associated with higher age, persistence of hypertension and impaired glucose metabolism.

Vascular endothelial cells contain a constitutive nitric oxide (NO) synthase that is Ca2(+)-dependent. In addition, we have found that these cells express, after activation with interferon-gamma and lipopolysaccharide, an inducible Ca2(+)-independent NO synthase that is distinct from the constitutive enzyme. The generation of NO by this enzyme was detectable after a lag period of 2 hr, reached a maximum between 6 and 12 hr, and was maintained for the duration of the experiment (48 hr). The expression of the inducible NO synthase was inhibited by the protein synthesis inhibitor cycloheximide, a compound that had no direct effect on the activity of either of the two enzymes. Furthermore, hydrocortisone and dexamethasone, but not progesterone, inhibited the expression of the inducible enzyme, without directly affecting the activity of either enzyme, without directly affecting the activity of either enzyme. The effect of these steroids was inhibited in a concentration-dependent manner by cortexolone, a partial agonist of glucocorticoid receptors. Thus, the inhibition of the induction of an NO synthase by glucocorticoids is a receptor-mediated event involving the inhibition of the synthesis of mRNA for de novo synthesis of this enzyme. The induction of this NO synthase may contribute to the pathophysiology of immunologically based conditions. Furthermore, the inhibition of this induction by anti-inflammatory steroids may explain some of the therapeutic and adverse effects of these compounds.

The first adult case of 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) deficiency is described. The impaired conversion of cortisol to cortisone (indicated by urinary cortisol and cortisone metabolites and failure to metabolize 11 alpha-[3H]cortisol to [3H]H2O), was associated with hypertension, hypokalemia, and suppression of the renin-angiotensin-aldosterone system. When established on a fixed Na+/K+ intake, dexamethasone, given orally, produced a natriuresis and potassium retention. Plasma renin activity became detectable. When hydrocortisone (10 mg daily s.c. for 4 d) was added, there was marked Na+ retention, a kaliuresis (urinary Na+/K+ falling from 1.2 to 0.15), with suppression of plasma renin activity and an increase in blood pressure. These changes were also seen with the subject on no treatment. Conversion of cortisone to cortisol was not affected. These results suggest that cortisol acts as a potent mineralocorticoid in 11 beta-OHSD deficiency. The major site for the oxidation of cortisol to cortisone is the kidney. In this patient congenital deficiency of 11 beta-OHSD results in high intrarenal cortisol levels which then act on renal type I mineralocorticoid receptors. This condition can be treated with dexamethasone, which suppresses cortisol secretion and binds to the type II glucocorticoid receptor. We suggest that 11 beta-OHSD exerts a critical paracrine role in determining the specificity of the type I receptor. In the normal state cortisol is converted by 11 beta-OHSD to cortisone which thus allows aldosterone to bind preferentially to the type I receptors in the kidney and gut. In this patient deficiency of 11 beta-OHSD results in high intrarenal cortisol concentrations that then bind to the type I receptor.