The Natural History of Salt-Wasting Disorders of Adrenal and Renal Origin*

Abstract

Twenty one patients with selective aldosterone deficiency due to type 2 corticosterone methyl-oxidase defect [hypoaldosteronism (HA)] and 7 with pseudohypoaldosteronism (PHA) were studied longitudinally for up to 18 yr. All individuals had spontaneous and progressive normalization of sodium and fluid balance with age. The severity of the clinical manifestations varied from acute salt-wasting crisis in infancy and unexplained short stature in childhood to an asymptomatic state in adults detectable only by biochemical studies. Infants with HA had extremely elevated plasma renin activity (PRA; 70–650 ng angiotensin I/ml: h), which gradually decreased with age, and PRA was normal in adults. Cortisol followed a similar pattern, but marked elevations of plasma deoxycorticosterone (DOC; 28-553 ng/dl) and 18-hydroxycorticosterone (18-OHB; 650-6500 ng/dl) relative to aldosterone (3–29 ng/dl) persisted throughout life in all untreated patients. The plasma 18-OHB/aldosterone ratio, normally 6.2 ± 3.5 (SD), ranged between 160–760. In contrast, patients with PHA had PRA (70–685 ng angiotensin 1/ml · h), DOC (56–1201 ng/dl), 18-OHB (650–6800 ng/dl), and aldosterone (150–2000 ng/dl) levels which all remained very elevated, but had normal 18-OHB/aldosterone ratios (6.9 ± 5.1). Comparative studies in 14 untreated patients with llβ-hydroxylase deficiency, who had moderate to severe manifestations of mineralocorticoid excess, revealed DOC levels (38–1384 ng/dl) that were remarkably similar to those of patients with HA and PHA. PRA, DOC, and 18-OHB correlated significantly with each other during all variations in sodium balance (P < 0.001). Sodium repletion partially suppressed these parameters in both disorders, but complete normalization was achieved only in HA when a mineralocorticoid was given. Although the degree of DOC and 18-OHB suppression was similar in all age groups, the changes in PRA were more marked in children than in adults since these were directly proportional to the initial elevations of PRA. Although angiotensin II and potassium increased plasma DOC and 18-OHB, dexamethasone failed to suppress them, indicating that these steroids originated predominantly from the zona glomerulosa. The spontaneous normalization of sodium balance is not due to quantitative differences in hormone secretion with age since the basic steroid abnormalities remain unchanged from infancy to adulthood. Although aldosterone requirements normally decrease throughput life as renal transport mechanisms become more effective, the major compensatory mechanism operative in patients with PHA and HA is progressive improvement in renal tubular responsiveness to mineralocorticoids. On the other hand, in HA, infantile salt-wasting unresponsive to endogenous mineralocorticoids may also be attributed to the effect of a natriuretic factor, whose exact nature remains to be determined.