Disorders of mineralocorticoid synthesis

Abnormalities of mineralocorticoid synthesis and/or metabolism profoundly affect the regulation of electrolyte and water balance and of blood pressure. Characteristic changes in extracellular potassium, sodium and hydrogen ion concentrations are usually diagnostic. Serious deficiency may be acquired, for example in Addison's disease, or inherited. In most of the inherited syndromes, the precise molecular changes in specific steroidogenic enzymes have been identified. Mineralocorticoid excess may be caused by aldosterone or 11-deoxycorticosterone by inadequate conversion of cortisol to cortisone by 11beta-hydroxysteroid dehydrogenase type 2 in target tissues (see Chapter 4), by glucocorticoid receptor deficiency or by constitutive activation of renal sodium channels. Changes in electrolyte balance and renin as well as the abnormal pattern of corticosteroid metabolism are usually diagnostic. Where these abnormalities are inherited (e.g. 11beta- or l7alpha-hydroxylase deficiencies, glucocorticoid remediable hyperaldosteronism (GRA), receptor defects, Liddle's syndrome), the molecular basis is again usually known and, in some cases, may provide the simplest diagnostic tests. Primary aldosteronism, although readily identifiable, presents problems of differential diagnosis, important because optimal treatment is different for each variant. Moreover, the mechanisms by which the variants develop are poorly understood. Finally, a significant proportion of patients with essential hypertension show characteristics of mild mineralocorticoid excess, for example low renin levels. Is this relevant to pathophysiology and, if so, is the effect induced via classic mechanisms of action or through newly discovered direct actions on the brain, heart and blood vessels? These questions are the subject of current research.