Primary aldosteronism: learning from the study of familial varieties.
Primary aldosteronism (PAL) has been traditionally regarded as a rare cause of hypertension and not worth looking for in the absence of hypokalemia. However, the availability of the aldosterone/renin ratio as a screening test and its application to a wider population of hypertensives has resulted in a marked increase in detection rate, suggesting that PAL is common, with most patients being normokalemic. The spectrum of PAL has been expanded further by the study of familial varieties, in which family screening efforts have permitted the recognition of earlier, sometimes even pre-clinical, stages of disease. Familial hyperaldosteronism type I(FH-I) In FH-I, inheritance of a 'hybrid' 11beta-hydroxylase/aldosterone synthase gene causes adrenocorticotrophic hormone (ACTH)-regulated aldosterone and 'hybrid steroid' (18hydroxy-cortisol and 18-oxo-cortisol) overproduction. Genetic testing, by Southern blot or polymerase chain reaction-based techniques, has greatly facilitated detection, being more convenient and more reliable than dexamethasone suppression testing, and has led to a fuller appreciation of the marked phenotypic variability in this disorder. The demonstration of excessive, abnormally regulated aldosterone production in normotensive subjects with FH-I suggests that absence of hypertension in such individuals cannot merely be attributed to lack of expression of the hybrid gene. Determinants of hypertension severity may include patient gender, gender of affected parent, degree of hybrid gene expression, and interactions with other genetic and environmental factors. Detailed biochemical studies, including analyses of aldosterone/PRA/cortisol 'day-curve' levels, have led to a fuller understanding of aldosterone regulation both before and in response to glucocorticoid treatment in this condition, and prompted a re-examination of current approaches to treatment Unless ACTH is completely suppressed by glucocorticoid treatment, the hybrid gene dominates over the wild-type aldosterone synthase genes in terms of aldosterone production, both in untreated and treated FH-I. This may in part be due to an abnormality affecting the functional expression of the 'wild-type' genes. Demonstration of persisting hybrid gene expression in patients rendered normotensive by very low doses of glucocorticoids suggests that currently recommended doses, aimed at normalizing aldosterone regulation (rather than blood pressure), may be too high, and may therefore place patients at unnecessary risk of developing Cushingoid side effects. Familial hyperaldosteronism type II (FH-II) Like FH-I, FH-II is associated with hyperaldosteronism and probable autosomal dominant inheritance. Unlike FH-I, hyperaldosteronism in FH-II is not dexamethasone suppressible, and is not associated with the hybrid gene mutation. Detection of adrenal mass lesions, which are frequently (17 of 57 patients in the Greenslopes Hospital series) responsible for PAL in FH-II, does not help to differentiate FH-II from FH-I, since mass lesions may also be common in that condition (detected in seven of 21 patients). Biochemically and morphologically, FH-II is indistinguishable from apparently non-familial PAL, and demonstrates similar variability even among individuals of the same family. In one informative family available for linkage analysis, FH-II does not segregate with either the AT1 gene or the CYP11B2 gene, or any other genetic defect in the chromosome 8q21-8qtel region. A genome-wide search is in progress. As has already occurred in FH-I, the elucidation of underlying genetic mutations in FH-II is likely to facilitate early detection, thereby helping to broaden its spectrum and to permit close follow-up and appropriately timed institution of specific therapy, and wider detection among patients with hypertension of potentially curable or specifically treatable forms.
Stowasser
M
M
University Department of Medicine, Greenslopes Hospital, Brisbane, Australia. m.stowasser@mailbox.uq.edu.au
Gordon
R D
RD
D005192:Family Health; D006801:Humans; D006929:Hyperaldosteronism / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D006973:Hypertension / Q000209:etiology*