Juvenile Hypertension, the Role of Genetically Altered Steroid Metabolism

Abstract

The importance of hypertension in the pediatric population is not as well appreciated as in adults. This might be related in part to the lower prevalence of high blood pressure in this age group. As with height and weight, blood pressure increases with age during childhood. The underlying causes of significant hypertension in children differ considerably from those in adults: while the prevalence of hypertension in pediatrics is lower than in adults, clinically identifiable causes of hypertension are common. Abnormalities in steroid biosynthesis have been known for years to cause hypertension in some cases of congenital adrenal hyperplasia. In these patients, hypertension usually accompanies a characteristic phenotype with abnormal sexual differentiation. Recently, the molecular basis of four forms of severe hypertension transmitted on an autosomal basis has been elucidated: (a) the glucocorticoid-remediable aldosteronism (GRA), (b) the syndrome of apparent mineralocorticoid excess (AME), (c) activating mutation of the mineralocorticoid receptor and (d) Liddle’s syndrome. All these conditions are characterized primarily by low or low-normal plasma renin, normal or low serum potassium and salt-sensitive hypertension, indicating an increased mineralocorticoid effect. These forms of juvenile hypertension are a consequence of abnormal biosynthesis, metabolism or action of steroid hormones: (a) GRA is due to expression of a chimeric gene produced by fusion of 11β-hydroxylase aldosterone-synthase genes. Expression of the chimeric enzyme occurs in the zona fasciculata of the adrenal cortex under the control of ACTH and can be suppressed by administration of glucocorticoids. (b) AME is caused by mutations of the 11β-hydroxysteroid dehydrogenase type 2 enzyme, an enzyme that metabolizes cortisol into its receptor inactive keto-form cortisone, thus protecting the mineralocorticoid receptor (MR) from occupation by glucocorticoids. (c) The activating mutation of the MR results in constitutive MR activity and alters receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups becoming potent agonists. (d) Liddle’s syndrome is due to mutations in the β or γ chain of the epithelial sodium channel in distal renal tubule cells. The hyperactivity of this channel caused by the mutations results in increased sodium reabsorption. With the advent of molecular biology in clinical practice it has become evident that some genetic defect may present with a more discrete phenotype, with only moderate hypertension with or without hypokalemia as presenting feature. Considering that hypertension in children and adolescents is often ‘nonessential’, a search for disorders should be integral part of the diagnostic work-up in young patients with hypertension.

Pediatric renal allograft transplantation does not normalize the increased cortisol/cortisone ratios of chronic renal failure

“…Therefore, we postulate that 11b-HSD2 cannot be restored to normal values by renal transplantation. The reduced activity of 11b-HSD2 leads to an increase in various metabolites inducing salt retention and leading to arterial hypertension (3,5,6,9,10,13,29,31,32). A very strict and aggressive antihypertensive drug therapy is necessary to avoid secondary complications of long-lasting arterial hypertension (12, 21, 33 -35).…”

“…The isoenzyme 11b-HSD type 1 catalyzes the reverse action from E to F in adipose tissue, human lung and liver (4,7). 11b-HSD2 dysregulation is involved in arterial hypertension in acquired disorders such as hypercortisolism and primary arterial hypertension (8,9). Absolute 11b-HSD2 deficiency is the cause of apparent mineralocorticoid excess (AME), a rare autosomal recessive defect due to a mutation in 11b-HSD2 (10,11).…”

Dietary salt modulates the adrenocortical expression of p450 11beta‐hydroxylase in mice

“…Therefore, it is suggested that HSD may modulate the plasma glucocorticoids level, at least partly, via regulating the gene expression of P450 11beta in the cortical cells. Genetic mutations in CYP11B1 gene, which encodes P450 11beta , have been reported to result in hypertension with cortisol deficiency in human (Ferrari et al, 2001). Thus, decrease in the adrenal expression of P450 11beta and the plasma corticosterone in the 4 days HSD group may represent perhaps a short-term effect of extra sodium loading on hypertension.…”

“…Therefore, it appears that the extended salt loading, likely as physiological stress, may increase the adrenal expression of P450 11beta by activating the hypothalamicpituitary-adrenal axis. As mentioned above, P450 11beta expression in the adrenal cortex is stimulated by ACTH, a hormone released in response to stress (Ferrari et al, 2001;Sewer and Waterman, 2003). However, no report has shown an increase in plasma ACTH by chronic salt loading.…”

Polymorphisms in CYP11B2 and CYP11B1 genes associated with primary hyperaldosteronism

“…2,3 Parallel 11b-hydroxylation of the 17-hydroxysteroid, which is catalyzed by the enzyme 11b-hydroxylase encoded by the gene CYP11B1, produces cortisol in the zona fasciculata. 4 CYP11B2 and CYP11B1 are situated B40 kb apart, on chromosome 8, band 8q24 in human. 5 Several frequent polymorphisms in CYP11B2 are suggested to have associations with essential hypertension and may influence aldosterone secretion.…”