Figure 314

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Distinguishing characteristics of hypokalemia associated with hypertension and metabolic alkalosis.

Aldosterone

Renin

Response to Dexamethasone

Primary aldosteronism

t

4

11 |3-hydroxysteroid

4

+

dehydrogenase deficiency

t

Glucocorticoid remediable

4

+

aldosteronism

Liddle's syndrome

4^

4

FIGURE 3-15

Mechanism of hypokalemia in Liddle's syndrome. The amiloride-sensitive sodium channel on the apical membrane of the distal tubule consists of homologous a, |3, and 7 subunits. Each subunit is composed of two transmembrane-spanning domains, an extracellular loop, and intracellular amino and carboxyl terminals. Truncation mutations of either the |3 or 7 subunit carboxyl terminal result in greatly increased sodium conductance, which creates a favorable electrochemical gradient for potassium secretion. Although patients with Liddle's syndrome are not universally hypokalemic, they may exhibit severe potassium wasting with thiazide diuretics. The hypokalemia, hypertension, and metabolic alkalosis that typify Liddle's syndrome can be corrected with amiloride or triamterene or restriction of sodium.

FIGURE 3-16

Mechanism of hypokalemia in the syndrome of apparent mineralo-corticoid excess (AME). Cortisol and aldosterone have equal affinity for the intracellular mineralocorticoid receptor (MR); however, in aldosterone-sensitive tissues such as the kidney, the enzyme 11 |3-hydroxysteroid dehydrogenase (11 |3-HSD) converts cortisol to cortisone. Since cortisone has a low affinity for the MR, the enzyme 11 |3-HSD serves to protect the kidney from the effects of glucocorticoids. In hereditary or acquired AME, 11 |3-HSD is defective or is inactiveted (by licorice or carbenoxalone). Cortisol, which is present at concentrations approximately 1000-fold that of aldosterone, becomes a mineralocorticoid. The hypermineralo-corticoid state results in increased transcription of subunits of the sodium channel and the Na+-K+-ATPase pump. The favorable electrochemical gradient then favors potassium secretion [7,15].

FIGURE 3-17

Genetics of glucocorticoid-remediable aldosteronism (GRA): schematic representation of unequal crossover in GRA. The genes for aldosterone synthase (Aldo S) and 11 ß-hydroxylase (11 ß-OHase) are normally expressed in separate zones of the adrenal cortex. Aldosterone is produced in the zona glomerulosa and cortisol, in the zona fasciculata. These enzymes have identical intron-extron structures and are closely linked on chromosome 8. If unequal crossover occurs, a new hybrid gene is produced that includes the 5' segment of the 11 P-OHase gene (ACTH-response element and the 11 p-OHase segment) plus the 3' segment of the Aldo S gene (aldosterone synthase segment). The chimeric gene is now under the contol of ACTH, and aldosterone secretion is enhanced, thus causing hypokalemia and hypertension. By inhibiting pituitary release of ACTH, glucocorticoid administration leads to a fall in aldosterone levels and correction of the clinical and biochemical abnormalities of GRA. The presence of Aldo S activity in the zona fasciculata gives rise to characteristic elevations in 18-oxidation products of cortisol (18-hydroxycortisol and 18-oxocortisol), which are diagnostic for GRA [8].

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