The best answer is D.
Lifton et al. described a single gene mutation on the hormone-binding domain of the mineralocorticoid receptor (MCR). Individuals with this missense mutation develop early-onset hypertension with characteristic low renin and aldosterone levels. The mutation causes the MCR to be constitutively active, regardless of aldosterone levels, and transforms the MCR so that steroid hormones that are typically antagonistic become agonistic (in particular, progesterone and cortisone).
During pregnancy, when progesterone levels increase 100-fold, the MCR becomes hyperactive and leads to sodium reabsorption and potassium secretion via the principal cell of the distal collecting tubule (Figure above). The avid sodium retention and volume expansion appropriately suppress renin and aldosterone levels. This condition is not associated with proteinuria, edema, or neurologic changes, which distinguishes it from pre-eclampsia.
Given the low levels of aldosterone, this condition is refractory to standard medical therapy aimed at reducing aldosterone levels through RAAS blockade. In fact, mineralocorticoid receptor antagonists can actually exacerbate hypertension in this condition! Delivery of the fetus may be necessary to treat severe, refractory hypertension during pregnancy.
Essential hypertension results from a complex interplay of both genetic and environmental influences. Uncommonly, an isolated genetic mutation can engender hypertension, like in this case. These monogenic forms of hypertension affect either electrolyte transport in the distal nephron, or the synthesis and/or activity of mineralocorticoids, leading to a common final pathway of increased distal tubular reabsorption of sodium and chloride, volume expansion, and hypertension.
Other low renin, monogenic forms of hypertension include:
- Familial Hyperaldosteronism Type 1 (aka, glucocorticoid-remediable aldosteronism)
- Familial Hyperaldosteronism Type II
- Syndrome of apparent mineralocorticoid excess
- Liddle syndrome
- Pseudohypoaldosteronism type II (aka, Gordon syndrome)
- Congenital Adrenal Hyperplasia
They provide excellent fodder for any number of board-style questions!
Michael Lattanzio DO