Genetic disorders of sodium transport

1. What is the difference between mendelian (or monogenic) forms of hypertension and essential hypertension?

Essential hypertension has a multifactorial etiology, including demographic and environmental (dietary) factors, and genetic predisposition, which results from multiple gene–gene and gene–environment interactions. Large genome-wide association studies among various populations mapped many gene loci for essential hypertension; however these loci have been predicted to have a very small effect on individual blood pressure variation, often estimated to be less than 2%. In contrast, Mendelian (or monogenic) forms of hypertension have a large effect on blood pressure level, with identifiable and often effectively treatable causes. The most common mechanism involves activation of the mineralocorticoid pathway, leading to increased kidney sodium reabsorption and volume expansion. Up to 20% of cases with resistant hypertension have either aldosterone-producing adrenal adenomas (APA) or bilateral adrenal hyperplasia. Based on recent DNA sequencing studies from adrenal adenoma tissues, ∼50% of APA cases are caused by somatic mutations in genes controlling adrenal zona glomerulosa cell proliferation and aldosterone production. APA is the most common form of secondary hypertension, estimated to affect up to ∼10% of patients with hypertension. Nevertheless, most monogenic forms of hypertension are exceedingly rare and estimated to be less than 2% of newly diagnosed hypertension. They result from mutations in a single gene and are mostly inherited in a Mendelian pattern. Since the early 1990s, more than 20 genes have been implicated in the etiology of Mendelian hypertension ( Table 72.1 ). Similarly, many Mendelian genes have been identified that lower blood pressure ( Table 72.2 ), with renal salt wasting being the main mechanism.

2. Which clinical characteristics support the diagnosis of monogenic hypertension?

Monogenic hypertension should be considered in patients below the age of 30 years, who present with severe or refractory hypertension and a family history of early-onset hypertension. In addition, associated biochemical abnormalities should raise suspicion. The presence of hypokalemia associated with metabolic alkalosis is suggestive of excess presence or activation of the mineralocorticoid pathway. Familial or spontaneous severe hypertension associated with hyperkalemia and metabolic acidosis (in setting of normal glomerular filtration rate) can be suggestive of pseudohypoaldosteronism type 2 (PHA 2; formerly known as Gordon syndrome).

A low renin value is shared by most of these disorders. Aldosterone activity may be decreased or increased. A typical example of low renin and aldosterone levels is Liddle syndrome. In contrast, a higher level of aldosterone release is seen in glucocorticoid-remediable aldosteronism (GRA, familial hyperaldosteronism type I). Both familial and sporadic forms of primary hyperaldosteronism exhibit typically a serum aldosterone-renin ratio (ARR) greater than 30 and a serum aldosterone value ≥15 ng/dL. A positive ARR should be confirmed with a 24-hour urine aldosterone measurement of greater than 14 μg in the setting of high salt intake (urine sodium over 200 mEq/day).

3. What is the genetic basis of unilateral aldosterone-producing adrenal adenomas (APA, familial hyperaldosteronism type 3)?

The etiology of APA is de novo, somatic mutations in adrenal zona glomerulosa cells. Exome sequencing from adrenal adenoma tissues identified that ∼30% of APA are due to somatic mutations in one gene, the inwardly rectifying potassium channel KCNJ5, causing amino acid substitutions in one of two highly conserved residues (G151R and L168R). In vitro experiments suggest that these rare somatic mutations lead to chronic depolarization of adrenal cells, causing constitutive aldosterone production as well as adrenal cell proliferation and unilateral adenoma. Interestingly, KCNJ5 mutations occur approximately twice as often in female than male individuals with APA. Also of interest, one rare genomic KCNJ5 mutation (T158A), transmitted in autosomal-dominant fashion, was identified in one family with bilateral familial adrenal adenomas associated with severe hypertension.

Less common APA-causing somatic mutations in other genes are more frequently seen in males, including ATP1A1 (Na/K ATPase α1 subunit) and ATP2B (Ca++ ATPase). The causes for these gender differences are unknown; hormonal differences could play a role. Another gene implicated in APA is CACNA1D (a voltage-gated calcium channel); affected individuals feature seizures and other neurological abnormalities. Additional, rarer APA genes have been recently identified.

4. Which hypertension syndrome features unusual steroid metabolites in the urine that typically do not exist?

GRA, familial hyperaldosteronism type 1, is an autosomal-dominant hypertensive disorder resulting from a hybrid gene located on chromosome 8. The defective gene consists of the regulatory gene of 11β-hydroxylase gene and the structural region of the aldosterone synthase gene. Normally, angiotensin-II (Ang-II) induces the production of aldosterone by stimulating the aldosterone gene, CYP11B2, whereas adrenocorticotropic hormone (ACTH) stimulation of the 11β-hydroxylase gene, CYP11B1, leads to cortisol production. A highly similar DNA sequence of these two genes and an unequal crossing over are the causes for GRA etiology. The ACTH-stimulated chimeric gene produces aldosterone in the zona fasciculata instead of the zona glomerulosa, and thus mineralocorticoid production is unresponsive to its traditional regulators Ang-II and potassium. Steroid analysis of urine in affected individuals shows the presence of unusual steroid metabolites of a chimeric protein normally not seen, 18-oxocortisol and 18-hydroxycortisol, which can be helpful to diagnose this condition.

In GRA, plasma renin is reduced, whereas aldosterone level can be increased. Hypokalemia is commonly seen. Given the severity of hypertension at presentation, patients suffer hemorrhagic strokes from ruptured aneurysms. Hence cerebral magnetic resonance angiography is a requisite in these patients at the time of diagnosis; repeat imaging every 5 years should be considered. Low-dose glucocorticoid therapy suppresses ACTH and aldosterone production, thereby serving an important therapeutic role. Both amiloride and spironolactone are also effective.

5. Which syndrome features elevated cortisol-to-cortisone ratio in the urine despite normal serum cortisol levels?

The syndrome of apparent mineralocorticoid excess (AME) is characterized by autosomal recessive hypertension and hypokalemia associated with metabolic alkalosis. In some cases, nephrocalcinosis and renal cysts are observed. The syndrome is caused by bi-allelic loss-of-function mutations in the kidney-specific isoform of 11β-hydroxysteroid dehydrogenase (11β-HSD 2), which allow concentrations of cortisol to rise in distal tubular cells and subsequent activation of the mineralocorticoid receptor (MR). Usually the 11β-HSD 2 enzymes “protect” MR from cortisol by oxidizing it to its inactive metabolite cortisone. The function of 11β-HSD 2 is important, since cortisol has the same affinity for the MR as aldosterone and typically a 10-fold greater level than aldosterone. An elevated urine (tetrahydro)cortisol-to-(tetrahydro)cortisone ratio greater than 0.5 establishes the diagnosis. The mainstay of therapy hinges on MR blockade with spironolactone. Adjunctive therapy includes potassium supplementation and low sodium diet.