Individuals homozygous for an inherited condition of SME may develop ­hypertension very early in life and become refractory to antihypertensive therapy (failing triple-drug treatment). However, the clinical phenotype varies and some patients may not be found to have SME before they reach adulthood (Table 2.2).

The pathophysiological mechanisms of mineralocorticoid excess syndromes are better understood at present with the advent of new techniques in molecular biology and genetics. The increasing availability of affordable genetic/molecular testing may elucidate further the pathogenesis of these rather rare genetic conditions and their implication in hypertension seen in the general public. Excessive production of aldosterone (primary: familial hypoaldosteronism, aldosterone-producing ­adenoma/carcinoma/hyperplasia [13–16] or secondary: reninoma [17–20]) and sometimes of deoxycorticosterone (DOC) (primary: DOC-secreting adrenocortical adenoma/­carcinoma [21–24] or secondary: 11beta-hydroxylase deficiency [25–27], 17alpha-hydroxylase deficiency [28–30], substances with high mineralocorticoid activity can lead to salt and water retention and consequently hypertension without causing hypernatremia.

11Beta-hydroxylase is responsible for the conversion of DOC to corticosterone (precursor of aldosterone) and 11-deoxycortisol to cortisol. In approximately 2/3 of individuals affected by a deficiency of this enzyme, monogenic low renin hypertension with low aldosterone levels ensues caused by accumulation of 11-­deoxycortisol and DOC. Also, adrenal androgens are produced in excess in individuals with 11beta-hydroxylase deficiency compared with 17alpha-hydroxylase deficiency where they are deficient [25–30]. In patients with 17alpha-hydroxylase deficiency a persistent elevation of ACTH increases DOC and corticosterone levels and as a consequence affected patients will develop hypertension, hypokalemia, low aldosterone, and suppressed renin [28–30].

AME is caused by deficiency of the enzyme 11βHSD2) [31–33]. This enzyme is responsible for the conversion of cortisol to the inactive cortisone in renal tubular cells. Cortisol and aldosterone have equal affinity for the mineralocorticoid receptor but normal circulating concentrations of cortisol are 100–1,000-fold higher than those of aldosterone [34]. If 11βHSD2 is oversaturated or defective, more cortisol will be available to bind to the mineralocorticoid receptor [35]. Diminished 11βHSD2 activity may be hereditary or acquired. Acquired deficiency of this enzyme may result from its inhibition by glycyrrhetinic acid, the active metabolite generated when using licorice, certain brands of chewing tobacco, and carbenoloxone. The mutations in the 11βHSD2 gene are responsible for the reduced activity of the enzyme, which causes Na retention, low K, renin, and aldosterone.

In Liddle syndrome, “gain of function” mutations in the genes coding for the beta- or gamma-subunit of the renal epithelial sodium channel, located on chromosome 16p13, lead to constitutive activation of renal sodium and water resorption, hypertension, low renin, and aldosterone [36].

Pseudohypoaldosteronism type 2 or Gordon syndrome is an autosomal ­dominantly inherited disorder with genes mapping to chromosomes 1, 12, and 17 [37, 38]. Mutations have been identified in WNK kinases WNK1 and WNK4 on ­chromosomes 12 and 17, respectively. More recently, mutations in the KLHL3, CUL3, and SPAK genes have been linked to Gordon syndrome. Published families with this condition (­hypertension, hyperkalemia, metabolic acidosis, normal renal function, low/normal aldosterone levels) are predominantly from Australia [38] or the United States (Lifton and coworkers at Yale University, CT). Hypertension in these patients may develop as a consequence of increased renal salt reabsorption; and hyperkalemia ensues as a result of reduced renal K excretion despite normal glomerular filtration and aldosterone secretion [39–41]. The reduced renal secretion of potassium makes this condition look like an aldosterone-deficient state, thus the term “pseudohypoaldosteronism.”

Activating mutations in the amiloride-sensitive sodium channel of the distal renal tubule may explain the pathogenesis of this condition. Overactivation of the NaCl cotransporter results in Na and water retention and increased blood pressure.

Glucocorticoid resistance or Chrousos syndrome (see Chap. 4 in this book) is caused by inactivating mutations of the glucocorticoid receptor gene [42–44]. Chronic elevation of ACTH can lead to stimulation of adrenal compounds with mineralocorticoid activity (corticosterone, DOC), and elevation of cortisol may lead to stimulation of the mineralocorticoid receptor, resulting in hypertension and increasing androgenic activity (androstenedione, DHEA, DHEAS) in women.

Constitutive activation of the MR is an autosomal-dominant condition determined by “gain of function” mutations in the MC gene on chromosome 4q31 [45].

Figure 2.2 provides an overview of these pathogenic mechanisms involved in mineralocorticoid excess syndromes Fig. 2.2.

As is true for measuring any hormone, when analyzing steroids, it is important to obtain accurate information. The most sensitive and specific method to detect a defect in adrenal steroid biosynthesis is urinary steroid profiling [47]. Particularly robust appears to be measuring steroid precursor/product ratios which are independent of 24-h excretion and usually not determined by commercial laboratories.

The diagnostic approach to syndromes of mineralocorticoid excess is based on the clinical presentation, laboratory, and genetic testing. The most important laboratory and genetic tests are described in Table 2.3.