Pathophysiology, Diagnosis, and Treatment of Mineralocorticoid Disorders Steven B. Magill*1 ABSTRACT The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure control, fluid, and electrolyte balance in humans. Chronic activation of mineralocorticoid production leads to dysregulation of the cardiovascular system and to hypertension. The key mineralocorticoid is aldosterone. Hyperaldosteronism causes sodium and fluid retention in the kidney. Combined with the actions of angiotensin II, chronic elevation in aldosterone leads to detrimental effects in the vasculature, heart, and brain. The adverse effects of excess aldosterone are heavily dependent on increased dietary salt intake as has been demonstrated in animal models and in humans. Hypertension develops due to complex genetic influences combined with environmental factors. In the last two decades, primary aldosteronism has been found to occur in 5% to 13% of subjects with hypertension. In addition, patients with hyperaldosteronism have more end organ manifestations such as left ventricular hypertrophy and have significant cardiovascular complications including higher rates of heart failure and atrial fibrillation compared to similarly matched patients with essential hypertension. The pathophysiology, diagnosis, and treatment of primary aldosteronism will be extensively reviewed. There are many pitfalls in the diagnosis and confirmation of the disorder that will be discussed. Other rare forms of hyper- and hypo-aldosteronism and unusual disorders of hyC 2014 American Physiological Society. Compr pertension will also be reviewed in this article. Physiol 4:1083-1119, 2014.
Introduction Hypertension affects over a billion individuals worldwide (414). Approximately 30% of the adult population in the United States has hypertension (78). There is a continuous, graded relationship between an increase in blood pressure and risk for cardiovascular disease, including myocardial infarction, congestive heart failure, atrial fibrillation, stroke, and peripheral vascular disease, as well as all cause mortality (50). Approximately 85-90% of patients with high blood pressure have essential hypertension. The remainder have secondary forms of hypertension, of which disorders of the mineralocorticoid system make up the majority. Hypertension develops due to complex genetic influences combined with environmental factors. Mineralocorticoids are intricately involved in the control of plasma volume and blood pressure (BP). Chronic activation of mineralocorticoids leads to dysregulation of the cardiovascular system and hypertension. Angiotensin II-induced increase in aldosterone production leads to activation of epithelial sodium channels in the distal tubule and collecting ducts of the kidney and thereby causes sodium and water retention and excretion of potassium. Aldosterone also has nonclassical effects in the heart, vasculature, and brain. Combined with the actions of angiotensin II, hyperaldosteronism leads to vascular inflammation and
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contributes to cardiac fibrosis and remodeling and eventually to left ventricular hypertrophy (LVH) and other deleterious sequelae. Primary aldosteronism (PA) is the most common form of secondary or endocrine hypertension. The syndrome was first described in a case report by Conn in 1954 and adrenalectomy cured the hypertension and hypokalemia. PA is a complex disorder as there are a number of subtypes of the syndrome. This secondary form of hypertension needs to be carefully evaluated to provide optimal treatment. In the last two decades, it has become well-established that patients with PA have much higher rates of cardiovascular complications, including atrial fibrillation, LVH, and congestive heart failure, than comparably matched patients with essential hypertension. It is important that PA be considered in the workup of subjects with hypertension, amidst the growing number of patients who meet criteria for screening of the disease. This report will review PA in detail. There are many pitfalls in the diagnosis and confirmation of the disorder that * Correspondence
to [email protected] of Endocrinology, Metabolism, and Clinical Nutrition, Department of Medicine, Medical College of Wisconsin, Menomonee Falls, Wisconsin Published online, July 2014 (comprehensivephysiology.com) DOI: 10.1002/cphy.c130042 C American Physiological Society. Copyright 1 Division
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will be discussed. Other rare forms of hyper- and hypoaldosteronism and unusual disorders of hypertension will also be reviewed in this article.
Overview of the Renin-Angiotensin-Aldosterone System and Aldosterone Hypertension is a complex disease that results from the interaction between genetic and environmental factors (314). Risk factors that can potentiate the development of high BP include obesity, sedentary lifestyle, smoking, medications, and salt intake (50). Even though about 50% of BP variability is due to genetic factors, the molecular etiology of hypertension is not yet known. A number of genes have been implicated in control of BP and include but are not limited to, altered epithelial sodium channel function (ENaC), angiotensinogen, 11-β-hydroxysteroid dehydrogenase type 2, endothelin 2, α 2 adrenergic receptor function, and genes associated with the renin-angiotensin aldosterone system (316). The reninangiotensin-aldosterone system (RAAS) system plays a key role in regulation of BP. In addition, there is increasing evidence that aldosterone may be involved in the pathogenesis of hypertension. RAAS is activated by reduction in plasma volume, decreased renal perfusion, or reduced renal tubular sodium chloride concentration. Rapid activation of RAAS occurs through synthesis of aldosterone and leads to retention of sodium and correction of hypovolemia to maintain BP. Intermediate and longer term activation of RAAS results in conservation of salt and water. Chronic activation over months to years, leads to vascular remodeling and eventually to cardiovascular end organ damage. Renin is synthesized from the precursor, prorenin, by the afferent arterioles of the kidney and is the key regulator of RAAS (379). Renin is stored in and released from storage granules and catalyzes the conversion of angiotensinogen to angiotensin I. Angiotensin I is converted to Ang II by converting enzyme (ACE) in the lungs which has the highest concentrations of ACE. However, formation of Ang II can also occur in the luminal membrane of vascular endothelial cells, in the glomeruli of the kidney, the adrenal glands and in the brain (171, 395). In anephric subjects, low levels of Ang II are detectable in the plasma and are likely from these extrarenal sources (408). Local production of Ang II by the vascular endothelium may help in regulation of vascular tone (251). Additionally, local generation of Ang II by the vascular endothelium plays a role in maintenance of vascular tone and may be a factor in the development of hypertension (170). The direct and indirect actions of Ang II lead to arteriolar vasoconstriction and sodium and water retention. The vasoconstrictive action of Ang II can occur via direct effect on vascular smooth muscle cells or indirectly by stimulation of the sympathetic nervous system. These effects then correct the hypovolemia and hypotension. Ang II directly stimulates
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sodium reabsorption in the early proximal convoluted tubule and also increases secretion of aldosterone (54, 153). Both systemic and locally produced Ang II from the adrenal gland contribute to aldosterone production (171). The effects of Ang II are mediated through the angiotensin type 1 (AT1 ) and type 2 (AT2 ) receptors (119). The vascular and renal tubular actions are mainly mediated by AT1 receptors. AT2 receptor function is not as well characterized but generally opposes the action of AT1 receptors in the vasculature and kidney. Ang II binds to the type I receptor in the zona glomerulosa and leads to upregulation of phospholipase C. This is a G protein-coupled receptor that activates protein kinase C, in turn generating inositol triphosphate and 1, 2 diacylglycerol (281). This generates an increase in intracellular calcium release and activation of protein kinases and transcription factors (282). This eventually leads to activation of aldosterone synthase and to the synthesis of aldosterone (410). Ang II also can activate the sympathetic nervous system via AT1 presynaptic receptors. This results in enhanced arginine vasopressin release, increased ACTH synthesis, and an increase in TSH and growth hormone. Ang II is an important regulator of BP in circumstances when renin secretion is enhanced such as in renal artery stenosis and in normotensive states associated with effectively reduced plasma volume such as in heart failure and cirrhosis of the liver (77, 325). Chronic activation of Ang II leads to vascular remodeling and increased stiffness in the vasculature. Aldosterone actions are modulated by the RAAS. Aldosterone interacts with the pathways regulated by Ang II and the type 1 Ang II receptor (187). Aldosterone increases reactive oxygen species formation, which in turn, activates pathways involved in cell growth, collagen formation and inflammation (223). Therefore, Ang II and aldosterone augment each others actions. Aldosterone also upregulates type 1 Ang II receptors in vascular smooth muscle cells which leads to enhanced vasoconstriction (43). The synergistic effects of aldosterone and Ang II trigger vascular inflammation and fibrosis and contribute to arterial hypertension. In the human, this ultimately leads to LVH and other adverse cardiac sequelae.
Classic Epithelial Actions of Aldosterone The classical actions of aldosterone occur in the kidney and in other transport epithelia such as the colon, the salivary and sweat glands. Aldosterone influences sodium and potassium flux through the ENaC in the distal nephron and collecting ducts. Aldosterone binds to the mineralocorticoid receptor (MR), one of a family of nuclear receptors. The activated receptor-hormone complex binds to hormone-response elements and thereby regulates gene transcription and ultimately sodium excretion (10). Aldosterone increases the residency time of ENaC in the apical epithelial surface leading to enhanced sodium reabsorption (312, 394). Activation of the cytoplasmic MR
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by aldosterone leads to expression of the serum and glucocorticoid inducible kinase 1 which is phosphorylated and activates the epithelial sodium channel (47). Sodium absorption is accompanied by water retention and there is a compensatory loss of potassium in the filtrate. The aldosterone-induced reabsorption of sodium and water is a short-lived phenomenon and edema does not usually develop due to “aldosterone escape.” Within days of activation of aldosterone, an increase in sodium wasting occurs with spontaneous diuresis which counteracts the sodium-retentive effects of aldosterone and returns the Na+ balance to equilibrium (15, 134). However, persistent mild hypervolemia leads to increased systemic vascular resistance and also to marked suppression of renin. The mechanism whereby this escape phenomenon occurs is not completely understood. However increased secretion of atrial natriuretic factor resulting from increased volume expansion likely plays a role (418). Additional regulatory processes that are likely to contribute to aldosterone escape include a decreased number of the thiazide-sensitive Na-Cl cotransporters which mediate reabsorption of sodium in the distal tubule (398) and to the mechanism of pressure natriuresis (132).
levels but had little effect on the BP. However, captopril prevented vascular injury in the kidney and reduced the level of proteinuria (291). When exogenous aldosterone was added back to the captopril-treated animals, the proteinuria and vascular injury in the kidney were restored (291). Aldosterone has also been shown to abolish any protective effect of combined ACE inhibition and angiotensin II receptor antagonism (ARB) in a remnant kidney model of hypertension (128). Studies on the role of aldosterone in the development of cerebral lesions were conducted in stroke prone hypertension rats (293). Rats were given 1% NaCl starting at nine weeks of age and were treated with a vehicle vs. eplerenone, an aldosterone antagonist. BP was elevated in both groups of animals. After only 4 weeks of treatment, there were already signs of neurologic injury in the vehicle-treated group and all animals had died by 10 weeks of treatment. There was evidence of severe cerebrovascular injury in the control animals. Nearly all the eplerenone-treated animals were protected from developing stroke or hemorrhagic lesions (293). These findings further demonstrate the importance of aldosterone in the hormonal mediation of vascular injury.
Nonepithelial actions of aldosterone
Aldosterone Synthesis, Secretion, and Action
It is known that aldosterone can also exert adverse effects on nonepithelial tissues including the brain, cardiac tissue, and the vasculature. Mineralocorticoid receptors have been identified in the fibroblasts of the heart, in vascular smooth muscle cells, and in the brain (199, 293, 369). For a time, it was thought that the heart could produce aldosterone under the influence of Ang I or excess sodium, as was demonstrated in a rat myocardial infarction model (335). However, more definitive studies using more sensitive immunoassays and polymerase chain reaction (PCR) studies have conclusively shown that the heart does not produce aldosterone but may take up aldosterone from the plasma (117). Aldosterone synthesized in small amounts in non-adrenal tissue may act in a paracrine fashion and may be important in regulation of cell and vascular function. Long-term effects of aldosterone lead to fibrosis and remodeling of the heart. Brilla et al. demonstrated that in the presence of salt-loading, excess aldosterone leads to collagen formation and cardiac fibrosis in a rat model (34, 35). Furthermore, uninephrectomized rats fed a high salt diet and given aldosterone were protected from the development of cardiac fibrosis by treatment with spironolactone, an aldosterone receptor antagonist. Aldosterone has been implicated as a mediator of vascular inflammation in the kidney and brain in the stroke-prone hypertensive rat. Saline drinking, stroke-prone rats treated with a mineralocorticoid blocker had reduced proteinuria, less renal vascular lesions, and a reduction in stroke and death (289, 290). This despite a nonsignificant reduction in BP in these animals. Additional studies using captopril to suppress RAAS were conducted in stroke prone hypertensive rats. Captopril treatment was shown to reduce aldosterone
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Increased aldosterone production is triggered by sodium depletion and by reduction in the plasma volume. This leads to stimulation of Ang II production through the release of renin from the kidney. Potassium also plays a critical role in modulating aldosterone. Very small increases in potassium (within the physiological range) can have a marked effect on the synthesis of aldosterone. This indicates the sensitivity of the ZG cells in responding to very small changes in the plasma potassium level (391). The effects of K+ and Ang II are synergistic, as aldosterone production in response to Ang II is modulated by the potassium concentration (48). Increased K+ causes depolarization of the cell membrane in the ZG cells. This in turn leads to opening of voltage dependent L- and T-type calcium channels leading to a rapid increase in the intracellular calcium concentration. The rise in calcium causes activation of calmodulin and Ca2+-calmodulin-dependent protein kinases that phosphorylate transcription factors stimulating CYP11β2 gene transcription (338). Visceral adipocytes also have been shown to secrete mineralocorticoid-releasing factors that upregulate aldosterone synthase expression and stimulate aldosterone secretion (79). The major adrenal hormones are synthesized in discrete zones of the adrenal cortex (Fig. 1). Aldosterone is produced in the zona glomerulosa (ZG), glucocorticoids, and sex hormones are produced in the zona fasciculata (ZF) and zona reticularis (ZR), respectively. The ZG has low activity of 17alpha-hydroxylase which limits cortisol and androgen production in this region of the adrenal cortex (283). Aldosterone synthase (CYP11β2) tightly regulates production of aldosterone. The gene for aldosterone synthase
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22
21 18
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12 19 1
9 10
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Adrenal steroid pathways
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Cholesterol
7
HO
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CYP11A1 StAR
O
O
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O 11-Deoxycorticosterone
Progesterone
OH
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OH
HO 17 α-Hydroxypregnenolone
HSD3B2
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O O 17 α-Hydroxyprogesterone 11-Deoxycortisol
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Corticosterone
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OH
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Cortisol zona fasciculate
Figure 1 Adrenocortical steroidogenic pathway. Adrenocortical steroidogenic pathways for the production of mineralocorticoids and glucocorticoids. Reprinted with permission (141); From Fig. 1. p 152.
is located on chromosome 8 in humans. Aldosterone and cortisol have the same early enzymatic pathway. CYP11β2 is expressed in the outermost zona glomerulosa and has three regulatory components. The 11 β-hydroxylase enzyme hydroxylates 11-deoxycorticosterone (DOC) to form corticosterone. 18-hydroxylase converts corticosterone to 18hydroxycorticosterone and finally, 18-oxidase catalyzes conversion of 18-hydroxycorticosterone to aldosterone. Expression of CYP11β2 is controlled by Ang II and potassium. CYP11β1 also has 11β-hydroxylase activity and is expressed in the zona fasciculata and the zona reticularis. As such, this enzyme catalyzes the conversion of 11-deoxycortisol to cortisol under ACTH action in the ZF and ZR (283). In rodents, CYP11β2 is expressed in a narrow zonal band that encircles the adrenal (249). Recently, Nishimoto and colleagues described a group of patients who had a clustering of subcapsular cells of the adrenal gland that expressed CYP11β2 (243). It has been proposed that this phenotype may develop in humans who have chronic excess salt ingestion and could potentially be a precursor to the development of aldosterone-secreting adenomas. Aldosterone production is regulated acutely (within minutes) of stimulation by expression and phosphorylation of the steroidogenic acute regulatory protein (141). This increases movement of cholesterol into the cell, then to the mitochondria. The cholesterol is then converted to pregnenelone and the cascade ensues. Longer term regulation of aldosterone production occurs through enzymes involved in synthesis of aldosterone and its precursors, especially CYP11β2, predominantly through gene expression (20).
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Aldosterone secretion is inversely correlated with extracellular volume. Renin-induced Ang II and potassium both chronically stimulate the secretion of aldosterone. ACTH contributes to the short-term regulation of aldosterone. Acutely, ACTH stimulates blood flow to the adrenal glands and increased aldosterone production by interaction with Gprotein coupled receptors in the ZG cells. Adenylate cyclase is activated leading to increased cAMP levels, in turn activating protein kinase A (318). The cAMP-mediated effects on gene transcription take hours. Chronic administration of ACTH leads to adrenal hyperplasia and hypertrophy of the ZG. With chronic administration of ACTH, CYP11β2 expression and aldosterone levels are suppressed both in humans (97) and in animal models (149). Morning aldosterone (plasma and serum) levels range from about 5 to 30 ng/dL (140-830 pmol/L in SI units) in seated subjects with no restriction in salt intake (6). Black individuals have lower aldosterone levels than whites (273). There is a diurnal variation in aldosterone concentration with the highest level on arising and the lowest at bedtime (165). Aldosterone concentration increases with sodium restriction or sodium diuresis and normally is suppressed with salt or saline loading. With upright posture, aldosterone levels increase (409). Aldosterone levels also rise during the luteal phase of the menstrual cycle (217) and increase up to 10 times normal during the third trimester of pregnancy (400). In PA, the aldosterone level is either elevated or inappropriately in the normal range given the suppressed renin. Dietary sodium is a major factor in regulation and action of aldosterone. The long-term effects of PA are critically
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dependent on excess sodium ingestion in the development of detrimental effects on the vasculature and heart. Aldosterone concentrations are also elevated in secondary aldosteronism due to increased renin and angiotensin levels. Examples of secondary aldosterone states include renal artery stenosis and in renin-secreting tumors. Secondary aldosteronism also occurs in chronic edematous states such as congestive heart failure, cirrhosis, and the nephrotic syndrome (57). In these disorders, there is a relative intravascular hypovolemia and metabolism of aldosterone may be impaired. Levels of aldosterone are low in a number of uncommon hypertensive disorders such as Liddle’s syndrome and in 11 β-hydroxysteroid dehydrogenase deficiency. Aldosterone concentrations are also low in acquired conditions such as ingestion of licorice and in ectopic Cushing’s syndrome (see below). The involvement of aldosterone in the development of hypertension in hyperaldosteronism is well established. A primary increase in aldosterone by an aldosterone secreting tumor or in subjects with idiopathic adrenal hyperplasia leads to sodium and water retention and eventually to hypertension. It has been more difficult to demonstrate a role for aldosterone in the development of essential hypertension. Large doses of aldosterone (threefold increase in plasma aldosterone) in combination with excess salt are required to cause arterial remodeling in human subjects. Under these circumstances, aldosterone stimulates collagen turnover, development of fibrosis, and inflammation in the vasculature. The fibrosis induced by aldosterone is independent of elevated BP. Aldosterone antagonists such as spironolactone block the deleterious cardiac effects of aldosterone (34). Baseline aldosterone concentration was evaluated in a prospective trial of normotensive individuals in the Framingham Offspring Study. Over a 4-year period, the group with the highest quartile of aldosterone concentration had a 1.61-fold increased risk of development of hypertension compared to the lowest quartile group (393). Additional evidence comes from a nested case-control study performed in France (214). The authors followed 1984 nonhypertensive subjects (ages 45-64) and compared them to gender- and BP-matched controls. Multivariate regression analysis demonstrated that plasma aldosterone and renin were positively and negatively associated, respectively, with increasing degree of systolic BP and the development of hypertension over a 5-year period (P = 0.01; P = 0.001, respectively). Aldosterone levels in the higher physiologic range may contribute to the development of hypertension; however, further studies are needed to confirm that this is true.
Primary Aldosteronism Overview PA was reported as a new clinical syndrome when Jerome Conn presented the initial case to the Central Society for Clinical Research in Chicago in 1954 (55). The case was a
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34-year-old woman who had a syndrome of “moderate hypertension,” hypokalemia, metabolic alkalosis, mild hypernatremia, and normal renal function. She did not have Cushingoid features, had no evidence of peripheral edema and was found to have an abundant salt-retaining corticoid in the urine (55, 115). The salt retaining adrenal steroid was hypothesized to be aldosterone, which had recently been discovered (336). The subject underwent lengthy metabolic studies over a 7-month period of hospitalization in 1953. Finally, Conn proposed that the patient be taken to surgery with the expectation that both adrenal glands would need to be surgically resected. He theorized that this would ameliorate the metabolic abnormalities in the patient. Of course in 1953, there were no anatomic localizing studies available, and this type of surgery had never been proposed before. At the time of surgery, a 4-cm adrenal tumor was found in the right adrenal gland and resected. Biopsy of the left adrenal gland demonstrated relative atrophy of the zona fasciculata (56). Within 10 days of the surgery, the metabolic derangements were completely resolved. The BP normalized by the eighteenth day after surgery. Finally, assay of the salt-retaining corticoid demonstrated a return to a normal level after the right adrenalectomy (56). Thus, was born a new syndrome of endocrine hypertension. Over the next decade, Conn and associates expanded the findings of the index case and fully described the syndrome of PA. An interesting side note was that Litynski reported two patients with progressive hypertension and adrenal masses, in the Polish literature in 1953 (197). At the time of necropsy, adrenocortical tumors were found and Litynski suggested that mineralocorticoids were responsible for the hypertension. This report went unrecognized in the English language scientific literature until 1991 (177). After studying a number of patients with the syndrome over the next decade, Conn predicted that PA could occur in up to 20% of all patients with hypertension (57). Others argued that PA was not nearly as common as suggested by Conn et al. and the true estimate was that 2.0 cm, which is larger than the majority of patients with APA. The mutations in KCNJ5 were found only in the affected tumors and not in the adjacent adrenocortical tissue. Thus the KCNJ5 mutations appear to occur in a background of proliferating adrenal cortex. A different mutation in KCNJ5 (T158A) was found in a familial form of PA which occurred in a father and his two young daughters. The affected family members presented with severe hypertension, marked hyperaldosteronism and massive BAH. Bilateral adrenalectomy cured the hypertension (52). This has been termed familial hyperaldosteronism type 3 (FH-III). It is not known why the KCNJ5 mutation in this family led to BAH rather than the development of APAs. Azizan et al. further categorized these mutations in a group of 73 patients from Australia and the United Kingdom and reported that 41% of APAs in their series had a KCNJ5 mutation in the selectivity filter (16). In this study, the subjects with the KCNJ5 mutations were shown to have nonresponsive plasma aldosterone levels to upright posture (16). This is in contrast to normotensive subjects, patients with IHA and in the group of patients with APA without these mutations. Upright posture activates RAAS and aldosterone response is thought to be Ang II-sensitive in these latter three conditions. Boulkroun and colleagues (European Network for the Study of Adrenal Tumors) reported that somatic KCNJ5 mutations were specific to APA and that 129 of 380 patients (34%) studied from a large group of patients in Europe had one of the mutations (31). The subjects with the KCNJ5 mutations were younger, more likely to be women and had higher aldosterone levels compared to control patients. Finally, no germline mutations were found in patients with IHA or in those with cortisol-producing adenomas in this study. Seccia et al. have demonstrated that subjects with an APA who have a KCNJ5 mutation have a higher aldosterone to cortisol ratio (A/C) (lateralization index) from the dominant
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side during adrenal vein sampling (AVS), compared to the subjects without a mutation (328). Taguchi et al. reported in a Japanese series that 15 of 23 patients (65.2%) with an APA had somatic mutations in the KCNJ5 gene (365). Using aldosterone to renin (ARR) screening for hyperaldosteronism in Japan, about 75% of patients with PA are found to have an APA (242). This is in contrast to a 50% to 60% prevalence in other centers around the world. This may account for the higher percentage of patients with an APA having KCNJ5 mutations in Japan. It is possible that in the future, other mutations may be found in the remaining patients with APAs which may contribute to the development of aldosterone producing tumors. The two-pore-domain potassium channel (K2p) family is a widely distributed group of channels encoded by the KCNK gene family. TWIK-related acid-sensitive K (TASK-1) and TASK-3 subunits are expressed in abundance in ZG cells (63, 200). These channels generate a background or leak of K+ and help maintain the negative resting membrane potential and the excitability of the ZG cells to approximately −70 mV (21, 351). In rats, TASK-1 (KCNK3) and TASK-3 (KCNK9) channels are inhibited by activation of AT1 receptors, which leads to depolarization of the cell membrane, a rise in the free calcium intracellular concentration, and an increase in aldosterone production (47). Abundant messenger RNA of TASK-1 has also been found in the adrenal glands of mice and humans (143). TASK channels are, therefore, necessary for constraining aldosterone production in the ZG under normal physiological conditions. Several animal models of hyperaldosteronism have been developed recently. Deletion of TASK-1 and TASK-3 channels in knock-out mice removes a background potassium current and leads to autonomous aldosterone production (66). Aldosterone production in these knock-outs was independent of renin compared to wild-type mice. Furthermore, aldosterone levels were increased on a low salt diet and not suppressed with sodium loading or with Ang II blockade (candesartan) in the affected mice (66). These characteristics are very similar to idiopathic adrenal hyperplasia or BAH in humans. As a further corollary, enhanced Ang-II sensitive aldosterone production is typical of the BAH subtype in PA in humans (58). In another model of hyperaldosteronism, inactivation of TASK1 in female mice led to marked elevation in aldosterone which was independent of sodium intake. The mice lacking TASK1 had low renin levels and developed hypertension and hypokalemia (143). The hyperaldosteronism was inhibited by treatment with glucocorticoids. Aldosterone synthase (CYP11β2) was absent from the outer cortex in these mice which corresponds to the ZG zone, but was abundant in the ZR and ZF. Deletion of TASK3 in mice led to autonomous aldosterone production that was salt-sensitive and caused a milder form of hypertension than those in the TASK1 knockouts (263). This model may be analogous to subjects with low renin
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hypertension. Some have proposed that low renin hypertension is an early stage of PA in that renin levels are suppressed but aldosterone concentrations are still in the normal range (129, 347). On a continuum of low renin hypertension, IHA is thought to represent the last stage and is typified by autonomous aldosterone production. These data indicate that TASK channels could be a pharmacologic target for treatment in hyperaldosteronism. Another model of hyperaldosteronism involves deletion of circadian clock genes in mice. RAAS activation occurs due to sympathetic neuronal activity and is a key regulator of BP (271). BP in mammals is under a circadian rhythm. The nadir of BP occurs in the night (dip) and rises in the morning to the highest level (surge). Subjects who do not have the characteristic dip in BP at night (“nondippers”) or have an excessive surge in the morning have worse cardiovascular outcomes (262). In hypertensive and nonhypertensive humans, peak renin, aldosterone, and cortisol concentrations occur near the time of arising from sleep and contribute to the surge in BP (152). There is similar circadian rhythm of these hormones in rodents. Cry proteins are repressor factors that have been shown to downregulate transcription of several circadian clock genes (178, 416). Deletion of two cryptochrome genes, Cry1 and Cry2 led to salt sensitive hypertension secondary to abnormal aldosterone production by the ZG cells (73). Cry gene inactivation resulted in dysregulation of the type IV 3 βhydroxyl-steroid dehydrogenase (Hsd3b6) enzyme in the ZG zone of the adrenal gland in these mice. HSD3β enzymatic activity was enhanced leading to increased aldosterone production and suppressed renin indicative of autonomous aldosteronism. The mutant mice had a nondipper phenotype and developed hypertension when exposed to a high salt diet. This mouse model of hypertension is similar to IHA (39). The comparable enzyme in humans is HSD3β1 and is also selectively expressed in the ZG. It is possible that polymorphisms that lead to increased HSD3β1 activity may contribute to the development of hypertension in a subset of human subjects, particularly those who are salt-sensitive and are nondippers (314).
Features of primary aldosteronism PA is a heterogeneous group of disorders in which aldosterone production is elevated, and is relatively independent of RAAS modulation. Patients present with hypertension, a suppressed PRA, varying degrees of metabolic alkalosis and mild hypernatremia. Hypokalemia may or may not be present. Patients may have a variable presentation. Many subjects will have symptoms that include muscle aches, cramping and weakness, headaches, palpitations, and polyuria (420). However, other subjects have minimal or no symptoms. Hypomagnesemia may or may not be present. In very rare cases, the subject can present with normal BP (175, 211, 433). Excess aldosterone raises the glomerular filtration rate (GFR) and renal perfusion pressure over time. Increased
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Table 2
Patients Who Should be Screened for Primary Aldostero-
nism
1 Young patients (age less than 35) with hypertension and a family history of early onset hypertension or stroke at a young age 2 Patients with hypertension who have hypokalemia 3 Patients with resistant hypertension 4 Patients who have hypertension and an adrenal nodule 5 Patients with obstructive sleep apnea and hypertension
urinary albumin excretion is common in patients with PA. Patients with hyperaldosteronism have higher levels of creatinine and lower estimated glomerular filtration (eGFR) rates compared to a control group of patients with hypertension (286). In this study, regression analysis demonstrated that age, male gender, hypokalemia, and higher aldosterone levels were independent predictors of a lower eGFR in PA. Many patients with PA have resistant hypertension. Patients with PA need to be distinguished from those patients with low renin hypertension, which makes up 25 to 30% of all cases of hypertension (182, 184). As more patients are being screened for hyperaldosteronism, the majority of subjects diagnosed with PA in the present era have normokalemia. In an international retrospective study of PA, less than 50% of all patients diagnosed with PA had hypokalemia at the time of presentation (231). An important clue is that many patients with PA have serum potassium (K+) levels in the low range of normal, i.e., K+ of 3.5 to 3.9 mmol/L (normal range 3.5-5.0 mmol/L). Patients who should be screened for PA include young patients (age less than 35) with hypertension who have a family history of early onset hypertension or stroke (Table 2). Patients who have hypertension and hypokalemia should obviously be screened. This is true whether or not the hypokalemia is provoked by diuretics. Patients with resistant hypertension have a high incidence of PA and should also be screened. This includes a substantial number of middle aged and older patients with hypertension. Resistant hypertension is defined as BP that remains above goal (generally considered BP >140/90 mmHg or >130/80 in patients with diabetes mellitus or chronic kidney disease) despite treatment with three or more maximally tolerated antihypertensive medications of different classes (36). A diagnosis of resistant hypertension increases the chance of having a secondary form of hypertension (51, 162). Patients who have resistant hypertension by definition, excludes those who have improperly measured BP, are nonadherent in taking antihypertensive agents or in following lifestyle modification, are on inadequate doses of BP lowering medications or have white coat hypertension (36, 71). Patients with resistant hypertension have a prevalence of PA of about 20% (37). In Birmingham, Alabama, 88 consecutive patients with resistant hypertension underwent testing and 20% were found to have PA based on rigorous screening and confirmatory testing (37). There was no difference in the rates of PA in black and
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white subjects in this study. Gallay and colleagues screened 90 consecutive patients with resistant hypertension and found a 17% prevalence of PA (103). Similar findings were found in Oslo, Norway (80). In a prospective study of 100 consecutive patients with type 2 diabetes and resistant hypertension, Umpierrez et al. found that 14% had PA following confirmatory testing (390). In a large retrospective study of 1616 patients with resistant hypertension, Douma et al. found that 11% were confirmed as having PA (75). Patients with an adrenal nodule who have hypertension should be screened for PA as should those with a familial form of hyperaldosteronism (Table 2). Approximately 1% of subjects with an adrenal incidentaloma have PA (422). The recommendations for case screening listed above are similar to but not identical to the Endocrine Society Practice Guidelines published in 2008 (100). The Japanese Society of Hypertension has similar recommendations for screening patients with hypertension for PA (159). Other patients who have a high probability of PA include those with obstructive sleep apnea. Obstructive sleep apnea was present in 85% of subjects with resistant hypertension in one study (274). Additionally, there was a significant correlation between plasma aldosterone levels and the severity of sleep apnea. In a study of 109 patients with resistant hypertension, 77% of the subjects had obstructive sleep apnea and 28% had hyperaldosteronism (118). Other investigators have suggested that there is a relationship between obesity, the metabolic syndrome and PA. In a prospective study of 466 patients with hypertension, 85 patients were found to have PA. The prevalence of the metabolic syndrome (according to criteria from the National Cholesterol Education Program Adult Treatment Panel III; (237) was 41.1% in subjects with PA and 29.6% in those with essential hypertension; P < 0.05 (83). The rates of hyperglycemia were also found to be higher in the patients with PA in this study. In a retrospective case control study in Germany, patients with PA had a prevalence of diabetes that was more than twofold higher than an age, gender and BP-matched cohort of subjects with hypertension (285). First phase insulin release was found to be significantly impaired during an intravenous glucose tolerance test in subjects with PA compared to normal controls and those with hypertension (92). Finally, hyperaldosteronism was recognized as an endocrine cause of diabetes mellitus by the American Diabetes Association in 2008 (72).
Cardiovascular effects of excess aldosterone in humans The initial series of 145 patients with hyperaldosteronism that Conn and his group reported in 1964 had a low number of cardiovascular events (59). Only in the last two decades has it been recognized that patients with PA have substantially higher risk for cardiovascular disease. Patients with PA have a higher propensity to develop LVH and LV mass compared to patients with essential hypertension (EH) who
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have similar BP readings. Greater LV mass was found in a group of subjects with PA compared with patients with other forms of hypertension, including EH, Cushing’s syndrome, and pheochromocytoma when matched for age, gender and duration of hypertension (372). Shigematsu et al. found that eccentric LVH preceded other end organ damage in subjects with PA compared to patients with EH (332). Rossi et al. also reported a higher prevalence of LVH and increased left ventricular mass in patients with PA compared to EH (308). Similarly, diastolic dysfunction has been reported to be more common in patients with PA (305). Endothelial dysfunction is also common in patients with hyperaldosteronism (364). These abnormalities contribute to remodeling and fibrosis in the heart. Dietary sodium intake in humans has a key role in the target organ damage that results from PA as was initially reported in animal studies. In a case control study of 21 patients with PA compared to 21 patients with EH, 24 h urinary sodium excretion was predictive of left ventricular wall thickness and mass in subjects with PA but not in those with EH (267). Milliez et al. were one of the first groups to report a higher number of cardiac events in subjects with PA compared to EH (220). In an evaluation of 124 patients with PA compared to a group of 465 patients with essential hypertension, the incidence of stroke was 12.9% for PA and 3.4% in patients with EH (odds ratio 4.2). The odds ratio of a nonfatal myocardial infarction was 6.5 times higher in those with PA compared to those with EH. Finally, the odds of atrial fibrillation were 12.1 in subjects with PA. In this retrospective study, cardiac complications were similar in patients with an aldosterone secreting adenoma and BAH (220). In a larger controlled study, Savard et al. compared the cardiovascular event rates in 459 patients with PA to 1290 control patients with EH who were matched for age, gender, and systolic BP (321). Patients with PA had a twofold higher likelihood of having LVH by echocardiogram than subjects with EH in this study. Subjects with PA had a higher prevalence of coronary artery disease (odds ratio of 1.9) than patients with EH. Similarly, the adjusted odds ratios of nonfatal myocardial infarction (2.6), congestive heart failure (2.9), and atrial fibrillation (5.0) were substantially higher in patients with PA compared to those with EH (321). These data underscore the adverse effects of excess aldosterone and that the higher cardiovascular complications from PA are at least in part independent of the BP. In another trial, 180 patients with PA were prospectively followed using serial echocardiogram and compared to 143 patients with EH (303). At baseline, the subjects with PA had greater LV mass than comparably matched patients with EH. At a mean follow-up of 36 months, the subgroup with APA who underwent adrenalectomy had similar BP control as those treated with mineralocorticoid antagonists and those with EH. There was significant regression of LVH and LV mass by reverse inward LV remodeling in both the surgically and medically treated group of patients with PA during the study (303).
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Additional evidence of the adverse effects of aldosterone on the heart come from studies conducted in patients with familial hyperaldosteronism. Stowasser’s group found concentric remodeling, increased left ventricular wall thickness, and reduced diastolic function in normotensive subjects with familial hyperaldosteronism type 1 (FH-1) compared to BPmatched control subjects (357). Further evidence of the adverse effects of excess aldosterone come from large randomized clinical trials. The Randomized Aldactone Evaluation Study (RALES) evaluated patients with congestive heart failure on standard treatment with ACE-inhibitors and diuretics, who were randomized to treatment with the MR antagonist, spironolactone versus placebo and the outcomes were striking (270). In patients with New York Heart Association Class III heart failure, the patients treated with an average dose of 26 mg/day of spironolactone had a 30% reduction in mortality and a 35% lower rate of hospitalization. About 10% of the men who were treated with spironolactone during the RALES trial developed gynecomastia. A second major trial, Eplerenone Postacute myocardial infarction Heart failure Efficacy and SUrvival Study (EPHESUS), involved treatment with the MR antagonist, eplerenone combined with standard treatment that included beta blockers and ACE-inhibitors and was conducted in 6632 patients who had heart failure following myocardial infarction (269). Eplerenone is a newer, selective aldosterone antagonist without progestational and androgenic side effects typical of spironolactone (432). The drug does not generally cause menstrual abnormalities, gynecomastia, or reduced libido as seen with spironolactone (401). At a mean of 16 months following randomization in the EPHESUS trial, there was a 15% reduction in mortality in the eplerenone treated group. There was a 17% lower cardiovascular mortality rate in those patients treated with eplerenone compared to placebo. A major difference in the RALES and EPHESUS trials was that only about 10% of the patients in the RALES trail were treated with beta blockers whereas 75% of the subjects received beta blockers in the EPHESUS trial. However, in the EPHESUS trial, a subset of patients with lower ejection fractions (LVEF
Introduction Hypertension affects over a billion individuals worldwide (414). Approximately 30% of the adult population in the United States has hypertension (78). There is a continuous, graded relationship between an increase in blood pressure and risk for cardiovascular disease, including myocardial infarction, congestive heart failure, atrial fibrillation, stroke, and peripheral vascular disease, as well as all cause mortality (50). Approximately 85-90% of patients with high blood pressure have essential hypertension. The remainder have secondary forms of hypertension, of which disorders of the mineralocorticoid system make up the majority. Hypertension develops due to complex genetic influences combined with environmental factors. Mineralocorticoids are intricately involved in the control of plasma volume and blood pressure (BP). Chronic activation of mineralocorticoids leads to dysregulation of the cardiovascular system and hypertension. Angiotensin II-induced increase in aldosterone production leads to activation of epithelial sodium channels in the distal tubule and collecting ducts of the kidney and thereby causes sodium and water retention and excretion of potassium. Aldosterone also has nonclassical effects in the heart, vasculature, and brain. Combined with the actions of angiotensin II, hyperaldosteronism leads to vascular inflammation and
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contributes to cardiac fibrosis and remodeling and eventually to left ventricular hypertrophy (LVH) and other deleterious sequelae. Primary aldosteronism (PA) is the most common form of secondary or endocrine hypertension. The syndrome was first described in a case report by Conn in 1954 and adrenalectomy cured the hypertension and hypokalemia. PA is a complex disorder as there are a number of subtypes of the syndrome. This secondary form of hypertension needs to be carefully evaluated to provide optimal treatment. In the last two decades, it has become well-established that patients with PA have much higher rates of cardiovascular complications, including atrial fibrillation, LVH, and congestive heart failure, than comparably matched patients with essential hypertension. It is important that PA be considered in the workup of subjects with hypertension, amidst the growing number of patients who meet criteria for screening of the disease. This report will review PA in detail. There are many pitfalls in the diagnosis and confirmation of the disorder that * Correspondence
to [email protected] of Endocrinology, Metabolism, and Clinical Nutrition, Department of Medicine, Medical College of Wisconsin, Menomonee Falls, Wisconsin Published online, July 2014 (comprehensivephysiology.com) DOI: 10.1002/cphy.c130042 C American Physiological Society. Copyright 1 Division
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will be discussed. Other rare forms of hyper- and hypoaldosteronism and unusual disorders of hypertension will also be reviewed in this article.
Overview of the Renin-Angiotensin-Aldosterone System and Aldosterone Hypertension is a complex disease that results from the interaction between genetic and environmental factors (314). Risk factors that can potentiate the development of high BP include obesity, sedentary lifestyle, smoking, medications, and salt intake (50). Even though about 50% of BP variability is due to genetic factors, the molecular etiology of hypertension is not yet known. A number of genes have been implicated in control of BP and include but are not limited to, altered epithelial sodium channel function (ENaC), angiotensinogen, 11-β-hydroxysteroid dehydrogenase type 2, endothelin 2, α 2 adrenergic receptor function, and genes associated with the renin-angiotensin aldosterone system (316). The reninangiotensin-aldosterone system (RAAS) system plays a key role in regulation of BP. In addition, there is increasing evidence that aldosterone may be involved in the pathogenesis of hypertension. RAAS is activated by reduction in plasma volume, decreased renal perfusion, or reduced renal tubular sodium chloride concentration. Rapid activation of RAAS occurs through synthesis of aldosterone and leads to retention of sodium and correction of hypovolemia to maintain BP. Intermediate and longer term activation of RAAS results in conservation of salt and water. Chronic activation over months to years, leads to vascular remodeling and eventually to cardiovascular end organ damage. Renin is synthesized from the precursor, prorenin, by the afferent arterioles of the kidney and is the key regulator of RAAS (379). Renin is stored in and released from storage granules and catalyzes the conversion of angiotensinogen to angiotensin I. Angiotensin I is converted to Ang II by converting enzyme (ACE) in the lungs which has the highest concentrations of ACE. However, formation of Ang II can also occur in the luminal membrane of vascular endothelial cells, in the glomeruli of the kidney, the adrenal glands and in the brain (171, 395). In anephric subjects, low levels of Ang II are detectable in the plasma and are likely from these extrarenal sources (408). Local production of Ang II by the vascular endothelium may help in regulation of vascular tone (251). Additionally, local generation of Ang II by the vascular endothelium plays a role in maintenance of vascular tone and may be a factor in the development of hypertension (170). The direct and indirect actions of Ang II lead to arteriolar vasoconstriction and sodium and water retention. The vasoconstrictive action of Ang II can occur via direct effect on vascular smooth muscle cells or indirectly by stimulation of the sympathetic nervous system. These effects then correct the hypovolemia and hypotension. Ang II directly stimulates
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sodium reabsorption in the early proximal convoluted tubule and also increases secretion of aldosterone (54, 153). Both systemic and locally produced Ang II from the adrenal gland contribute to aldosterone production (171). The effects of Ang II are mediated through the angiotensin type 1 (AT1 ) and type 2 (AT2 ) receptors (119). The vascular and renal tubular actions are mainly mediated by AT1 receptors. AT2 receptor function is not as well characterized but generally opposes the action of AT1 receptors in the vasculature and kidney. Ang II binds to the type I receptor in the zona glomerulosa and leads to upregulation of phospholipase C. This is a G protein-coupled receptor that activates protein kinase C, in turn generating inositol triphosphate and 1, 2 diacylglycerol (281). This generates an increase in intracellular calcium release and activation of protein kinases and transcription factors (282). This eventually leads to activation of aldosterone synthase and to the synthesis of aldosterone (410). Ang II also can activate the sympathetic nervous system via AT1 presynaptic receptors. This results in enhanced arginine vasopressin release, increased ACTH synthesis, and an increase in TSH and growth hormone. Ang II is an important regulator of BP in circumstances when renin secretion is enhanced such as in renal artery stenosis and in normotensive states associated with effectively reduced plasma volume such as in heart failure and cirrhosis of the liver (77, 325). Chronic activation of Ang II leads to vascular remodeling and increased stiffness in the vasculature. Aldosterone actions are modulated by the RAAS. Aldosterone interacts with the pathways regulated by Ang II and the type 1 Ang II receptor (187). Aldosterone increases reactive oxygen species formation, which in turn, activates pathways involved in cell growth, collagen formation and inflammation (223). Therefore, Ang II and aldosterone augment each others actions. Aldosterone also upregulates type 1 Ang II receptors in vascular smooth muscle cells which leads to enhanced vasoconstriction (43). The synergistic effects of aldosterone and Ang II trigger vascular inflammation and fibrosis and contribute to arterial hypertension. In the human, this ultimately leads to LVH and other adverse cardiac sequelae.
Classic Epithelial Actions of Aldosterone The classical actions of aldosterone occur in the kidney and in other transport epithelia such as the colon, the salivary and sweat glands. Aldosterone influences sodium and potassium flux through the ENaC in the distal nephron and collecting ducts. Aldosterone binds to the mineralocorticoid receptor (MR), one of a family of nuclear receptors. The activated receptor-hormone complex binds to hormone-response elements and thereby regulates gene transcription and ultimately sodium excretion (10). Aldosterone increases the residency time of ENaC in the apical epithelial surface leading to enhanced sodium reabsorption (312, 394). Activation of the cytoplasmic MR
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Pathophysiology, Diagnosis, and Treatment of Mineralocorticoid Disorders
by aldosterone leads to expression of the serum and glucocorticoid inducible kinase 1 which is phosphorylated and activates the epithelial sodium channel (47). Sodium absorption is accompanied by water retention and there is a compensatory loss of potassium in the filtrate. The aldosterone-induced reabsorption of sodium and water is a short-lived phenomenon and edema does not usually develop due to “aldosterone escape.” Within days of activation of aldosterone, an increase in sodium wasting occurs with spontaneous diuresis which counteracts the sodium-retentive effects of aldosterone and returns the Na+ balance to equilibrium (15, 134). However, persistent mild hypervolemia leads to increased systemic vascular resistance and also to marked suppression of renin. The mechanism whereby this escape phenomenon occurs is not completely understood. However increased secretion of atrial natriuretic factor resulting from increased volume expansion likely plays a role (418). Additional regulatory processes that are likely to contribute to aldosterone escape include a decreased number of the thiazide-sensitive Na-Cl cotransporters which mediate reabsorption of sodium in the distal tubule (398) and to the mechanism of pressure natriuresis (132).
levels but had little effect on the BP. However, captopril prevented vascular injury in the kidney and reduced the level of proteinuria (291). When exogenous aldosterone was added back to the captopril-treated animals, the proteinuria and vascular injury in the kidney were restored (291). Aldosterone has also been shown to abolish any protective effect of combined ACE inhibition and angiotensin II receptor antagonism (ARB) in a remnant kidney model of hypertension (128). Studies on the role of aldosterone in the development of cerebral lesions were conducted in stroke prone hypertension rats (293). Rats were given 1% NaCl starting at nine weeks of age and were treated with a vehicle vs. eplerenone, an aldosterone antagonist. BP was elevated in both groups of animals. After only 4 weeks of treatment, there were already signs of neurologic injury in the vehicle-treated group and all animals had died by 10 weeks of treatment. There was evidence of severe cerebrovascular injury in the control animals. Nearly all the eplerenone-treated animals were protected from developing stroke or hemorrhagic lesions (293). These findings further demonstrate the importance of aldosterone in the hormonal mediation of vascular injury.
Nonepithelial actions of aldosterone
Aldosterone Synthesis, Secretion, and Action
It is known that aldosterone can also exert adverse effects on nonepithelial tissues including the brain, cardiac tissue, and the vasculature. Mineralocorticoid receptors have been identified in the fibroblasts of the heart, in vascular smooth muscle cells, and in the brain (199, 293, 369). For a time, it was thought that the heart could produce aldosterone under the influence of Ang I or excess sodium, as was demonstrated in a rat myocardial infarction model (335). However, more definitive studies using more sensitive immunoassays and polymerase chain reaction (PCR) studies have conclusively shown that the heart does not produce aldosterone but may take up aldosterone from the plasma (117). Aldosterone synthesized in small amounts in non-adrenal tissue may act in a paracrine fashion and may be important in regulation of cell and vascular function. Long-term effects of aldosterone lead to fibrosis and remodeling of the heart. Brilla et al. demonstrated that in the presence of salt-loading, excess aldosterone leads to collagen formation and cardiac fibrosis in a rat model (34, 35). Furthermore, uninephrectomized rats fed a high salt diet and given aldosterone were protected from the development of cardiac fibrosis by treatment with spironolactone, an aldosterone receptor antagonist. Aldosterone has been implicated as a mediator of vascular inflammation in the kidney and brain in the stroke-prone hypertensive rat. Saline drinking, stroke-prone rats treated with a mineralocorticoid blocker had reduced proteinuria, less renal vascular lesions, and a reduction in stroke and death (289, 290). This despite a nonsignificant reduction in BP in these animals. Additional studies using captopril to suppress RAAS were conducted in stroke prone hypertensive rats. Captopril treatment was shown to reduce aldosterone
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Increased aldosterone production is triggered by sodium depletion and by reduction in the plasma volume. This leads to stimulation of Ang II production through the release of renin from the kidney. Potassium also plays a critical role in modulating aldosterone. Very small increases in potassium (within the physiological range) can have a marked effect on the synthesis of aldosterone. This indicates the sensitivity of the ZG cells in responding to very small changes in the plasma potassium level (391). The effects of K+ and Ang II are synergistic, as aldosterone production in response to Ang II is modulated by the potassium concentration (48). Increased K+ causes depolarization of the cell membrane in the ZG cells. This in turn leads to opening of voltage dependent L- and T-type calcium channels leading to a rapid increase in the intracellular calcium concentration. The rise in calcium causes activation of calmodulin and Ca2+-calmodulin-dependent protein kinases that phosphorylate transcription factors stimulating CYP11β2 gene transcription (338). Visceral adipocytes also have been shown to secrete mineralocorticoid-releasing factors that upregulate aldosterone synthase expression and stimulate aldosterone secretion (79). The major adrenal hormones are synthesized in discrete zones of the adrenal cortex (Fig. 1). Aldosterone is produced in the zona glomerulosa (ZG), glucocorticoids, and sex hormones are produced in the zona fasciculata (ZF) and zona reticularis (ZR), respectively. The ZG has low activity of 17alpha-hydroxylase which limits cortisol and androgen production in this region of the adrenal cortex (283). Aldosterone synthase (CYP11β2) tightly regulates production of aldosterone. The gene for aldosterone synthase
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22
21 18
20 17
12 19 1
9 10
2 3
A
11
5
B
C 8
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Adrenal steroid pathways
23 27
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Cholesterol
7
HO
4
6
CYP11A1 StAR
O
O
HSD3B2 HO
O 11-Deoxycorticosterone
Progesterone
OH
O
O
OH
OH
HO 17 α-Hydroxypregnenolone
HSD3B2
CYP21
O O 17 α-Hydroxyprogesterone 11-Deoxycortisol
OH O
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CYP21
O Pregnenolone
CYP17
OH
OH O
HO
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CYP11B2
O
OH O
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O 18-Hydroxycorticosterone
Corticosterone
O
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O
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Aldosterone zona glomerulosa
OH
OH
CYP11B1 HO
O
O OH
Cortisol zona fasciculate
Figure 1 Adrenocortical steroidogenic pathway. Adrenocortical steroidogenic pathways for the production of mineralocorticoids and glucocorticoids. Reprinted with permission (141); From Fig. 1. p 152.
is located on chromosome 8 in humans. Aldosterone and cortisol have the same early enzymatic pathway. CYP11β2 is expressed in the outermost zona glomerulosa and has three regulatory components. The 11 β-hydroxylase enzyme hydroxylates 11-deoxycorticosterone (DOC) to form corticosterone. 18-hydroxylase converts corticosterone to 18hydroxycorticosterone and finally, 18-oxidase catalyzes conversion of 18-hydroxycorticosterone to aldosterone. Expression of CYP11β2 is controlled by Ang II and potassium. CYP11β1 also has 11β-hydroxylase activity and is expressed in the zona fasciculata and the zona reticularis. As such, this enzyme catalyzes the conversion of 11-deoxycortisol to cortisol under ACTH action in the ZF and ZR (283). In rodents, CYP11β2 is expressed in a narrow zonal band that encircles the adrenal (249). Recently, Nishimoto and colleagues described a group of patients who had a clustering of subcapsular cells of the adrenal gland that expressed CYP11β2 (243). It has been proposed that this phenotype may develop in humans who have chronic excess salt ingestion and could potentially be a precursor to the development of aldosterone-secreting adenomas. Aldosterone production is regulated acutely (within minutes) of stimulation by expression and phosphorylation of the steroidogenic acute regulatory protein (141). This increases movement of cholesterol into the cell, then to the mitochondria. The cholesterol is then converted to pregnenelone and the cascade ensues. Longer term regulation of aldosterone production occurs through enzymes involved in synthesis of aldosterone and its precursors, especially CYP11β2, predominantly through gene expression (20).
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Aldosterone secretion is inversely correlated with extracellular volume. Renin-induced Ang II and potassium both chronically stimulate the secretion of aldosterone. ACTH contributes to the short-term regulation of aldosterone. Acutely, ACTH stimulates blood flow to the adrenal glands and increased aldosterone production by interaction with Gprotein coupled receptors in the ZG cells. Adenylate cyclase is activated leading to increased cAMP levels, in turn activating protein kinase A (318). The cAMP-mediated effects on gene transcription take hours. Chronic administration of ACTH leads to adrenal hyperplasia and hypertrophy of the ZG. With chronic administration of ACTH, CYP11β2 expression and aldosterone levels are suppressed both in humans (97) and in animal models (149). Morning aldosterone (plasma and serum) levels range from about 5 to 30 ng/dL (140-830 pmol/L in SI units) in seated subjects with no restriction in salt intake (6). Black individuals have lower aldosterone levels than whites (273). There is a diurnal variation in aldosterone concentration with the highest level on arising and the lowest at bedtime (165). Aldosterone concentration increases with sodium restriction or sodium diuresis and normally is suppressed with salt or saline loading. With upright posture, aldosterone levels increase (409). Aldosterone levels also rise during the luteal phase of the menstrual cycle (217) and increase up to 10 times normal during the third trimester of pregnancy (400). In PA, the aldosterone level is either elevated or inappropriately in the normal range given the suppressed renin. Dietary sodium is a major factor in regulation and action of aldosterone. The long-term effects of PA are critically
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dependent on excess sodium ingestion in the development of detrimental effects on the vasculature and heart. Aldosterone concentrations are also elevated in secondary aldosteronism due to increased renin and angiotensin levels. Examples of secondary aldosterone states include renal artery stenosis and in renin-secreting tumors. Secondary aldosteronism also occurs in chronic edematous states such as congestive heart failure, cirrhosis, and the nephrotic syndrome (57). In these disorders, there is a relative intravascular hypovolemia and metabolism of aldosterone may be impaired. Levels of aldosterone are low in a number of uncommon hypertensive disorders such as Liddle’s syndrome and in 11 β-hydroxysteroid dehydrogenase deficiency. Aldosterone concentrations are also low in acquired conditions such as ingestion of licorice and in ectopic Cushing’s syndrome (see below). The involvement of aldosterone in the development of hypertension in hyperaldosteronism is well established. A primary increase in aldosterone by an aldosterone secreting tumor or in subjects with idiopathic adrenal hyperplasia leads to sodium and water retention and eventually to hypertension. It has been more difficult to demonstrate a role for aldosterone in the development of essential hypertension. Large doses of aldosterone (threefold increase in plasma aldosterone) in combination with excess salt are required to cause arterial remodeling in human subjects. Under these circumstances, aldosterone stimulates collagen turnover, development of fibrosis, and inflammation in the vasculature. The fibrosis induced by aldosterone is independent of elevated BP. Aldosterone antagonists such as spironolactone block the deleterious cardiac effects of aldosterone (34). Baseline aldosterone concentration was evaluated in a prospective trial of normotensive individuals in the Framingham Offspring Study. Over a 4-year period, the group with the highest quartile of aldosterone concentration had a 1.61-fold increased risk of development of hypertension compared to the lowest quartile group (393). Additional evidence comes from a nested case-control study performed in France (214). The authors followed 1984 nonhypertensive subjects (ages 45-64) and compared them to gender- and BP-matched controls. Multivariate regression analysis demonstrated that plasma aldosterone and renin were positively and negatively associated, respectively, with increasing degree of systolic BP and the development of hypertension over a 5-year period (P = 0.01; P = 0.001, respectively). Aldosterone levels in the higher physiologic range may contribute to the development of hypertension; however, further studies are needed to confirm that this is true.
Primary Aldosteronism Overview PA was reported as a new clinical syndrome when Jerome Conn presented the initial case to the Central Society for Clinical Research in Chicago in 1954 (55). The case was a
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34-year-old woman who had a syndrome of “moderate hypertension,” hypokalemia, metabolic alkalosis, mild hypernatremia, and normal renal function. She did not have Cushingoid features, had no evidence of peripheral edema and was found to have an abundant salt-retaining corticoid in the urine (55, 115). The salt retaining adrenal steroid was hypothesized to be aldosterone, which had recently been discovered (336). The subject underwent lengthy metabolic studies over a 7-month period of hospitalization in 1953. Finally, Conn proposed that the patient be taken to surgery with the expectation that both adrenal glands would need to be surgically resected. He theorized that this would ameliorate the metabolic abnormalities in the patient. Of course in 1953, there were no anatomic localizing studies available, and this type of surgery had never been proposed before. At the time of surgery, a 4-cm adrenal tumor was found in the right adrenal gland and resected. Biopsy of the left adrenal gland demonstrated relative atrophy of the zona fasciculata (56). Within 10 days of the surgery, the metabolic derangements were completely resolved. The BP normalized by the eighteenth day after surgery. Finally, assay of the salt-retaining corticoid demonstrated a return to a normal level after the right adrenalectomy (56). Thus, was born a new syndrome of endocrine hypertension. Over the next decade, Conn and associates expanded the findings of the index case and fully described the syndrome of PA. An interesting side note was that Litynski reported two patients with progressive hypertension and adrenal masses, in the Polish literature in 1953 (197). At the time of necropsy, adrenocortical tumors were found and Litynski suggested that mineralocorticoids were responsible for the hypertension. This report went unrecognized in the English language scientific literature until 1991 (177). After studying a number of patients with the syndrome over the next decade, Conn predicted that PA could occur in up to 20% of all patients with hypertension (57). Others argued that PA was not nearly as common as suggested by Conn et al. and the true estimate was that 2.0 cm, which is larger than the majority of patients with APA. The mutations in KCNJ5 were found only in the affected tumors and not in the adjacent adrenocortical tissue. Thus the KCNJ5 mutations appear to occur in a background of proliferating adrenal cortex. A different mutation in KCNJ5 (T158A) was found in a familial form of PA which occurred in a father and his two young daughters. The affected family members presented with severe hypertension, marked hyperaldosteronism and massive BAH. Bilateral adrenalectomy cured the hypertension (52). This has been termed familial hyperaldosteronism type 3 (FH-III). It is not known why the KCNJ5 mutation in this family led to BAH rather than the development of APAs. Azizan et al. further categorized these mutations in a group of 73 patients from Australia and the United Kingdom and reported that 41% of APAs in their series had a KCNJ5 mutation in the selectivity filter (16). In this study, the subjects with the KCNJ5 mutations were shown to have nonresponsive plasma aldosterone levels to upright posture (16). This is in contrast to normotensive subjects, patients with IHA and in the group of patients with APA without these mutations. Upright posture activates RAAS and aldosterone response is thought to be Ang II-sensitive in these latter three conditions. Boulkroun and colleagues (European Network for the Study of Adrenal Tumors) reported that somatic KCNJ5 mutations were specific to APA and that 129 of 380 patients (34%) studied from a large group of patients in Europe had one of the mutations (31). The subjects with the KCNJ5 mutations were younger, more likely to be women and had higher aldosterone levels compared to control patients. Finally, no germline mutations were found in patients with IHA or in those with cortisol-producing adenomas in this study. Seccia et al. have demonstrated that subjects with an APA who have a KCNJ5 mutation have a higher aldosterone to cortisol ratio (A/C) (lateralization index) from the dominant
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side during adrenal vein sampling (AVS), compared to the subjects without a mutation (328). Taguchi et al. reported in a Japanese series that 15 of 23 patients (65.2%) with an APA had somatic mutations in the KCNJ5 gene (365). Using aldosterone to renin (ARR) screening for hyperaldosteronism in Japan, about 75% of patients with PA are found to have an APA (242). This is in contrast to a 50% to 60% prevalence in other centers around the world. This may account for the higher percentage of patients with an APA having KCNJ5 mutations in Japan. It is possible that in the future, other mutations may be found in the remaining patients with APAs which may contribute to the development of aldosterone producing tumors. The two-pore-domain potassium channel (K2p) family is a widely distributed group of channels encoded by the KCNK gene family. TWIK-related acid-sensitive K (TASK-1) and TASK-3 subunits are expressed in abundance in ZG cells (63, 200). These channels generate a background or leak of K+ and help maintain the negative resting membrane potential and the excitability of the ZG cells to approximately −70 mV (21, 351). In rats, TASK-1 (KCNK3) and TASK-3 (KCNK9) channels are inhibited by activation of AT1 receptors, which leads to depolarization of the cell membrane, a rise in the free calcium intracellular concentration, and an increase in aldosterone production (47). Abundant messenger RNA of TASK-1 has also been found in the adrenal glands of mice and humans (143). TASK channels are, therefore, necessary for constraining aldosterone production in the ZG under normal physiological conditions. Several animal models of hyperaldosteronism have been developed recently. Deletion of TASK-1 and TASK-3 channels in knock-out mice removes a background potassium current and leads to autonomous aldosterone production (66). Aldosterone production in these knock-outs was independent of renin compared to wild-type mice. Furthermore, aldosterone levels were increased on a low salt diet and not suppressed with sodium loading or with Ang II blockade (candesartan) in the affected mice (66). These characteristics are very similar to idiopathic adrenal hyperplasia or BAH in humans. As a further corollary, enhanced Ang-II sensitive aldosterone production is typical of the BAH subtype in PA in humans (58). In another model of hyperaldosteronism, inactivation of TASK1 in female mice led to marked elevation in aldosterone which was independent of sodium intake. The mice lacking TASK1 had low renin levels and developed hypertension and hypokalemia (143). The hyperaldosteronism was inhibited by treatment with glucocorticoids. Aldosterone synthase (CYP11β2) was absent from the outer cortex in these mice which corresponds to the ZG zone, but was abundant in the ZR and ZF. Deletion of TASK3 in mice led to autonomous aldosterone production that was salt-sensitive and caused a milder form of hypertension than those in the TASK1 knockouts (263). This model may be analogous to subjects with low renin
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hypertension. Some have proposed that low renin hypertension is an early stage of PA in that renin levels are suppressed but aldosterone concentrations are still in the normal range (129, 347). On a continuum of low renin hypertension, IHA is thought to represent the last stage and is typified by autonomous aldosterone production. These data indicate that TASK channels could be a pharmacologic target for treatment in hyperaldosteronism. Another model of hyperaldosteronism involves deletion of circadian clock genes in mice. RAAS activation occurs due to sympathetic neuronal activity and is a key regulator of BP (271). BP in mammals is under a circadian rhythm. The nadir of BP occurs in the night (dip) and rises in the morning to the highest level (surge). Subjects who do not have the characteristic dip in BP at night (“nondippers”) or have an excessive surge in the morning have worse cardiovascular outcomes (262). In hypertensive and nonhypertensive humans, peak renin, aldosterone, and cortisol concentrations occur near the time of arising from sleep and contribute to the surge in BP (152). There is similar circadian rhythm of these hormones in rodents. Cry proteins are repressor factors that have been shown to downregulate transcription of several circadian clock genes (178, 416). Deletion of two cryptochrome genes, Cry1 and Cry2 led to salt sensitive hypertension secondary to abnormal aldosterone production by the ZG cells (73). Cry gene inactivation resulted in dysregulation of the type IV 3 βhydroxyl-steroid dehydrogenase (Hsd3b6) enzyme in the ZG zone of the adrenal gland in these mice. HSD3β enzymatic activity was enhanced leading to increased aldosterone production and suppressed renin indicative of autonomous aldosteronism. The mutant mice had a nondipper phenotype and developed hypertension when exposed to a high salt diet. This mouse model of hypertension is similar to IHA (39). The comparable enzyme in humans is HSD3β1 and is also selectively expressed in the ZG. It is possible that polymorphisms that lead to increased HSD3β1 activity may contribute to the development of hypertension in a subset of human subjects, particularly those who are salt-sensitive and are nondippers (314).
Features of primary aldosteronism PA is a heterogeneous group of disorders in which aldosterone production is elevated, and is relatively independent of RAAS modulation. Patients present with hypertension, a suppressed PRA, varying degrees of metabolic alkalosis and mild hypernatremia. Hypokalemia may or may not be present. Patients may have a variable presentation. Many subjects will have symptoms that include muscle aches, cramping and weakness, headaches, palpitations, and polyuria (420). However, other subjects have minimal or no symptoms. Hypomagnesemia may or may not be present. In very rare cases, the subject can present with normal BP (175, 211, 433). Excess aldosterone raises the glomerular filtration rate (GFR) and renal perfusion pressure over time. Increased
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Table 2
Patients Who Should be Screened for Primary Aldostero-
nism
1 Young patients (age less than 35) with hypertension and a family history of early onset hypertension or stroke at a young age 2 Patients with hypertension who have hypokalemia 3 Patients with resistant hypertension 4 Patients who have hypertension and an adrenal nodule 5 Patients with obstructive sleep apnea and hypertension
urinary albumin excretion is common in patients with PA. Patients with hyperaldosteronism have higher levels of creatinine and lower estimated glomerular filtration (eGFR) rates compared to a control group of patients with hypertension (286). In this study, regression analysis demonstrated that age, male gender, hypokalemia, and higher aldosterone levels were independent predictors of a lower eGFR in PA. Many patients with PA have resistant hypertension. Patients with PA need to be distinguished from those patients with low renin hypertension, which makes up 25 to 30% of all cases of hypertension (182, 184). As more patients are being screened for hyperaldosteronism, the majority of subjects diagnosed with PA in the present era have normokalemia. In an international retrospective study of PA, less than 50% of all patients diagnosed with PA had hypokalemia at the time of presentation (231). An important clue is that many patients with PA have serum potassium (K+) levels in the low range of normal, i.e., K+ of 3.5 to 3.9 mmol/L (normal range 3.5-5.0 mmol/L). Patients who should be screened for PA include young patients (age less than 35) with hypertension who have a family history of early onset hypertension or stroke (Table 2). Patients who have hypertension and hypokalemia should obviously be screened. This is true whether or not the hypokalemia is provoked by diuretics. Patients with resistant hypertension have a high incidence of PA and should also be screened. This includes a substantial number of middle aged and older patients with hypertension. Resistant hypertension is defined as BP that remains above goal (generally considered BP >140/90 mmHg or >130/80 in patients with diabetes mellitus or chronic kidney disease) despite treatment with three or more maximally tolerated antihypertensive medications of different classes (36). A diagnosis of resistant hypertension increases the chance of having a secondary form of hypertension (51, 162). Patients who have resistant hypertension by definition, excludes those who have improperly measured BP, are nonadherent in taking antihypertensive agents or in following lifestyle modification, are on inadequate doses of BP lowering medications or have white coat hypertension (36, 71). Patients with resistant hypertension have a prevalence of PA of about 20% (37). In Birmingham, Alabama, 88 consecutive patients with resistant hypertension underwent testing and 20% were found to have PA based on rigorous screening and confirmatory testing (37). There was no difference in the rates of PA in black and
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white subjects in this study. Gallay and colleagues screened 90 consecutive patients with resistant hypertension and found a 17% prevalence of PA (103). Similar findings were found in Oslo, Norway (80). In a prospective study of 100 consecutive patients with type 2 diabetes and resistant hypertension, Umpierrez et al. found that 14% had PA following confirmatory testing (390). In a large retrospective study of 1616 patients with resistant hypertension, Douma et al. found that 11% were confirmed as having PA (75). Patients with an adrenal nodule who have hypertension should be screened for PA as should those with a familial form of hyperaldosteronism (Table 2). Approximately 1% of subjects with an adrenal incidentaloma have PA (422). The recommendations for case screening listed above are similar to but not identical to the Endocrine Society Practice Guidelines published in 2008 (100). The Japanese Society of Hypertension has similar recommendations for screening patients with hypertension for PA (159). Other patients who have a high probability of PA include those with obstructive sleep apnea. Obstructive sleep apnea was present in 85% of subjects with resistant hypertension in one study (274). Additionally, there was a significant correlation between plasma aldosterone levels and the severity of sleep apnea. In a study of 109 patients with resistant hypertension, 77% of the subjects had obstructive sleep apnea and 28% had hyperaldosteronism (118). Other investigators have suggested that there is a relationship between obesity, the metabolic syndrome and PA. In a prospective study of 466 patients with hypertension, 85 patients were found to have PA. The prevalence of the metabolic syndrome (according to criteria from the National Cholesterol Education Program Adult Treatment Panel III; (237) was 41.1% in subjects with PA and 29.6% in those with essential hypertension; P < 0.05 (83). The rates of hyperglycemia were also found to be higher in the patients with PA in this study. In a retrospective case control study in Germany, patients with PA had a prevalence of diabetes that was more than twofold higher than an age, gender and BP-matched cohort of subjects with hypertension (285). First phase insulin release was found to be significantly impaired during an intravenous glucose tolerance test in subjects with PA compared to normal controls and those with hypertension (92). Finally, hyperaldosteronism was recognized as an endocrine cause of diabetes mellitus by the American Diabetes Association in 2008 (72).
Cardiovascular effects of excess aldosterone in humans The initial series of 145 patients with hyperaldosteronism that Conn and his group reported in 1964 had a low number of cardiovascular events (59). Only in the last two decades has it been recognized that patients with PA have substantially higher risk for cardiovascular disease. Patients with PA have a higher propensity to develop LVH and LV mass compared to patients with essential hypertension (EH) who
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have similar BP readings. Greater LV mass was found in a group of subjects with PA compared with patients with other forms of hypertension, including EH, Cushing’s syndrome, and pheochromocytoma when matched for age, gender and duration of hypertension (372). Shigematsu et al. found that eccentric LVH preceded other end organ damage in subjects with PA compared to patients with EH (332). Rossi et al. also reported a higher prevalence of LVH and increased left ventricular mass in patients with PA compared to EH (308). Similarly, diastolic dysfunction has been reported to be more common in patients with PA (305). Endothelial dysfunction is also common in patients with hyperaldosteronism (364). These abnormalities contribute to remodeling and fibrosis in the heart. Dietary sodium intake in humans has a key role in the target organ damage that results from PA as was initially reported in animal studies. In a case control study of 21 patients with PA compared to 21 patients with EH, 24 h urinary sodium excretion was predictive of left ventricular wall thickness and mass in subjects with PA but not in those with EH (267). Milliez et al. were one of the first groups to report a higher number of cardiac events in subjects with PA compared to EH (220). In an evaluation of 124 patients with PA compared to a group of 465 patients with essential hypertension, the incidence of stroke was 12.9% for PA and 3.4% in patients with EH (odds ratio 4.2). The odds ratio of a nonfatal myocardial infarction was 6.5 times higher in those with PA compared to those with EH. Finally, the odds of atrial fibrillation were 12.1 in subjects with PA. In this retrospective study, cardiac complications were similar in patients with an aldosterone secreting adenoma and BAH (220). In a larger controlled study, Savard et al. compared the cardiovascular event rates in 459 patients with PA to 1290 control patients with EH who were matched for age, gender, and systolic BP (321). Patients with PA had a twofold higher likelihood of having LVH by echocardiogram than subjects with EH in this study. Subjects with PA had a higher prevalence of coronary artery disease (odds ratio of 1.9) than patients with EH. Similarly, the adjusted odds ratios of nonfatal myocardial infarction (2.6), congestive heart failure (2.9), and atrial fibrillation (5.0) were substantially higher in patients with PA compared to those with EH (321). These data underscore the adverse effects of excess aldosterone and that the higher cardiovascular complications from PA are at least in part independent of the BP. In another trial, 180 patients with PA were prospectively followed using serial echocardiogram and compared to 143 patients with EH (303). At baseline, the subjects with PA had greater LV mass than comparably matched patients with EH. At a mean follow-up of 36 months, the subgroup with APA who underwent adrenalectomy had similar BP control as those treated with mineralocorticoid antagonists and those with EH. There was significant regression of LVH and LV mass by reverse inward LV remodeling in both the surgically and medically treated group of patients with PA during the study (303).
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Additional evidence of the adverse effects of aldosterone on the heart come from studies conducted in patients with familial hyperaldosteronism. Stowasser’s group found concentric remodeling, increased left ventricular wall thickness, and reduced diastolic function in normotensive subjects with familial hyperaldosteronism type 1 (FH-1) compared to BPmatched control subjects (357). Further evidence of the adverse effects of excess aldosterone come from large randomized clinical trials. The Randomized Aldactone Evaluation Study (RALES) evaluated patients with congestive heart failure on standard treatment with ACE-inhibitors and diuretics, who were randomized to treatment with the MR antagonist, spironolactone versus placebo and the outcomes were striking (270). In patients with New York Heart Association Class III heart failure, the patients treated with an average dose of 26 mg/day of spironolactone had a 30% reduction in mortality and a 35% lower rate of hospitalization. About 10% of the men who were treated with spironolactone during the RALES trial developed gynecomastia. A second major trial, Eplerenone Postacute myocardial infarction Heart failure Efficacy and SUrvival Study (EPHESUS), involved treatment with the MR antagonist, eplerenone combined with standard treatment that included beta blockers and ACE-inhibitors and was conducted in 6632 patients who had heart failure following myocardial infarction (269). Eplerenone is a newer, selective aldosterone antagonist without progestational and androgenic side effects typical of spironolactone (432). The drug does not generally cause menstrual abnormalities, gynecomastia, or reduced libido as seen with spironolactone (401). At a mean of 16 months following randomization in the EPHESUS trial, there was a 15% reduction in mortality in the eplerenone treated group. There was a 17% lower cardiovascular mortality rate in those patients treated with eplerenone compared to placebo. A major difference in the RALES and EPHESUS trials was that only about 10% of the patients in the RALES trail were treated with beta blockers whereas 75% of the subjects received beta blockers in the EPHESUS trial. However, in the EPHESUS trial, a subset of patients with lower ejection fractions (LVEF
