4 FORMS OF MINERALOCORTICOID HYPERTENSION
PAOLO FERRARI AND OLIVIER BONNY
Division of Nephrology and Hypertension, Inselspital, University of Berne, 3010 Berne, Switzerland
I. Introduction
II. Evolution, Salt, and the Renin-Angiotensin- Aldosterone System
III. Key Elements of Mineralocorticoid Activity
A. Aldosterone Synthase
B. 11B-Hydroxysteroid Dehydrogenase Type 2
C. Mineralocorticoid Receptor
D. Epithelial Sodium Channel
IV. Mineralocorticoid Hypertension
V. Primary Aldosteronism
A. Prevalence
B. Clinical and Laboratory Findings
C. Screening
D. Further Evaluation and Diagnosis
E. Subtype Delineation
F. Therapy
VI. Genetic Forms of Mineralocorticoid Hypertension
A. Mutations of the 11}-Hydroxylase or 17a-Hydroxylase Gene: Congenital Adrenal Hyperplasia
B. Chimeric 11ß-Hydroxlase-Aldosterone Synthase Gene: Glucocorticoid-Remediable Aldosteronism
C. Mutations of the 110-Hydroxysteroid Dehydrogenase Type 2 Gene: Apparent Mineralocorticoid Excess
D. Mutations of the Mineralocorticoid Receptor Gene
E. Mutations of the Epithelial Sodium Channel Genes: Liddle Syndrome
VII. Aldosterone-Dependent Essential Hypertension References
Hypertension with hypokalemia, metabolic alkalosis, and suppressed plasma renin activity defines mineralocorticoid hypertension. Miner- alocorticoid hypertension is the consequence of an overactivity of the epithelial sodium channel expressed at the apical membrane of renal cells in the distal nephron. This is usually the case when the mineralocorticoid receptor is activated by its physiologic substrate aldosterone. The best known form of mineralocorticoid hypertension is an aldosterone- producing adrenal tumor leading to primary aldosteronism. Primary aldosteronism can also be caused by unilateral or bilateral adrenal hyperplasia and rarely adrenal carcinoma. Interestingly, most of the inherited monogenic disorders associated with hypertension involve an excessive activation of the mineralocorticoid axis. In some of these disorders, mineralocorticoid hypertension results from activation of the mineralocorticoid receptor by other steroids (cortisol, deoxycorticoster- one), by primary activation of the receptor itself, or by constitutive overactivity of the renal epithelial sodium channel. The present review addresses the physiology and significance of the key players of the mineralocorticoid axis, placing emphasis on the conditions leading to mineralocorticoid hypertension. @ 2003 Elsevier Science (USA).
I. INTRODUCTION
Mineralocorticoid hypertension refers to a primary, renin-independent activation of the mineralocorticoid axis, leading to hypertension because of excessive sodium and water retention by the distal tubule of the kidney. The resulting blood volume expansion suppresses endogenous plasma renin activity. At the cellular level mineralocorticoid hypertension is the consequence of overactivity of the renal epithelial sodium channel. The channel activity is regulated by aldosterone via the mineralocorticoid receptor; however, other steroids, including cortisol, show mineralocorticoid activity. In mineralocorticoid target tissues the enzyme 113-hydroxysteroid dehydrogenase inactivates cortisol into cortisone, thus preventing
overactivation of the receptor by glucocorticoids. The paradigm for mineralocorticoid hypertension is aldosteronoma, an aldosterone-producing adrenal tumor. Moreover, the vast majority of inherited monogenic hypertensive disorders involve an excessive activation of the mineralocorti- coid axis. In some of these disorders, hypertension is not the sole feature, as is the case for congenital adrenal hyperplasia, in which hypertension is accompanied by abnormal sexual differentiation. In other cases hyperten- sion is the unique or preeminent abnormality of the genetic defect. The molecular basis of several forms of severe hypertension transmitted on an autosomal basis has been elucidated. These disorders are a consequence of either abnormal biosynthesis, metabolism, or action of steroid hormones and are ultimately characterized by an overactivation of the epithelial sodium channel. This review details some aspects of the physiology of the renin-angiotensin-aldosterone system and of the key players of the mineralocorticoid axis. Specific conditions leading to mineralocorticoid hypertension are addressed in the second part of the overview.
II. EVOLUTION, SALT, AND THE RENIN- ANGIOTENSIN-ALDOSTERONE SYSTEM
There is little doubt that life on our planet first generated in the sea (Griffith, 1987). This is not surprising, because the sodium concentration in seawater averages 170 mmol/liter, a value remarkably close to the extracellular sodium concentration in mammals. Evolution to terrestrial life meant leaving behind the sea and its continuous source of salt and water. Water on land, when available, was fresh, and thus adaptation to land necessitated the development of mechanisms to preserve salinity (Cirillo et al., 1994). This task of regulating salt and water balance was taken over by the kidney (Frassetto et al., 2001; Smith, 1964). Regulation of salt and water occurs in the renal medulla, which developed differently among species, being more prominent in those with a high urine-concentrating capacity (Kriz, 1981). It is therefore not surprising that the nephron in salt- water fish possesses only primitive segments responsible for concentration of the urine, such as the intermediate segment and the collecting duct, and an overdimensioned proximal tubule, whose function is to warrant isotonic reabsorption. Freshwater fish must deal with an excess supply of free water, and therefore their nephrons have an extremely developed distal tubule, whose function is to dilute the urine. The appearance of well-developed nephron elements, such as the loop of Henle and the collecting duct, in order to provide sufficient concentration of the urine by increasing sodium and water reabsorption can best be observed in humans and other terrestrial mammals. Of interest is the observation that a regulated renal tubular sodium reabsorption can largely be documented only in mammals, because
| Structure | Function | ||||
|---|---|---|---|---|---|
| Juxtaglomerular cells | Macula densa | Aldosterone | Pressor | Na+ transport | |
| Seawater fish | Granules | - | - | + | - |
| Freshwater fish | Granules | - | - | + | - |
| Amphibians | + | + | (+)ª | + | - |
| Reptiles | + | + | (+) | + | - |
| Mammals | + | + | + | + | + |
aldosterone can be found almost exclusively in mammals (Table I). This evolutionary adaptation of the nephron indicates the central role of the kidney in the regulation of sodium and water balance and hence of blood pressure.
Normal regulation of salt and water homeostasis in mammals is controlled in a negative-feedback loop by the renin-angiotensin-aldosterone system (Corvol et al., 1984). The key players of this system are renin, released by the juxtaglomerular cells of the afferent arterioles and macula densa cells of the kidney, and aldosterone, produced by the adrenal glands (Fig. 1). Renin cleaves the biologically inactive decapeptide angiotensin I from its precursor angiotensinogen, which is released in the circulation by the liver. Angiotensin I is rapidly transformed to the active octapeptide angiotensin II by the angiotensin-converting enzyme present in large amounts in the membrane of endothelial cells of the lungs. Angiotensin II has several important direct and indirect effects for the maintenance of circulatory homeostasis. Direct effects include the vasoconstriction of the renal and systemic circulations and the reabsorption of sodium in proximal segments of the nephron. Indirect effects are mediated by stimulating the adrenal cortex to secrete aldosterone (Fig. 1), which promotes the reabsorption of sodium (in exchange for potassium) in epithelial tissues such as the cortical collecting duct of the kidney, the colon, and the salivary and sweat glands. Plasma concentrations of renin, angiotensin II, and aldoster- one rise in response to a contraction of intravascular volume and a reduction in renal perfusion and are suppressed by intravascular volume expansion. Angiotensin II is the principal stimulator of aldosterone production when intravascular volume is reduced (Miller et al., 1968; Tobian, 1967) (Fig. 1). Potassium is also a major physiologic stimulus to aldosterone production; aldosterone secretion is integral to potassium homeostasis because aldosterone has the ability to increase potassium excretion in urine, feces, sweat, and saliva (Silva et al., 1977). Aldosterone thereby serves to prevent hyperkalemia during periods of high potassium
Angiotensinogen
Renin
Angiotensin I
Afferent arteriole
Granular cells
Angiotensin II
Efferent arteriole
Sympathetic nervous system
Juxtaglomerular apparatus
Macula densa
Aldosterone
Adrenal gland
intake. For example, aldosterone secretion rises after the consumption of foods high in potassium content or after vigorous physical activity that causes the release of potassium from skeletal muscle. Although there is some evidence that adrenocorticotropin (ACTH) might regulate the expression of aldosterone synthase in rodents, a physiologic role for ACTH-regulated aldosterone secretion in humans is lacking.
III. KEY ELEMENTS OF MINERALOCORTICOID ACTIVITY
A. ALDOSTERONE SYNTHASE
The most potent corticosteroids are 113-hydroxylated compounds. In humans, two cytochrome P450 isoenzymes with 113-hydroxylase activity, catalyzing the biosynthesis of cortisol and aldosterone, are present in the
Cholesterol
CYP17
Pregnenolone
17a-OH-progesterone
Dehydro- epiandrosterone
Progesterone
17a-OH-progesterone
4-Androstendione
11-Deoxycorticosterone
11-Deoxycortisol
CYP11B1
Corticosterone
Cortisol
CYP11B2
18-OH-corticosterone
Aldosterone
| MINERALOCORTICOIDS | GLUCOCORTICOIDS | ANDROGENS |
|---|---|---|
| Zona glomerulosa | Zona fasciculata | Zona reticularies |
FIGURE 2. The pathways of biosynthesis of aldosterone and cortisol from cholesterol. Adrenal steroid biosynthesis is catalyzed by several forms of cytochrome P450 and two hydroxysteroid dehydrogenases. Inherited forms of mineralocorticoid hypertension can result from genetic variants in the enzymes enclosed in boxes. The last three enzymatic conversions required for aldosterone biosynthesis are mediated by a single enzyme, aldosterone synthase (encoded by CYP11B2). Deficiencies in 17a-hydroxylase (CYP17) and 113-hydroxylase (CYP11B2) result in hypertension associated with excess 11-deoxycorticosterone.
adrenal cortex: 113-hydroxylase and aldosterone synthase (Fig. 2). The gene encoding aldosterone synthase (CYP11B2) is expressed in the zona glomerulosa under primary control of the renin-angiotensin system. Aldosterone synthase has 113-hydroxylase activity as well as 18-hydroxylase activity and 18-oxidase activity (Fig. 2). The 113-hydroxylase gene (CYP11B1) is expressed in the zona fasciculata and is under the control of ACTH. The substrate for the CYP11B2-encoded protein is 11-deoxycorti- costerone, and that of the CYP11B1-encoded protein is 11-deoxycortisol. The CYP11B2 gene was isolated as a cross-hybridizing gene while cloning and analyzing the CYP11B1 gene (Mornet et al., 1989). The sequence of CYP11B2 is approximately 95% identical to CYP11B1 in coding regions and 90% identical in introns. The 5’-upstream region has diverged considerably from that of CYP11B1, suggesting that this second gene, if expressed, may be regulated differently. Both putative proteins contain
503 amino acids, including a 24-residue signal peptide. This gene was previously thought to be a pseudogene or a less active gene closely related to CYP11B1. Kawamoto et al. (1992) showed that the nucleotide sequence of the promoter region of the CYP11B2 gene, which encodes steroid 18-hydroxylase, is strikingly different from that of the CYP11B1 gene, although the sequences of their exons are almost identical. Studies in cultured cells demonstrated that CYP11B2 encodes an enzyme with steroid 18-hydroxylase activity to catalyze the synthesis of aldosterone and 18-oxocortisol and exhibits steroid 113-hydroxylase activity as well. On the other hand, CYP11B1 as expressed in the cultured cells exhibited steroid 113-hydroxylase activity exclusively. These findings indicated that the two enzymes are products of two different genes and that the 11,3- hydroxylase enzyme participates in the synthesis of glucocorticoids, whereas the C-18 enzyme participates in the synthesis of mineralocorticoids in humans (Kawamoto et al., 1992). Curnow et al. (1991) likewise identified the CYP11B2 gene as that for the aldosterone-synthesizing enzyme.
B. 113-HYDROXYSTEROID DEHYDROGENASE TYPE 2
The 113-hydroxysteroid dehydrogenase (113HSD) enzymes catalyze the interconversion of the endogenous cortisol and cortisone in humans (Fig. 3) or of corticosterone and dehydrocorticosterone in rodents (Funder et al., 1988). Cortisone and dehydrocorticosterone exhibit hardly any biological activity because they have negligible affinity for glucocorticoid and mineralocorticoid receptors. Depending on the equilibrium between the biologically active 113-hydroxysteroids and the inactive 11-ketosteroids in a given cell, it might be predicted which cells do and do not respond to cortisol or corticosterone via either glucocorticoid or mineralocorticoid receptor activation (Edwards et al., 1988; Escher et al., 1997; Funder et al., 1988, 1990). Two kinetically distinct forms of 113HSD (113HSD1 und 113HSD2), differentiated in addition by cofactor specificity and differential tissue expression, have been cloned (Agarwal et al., 1989, 1995; Albiston et al., 1994; Tannin et al., 1991; Walker et al., 1992). 113HSD1 activity and expression is found in most tissues; its Km for cortisol is more than an order of magnitude higher than that of 113HSD2; it is NADP(H) preferring and has been shown to have predominantly reductase activity in vivo (Agarwal et al., 1989; Tannin et al., 1991). The role of 113HSD1 was investigated in mice lacking 113HSD1. These animals are unable to convert 11-dehydrocorticosterone to corticosterone in vivo, confirming 113HSD1 as the sole 11-reductase in the mouse, and show reduced activation of glucocorticoid-induced processes (Holmes et al., 2001; Kotelevtsev et al., 1997). 113HSD1-deficient mice have elevated circulating levels of plasma corticosterone levels and adrenal hyperplasia, but they also have attenuated glucocorticoid-induced activation of gluconeogenic enzymes in response to
CH2OH
CH2OH
NAD
HO
C=0
C=0
OH
11ßHSD2
0
OH
O
O
Cortisol
Cortisone
HO CH2OH
O
HC C=O
MR
O
Aldosterone
FIGURE 3. Peripheral cortisol metabolism and mineralocorticoid receptor selectivity. Cortisol and aldosterone bind with equal affinity to the mineralocorticoid receptor (MR). Plasma concentrations of cortisol are much higher than those of aldosterone, but in mineralocorticoid-responsive cells 113-hydroxysteroid dehydrogenase type 2 (113HSD2) in the endoplasmic reticulum converts cortisol to cortisone, which is not a ligand for the MR, permitting aldosterone to occupy the receptor. The hemiacetal conformation of the 11-hydroxyl group with the 18-aldehyde group of aldosterone renders this steroid a poor substrate for the enzyme.
fasting, and lower glucose levels in response to obesity or stress. Also, 113HSD1 deficiency produces an improved lipid profile, hepatic insulin sensitization, and a potentially atheroprotective phenotype (Morton et al., 2001). In contrast, 113HSD2 has been identified to date in a limited range of tissues (Agarwal et al., 1995; Albiston et al., 1994; Walker et al., 1992); it has a high affinity for cortisol, is NAD requiring, and appears to show only dehydrogenase activity for endogenous glucocorticosteroids (Albiston et al., 1994; Li et al., 1997; Walker et al., 1992) (Fig. 3), although reduction of dehydrodexamethasone has been demonstrated in vitro (Ferrari et al., 1996c). Importantly, immunohistochemical studies have consistently localized 113HSD2 to the distal tubules (Agarwal et al., 1994; Albiston et al., 1994; Krozowski et al., 1995; Naray-Fejes-Toth et al., 1991; Walker et al., 1992). The microsomal 113HSD2 enzyme has a luminal orientation with the catalytic domain facing the cytoplasm (Odermatt et al., 1999).
Whereas the relevance of 113HSD enzymes for the regulation of the access of steroid molecules to the glucocorticoid receptor has been established only in cell culture experiments (Escher et al., 1997; Teelucksingh et al., 1990; Whorwood et al., 1993) and in transgenic mice (Holmes et al., 2001; Kotelevtsev et al., 1997), the clinical relevance of 113HSD2 activity for mineralocorticoid receptor activation is well defined for some disease states in humans. The activity of the 113HSD2 enzyme can be reliably assessed in vivo by measuring the ratio of biologically active cortisol (F) to inactive cortisone (E), or their tetrahydrometabolites (THF and THE), in the urine, using gas chromatography with mass spectrometry (Ferrari et al., 2001b; Shackleton, 1993). An increased urinary free F:E ratio or urinary (THF + 5aTHF): THE ratio indicates decreased 113HSD2 activity.
C. MINERALOCORTICOID RECEPTOR
There are two types of classic corticosteroid receptor: the high-affinity type 1 or mineralocorticoid receptor (MR) (Arriza et al., 1987) and the lower affinity type 2 or glucocorticoid receptor (GR) (Hollenberg et al., 1985), which are structurally highly homologous. Glucocorticosteroids, corticosterone in rodents and cortisol in humans, bind to MR with high affinity, similar to that of the mineralocorticoid hormone aldosterone (Krozowski and Funder, 1983), and, conversely, aldosterone binds to the human GR with lower affinity, similar to that of cortisol. Molecular cloning of the GR and MR allowed the determination of their primary amino acid structures and prediction of common functional domains. GR and MR display a high degree of identity in their amino acid sequences, with the exception of the variable N-terminal region. The human MR gene encodes a protein of 984 amino acid residues with a predicted molecular size of 107 kDa (Arriza et al., 1987). Structurally and functionally defined domains are observed within the MR and GR receptors (Mangelsdorf and Evans, 1995). The N-terminal part contains the domain A/B, which is involved in transcriptional activation. The central part includes the DNA-binding domain (DBD or C), which is responsible for DNA binding and recognition of the specific hormone-responsive element (HRE) sequences. Domain E, which represents the ligand-binding domain (LBD or E), also contains sequences that are involved in nuclear translocation, receptor dimerization, hormone-regulated transactivation, and interaction with heat shock proteins. On binding to an agonist, the receptor undergoes a major conformational change (transconformation). A number of contact sites are required for proper transconformation and have been identified by site- directed mutagenesis (Fagart et al., 1998) and by the discovery of a gain- of-function mutation leading to a constitutively active receptor, causing a severe hypertensive phenotype (Geller et al., 2000). Dimerization of steroid receptors is a prerequisite for binding to specific HREs lying in the promoter
Extracellular loops
a
Y
₿
a
C
Cytoplasmatic domains
N
C
N
region of the target gene. In aldosterone target cells, MR is always coexpressed with GR and it has been proposed that MR can heterodimerize with GR, or other transcription factors such as AP-1, allowing more diversity in the physiological response to mineralo- or glucocorticoid hormones, but the in vivo relevance of the phenomenon remains to be established (Bamberger et al., 1997; Pearce and Yamamoto, 1993).
D. EPITHELIAL SODIUM CHANNEL
The epithelial sodium channel (ENaC) is characterized by a high selectivity for sodium over potassium, a low unitary conductance, long open and closed time, and a high affinity for the potassium-sparing diuretics amiloride and triamterene (Garty and Palmer, 1997). The genes encoding ENaC were identified by functional expression cloning (Canessa et al., 1993, 1994b). ENaC is a heteromultimeric protein made of three subunits, termed a, 3, and y ENaC (Canessa et al., 1994b) (Fig. 4). All three subunits share about 35% homology at the amino acid level and adopt the same topology, with two transmembrane domains, short intracellular amino and carboxy ends, and a large extracellular loop corresponding to about 70% of the protein mass. When all three subunits are expressed in the same cell, they assemble according to a preferential heterotetrameric structure (Firsov et al., 1998). All three subunits are expressed in the main aldosterone-sensitive target cells or tissues, namely, the last part of the nephron in the kidney (Duc et al., 1994; Loffing et al., 2000), in the distal colon, in the ducts of salivary and sweat glands (Duc et al., 1994), and in the lung, where they could be expressed differentially along the pulmonary tree (Matsushita et al., 1996; Talbot et al., 1999). A highly conserved region in the cytoplasmic
N-terminal domain is involved in the gating of the channel (Grunder et al., 1997, 1999). Another important feature of the N-terminal region is the presence of numerous lysine residues. Staub et al. (1997) demonstrated that these residues (especially on the y and & subunits) can be ubiquitinated, and are key elements determining the half-life of the channel. The extracellular loop is the largest domain of the protein, encoded by 10 different exons, in comparison with the N and C termini, which are each encoded by 1 exon. It contains several glycosylation sites (Canessa et al., 1994a; Snyder et al., 1994). Schild et al. (1997) found point mutations that affect substantially the amiloride sensitivity on the three subunits. The intracellular C terminus contains several functional domains involved in the regulation of the number of channels present at the cell surface. A PPPxY motif is present on all three ENaC subunits. Deletion or missense mutations of this motif on the 3 and y subunits are found in patients affected by Liddle syndrome, underscoring its importance in channel regulation (Hansson et al., 1995a,b; Shimkets et al., 1994; Snyder et al., 1995). In Liddle syndrome, the channel is hyperactive because of two factors: an increased number of channels present at the cell surface and an increased intrinsic activity of ENaC. The so-called PY motif is the target of Nedd4, a ubiquitin-protein ligase, which binds to the PY motif through its WW domains (Staub et al., 1996). The binding allows the ubiquitination of ENaC and its degradation. The PY motif could also play a role in the regulation of the number of channels present at the cell surface by acting as an endocytic signal (Shimkets et al., 1997). Another possibility of ENAC regulation is phosphorylation. Aldosterone and insulin were found to increase basal phosphorylation of the 3 and y subunits, when channel subunits were stably expressed in MDCK cells (Shimkets et al., 1998). However, the phosp- horylated residues are not yet identified and the functional relevance has not been established.
ENaC is regulated by intracellular as well as by extracellular signaling pathways. Hormones such as aldosterone, vasopressin, insulin, or gluco- corticoids regulate ENaC expression and/or activity by intracellular signaling cascades (Garty and Palmer, 1997; Verrey, 2001). A high intracellular concentration of sodium inhibits ENaC by a feedback mechanism (Abriel and Horisberger, 1999). Several kinases have been implicated in the regulation of ENaC (Garty and Palmer, 1997). In particular, the aldosterone-induced SGK (serum and glucocorticoid- regulated kinase) was shown to increase ENaC activity and the number of channels present at the cell surface (Chen et al., 1999; Loffing et al., 2001; Naray-Fejes-Toth et al., 1999) and this effect is mediated by the phosphorylation of Nedd4 (Debonneville et al., 2001). Cytoskeleton elements could also play a role in regulating ENaC function. Actin (Jovov et al., 1999), a-spectrin (Rotin et al., 1994), and syntaxins (Saxena et al., 1999) were reported to influence ENaC function.
Luminal high sodium concentrations have been described to down- regulate ENaC by self-inhibition (Palmer et al., 1998). Extracellular serine proteases [trypsin and channel-activating protease (CAP-1)] activate ENaC by an extracellular signaling pathway (Vallet et al., 1997; Vuagniaux et al., 2000), but the molecular mechanisms of their effect has not yet been elucidated.
IV. MINERALOCORTICOID HYPERTENSION
Mineralocorticoid hypertension results from excessive sodium and water retention by distal nephron segments because of a renin-independent activation of the mineralocorticoid axis, and it can occur as a sporadic condition (primary aldosteronism) or as a consequence of mutations in key elements of the adrenal-renal axis (Ferrari, 2002; Ferrari et al., 2001a; Stewart, 1999) (Fig. 5 and Table II). The resulting blood volume expansion suppresses endogenous plasma renin activity. Because sodium reabsorption in the distal nephron is coupled with enhanced tubular secretion of potassium and protons, hypokalemia and metabolic alkalosis are also common metabolic features of mineralocorticoid hypertension. Overt hypernatremia possibly related to a reset osmostat is rare (Gregoire, 1994), presumably because intravascular volume expands commensurately with sodium retention. The paradigm for this form of hypertension with sodium retention is aldosteronoma (Ganguly, 1998; Stowasser, 2001), a condition in which overproduction of aldosterone by an adrenal tumor results in excessive stimulation of the MR. At a cellular and molecular level mineralocorticoid hypertension is the consequence of overactivity of the ENaC, the gradient-driven sodium channel located in the apical membrane of the principal cells of the cortical collecting duct of the kidney (Figs. 5 and 6). This is usually the case when the MR is activated by its physiologic substrate aldosterone. The MR is a specific nuclear receptor that on binding with aldosterone enhances the expression of the apical ENaC and basolateral Na+,K+-ATPase (Horisberger and Rossier, 1992) (Fig. 6). Aldosterone is not the sole agonist of the MR, and other steroids, showing mineralocorticoid activity in vivo, are 11-deoxycorticosterone (DOC) and cortisol (Fig. 5). In mineralocorticoid target tissues the microsomal enzyme 113HSD (Funder et al., 1988) converts the biologically active 11- hydroxysteroids to their inactive 11-ketosteroid forms (Fig. 3), thus protecting the nonselective MR from excess occupation by glucocorticoids. Abnormalities in steroid synthesis have long been known to cause hypertension in some cases of congenital adrenal hyperplasia. In these patients, hypertension usually accompanies a characteristic phenotype with abnormal sexual differentiation. The molecular basis of four forms of severe hypertension transmitted on an autosomal basis but without additional
A
B DOC
Aldosterone
Cortisol
C
D
MR
Cortisone
E
ENaC
Îl Renal Na+-reabsorption, volume expansion, hypertension
phenotypic features has been elucidated. All these conditions are characterized primarily by low plasma renin, normal or low serum potassium, and salt-sensitive hypertension, indicating an increased miner- alocorticoid effect. These disorders are a consequence of either abnormal biosynthesis, metabolism, or action of steroid hormones and are ultimately characterized by an overactivation of the epithelial sodium channel in the distal renal tubule causing sodium retention and salt-sensitive hypertension.
V. PRIMARY ALDOSTERONISM
The term primary aldosteronism (PA) is used to describe a heterogeneous group of conditions characterized by an overproduction of aldosterone by the zona glomerulosa of the adrenal gland (Table II). Aldosterone secretion
| Cause | Mineralocorticoid | Genetic abnormalityª |
|---|---|---|
| Primary aldosteronism | Sporadic Aldosterone | — |
| Aldosterone-producing adenoma | ||
| Bilateral idiopathic hyperplasia | ||
| Adrenal carcinoma | ||
| Deoxycorticosterone-secreting adrenal tumor | Deoxycorticosterone | — |
| Inherited | ||
| Congenital adrenal hyperplasia | Deoxycorticosterone | |
| 113-Hydroxylase deficiency | CYP11B1 | |
| 17a-Hydroxylase deficiency | CYP17 | |
| Familial hyperaldosteronism type I | Aldosterone | |
| Glucocorticoid-remediable aldosteronism | Chimeric (CYP11B1/CYP11B2) | |
| 113-Hydroxysteroid dehydrogenase type 2 deficiency | Cortisol | |
| Apparent mineralocorticoid excess | HSD11B2 | |
| Mineralocorticoid receptor mutations | Progesterone | |
| Activating mutation of the mineralocorticoid receptor | MR | |
| Liddle syndrome | None | |
| 3 subunit of ENaC | SCNN1B | |
| y subunit of ENaC | SCNN1G |
ªCYP11B1, Cytochrome P450, subfamily XIB, polypeptide 1 (113-hydroxylase); CYP11B2, cytochrome P450, subfamily XIB, polypeptide 2 (aldosterone synthase); CYP17, cytochrome P450, subfamily XVII (17a-hydroxylase); HSD11B2, 113-hydroxysteroid dehydrogenase type 2; MR, mineralocorticoid receptor; SCNN1B/G, sodium channel, nonvoltage gated 1, 3/y subunit.
in primary aldosteronism is partially autonomous, and the plasma renin level is low. Known causes of PA are adrenocortical adenoma, bilateral micronodular or macronodular adrenal hyperplasia (idiopathic aldosteron- ism), unilateral adrenal hyperplasia, adrenal carcinoma, or a genetic form, called glucocorticoid-remediable aldosteronism (Table II). The latter, also known as familial hyperaldosteronism type I, is discussed in detail in Section VI. Moreover, a few cases of extraadrenal aldosterone-producing tumor (Abdelhamid et al., 1996) and some cases of familial hyperaldosteronism (type II) associated with aldosteronoma or hyperplasia have also been described (Stowasser and Gordon, 2001).
The most common cause of PA is adrenocortical adenoma (aldoster- onoma), a disorder first reported by J. Conn (1955). Aldosteronomas are usually small (<2 cm in diameter), are benign by definition, and represent one of a few potentially curable forms of hypertension. There are at least
Lumen
Interstitium
Cortisol HO
NAD
Cortisone
O
11ßHSD2
Aldosterone
HRE
MR
DNA
Nedd4
MR
Na/K-ATPas
ENaC
mRNA
Na+
K+
Na+
Proteins
two functionally and perhaps histologically different types of aldosterono- ma: a corticotropin-responsive (and renin-unresponsive) type and a renin- responsive type. In most cases of aldosteronoma, aldosterone secretion cannot be suppressed by volume expansion or increased sodium intake (sodium loading), it appears to be unresponsive to angiotensin II, and is strongly influenced by corticotropin (Espiner and Donald, 1980). This is evident by the abnormal aldosterone response on postural testing, the parallel circadian rhythms of aldosterone and cortisol, and the transient decrease in the plasma aldosterone concentration in response to glucocorti- coids such as dexamethasone (Ganguly et al., 1977). However, approxi- mately 20% of patients with aldosteronomas are responsive to small
increases in the plasma level of angiotensin II and have a normal plasma aldosterone response on postural testing (Espiner and Donald, 1980; Irony et al., 1990; Wisgerhof et al., 1981).
Idiopathic aldosteronism, which is characterized by bilateral micronod- ular or macronodular adrenal hyperplasia, constitutes 20 to 30% of cases of primary aldosteronism (Biglieri et al., 1984; Irony et al., 1990; Jeck et al., 1994; Weinberger et al., 1979), although it is considered by some to be a variant of essential hypertension (Lim et al., 2002). Patients with idiopathic aldosteronism are responsive to small increases in circulating angiotensin II and have a normal plasma aldosterone response on postural testing (Mantero et al., 1976; Wisgerhof et al., 1981). Unilateral adrenal hyperplasia has also been reported (Magill et al., 2001; Morioka et al., 2000).
Adrenal carcinomas are usually larger than the more common, benign aldosteronomas; they often, but not invariably, produce other adrenal hormones, and may show evidence of local invasion or distant metastasis (Isles et al., 1987; Sasano et al., 1993).
A. PREVALENCE
The prevalence of primary aldosteronism in patients with hypertension has not been systematically assessed. In earlier reports, when aldosteronism was investigated only in the presence of severe hypokalemia and not by means of renin and aldosterone measurements, the prevalence of PA was <1% in unselected hypertensive patients (Bech and Hilden, 1975; Berglund et al., 1976; Danielson and Dammstrom, 1981; Lund et al., 1981; Streeten et al., 1979; Tucker and Labarthe, 1977), although Lund et al. (1981) found that 9.3% of patients with hypokalemia had aldosterone-producing adenomas. The introduction of the plasma aldosterone-to-renin activity ratio (ARR) test by Hiramatsu and co-workers (1981) made it possible to include normokalemic, and not just hypokalemic, hypertensive subjects in a screening for PA. This has led independent groups from several countries to report marked increases in detection rate and to estimate the prevalence of PA to be possibly 10-fold or more higher than was previously assumed (Brown et al., 1996; Fardella et al., 2000; Gallay et al., 2001; Gordon et al., 1993, 1994; Hiramatsu et al., 1981; Lim et al., 1999b, 2000; Lins and Adamson, 1986; Loh et al., 2000; Nishikawa and Omura, 2000; Rayner et al., 2000, 2001) (Table III). Depending on the cutoff for the ARR and on whether unselected hypertensive patients, patients with resistant hyperten- sion or requiring more than two antihypertensives for blood pressure control, or hypertensive patients with or without hypokalemia are considered the prevalence of PA ranges between 5 and 15% (Table III). Nevertheless, it should be noted that the prevalence of aldosteronomas, one of the few forms of surgically curable PA, is only approximately 3% in the reported studies (Table III). Moreover, the prevalence of hypertension in
| Ref. | Region | Number of patients | K ≥ 3.5b (%) | ARRc | Prevalence of PA (%) | Number of APAS |
|---|---|---|---|---|---|---|
| Hiramatsu et al. (1981) | Asia | 348 | 91 | >2080 | 7.4 | 9 |
| Lins and Adamson (1986) | Europe | 32 | 0 | >760 | 50 | 12 |
| Gordon et al. (1993) | Australia | 52 | 100 | >690 | 12 | 6 |
| Gordon et al. (1994) | Australia | 199 | 100 | >830 | 8.5 | 5 |
| Brown et al. (1996) | Australia | 74 | 100 | >830 | 6.7 | 2 |
| Lim et al. (1999b) | Europe | 495ª | NA | >750 | 16.6 | NA |
| 135ª | NA | 14.4 | NA | |||
| Loh et al. (2000) | Asia | 350 | 97 | >550 | 4.6 | 6 |
| Nishikawa and | Asia | 1020 | 72 | >400 | 5.4 | 45 |
| Omura (2000) | ||||||
| Fardella et al. | South | 305 | 100 | >690 | 5.2 | 1 |
| (2000) | America | |||||
| Lim et al. (2000) | Europe | 465 | 95 | >750 | 9.2 | 5 |
| Rayner et al. (2000) | Africa | 216 | 71 | >1000 | 32 | 7 |
| Gallay et al. (2001) | North | 90 | NA | >2700 | 17 | 10 |
| America | ||||||
| Rayner et al. (2001) | Africa | 154 | NA | >1000 | 7.1 | NA |
Abbreviations: APA, Aldosterone-producing adenoma; ARR, aldosterone-to-renin ratio;
NA, not available; PA, primary aldosteronism.
“Introduced by Hiramatsu et al. (1981)
bK≥3.5, percentage of patients with serum potassium ≥3.5 mmol/liter.
“The ARR is indicated with equivalent figures when converted in (pmol/liter) per (ng/ml per h).
ªPatient characteristics: Referred.
Patient characteristics: Family practice.
patients with incidentally discovered adrenocortical adenoma (inciden- taloma) is higher than in an age-matched control population (Bernini et al., 2002; Mantero et al., 2000; Russell et al., 1972). Using the ARR to identify PA in normokalemic patients with adrenal incidentalomas, Bernini et al. (2002) were able to identify 5.6% of subjects as having aldosterone- producing adenoma.
B. CLINICAL AND LABORATORY FINDINGS
Aldosteronomas are rarely found in children (Rogoff et al., 2001). Clinical features of PA are not specific, some patients are completely asymptomatic or have nonspecific symptoms related to hypertension. Others have symptoms-related hypokalemia, such as muscle cramps or weakness, but only rarely paresthesia, or paralysis (Cain et al., 1972;
Weinberger et al., 1979; Young et al., 1990). Blood pressure can exhibit moderate or marked elevation, and is often resistant to therapy. A few patients have normal blood pressure (Matsunaga et al., 1983; Stowasser et al., 1999). Retinopathy is almost invariably mild, and exudates or hemorrhages are uncommon. As is the case for other forms of mineralocorticoid hypertension, peripheral edema is uncommon, although hypertension in PA is primarily a consequence of renal sodium and fluid retention.
In classic PA, spontaneous hypokalemia with metabolic alkalosis and a serum sodium level at the high end of the normal range are often observed. Hypokalemia can be accentuated or induced in a subject with a normal level of serum potassium by oral sodium loading. An increased urinary excretion of potassium (>30 mmol/day in the presence of hypokalemia) is highly suggestive of classic PA. Thus, routine laboratory data can be suggestive but not diagnostic of classic primary aldosteronism. The use of the ARR as a screening test has made PA due to unilateral aldosteronoma and also that due to bilateral idiopathic aldosteronism increasingly diagnosed (Gordon, 1994). When screening with the ARR is performed, a high incidence of PA with normokalemia is found (Brown et al., 1996; Fardella et al., 2000; Gordon et al., 1994; Hiramatsu et al., 1981; Lim et al., 2000; Loh et al., 2000; Rayner et al., 2000) (Table III). Hypokalemia tends to be more severe in patients with aldosteronoma and less severe, or absent, in patients with idiopathic aldosteronism. Hypomagnesemia or abnormal glucose tolerance can be present. Also, parathyroid hypersecretion is a common feature of PA and seems to be a consequence of increased steroid-mediated distal tubular calcium excretion (Ferrari et al., 2002; Resnick and Laragh, 1985; Rossi et al., 1995).
C. SCREENING
The sensitivity of serum potassium measurements for the screening of PA is poor, although spontaneous hypokalemia in a patient with hypertension is a strong indicator that classic PA is present. Most patients with PA have normal serum potassium levels (Table III), whereas other hypertensive patients may have hypokalemia associated with other forms of miner- alocorticoid excess, or as a result of diuretic therapy or secondary aldosteronism. On the other hand, the prevalence of PA in hypertensive patients with severe hypokalemia was reported to be as high as 50% (Lins and Adamson, 1986). Plasma renin activity is suppressed in almost all patients with untreated PA. However, many patients with essential hypertension may present with low-renin, high-aldosterone hypertension (Brunner et al., 1972), although plasma renin levels are sensitive to changes in sodium intake and the intake of various medications in those patients. Thus, neither measurements of serum potassium nor measurements of plasma renin are suitable or reliable methods of screening for PA.
Plasma aldosterone and renin
ARR ÎÌ
No
Renin
SECONDARY ALDOSTERONISM
OTHER MINERALOCORTCOID HYPERTENSION
Renin
CT scan
Adrenal mass
LOW-RENIN ESSENTIAL HYPERTENSION
No
FST
Aldo V
Yes
Aldo
Familial HTN
Yes
Test for GRA
No
AVS
Surgery
Yes
Lateral.
No
Spiro
PRIMARY ALDOSTERONISM
Determining the ARR in patients with untreated hypertension seems to be the most appropriate screening method for distinguishing patients with PA from those with essential hypertension (Blumenfeld et al., 1994; Fardella et al., 2000; Gordon et al., 1994; Lim et al., 2000) (Fig. 7 and Table IV). In the presence of severe or symptomatic hypertension, patients should take only antihypertensive medications that are least likely to affect measurements of
| Plasma renin | ||||
|---|---|---|---|---|
| Activity | Immunoreactive | |||
| ng/ml per h | pmol/liter per min | mU/liter | ng/liter | |
| Plasma aldosterone | ||||
| ng/dl | >27 | >2.1 | >3.3 | >5.2 |
| pmol/liter | >750 | >59 | >89 | >145 |
Patients with ARR ≥ 750 (pmol/liter) per (ng/ml per h) have >90% probability of having nonsuppressible plasma aldosterone with FST (Lim et al., 2000).
renin and aldosterone, such as a-blockers or calcium channel blockers (Barbieri et al., 1981; Carpene et al., 1989). Accuracy of diagnosis of PA can be increased by the administration of a single dose of the angiotensin- converting enzyme inhibitor captopril, followed by the measurement of the ARR (Castro et al., 2002). Some authors suggest that given the low prevalence of PA, routine measurement of plasma aldosterone and renin to screen for the condition in persons with hypertension would not be cost- effective and should be reserved for patients with unexplained hypokalemia, with resistant hypertension or requiring more than two antihypertensives for blood pressure control (Kaplan, 2001). However, there are two reasons for a more liberal approach to screening, with application of the ARR to all patients with hypertension. The first is that even mildly hypertensive individuals deserve at least one chance at a cure. The second is that measurements of the ARR are also valuable if PA fails to be demonstrated, because a raised ARR indicates inappropriate aldosterone activity. Lim et al. (1999a) demonstrated that a vast majority of subjects with increased ARR failed to suppress plasma aldosterone on salt loading and showed a marked response to spironolactone treatment.
D. FURTHER EVALUATION AND DIAGNOSIS
All patients with hypertension who have an increased ARR should receive further evaluation (Fig. 7). Clearly, patients with hypertension who have spontaneous or profound diuretic-induced hypokalemia and patients with adrenal incidentalomas (Bernini et al., 2002; Kievit and Haak, 2000) or with resistant hypertension are those who most need further evaluation. Inhibiting and stimulating aldosterone and renin secretion by physiologic or pharmacologic interventions including sodium loading and depletion or by using the MR agonist fludrocortisone can provide the definitive biochemical diagnosis of aldosteronism. Using sodium loading following findings
establishes the diagnosis of PA: (1) a high plasma aldosterone level after intravenous infusion of normal saline (1.25 liters over a 2-h period in the morning), or (2) a high rate of urinary aldosterone excretion while on a diet high in sodium chloride (6 to 9 g/day for 3 days) (Bravo, 1994; Irony et al., 1990; Weinberger et al., 1979). A plasma aldosterone level of <250 pmol/ liter (<8.5 ng/dl) at the end of saline infusion or a urinary aldosterone excretion of <14 µg/24 h after sodium loading rule out PA. Sodium depletion by furosemide challenge has a poor predictive value of 42% in patients prescreened with the ARR (Lim et al., 2000) and is therefore not helpful. Some authors have demonstrated poor sensitivity with saline infusion testing (Gordon et al., 1993; Holland et al., 1984) and therefore suggest that PA should be confirmed by the fludrocortisone suppression test (FST) (Fardella et al., 2000; Gordon, 1995b; Gordon et al., 1993). With the FST the diagnosis of PA is based on failure of aldosterone to be suppressed to <180 pmol/liter (<6 ng/dl) after 4 days of fludrocortisone (0.1 mg every 6 h) (Gordon, 1995b). The major drawback of this test is that it must be carried out with the patient in hospital for 4 days under a strict regimen of sodium intake and potassium substitution.
E. SUBTYPE DELINEATION
Once the biochemical diagnosis of aldosteronism has been established, the cause can be determined by a variety of tests and techniques. Subtype delineation is critical to decide on the optimal treatment. Discriminant analyses with using plasma aldosterone and potassium levels have been advocated. A postural test in which the plasma aldosterone level fails to increase in a patient who has maintained an upright posture in the morning after recumbency strongly suggests the presence of an aldosteronoma, whereas subjects with idiopathic aldosteronism almost invariably have a normal increment in plasma aldosterone (Ganguly et al., 1973). However, some patients with unilateral adrenal hyperplasia or primary adrenal hyperplasia may have similar postural responses as patients with aldoster- onoma (Espiner and Donald, 1980; Irony et al., 1990; Mantero et al., 1976). Likewise, about 20% of patients with aldosteronoma are responsive to angiotensin II and therefore have a true increase in plasma aldosterone when undergoing this test (Feltynowski et al., 1994; Gordon, 1994; Irony et al., 1990). Therefore, none of these tests is sufficiently specific to warrant appropriate discrimination of the cause of PA. Localization of the abnormal adrenal gland should be undertaken by radiological imaging techniques after the biochemical basis of the aldosteronism has been established. However, because patients with ARR ≥750 have a >90% probability of having nonsuppressible plasma aldosterone with FST (Lim et al., 2000), radiological imaging to search for adrenal mass in all patients with increased ARR seems to be a reasonable approach, particularly in view of the complexity and costs
of FST (Gordon et al., 1993, 1994) (Fig. 7). Adrenal computed tomographic (CT) imaging can detect most (Fig. 7), but not all, aldosteronomas, because a unilateral excess of aldosterone secretion in the absence of adenoma or hyperplasia may be caused by an adrenal microadenoma not detectable by radiologic imaging (Omura et al., 2002). Conversely, the appearance of a nonfunctional incidentally discovered adrenocortical adenoma on adrenal CT imaging can occasionally cause confusion regarding the diagnosis of idiopathic hyperaldosteronism or aldosteronoma (Doppman et al., 1992; Fallo et al., 1997). In patients with idiopathic aldosteronism, the adrenal glands appear either bilaterally enlarged or normal in size. In a few of these patients, however, one of the adrenal glands may have a nodule, whereas patients with unilateral aldosteronomas may have bilateral nodules (Dopp- man et al., 1992; Radin et al., 1992). The finding of a large adrenal tumor (>3 cm in diameter) should raise the possibility of an adrenal carcinoma (Mantero et al., 2000), in which case other adrenal steroids (androgens, cortisol, and estrogen) in the plasma or urine should be measured (Isles et al., 1987; Sasano et al., 1993). Experience with magnetic resonance (MR) imaging is promising, particularly because MR imaging is a reliable method in characterization of benign and malignant adrenal masses (Honigschnabl et al., 2002; Slapa et al., 2000). CT scanning, however, remains preferable because of its reliability and lower cost. Adrenal venous sampling (AVS) for measurement of aldosterone and cortisol is invasive but is the most reliable method (Gordon et al., 1994; Magill et al., 2001; Radin et al., 1992; Young et al., 1996) (Fig. 7). This procedure requires considerable skill and experience on the part of the radiologist and carries some risk of adrenal hemorrhage. Measurement of cortisol as well as aldosterone in samples from both adrenal veins and from the inferior vena cava are crucial for evaluating the accuracy of AVS. It was reported that corticotropin stimulation may increase the specificity of AVS (Weinberger et al., 1979). If the blood sampling is reliable, a unilateral excess of aldosterone secretion usually suggests the presence of an aldosteronoma, although in some cases the diagnosis may be unilateral adrenal hyperplasia. If the radiologic diagnosis is difficult or if AVS cannot be performed, scintigraphic localization of adrenal lesions with radiolabeled iodocholesterol or [13]]] iodomethyl-19-norcholes- terol can be helpful (Gross et al., 1984; Kazerooni et al., 1990). The uptake of tracer is increased in patients with aldosteronoma and absent in those with idiopathic aldosteronism and usually also in those with adrenal carcinoma. Nevertheless, adrenal scintigraphy without adrenal vein sampling may lead to serious errors in patient management (Mansoor et al., 2002).
F. THERAPY
In the presence of an aldosteronoma the best treatment option is removal of the adrenal tumor, which has been found to improve blood pressure
control or cure hypertension in the majority of patients (Jeck et al., 1994; Weinberger et al., 1979; Young et al., 1990) (Fig. 7). Spironolactone therapy before surgery can be a predictor of surgical outcome in patients with aldosteronoma, may restore potassium levels in the body to normal before surgery, and may minimize postoperative hypoaldosteronism (Spark and Melby, 1968). If blood pressure fails to normalize after adrenalectomy, idiopathic aldosteronism with micronodular hyperplasia should be considered (McLeod et al., 1989). Laparoscopic adrenalectomy is now widely and successfully used to resect aldosteronomas and other adrenal masses, including adrenal carcinomas (Henry et al., 1999; Rossi et al., 2002; Schell et al., 1999). The advantages of the laparoscopic technique are evident both in terms of safety (fewer complications) (Brunt, 2002) and costs (shorter hospitalization and recovery periods) (Schell et al., 1999).
In idiopathic aldosteronism, unilateral or bilateral adrenalectomy does not usually achieve satisfactory blood pressure control and, therefore, medical treatment is the option of choice (Fig. 7). In patients with unilateral adrenal hyperplasia surgical treatment may improve hypertension, although a cure is unlikely. The most obvious drug strategy is to antagonize aldosterone at the receptor level, using spironolactone (Kremer et al., 1973; Lim et al., 2001; Young et al., 1990) or eplerenone (Delyani et al., 2001), an investigational selective aldosterone receptor antagonist that has less antiandrogenic and antiprogestational effects than spironolactone. Dosage of spironolactone to provide an effective control blood pressure and hypokalemia varies from 25 to 400 mg/day (Kremer et al., 1973; Lim et al., 2001; Young et al., 1990) and, because of the competitive nature of the compound on the receptor (Fanestil, 1968), high doses (>100 mg/day) are often needed. This is often associated with considerable side effects, especially gastrointestinal symptoms, fatigue, impotence, and gynecomastia. Other potassium-sparing agents, including amiloride, have been tried but are not as effective as spironolactone (Kremer et al., 1973; Lim et al., 2001). Spironolactone can be used in combination with other antihypertensive agents, such as calcium channel blockers or angiotensin-converting enzyme inhibitors (Carpene et al., 1989; Lim et al., 2001; Young et al., 1990).
VI. GENETIC FORMS OF MINERALOCORTICOID HYPERTENSION
A. MUTATIONS OF THE 116-HYDROXYLASE OR 17a-HYDROXYLASE GENE: CONGENITAL ADRENAL HYPERPLASIA
Several autosomal recessive disorders can cause congenital adrenal hyperplasia (CAH). The most common type, 21-hydroxylase deficiency, responsible for nearly 90% of all CAH, is not associated with hypertension
(White and Speiser, 2000), but precursors proximal to the enzyme block accumulate and are shunted into adrenal androgens. The clinical manifestation of CAH, often obvious at birth, varies with the degree of enzymatic deficiency and the mix of steroids secreted by the adrenal glands. When the enzyme block causes androgens to accumulate, the disorder is a virilizing form of CAH, causing varying degrees of virilization of an affected female fetus. If the enzyme block impairs androgen synthesis, it is an undervirilizing form, causing inadequate virilization of an affected male fetus. The two forms of CAH associated with hyper- tension are 11-hydroxylase deficiency, wherein 11-DOC is present in excess along with adrenal androgens, and 17-hydroxylase deficiency, which also has an excess of DOC but a deficiency of androgen production (Table II). Although these are rare causes of hypertension, partial enzymatic deficiencies have been observed in hirsute women (Lucky et al., 1986), so some hypertensive adolescents may have unrecognized, subtle forms of CAH.
An 113-hydroxylase deficiency causes 3 to 5% of all cases of CAH. The condition is usually diagnosed in infancy, because the defect sets off production of excessive androgens, although clinical variability is high (Rosler et al., 1982). The enzyme deficiency prevents the hydroxylation of 11-deoxycortisol to cortisol, resulting in cortisol deficiency (Fig. 2 and Table II). The defect also prevents the conversion of DOC to corticosterone and aldosterone. The characteristic steroid profile is elevation of urinary 17-hydroxycorticosteroids and of DOC (Levine et al., 1980). Because of the mineralocorticoid activity of DOC, patients exhibit salt retention and hypertension with hypokalemic alkalosis. Plasma renin activity is low and virilization also occurs. The enzymatic defect has been attributed to several mutations in the CYP11B1 gene (Geley et al., 1996; White et al., 1991). The syndrome is diagnosed by finding high levels of 11- deoxycortisol and DOC in the urine and plasma (Zachmann et al., 1983). The treatment is cortisol replacement; mineralocorticoid replacement may also be necessary.
The enzyme that catalyzes the 113-hydroxylation of 11-deoxycortisol to form cortisol is a cytochrome P450 protein encoded by the CYP11B1 gene (Fig. 2). The CYP11B1 gene was cloned by Mornet et al. (1989), who found that the gene is 6.5 kb long from the start of transcription to the polyadenylation site and contains nine exons. Thereafter, several mutations in this gene have been reported in many families throughout the world. Phenotypic expression of these mutations occurs in the homozygous or compound heterozygous state owing to the loss of function of the mutant protein. This distinguishes CAH due to CYP11B1 mutations from glucocorticoid-remediable aldosteronism (GRA), a condition expressed in the heterozygous state, in which a chimeric gene encodes a fused P450 protein consisting of the amino-terminal portion (exons 1-4) of CYP11B1
and the carboxyl-terminal part (exons 5-9) of CYP11B2 (Lifton et al., 1992a; Miyahara et al., 1992). In GRA the chimeric gene results in a gain of function and is discussed separately (Section VI.B).
Joehrer et al. (1997) described a female patient with partial steroid 11,3- hydroxylase deficiency, found to have a compound heterozygosity of the CYP11B1 gene for two missense mutations: Asn-133 to histidine (N133H) and Thr-319 to methionine (T319M). In an analysis of DNA from nine patients with severe manifestations of CAH due to 113-hydroxylase deficiency, Geley et al. (1996) identified seven mutations in the CYP11B1 gene. Curnow et al. (1993) reported eight previously uncharacterized mutations in the CYP11B1 gene causing a hypertensive form of congenital adrenal hyperplasia. They pointed out that 7 of a total of 10 known mutations are clustered in exons 6-8.
A 17a-hydroxylase deficiency is associated with an absence of sex hormones, leading to incomplete masculinization in males and primary amenorrhea in females (Fig. 2 and Table II). 17-Hydroxylase is necessary for both cortisol and estrogen synthesis. Lack of these hormones results in increases in ACTH and follicle-stimulating hormone (FSH). Production of excessive corticosterone and DOC results in hypertension and hypokalemic alkalosis. Aldosterone synthesis is almost totally absent. Estrogen deficiency results in primary amenorrhea and absent sexual maturation. To date approximately 150 cases of 17-hydroxylase deficiency have been recognized (Hermans et al., 1996; Yanase et al., 1991). However, adolescents with hypertension and hypokalemia or abnormal sexual development should be considered suspect.
P45017 is a single enzyme that mediates both 17-hydroxylase and 17, 20-lyase activity; it catalyzes 17a-hydroxylation of both pregnenolone and progesterone and 17,20-lysis of 17a-hydroxypregnenolone and 17a-hydroxyprogesterone. The gene CYP17, which encodes this enzyme, is the sole member of a unique gene family within the P450 supergene family (Chung et al., 1987). Phenotypic expression may be variable depending on the degree of residual activity of mutant enzymes. In some cases hypertension is the main feature, while the signs of abnormal sexual development or differentiation may be discrete (Table II). In some cases patients with a 46,XY karyotype are phenotypic females (Jones et al., 1992). A partial combined 17a-hydroxylase/17,20-lyase deficiency identified at the age of 20 years in a female Japanese patient was diagnosed because of hypertension and hypokalemia (Yanase et al., 1989). Menstruation was irregular, the breasts were hypoplastic, and pubic or axillary hair was absent (Yanase et al., 1989). Oshiro et al. (1995) also described a mutation in the CYP17 gene in another adult female referred because of hypertension and amenorrhea.
B. CHIMERIC 11-HYDROXLASE-ALDOSTERONE SYNTHASE GENE: GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM
Sutherland et al. (1966) and Salti et al. (1969) described a father and son with hypertension, low plasma renin activity, increased aldosterone secretion responsive to dexamethasone, and normal growth and sexual development. Because this form of aldosteronism was corrected by dexamethasone the condition was termed glucocorticoid-remediable aldos- teronism (GRA). The hypertension, variable hyperaldosteronism, and abnormal steroid production are all under the control of ACTH and suppressible by glucocorticoids. In GRA there are high levels of the abnormal adrenal steroids 18-oxocortisol and 18-hydroxycortisol, and plasma aldosterone levels may be variable (Gomez-Sanchez et al., 1984; Jamieson et al., 1996; Lifton et al., 1992b; Mulatero et al., 1998). GRA is the result of aldosterone synthase (CYP11B2) activity under the control of ACTH (which normally regulates CYP11B1) and results from an unequal crossing-over involving the CYP11B1 and CYP11B2 genes (Table II). Aldosterone synthase, like steroid 113-hydroxylase, is expressed in both adrenal fasciculata and glomerulosa; the two genes are 95% identical and lie on chromosome 8q immediately adjacent in a head-to-tail orientation with the CYP11B2 gene 5’ to the CYP11B1 gene (Mornet et al., 1989). A chimeric gene duplication between the CYP11B1 and CYP11B2 genes is the cause of GRA (Jonsson et al., 1995; Lifton et al., 1992a,b; Pascoe et al., 1992). This chimeric gene encodes aldosterone synthase (functional elements of CYP11B2) but is under the control of ACTH (regulatory elements of CYP11B1).
The number of reported cases with “classic GRA” is small; however, this condition might be underdiagnosed. A report on 21 affected members of approximately 1000 descendants of an English convict in Australia (Gordon, 1995a) revealed an extreme phenotypic heterogeneity in GRA, associated with hybrid genes showing somewhat different cross-over points linking the CYP11B1 and CYP11B2 portions. The affected members were often normokalemic, and some remained normotensive until late in life (Gordon, 1995a). In normotensive subjects, biochemical abnormalities are similar to those of hypertensive siblings (Stowasser et al., 1999). Gates et al. (1996) described two large pedigrees with many subjects who had the abnormal chimeric gene associated with glucocorticoid-remediable aldos- teronism. Most of the affected members, who had only mild hypertension and normal biochemistry, were clinically indistinguishable from patients with essential hypertension. Thus, for young hypertensive patients with positive family history, and absent postural increase in plasma aldosterone, treatment with glucocorticoid should be given for 4 to 6 weeks. Abnormal activity of CYP11B2 may be characterized phenotypically by elevated
urinary excretion of tetrahydroaldosterone and aldosterone (Davies et al., 1999) or by a decline in plasma aldosterone in response to dexamethasone (Litchfield et al., 1997; Mulatero et al., 1998). Preferably, gas chromatography- mass spectrometry analysis of the urine with 18-hydroxycortisol assay should be performed whenever available.
C. MUTATIONS OF THE 118-HYDROXYSTEROID DEHYDROGENASE TYPE 2 GENE: APPARENT MINERALOCORTICOID EXCESS
In 1974 Werder et al. (1974) described a disorder in the peripheral metabolism of cortisol, manifested by hypertension, hypokalemia, low plasma renin activity, and subnormal aldosterone levels. Although the features suggested primary mineralocorticoid excess, no overproduction of mineralocorticoids could be demonstrated. Biochemical characterization of this condition was provided by New et al. (1977) and Ulick et al. (1979) who found a decreased rate of conversion of cortisol to cortisone in two affected subjects, reflecting a deficiency of an 113HSD enzyme (Fig. 3). This form of mineralocorticoid hypertension was called apparent mineralocorti- coid excess (AME). It is an autosomal recessive disorder that results from overactivation of the MR by cortisol (Ulick et al., 1979). Symptoms of the disease respond to spironolactone or amiloride administration or a low- sodium diet. AME is caused by mutations in the 113HSD type 2 enzyme (Table II).
The molecular basis of the syndrome of AME has been elucidated (Ferrari et al. 1996a,b; Mune et al., 1995; Obeyesekere et al., 1995; Rogoff et al., 1998; Stewart et al., 1996; Wilson et al., 1995a,b, 1998). Mutations in the 113HSD2 gene result in an enzyme with abolished or markedly decreased activity, which causes renal sodium retention, urinary potassium wasting, and low-renin, low-aldosterone hypertension. So far, 50 patients with “classic AME” in 25 kindreds have had DNA analysis, revealing a total of 20 different mutations in the 113HSD2 gene (Ferrari and Krozowski, 2000; Wilson et al., 1998). We reported on a form of low- renin hypertension in which a gene mutation produces a mild deficiency in the 113HSD2 enzyme but without other phenotypic features that could lead to the diagnosis of AME (Wilson et al., 1998). Along with other findings (Lovati et al., 1999; Soro et al., 1995; Walker et al., 1993), these data suggest that impaired 113HSD2 activity may play a role in the pathogenesis of essential hypertension in some patients and that this may be genetically determined (Ferrari et al., 2000). The prevalence of mutations in the coding region of the 113HSD2 gene in the general population of patients with essential hypertension is presently unknown, but it has been estimated as <1/250,000 among white individuals (Zaehner et al., 2000).
D. MUTATIONS OF THE MINERALOCORTICOID RECEPTOR GENE
In a screening for mutation of all coding regions of the MR among 75 independent patients with severe hypertension, suppressed plasma renin activity, low aldosterone, and no other underlying cause of hypertension a 15-year-old boy was found to be heterozygous for a missense mutation, resulting in substitution of a leucine for serine at codon 810 (S810L) (Geller et al., 2000) (Table II). The S810L mutation lies in the MR hormone- binding domain, altering an amino acid that is conserved in all MRs from Xenopus to human but not found in other nuclear receptors. This mutation results in constitutive MR activity and alters receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups, normally MR antagonists, becoming potent agonists. Spironolactone was also a potent agonist of MR-L810, suggesting that this medication is contraindicated in MR-L810 carriers (Geller et al., 2000). Among the 23 relatives of the index patient analyzed, 11 had been diagnosed with severe hypertension before age 20 years, a rare trait in the general population, whereas the remaining 12 had unremarkable blood pressures. Carriers of the mutant allele revealed a marked increase in blood pressure, suppression of aldosterone secretion, and a nonsignificant trend toward lower serum potassium levels (Geller et al., 2000). Two females later found to be MR-L810 carriers had previously undergone five pregnancies. Because progesterone levels normally increase 100-fold in pregnancy it was not surprising to notice that all pregnancies had been complicated by marked exacerbation of hypertension. To date no further cases of activating mutations of the MR have been reported.
E. MUTATIONS OF THE EPITHELIAL SODIUM CHANNEL GENES: LIDDLE SYNDROME
In the early 1960s Liddle et al. (1963) described a young female with hypertension associated with hypokalemic alkalosis not due to hyperaldos- teronism but rather to a renal tubular defect. Renal failure eventually developed in this patient, who received a cadaveric renal transplant in 1989, following which her disorder resolved with normalization of the aldosterone and renin responses to salt restriction (Botero-Velez et al., 1994). This condition, later called Liddle syndrome or pseudoaldosteronism, is characterized by hypoaldosteronism, hypokalemia, and decreased renin and angiotensin (Table II). Further studies demonstrated that amiloride and triamterene, but not spironolactone, were effective treatments for hyperten- sion and hypokalemia in patients with this syndrome as long as dietary sodium intake was restricted (Wang et al., 1981). This form of mineralocorticoid hypertension is inherited as an autosomal dominant trait (Warnock, 1998).
The cloning of ENaC led to the discovery that this hereditary monogenic form of hypertension was caused by mutations deleting the PY motif present in the C terminus of the 3 or y subunits of ENaC (Hansson et al., 1995a,b; Shimkets et al., 1994). Shimkets et al. demonstrated complete linkage of the disorder in the index patient described by Liddle to the gene encoding the 3 subunit of ENaC (Shimkets et al., 1994). Implication of ENaC in tight regulation of salt homeostasis, control of extracellular volume, and blood pressure has opened a new field of investigation and pointed out ENaC and all its regulating factors as candidate proteins potentially involved in salt sensitivity and salt resistance (Rossier et al., 2002). ENaC, expressed on the apical side of the cells from the distal tubule and cortical collecting duct, is the key modulator of sodium transport in the kidney (Canessa et al., 1994a; Shimkets et al., 1994) (Figs. 5 and 6). Expression and function of this transporter are under the control of aldosterone (Horisberger and Rossier, 1992; Palmer and Frindt, 1992). In Liddle syndrome the channel is hyperactive, because of two factors: an increased number of channels present at the cell surface and an increased intrinsic activity of ENaC. Staub et al. (1996) demonstrated that the so-called PY motif is the target of Nedd4, a ubiquitin-protein ligase, which binds to the PY motif through its WW domains (Fig. 6). The binding allows the ubiquitination of ENaC and its degradation. In Liddle syndrome, this interaction between Nedd4 and the PY motif of the 3 and y subunits is no longer possible and this leads to a higher number of hyperactive channels at the cell surface (Staub et al., 2000) so that sodium can freely diffuse from the tubular lumen into the cell and is then extruded into the interstitium by the Na+, K+-ATPase. Sodium and water retention leads to an increase in blood volume, hypertension, suppression of plasma renin, and low aldosterone in plasma and urine (Warnock, 1998). The number of patients with “classic” Liddle syndrome is extremely low. However, evidence of a relevant mutation in the 3 subunit of ENaC (T594M) was demonstrated in black “essential” hypertensive subjects (Baker et al., 1998), and a variant in the promoter region of the & subunit was described in Japanese hypertensive subjects (Iwai et al., 2002), indicating that mutations of ENaC might be a frequent cause of secondary hypertension. The lack of association between molecular variants of either the 3 or y subunit of ENAC and hypertension in unselected hypertensive patients (Chang and Fujita, 1996; Fodinger et al., 1998) suggests that careful patient selection based on phenotypical characteristics, such as plasma renin levels or salt sensitivity, may be crucial in order to increase the probability to detect such mutations. For instance, hypertensive patients with a marked response to a therapy with amiloride but unresponsive to spironolactone represent an ideal target; however, these subjects have not been systematically investigated so far and therefore represent a candidate group for genetic analysis.
VII. ALDOSTERONE-DEPENDENT ESSENTIAL HYPERTENSION
It has been estimated that approximately one-third of the hypertensive population have low renin levels, with a higher proportion of low renin in black than in white subjects (Brunner et al., 1972). Moreover, up to 15% of hypertensive subjects have a raised ARR, and in most of these subjects plasma aldosterone is only partially suppressible on salt loading, the current diagnostic criterion for primary aldosteronism (Coghlan et al., 1972; Gordon, 1995b; Luetscher et al., 1969). As discussed previously, renin- angiotensin system control is intact in patients with idiopathic aldosteron- ism. The degree of integrity of this feedback regulation, although differing in the degree of sensitivity, is similar to that observed in patients with low- renin essential hypertension. Data suggest that with angiotensin II stimulation, the predominant AT-1 receptors (Belloni et al., 1998) in the zona glomerulosa of adrenal gland are paradoxically upregulated, thus enhancing angiotensin II adrenal sensitivity (Hauger et al., 1978). If adrenal stimulation by angiotensin II is sufficiently prolonged and sustained it could produce adrenal hyperplasia with increased aldosterone secretion (Lim et al., 2002). It has been suggested that the natural history of hypertension proceeds from essential (high to normal renin) hypertension through to low- renin hypertension to idiopathic aldosteronism over time, a condition that has been described as tertiary aldosteronism (Lim et al., 2002). However, the rate of this progression may be different depending on genetic susceptibility. Evidence of genetic variants in CYP11B2 has been found in a hypertensive population, suggesting that mutations of this enzyme may be relevant in essential hypertension (Brand et al., 1998; Davies et al., 1999). Davies et al. (1999) described a polymorphism in the promoter of the CYP11B2 gene, with a single nucleotide C-to-T transition at position -344, in association with hypertension. The T allele was significantly more frequent than the C allele in the hypertensive compared with the control group patients and subjects with the genotypes TT or TC had significantly higher aldosterone excretion rates than did those with the CC genotype (Davies et al., 1999). An increased frequency of the T allele and a relative excess of TT homozygosity over CC homozygosity were found in patients with idiopathic low-renin hypertension in comparison with both normal to high-renin hypertensive subjects and normotensive control subjects by two independent European and Japanese groups (Rossi et al., 2001; Tamaki et al., 1999). Interestingly, we found that the CYP11B2 genotype predicted long-term graft function in renal transplant patients, with more patients having the CYP11B2 TT than the CC genotype experiencing worsening renal function (Nicod et al., 2002). This association remained when the effect of the CYP11B2 polymorphism was controlled for potential epistatic interactions with the angiotensinogen M235T mutation, the ACE 287-bp deletion/
insertion (D/I) polymorphism, and angiotensin receptor A1166C gene polymorphisms (Nicod et al., 2002).
Expression of the CYP11B2 gene is regulated by angiotensin II. Angiotensin II acts on the CYP11B2 gene promoter region with its variety of control factors, one of which is steroidogenic factor 1 (SF-1) (Clyne et al., 1997; Honda et al., 1993). The -344 C/T single nucleotide difference at this site alters the sensitivity to angiotensin II (Davies et al., 1999). The reported polymorphism causing increased sensitivity of CYP11B2 to angiotensin II (Davies et al., 1999) can be expected to be more prevalent in hypertensive patients responding to MR antagonists; however, to date, this hypothesis has not been investigated and thus needs to be addressed with an appropriate pharmacogenomic study (Ferrari, 1998).
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