Mineralocorticoid and Apparent Mineralocorticoid Syndromes of Secondary Hypertension

Mineralocorticoid and Apparent Mineralocorticoid Syndromes of Secondary Hypertension Sivakumar Ardhanari, Rohini Kannuswamy, Kunal Chaudhary, Warren Lockette, and Adam Whaley-Connell The mineralocorticoid aldosterone is a key hormone in the regulation of plasma volume and blood pressure in man. Excessive levels of this mineralocorticoid have been shown to mediate metabolic disorders and end-organ damage more than what can be attributed to its effects on blood pressure alone. Inappropriate excess levels of aldosterone contribute significantly to the cardiorenal metabolic syndrome and target organ injury that include atherosclerosis, myocardial hypertrophy, fibrosis, heart failure, and kidney disease. The importance of understanding the role of excess mineralocorticoid hormones such as aldosterone in resistant hypertension and in those with secondary hypertension should be visited. Primary aldosteronism is one of the commonly identified causes of hypertension and is treatable and/or potentially curable. We intend to review the management of mineralocorticoidinduced hypertension in the adult population along with other disease entities that mimic primary aldosteronism. Q 2015 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Secondary hypertension, Resistant hypertension, Aldosteronism, Apparent mineralocorticoid excess

INTRODUCTION Reduction in kidney perfusion pressure is a strong stimulus for the secretion of renin by juxtaglomerular cells of the kidney. Angiotensinogen is synthesized in the liver and is converted to angiotensin I by renin and ultimately to angiotensin II by the angiotensin-converting enzyme. Angiotensin II stimulates the synthesis and secretion of aldosterone from the adrenal gland through the angiotensin II receptor type 1 in the zona glomerulosa through G protein-coupled signaling. Activation of the angiotensin II receptor type 1 causes membrane depolarization to increase intracellular calcium (Ca21) levels through activation of voltage-gated Ca21 channels. This in turn leads to a phosphorylation cascade that positively regulates transcription that encodes for aldosterone synthase which then regulates synthesis of aldosterone. However, in addition to angiotensin II, potassium (K1) and adrenal corticotropin hormone (ACTH) are physiologically relevant stimuli for aldosterone secretion in response to hypokalemia and low blood pressure, respectively.1 Aldosterone acts through its mineralocorticoid receptor in the distal nephron to secrete K1 and to reabsorb sodium (Na1) to increase blood volume in an effort to increase kidney perfusion pressure. Although mineralocorticoid secretion is regulated primarily by the renin-angiotensin-aldosterone system, glucocorticoids and adrenal androgens are predominantly regulated by the hypothalamic pituitary axis despite having actions similar to mineralocorticoids. CAUSES OF MINERALOCORTICOID EXCESS Primary Aldosteronism Primary aldosteronism was first recognized in 1955 by Conn2 Since then primary aldosteronism has evolved as a commonly identifiable cause of hypertension that is potentially curable.3-6 Among patients referred for the evaluation of hypertension, the prevalence of primary aldosteronism is roughly 4% in primary care settings and can range up to 10% in tertiary referral centers.7 In this context, a majority of cases and in some estimates up to nearly 95% of the cases of primary aldosteronism are attributed to either aldosterone-producing adrenal adenomas or bilateral adrenal hyperplasia.8 Other less

common causes include unilateral adrenal hyperplasia, unilateral multiple adrenocortical nodules, and adrenal carcinoma, in addition to bilateral etiologies such as glucocorticoid-remediable hyperaldosteronism and familial hyperaldosteronism type II.9-14 The mechanisms behind these entities were largely unknown until recent immense interest in the genetic basis of the disease has emerged.15,16 Although most cases of primary aldosteronism are sporadic, 3 types of familial hyperaldosteronism display Mendelian inheritance.17 The hallmark of primary aldosteronism is increased circulating levels of aldosterone resulting from adrenocortical oversecretion. The consequent excess aldosterone levels contribute to Na1 and water retention, K1 secretion resulting in hypokalemia, and hypertension. In addition, compared with matched patients with essential hypertension, there is a significantly higher rate of kidney disease and cardiovascular events in patients with primary aldosteronism.18 Additionally, in those with primary aldosteronism, albuminuria and increased intrarenal vascular resistance consistent with glomerular hyperfiltration are present.19,20 The presence of primary aldosteronism increases the risk for cardiovascular outcomes such as stroke, myocardial infarction, and atrial fibrillation

From Department of Medicine, University of Missouri-Columbia School of Medicine, Columbia, MO; Division of Cardiovascular Medicine, University of Missouri-Columbia School of Medicine, Columbia, MO; Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, MO; Division of Nephrology and Hypertension, University of Missouri-Columbia School of Medicine, Columbia, MO; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO; and Division of Endocrinology and Metabolism, University of Missouri-Columbia School of Medicine, Columbia, MO. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Sivakumar Ardhanari, MD, Department of Medicine, Division of Cardiovascular Medicine, Room CE-305 University of Missouri Health Sciences Center, 5 Hospital Drive, Columbia, MO 65202. E-mail: [email protected] Ó 2015 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2015.03.002

Advances in Chronic Kidney Disease, Vol 22, No 3 (May), 2015: pp 185-195

185

186

Ardhanari et al

compared with matched subjects with essential with bilateral secretion, whereas a ratio greater than 4:1 hypertension.18 Pressure-independent left ventricular hy(mean 18:1) is consistent with unilateral overproduction. pertrophy, heart failure, ischemic and hemorrhagic It is important to confirm successful adrenal vein cannulastrokes, and ventricular arrhythmias are also known to tion via the selectivity index, defined as adrenal vein be associated with primary aldosteronism.4,21 cortisol divided by inferior vena cava cortisol 3:1 or Patients with primary aldosteronism do not have specific more. Some centers perform testing before and after clinical clues; however, resistant hypertension, muscle administration of low-dose ACTH, although the true value weakness, hypokalemia (although present only in less of stimulated AVS remains contentious.26 In this context, localization and subtype identification than half of patients), and metabolic alkalosis usually raise are critical for management of these patients. In spite of suspicion.22 In these patients, the morning plasma aldosterone-to-renin ratio (ARR) is the initial screening the extensive knowledge of the pathophysiology and clinmodality. Low plasma renin levels can cause a high ARR ical features, primary aldosteronism still remains an even with normal or low aldosterone levels.23 In addition, underdiagnosed condition. In view of the potential several clinical conditions including essential hypertenmorbidity and mortality in untreated patients, it is impersion can cause an abnormal high plasma ARR. In this reative to have a high clinical suspicion and a thorough gard, patients with primary aldosteronism typically workup before a curative treatment can be offered. Apart demonstrate a greater degree of elevation in ARR. Trenkel from primary aldosteronism, a number of other diseases and colleagues24 demonstrated that the sensitivity and result in clinical syndromes resembling mineralocorticoid specificity of ARR $50 are 89% and 96%, respectively, excess. These include the syndrome of apparent mineralowith an increase in specificity if an absolute plasma aldocorticoid excess (AME), Liddle syndrome, Cushing sterone level $200 pg/mL is syndrome, and congenital present. To avoid misclassifiadrenal hyperplasia (CAH). CLINICAL SUMMARY cation of low renin hypertenLess common etiologies are sion, Ducher and others25 Chrousos syndrome (inacti Primary aldosteronism is a commonly identified cause of demonstrated that a ratio of vated glucocorticoid recephypertension that is potentially curable. 32 with minimum renin contor gene), Geller syndrome  Aldosterone-producing adenoma and bilateral adrenal centration of 5 ng/L yielded (activating mineralocortihyperplasia are the main etiologies of primary 100% sensitivity and 72% coid mutation), and Gordon aldosteronism. specificity. The most syndrome (pseudohypoal Unilateral adrenalectomy offers a potential cure for commonly used cutoff for dosteronism type II).27-30 adenomatous disease, whereas mineralocorticoid ARR is more than 15 to 20 receptor antagonists are the cornerstone of therapy for Aldosterone-Producing with plasma aldosterone bilateral adrenal hyperplasia. Adrenal Adenoma (Conn $15 ng/dL and renin activity expressed as nanogram per Syndrome)  Glucocorticoid-remediable aldosteronism, Liddle First described by Conn milliliter per hour. syndrome, and syndrome of apparent mineralocorticoid excess are identifiable causes of monogenic hypertension. in 1955, aldosteroneAs a high ARR is not exclusive to primary aldosteproducing adrenal ade Congenital adrenal hyperplasia is an autosomal recessive ronism, it is essential to nomas are benign, solitary, hereditary disorder of abnormal steroidogenesis leading well-circumscribed tumors confirm whether the aldosteto accumulation of precursor compounds with rone secretion is physiologiderived from the adrenal mineralocorticoid activity. cally suppressible. This is cortex.2 Based on a size crite1 rion of 6 mm, Omura and normally achieved by Na loading through either a saline suppression test or 24colleagues31 demonstrated that the tumors could be microhour urine collection for aldosterone on a more than adenoma or macroadenoma. They also demonstrated that 200 mmol/d Na1 diet. In the former, plasma aldosterone patients with aldosterone-producing microadenomas levels are measured before and after intravenous adminishave clinical and radiological features resembling patients tration of 2 L of normal saline over 4 hours. Post-infusion with idiopathic hyperaldosteronism rather than level less than 5 ng/dL makes the diagnosis less likely aldosterone-producing macroadenomas. In their study, and level greater than 10 ng/dL favors primary aldostepatients with microadenomas and idiopathic hyperaldosronism. For the urine collection, a diet containing more teronism have lesser tendency for hypokalemia, milder than 200 mmol/d of Na1 for 3 days is consumed with a elevation of plasma aldosterone level, and lesser elevations 24-hour urine collected on the third day. Urine aldosterone in ARR compared with patients with macroadenomas. In of 12 to 14 mg or more is consistent with primary aldoste22 of 25 patients with microadenomas, thin-slice high-resronism. Lateralization of the aldosterone secretion olution computed tomography (CT) scan could not clarify through adrenal vein sampling (AVS) is important for the abnormalities of the adrenal gland and, in the other 5 determining candidates for laparoscopic adrenalectomy. patients, revealed macroadenomas of the contralateral adAVS requires considerable technical experience and can renal gland. However, pathologically, immunoreactivity be challenging to interpret. Measured aldosterone levels to a variety of enzymes in patients with microadenoma are divided by simultaneously measured cortisol to acand macroadenoma was similar, in sharp contrast to idiocount for hemodilution by draining veins. An ipsilateral pathic hyperaldosteronism. It should be noted that unilatto contralateral ratio of 3:1 or less (mean 1.8:1) is consistent eral adrenalectomy has a higher cure rate for hypertension

Mineralocorticoid Hypertension

in patients with microadenoma than in those with macroadenoma.31 Aldosterone-producing adrenal adenomas typically retain their benign features without metastasis.32 At the cellular level, these tumors exhibit continuous hormone production and cell proliferation. Various somatic mutations have been described in aldosterone-producing adrenal adenomas, including KCNJ5, ATP1A1, ATP2B3, and CACNA1D.33 One study estimated the occurrence of KCNJ5 mutations at 65% of patients with aldosteroneproducing adrenal adenomas.34 KCNJ5 encodes inwardly rectifying K1 channels, mutations (G151 R and L168 R) of which alter K1 selectivity to permit increased Na1 conductance resulting in cell depolarization.16 This enhances Ca21 entry in adrenal zona glomerulosa cells to signal aldosterone production. Patients with aldosteroneproducing adrenal adenomas bearing mutations in KCNJ5 display clinical features different from those with other mutations. In this regard, there is a female preponderance, primary aldosteronism tends to be more severe and presents earlier in life, and the tumors tend to be larger and composed predominantly of cells resembling zona fasciculata.16,33-39 ATP1A1 codes for the a1 subunit of the Na1/K1-ATPase, and it also results in aldosterone production by altering intracellular Ca21 levels. ATP2B3 codes for the plasma membrane Ca21-ATPase, type 3. CACNA1D codes for a-1d unit of the L-type calcium channel. Patients with mutations in CACNA1D tend to have smaller adenomas. Among newly diagnosed hypertensives, roughly 5% have aldosterone-producing adrenal adenomas, constituting about a third of patients with primary aldosteronism.40 It usually presents between the third and seventh decades of life with hypertension associated with or without hypo-K1, high aldosterone, and low plasma renin activity (PRA). Patients with aldosteroneproducing adrenal adenomas demonstrate a greater level of renin activity suppression compared with patients with adrenal hyperplasia or essential hypertension. Ducher and colleagues41 concluded that this results in a higher ARR in patients with aldosterone-producing adrenal adenomas, and a cut-off value of ARR of 32 or more may help in the differential diagnosis. Adrenal masses identified by imaging, typically CT, provide additional anatomical information particularly for unilateral aldosterone-producing adrenal adenomas and may guide therapy.42,43 However, an adrenal nodule in a patient with primary aldosteronism can also be an incidentaloma or a macronodule within the context of bilateral adrenal hyperplasia.44 It should be noted that imaging has an important functional limitation given the inability to localize the site of secretion.45 Highresolution CT scans also will not delineate a mass less than 6 mm in size.31,46,47 Radioactive iodocholesterol scintigraphy is no longer routinely used.48 Demonstrating excess aldosterone secretion from a unilateral adrenal gland is the cornerstone of identifying surgical candidates. This is usually achieved by selective AVS described earlier45; however, AVS also has limitations.49 This includes relatively high complication and failure rates, expense, lack of universal availability, and difficult interpretation.50-52

187

For individuals with a unilateral adenoma, adrenalectomy may cure or significantly attenuate the hypertension and is widely considered the treatment of choice.53-55 Notably, tumor recurrence is extremely rare.56 The Aldosteronoma Resolution Score is calculated from the number of antihypertensive medications used, body mass index, duration of hypertension, and gender. This score identified the likelihood for complete resolution of hypertension after surgery with a predictive accuracy of 27%, 46%, and 75%, for low, intermediate, and high scores, respectively.50,53,54,57,58 In spite of preoperative localization, up to 25% of patients may not have cure or improvement in hypertension, and this may suggest a diagnosis of bilateral hyperplasia.59 Postoperative functional histopathology may help distinguish between aldosteroneproducing adrenal adenomas and hyperplasia.53 Medical management with mineralocorticoid receptor antagonists is usually reserved for patients who are not surgical candidates.32 Glomerular hyperfiltration is a common consequence of aldosterone excess. With correction of aldosterone excess, either by initiation of mineralocorticoid antagonists or surgical adrenalectomy, the glomerular filtration rate often declines.60 However, factors such as age, level of preoperative estimated glomerular filtration rate, and the duration of hypertension all predict postoperative progression to CKD.61,62 Bilateral Adrenal Hyperplasia (Bilateral Idiopathic Hyperaldosteronism) Idiopathic bilateral adrenal hyperplasia63 was first reported in 1956 by Doorenbos and coworkers.64 Presently, it constitutes about 60% of cases of primary aldosteronism.65 An inherited germ line mutation in KCNJ5 (T158 A) was recently discovered to cause a Mendelian form of primary aldosteronism in patients with bilateral adrenal hyperplasia. These patients have severe childhood-onset elevations in blood pressure. Individuals also have laboratory abnormalities that include hypo-K1 and markedly elevated aldosterone, 18-hydroxycortisol, and 18-oxo-cortisol levels. Unlike in glucocorticoidremediable aldosteronism (GRA), the abnormalities are not glucocorticoid suppressible, and there is marked diffuse hyperplasia of the zona fasciculata.66 Several studies have reported considerable variation from mildto-florid primary aldosteronism with normal appearing adrenals, to significant adrenal hyperplasia that appears at least partly related to the KCNJ5 genotype.16,66-70 This disorder has a similar presentation to aldosteroneproducing adrenal adenomas with hypo-K1, increased aldosterone levels, suppressed renin levels, and moderate-to-severe hypertension but exhibits certain unique differences. Pathologically, this disorder is characterized by bilateral macronodular or micronodular adrenal cortical hyperplasia. Unlike aldosterone-producing adrenal adenomas, there is a male predominance and patients present at a comparatively older age. Biochemical abnormalities tend to be less pronounced compared with patients with aldosterone-producing adrenal adenomas with elevated aldosterone levels in almost all cases. Medical management is usually recommended as adrenalectomy yields poor outcomes.10,71

188

Ardhanari et al

Table 1. Summary of Mineralocorticoid and Apparent Mineralocorticoid Excess Syndromes Primary Aldosteronism Inherited Sporadic Characteristic

APA

Familial Hyperaldosteronism BAH

Type I (GRA)

Type II

Type III

Liddle syndrome

Age on presentation/ sex predilection Prevalence

Third to seventh decade F.M 4%-10% of hypertensives 1/3 of patients with PA

Third to seventh decade M.F 2/3 of patients with PA

Childhood

Childhood

Childhood

Early onset

Most common cause of monogenic hypertension Rare ,1% of familial PA

6% of patients with familial PA

Rare

Rare Second most common cause of monogenic hypertension

Genetics

Sporadic mutations involving KCNJ5, ATP1A1, ATP2B3, and CACNA1D; Chromosome 7p22

Sporadic mutations

Chimeric mutation involving 11b-hydroxylase and aldosterone synthase

Autosomal dominant

KCNJ5 mutations coding for K1 channel GIRK4

Gain of function in SCNN1B and SCNN1G genes Leads to alteration in renal epithelial Na1 channel

Pathology

Benign, solitary, Bilateral microadenoma micronodular or macroadenoma or macronodular Metastasis and adrenal tumor recurrence hyper-rplasia rare HTN, hypokalemia HTN, hypokalemia (less severe compared with APA)

Adrenal nodules in some cases

Often adrenal adenomas

Juxtaglomerular apparatus atrophy Loss of reninsecreting granules

Variable Severe HTN Increased risk of early-onset stroke and rupture of intracranial aneurysms

HTN more prevalent than in GRA

Massive bilateral hyperplasia; Cellular hypertrophy of fasciculata with atrophy of glomerulosa Severe HTN and hypokalemia

Presentation

Laboratory abnormalities PRA Aldosterone ARR 18-Hydroxycortisol and 18-oxocortisol 11-Deoxycortisol Deoxycorticosterone 17-OH progesterone Potassium levels Other comments

Y [ [ [

Y [ [

Y

Y Similar to APA but less pronounced

Adrenal imaging

Unilateral adenoma

Confirmatory test

AVS

Treatment

Unilateral adrenalectomy

Bilateral hyperplasia

Medical management

Y Y [ [[

Spontaneous hypokalemia is uncommon

Salt-sensitive HTN Hypokalemia Nephrocalcinosis Renal cysts Muscle weakness

Y Y [[

No suppression of aldosterone with exogenous dexamethasone Massive bilateral hyperplasia

Adrenal nodules in some cases Aldosterone Based on identifying suppression by 2 or more firstdexamethasone degree members Sequencing for the in the same family CYP11B1/CYP11B2 with confirmed PA chimeric gene phenotypes. Resistant to Based on the Difficult to control treatment pathology. Surgery hypertension in patients Dexamethasone with APA and Caution with diuretics mineralocorticoid as it can lead to antagonists in significant adrenal hyperplasia. hypokalemia

Y; Kaliuresis Metabolic alkalosis

Does not respond to MR antagonist but does respond to amiloride.

Abbreviations: ACTH, adrenocoticotrophic hormone; AME, apparent mineralocorticoid excess; APA, aldosterone-producing adrenal adenoma; ARR, aldosterone-to-renin ratio; AVS, adrenal vein sampling; BAH, bilateral adrenal hyperplasia; CAH, congenital adrenal hyperplasia; GRA, glucocorticoid remediable aldosteronism; HTN, hypertension; MR, mineralocorticoid receptor; PA, primary aldosteronism; PRA, plasma renin activity; RTA, renal tubular acidosis.

189

Mineralocorticoid Hypertension

CAH 11b-Hydroxylase Deficiency

AME

17a-Hydroxylase Deficiency

Gordon Syndrome (Pseudohypoaldosteronism Type 2)

Chrousos Syndrome (Glucocorticoid Resistance)

Geller Syndrome

Infancy/childhood

Infancy/childhood

Infancy/childhood

Any

Childhood

Second decade

Very rare Third most common cause of monogenic hypertension

Rare 5%-8% of CAH 1:100,000 births Particularly common in Moroccan Jews—1:7000 births Autosomal recessive inheritance Mutations in the gene CYP11B1

Rare 1% of CAH 1:50,000 to 1:100,000 newborns

Rare

Rare

Rare

Autosomal recessive inheritance Mutations in CYP17

Autosomal dominant Gain-of-function mutation in WNK1 and WNK4 coding for NaCl co-transporter in distal tubule Other mutations KLHL3, CUL3, SPAK

Glucocorticoid resistance

Autosomal dominant Gain-of-function mutation in mineralocorticoid receptor Chromosome 4q31

Autosomal recessive Markedly decreased levels of 11b-hydroxysteroid dehydrogenase type 2 because of loss-of-function mutation.

Progesterone has an agonistic property on this abnormal receptor

Ambiguous genitalia and precocious puberty in children and adolescents. Acne, hirsutism, and infertility in adult women.

HTN, worse during pregnancy

HTN, hypokalemia, metabolic alkalosis Growth retardation Nephrocalcinosis

Virilization, amenorrhea, and hirsutism in women. Precocious puberty in male children. Short stature HTN

Masculinization variably impaired in males. Sexual infantilism in women. Na and water retention and HTN

HTN Short stature Mild mental retardation Muscle weakness Hyperkalemia and hyperchloremic metabolic acidosis Distal RTA with normal renal function

Y YY

Y Y

Y YY

Y Y/Normal

Y Y

[ [ [ Variable ACTH [

Y [ Y [ Hyperchloremic metabolic acidosis

Normal

Amiloride Triamterene

Spironolactone is contraindicated because of paradoxical agonist property

Metabolic alkalosis Increased urinary-free cortisol to free cortisone ratio

Hypokalemia Testosterone Y

Urinary tetrahydrocortisol and allotetrahydrocortisol to tetrahydrocortisone ratios are pathognomonic Genetic testing Low sodium diet MR antagonists Dexamethasone to suppress endogenous corticosteroid steroids Renal transplant offers cure

Corticosterone [

Exogenous steroids Bilateral adrenalectomy in highly selected cases

Exogenous steroid therapy

190

Ardhanari et al

Figure 1. Adrenal steroidogenesis: enzymes are in red. Highlighted enzymes are discussed in our review. Abbreviations: 11b-HSD1, 11 beta-hydroxysteroid dehydrogenase type 1; 11b, HSD2–11 beta hydroxysteroid dehydrogenase type 2; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; DOC, deoxycorticosterone.

Familial Hyperaldosteronism Type I (GRA) GRA72 was first reported in 1966 as a case of inherited hypertension.12 This is the most common cause of monogenic hypertension with an autosomal dominant pattern of inheritance. This condition is rare and accounts for probably ,1% of all cases of primary aldosteronism; however, the exact prevalence is not yet established.73-75 The syndrome results from a characteristic unequal genetic crossover event that results in the ACTHresponsive promoter of 11b-hydroxylase (CYP11B1) fusing to aldosterone synthase (CYP11B2).76 This results in production of aldosterone under the control of ACTH. Aldosterone production is suppressible by exogenously administered glucocorticoids and reduction in ACTH release.72,77 The disease is characterized by hypertension with variable hyperaldosteronism resulting in hypo-K1, increased plasma volume, and low PRA. Adrenal nodules may be found in some cases. GRA has several unique features. First, hypertension manifests early in life; the majority of children with gene chimerisms are hypertensive by 13 years, and about half of them have moderate-severe hypertension at diagnosis.78 Second, spontaneous hypo-K1 is uncommon, but hypo-K1 may develop on exposure to K1 wasting diuretics.79,80 More than half of patients with primary aldosteronism have normokalemia; however, 90% of such individuals become hypokalemic with saltloading test.22,81 Patients with GRA are typically normokalemic despite excess dietary salt intake. Litchfield and colleagues82 demonstrated that patients with GRA have a milder form of hyperaldosteronism as there is a failure of aldosterone secretion in response to a potassium load, and total aldosterone secretion is less because of the diurnal nature of ACTH secretion in contrast to the constitutional secretion of aldosterone in patients with primary aldosteronism. This milder form of hyperaldosteronism can suppress PRA but is insufficient to cause excessive kaliuresis. Third, aldosterone secretion is primarily under regulation of ACTH in this condition and is suppressible by exogenous glucocorticoid therapy. Fourth, there are abnormally high levels of 18hydroxycortisol and 18-oxocortisol.83 Finally, these

patients have an increased incidence of cerebrovascular complications, particularly early-onset hemorrhagic stroke and rupture of intracranial aneurysms. This has led to the recommendation for screening cerebral magnetic resonance angiography for patients with GRA. This approach, however, has not yielded a demonstrable reduction in event rates.84 The potential mechanisms behind the higher incidence of cardiovascular complications include the following. First, hyperaldosteronism has been shown to induce vascular fibrosis as a result of inflammation, oxidative stress, and endothelial dysfunction. These effects are mediated through both mineralocorticoid receptor dependent and/or independent actions via genomic and nongenomic pathways.85 It is a possibility that mineralocorticoid induced vascular fibrosis could lead to aneurysm formation, but the causation is yet to be proved.86 Second, hypertension can increase the likelihood of subarachnoid hemorrhage as it does in any other patient with hypertension.87 Finally, the combination of hypertension and/or mineralocorticoid excess in early life could predispose patients to formation of intracranial aneurysms, as can be seen in disorders such as polycystic kidney disease, Liddle syndrome, and congenital 11b-hydroxylase deficiency.88-91 Aldosterone suppression by dexamethasone has been the traditional confirmatory test, although positive tests with a normal genotype have been reported.92-94 Elevated 18-hydroxycortisol levels have also been used with aldosterone suppression to differentiate GRA from other forms of primary aldosteronism. However, this test also lacks specificity, and sequencing for the CYP11B1/ CYP11B2 chimeric gene is the recommended approach for making a definitive diagnosis.95,96 Hypertension in this population is often difficult to control with standard antihypertensive therapies. It should be noted that particular caution is needed using K1-wasting diuretics in view of the propensity for significant hypoK1. Suppression of pituitary ACTH secretion with a long-acting exogenous glucocorticoid with minimal mineralocorticoid activity like dexamethasone remains first-line therapy. Dexamethasone is administered nightly to suppress the early morning peak of ACTH and at the lowest possible dose to normalize blood pressure and

Mineralocorticoid Hypertension

K1. Second-line therapy is a mineralocorticoid receptor antagonist given the possibility of partial ACTH suppression or coexistent essential hypertension.97 Familial Hyperaldosteronism Type II First identified in 1992, patients with familial hyperaldosteronism type II have an autosomal dominant pattern of inheritance.13,98 Chromosomal region 7p22 has been implicated in some of these families, as has been KCNJ5 on chromosome 11.13,67 This entity is characterized by primary aldosteronism that is not suppressible by glucocorticoids and often involves formation of adrenocortical adenomas. The diagnosis is based on identifying 2 or more first-degree relatives in the same family with confirmed primary aldosteronism.99 It is estimated that familial hyperaldosteronism type II may account for approximately 6% of familial aldosteronism. Treatment includes mineralocorticoid antagonists in patients with adrenal hyperplasia and unilateral adrenalectomy in patients with APA.99 Familial Hyperaldosteronism Type III A novel form of familial hyperaldosteronism secondary to massive bilateral adrenal hyperplasia is also recognized.66 Similar to aldosterone-producing adrenal adenomas, mutations in KCNJ5 that codes for the potassium channel GIRK4 have been identified in these patients.16,37 Pathologically, there is cellular hypertrophy of zona fasciculata with atrophy of zona glomerulosa. The presentation is remarkable for aggressive hypertension and hypo-K1. Hypertension presents early in life and is highly resistant to treatment. Biochemically, there is a substantial elevation in 18-oxocortisol and 18hydroxycortisol levels, and there is no suppression of aldosterone with exogenous dexamethasone. LIDDLE SYNDROME (PSEUDOALDOSTERONISM) This disorder was first reported in 1963 and is recognized as the second most common cause of monogenic hypertension.100,101 The primary abnormality is constitutive activation of the distal epithelial Na1 channel of the kidney sensitive to amiloride. Gain-of-function mutations leading to this disorder are derived from more than 20 mutations in the SCNN1B and SCNN1G genes.102 Aldosterone secretion is chronically suppressed, and pathologically, there is juxtaglomerular apparatus atrophy with loss of renin-secreting granules.103 Liddle syndrome is characterized by a salt-sensitive hypertension that characteristically has an early onset in life. This is also associated with hypo-K1 and metabolic alkalosis, thereby resembling primary aldosteronism albeit with several contrasting features. First, basal aldosterone secretion levels are not elevated, and there is no increase in aldosterone secretion on ingestion of a low Na1 diet or correction of hypo-K1. PRA is also suppressed. Second, the electrolyte abnormality and the hypertension do not respond to mineralocorticoid antagonists but typically improve with epithelial Na1 channel blockers amiloride or triamterene. These individuals have an increased mortality risk because of stroke and heart failure, and ESRD because of nephrosclerosis has been reported.104,105

191

Interestingly, the index case originally described in 1963 underwent cadaveric kidney transplantation in 1989, resulting in normalization of aldosterone and renin secretion to Na1 restriction.90 SYNDROME OF APPARENT MINERALOCORTICOID EXCESS AME was first identified in 1977 and comprises features of primary aldosteronism with undetectable aldosterone levels.106 AME is the third most common cause of monogenic hypertension.101 This disorder is inherited in an autosomal recessive fashion and results in a marked decrease in levels of 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2).107-111 This enzyme is expressed in tubular epithelial cells of the kidney and is responsible for intracellular conversion of cortisol to cortisone. Cortisol has significant mineralocorticoid activity with a mineralocorticoid receptor affinity similar to aldosterone. Cortisone, on the other hand, has predominately glucocorticoid activity with only minimal affinity for the mineralocorticoid receptor. Under normal circumstances, cortisol is converted to cortisone, preventing unnecessary activation of the mineralocorticoid receptor in tubular epithelial cells of the kidney. Deficiency of 11b-HSD2 leads to increased intracellular levels of cortisol, resulting in excessive mineralocorticoid activity with Na1 retention, K1 wasting, metabolic alkalosis, and hypertension. The disorder often presents in infancy with severe hypertension and can lead to serious cardiovascular and cerebrovascular comorbidities in untreated cases over time. Nephrocalcinosis and kidney cysts may ultimately develop, and this may be a consequence of long-standing hypokalemia.112 A marked increase in the urinary-free cortisol to free cortisone ratio is consistent with the diagnosis, although a similar abnormality can be seen in patients with Liddle syndrome. Elevated urinary tetrahydrocortisol and allotetrahydrocortisol to tetrahydrocortisone ratios are pathognomonic of syndrome of AME. More commonly, genetic testing rather than urine profiling is used to confirm the diagnosis. Management options include antagonism of the mineralocorticoid receptor and K1-sparing diuretics. An additional strategy is suppression of endogenous corticosteroid secretion by administration of dexamethasone. There is at least 1 case of documented improvement of hypertension and normalization of cortisol metabolism with kidney transplantation.113,114 Several clinical conditions lead to abnormalities in the function of 11b-HSD2. Chewing tobacco, ingestion of licorice, or licorice-like compounds lead to generation of glycyrrhetinic acid. Glycyrrhetinic acid is a potent inhibitor of 11b-HSD2 resulting in decreased function of this enzyme leading to a clinical syndrome similar to AME.115 In pregnancy-induced hypertension, there is reduction in activity of 11b-HSD2 that may contribute to the generation of elevated blood pressure.116 CONGENITAL ADRENAL HYPERPLASIA CAH comprises a group of autosomal recessive hereditary disorders of adrenocortical hormone synthesis because of

192

Ardhanari et al

deficiencies of enzymes 21-hydroxylase, 17a-hydroxylase, 11b-hydroxylase, 3-b-hydroxysteroid dehydrogenase, and 20,22-desmolase. The resulting phenotype is influenced by levels of cortisol, aldosterone, deoxycorticosterone, and sex hormones. Among the above enzymes, 17a-hydroxylase and 11b-hydroxylase deficiencies present as mineralocorticoid excess syndromes.117 11b-HYDROXYLASE DEFICIENCY 11b-hydroxylase deficiency is a rare cause of CAH (5%8%) and results from mutations in the gene CYP11B1.118 Moroccan Jews, in particular, have a higher prevalence.119 11b-hydroxylase functions to convert 11-deoxycortisol and 11-deoxycorticosterone to cortisol and corticosterone, respectively. Enzyme deficiency results in the accumulation of these substrates and deficiency of cortisol and aldosterone. Secondary ACTH stimulation results in further precursor accumulation. Hypertension results from the mineralocorticoid effects of 11-deoxycorticosterone. Shunting of steroidogenesis intermediates to sex hormone pathways generates excess 17a-hydroxyprogesterone and androstenedione, resulting in virilization of female children and precocious puberty in men. Exogenous steroid to suppress the endogenous steroidogenesis is the mainstay of treatment for normalization of growth in children with this disorder. Bilateral adrenalectomy in highly selected cases for control of blood pressure has been advocated, and mineralocorticoid replacement is necessary. 17a-HYDROXYLASE DEFICIENCY 17a-hydroxylase accounts for less than 1% of patients with CAH, affecting both gonadal and adrenal steroidogenesis. The disorder results in both decreased sex hormone and cortisol production with excess synthesis of mineralocorticoids. These include deoxycorticosterone and corticosterone leading to Na1 and water retention and hypertension. Masculinization is variably impaired depending on the severity of the enzyme deficiency.120 Exogenous steroid therapy with hydrocortisone to maximize the growth potential and based on the gender, exogenous estrogen and testosterone treatment is recommended. Table 1 summarizes the salient features of disorders discussed in this review. Figure 1 depicts the adrenocortical steroidogensis with special reference to the disorders discussed in this review. CONCLUSIONS Hormones with mineralocorticoid activity are fundamental to mechanisms of blood pressure regulation, and syndromes of mineralocorticoid excess are important causes of secondary hypertension. These syndromes are associated with kidney, cardiovascular, and cerebrovascular morbidity and mortality. Prompt and proper diagnosis of specific syndromes offers the potential for minimization of adverse consequences and, in some cases, cure of hypertension. REFERENCES 1. Spat A, Hunyady L. Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiol Rev. 2004; 84(2):489-539.

2. Conn JW. Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med. 1955; 45(1):3-17. 3. Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008;93(9):3266-3281. 4. Catena C, Colussi G, Nadalini E, et al. Cardiovascular outcomes in patients with primary aldosteronism after treatment. Arch Intern Med. 2008;168(1):80-85. 5. Savard S, Amar L, Plouin PF, Steichen O. Cardiovascular complications associated with primary aldosteronism: a controlled crosssectional study. Hypertension. 2013;62(2):331-336. 6. Turchi F, Ronconi V, di Tizio V, Ceccoli L, Boscaro M, Giacchetti G. Primary aldosteronism and essential hypertension: assessment of cardiovascular risk at diagnosis and after treatment. Nutr Metab Cardiovasc Dis. 2014;24(5):476-482. 7. Hannemann A, Wallaschofski H. Prevalence of primary aldosteronism in patient’s cohorts and in population-based studies—a review of the current literature. Horm Metab Res. 2012;44(3):157-162. 8. Amar L, Plouin PF, Steichen O. Aldosterone-producing adenoma and other surgically correctable forms of primary aldosteronism. Orphanet J Rare Dis. 2010;5:9. 9. Ross EJ. Conn’s syndrome due to adrenal hyperplasia with hypertrophy of zona glomerulosa, relieved by unilateral adrenalectomy. Am J Med. 1965;39(6):994-1002. 10. Banks WA, Kastin AJ, Biglieri EG, Ruiz AE. Primary adrenal hyperplasia: a new subset of primary hyperaldosteronism. J Clin Endocrinol Metab. 1984;58(5):783-785. 11. Foye LV Jr, Feichtmeir TV. Adrenal cortical carcinoma producing solely mineralocorticoid effect. Am J Med. 1955;19(6):966-975. 12. Sutherland DJ, Ruse JL, Laidlaw JC. Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can Med Assoc J. 1966;95(22):1109-1119. 13. Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Finn WL, Krek AL. Clinical and pathological diversity of primary aldosteronism, including a new familial variety. Clin Exp Pharmacol Physiol. 1991;18(5):283-286. 14. Omura M, Sasano H, Fujiwara T, Yamaguchi K, Nishikawa T. Unique cases of unilateral hyperaldosteronemia due to multiple adrenocortical micronodules, which can only be detected by selective adrenal venous sampling. Metabolism. 2002;51(3):350-355. 15. Stowasser M. Update in primary aldosteronism. J Clin Endocrinol Metab. 2015;100(1):1-10. 16. Choi M, Scholl UI, Yue P, et al. K1 channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011;331(6018):768-772. 17. Zennaro MC, Rickard AJ, Boulkroun S. Genetics of mineralocorticoid excess: an update for clinicians. Eur J Endocrinol. 2013;169(1):R15-R25. 18. Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45(8):12431248. 19. Rossi GP, Bernini G, Desideri G, et al. Renal damage in primary aldosteronism: results of the PAPY Study. Hypertension. 2006; 48(2):232-238. 20. Sechi LA, Di Fabio A, Bazzocchi M, Uzzau A, Catena C. Intrarenal hemodynamics in primary aldosteronism before and after treatment. J Clin Endocrinol Metab. 2009;94(4):1191-1197. 21. Born-Frontsberg E, Reincke M, Rump LC, et al. Cardiovascular and cerebrovascular comorbidities of hypokalemic and normokalemic primary aldosteronism: results of the German Conn’s Registry. J Clin Endocrinol Metab. 2009;94(4):1125-1130. 22. Rimoldi SF, Scherrer U, Messerli FH. Secondary arterial hypertension: when, who, and how to screen? Eur Heart J. 2014; 35(19):1245-1254.

Mineralocorticoid Hypertension

23. Stowasser M, Ahmed AH, Pimenta E, Taylor PJ, Gordon RD. Factors affecting the aldosterone/renin ratio. Horm Metab Res. 2012; 44(3):170-176. 24. Trenkel S, Seifarth C, Schobel H, Hahn EG, Hensen J. Ratio of serum aldosterone to plasma renin concentration in essential hypertension and primary aldosteronism. Exp Clin Endocrinol Diabetes. 2002;110(2):80-85. 25. Ducher M, Mounier-Vehier C, Baguet JP, et al. Aldosterone-to-renin ratio for diagnosing aldosterone-producing adenoma: a multicentre study. Arch Cardiovasc Dis. 2012;105(12):623-630. 26. Lethielleux G, Amar L, Raynaud A, Plouin PF, Steichen O. Influence of diagnostic criteria on the interpretation of adrenal vein sampling. Hypertension. 2015;65(4):849-854. 27. Chrousos GP, Vingerhoeds A, Brandon D, et al. Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease. J Clin Invest. 1982;69(6):1261-1269. 28. Charmandari E, Kino T, Ichijo T, Chrousos GP. Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder. J Clin Endocrinol Metab. 2008;93(5):1563-1572. 29. Geller DS, Farhi A, Pinkerton N, et al. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science. 2000;289(5476):119-123. 30. Gordon RD, Geddes RA, Pawsey CG, O’Halloran MW. Hypertension and severe hyperkalaemia associated with suppression of renin and aldosterone and completely reversed by dietary sodium restriction. Australas Ann Med. 1970;19(4):287-294. 31. Omura M, Sasano H, Saito J, Yamaguchi K, Kakuta Y, Nishikawa T. Clinical characteristics of aldosterone-producing microadenoma, macroadenoma, and idiopathic hyperaldosteronism in 93 patients with primary aldosteronism. Hypertens Res. 2006;29(11):883-889. 32. Ghose RP, Hall PM, Bravo EL. Medical management of aldosteroneproducing adenomas. Ann Intern Med. 1999;131(2):105-108. 33. Fernandes-Rosa FL, Williams TA, Riester A, et al. Genetic spectrum and clinical correlates of somatic mutations in aldosteroneproducing adenoma. Hypertension. 2014;64(2):354-361. 34. Taguchi R, Yamada M, Nakajima Y, et al. Expression and mutations of KCNJ5 mRNA in Japanese patients with aldosterone-producing adenomas. J Clin Endocrinol Metab. 2012;97(4):1311-1319. 35. Akerstrom T, Crona J, Delgado Verdugo A, et al. Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter. PLoS One. 2012;7(7):e41926. 36. Azizan EA, Murthy M, Stowasser M, et al. Somatic mutations affecting the selectivity filter of KCNJ5 are frequent in 2 large unselected collections of adrenal aldosteronomas. Hypertension. 2012;59(3):587-591. 37. Boulkroun S, Beuschlein F, Rossi GP, et al. Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteronism. Hypertension. 2012;59(3):592-598. 38. Monticone S, Hattangady NG, Nishimoto K, et al. Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells. J Clin Endocrinol Metab. 2012;97(8):E1567E1572. 39. Azizan EA, Lam BY, Newhouse SJ, et al. Microarray, qPCR, and KCNJ5 sequencing of aldosterone-producing adenomas reveal differences in genotype and phenotype between zona glomerulosaand zona fasciculata-like tumors. J Clin Endocrinol Metab. 2012; 97(5):E819-E829. 40. Rossi GP, Bernini G, Caliumi C, et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006;48(11):2293-2300. 41. Berge C, Courand PY, Harbaoui B, et al. Decreased plasma prorenin levels in primary aldosteronism: potential diagnostic implications. J Hypertens. 2015;33(1):118-125. 42. Phillips JL, Walther MM, Pezzullo JC, et al. Predictive value of preoperative tests in discriminating bilateral adrenal hyperplasia from

43.

44.

45.

46.

47.

48.

49.

50. 51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

193

an aldosterone-producing adrenal adenoma. J Clin Endocrinol Metab. 2000;85(12):4526-4533. Jeck T, Weisser B, Mengden T, Erdmenger L, Grune S, Vetter W. Primary aldosteronism: difference in clinical presentation and longterm follow-up between adenoma and bilateral hyperplasia of the adrenal glands. Clin Investig. 1994;72(12):979-984. Mulatero P, Dluhy RG, Giacchetti G, Boscaro M, Veglio F, Stewart PM. Diagnosis of primary aldosteronism: from screening to subtype differentiation. Trends Endocrinol Metab. 2005;16(3):114-119. Kempers MJ, Lenders JW, van Outheusden L, et al. Systematic review: diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism. Ann Intern Med. 2009;151(5):329-337. Raman SP, Lessne M, Kawamoto S, et al. Diagnostic performance of multidetector computed tomography in distinguishing unilateral from bilateral abnormalities in primary hyperaldosteronism: comparison of multidetector computed tomography with adrenal vein sampling [e-pub ahead of print; Jan 15, 2015]. J Comput Assist Tomogr. 2015. Young WF, Stanson AW, Thompson GB, Grant CS, Farley DR, van Heerden JA. Role for adrenal venous sampling in primary aldosteronism. Surgery. 2004;136(6):1227-1235. Nocaudie-Calzada M, Huglo D, Lambert M, et al. Efficacy of iodine-131 6beta-methyl-iodo-19-norcholesterol scintigraphy and computed tomography in patients with primary aldosteronism. Eur J Nucl Med. 1999;26(10):1326-1332. Rossi GP, Auchus RJ, Brown M, et al. An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism. Hypertension. 2014;63(1):151-160. Stewart PM, Allolio B. Adrenal vein sampling for primary aldosteronism: time for a reality check. Clin Endocrinol. 2010;72(2):146-148. Vonend O, Ockenfels N, Gao X, et al. Adrenal venous sampling: evaluation of the German Conn’s registry. Hypertension. 2011; 57(5):990-995. Kline GA, Harvey A, Jones C, et al. Adrenal vein sampling may not be a gold-standard diagnostic test in primary aldosteronism: final diagnosis depends upon which interpretation rule is used. Variable interpretation of adrenal vein sampling. Int Urol Nephrol. 2008; 40(4):1035-1043. Volpe C, Hamberger B, Hoog A, et al. Primary aldosteronism: functional histopathology and long-term follow-up after unilateral adrenalectomy [e-pub ahead of print; Oct 27, 2014]. Clin Endocrinol. 2014. http://dx.doi.org/10.1111/cen.12645. Zarnegar R, Young WF Jr, Lee J, et al. The aldosteronoma resolution score: predicting complete resolution of hypertension after adrenalectomy for aldosteronoma. Ann Surg. 2008;247(3):511-518. Hennings J, Andreasson S, Botling J, Hagg A, Sundin A, Hellman P. Long-term effects of surgical correction of adrenal hyperplasia and adenoma causing primary aldosteronism. Langenbecks Arch Surg. 2010;395(2):133-137. Calvo-Romero JM, Ramos-Salado JL. Recurrence of adrenal aldosterone-producing adenoma. Postgrad Med J. 2000;76(893): 160-161. Aronova A, Gordon BL, Finnerty BM, Zarnegar R, Fahey TJ III. Aldosteronoma resolution score predicts long-term resolution of hypertension. Surgery. 2014;156(6):1387-1393. Utsumi T, Kamiya N, Endo T, et al. Development of a novel nomogram to predict hypertension cure after laparoscopic adrenalectomy in patients with primary aldosteronism. World J Surg. 2014;38(10):2640-2644. Steichen O, Zinzindohoue F, Plouin PF, Amar L. Outcomes of adrenalectomy in patients with unilateral primary aldosteronism: a review. Horm Metab Res. 2012;44(3):221-227. Favia G, Lumachi F, Scarpa V, D’Amico DF. Adrenalectomy in primary aldosteronism: a long-term follow-up study in 52 patients. World J Surg. 1992;16(4):680-683. discussion 683–684. Tanase-Nakao K, Naruse M, Nanba K, et al. Chronic kidney disease score for predicting postoperative masked renal insufficiency in

194

62.

63. 64. 65. 66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79. 80.

81. 82.

Ardhanari et al

patients with primary aldosteronism. Clin Endocrinol. 2014; 81(5):665-670. Utsumi T, Kawamura K, Imamoto T, et al. Preoperative masked renal damage in Japanese patients with primary aldosteronism: identification of predictors for chronic kidney disease manifested after adrenalectomy. Int J Urol. 2013;20(7):685-691. Ganguly A. Primary aldosteronism. N Engl J Med. 1998;339(25): 1828-1834. Doorenbos H, Elings HS, Van Buchem FS. Primary aldosteronism due to adrenocortical hyperplasia. Lancet. 1956;271(6938):335-337. Young WF. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol. 2007;66(5):607-618. Geller DS, Zhang J, Wisgerhof MV, Shackleton C, Kashgarian M, Lifton RP. A novel form of human Mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. 2008;93(8):3117-3123. Mulatero P, Tauber P, Zennaro MC, et al. KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism. Hypertension. 2012;59(2):235-240. Charmandari E, Sertedaki A, Kino T, et al. A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and earlyonset autosomal dominant hypertension. J Clin Endocrinol Metab. 2012;97(8):E1532-E1539. Scholl UI, Nelson-Williams C, Yue P, et al. Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. Proc Natl Acad Sci U S A. 2012;109(7):2533-2538. Monticone S, Hattangady NG, Penton D, et al. A novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III. J Clin Endocrinol Metab. 2013;98(11):E1861-E1865. Weinberger MH, Grim CE, Hollifield JW, et al. Primary aldosteronism: diagnosis, localization, and treatment. Ann Intern Med. 1979;90(3):386-395. Lifton RP, Dluhy RG, Powers M, et al. A chimaeric 11 betahydroxylase/aldosterone synthase gene causes glucocorticoidremediable aldosteronism and human hypertension. Nature. 1992;355(6357):262-265. Adler G, Widecka K, Peczkowska M, et al. Genetic screening for glucocorticoid-remediable aldosteronism (GRA): experience of three clinical centres in Poland. J Appl Genet. 2005;46(3):329-332. Pizzolo F, Trabetti E, Guarini P, et al. Glucocorticoid remediable aldosteronism (GRA) screening in hypertensive patients from a primary care setting. J Hum Hypertens. 2005;19(4):325-327. Aglony M, Martinez-Aguayo A, Carvajal CA, et al. Frequency of familial hyperaldosteronism type 1 in a hypertensive pediatric population: clinical and biochemical presentation. Hypertension. 2011;57(6):1117-1121. Pascoe L, Jeunemaitre X, Lebrethon MC, et al. Glucocorticoid-suppressible hyperaldosteronism and adrenal tumors occurring in a single French pedigree. J Clin Invest. 1995;96(5):2236-2246. Lifton RP, Dluhy RG, Powers M, et al. Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase. Nat Genet. 1992;2(1):66-74. Dluhy RG, Anderson B, Harlin B, Ingelfinger J, Lifton R. Glucocorticoid-remediable aldosteronism is associated with severe hypertension in early childhood. J Pediatr. 2001;138(5):715-720. Grim CE, Weinberger MH. Familial, dexamethasone-suppressible, normokalemic hyperaldosteronism. Pediatrics. 1980;65(3):597-604. Vonend O, Altenhenne C, Buchner NJ, et al. A German family with glucocorticoid-remediable aldosteronism. Nephrol Dial Transplant. 2007;22(4):1123-1130. Bravo EL, Tarazi RC, Dustan HP, et al. The changing clinical spectrum of primary aldosteronism. Am J Med. 1983;74(4):641-651. Litchfield WR, Coolidge C, Silva P, et al. Impaired potassiumstimulated aldosterone production: a possible explanation for normokalemic glucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. 1997;82(5):1507-1510.

83. Rich GM, Ulick S, Cook S, Wang JZ, Lifton RP, Dluhy RG. Glucocorticoid-remediable aldosteronism in a large kindred: clinical spectrum and diagnosis using a characteristic biochemical phenotype. Ann Intern Med. 1992;116(10):813-820. 84. Litchfield WR, Anderson BF, Weiss RJ, Lifton RP, Dluhy RG. Intracranial aneurysm and hemorrhagic stroke in glucocorticoidremediable aldosteronism. Hypertension. 1998;31(1 Pt 2):445-450. 85. Briet M, Schiffrin EL. Vascular actions of aldosterone. J Vasc Res. 2013;50(2):89-99. 86. Hall CE, Hall OF. Hypertension and hyperalimentation. I. Aldosterone hypertension. Lab Invest. 1965;14:285-294. 87. Knekt P, Reunanen A, Aho K, et al. Risk factors for subarachnoid hemorrhage in a longitudinal population study. J Clin Epidemiol. 1991;44(9):933-939. 88. Hague WM, Honour JW. Malignant hypertension in congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. Clin Endocrinol. 1983;18(5):505-510. 89. Wiebers DO, Whisnant JP, O’Fallon WM. The natural history of unruptured intracranial aneurysms. N Engl J Med. 1981;304(12):696698. 90. Botero-Velez M, Curtis JJ, Warnock DG. Brief report: Liddle’s syndrome revisited–a disorder of sodium reabsorption in the distal tubule. N Engl J Med. 1994;330(3):178-181. 91. Chapman AB, Rubinstein D, Hughes R, et al. Intracranial aneurysms in autosomal dominant polycystic kidney disease. N Engl J Med. 1992;327(13):916-920. 92. Litchfield WR, New MI, Coolidge C, Lifton RP, Dluhy RG. Evaluation of the dexamethasone suppression test for the diagnosis of glucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. 1997;82(11):3570-3573. 93. Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab. 2000; 85(5):1863-1867. 94. Mulatero P, Veglio F, Pilon C, et al. Diagnosis of glucocorticoidremediable aldosteronism in primary aldosteronism: aldosterone response to dexamethasone and long polymerase chain reaction for chimeric gene. J Clin Endocrinol Metab. 1998; 83(7):2573-2575. 95. Nicod J, Dick B, Frey FJ, Ferrari P. Mutation analysis of CYP11B1 and CYP11B2 in patients with increased 18-hydroxycortisol production. Mol Cell Endocrinol. 2004;214(1-2):167-174. 96. Kamrath C, Maser-Gluth C, Haag C, Schulze E. Diagnosis of glucocorticoid-remediable aldosteronism in hypertensive children. Horm Res Paediatr. 2011;76(2):93-98. 97. Halperin F, Dluhy RG. Glucocorticoid-remediable aldosteronism. Endocrinol Metab Clin North Am. 2011;40(2):333-341. viii. 98. Stowasser M, Gordon RD, Tunny TJ, Klemm SA, Finn WL, Krek AL. Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism. Clin Exp Pharmacol Physiol. 1992;19(5):319-322. 99. Mulatero P, Tizzani D, Viola A, et al. Prevalence and characteristics of familial hyperaldosteronism: the PATOGEN study (Primary Aldosteronism in TOrino-GENetic forms). Hypertension. 2011;58(5):797-803. 100. Yang KQ, Xiao Y, Tian T, Gao LG, Zhou XL. Molecular genetics of Liddle’s syndrome. Clin Chim Acta. 2014;436:202-206. 101. Mantero F, Palermo M, Petrelli MD, Tedde R, Stewart PM, Shackleton CH. Apparent mineralocorticoid excess: type I and type II. Steroids. 1996;61(4):193-196. 102. Shimkets RA, Warnock DG, Bositis CM, et al. Liddle’s syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell. 1994;79(3):407-414. 103. Wang C, Chan TK, Yeung RT, Coghlan JP, Scoggins BA, Stockigt JR. The effect of triamterene and sodium intake on renin, aldosterone, and erythrocyte sodium transport in Liddle’s syndrome. J Clin Endocrinol Metab. 1981;52(5):1027-1032.

Mineralocorticoid Hypertension

104. Palmer BF, Alpern RJ. Liddle’s syndrome. Am J Med. 1998; 104(3):301-309. 105. Tamura H, Schild L, Enomoto N, Matsui N, Marumo F, Rossier BC. Liddle disease caused by a missense mutation of beta subunit of the epithelial sodium channel gene. J Clin Invest. 1996;97(7):17801784. 106. New MI, Levine LS, Biglieri EG, Pareira J, Ulick S. Evidence for an unidentified steroid in a child with apparent mineralocorticoid hypertension. J Clin Endocrinol Metab. 1977;44(5):924-933. 107. Morineau G, Sulmont V, Salomon R, et al. Apparent mineralocorticoid excess: report of six new cases and extensive personal experience. J Am Soc Nephrol. 2006;17(11):3176-3184. 108. Alzahrani AS, Aljuhani N, Qasem E, et al. Apparent mineralocorticoid excess caused by a novel mutation in 11-beta hydroxysteroid dehydrogenase type 2 enzyme: its genetics and response to therapy. Endocr Pract. 2014;20(9):e151-e156. 109. Kamide K, Kokubo Y, Hanada H, et al. Genetic variations of HSD11B2 in hypertensive patients and in the general population, six rare missense/frameshift mutations. Hypertens Res. 2006; 29(4):243-252. 110. Mune T, Rogerson FM, Nikkila H, Agarwal AK, White PC. Human hypertension caused by mutations in the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase. Nat Genet. 1995;10(4):394-399. 111. New MI, Geller DS, Fallo F, Wilson RC. Monogenic low renin hypertension. Trends Endocrinol Metabol. 2005;16(3):92-97. 112. Moudgil A, Rodich G, Jordan SC, Kamil ES. Nephrocalcinosis and renal cysts associated with apparent mineralocorticoid excess syndrome. Pediatr Nephrol. 2000;15(1-2):60-62.

195

113. Palermo M, Delitala G, Sorba G, et al. Does kidney transplantation normalise cortisol metabolism in apparent mineralocorticoid excess syndrome? J Endocrinol Invest. 2000;23(7):457-462. 114. Palermo M, Cossu M, Shackleton CH. Cure of apparent mineralocorticoid excess by kidney transplantation. N Engl J Med. 1998; 339(24):1787-1788. 115. Farese RV Jr, Biglieri EG, Shackleton CH, Irony I, Gomez-Fontes R. Licorice-induced hypermineralocorticoidism. N Engl J Med. 1991; 325(17):1223-1227. 116. Heilmann P, Buchheim E, Wacker J, Ziegler R. Alteration of the activity of the 11beta-hydroxysteroid dehydrogenase in pregnancy: relevance for the development of pregnancy-induced hypertension? J Clin Endocrinol Metab. 2001;86(11):5222-5226. 117. Melcescu E, Phillips J, Moll G, Subauste JS, Koch CA. 11Beta-hydroxylase deficiency and other syndromes of mineralocorticoid excess as a rare cause of endocrine hypertension. Horm Metab Res. 2012;44(12):867-878. 118. Paperna T, Gershoni-Baruch R, Badarneh K, Kasinetz L, Hochberg Z. Mutations in CYP11B1 and congenital adrenal hyperplasia in Moroccan Jews. J Clin Endocrinol Metab. 2005;90(9):54635465. 119. White PC, Dupont J, New MI, Leiberman E, Hochberg Z, Rosler A. A mutation in CYP11B1 (Arg-448––His) associated with steroid 11 beta-hydroxylase deficiency in Jews of Moroccan origin. J Clin Invest. 1991;87(5):1664-1667. 120. Yanase T, Simpson ER, Waterman MR. 17 alpha-hydroxylase/17,20lyase deficiency: from clinical investigation to molecular definition. Endocr Rev. 1991;12(1):91-108.