Chapter 10. Endocrine Hypertension

• 11β-HSD2 11β-Hydroxysteroid dehydrogenase type 2
• ACE Angiotensin-converting enzyme
• ACTH Corticotropin
• AME Apparent mineralocorticoid excess
• ANP Atrial natriuretic peptide
• APA Aldosterone-producing adenoma
• ARB Angiotensin receptor blocker
• AVS Adrenal venous sampling
• CAH Congenital adrenal hyperplasia
• CT Computed tomography
• DOC Deoxycorticosterone
• FH Familial hyperaldosteronism
• GH Growth hormone
• GRA Glucocorticoid-remediable aldosteronism
• HU Hounsfield units
• IHA Idiopathic hyperaldosteronism
• IVC Inferior vena cava
• PAC Plasma aldosterone concentration
• PAH Primary adrenal hyperplasia
• PRA Plasma renin activity

Hypertension affects one in four adults in the developed world. Although hypertension is essential or idiopathic in most cases, a cause can be detected in approximately 15% of the hypertensive population. The secondary causes of hypertension can be divided into renal (eg, renal vascular or parenchymal disease) and endocrine causes. There are at least 14 endocrine disorders in which hypertension may be the initial clinical presentation (Table 10–1). The diagnosis of endocrine hypertension presents the clinician an opportunity to provide a surgical cure or to achieve a marked response with targeted pharmacologic therapy. Pheochromocytoma and Cushing syndrome are reviewed in detail in Chapters 11 and 9, respectively. The renin-angiotensin-aldosterone system, the diagnostic and therapeutic approaches to mineralocorticoid hypertension (eg, primary aldosteronism), and less common forms of endocrine hypertension are reviewed in this chapter.

The components of the renin-angiotensin-aldosterone system are shown in Figure 10–1. Aldosterone is secreted from the zona glomerulosa under the primary control of angiotensin II, potassium, and corticotropin (ACTH). The secretion of aldosterone is restricted to the zona glomerulosa because of zonal-specific expression of aldosterone synthase (CYP11B2). Atrial natriuretic peptide (ANP), dopamine, and heparin inhibit aldosterone secretion.

Renin and Angiotensin

Renin is an enzyme produced in the juxtaglomerular apparatus of the kidney, stored in granules, and released in response to specific secretagogues. The first 43 amino acids of the 340 amino acid renin protein are a prosegment cleaved to produce the active enzyme. The release of renin into the circulation is the rate-limiting step in the activation of the renin-angiotensin-aldosterone system. Renal renin release is controlled by juxtaglomerular cells acting as pressure transducers that sense stretch of the afferent arteriolar wall and thus renal perfusion pressure; the macula densa, a specialized group of convoluted distal tubular cells that function as chemoreceptors for monitoring the sodium and chloride loads present in the distal tubule; the sympathetic nervous system, which modifies the release of renin, particularly in response to upright posture; and humoral factors, including potassium, angiotensin II, and ANPs. Thus, renin release is maximized in conditions of low renal perfusion pressure or low tubular sodium content (eg, renal artery stenosis, hemorrhage, dehydration). Renin release is suppressed by elevated perfusion pressure at the kidney (eg, hypertension) and high sodium diets. Renin release is increased directly by hypokalemia and decreased by hyperkalemia.

Angiotensinogen, an α2-globulin synthesized in the liver, is the substrate for renin and is broken down into the angiotensin peptides. Angiotensinogen consists of 485 amino acids, 33 of which constitute a signal peptide that is cleaved prior to secretion. The action of renin on angiotensinogen produces angiotensin I. Angiotensin I is composed of the first 10 amino acid sequence following the signal peptide and does not have biologic activity. Angiotensin II, the main form of biologically active angiotensin, is formed by cleavage of the two carboxyl-terminal amino acids of angiotensin I by angiotensin-converting enzyme (ACE) (Figure 10–2). ACE is localized to cell membranes in the lung and intracellular granules in certain tissues that produce angiotensin II. Amino peptidase A removes the amino-terminal aspartic acid to produce the heptapeptide, angiotensin III. Angiotensin II and angiotensin III have equivalent efficacy in promoting aldosterone secretion and modifying renal blood flow. The half-life in the circulation of angiotensin II is short (< 60 seconds). Elements of the renin-angiotensin-aldosterone system are present in the adrenal glands, the kidneys, the heart, and the brain. For example, the adrenal glomerulosa cells contain the proteins needed to produce and secrete angiotensin II. Other tissues contain one or more components of the renin-angiotensin system and require other cells or circulating components, or both, to generate angiotensin II.

Angiotensin II functions through the angiotensin receptor to maintain normal extracellular volume and blood pressure by (a) increasing aldosterone secretion from the zona glomerulosa by increasing transcription of CYP11B2; (b) constriction of vascular smooth muscle, thereby increasing blood pressure and reducing renal blood flow; (c) enhancing the release of norepinephrine and epinephrine from the adrenal medulla; (d) enhancement of the activity of the sympathetic nervous system by increasing central sympathetic outflow, thereby increasing norepinephrine discharge from sympathetic nerve terminals; and (e) promotion of the release of vasopressin.

Aldosterone

Aldosterone is produced in the zona glomerulosa of the adrenal cortex. Approximately 50% to 70% of aldosterone circulates bound to either albumin or corticosteroid-binding globulin; 30% to 50% of total plasma aldosterone is free. Aldosterone is rapidly inactivated to tetrahydroaldosterone in the liver and has a half-life of 15 to 20 minutes. Aldosterone regulates extracellular volume and potassium homeostasis by binding to renal cortical collecting duct principal epithelial cell mineralocorticoid receptors (Figure 10–3). The mineralocorticoid receptor—a member of the nuclear receptor family and also found in the heart, colon, and hippocampus—is localized to the cytoplasm prior to activation, undergoes a conformation change on binding to aldosterone, and translocates into the nucleus where it functions as a transcription factor. The aldosterone-regulated serum- and glucocorticoid-inducible kinase appears to be a key intermediary (see Figure 10–3). Aldosterone increases expression of this kinase which phosphorylates and inactivates neural-precursor-cell-expressed, developmentally down regulated (Nedd) 4-2, a ubiquitin ligase which is responsible for degrading the epithelial sodium channel. This, in turn, leads to an increased number of open sodium channels in the luminal membrane of the principal cells in the cortical collecting tubule, resulting in increased sodium ion reabsorption. The sodium loss increases luminal electronegativity, which augments tubular secretion of potassium by the renal tubular cells and hydrogen ion by the renal interstitial cells. Another mediator of the mineralocorticoid receptor transcriptional response is the activation is the sodium-potassium ATPase at the basolateral membrane, which drives the uptake of potassium and export of sodium (see Figure 10–3). Although glucocorticoids and mineralocorticoids bind equally to the mineralocorticoid receptor, specificity of action is due to the glucocorticoid-degrading enzyme, 11β-hydroxysteroid dehydrogenase, which is strongly expressed in the kidney and prevents glucocorticoids from interacting with the receptor.

Aldosterone has nonclassic effects that, although probably genomic and therefore mediated by activation of the cytosolic mineralocorticoid receptor, do not include modification of sodium-potassium balance. Aldosterone-mediated actions include the expression of several collagen genes; activation of genes controlling tissue growth factors, such as transforming growth factor β and plasminogen activator inhibitor type 1; or increased expression of genes mediating inflammation. The resultant actions lead to microangiopathy, necrosis (acutely), and fibrosis in various tissues such as the heart, the vasculature, and the kidney. Increased levels of aldosterone are not necessary to cause this damage; an imbalance between the volume or sodium balance state and the level of aldosterone appear to be the critical factors. Spironolactone and eplerenone are mineralocorticoid receptor antagonists. Mineralocorticoid receptor blockade has proven to be clinically important in patients with cardiovascular disease. For example, when spironolactone was added to the treatment program for patients with New York Heart Association class IV heart failure or class III heart failure, it resulted in a significant 30% reduction in overall mortality due to reductions in death from heart failure and sudden death. When eplerenone was added to the treatment program for patients who had a myocardial infarction 3 to 14 days previously and had a left ventricular ejection fraction of ≤40 percent, it resulted in a significantly lower rate of cardiovascular mortality and sudden cardiac death. The effect of mineralocorticoid receptor antagonists on survival in patients with primary aldosteronism has not yet been studied.

The action of angiotensin II on aldosterone synthesis and secretion involves a feedback loop that also includes extracellular fluid volume (see Figure 10–1). A decrease in circulating blood volume results in decreased renal perfusion pressure that is detected by the renal juxtaglomerular cells. Activation of the juxtaglomerular cells increases renin release, which catalyzes the conversion of angiotensinogen to angiotensin I. Angiotensin-converting enzyme (ACE) in the pulmonary and renal endothelium catalyzes the conversion of angiotensin I to angiotensin II and III, which act on the adrenal zona glomerulosa angiotensin receptor to stimulate aldosterone release. Aldosterone acts at the renal mineralocorticoid receptors to stimulate sodium and water retention to preserve the circulating blood volume. Renin release can also be triggered by catecholamines, hypokalemia, and a decrease in sodium chloride absorption in the macula densa cells. Aldosterone secretion can be directly stimulated by ACTH and hyperkalemia. Thus, sodium restriction activates and sodium overload suppresses the renin-angiotensin-aldosterone axis. Mineralocorticoid escape refers to the counterregulatory mechanisms that occur after 3 to 5 days of excessive mineralocorticoid administration. Several mechanisms contribute to this escape, including renal hemodynamic factors and increased release of ANP.

Excess aldosterone secretion causes hypertension through two main mechanisms: (1) mineralocorticoid-induced expansion of plasma and extracellular fluid volume; and (2) increase in total peripheral vascular resistance.

Hypertension, suppressed plasma renin activity (PRA), and increased aldosterone excretion characterize the syndrome of primary aldosteronism. Aldosterone-producing adenoma (APA) and bilateral idiopathic hyperaldosteronism (IHA) are the two most common subtypes of primary aldosteronism (Table 10–2). A much less common form, unilateral hyperplasia, is caused by micronodular or macronodular hyperplasia of the zona glomerulosa of predominantly one adrenal gland. Unilateral hyperplasia is referred to as primary adrenal hyperplasia (PAH). Familial hyperaldosteronism (FH) is also rare and two types have been described: FH type I and FH type II. FH type I, or glucocorticoid-remediable aldosteronism (GRA), is autosomal dominant in inheritance and associated with variable degrees of hyperaldosteronism, high levels of hybrid steroids (eg, 18-hydroxycortisol and 18-oxocortisol), and suppression with exogenous glucocorticoids. FH type II refers to the familial occurrence of APA or IHA or both.

Prevalence

In the past, clinicians would not consider the diagnosis of primary aldosteronism unless the patient presented with spontaneous hypokalemia, and then the diagnostic evaluation would require discontinuing antihypertensive medications for at least 2 weeks. The spontaneous hypokalemia/no antihypertensive drug diagnostic approach resulted in predicted prevalence rates of less than 0.5% of hypertensive patients. However, it is now recognized that most patients with primary aldosteronism are not hypokalemic and that case-detection testing can be completed with a simple blood test (plasma aldosterone concentration [PAC]-to-plasma renin activity [PRA] ratio) while the patient is taking most antihypertensive drugs. Using the PAC-PRA ratio as a case-detection test, followed by aldosterone suppression confirmatory testing, has resulted in much higher prevalence estimates (5%-10% of all patients with hypertension) for primary aldosteronism.

Clinical Presentation

The diagnosis of primary aldosteronism is usually made in patients who are in the third to sixth decade of life. Few symptoms are specific to the syndrome. Patients with marked hypokalemia may have muscle weakness and cramping, headaches, palpitations, polydipsia, polyuria, nocturia, or a combination of these. Periodic paralysis is a very rare presentation in Caucasians, but it is not an infrequent presentation in patients of Asian descent. The polyuria and nocturia are a result of a hypokalemia-induced renal concentrating defect and the presentation is frequently mistaken for prostatism in men. There are no specific physical findings. Edema is not a common finding because of mineralocorticoid escape. The degree of hypertension is usually moderate to severe and may be resistant to usual pharmacologic treatments. Although not common, primary aldosteronism may present with hypertensive urgencies. Patients with APA tend to have higher blood pressures than those with IHA. Hypokalemia is frequently absent; thus, all patients with hypertension are candidates for this disorder. In other patients, the hypokalemia only becomes evident with addition of a potassium-wasting diuretic (eg, hydrochlorothiazide, furosemide). Aldosterone excess also leads to a mild metabolic alkalosis because of increased urinary hydrogen excretion mediated both by hypokalemia and by the direct stimulatory effect of aldosterone on distal renal tubule acidification. Because of a reset osmostat, the serum sodium concentration tends to be high-normal or slightly above the upper limit of normal—this clinical finding is very useful when initially assessing the potential for primary aldosteronism.

Several studies have shown that patients with primary aldosteronism may be at higher risk than other patients with hypertension for target organ damage of the heart and kidney. When matched for age, blood pressure, and duration of hypertension, patients with primary aldosteronism have greater left ventricular mass by echocardiographic measurements than patients with other types of hypertension (eg, pheochromocytoma, Cushing syndrome, or essential hypertension). In patients with APA, the left ventricular wall thickness and mass decreases markedly 1 year after adrenalectomy. Patients presenting with either APA or IHA have a significantly higher rate of cardiovascular events (eg, stroke, atrial fibrillation, and myocardial infarction) than matched patients with essential hypertension who have similar degrees of hypertension duration and control.

Diagnosis

The diagnostic approach to primary aldosteronism can be considered in three parts: case-detection tests, confirmatory tests, and subtype evaluation tests.

Case-Detection Tests

Spontaneous hypokalemia is uncommon in patients with uncomplicated hypertension and, when present, strongly suggests associated mineralocorticoid excess. However, most patients with primary aldosteronism have baseline serum levels of potassium in the normal range. Therefore, hypokalemia is not and should not be the only criterion used to determine whom to test for primary aldosteronism. Patients with hypertension and hypokalemia (regardless of presumed cause), treatment-resistant hypertension (three antihypertensive drugs and poor control), severe hypertension (≥160 mm Hg systolic or ≥100 mm Hg diastolic), hypertension and an incidental adrenal mass, and onset of hypertension at a young age should undergo case-detection testing for primary aldosteronism (Figure 10–4). In addition, primary aldosteronism should be tested for when considering a secondary hypertension evaluation (eg, when testing for renovascular disease or pheochromocytoma).

In patients with suspected primary aldosteronism, case detection can be accomplished by measuring a morning (preferably between 8 am and 10 am) ambulatory paired random PAC and PRA (see Figure 10–4). This test may be performed while the patient is taking most antihypertensive medications and without posture stimulation. Hypokalemia reduces the secretion of aldosterone, and it is optimal in patients with hypokalemia to restore the serum level of potassium to normal before performing diagnostic studies. Mineralocorticoid receptor antagonists (eg, spironolactone and eplerenone) are the only medications that absolutely interfere with interpretation of the ratio and should be discontinued at least 6 weeks before testing. ACE-inhibitors and angiotensin receptor blockers (ARB) have the potential to falsely elevate PRA. Therefore, in a patient treated with an ACE inhibitor or ARB, the finding of a detectable PRA level or a low PAC-PRA ratio does not exclude the diagnosis of primary aldosteronism. However, a very useful clinical point is that when a PRA level is undetectably low in a patient taking an ACE inhibitor or ARB, primary aldosteronism is likely. A second important clinical point is that PRA is suppressed (< 1.0 ng/mL/h) in almost all patients with primary aldosteronism, regardless of concurrent medications.

The PAC-PRA ratio is based on the concept of paired hormone measurements. For example, in a hypertensive hypokalemic patient: (a) secondary hyperaldosteronism should be considered when both PRA and PAC are increased and the PAC-PRA ratio is less than 10 (eg, renovascular disease); (b) an alternate source of mineralocorticoid receptor agonism should be considered when both PRA and PAC are suppressed (eg, hypercortisolism); and (c) primary aldosteronism should be suspected when PRA is suppressed (< 1.0 ng/mL/h) and PAC is increased (Figure 10–5). Although there is some uncertainty about test characteristics and lack of standardization, the PAC-PRA ratio is widely accepted as the case-detection test of choice for primary aldosteronism. It is important to understand that the lower limit of detection varies among different PRA assays and can have a dramatic effect on the PAC-PRA ratio. As an example, if the lower limit of detection for PRA is 0.6 ng/mL/h and the PAC is 18 ng/dL, then the PAC-PRA ratio would be 30; however, if the lower limit of detection for PRA is 0.1 ng/mL/h and the PAC is 18 ng/dL, then the PAC-PRA ratio would be 180. Thus, the cutoff for a high PAC-PRA ratio is laboratory dependent and, more specifically, PRA assay dependent. At Mayo Clinic, a PAC (in ng/dL)-PRA (in ng/mL/h) ratio of 20 or more and PAC of at least 15 ng/dL are found in more than 90% of patients with surgically confirmed APA. In patients without primary aldosteronism, most of the variation occurs within the normal range. The sensitivity and specificity of the PAC-PRA ratio in the diagnosis of primary aldosteronism are approximately 80% and 75%, respectively. A high PAC-PRA ratio with a PAC of at least 15 ng/dL is a positive case-detection test result, a finding that warrants further testing. Other initial case-detection strategies include measurement of isolated plasma renin activity or 24-hour urinary aldosterone excretion.

Confirmatory Tests

An increased PAC-PRA ratio is not diagnostic by itself, and primary aldosteronism must be confirmed by demonstrating lack of normal suppressiblity of aldosterone secretion. The list of drugs and hormones capable of affecting the renin-angiotensin-aldosterone axis is extensive and frequently a medication-contaminated evaluation is unavoidable. Calcium channel blockers and α1-adrenergic receptor blockers do not affect the diagnostic accuracy in most cases. It is impossible to interpret data obtained from patients receiving treatment with mineralocorticoid receptor antagonists (eg, spironolactone, eplerenone) when PRA is not suppressed. Therefore, treatment with a mineralocorticoid receptor antagonist should not be initiated until the evaluation has been completed and the final decisions about treatment have been made. If primary aldosteronism is suspected in a patient receiving treatment with spironolactone or eplerenone, the treatment should be discontinued for at least 6 weeks before further diagnostic testing. Aldosterone suppression testing can be performed with orally administered sodium chloride and measurement of urinary aldosterone or with intravenous sodium chloride loading and measurement of PAC:

1. Oral sodium loading test—After hypertension and hypokalemia are controlled, patients should receive a high- sodium diet (supplemented with sodium chloride tablets if needed) for 3 days, with a goal sodium intake of 5000 mg of sodium (equivalent to 12.8 g sodium chloride or 218 mEq of sodium). The risk of increasing dietary sodium in patients with severe hypertension must be assessed in each case. Because the high-sodium diet can increase kaliuresis and hypokalemia, vigorous replacement of potassium chloride may be needed, and the serum level of potassium should be monitored daily. On the third day of the high- sodium diet, a 24-hour urine specimen is collected for measurement of aldosterone, sodium, and creatinine. To document adequate sodium repletion, the 24-hour urinary sodium excretion should exceed 200 mEq. Urinary aldosterone excretion more than 12 mcg/24 h is consistent with autonomous aldosterone secretion. The sensitivity and specificity of the oral sodium loading test are 96% and 93%, respectively.

2. Intravenous saline infusion test—The intravenous saline infusion test has also been used for the confirmation of primary aldosteronism. Normal subjects show suppression of PAC after volume expansion with isotonic saline; subjects with primary aldosteronism do not show this suppression. The risks associated with rapid intravenous volume expansion should be assessed in each case. The test is done after an overnight fast. Two liters of 0.9% sodium chloride solution are infused intravenously with an infusion pump over 4 hours into the recumbent patient. Blood pressure and heart rate are monitored during the infusion. At the completion of the infusion, blood is drawn for measurement of PAC. PAC levels in normal subjects decrease to less than 5 ng/dL; most patients with primary aldosteronism do not suppress to less than 10 ng/dL; postsaline infusion PAC values between 5 and 10 ng/dL are indeterminate and can be seen in patients with IHA.

Subtype Studies

Following case-detection and confirmatory testing, the third management step guides the therapeutic approach by distinguishing APA and PAH from IHA and GRA. Unilateral adrenalectomy in patients with APA or PAH results in normalization of hypokalemia in all; hypertension is improved in all and is cured in approximately 30% to 60% of them. In IHA and GRA, unilateral or bilateral adrenalectomy seldom corrects the hypertension. IHA and GRA should be treated medically. APA is found in approximately 35% of cases and bilateral IHA in approximately 60% of cases (see Table 10–2). APAs are usually hypodense nodules (< 2 cm in diameter) on CT and are golden yellow in color on cut section. IHA adrenal glands may be normal on CT or show nodular changes. Aldosterone-producing adrenal carcinomas are almost always greater than 4 cm in diameter and have a suspicious imaging phenotype on CT. Patients with aldosterone-producing adrenocortical carcinomas usually have severe aldosterone excess with serum potassium concentrations frequently less than 2.0 mEq/L.

1. Adrenal CT— Primary aldosteronism subtype evaluation may require one or more tests, the first of which is imaging the adrenal glands with CT (Figure 10–6). This imaging test is usually ordered as CT of the abdomen limited to the adrenal glands with 2-mm contiguous cuts. Although contrast enhancement is not necessary, contrast administration result in improved discrimination between normal adrenal cortex and the small lipid-rich cortical adenoma. When a solitary unilateral hypodense (Hounsfield units [HU] < 10) macroadenoma (> 1 cm) and normal contralateral adrenal morphology are found on CT in a young patient (adrenal incidentalomas are uncommon in patients < 40 years) with primary aldosteronism, unilateral adrenalectomy is a reasonable therapeutic option (Figure 10–7). However, in many cases, CT may show normal-appearing adrenals, minimal unilateral adrenal limb thickening, unilateral microadenomas (< 1 cm), bilateral macroadenomas, or a large (eg, > 2 cm) unilateral macroadenomas that would be atypical for primary aldosteronism. In these cases, when the patient wants to pursue the surgical treatment option for primary aldosteronism, additional testing is required to determine the source of excess aldosterone secretion (Figure 10–8). Small APAs may be labeled incorrectly as IHA on the basis of CT findings of bilateral nodularity or normal-appearing adrenals. Also, apparent adrenal microadenomas may actually represent areas of hyperplasia, and unilateral adrenalectomy would be inappropriate. In addition, nonfunctioning unilateral adrenal macroadenomas are not uncommon, especially in individuals more than 40 years of age. Unilateral PAH may be visible on CT or the PAH adrenal may appear normal on CT. In general, patients with APAs have more severe hypertension, more frequent hypokalemia, higher plasma (> 25 ng/dL) and urinary (> 30 mcg/24 h) levels of aldosterone than those with IHA.

   Adrenal CT is not accurate in distinguishing between APA and IHA. In one study of 203 patients with primary aldosteronism who were evaluated with both CT and adrenal venous sampling (AVS), CT was accurate in only 53% of patients; based on CT findings, 42 patients (22%) would have been incorrectly excluded as candidates for adrenalectomy and 48 (25%) might have had unnecessary or inappropriate surgery. Therefore, AVS is essential to direct appropriate therapy in patients older than 40 years of age with primary aldosteronism who have a high probability of APA and who seek a potential surgical cure. However, it is important to recognize that the surgical option is not mandatory in patients with APA—pharmacologic therapy with a mineralocorticoid receptor antagonist is the medication equivalent of adrenalectomy (see later).

2. Adrenal venous sampling—AVS is the criterion standard test to distinguish between unilateral and bilateral disease in patients with primary aldosteronism who want to pursue surgical management for their hypertension. AVS is an intricate procedure because the right adrenal vein is small and may be difficult to locate and cannulate—the success rate depends on the proficiency of the angiographer. The five keys to a successful AVS program are (1) appropriate patient selection; (2) careful patient preparation; (3) focused technical expertise; (4) defined protocol; and (5) accurate data interpretation. A center-specific, written protocol is mandatory. The protocol should be developed by an interested group of endocrinologists, hypertension specialists, internists, radiologists, and laboratory personnel. Safeguards should be in place to prevent mislabeling of the blood tubes in the radiology suite and to prevent sample mix-up in the laboratory. At Mayo Clinic, we use continuous cosyntropin infusion during AVS (50 μg/h started 30 minutes before sampling and continued throughout the procedure) for the following reasons: (a) to minimize stress-induced fluctuations in aldosterone secretion during nonsimultaneous AVS; (b) to maximize the gradient in cortisol from adrenal vein to inferior vena cava (IVC) and thus confirm successful sampling of the adrenal veins; and (c) to maximize the secretion of aldosterone from an APA. The adrenal veins are catheterized through the percutaneous femoral vein approach, and the position of the catheter tip is verified by gentle injection of a small amount of nonionic contrast medium and radiographic documentation (see Figure 10–8). Blood is obtained from both adrenal veins and the IVC below the renal veins and assayed for aldosterone and cortisol concentrations. To be sure there is no cross-contamination, the IVC sample should be obtained from the external iliac vein. The venous sample from the left side typically is obtained from the common phrenic vein immediately adjacent to the entrance of the adrenal vein. The cortisol concentrations from the adrenal veins and IVC are used to confirm successful catheterization; the adrenal vein-IVC cortisol ratio is typically more than 10:1.

   Dividing the right and left adrenal vein PACs by their respective cortisol concentrations corrects for the dilutional effect of the inferior phenic vein flow into the left adrenal vein; these are termed cortisol-corrected ratios (see Figure 10–8). In patients with APA, the mean cortisol-corrected aldosterone ratio (APA-side PAC/cortisol:normal adrenal PAC/cortisol) is 18:1. A cutoff of the cortisol-corrected aldosterone ratio from high side to low side more than 4:1 is used to indicate unilateral aldosterone excess (see Figure 10–8). In patients with IHA, the mean cortisol-corrected aldosterone ratio is 1.8:1 (high side:low side); a ratio less than 3:1 is suggestive of bilateral aldosterone hypersecretion. Therefore, most patients with a unilateral source of aldosterone will have cortisol-corrected aldosterone lateralization ratios greater than 4.0; ratios greater than 3.0 but less than 4.0 represent a zone of overlap. Ratios no more than 3.0 are consistent with bilateral aldosterone secretion. The test characteristics of AVS for detecting unilateral aldosterone hypersecretion (APA or PAH) have sensitivity of 95% and specificity of 100%. However, since all patients who undergo AVS are not sent to surgery, the true diagnostic sensitivity of AVS is unknown. At centers with experience with AVS, the complication rate is 2.5% or less. Complications can include symptomatic groin hematoma, adrenal hemorrhage, and dissection of an adrenal vein.

   Some centers and clinical practice guidelines recommend that AVS should be performed in all patients who have the diagnosis of primary aldosteronism. However, a more practical approach is to consider the use of AVS based on patient preferences, patient age, clinical comorbidities, and clinical probability of finding an APA (see Figure 10–6).

3. Glucocorticoid-remediable aldosteronism—familial hyperaldosteronism type I—This syndrome is inherited in an autosomal dominant fashion and is extremely rare (responsible for fewer than 1% of cases of primary aldosteronism) (see Table 10–2). GRA is characterized by hypertension of early onset that is usually severe and refractory to conventional antihypertensive therapies, aldosterone excess, suppressed PRA, and excess production of 18-hydroxycortisol and 18-oxycortisol. GRA is caused by a chimeric gene duplication that results from unequal crossing over between the promoter sequence of CYP11B1 gene (encoding 11β-hydroxylase) and the coding sequence of CYP11B2 (encoding aldosterone synthase). This chimeric gene contains the 3′ ACTH-responsive portion of the promoter from the 11β-hydroxylase gene fused to the 5′ coding sequence of the aldosterone synthase gene. The result is ectopic expression of aldosterone synthase activity in the cortisol-producing zona fasciculata. Thus, mineralocorticoid production is regulated by ACTH instead of the normal secretagogue, angiotensin II. Aldosterone secretion can be suppressed by glucocorticoid therapy. In the absence of glucocorticoid therapy, this mutation results in overproduction of aldosterone and the hybrid steroids 18-hydroxycortisol and 18-oxycortisol, which can be measured in the urine to make the diagnosis.

   Genetic testing is a sensitive and specific means of diagnosing GRA and obviates the need to measure the urinary levels of 18-oxocortisol and 18-hydroxycortisol or to perform dexamethasone suppression testing. Genetic testing for GRA should be considered for primary aldosteronism patients with a family history of primary aldosteronism or onset of primary aldosteronism at a young age (eg, < 20 years), or in primary aldosteronism patients who have a family history of strokes at a young age. Cerebrovascular complications (eg, hemorrhagic stroke) associated with intracranial aneurysms affect approximately 20% of all patients with GRA—a frequency of cerebral aneurysm similar to that found in adult polycystic kidney disease.

4. Familial hyperaldosteronism type II—FH type II is autosomal dominant and may be monogenic. The hyperaldosteronism in FH type II does not suppress with dexamethasone, and GRA mutation testing is negative. FH type II is more common than FH type I, but it still represents less than 2% of all patients with primary aldosteronism. The molecular basis for FH type II is unclear, although a recent linkage analysis study showed an association with chromosomal region 7p22.

Treatment

The treatment goal is to prevent the morbidity and mortality associated with hypertension, hypokalemia, and cardiovascular damage. The cause of the primary aldosteronism helps to determine the appropriate treatment. Normalization of blood pressure should not be the only goal in managing a patient who has primary aldosteronism. In addition to the kidney and colon, mineralocorticoid receptors occur in the heart, brain, and blood vessels. Excessive secretion of aldosterone is associated with increased risk of cardiovascular disease and morbidity. Therefore, normalization of circulating aldosterone or mineralocorticoid receptor blockade should be part of the management plan for all patients with primary aldosteronism. However, clinicians must understand that most patients with long-standing primary aldosteronism have some degree of renal insufficiency that is masked by the glomerular hyperfiltration associated with aldosterone excess. The true degree of renal insufficiency may only become evident after effective pharmacologic or surgical therapy.

Surgical Treatment of Aldosterone-Producing Adenoma and Unilateral Hyperplasia

Unilateral laparoscopic adrenalectomy is an excellent treatment option for patients with APA or PAH (unilateral hyperplasia). Although blood pressure control improves in nearly 100% of patients postoperatively, average long-term cure rates of hypertension after unilateral adrenalectomy for APA range from 30% to 60%. Persistent hypertension following adrenalectomy is correlated directly with having more than one first-degree relative with hypertension, use of more than two antihypertensive agents preoperatively, older age, increased serum creatinine level, and duration of hypertension.

Laparoscopic adrenalectomy is the preferred surgical approach and is associated with shorter hospital stays and less long-term morbidity than the open approach. Because APAs are small and may be multiple, the entire adrenal gland should be removed. To decrease the surgical risk, hypokalemia should be corrected with potassium supplements and/or a mineralocorticoid receptor antagonist preoperatively. The mineralocorticoid receptor antagonist and potassium supplements should be discontinued postoperatively. PAC should be measured 1 to 2 days after the operation to confirm a biochemical cure. Serum potassium levels should be monitored weekly for 4 weeks after surgery and a generous sodium diet should be followed to avoid the hyperkalemia of hypoaldosteronism that may occur because of the chronic suppression of the renin-angiotensin-aldosterone axis. In approximately 5% of APA patients clinically significant hyperkalemia may develop after surgery and short-term fludrocortisone supplementation may be required. Typically, the component of hypertension that was associated with aldosterone excess resolves in 1 to 3 months postoperatively.

Pharmacologic Treatment

IHA and GRA should be treated medically. In addition, APA patients may be treated medically if the medical treatment includes mineralocorticoid receptor blockade. A sodium-restricted diet (< 100 mEq of sodium per day), maintenance of ideal body weight, tobacco avoidance, and regular aerobic exercise contribute significantly to the success of pharmacologic treatment. No placebo-controlled randomized trials have evaluated the relative efficacy of drugs in the treatment of primary aldosteronism. Spironolactone, available as 25-, 50-, and 100-mg tablets, has been the drug of choice to treat primary aldosteronism for more than four decades. The initial dosage is 12.5 to 25 mg/d and is increased to 400 mg/d if necessary to achieve a high-normal serum potassium concentration without the aid of oral potassium chloride supplementation. Hypokalemia responds promptly, but hypertension may take as long as 4 to 8 weeks to correct. After several months of therapy, this dosage often can be decreased to as little as 25 to 50 mg/d; dosage titration is based on a goal serum potassium level in the high-normal range. Serum potassium and creatinine should be monitored frequently during the first 4 to 6 weeks of therapy (especially in patients with renal insufficiency or diabetes mellitus). Spironolactone increases the half-life of digoxin, and for patients taking this drug, the dosage may need to be adjusted when treatment with spironolactone is started. Concomitant therapy with salicylates should be avoided because they interfere with the tubular secretion of an active metabolite and decrease the effectiveness of spironolactone. Spironolactone is not selective for the mineralocorticoid receptor. For example, antagonism at the testosterone receptor may result in painful gynecomastia, erectile dysfunction, and decreased libido in men; agonist activity at the progesterone receptor results in menstrual irregularity in women.

Eplerenone is a steroid-based antimineralocorticoid that acts as a competitive and selective mineralocorticoid receptor antagonist. It has a marked reduction in progestational and antiandrogenic actions compared with spironolactone. Treatment trials comparing the efficacy of eplerenone versus spironolactone for the treatment of primary aldosteronism have not been published. Eplerenone is available as 25- and 50-mg tablets. For primary aldosteronism, it is reasonable to start with a dose of 25 mg twice daily (twice daily because of the shorter half-life of eplerenone compared to spironolactone) and titrated upward for a target high-normal serum potassium concentration without the aid of potassium supplements. Potency studies with eplerenone show 50% less milligram per milligram potency when compared with spironolactone. As with spironolactone, it is important to follow blood pressure, serum potassium, and serum creatinine levels closely.

Patients with IHA frequently require a second antihypertensive agent to achieve adequate blood pressure control. Hypervolemia is a major reason for resistance to drug therapy, and low doses of a thiazide (eg, 12.5-50 mg of hydrochlorothiazide daily) or a related sulfonamide diuretic are effective in combination with the mineralocorticoid receptor antagonist. Because these agents often lead to further hypokalemia, serum potassium levels should be monitored.

Before initiating treatment, GRA should be confirmed with genetic testing. In the GRA patient, chronic treatment with physiologic doses of a glucocorticoid normalizes blood pressure and corrects hypokalemia. The clinician should avoid iatrogenic Cushing syndrome with excessive doses of glucocorticoids, especially with the use of dexamethasone in children. The smallest effective dose of shorter acting agents such as prednisone or hydrocortisone should be prescribed in relation to body surface area (eg, hydrocortisone, 10-12 mg/m2/d). Target blood pressure in children should be guided by age-specific blood pressure percentiles. Children should be monitored by pediatricians with expertise in glucocorticoid therapy, with careful attention paid to preventing retardation of linear growth by overtreatment. Treatment with mineralocorticoid receptor antagonists in these patients may be just as effective and avoids the potential disruption of the hypothalamic-pituitary-adrenal axis and risk of iatrogenic side effects. In addition, glucocorticoid therapy or mineralocorticoid receptor blockade may even have a role in normotensive GRA patients.

The medical disorders associated with excess mineralocorticoid effect from 11-deoxycorticosterone (DOC) and cortisol are listed in Table 10–2. These diagnoses should be considered when PAC and PRA are low in patients with hypertension and hypokalemia.

Hyperdeoxycorticosteronism

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is caused by enzymatic defects in adrenal steroidogenesis that result in deficient secretion of cortisol (see Chapter 14). The lack of inhibitory feedback by cortisol on the hypothalamus and pituitary produces an ACTH-driven buildup of cortisol precursors proximal to the enzymatic deficiency. A deficiency of 11β-hydroxylase (CYP11B) or 17α-hydroxylase (CYP17) causes hypertension and hypokalemia because of hypersecretion of the mineralocorticoid DOC. The mineralocorticoid effect of increased circulating levels of DOC also decreases PRA and aldosterone secretion. These defects are autosomal recessive in inheritance and typically are diagnosed in childhood. However, partial enzymatic defects have been shown to cause hypertension in adults.

1. 11β-Hydroxylase deficiency—Approximately 5% of all cases of CAH are due to 11β-hydroxylase deficiency; the prevalence in Caucasians is 1 in 100,000. More than 40 mutations have been described in CYP11B1, the gene encoding 11β-hydroxylase. There is an increased prevalence among Sephardic Jews from Morocco, suggestive of a founder effect. The impaired conversion of DOC to corticosterone results in high levels of DOC, 11-deoxycortisol, and adrenal androgens (see Chapter 14). Females present in infancy or childhood with hypertension, hypokalemia, acne, hirsutism, and virilization. Males present with pseudoprecocious puberty. Approximately two-thirds of patients have mild to moderate hypertension. Markedly increased levels of DOC, 11-deoxycortisol, and adrenal androgens confirm the diagnosis. Glucocorticoid replacement normalizes the steroid abnormalities and hypertension.

2. 17α-Hydroxylase deficiency—17α-Hydroxylase deficiency is a rare cause of CAH. 17α-Hydroxylase is essential for the synthesis of cortisol and gonadal hormones, and deficiency results in decreased production of cortisol and sex hormones. Genetic 46,XY males present with either pseudohermaphroditism or as phenotypic females, and 46,XX females present with primary amenorrhea. Therefore, a person with this form of CAH may not come to medical attention until puberty. Patients present with eunuchoid proportions and appearance. The biochemical findings include low concentrations of plasma adrenal androgens, plasma 17α-hydroxyprogesterone and cortisol. The plasma concentrations of DOC, corticosterone, and 18-hydroxycorticosterone (all produced in the zona fasciculata) are increased. Aldosterone (produced in zona glomerulosa) and PRA are suppressed. Although rare, there is an increased prevalence among Dutch Mennonites. As with 11β-hydroxylase deficiency, glucocorticoid replacement normalizes the steroid abnormalities and hypertension.

Deoxycorticosterone-Producing Tumor

DOC-producing adrenal tumors are usually large and malignant. Some of them secrete androgens and estrogens in addition to DOC, which may cause virilization in women and feminization in men. A high level of plasma DOC or urinary tetrahydrodeoxycorticosterone and a large adrenal tumor seen on CT confirm the diagnosis. Aldosterone secretion in these patients is typically suppressed. Optimal treatment is complete surgical resection.

Primary Cortisol Resistance

Increased cortisol secretion and plasma cortisol concentrations without evidence of Cushing syndrome are found in patients with primary cortisol resistance (or glucocorticoid resistance), a rare familial syndrome. Cortisol resistance leads to elevations in ACTH secretion which, in turn, increases adrenal steroid production. The syndrome is characterized by hypokalemic alkalosis, hypertension, increased plasma concentrations of DOC, as well as cortisol, and increased adrenal androgen secretion. The hypertension and hypokalemia are likely due to the combined effects of excess DOC and increased cortisol access to the mineralocorticoid receptor (high rates of cortisol production that overwhelm 11β-hydroxysteroid dehydrogenase type 2 [11β-HSD2] activity). Primary cortisol resistance is caused by defects in glucocorticoid receptors and assembly of the steroid–receptor complex. The treatment for the mineralocorticoid-dependent hypertension is blockade of the mineralocorticoid receptor with a mineralocorticoid receptor antagonist or suppression of ACTH secretion with dexamethasone.

Apparent Mineralocorticoid Excess Syndrome

Type 1 apparent mineralocorticoid excess (AME) is the result of impaired activity of the microsomal enzyme 11β-HSD2, which normally inactivates cortisol in the kidney by converting it to cortisone (Figure 10–9). Cortisol can be a potent mineralocorticoid, and as a result of the enzyme deficiency, high levels of cortisol accumulate in the kidney. Thus, 11β-HSD2 normally excludes physiologic glucocorticoids from the nonselective mineralocorticoid receptor by converting them to the inactive 11-keto compound, cortisone. The characteristic abnormal urinary cortisol-cortisone metabolite profile seen in apparent mineralocorticoid excess reflects decreased 11β-HSD2 activity (ratio of cortisol to cortisone increased 10-fold from normal).

Decreased 11β-HSD2 activity may be hereditary or secondary to pharmacologic inhibition of enzyme activity by glycyrrhizic acid, the active principle of licorice root (Glycyrrhiza glabra) and some chewing tobaccos. The congenital form is a rare autosomal recessive disorder, and children present with low birth weight, failure to thrive, hypertension, polyuria and polydipsia, and poor growth. The clinical phenotype of patients with AME includes hypertension, hypokalemia, metabolic alkalosis, low PRA, low PAC, and normal plasma cortisol levels. The diagnosis is confirmed by demonstrating an abnormal ratio of cortisol to cortisone in a 24-hour urine collection. Treatment includes blockade of the mineralocorticoid receptor with a mineralocorticoid receptor antagonist or suppression of endogenous cortisol secretion with dexamethasone.

Carbenoxolone (18β-glycyrrhetinic acid sodium hemisuccinate) is a glycyrrhizic acid metabolite that is used in some countries to treat gastroesophageal reflux disorder. Carbenoxolone acts by protecting the gastrointestinal mucosal barrier from acid-pepsin attack and increasing mucosal mucin production. However, carbenoxolone is also an inhibitor of 11β-HSD2 and side effects include sodium retention, hypokalemic alkalosis, suppressed plasma renin, and hypertension.

Type 2 AME caused by ectopic ACTH secretion, seen in patients with Cushing syndrome, is related to the high rates of cortisol production that overwhelm 11β-HSD2 activity. DOC levels may also be increased in severe ACTH-dependent Cushing syndrome and contribute to the hypertension and hypokalemia in this disorder.

Liddle Syndrome—Abnormal Renal Tubular Ionic Transport

In 1963, Liddle described an autosomal dominant renal disorder that appeared to be primary aldosteronism with hypertension, hypokalemia, and inappropriate kaliuresis. However, PAC and PRA were very low in patients with Liddle syndrome; thus, another name for this disorder is “pseudoaldosteronism.” Liddle syndrome is caused by mutations in the β or γ subunits of the amiloride-sensitive epithelial sodium channel—resulting in enhanced activity of the epithelial sodium channel with increased sodium reabsorption, potassium wasting, hypertension, and hypokalemia. Clinical genetic testing is available (www.genetests.org). As would be predicted, amiloride and triamterene are very effective agents to treat the hypertension and hypokalemia. However, spironolactone is ineffective in these patients. Liddle syndrome can easily be distinguished from AME based on a good clinical response to amiloride or triamterene, lack of efficacy of spironolactone and dexamethasone, and normal 24-hour urine cortisone-cortisol ratio.

Hypertension Exacerbated by Pregnancy

Hypertension exacerbated by pregnancy is a rare autosomal dominant disorder found in women with early-onset hypertension with suppressed levels of aldosterone and renin. During pregnancy, both the hypertension and hypokalemia are severely exacerbated. These patients have an activating mutation in the gene encoding the mineralocorticoid receptor which allows progesterone and other mineralocorticoid antagonists to become agonists.

Cushing Syndrome

Hypertension occurs in 75% to 80% of patients with Cushing syndrome (see Chapter 9). Most patients with endogenous Cushing syndrome have ACTH-dependent disease due to a corticotroph pituitary adenoma (see Table 10–2). Ectopic ACTH secretion is the second most common cause of endogenous Cushing syndrome. The ACTH-independent causes (eg, adrenal cortisol-secreting adenoma or carcinoma) of Cushing syndrome are less common. ACTH-independent macronodular hyperplasia is associated with massive hyperplasia of both adrenal glands—usually a result of activation of one or several G protein–coupled receptors aberrantly expressed in the adrenal cortex. ACTH-independent primary pigmented nodular adrenal disease (PPNAD) is a bilateral form of micronodular adrenal hyperplasia that leads to Cushing syndrome. Germline mutations in PRKAR1A cause PPNAD in the setting of Carney complex (see Chapter 9). The mechanisms of hypertension in the setting of Cushing syndrome include increased production of DOC, enhanced pressor sensitivity to endogenous vasoconstrictors (eg, epinephrine and angiotensin II), increased cardiac output, activation of the renin-angiotensin system by increasing the hepatic production of angiotensinogen, and overload of the cortisol inactivation system with stimulation of the mineralocorticoid receptor. The source of excess glucocorticoids may be exogenous (iatrogenic) or endogenous. Mineralocorticoid production is usually normal in endogenous Cushing syndrome; aldosterone and renin levels are usually normal and DOC levels are normal or mildly increased. In patients with adrenal carcinoma, DOC and aldosterone may be elevated.

The case-detection studies for endogenous cortisol excess include: (a) measurement of free cortisol in a 24-hour urine collection; (b) midnight salivary cortisol measurement; and (c) 1-mg overnight dexamethasone suppression test. Further studies to confirm Cushing syndrome and to determine the cause of the cortisol excess state are outlined in Chapter 9.

The hypertension associated with Cushing syndrome should be treated until a surgical cure is obtained. Mineralocorticoid receptor antagonists, at dosages used to treat primary aldosteronism, are effective in reversing the hypokalemia. Second-step agents (eg, thiazide diuretics) may be added for optimal control of blood pressure. The hypertension associated with the hypercortisolism usually resolves over several weeks after a surgical cure, and antihypertensive agents can be tapered and withdrawn.

Thyroid Dysfunction

Hyperthyroidism

When excessive amounts of circulating thyroid hormones interact with thyroid hormone receptors on peripheral tissues, both metabolic activity and sensitivity to circulating catecholamines increase. Thyrotoxic patients usually have tachycardia, high cardiac output, increased stroke volume, decreased peripheral vascular resistance, and increased systolic blood pressure. The initial management of patients with hypertension who have hyperthyroidism includes a β-adrenergic blocker to treat hypertension, tachycardia, and tremor. The definitive treatment of hyperthyroidism is cause specific (see Chapter 7).

Hypothyroidism

The frequency of hypertension, usually diastolic, is increased three fold in hypothyroid patients and may account for as much as 1% of cases of diastolic hypertension in the population. The mechanisms for the elevation in blood pressure include increased systemic vascular resistance and extracellular volume expansion. Treatment of thyroid hormone deficiency decreases blood pressure in most patients with hypertension and normalizes blood pressure in one-third of them. Synthetic levothyroxine is the treatment of choice for hypothyroidism (see Chapter 7).

Acromegaly

Chronic growth hormone (GH) excess from a GH-producing pituitary tumor results in the clinical syndrome of acromegaly. The effects of chronic excess of GH include acral and soft tissue overgrowth, progressive dental malocclusion, degenerative arthritis related to chondral and synovial tissue overgrowth within joints, low-pitched sonorous voice, excessive sweating and oily skin, perineural hypertrophy leading to nerve entrapment (eg, carpal tunnel syndrome), cardiac dysfunction, and hypertension (see Chapter 4). Hypertension occurs in 20% to 40% of the patients and is associated with sodium retention and extracellular volume expansion. Pituitary surgery is the treatment of choice; if necessary, it is supplemented with medical therapy or irradiation or both. The hypertension of acromegaly is treated most effectively by eliminating GH excess. If a surgical cure is not possible, the hypertension usually responds well to diuretic therapy.

Primary Aldosteronism

Other Forms of Mineralocorticoid Excess or Effect

Other Endocrine Disorders Associated with Hypertension