Hipertension Secundaria

Secondary HypertensionRory F. McQuillan | Peter J. Conlon

67

Hypertension is a risk factor for cardiovascular disease including myocardial infarction and stroke, and it is a worldwide public health concern. In 2000, one quarter of the world’s population was estimated to have hypertension. In the United States, one in three adults is hypertensive. The majority of cases are the result of a complex interac-tion of genetic traits with lifestyle factors such as weight, sodium intake, and stress, and are termed essential or idio-pathic hypertension. Ten to fifteen percent of cases reflect a specific underlying pathophysiology and are considered secondary hypertension. It is important that physicians identify patients for whom screening for secondary hyper-tension is appropriate so as to minimize overinvestigation of essential hypertension while not failing to diagnose a readily treatable underlying condition. Many causes of sec-ondary hypertension are reversible, and specific treatment may allow significant improvement or normalization of the blood pressure.

Box 67.1 lists some clinical clues that may suggest the presence of secondary hypertension. Box 67.2 summa-rizes the many causes of secondary hypertension. This chapter provides a concise overview of these conditions, and suggests a practical clinical approach to the diagno-sis and treatment of the patient with suspected secondary hypertension.

KIDNEY CAUSES OF SECONDARY HYPERTENSION

RENOVASCULAR HYPERTENSION

Renovascular disease is the most common correctable cause of secondary hypertension. Its prevalence varies according to the clinical circumstances; it is relatively rare in patients with mild hypertension, but accounts for 10% to 45% of severe or refractory hypertension.

Renovascular hypertension is mediated by activation of the renin-angiotensin-aldosterone system (RAAS) resulting from unilateral or bilateral renal artery stenosis (RAS). To trigger renin release, the stenosis must cause a translesional peak systolic gradient of 15 to 25 mm Hg. This generally only occurs with lesions that result in greater than 70% occlusion of the artery. Because of RAAS activation and sympathetic overactivity, patients with renovascular hyper-tension have a high incidence of end-organ damage com-pared to those with essential hypertension. In addition to renovascular hypertension, RAS may cause kidney function impairment and otherwise unexplained episodes of acute pulmonary edema.

601

The majority of cases of RAS are caused either by ath-erosclerotic renal artery stenosis (ARAS) or fibromuscular dysplasia (FMD). Rarely, RAS may be caused by extrinsic renal artery compression, neurofibromatosis type 1, or Wil-liams syndrome.

ARAS is usually found in patients older than 50 years with other cardiovascular risk factors or known cardiovascular disease. It constitutes more than 85% of all renovascular disease. Lesions tend to progress, and there is often a coexistent reduction in kidney function. The optimal treatment of ARAS remains controversial. FMD is a non-atherosclerotic, noninflammatory vascular disease that causes stenosis in medium-sized and small arteries, most commonly in the renal and carotid arteries. Renovascular hypertension is the most common clinical manifestation, usually occurring in 30- to 50-year-old women. The pro-gression of stenosis is slow, and renal kidney function is usually well preserved. The most common subtype of the disease causes medial dysplasia of the affected artery, with multiple contiguous stenoses creating the appearance on imaging of a string of beads. FMD has an estimated prev-alence among hypertensive patients of less than 1%, but this may be an underestimate because many cases likely go undetected. FMD can be a familial disease. Diagnosis of renal artery FMD should prompt screening of the carotid arteries for associated lesions. Revascularization with per-cutaneous angioplasty generally improves the associated hypertension.

DIAGNOSISSeveral well-recognized clinical situations that suggest the presence of renovascular disease are summarized in Box 67.3. Clinical examination may show evidence of sys-temic atherosclerotic disease, such as carotid or femoral bruits or absent pedal pulses. The presence or absence of abdominal bruits is not particularly useful. The urine sediment is usually bland, with mild to moderate protein-uria. A kidney ultrasound may show a discrepancy in size between the two kidneys. Renal artery narrowing is often an incidental finding, particularly in elderly patients, and may coexist with essential hypertension. It is important therefore that investigation only be pursued in patients who are potential candidates for revascularization of the renal arteries.

The imaging modalities available for evaluating renovas-cular disease are summarized in Table 67.1. Most centers do not proceed directly to intraarterial angiography (Fig. 67.1) because of the risk of contrast nephrotoxicity, cholesterol embolization, and damage to the renal or femoral arteries, but first perform one of several available screening tests.

602 SECTION 12 — HYPERTENSION

SCREENING TESTSThe most commonly used screening tests are duplex ultra-sonography, magnetic resonance angiography (MRA), and computed tomography angiography (CTA). Duplex ultra-sonography of the renal arteries reliably detects RAS when performed by an experienced ultrasonographer. However, its accuracy is operator dependent; the sensitivity and speci-ficity of Doppler ultrasonography are estimated at about

Kidney Causes

Renovascular hypertensionRenal parenchymal hypertension

Endocrine Causes

Primary hyperaldosteronismCushing syndromePheochromocytomaRenin secreting tumorHypothyroidism or hyperthyroidismAcromegalyHyperparathyroidism

Cardiovascular or Cardiopulmonary Causes

Coarctation of the aortaObstructive sleep apnea

Drugs

GlucocorticoidsNonsteroidal antiinflammatory drugsHAARTCombined oral contraceptive pillsVEGF inhibitors, e.g., Bevacizumab, SunitinibVenlafaxineCalcineurin inhibitorsPhenylephrineCaffeineExcess alcoholErythrocyte stimulating agentsLicorice

Inherited Causes

Glucocorticoid-remediable aldosteronismSAMEGordon syndrome (i.e., type 2 pseudohypoaldosteronism)Liddle syndrome

HAART, Highly active antiretroviral therapy; SAME, syndrome of appar-ent mineralocorticoid excess; VEGF, vascular endothelial growth factor.

Box 67.2 Causes of Secondary Hypertension

Young age at onset (less than 30 yr)Sudden onset of hypertensionUncontrolled or refractory hypertensionMalignant hypertensionFeatures of a recognized underlying cause

Box 67.1 Clues to the Presence of Secondary Hypertension

80% to 85% in most published trials, but they have been as high as 97% to 99% in a trial enrolling patients who later underwent conventional angiography. Duplex ultrasound allows the operator to predict the severity of stenosis based on the peak systolic velocity (PSV) in the renal artery, which may then be expressed in relation to the PSV in the aorta, termed the renal-aortic ratio (RAR). Renal PSV greater than 200 cm/s, RAR greater than 3.5, and the presence of post-stenotic turbulence in the renal artery are highly suggestive of significant RAS. A related measurement is the resistive index, which is calculated by subtracting the peak diastolic velocity (PDV) in the renal artery from the PSV, and divid-ing by the PSV. As the PDV falls, the resistive index increases. A low resistive index has been suggested as a predictor of response to revascularization, with a resistive index greater than 0.8 predictive of a poor response.

MRA has been the screening investigation of choice for RAS in most centers (Fig. 67.2). It is noninvasive, avoids ionizing radiation, and uses a nonnephrotoxic contrast agent (gadolin-ium). Recently, nephrogenic systemic fibrosis (NSF) has been linked to gadolinium exposure in patients with GFR less than 30 mL/min. The causal link is based on research showing gad-olinium in skin biopsies of patients with NSF. NSF is a rapidly progressive, debilitating condition that causes cutaneous and visceral fibrosis for which there is no well-defined treatment. Gadolinium should therefore be avoided in patients with GFR less than 30 mL/min (see Chapter 6). Improvements in MR technology may allow for vascular imaging without gadolinium.

The accuracy of CTA is reduced in patients with serum creatinine levels greater than 2 mg/dl, probably because of reduced renal blood flow. The need for a significant contrast load in patients with coexistent reduced kidney function is also a limitation. The accuracy of CTA and MRA for detect-ing RAS is debatable. Metaanalyses have estimated sensitiv-ity and specificity at 97% and 93% for MRA, and 96% and 99% for CTA. This is contradicted, however, by a large, well-designed, prospective study showing that, although both tests had reasonable specificity (88% for MRA and 94% for CTA), sensitivity was relatively poor at 78% and 77%, respec-tively. We therefore recommend catheter angiography in the setting of high clinical suspicion despite inconclusive noninvasive imaging.

Captopril renography was formerly used extensively. However, it is cumbersome, does not provide images of the renal artery, and has poor predictive value in identifying sig-nificant RAS. It is no longer commonly used.

p9120

Abrupt onset of or accelerated hypertension at any ageEpisodes of flash pulmonary edema with normal ventricular

functionAcute, unexplained rise in the serum creatinine level after use

of an angiotensin-converting enzyme inhibitor or ARBElevated serum creatinine level in patients with severe or

refractory hypertensionAsymmetric kidney size

ARB, Angiotensin receptor blocker.

Box 67.3 Clinical Clues to the Presence of Renovascular Disease

603 CHAPTER 67 — SECONDARY HYPERTENSION

Table 67.1 Investigations to Evaluate Renal Artery Stenosis

Advantages Disadvantages

Duplex Ultrasound NoninvasiveNo radiationHighly sensitive/specific if operator has appropriate

expertiseResistive index may predict response to

revascularization

Highly operator dependentUtility of resistive index not universally accepted

MRA NoninvasiveNot nephrotoxic

Gadolinium a risk for NSF in patients with GFR < 30 mL/min

Questionable accuracyCTA Noninvasive Nephrotoxicity

Sensitivity reduced in advanced CKDCaptopril Renography Noninvasive

Theoretically provides information about functional effect of stenosis

Poor predictive value for degree of stenosis

Intraarterial Angiography Most accurate determination of stenosisAllows for measurement of transstenotic gradient

InvasiveNephrotoxicityDamage to femoral and renal arteries and other

mechanical complicationsCholesterol emboli

Renal Vein Renin Sampling Lateralization in bilateral disease Inaccurate unless complete occlusion

CKD, Chronic kidney disease; CTA, computed tomography angiography; MRA, magnetic resonance angiography; NSF, nephrogenic systemic fibrosis.

CONFIRMATORY TESTSConventional intraarterial angiography is considered the gold standard for detecting and quantifying the degree of RAS. Newer techniques allow for the measurement of transstenotic pressure gradients. One study that measured the transstenotic gradient after intraarterial infusion of papaverine showed a gradient of at least 21 mm Hg to be highly predictive of an improvement in hypertension at 1 year following revascular-ization, having a predictive value of 84% compared to only 69% for visual estimation of stenosis as greater than 60%.

Figure 67.1 Conventional renal angiography demonstrates the classic beadlike appearance of fibromuscular dysplasia in both renal arteries (arrows). (Courtesy Professor Mick Lee, Beaumont Hos-pital, Dublin, Ireland.)

Renal vein renin sampling is no longer commonly used in the evaluation of RAS, as it performs poorly at lateralizing lesions unless the renal artery is completely occluded.

TREATMENTAll patients with RAS should receive appropriate antihyper-tensive therapy. Given the role of the RAAS in mediating hypertension, an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) should be the first-line choice of therapy. Treatment with lipid- lowering drugs and antiplatelet agents is advised in the setting of ARAS

Figure 67.2 Magnetic resonance angiography shows diffuse atherosclerotic disease of the aorta and right renal artery, and a tight ostial stenosis of the left renal artery. (Courtesy Professor Mick Lee, Beaumont Hospital, Dublin, Ireland.)


Figure 67.3 Algorithm for inves-tigation and management of renal artery stenosis. ACE, Angiotensin converting enzyme; AKI, acute kidney injury; ARB, angiotensin receptor blockers; ASA, aspirin; BP, blood pressure; RAS, renal artery stenosis.

HypertensionSuspicion of renal artery stenosis

Medical management(ACE/ARB+/-ASA and Statin)

Follow up

Controlled BPStable kidney function

Uncontrolled BPAKI with ACERapidly declining kidney functionFlash pulmonary edema

Noninvasive screening for RAS

Angiogram with transstenotic gradient+/- Angioplasty with stenting

RAS

Candidate for revascularization?

No RASMedical managementFollow up

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thwPcaauhiyt

AkSpaoeRaiatstntsrA

iven the high burden of cardiovascular disease. Figure 67.3 resents a management algorithm for renovascular disease.Hypertensive patients with FMD should initially be

reated with an ACE inhibitor or ARB. If they remain ypertensive, the treatment of choice is revascularization ith percutaneous transluminal renal angioplasty (PTRA). TRA in patients with FMD is almost always technically suc-essful with a low restenosis rate, minimal risk, and usually n improvement, though not complete “cure,” of the associ-ted hypertension. There is sparse literature addressing the se of stenting in this disease, presumably because of the igh rate of prolonged success with angioplasty alone. Stent-

ng is an option in cases of restenosis, although in view of the oung age of many of these patients, surgical revasculariza-ion should also be considered.

Revascularization for ARAS is not as straightforward. lthough intuitively attractive, restoration of blood flow to the idneys in unselected patients has had disappointing results. everal randomized controlled trials (Table 67.2) have com-ared angioplasty with and without stenting to medical man-gement alone. None have demonstrated any benefit in terms f blood pressure control, kidney function, or cardiovascular vents with intervention compared to medical management. evascularization may cause serious adverse events. There re several important limitations to these trials. First, patients ncluded were, by and large, clinically stable: The Angioplasty nd Stent Therapy for Renal Artery Lesion (ASTRAL) trial, he largest to date, used physician uncertainty as its key inclu-ion criterion leading to the recruitment and randomization o intervention of patients with nonsignificant degrees of ste-osis that might be less likely to benefit from revasculariza-

ion. The STent placement for Atherosclerotic Renal-artery tenosis (STAR) trial was similarly compromised. These esults must therefore not be extrapolated to patients with RAS and malignant range hypertension, rapidly advancing

kidney failure, or flash pulmonary edema. The ASTRAL, Dutch Renal Artery STenosis Intervention Cooperative study group (DRASTIC), and Essai Multicentrique Medicaments vs. Angioplastie (EMMA) trials all allowed crossover from the medical to interventional arms, which reduced their ability to detect a difference between treatments. The medical man-agement of hypertension was not well defined in these trials, RAAS blockade was not universal, and the control of BP was often inadequate in both groups.

The DRASTIC and EMMA trials used angioplasty without stenting, which is associated with higher rates of restenosis and is not recommended. Figure 67.4 shows a stent in the left renal artery after percutaneous intervention.

For patients with significant disease in whom there is clini-cal uncertainty regarding treatment, the ongoing Cardiovas-cular Outcomes in Renal Artery Lesions (CORAL) trial may provide some guidance. CORAL is a randomized trial that seeks to recruit 1080 patients to determine whether stenting is superior to medical management in terms of controlling hypertension, arresting the decline in kidney function, and preventing cardiovascular events. Its inclusion criteria, which either include more than 80% stenosis on catheter angiog-raphy or more than 60% with a demonstrable transstenotic pressure gradient of greater than 20 mm Hg, should ensure that only patients with hemodynamically significant RAS are included. All patients will be treated with RAAS blockade.

Pending results from CORAL, management of patients with ARAS must be evaluated on a case-by-case basis with careful consideration given to the clinical situation and cor-relation with investigations. It is helpful to decide before recommending revascularization procedures whether the indication for intervention is treatment of renovascular hypertension, preservation of kidney function, or both. Renovascular hypertension typically manifests as an abrupt onset of severe hypertension or a marked deterioration from

605 C

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PTER 67 — SEC

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DA

RY HYPERTEN

SION

gement

Limitations

e in pri-ome, BP, ascular

Enrollment biasNot standardized imaging

(42% of patients less than 70% stenosis)

6% crossovert differ-mary r BP

Included patients with minor disease

28% of treatment group did not receive stent due to trivial nature of stenosis

e in BP or

defined s of anti-ve drugs

44% crossoverNo stentsShort follow-upInadequate BP control in

both groups

e in BP or clearance in defined s of anti-ve drugs

27% crossoverFew stentsShort follow-upRAAS blockade avoided

t differ-rdiovas-ts, BP, or

No stentsShort follow-upInadequate BP control in

both groupsExcluded patients on

ACE inhibitors

l Artery Stenosis Intervention Cooperative RAAS, renin-angiotensin aldosterone

Table 67.2 Prospective Randomized Control Trials Comparing Percutaneous Transluminal Angioplasty to Medical Manain Renal Artery Stenosis

TrialNumber of Patients

Year of Publication Inclusion Criteria

Primary Outcome

Treatment in Revascularization Group

Treatment in Comparison Group Outcome

ASTRAL 806 2009 Significant RAS and physician uncertainty regarding benefit of revascularization

Reciprocal creatinine concentration over time

Medication plus PTA with or without stent

Antihypertensive medication

No differencmary outcor cardiovevents

STAR 140 2009 RAS greater than 50%GFR 15 to 80 mL/minStable BP

Decrease in GFR ≥20%

Medication plus PTA with stent


No significanence in prioutcome o

DRASTIC 106 2000 Unilateral or bilateral RAS ≥50%

Diastolic BP ≥95 mm Hg on 2 drugs or an increase in creatinine ≥20 µmol/L on ACE inhibitors

Office BP PTA Antihypertensive medication

No differenccreatinine

Reduction indaily dosehypertensi

EMMA 49 1998 Unilateral RAS ≥75% or ≥60% plus a positive renography

24 hr ambula-tory BP

PTA (2 patients received a stent)


No differenccreatinine reduction daily dosehypertensi

Webster et al.

55 1998 Unilateral or bilateral RAS

Diastolic BP greater than 95 mm Hg on 2 drugs

Office BP PTA Antihypertensive medication

No significanence in cacular evenGFR

ACE, Angiotensin converting enzyme; ASTRAL, the Angioplasty and Stent Therapy for Renal Artery Lesion; BP, blood pressure; DRASTIC, Dutch Renastudy group; EMMA, Essai Multicentrique Medicaments vs. Angioplastie; GFR, glomerular filtration rate; PTA, percutaneous transluminal angioplasty;system; RAS, renal artery stenosis; STAR, STent placement for Atherosclerotic Renal-artery stenosis.


a previously stable baseline. Chronic stable hypertension present for many years is unlikely to be caused by progres-sive RAS, and is therefore unlikely to respond to interven-tion. Data suggest that revascularization cannot improve blood pressure in patients who have already lost more than 60% of kidney function.

Although ischemic nephropathy is a significant cause of end-stage renal disease, the issue of revascularization for preservation of kidney function is controversial. Patients (especially those with serum creatinine levels of ≥2.5 mg/dl) often already have significant, irreversible renal parenchy-mal disease, and kidney function is unlikely to be improved by revascularization. Other signs of poor response to inter-vention include kidney size less than 9 cm, a renal resistive index greater than 80 on Doppler ultrasonography, signifi-cant proteinuria, evidence of another kidney disease, or findings of marked chronicity on kidney biopsy. In patients with known RAS greater than 60%, following serial serum creatinine measurements can identify those who are pro-gressively losing kidney function that may still be salvaged. There is some evidence that this group responds better to intervention than those with chronic, stable kidney function impairment.

ARAS may also manifest as recurrent episodes of flash pul-monary edema. There is evidence from small, nonrandom-ized trials that this subgroup of patients benefit from renal artery stenting, and treatment is strongly recommended by the American College of Cardiology.

RENAL PARENCHYMAL HYPERTENSION

Hypertension is a common feature of acute and chronic kidney disease (CKD), particularly in glomerular and vas-cular disorders. Hypertension results from a combination of a positive salt balance, increased activity of the RAAS, and overactivity of the sympathetic nervous system. Treatment of hypertension in CKD consists of dietary salt restriction and promotion of salt excretion with diuretics, blockade of the RAAS system with ACE inhibitors and ARBs, and inhibition of the sympathetic nervous system. The recent Symplicity HTN-2 Trial demonstrated that catheter-based renal sym-pathetic denervation can be used to reduce blood pressure substantially in treatment-resistant hypertensive patients. Clues to the presence of renal parenchymal disease in

Figure 67.4 A stent can be seen in the ostium of the left renal ar-tery. (Courtesy Professor Mick Lee, Beaumont Hospital, Dublin, Ireland.)

hypertensive patients are elevated serum creatinine levels and abnormal urinalyses. A kidney ultrasound is a useful noninvasive screening test to assess kidney size and asym-metry, and to rule out major kidney structural abnormali-ties or obstructive lesions. The varied disorders have many treatments available, and a discussion of each is beyond the scope of this chapter.

ENDOCRINE CAUSES OF SECONDARY HYPERTENSION

Hypertension is a feature of several endocrine conditions (see Box 67.2) with the best-characterized associations being primary hyperaldosteronism, Cushing syndrome, and pheochromocytoma.

PRIMARY HYPERALDOSTERONISM

Primary hyperaldosteronism is the most common endo-crine cause of hypertension, and its incidence increases with the severity of hypertension. Among patients with resistant hypertension, the prevalence of primary hyperaldosteron-ism is estimated to be 17% to 20%.

As a group, African-American patients tend to have lower renin levels, but no ethnic differences in the prevalence of primary hyperaldosteronism have been described. No dif-ference between the sexes has been reported.

Primary hyperaldosteronism may be caused by bilateral adrenal hyperplasia (65% of cases), aldosterone produc-ing adenoma (30% of cases), or, rarely, a secretory adrenal carcinoma or inherited endocrinopathy (discussed later). Patients with adrenal adenomas tend to be younger and have a more severe clinical picture than those with adrenal hyperplasia.

CLINICAL SYNDROMEConn first described the clinical syndrome of primary hyperaldosteronism in 1955 in a 34-year-old woman with hypertension, episodic paralysis, hypokalemia, and meta-bolic alkalosis. She was subsequently cured by the removal of an adrenal adenoma.

DIAGNOSISAlthough hypokalemia may arouse suspicions of hyperaldo-steronism, the latter is not present in most cases. Testing for hyperaldosteronism should be considered in any of the fol-lowing circumstances: hypertension and spontaneous hypo-kalemia (or hypokalemia induced by low-dose diuretic), severe hypertension (i.e., systolic pressure greater than 160 mm Hg, diastolic pressure greater than 100 mm Hg, or both); a patient requiring three or more antihypertensive drugs; hypertension manifesting at a young age (less than 40 years); hypertensive patients with an incidental adrenal mass; and hypertensive relatives of a patient with primary hyperaldosteronism. Figure 67.5 is an algorithm to evaluate suspected primary hyperaldosteronism.

SCREENING TESTSMeasurement of the ratio of plasma aldosterone concen-tration (PAC) to plasma renin activity (PRA) is the screen-ing test of choice for patients with suspected primary


Figure 67.5 Algorithm for the evaluation and manage-ment of suspected primary hyperaldosteronism. CT, Computed tomography; PAC, plasma aldosterone con-centration; PRA, plasma renin activity.

Hypertensive patients at risk for primary hyperaldosteronism

PAC: PRA

Conduct confirmatory testing

>20

Adrenal CT

+

Adrenal vein sampling

Mineralocorticoid receptor antagonist Laproscopic adrenalectomy

Surgery considered

UnilateralBilateral

Not surgical candidate

hyperaldosteronism. A PAC/PRA ratio greater than 20 in combination with a PAC greater than 15 ng/dl (416 pmol/L) is considered a positive screening test result. The test is per-formed in the morning on an ambulatory patient. Hypoka-lemia, if present, should be first corrected, as it may suppress aldosterone secretion. Aldosterone antagonists and amiloride should be stopped 6 weeks before testing. As ACE inhibitors, ARBs, and diuretics can falsely elevate the PRA value, the pres-ence of a detectable PRA or a low PAC/PRA ratio in patients taking these agents does not exclude a diagnosis of primary hyperaldosteronism. However, if the PRA is undetectable in a patient taking an ACE inhibitor or ARB, then a diagnosis of primary hyperaldosteronism should be considered, and the ACE inhibitors or ARB need not be stopped. Adrenergic inhibitors (i.e., β-blockers and, to a lesser extent, α2-agonists) suppress renin and reduce aldosterone levels, although to a lesser degree, in normal individuals. The PAC/PRA ratio may be increased in hypertensive patients without hyperaldoste-ronism who are taking adrenergic antagonists, but the PAC will not be greater than 15 ng/dl, and the diagnostic power of the test is therefore unaffected. Table 67.3 summarizes how some commonly used antihypertensive medications may affect the interpretation of the PRA/PAC. Verapamil (a non-dihydropyridine calcium channel blocker), hydralazine, and α-adrenergic agents such as prazosin, doxazosin, and terazo-sin have little or no effect on PRA/PAC, and may be used to control hypertension during testing.

CONFIRMATORY TESTSThe PAC/PRA ratio is a screening tool, and confirma-tory tests are necessary to confirm autonomous adrenal

production of aldosterone. The hallmark of primary hyper-aldosteronism is nonsuppressible aldosterone secretion with nonstimulable renin secretion. In principle, admin-istration of a sodium load should result in suppression of aldosterone in normal individuals, whereas in patients with hyperaldosteronism, suppression will not occur. This may be achieved by means of oral sodium chloride load over sev-eral days, or by administration of intravenous saline over several hours.

Table 67.3 Commonly Used Antihypertensive Agents Affecting the Plasma Aldosterone Concentration to Plasma Renin Activity Ratio

PAC PRA PAC:PRAClinical Consequence

ACE inhibitor ↓ ↑ ↓ False negativeARB ↓ ↑ ↓ False negativeβ Blockers ↓ ↓↓ ↑ False positiveCentral α-blockers

↓ ↓↓ ↑ False positive

Diuretics ↑ ↑↑ ↓ False negativeDihydropyridineCa Channel

Blockers

↓ ↑ ↓ False negative

ACE, Angiotensin converting enzyme; ARB, angiotensin receptor blocker; Ca, calcium; PAC, plasma aldosterone concentration; PRA, plasma renin activity.


An alternative is the fludrocortisone suppression test, in which fludrocortisone acetate is administered at a dosage of 0.1 mg every 6 hours for 4 days together with a high-sodium diet. In the normal individual, aldosterone is suppressed.

These tests have potential risks, particularly for patients with poor left ventricular function. An alternative is the captopril suppression test, in which oral administration of captopril does not suppress aldosterone levels below 15 ng/dl in patients with primary hyperaldosteronism. This test has the advantage of avoiding salt loading in individuals in whom this is contraindicated, but it may cause profound hypotension in some patients.

All of these tests are cumbersome and time consuming, and many centers now directly proceed to imaging after a positive biochemical screening test result.

IMAGINGThe adrenal glands are best imaged with computed tomog-raphy (CT) to determine the cause of primary hyperaldo-steronism. Adenomas 10 mm in diameter and sometimes even smaller can be detected. Magnetic resonance imaging (MRI) is less attractive, because it is more expensive than CT with less spatial resolution. Radionuclide scintigraphy with [131I]iodocholesterol is sensitive for adenomas, but not widely available. There have also been several case reports documenting missed lesions.

Incidentally detected nonfunctioning adenomas may be detected in 4% of the general population on CT, rising to 7% at autopsy. They are particularly common after the age of 40 years. For a patient younger than 40 years with profound hyperaldosteronism (e.g., PAC greater than 30 ng/dl or 832 pmol/L), an adenoma found on CT that is larger than 1 cm, of uniform diameter, and hypodense (less than 10 Houn-sfield units), and a contralateral adrenal gland that appears normal on imaging, it is reasonable to proceed to adrenalec-tomy, because the chance of an aldosterone-producing ade-noma is high. In older individuals, adrenal vein sampling should be performed if an adenoma is detected, because aldosterone-producing adenomas become increasingly rare with advancing age. If the adrenal glands appear normal on imaging, patients should proceed directly to adrenal vein sampling. This technique can strongly predict a therapeu-tic response to unilateral adrenalectomy. An experienced radiologist must perform adrenal vein sampling, and it is more accurate when performed after adrenocorticotropic hormone (ACTH) stimulation. The position in the adre-nal vein is confirmed by simultaneously measuring adrenal vein and peripheral vein cortisol levels. A greater than five-fold increase in PAC compared with the contralateral side is expected on the side of an active adenoma. In adrenal hyperplasia, there should be little difference between the two adrenal vein levels. Occasionally, the adenoma may be extraadrenal, and the result of adrenal vein sampling is nor-mal. If imaging and adrenal vein sampling are negative, the rare diagnosis of glucocorticoid-remediable aldosteronism (discussed later) should be considered.

TREATMENTPatients with adenomas should be referred for unilateral laparoscopic adrenalectomy as removal of well-localized uni-lateral lesions is very successful. Embolization of adenomas with ethanol may be an option in patients medically unfit

for surgery. Selective hypoaldosteronism may occur for some months after surgery, and potassium should be supple-mented cautiously during this period. The drugs of choice for medical management of adrenal hyperplasia and pre-operative management of adenomas in the past have been spironolactone, amiloride, and ACE inhibitors. Eplerenone, a newer selective aldosterone receptor antagonist, is popu-lar because it causes much less gynecomastia than spirono-lactone. However, a recent well-powered double-blinded randomized controlled trial demonstrated that eplerenone is less effective than spironolactone for controlling blood pressure.

HYPERRENINISM

Renin-secreting tumors are rare. Affected patients are typi-cally hypertensive and hypokalemic, with high PRA along with elevated aldosterone levels and urinary potassium excretion. These tumors usually originate from the juxta-glomerular apparatus in the kidney, but renin production has been reported with other malignancies, including tera-tomas and ovarian tumors.

CUSHING SYNDROME

Cushing syndrome is a clinical condition resulting from excess effects of exogenous or endogenous glucocorticoids. Patients develop a characteristic clinical appearance, with the classic cushingoid moon facies related to facial fat deposi-tion, along with truncal obesity, abdominal striae, hirsutism, and kyphoscoliosis. Patients have varying degrees of multi-organ involvement, with diabetes mellitus, cataracts, neuro-psychiatric disorders, proximal myopathy, avascular necrosis of humeral and femoral heads, osteoporosis, and second-ary hypertension among the more prominent. The original syndrome described by Cushing related to a patient with pituitary ACTH excess driving excess cortisol production. As a consequence, pituitary-dependent disease is known as Cushing disease. Hypertension resulting from the mineralo-corticoid effect of the glucocorticoids is a common feature. Causes of Cushing syndrome are listed in Box 67.4. The most common cause of endogenous glucocorticoid excess is a pituitary adenoma.

DIAGNOSISThe presence of cortisol excess must be confirmed biochem-ically. This can be achieved with the low-dose dexametha-sone suppression test, measurement of 24-hour urinary free-cortisol levels, or assessment of the circadian pattern

Exogenous glucocorticoid administrationEndogenous glucocorticoid excessACTH excess

Ectopic productionPituitary secretory adenoma (Cushing disease)

Cortisol excess

ACTH, Adrenocorticotropic hormone.

Box 67.4 Causes of Cushing Syndrome

of cortisol secretion. In the overnight, low-dose dexametha-sone suppression test, a 2-mg dose of dexamethasone is taken at 11 pm, and a plasma cortisol sample is drawn at 9 am the next morning. Suppression is defined as a cortisol level of less than 5 mg/dl. To assess circadian cortisol secretion, cortisol levels are measured at 9 am and 11 pm. They are usu-ally highest in the morning and lowest at night.

Other causes of abnormally high cortisol secretion include stress, major depression, and chronic excess alcohol consumption. A normal response to an insulin stimulating test suggests major depression.

When cortisol excess is confirmed, further testing to elu-cidate a pituitary, adrenal, or ectopic source should follow. Extremely high plasma or urinary cortisol levels suggest adrenal carcinoma or ectopic ACTH secretion. An adrenal carcinoma often causes marked virilization and severe hypo-kalemic metabolic alkalosis.

If there is an adrenal source of glucocorticoids, plasma ACTH levels should be suppressed below the normal range. A normal or moderately raised level suggests pituitary dis-ease. High levels suggest ectopic disease.

The high-dose dexamethasone suppression test is per-formed by administering dexamethasone 2 mg every 6 hours for 2 days. Cortisol levels are measured at 9 am on day 1 and day 3. Reduction of cortisol to less than 50% of the day 1 level is defined as suppression. Pituitary-dependent Cushing disease should respond in this way, whereas ectopic ACTH production should not.

IMAGINGCT or MRI of the adrenals or the pituitary, depending on the clinical suspicion, should be performed. If ectopic ACTH is diagnosed, a bronchial neoplasm should be aggres-sively ruled out.

TREATMENTIf the cause is exogenous steroid use, efforts should be made to withdraw the medication dose carefully and slowly if the patient is able and the clinical condition being treated allows. Steroid-sparing agents may help.

Endogenous Cushing syndrome is best treated by surgi-cal excision. In patients who are not deemed surgical can-didates, or in those with recurrent disease after resection, radiation is an alternative therapy. If there is adrenal over-activity without tumor localization or ectopic ACTH activity, symptoms may be relieved by suppressing the adrenal gland with medications such as metyrapone, aminoglutethimide, or mitotane.

PHEOCHROMOCYTOMA

Pheochromocytoma is a secretory tumor of neurochromaf-fin cells in the adrenal medulla. It is a rare condition respon-sible for less than 0.2% of all hypertensive cases. Symptoms result from catecholamine hypersecretion.

Patients classically present with the triad of episodic headache, sweating, and tachycardia; most have at least two of these symptoms. Pallor, paroxysmal hypotension, orthostatic hypotension, visual blurring, papilledema, high erythrocyte sedimentation rate, weight loss, polyuria, polydipsia, psychiatric disorders, hyperglycemia, dilated cardiomyopathy, and, rarely, secondary erythrocytosis are


less common clinical features. About one half of patients have paroxysms of hypertension, whereas most of the remainder have apparent essential hypertension. Many have no symptoms and are detected serendipitously with abdominal radiology, at surgery, or at postmortem examination.

When referring to these tumors, the “10% rule” is often cited, and is still clinically useful: approximately 10% of cases are extraadrenal, 10% are malignant, 10% are bilat-eral, and 10% are associated with familial syndromes. There are two main familial syndromes associated with pheochromocytoma:

1. In patients with von Hippel-Lindau syndrome, pheochro-mocytoma occurs in 10% to 20% of cases.

2. Multiple endocrine neoplasia syndrome type 2 is associ-ated with medullary thyroid carcinoma and hyperpara-thyroidism. Pheochromocytoma occurs in 20% to 50% of affected individuals.

Pheochromocytoma is found in less than 5% of patients with neurofibromatosis type 1. Genetic screening is recommended in patients younger than 21 years of age, with extraadrenal or bilateral disease, or multiple paragangliomas.

DIAGNOSISA classic history of the typical triad of symptoms or a family history may suggest the diagnosis. The screening tests used are measurements of urinary and plasma catecholamines or their metabolites.

Urinary, Plasma, and Platelet Catecholamine Levels

A study based on prospective data from 152 consecutive patients with pheochromocytoma compared the relative diagnostic sensitivities of the various catecholamine and catecholamine metabolite levels. It showed that the most sensitive tests were urinary normetanephrine and plate-let norepinephrine levels, with sensitivities of 96.9% and 93.8%, respectively. For patients in whom a pheochromo-cytoma is clinically suspected but cannot be confirmed by urinary, plasma, or platelet catecholamine levels, a 131I-labeled metaiodobenzylguanidine (MIBG) radioiso-tope scan may be performed. MIBG is an analogue of epinephrine. It improves the sensitivity of platelet epi-nephrine to 100%. When combined with an MIBG plasma norepinephrine assay, it has a sensitivity of 97.1% in pre-dicting the presence of pheochromocytoma. The likely reason for the increased sensitivity of platelet epinephrine is that the neurosecretory granules in the platelets concen-trate the catecholamines that are intermittently secreted by the pheochromocytoma. Measurement of platelet epi-nephrine should be part of the standard screening for pheochromocytoma.

Clonidine Suppression Test

The clonidine suppression test is an alternative method for confirming a diagnosis when catecholamine levels are suggestive but not diagnostic of pheochromocytoma. Cloni-dine is administered after all antihypertensives have been withheld for at least 12 hours; plasma catecholamines are measured 3 hours later and should fall to less than 500 pg/mL in normal individuals. This test is 90% sensitive for pheochromocytoma.


Imaging

Imaging should be performed after biochemical confir-mation of the diagnosis using the assays already described. Ninety-five percent of pheochromocytomas are intraabdom-inal, with 90% located in the adrenal glands. CT or MRI is the initial modality of choice (Fig. 67.6); both are up to 98% sensitive but only about 70% specific because of the high prevalence of nonfunctional adrenal adenomas, particularly with increasing age.

If CT or MRI imaging is negative despite positive screen-ing assays, the diagnosis should be reconsidered. If pheo-chromocytoma is still strongly suspected, an MIBG or total-body MRI should be performed. In addition to the role previously described, MIBG scans can be used to detect pheochromocytomas when the result of CT or MRI is nega-tive or extraadrenal or metastatic disease is suspected. Positron emission tomographic (PET) scanning may have a future role in detecting metastatic disease.

TREATMENTThe definitive treatment for a pheochromocytoma is surgi-cal excision, but medical treatment to control the effects of catecholamine excess is crucial preoperatively. There are several accepted approaches. The most widely used is admin-istration of the α-blocker phenoxybenzamine, starting at a dose of 10 mg once daily and increasing the dose every few days until blood pressure and symptoms are controlled. A β-blocker may then be added to control tachycardia. Using this approach, a patient should be ready for surgery in 10 to 14 days.

A β-blocker should never be administered first, as the subsequent unopposed α-agonist vasoconstrictive action can markedly worsen hypertension. A hypertensive crisis pre-cipitated by β-blockade may be a clue to the presence of a pheochromocytoma in a patient with hypertension.

Surgery for pheochromocytoma has a perioperative mortality rate of 2.4% and a morbidity rate of 24%. Associ-ated metastases should be resected if possible, and skeletal lesions irradiated. Chemotherapy may be used in selected patients.

Figure 67.6 Computed tomography shows a pheochromocyto-ma arising from the left adrenal gland (arrow). (Courtesy Professor Mick Lee, Beaumont Hospital, Dublin, Ireland.)

PROGNOSISLong-term follow-up is indicated in all patients because of the high incidence of recurrent hypertension, even with complete tumor removal. The tumor recurs in about 10% of patients. Recurrences are more common in familial cases, and a significant proportion of recurrences are malignant.

CARDIOVASCULAR AND CARDIOPULMONARY CAUSES OF SECONDARY HYPERTENSION

COARCTATION OF THE AORTA

Coarctation is a congenital narrowing of the aortic lumen occurring most commonly just distal to the origin of the left subclavian artery. Clinically, patients have hypertension when blood pressure is measured in the upper limbs, with reduced or unmeasurable blood pressure in the legs. If the coarctation is proximal to the origin of the left subclavian artery, the blood pressure and brachial pulsation in the left upper limb may be reduced. The femoral pulses may be delayed or diminished compared with the radial or brachial pulses, and there may be an audible bruit over the patient’s back. Diagnosis is confirmed with aortic imaging, and treat-ment is surgical.

SLEEP APNEA SYNDROME

The association of obesity, obstructive sleep apnea, and hypertension has long been recognized. Owing to a combi-nation of factors inherent to sleep apnea, including apnea, hypoxia, hypercapnia, and arousal from sleep, activation of the sympathetic nervous system leads to hypertension. Many cases of obstructive sleep apnea go undiagnosed unless the physician is alert to the possibility. In most studies of patients with sleep apnea and hypertension, daytime and nighttime levels of blood pressure improved significantly after treat-ment with continuous positive airway pressure (CPAP) or related modalities.

INHERITED CAUSES OF SECONDARY HYPERTENSION

Several monogenetic disorders are associated with hyper-tension. Although all are probably significantly underdiag-nosed, each is rare. They are all associated with upregulation of sodium reabsorption in the distal nephron with accompa-nying expansion of extracellular volume. The PRA is uni-formly suppressed. These conditions may be divided into primary disorders of the distal nephron and primary adre-nal disorders. They are summarized in Table 67.4.

DISTAL NEPHRON DISORDERS

LIDDLE SYNDROMEIn 1963, Liddle and colleagues described a familial syn-drome of severe hypertension, hypokalemia, and metabolic alkalosis mimicking hyperaldosteronism. This disorder affects the handling of sodium in the distal nephron. Reab-sorption of sodium in the collecting duct depends on the


Table 67.4 Inherited Causes of Hypertension

Inherited Disorder Mode of Transmission Chromosome Defective Protein OMIM Number

Liddle Syndrome Autosomal dominant 16p12.2 β and γ subunits of ENaC 177200Gordon Syndrome Autosomal dominant 17q21.31 WNK 4 601844

Autosomal dominant 12p13.33 WNK 1 605232Syndrome of AME Autosomal recessive 16q22.1 11β-hydroxysteroid

dehydrogenase type II614232

Autosomal Dominant Early Onset Hypertension Exacerbated by Pregnancy

Autosomal dominant 4q31.23 Mineralocorticoid receptor S810L

605115

Glucocorticoid Remediable Hyperaldosteronism

Autosomal dominant 8q24.3 11β-hydroxylase:fusion of CYP11B2

CYP11B1

103900

Familial Hyperaldosteronism Type 2 Autosomal dominant 17p22 Unknown 605635Congenital Adrenal Hyperplasia Autosomal recessive 8q24.3 11β-hydroxylase 610613

Autosomal recessive 10q24.32 17α-hydroxylase 202110

AME, Apparent mineralocorticoid excess; ENaC, epithelial sodium channel; OMIM; Online Mendelian Inheritance in Man. www.ncbi.nlm.nih.gov/omim.

activity of the amiloride-sensitive epithelial sodium chan-nel (ENaC). The activity of ENaC is based on recycling of the channel between the apical membrane and subapical vesicles. Mutations in the genes coding for either the beta or gamma subunits of ENaC result in deletion of the bind-ing site necessary for degradation or recycling, leading to an increased number of functional sodium transport channels.

Hypertension usually begins in childhood but may not be diagnosed until early adulthood. Hypokalemia and alkalosis occur as the electronegativity of the collecting duct lumen is increased by excess sodium reabsorption. This favors potas-sium and hydrogen ion excretion, although the actual pres-ence of metabolic alkalosis and hypokalemia is variable. PRA and PAC are suppressed. Treatment involves a low-salt diet and an agent that directly inhibits ENaC, such as amiloride or triamterene. Mineralocorticoid receptor antagonists do not have an effect since the defective sodium transport is independent of aldosterone.

GORDON SYNDROME: TYPE 2 PSEUDOHYPOALDOSTERONISMGordon and colleagues first described this syndrome of hypertension and hyperkalemia in 1970. It has since been characterized as an autosomal dominant disorder caused by mutations in two members of the WNK family of serine-threonine kinases, a group of enzymes involved in regulat-ing the activity of the thiazide-sensitive NaCl cotransporter (NCCT) in the distal convoluted tubule. WNK4 phosphory-lates NCCT, preventing incorporation of the transporter into the apical membrane. Missense mutations in the WNK4 gene (chromosome 17) produce mutant proteins that allow increased NCCT expression, a lesion complementary to the deficiency of NCCT expression in Gitelman syndrome. WNK1 is predominantly a cytoplasmic protein that inhib-its WNK4 function. Mutations in the WNK1 gene (chromo-some 12) that increase WNK1 production lead to excess WNK4 inhibition and to increased NCCT expression. Both WNK kinase mutations cause overactivity of the NCCT, with resultant excess salt reabsorption. This causes volume-dependent hypertension and suppression of the RAAS.

Augmented absorption at this site reduces collecting duct sodium delivery to the ENaC channel, leading to a reduc-tion in lumen electronegativity with consequent potassium and acid retention, and thus development of a hyperkale-mic metabolic acidosis. The hyperkalemia may be exac-erbated by the fact that the same mutation in WNK4 that releases NCCT from suppression has an inhibitory effect on the secretory renal outer medullary potassium channels (ROMK). The PRA value is low. Aldosterone levels vary, and may be increased by hyperkalemia, although not enough to correct it. The metabolic abnormalities tend to precede the onset of hypertension, which often does not manifest until adult life. Spitzer-Weinstein syndrome, which consists of hyperkalemia, metabolic acidosis, and growth failure but not hypertension, is thought to be an early manifestation of Gordon syndrome. Treatment typically involves a com-bination of dietary salt restriction with a low-dose thiazide or loop diuretics, and is usually very effective. WNK kinases and their targets may offer novel targets for future antihy-pertensive agents.

SYNDROME OF APPARENT MINERALOCORTICOID EXCESSApparent mineralocorticoid excess (AME) is a rare autoso-mal recessive disorder in which the enzyme 11β-hyroxysteroid dehydrogenase type 2 (11HD2) is inactive. In aldosterone-sensitive tissues, this enzyme usually converts cortisol to inac-tive cortisone and prevents its mineralocorticoid effect. In AME, cortisol acts on the mineralocorticoid receptor, caus-ing apparent hyperaldosteronism despite suppressed aldo-sterone levels. Because of the lack of 11HD2, the conversion of cortisol to cortisone is impaired, resulting in an abnor-mal ratio of cortisol metabolites (i.e., tetrahydrocortisol and allotetrahydrocortisol) to cortisone metabolites (e.g., tetra-hydrocortisone) in the urine. The disease was thought to be invariably present from childhood, with patients presenting with low birth weight, failure to thrive, hypokalemia, and metabolic alkalosis. It has been associated with end-organ damage and a high mortality rate if untreated. However, milder phenotypes with only partial inactivation of 11HD2

http://www.ncbi.nlm.nih.gov/omim

http://www.ncbi.nlm.nih.gov/omim


have been described. Mineralocorticoid receptor blockers, potassium supplementation, and dietary sodium restriction are the mainstays of treatment. A mild acquired variant may be encountered in patients with excessive licorice intake. The principal metabolite of licorice, glycyrrhizic acid, inhib-its 11HD2 causing a weak mineralocorticoid effect. Carben-oxolone, a licorice derivative previously used for treatment of peptic ulcers was also associated with hypertension.

AUTOSOMAL DOMINANT EARLY ONSET HYPERTENSION EXACERBATED BY PREGNANCYAutosomal Dominant Early Onset Hypertension Exac-erbated by Pregnancy is a recently described rare genetic condition in which an activating mutation of the miner-alocorticoid receptor renders it especially sensitive to non-mineralocorticoid steroids such as progesterone. Since progesterone levels increase 100-fold during pregnancy, this condition typically is detected in pregnant women, although affected individuals are often hypertensive before concep-tion and males can also be affected. The mineralocorticoid receptor in these patients can also be activated by spirono-lactone, and this agent is contraindicated in this condition.

ADRENAL DISORDERS

GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM: FAMILIAL HYPERALDOSTERONISM TYPE 1Glucocorticoid-remediable aldosteronism is a rare sub-type of primary hyperaldosteronism in which the hyperal-dosteronism can be reversed with steroid administration. Glucocorticoid-remediable aldosteronism is inherited as an autosomal dominant trait and should be suspected in patients with onset of hypertension before the age of 21 years along with a family history of early hypertension or intracerebral hemorrhage. Individuals are otherwise phe-notypically normal. The plasma potassium concentration may be low, but is often normal. One clue indicating this condition is severe hypokalemia after administration of a thiazide diuretic, which is due to increased sodium delivery to the aldosterone-sensitive potassium-secretory site in the cortical collecting tubule. As many as 18% of patients suffer a cerebrovascular complication, mainly hemorrhage from ruptured berry aneurysms. The incidence of aneurysm is similar to that among patients with autosomal dominant polycystic kidney disease. Surveillance MRA has been rec-ommended, but the benefit of this approach has not been proved. Mean age of onset of cerebral hemorrhage if an aneurysm is present is 32 years.

In the adrenal cortex, aldosterone is normally synthe-sized in the zona glomerulosa, whereas glucocorticoids are predominantly synthesized in the adjacent zona fasciculata. Two isozymes of 11β-hydroxylase, encoded by chromosome 8, are responsible for the synthesis of aldosterone and corti-sol. The isozyme in the zona glomerulosa (aldosterone syn-thase or CYP11B2) mediates aldosterone production under the influence of potassium and angiotensin II, whereas the isozyme in the zona fasciculata (CYP11B1) induces cortisol production under the influence of ACTH. In glucocorti-coid-remediable aldosteronism, the promoter region for CYP11B1 fuses with the coding sequences of the aldosterone synthase enzyme, CYP11B2, resulting in ACTH-dependent aldosterone synthesis in the zona fasciculata.

The diagnosis is made by dexamethasone suppression test-ing demonstrating the production of 18-carbon oxidation products of cortisol. However, a genetic test demonstrating the pathologic chimeric gene is recommended since there is a significant false-positive rate for patients with primary hyperaldosteronism when tested with dexamethasone.

Corticosteroids suppress ACTH and lower the blood pressure to normal. The target dose should be enough to suppress aldosterone levels sufficiently without causing debilitating side effects.

FAMILIAL HYPERALDOSTERONISM TYPE IIIn familial hyperaldosteronism type II, excess mineralo-corticoid production is responsible for hypertension, but it is not suppressible by dexamethasone. Autosomal dominance suggests a single gene mutation, and the locus has been narrowed to a band on chromosome 7. Familial hyperaldosteronism type II is clinically and biochemically indistinguishable from sporadic primary hyperaldoste-ronism, and can be detected only by a positive family history.

CONGENITAL ADRENAL HYPERPLASIACongenital adrenal hyperplasia is an autosomal recessive dis-order that results in an inability to synthesize cortisol. In this condition, defects in the final steps of steroid biosynthesis cause excess mineralocorticoid and androgen effects, with coincident signs of glucocorticoid deficiency. The most com-mon forms, 17α-hydroxylase deficiency and 11β-hydroxylase deficiency, may induce hypertension through overproduc-tion of cortisol precursors that are metabolized to mineralo-corticoid agonists.

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Hipertension Secundaria

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Transcript of Hipertension Secundaria