Hipertension Secundaria

1. 601
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.
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.
DIAGNOSIS
Several 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.
Secondary Hypertension
Rory F. McQuillan | Peter J. Conlon
67

2. 602 SECTION 12 — HYPERTENSION
SCREENING TESTS
The 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
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
technologymayallowforvascularimagingwithoutgadolinium.
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
Kidney Causes
Renovascular hypertension
Renal parenchymal hypertension
Endocrine Causes
Primary hyperaldosteronism
Cushing syndrome
Pheochromocytoma
Renin secreting tumor
Hypothyroidism or hyperthyroidism
Acromegaly
Hyperparathyroidism
Cardiovascular or Cardiopulmonary Causes
Coarctation of the aorta
Obstructive sleep apnea
Drugs
Glucocorticoids
Nonsteroidal antiinflammatory drugs
HAART
Combined oral contraceptive pills
VEGF inhibitors, e.g., Bevacizumab, Sunitinib
Venlafaxine
Calcineurin inhibitors
Phenylephrine
Caffeine
Excess alcohol
Erythrocyte stimulating agents
Licorice
Inherited Causes
Glucocorticoid-remediable aldosteronism
SAME
Gordon 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
Abrupt onset of or accelerated hypertension at any age
Episodes of flash pulmonary edema with normal ventricular
function
Acute, unexplained rise in the serum creatinine level after use
of an angiotensin-converting enzyme inhibitor or ARB
Elevated serum creatinine level in patients with severe or
refractory hypertension
Asymmetric kidney size
ARB, Angiotensin receptor blocker.
Box 67.3 Clinical Clues to the Presence
of Renovascular Disease
Young age at onset (less than 30 yr)
Sudden onset of hypertension
Uncontrolled or refractory hypertension
Malignant hypertension
Features of a recognized underlying cause
Box 67.1 Clues to the Presence of
Secondary Hypertension

3. 603CHAPTER 67 — SECONDARY HYPERTENSION
CONFIRMATORY TESTS
Conventional 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%.
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.
TREATMENT
All 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
Table 67.1 Investigations to Evaluate Renal Artery Stenosis
Advantages Disadvantages
Duplex Ultrasound Noninvasive
No radiation
Highly sensitive/specific if operator has appropriate
expertise
Resistive index may predict response to
revascularization
Highly operator dependent
Utility of resistive index not universally accepted
MRA Noninvasive
Not nephrotoxic
Gadolinium a risk for NSF in patients with
GFR 30 mL/min
Questionable accuracy
CTA Noninvasive Nephrotoxicity
Sensitivity reduced in advanced CKD
Captopril Renography Noninvasive
Theoretically provides information about functional
effect of stenosis
Poor predictive value for degree of stenosis
Intraarterial Angiography Most accurate determination of stenosis
Allows for measurement of transstenotic gradient
Invasive
Nephrotoxicity
Damage to femoral and renal arteries and other
mechanical complications
Cholesterol 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.
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.)
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.)

4. 604 SECTION 12 — HYPERTENSION
given the high burden of cardiovascular disease. Figure 67.3
presents a management algorithm for renovascular disease.
Hypertensive patients with FMD should initially be
treated with an ACE inhibitor or ARB. If they remain
hypertensive, the treatment of choice is revascularization
with percutaneous transluminal renal angioplasty (PTRA).
PTRA in patients with FMD is almost always technically suc-
cessful with a low restenosis rate, minimal risk, and usually
an improvement, though not complete “cure,” of the associ-
ated hypertension. There is sparse literature addressing the
use of stenting in this disease, presumably because of the
high rate of prolonged success with angioplasty alone. Stent-
ing is an option in cases of restenosis, although in view of the
young age of many of these patients, surgical revasculariza-
tion should also be considered.
Revascularization for ARAS is not as straightforward.
Although intuitively attractive, restoration of blood flow to the
kidneys in unselected patients has had disappointing results.
Several randomized controlled trials (Table 67.2) have com-
pared angioplasty with and without stenting to medical man-
agement alone. None have demonstrated any benefit in terms
of blood pressure control, kidney function, or cardiovascular
events with intervention compared to medical management.
Revascularization may cause serious adverse events. There
are several important limitations to these trials. First, patients
included were, by and large, clinically stable: The Angioplasty
and Stent Therapy for Renal Artery Lesion (ASTRAL) trial,
the largest to date, used physician uncertainty as its key inclu-
sion criterion leading to the recruitment and randomization
to intervention of patients with nonsignificant degrees of ste-
nosis that might be less likely to benefit from revasculariza-
tion. The STent placement for Atherosclerotic Renal-artery
stenosis (STAR) trial was similarly compromised. These
results must therefore not be extrapolated to patients with
ARAS 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
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.
Hypertension
Suspicion of renal artery stenosis
Medical management
(ACE/ARB+/-ASA and Statin)
Follow up
Controlled BP
Stable kidney function
Uncontrolled BP
AKI with ACE
Rapidly declining kidney function
Flash pulmonary edema
Noninvasive screening for RAS
Angiogram with transstenotic gradient
+/- Angioplasty with stenting
RAS
Candidate for revascularization?
No RASMedical management
Follow up

5. 605CHAPTER67—SECONDARYHYPERTENSION
Table 67.2 Prospective Randomized Control Trials Comparing Percutaneous Transluminal Angioplasty to Medical Management
in Renal Artery Stenosis
Trial
Number of
Patients
Year of
Publication Inclusion Criteria
Primary
Outcome
Treatment in
Revascularization
Group
Treatment in
Comparison
Group Outcome Limitations
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 difference in pri-
mary outcome, BP,
or cardiovascular
events
Enrollment bias
Not standardized imaging
(42% of patients less
than 70% stenosis)
6% crossover
STAR 140 2009 RAS greater than 50%
GFR 15 to 80 mL/min
Stable BP
Decrease in
GFR ≥20%
Medication plus
PTA with stent
Antihypertensive
medication
No significant differ-
ence in primary
outcome or BP
Included patients with
minor disease
28% of treatment group
did not receive stent
due to trivial nature of
stenosis
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 difference in BP or
creatinine
Reduction in defined
daily doses of anti-
hypertensive drugs
44% crossover
No stents
Short follow-up
Inadequate BP control in
both groups
EMMA 49 1998 Unilateral RAS ≥75% or
≥60% plus a positive
renography
24 hr ambula-
tory BP
PTA (2 patients
received a
stent)
Antihypertensive
medication
No difference in BP or
creatinine clearance
reduction in defined
daily doses of anti-
hypertensive drugs
27% crossover
Few stents
Short follow-up
RAAS blockade avoided
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 significant differ-
ence in cardiovas-
cular events, BP, or
GFR
No stents
Short follow-up
Inadequate BP control in
both groups
Excluded patients on
ACE inhibitors
ACE, Angiotensin converting enzyme; ASTRAL, the Angioplasty and Stent Therapy for Renal Artery Lesion; BP, blood pressure; DRASTIC, Dutch Renal Artery Stenosis Intervention Cooperative
study group; EMMA, Essai Multicentrique Medicaments vs. Angioplastie; GFR, glomerular filtration rate; PTA, percutaneous transluminal angioplasty; RAAS, renin-angiotensin aldosterone
system; RAS, renal artery stenosis; STAR, STent placement for Atherosclerotic Renal-artery stenosis.

6. 606 SECTION 12 — HYPERTENSION
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
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 SYNDROME
Conn 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.
DIAGNOSIS
Although 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 TESTS
Measurement 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 67.4 A stent can be seen in the ostium of the left renal ar-
tery. (Courtesy Professor Mick Lee, Beaumont Hospital, Dublin, Ireland.)

7. 607CHAPTER 67 — SECONDARY HYPERTENSION
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 TESTS
The 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.
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
Table 67.3 Commonly Used Antihypertensive
Agents Affecting the Plasma
Aldosterone Concentration to Plasma
Renin Activity Ratio
PAC PRA PAC:PRA
Clinical
Consequence
ACE inhibitor ↓ ↑ ↓ False negative
ARB ↓ ↑ ↓ False negative
β Blockers ↓ ↓↓ ↑ False positive
Central
α-blockers
↓ ↓↓ ↑ False positive
Diuretics ↑ ↑↑ ↓ False negative
Dihydropyridine
Ca Channel
Blockers
↓ ↑ ↓ False negative
ACE, Angiotensin converting enzyme; ARB, angiotensin receptor
blocker; Ca, calcium; PAC, plasma aldosterone concentration;
PRA, plasma renin activity.

8. 608 SECTION 12 — HYPERTENSION
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.
IMAGING
The 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.
TREATMENT
Patients 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.
DIAGNOSIS
The 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 administration
Endogenous glucocorticoid excess
ACTH excess
Ectopic production
Pituitary secretory adenoma (Cushing disease)
Cortisol excess
ACTH, Adrenocorticotropic hormone.
Box 67.4 Causes of Cushing Syndrome

9. 609CHAPTER 67 — SECONDARY HYPERTENSION
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.
IMAGING
CT 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.
TREATMENT
If 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.
DIAGNOSIS
A 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.

10. 610 SECTION 12 — HYPERTENSION
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.
TREATMENT
The 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.
PROGNOSIS
Long-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 SYNDROME
In 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
Figure 67.6 Computed tomography shows a pheochromocyto-
ma arising from the left adrenal gland (arrow). (Courtesy Professor
Mick Lee, Beaumont Hospital, Dublin, Ireland.)

11. 611CHAPTER 67 — SECONDARY HYPERTENSION
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
PSEUDOHYPOALDOSTERONISM
Gordon 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
EXCESS
Apparent 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
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 177200
Gordon Syndrome Autosomal dominant 17q21.31 WNK 4 601844
Autosomal dominant 12p13.33 WNK 1 605232
Syndrome of AME Autosomal recessive 16q22.1 11β-hydroxysteroid
dehydrogenase type II
614232
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 605635
Congenital 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.

12. 612 SECTION 12 — HYPERTENSION
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 PREGNANCY
Autosomal 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 1
Glucocorticoid-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 II
In 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 HYPERPLASIA
Congenital 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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