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Symptom to Diagnosis: An Evidence-Based Guide, 3e >

23: Hypertension
Figure 23-1.

CHIEF COMPLAINT

PATIENT

Mr. U is a 48-year-old man with a BP of 165/90 mm Hg.

What is the di erential diagnosis of hypertension? How would you frame the di erential?

CONSTRUCTING A DIFFERENTIAL DIAGNOSIS

First, what is normal BP, and when is a patient hypertensive? The first step is accurately measuring the BP.
Table 23-1 summarizes guidelines for obtaining valid BP measurements.

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Table 23-1.
Guidelines for measuring BP.

• The patient should sit for several minutes in a quiet room before BP measurements are taken. Pain, stress,
a full urinary bladder, a recent meal, and talking or active listening during measurement a ect BP. Having
smoked a cigarette within 15–20 minutes can elevate the BP by 5–20 mm Hg.

• Take at least 2 measurements spaced by 1–2 minutes and additional measurements if the first 2 are quite
di erent.

• Using a bladder that is too narrow yields false high readings. Instead of the standard cu (12–13 cm long,
35 cm wide) use an appropriate larger cu in patients with increased arm circumference.

• Use phase I (first tapping sound) and V (disappearance) Korotko sounds to identify systolic and diastolic
BP values, respectively.

• Do not deflate the cu too rapidly, otherwise individual Korotko sounds are missed and too low a value is
measured; start with a deflation rate of 2 mm/s.

• Measure the heart rate by palpation and watch out for arrhythmia, which mandates repeated BP
measurements.

• At the first visit, measure BP in both arms and take the higher value as the reference; measure BP at 1
minute and 5 minutes a er standing upright if the patient has a disorder that frequently causes orthostatic
hypotension.

Adapted, with permission, from Messerli FH, Williams B, Ritz E. Essential hypertension. Lancet. 2007;370:591–603.

Consensus guidelines classify BP as follows, based on the mean of 2 seated BP measurements on each of 2
or more o ice visits:

A. Optimal: systolic BP (SBP) < 120 mm Hg and diastolic BP (DBP) < 80 mm Hg

B. Normal: SBP 120–129 mm Hg and DBP 80–84 mm Hg

C. High normal: SBP 130–139 mm Hg or DBP 85–89 mm Hg

D. Grade 1 hypertension: SBP 140–159 mm Hg or DBP 90–99 mm Hg

E. Grade 2 hypertension: SBP 160–179 mm Hg or DBP 100–109 mm Hg

F. Grade 3 hypertension: SBP ≥ 180 mm Hg or DBP≥ 110 mm Hg

G. Isolated systolic hypertension: SBP ≥ 140 mm Hg and DBP < 90 mm Hg

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Hypertension is either primary (essential) or secondary (resulting from a specific identifiable cause).
Causes of secondary hypertension can be organized using an organ/system framework:

A. Primary (essential) hypertension

B. Secondary hypertension

1. Endocrine

a. Primary aldosteronism

b. Pheochromocytoma

c. Thyroid disease

d. Hyperparathyroidism

e. Cushing syndrome

2. Renal

a. Chronic kidney disease (CKD)

b. Acute kidney injury

3. Vascular

a. Renovascular disease

b. Coarctation of the aorta

4. Pulmonary: sleep apnea

5. GI: obesity

6. Drug-induced or drug-related

a. Prolonged corticosteroid therapy

b. Nonselective nonsteroidal antiinflammatory drugs (NSAIDs)

c. Cyclooxygenase (COX)-2 inhibitors

d. Cocaine

e. Alcohol

f. Sympathomimetics (decongestants, anorectics)

g. Oral contraceptives

h. Cyclosporine and tacrolimus

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i. Erythropoietin

j. Stimulants (modafinil, amphetamines)

Mr. U’s BP is high. He has wanted to avoid taking medication and has been trying to watch his diet and lose
weight. Both of his parents and several of his siblings have hypertension. His medical history is notable
only for smoking 1 pack/day for 30 years; he does not use alcohol and takes no medications.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a
must not miss diagnosis? Given this di erential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

Ninety-five to 99% of patients with hypertension have essential hypertension. A family history of
hypertension increases the pretest probability of essential hypertension and is a pivotal clue in Mr. U’s
history. Patients between the ages of 20 and 50 have about twice the risk of developing hypertension if they
have 1 first-degree relative with hypertension; the relative risk is 3–4 if 2 first-degree relatives have
hypertension. Common conditions that can contribute to or cause hypertension include obesity,
hyperthyroidism or hypothyroidism, acute kidney injury or CKD, excessive alcohol use, sleep apnea, and
the use of drugs listed previously. Other secondary causes are quite rare in unselected populations, with
estimated prevalences of 0.18–4.4% for renovascular hypertension, 0.04–0.2% for pheochromocytoma,
0.01–0.4% for primary hyperaldosteronism, and 0.3% for Cushing syndrome. These conditions are more
prevalent in populations of patients with resistant hypertension. Table 23-2 lists the di erential diagnosis.

Mr. U’s review of symptoms is negative for chest pain, shortness of breath, claudication, headache,
dizziness, palpitations, weight change, constipation, daytime sleepiness, and snoring. On physical exam,
BP is 165/90 mm Hg in both arms; pulse, 84 bpm; RR, 16 breaths per minute. He weighs 220 pounds, with a
body mass index (BMI) of 30 kg/m2. Fundoscopic exam shows some arteriolar narrowing with no
hemorrhages or exudates. Jugular venous pressure is normal. Lungs are clear, and cardiac exam shows an
S4 but no S3 or murmurs. There are no abdominal bruits; carotid, radial, femoral, posterior tibialis, and
dorsalis pedis pulses are normal. There is no peripheral edema. Neurologic exam is normal.

Is the clinical information su icient to make a diagnosis? If not, what other information do you
need?

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Table 23-2.
Diagnostic hypotheses for Mr. U.

Diagnostic
Demographics, Risk Factors, Symptoms and Signs Important Tests
Hypotheses

Leading Hypothesis

Essential Family history HgbA1C

hypertension Obesity
Coexistent diabetes

Active Alternatives—Most Common

Chronic kidney O en none Serum creatinine

disease Sometimes edema, malaise Estimated GFR
Urinalysis

Sleep apnea Obesity Polysomnogram

Neck circumference > 17 in Frequent snoring
Daytime somnolence
Witnessed apnea

Thyroid disease Hyperthyroidism: TSH

Weight loss
Loose stools
Palpitations
Sweating

Hypothyroidism:
Weight gain
Constipation
Fatigue

Alcohol Alcohol history Alcohol history

CAGE questionnaire

Drug/medication use Medication/drug history Medication/drug

history

Other Hypotheses

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Diagnostic
Demographics, Risk Factors, Symptoms and Signs Important Tests
Hypotheses

Renal artery stenosis Abrupt onset or accelerated hypertension Duplex

Azotemia a er use of ACE inhibitor ultrasonography
Hypertension refractory to ≥ 3 medications MRA with gadolinium

Abdominal or flank bruit CT angiography

Other vascular disease (coronary, carotid, or
peripheral)
Smoking
Severe retinopathy

Hyperaldosteronism Resistant hypertension Aldosterone/renin ratio

Hypokalemia

Pheochromocytoma Labile BP/paroxysmal hypertension Plasma metanephrine

Headache
Sweating
Orthostasis
Tachycardia

ACE, angiotensin-converting enzyme; GFR, glomerular filtration rate; MRA, magnetic resonance angiography; TSH,
thyroid-stimulating hormone.

Leading Hypothesis: Essential Hypertension

Textbook Presentation

Essential hypertension generally presents as the gradual onset of elevated BP, most o en in middle-aged
people with positive family histories. Coexisting diabetes or obesity is common.

Disease Highlights

A. Patients who are normotensive at age 55 have a 90% lifetime risk of developing hypertension.

B. Across the BP range of 115/75 mm Hg to 185/115 mm Hg, each increment of 20 mm Hg systolic BP or 10

mm Hg diastolic BP doubles the risk of cardiovascular disease.

Evidence-Based Diagnosis

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The evaluation of patients with hypertension focuses primarily on assessing other cardiovascular risk
factors and assessing the presence or absence of target organ damage (TOD). Extensive testing for
secondary causes is generally not done unless the patient has specific symptoms strongly suggestive of a
specific secondary cause or if BP control cannot be achieved. Therefore, there are 3 objectives of testing in
patients with hypertension:

A. Objective 1: Assess presence or absence of TOD (Table 23-3).

B. Objective 2: Assess presence or absence of other cardiovascular risk factors.

1. Smoking

2. Obesity (BMI > 30 kg/m2)

3. Physical inactivity

4. Dyslipidemia

5. Diabetes

6. Microalbuminuria or estimated glomerular filtration rate (GFR) < 60 mL/min

7. Age (> 55 for men, > 65 for women)

8. Family history of premature cardiovascular disease (men < 55, women < 65)

9. Calculate a global risk score such as the Framingham Risk Score (see Chapter 2, Screening & Health
Maintenance)

C. Objective 3: Identify secondary hypertension.

1. In the absence of any of the clinical clues listed previously, it is unlikely that the patient has renal
artery stenosis, hyperaldosteronism, or pheochromocytoma.

2. Testing should focus on screening for more common causes or contributors to hypertension, such
as kidney or thyroid disease, that are easily diagnosed with simple blood tests.

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Table 23-3.
Assessing target organ damage in patients with hypertension.

Target organ Clinical Manifestations Important Tests

Heart Le ventricular hypertrophy Physical exam

ECG
Echocardiography in selected
patients

Coronary artery disease (angina, myocardial History

infarction) ECG
Stress test in selected patients

Heart failure History

Physical exam
Echocardiography

Brain Stroke, transient ischemic attack History

Physical exam

Kidneys Proteinuria Albumin/creatinine ratio

Chronic kidney disease Serum creatinine, urinalysis

Eyes Retinopathy Fundoscopic or ophthalmologic

exam

Peripheral Peripheral vascular disease History and physical exam

vasculature ABI measurements in selected
patients

ABI, ankle-brachial index; ECG, electrocardiogram.

Initial testing in a patient with hypertension and no clinical clues should include an ECG,
electrolytes, BUN, creatinine, calcium, TSH, urine albumin–creatinine ratio, fasting glucose, and fasting
lipid panel (total cholesterol, high-density lipoprotein [HDL], triglycerides, low-density lipoprotein [LDL]).

Treatment

A. Goal 1: reduce BP to recommended target (2013 European Society of Hypertension guidelines)

1. The SBP goal is < 140 mm Hg in all patients, including those with diabetes and CKD, except

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a. In patients 65–80 years of age, a SBP of 140–150 mm Hg is acceptable; a target of < 140 mm Hg
should be considered in patients with high functional status and the ability to tolerate additional
medication.

b. In patients over 80 years of age, the target SBP is 140–150 mm Hg.

(1) All of the studies of hypertension treatment in the elderly included only patients with SBP ≥
160 mm Hg.

(2) Decisions regarding whether to treat hypertension and target SBP in the elderly should be
adapted based on the patient’s functional status, comorbid conditions, and medication side
e ects.

2. The DBP goal is < 90 mm Hg in all patients except

a. In patients with diabetes, the DBP target is < 85 mm Hg.

b. The American Diabetes Association recommends a DBP target of < 80 mm Hg.

3. Lifestyle changes (Tables 23-4 and 23-5) should be initiated in all patients with any grade of
hypertension, and in patients with high normal BP plus additional cardiovascular risk factors, CKD,
diabetes mellitus, or TOD.

a. Low-risk patients (grade 1 hypertension, no other cardiovascular risk factors, no TOD) should be
given several months to achieve their target BP with lifestyle changes.

b. Moderate-risk patients (grade 1–2 hypertension with < 3 other risk factors) should start taking
medication if goal BP is not achieved a er several weeks of lifestyle changes. Many clinicians
would start medication simultaneously with the initiation of lifestyle changes.

c. High-risk patients (grade 3 hypertension, lower grade hypertension with multiple risk factors,
TOD, CKD stage 3, or diabetes mellitus) should start taking medication simultaneously with the
initiation of lifestyle changes.

4. Selecting antihypertensive medication: general principles

a. Monotherapy is successful in a limited number of patients.

b. Combining 2 agents from any 2 classes reduces BP more than increasing the dose of a single
agent.

(1) Low-risk and many moderate-risk patients can be given 1 medication initially.

(2) Patients with grade 3 hypertension or high cardiovascular risk may be given 2 medications
initially.

c. Current randomized trial evidence does not demonstrate major di erences in clinical
cardiovascular outcomes for di erent antihypertensive classes.

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d. Some patients have specific conditions that guide medication selection.

e. Diuretics (thiazides, chlorthalidone, and indapamide), beta-blockers, dihydropyridine calcium

antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers
(ARBs) can all be used as initial monotherapy in patients with no indications for specific agents;
beta-blockers are possibly somewhat less e ective in preventing cardiovascular outcomes than
the other classes.

f. Preferred 2 drug combinations include diuretics plus dihydropyridine calcium antagonists,

diuretics plus ACE inhibitors or ARBs, and dihydropyridine calcium antagonists plus ACE
inhibitors or ARBs

g. ACE inhibitors and ARBs should not be used together since the combination has been shown to
accelerate CKD.

h. If target BP is not achieved using 1 of the preferred 2 drug combinations, add the class not
already being used (diuretic, ACE inhibitor or ARB, or dihydropyridine calcium antagonist).

i. If target BP is not achieved using the 3 preferred drug classes, the next class added is usually
beta-blockers, followed by spironolactone, direct vasodilators (such as hydralazine), or alpha-
adrenergic blockers.

j. Antihypertensive therapy for patients with specific indications

(1) Le ventricular hypertrophy: ACE inhibitors/ARBs, dihydropyridine calcium antagonists

(2) Heart failure: loop diuretics, ACE inhibitors/ARBs, beta-blockers, spironolactone (see Chapter
15, Dyspnea, for a more detailed discussion of the treatment of heart failure)

(3) Ischemic heart disease

(a) Stable angina: beta-blockers

(b) Acute coronary syndromes: use beta-blockers and ACE inhibitors

(c) Postmyocardial infarction: use beta-blockers, ACE inhibitors or ARBs

(4) Diabetes mellitus: ACE inhibitors/ARBs

(5) CKD or microalbuminuria: ACE inhibitors/ARBs

B. Goal 2: Optimize other cardiovascular risk factors

1. Lipid lowering: The American College of Cardiology/American Heart Association (ACC/AHA) issued
updated cholesterol treatment guidelines in 2013, based on the following findings:

a. Statin therapy has been shown to reduce atherosclerotic cardiovascular disease (ASCVD) events
in both primary and secondary prevention populations.

(1) The relative risk reduction is about the same in all populations.
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(2) However, the number of events avoided per 1000 patients treated is smaller in lower risk
populations (Figure 23-1).

b. There was no randomized controlled trial evidence to support titrating drug therapy to a certain
target LDL or to support the use of non-statin therapy in patients who can tolerate statins.

c. High intensity statins lower LDL by ≥ 50% (Table 23-6).

d. Moderate intensity statins lower LDL by 30–50% (Table 23-6).

e. Low intensity statins lower LDL by < 30%.

2. The guidelines are found in Table 23-7.

3. There are no recommendations for patients with NYHA class II–IV ischemic systolic heart failure or
patients receiving maintenance hemodialysis, since these patients were not included in the clinical
trials; it is possible they would also benefit.

4. All patients should be counseled regarding exercise and diet.

5. Smoking cessation

6. Antiplatelet therapy (aspirin 81 mg daily, or clopidogrel in aspirin-allergic patients) if the

Framingham Risk Score is > 10%

Table 23-4.
E ects of lifestyle changes on BP.

Approximate Reduction in
Intervention
Systolic BP

Weight reduction 5–20 mm Hg/10 kg weight loss

DASH diet (see Table 23-5) 8–14 mm Hg

Reduced sodium diet (< 2.4 g sodium/day) 2–8 mm Hg

Aerobic exercise, 30 minutes/day, several days/week 4–9 mm Hg

Limitation of alcohol consumption to ≤ 2 drinks/day for men and ≤ 1 2–4 mm Hg

drink/day for women

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Table 23-5.
DASH diet.

Food group Number of Servings

Grains/grain products 7–8/day

Vegetables 4–5/day

Fruits 4–5/day

Low-fat dairy products 2–3/day

Meats, poultry, fish 2–3/day

Fats, oils 2–3/day

Sweets 5/week

Nuts, seeds, dried beans 4–5/week

Figure 23-1.
Predicted 5-year benefits of LDL cholesterol reductions with statin treatment at di erent levels of risk. (A)
Major vascular events, and (B) vascular deaths. Lifetable estimates using major vascular event risk or
vascular death risk in the respective risk categories and overall treatment e ects per 1.0 mmol/L reduction
in LDL cholesterol with statin (1 mmol/L = 38 mg/dL). Reproduced, with permission from Cholesterol
Treatment Trialists’ (CTT) Collaborators, Mihaylova B, Emberson J, Blackwell L et al. The e ects of lowering
LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual
data from 27 randomised trials. Lancet. 2012 Aug 11;380(9841):581–90.

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Table 23-6.
Intensity of statin therapy.

High Intensity Moderate Intensity Low Intensity

Atorvastatin 40–80 mg Atorvastatin 10–20 mg Simvastatin 10 mg

Rosuvastatin 20 mg Rosuvastatin 5–10 mg Pravastatin 10–20 mg
Simvastatin 20–40 mg Lovastatin 20 mg
Pravastatin 40–80 mg
Lovastatin 40 mg

Table 23-7.
2013 ACC/AHA guidelines for treatment of high cholesterol.

Clinical Group Treatment Recommendation

Patients with clinical ASCVD Age ≤ 75: high intensity statin

Age > 75: moderate intensity statin

Patients without clinical ASCVD

LDL ≥ 190 mg/dL (aged 20–75) High intensity statin

LDL 70–189 mg/dL (aged 40–79)

With diabetes 10-year ASCVD risk1 < 7.5%: moderate intensity statin
10-year ASCVD risk1 ≥ 7.5%: high intensity statin

Without diabetes 10-year ASCVD risk1 ≥ 7.5%: moderate to high intensity statin

110-year ASCVD risk based on Pooled Cohort Equations assessment (see Chapter 2, Screening & Health Maintenance).

ASCVD, atherosclerotic cardiovascular disease.

MAKING A DIAGNOSIS

Mr. U’s initial test results are as follows:

ECG: Le ventricular hypertrophy by voltage, otherwise normal

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TSH, 1.0 microunit/mL

Urine albumin–creatinine ratio: normal

Na, 145 mEq/L; K, 4.2 mEq/L; Cl, 100 mEq/L; BUN, 11 mg/dL; creatinine, 0.5 mg/dL

Fasting glucose, 90 mg/dL

Fasting lipid panel: total cholesterol, 240 mg/dL; HDL, 40 mg/dL; triglycerides, 100 mg/dL; LDL, 180 mg/dL

Have you crossed a diagnostic threshold for the leading hypothesis, essential hypertension?
Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative
diagnoses?

Based on Mr. U’s history, physical exam, and initial laboratory test results, it is not necessary to do any
further testing for secondary causes of hypertension. He does have other modifiable cardiovascular risk
factors (smoking, obesity, and hypercholesterolemia), and some evidence for TOD (early retinopathy and
le ventricular hypertrophy).

CASE RESOLUTION

Mr. U is counseled regarding smoking cessation and referred to a nutritionist for guidance regarding diet
and exercise programs. He is started on hydrochlorothiazide, 12.5 mg daily, for his hypertension and
atorvastatin, 40 mg daily, for his hypercholesterolemia (Table 23-6). One month later, his BP is 145/85 mm
Hg. He has not yet started to exercise and has not quit smoking. You again counsel him regarding the
importance of these lifestyle modifications and the possibility of avoiding a second medication if he
exercises and loses weight. Six months later, a er changing his diet and faithfully exercising 3 times a week,
he has lost 5 pounds, and his BP is 135/82 mm Hg. He continues to smoke.

CHIEF COMPLAINT

PATIENT

Mrs. X is a 58-year-old woman who comes to see you for a new patient visit. According to records from her
previous doctor, she has a long history of hypertension treated with hydrochlorothiazide (25 mg daily),
lisinopril (40 mg daily), and amlodipine (10 mg daily). Other than her antihypertensive medications, she
takes only pravastatin 10 mg daily. Her BP, when last checked 1 year ago, was 138/88 mm Hg, and her BMI
was 30. She last took her medications 1 month ago. She feels fine, with no headache, chest pain, shortness
of breath, or edema. Her medical history is also notable for smoking 1 pack/day for 40 years, peripheral
vascular disease manifested by stable claudication on walking 6 blocks, and CKD, with a serum creatinine
of 1.7 mg/dL. In your o ice, her BP is 170/98 mm Hg and her BMI is 35. Physical exam is notable for clear
lungs, an S4 without an S3 or murmurs, and decreased posterior tibial and dorsalis pedis pulses. Abdominal
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exam is normal. There is no peripheral edema, and there are no femoral or abdominal bruits. You refill her
medications, order blood tests, and ask her to return in 6 weeks.

When she returns, her BP is 150/92 mm Hg. She reports that she takes all of her medications every day and
that her home BP readings have been similar to those obtained in the o ice. A repeat BP with a larger cu is
the same.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a
must not miss diagnosis? Given this di erential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

Mrs. X’s BP is uncontrolled. She could have resistant hypertension, which is defined as a failure to reach a
BP goal despite the use of 3 optimally dosed antihypertensive medications of di erent classes, ideally
including a diuretic. Alternatively, she could have “pseudoresistance,” meaning that her BP is uncontrolled
due to poor BP measurement technique, poor adherence, white-coat e ect, or an inadequate treatment
regimen. The first steps in assessing patients with uncontrolled BP include repeating the BP measurement
with a properly sized cu (if the cu is too small, the systolic BP can be elevated as much as 15 mm Hg),
reviewing medication adherence, obtaining home BP measurements, and reviewing the medication
regimen itself. Mrs. X is adherent to her medications, is taking optimal doses of 3 medications from di erent
classes including a diuretic, and has consistent BP readings at home and in the o ice. Thus, she meets the
criteria for resistant hypertension.

A er establishing that a patient has resistant hypertension, the next step is to consider the many potential
causes (Table 23-8). Lifestyle factors are common contributors to resistant hypertension. Elderly patients,
African-American patients, and those with CKD tend to be particularly salt sensitive. About 12–14% of
people consuming more than 2 drinks/day are hypertensive. For every 10% increase in body weight,
systolic BP increases by 6.5 mm Hg. Secondary causes of hypertension are more common in patients with
resistant hypertension referred to hypertension specialty clinics, with about 20% having an identifiable
secondary cause.

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Table 23-8.
Causes of resistant hypertension.

Lifestyle factors Dietary salt

Alcohol consumption
Obesity

Drugs/medications NSAIDs
Sympathomimetic agents (decongestants, cocaine)
Stimulants (methylphenidate, modafinil)
Oral contraceptives
Corticosteroids
Erythropoietin
Tricyclic antidepressants

Common secondary causes Primary hyperaldosteronism

Renal artery stenosis
Chronic kidney disease
Obstructive sleep apnea

Rare secondary causes Pheochromocytoma

Cushing disease
Coarctation of aorta
Intracranial tumor
Carcinoid syndrome
Hyperparathyroidism
Hypothyroidism or hyperthyroidism

NSAIDs, nonsteroidal antiinflammatory drugs.

The clinical clues in Mrs. X’s presentation include her vascular risk factors, suggesting she is at risk for renal
artery stenosis. In addition, she does have preexisting CKD, a common cause of resistant hypertension. Her
obesity is a risk factor for obstructive sleep apnea, another common cause. Hyperaldosteronism should be
considered since it is found in 15–20% of patients with resistant hypertension. She has no symptoms to
suggest a rare cause of secondary hypertension, pheochromocytoma (0.1–0.6% of patients). Table 23-9 lists
the di erential diagnosis.

She never adds salt to her food and reads food labels carefully. She does not drink alcohol and is afraid to
use over-the-counter medications. She attributes her weight gain to being somewhat less active due to
symptomatic knee osteoarthritis. A recent polysomnogram was normal. Laboratory tests include the

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following: Na, 140 mEq/L; K, 3.4 mEq/L; Cl, 100 mEq/L; HCO2, 26 mEq/L; BUN, 35 mg/dL; creatinine, 1.8
mg/dL; TSH, 3.2 microunit/mL.

Is the clinical information su icient to make a diagnosis? If not, what other information do you
need?

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Table 23-9.
Diagnostic hypotheses for Mrs. X.

Demographics, Risk Factors, Symptoms and

Diagnostic Hypotheses Important Tests
Signs

Leading Hypothesis

Renal artery stenosis Abrupt onset or accelerated hypertension Duplex

Azotemia a er use of ACE inhibitor ultrasonography
Hypertension refractory to ≥ 3 medications MRA with
Abdominal or flank bruit gadolinium
Other vascular disease (coronary, carotid, or CT angiography
peripheral)
Smoking
Severe retinopathy

Active Alternatives—Most Common

Worsening CKD None Serum creatinine

Sometimes edema, malaise Estimated GFR

Lifestyle factors History History

Use of medications/drugs that History History

increase BP

Obstructive sleep apnea Obesity Polysomnogram

Neck circumference > 17 inches
Frequent snoring
Daytime somnolence

Other Hypotheses

Hyperaldosteronism Resistant hypertension Aldosterone/renin

Hypokalemia ratio

ACE, angiotensin-converting enzyme; CKD, chronic kidney disease; GFR, glomerular filtration rate; MRA, magnetic
resonance angiography.

Leading Hypothesis: Atherosclerotic Renal Artery Stenosis

Textbook Presentation

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Patients generally have either very abrupt hypertension, hypertension that worsens over 6 months, or
hypertension refractory to treatment with 3 drugs. The classic patient with atherosclerotic renal artery
stenosis has other vascular disease (cerebrovascular disease, coronary artery disease, peripheral arterial
disease) or risk factors such as smoking or diabetes.

Disease Highlights

A. Must distinguish renovascular disease from renovascular hypertension

1. Renovascular disease means significant stenosis of 1 or both renal arteries.

a. Can be due to fibromuscular dysplasia (most commonly in young women) or atherosclerosis

(90% of cases)

(1) Atherosclerotic renal artery stenosis (ARAS) is present in 1–6% of unselected patients with
hypertension.

(2) ARAS is found in more than 30% of patients undergoing cardiac catheterization.

b. Does not necessarily cause hypertension and can exist in patients with essential hypertension.

2. Renovascular hypertension means hypertension caused by renal hypoperfusion as a result of renal

artery stenosis.

a. Stenosis leads to renal ischemia, activating the renin–angiotensin system, which leads to release
of renin and production of angiotensin II.

b. Although plasma renin levels are high initially, they decrease over time.

c. Aldosterone secretion and vasoconstriction then occur, leading to hypertension.

d. Aldosterone secretion also causes salt and water retention and hypokalemia.

e. Ischemic nephropathy occurs when renal blood flow is so reduced that GFR decreases and there
is loss of renal function.

f. Some patients with bilateral renal artery stenosis present with episodic, unexplained pulmonary
edema (“flash pulmonary edema”); echocardiograms in such patients show normal systolic
function.

B. About 50% of patients with renal artery stenosis have renovascular hypertension.

Evidence-Based Diagnosis

A. Clinical clues to identify patients with high risk of having ARAS

1. Onset of hypertension before age 30, or severe hypertension a er age 55

2. Accelerated, resistant, or malignant hypertension

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3. New azotemia or worsening renal function a er use of an ACE inhibitor or ARB

a. A reversible increase in serum creatinine can develop in some patients with bilateral renal artery
stenosis (or unilateral stenosis in patients with only 1 functioning kidney) when starting ACE
inhibitor therapy.

(1) The peak creatinine occurs somewhere between 4 days and 2 months.

(2) Creatinine returns to baseline within 1 week of stopping the ACE inhibitor.

b. One study reported that, in a population of high-risk patients, a 20% increase in creatinine had
100% sensitivity and 70% specificity for the diagnosis of renal artery stenosis (defined as > 50%
bilateral stenosis).

4. Unexplained atrophic kidney or size discrepancy of > 1.5 cm between the kidneys

5. Sudden, unexplained pulmonary edema; unexplained heart failure; refractory angina

6. Multivessel coronary artery disease or peripheral arterial disease

7. Unexplained renal dysfunction

B. Abdominal bruits may be present.

1. Should listen over all 4 abdominal quadrants and also spine and flanks between T12 and L2

2. Must di erentiate between systolic bruits and continuous (systolic and diastolic) bruits

a. Systolic bruits occur in 4–20% of healthy persons, more commonly in people under 40 years of
age.

(1) May originate from the celiac artery

(2) Modestly increase the likelihood of renal artery stenosis: LR+, 5.6; LR–, 0.6

b. Continuous systolic-diastolic bruits o en radiate to the side and strongly increase the likelihood
of renal artery stenosis: LR+, 38.9; LR–, 0.6.

C. Family history of hypertension is o en absent.

D. Hypokalemia is o en seen as a result of stimulation of aldosterone release; metabolic alkalosis is also

o en seen.

E. Imaging studies

1. Intra-arterial digital subtraction angiography is the gold standard.

a. Can also be therapeutic through performance of angioplasty or placement of stent in the rare
cases this is indicated

b. Complications include bleeding, dissection, embolization, and contrast nephropathy.

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2. Duplex ultrasonography (2-dimensional ultrasound imaging combined with Doppler flow

measurements)

a. Results can vary depending on the level of experience of the technician and the body habitus of
the patient.

b. Accuracy ranges from 60% to 90%

c. In optimal circumstances, sensitivity is 85% and specificity, 92% (LR+, 10; LR–, 0.16)

3. Magnetic resonance angiography with gadolinium

a. The largest single study found that for ARAS the sensitivity was 78% and specificity was 88%
(LR+ = 6.5, LR− = 0.25); for fibromuscular dysplasia, the sensitivity was only 22% but the
specificity was 96%.

b. Smaller studies report sensitivities and specificities over 90%.

4. CT angiography

a. Preferable to avoid in patients with CKD due to the necessary IV contrast (see Chapter 28, Acute
Kidney Injury)

b. In the large study noted above, for ARAS, the sensitivity was 77% and specificity was 94% (LR+ =
12.8, LR− = 0.24); for fibromuscular dysplasia, the sensitivity was 28% and specificity was 99%.

c. Smaller studies report sensitivities and specificities over 90%.

Treatment

A. All patients with ARAS should have optimal medical therapy with ACE inhibitors or ARBs, statins, and
aspirin.

B. Most patients require multiple antihypertensive medications to reach BP goals.

C. Patients should stop smoking, and diabetes should be optimally controlled.

D. The role of renal artery revascularization is limited.

1. Randomized, controlled trials have not shown that stenting is better than medical therapy with
regard to preventing progression of renal disease or cardiovascular events.

2. ACC/AHA guidelines recommend considering revascularization in patients with hemodynamically

significant bilateral ARAS (or unilateral in patients with 1 kidney) and recurrent, unexplained heart
failure or pulmonary edema. Other potential indications include progressive CKD, resistant or
accelerated hypertension, and unstable angina.

MAKING A DIAGNOSIS

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A er you explain that most patients with ARAS are treated with aspirin, statins, and good BP control, Mrs. X
declines any imaging studies.

Have you crossed a diagnostic threshold for the leading hypothesis, renovascular
hypertension? Have you ruled out the active alternatives? Do other tests need to be done to exclude the
alternative diagnoses?

Worsening CKD, lifestyle factors, and medications/drugs have been ruled out by the history and unchanged
serum creatinine. Primary aldosteronism needs to be considered in patients with resistant hypertension,
especially those with hypokalemia.

Alternative Diagnosis: Primary Hyperaldosteronism

Textbook Presentation

Primary hyperaldosteronism is usually diagnosed when a patient with hypertension has unexplained
hypokalemia or when a patient has resistant hypertension.

Disease Highlights

A. Etiology

1. Results from a unilateral aldosterone-producing adenoma in 30–35% of cases (Conn syndrome)

2. Results from idiopathic bilateral adrenal hyperplasia in most other patients (60–70%)

3. Rarer causes include microadenomas, unilateral adrenal hyperplasia, and adrenal carcinoma.

B. The overall prevalence, based on community cohorts, is about 11%.

1. Prevalence of 8–15.5% in patients with grade 2 hypertension (160–179/100–109 mm Hg) and of 13–
19% in patients with grade 3 hypertension (≥ 180/≥ 110 mm Hg)

2. Found in 17–23% of patients with resistant hypertension

3. Prevalence uncertain in patients with hypertension and unprovoked hypokalemia; 1 study reported
a prevalence of 50%

C. Pathophysiology

1. High aldosterone levels lead to salt and water retention and potassium wasting.

2. Because aldosterone is being produced autonomously, it is not suppressed by volume expansion, as

it is normally.

3. Volume expansion suppresses plasma renin levels.

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D. Most patients have a normal potassium level; 48% of those with aldosterone-producing adenomas and
17% of those with bilateral adrenal hyperplasia are hypokalemic.

A normal potassium level does not rule out hyperaldosteronism.

Evidence-Based Diagnosis

A. The Endocrine Society recommends screening for primary hyperaldosteronism in hypertensive patients
with moderate-severe hypertension (BP > 160/100 mm Hg), resistant hypertension, unprovoked (by
diuretics) hypokalemia associated with renal potassium wasting, an adrenal incidentaloma, diuretic-
associated hypokalemia (especially in treatment resistant patients or when hypokalemia persists when
potassium-sparing diuretics, ACE inhibitors, or ARBs are used), a family history of early onset
hypertension, or cerebrovascular accident at < 40 years of age.

B. There are 3 steps in the diagnosis of primary hyperaldosteronism: screening, confirmatory testing, and
determining the subtype.

1. The plasma aldosterone concentration/plasma renin activity ratio (ARR) is the most commonly used
screening test; since patients with primary hyperaldosteronism have elevated levels of aldosterone
and suppressed renin levels, the ratio should be elevated.

a. The ARR can be a ected by potassium status, dietary sodium, medications, and age.

b. Ideally, prior to measurement, the patient should have a normal potassium level and liberal
sodium intake.

c. Medications that minimally a ect aldosterone levels include verapamil, hydralazine, and alpha-
adrenergic blockers; other antihypertensive medications and NSAIDs should be stopped for 2–4
weeks when possible.

d. The optimal cut point is unclear; a ratio > 20–30 is generally considered a positive test.

e. Sensitivity ranges from 73% to 87%, with a specificity of about 75%.

2. If the ARR is abnormal, the patient should be referred to an endocrinologist for confirmatory testing
(oral sodium loading, saline infusion, fludrocortisone suppression, or captopril challenge).

3. Patients with abnormal confirmatory testing should undergo adrenal CT, possibly followed by
adrenal vein sampling.

Treatment

A. Laparoscopic adrenalectomy should be considered when lateralized aldosterone excess is

demonstrated by adrenal vein sampling.

B. Otherwise, treat with the aldosterone antagonist spironolactone.

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CASE RESOLUTION

Mrs. X has an elevated ARR; however, confirmatory testing by the endocrinologist is negative. You stop the
hydrochlorothiazide, substituting chlorthalidone, a longer acting diuretic. Her BP improves slightly, and
she requires the addition of labetolol to achieve her BP goal.

CHIEF COMPLAINT

PATIENT

Mr. J is 45-year-old man with a 10-year history of hypertension. When you last saw him 1 year ago, his BP
was 160/95 mm Hg. He ran out of his medications 6 months ago and was unable to obtain refills because of
financial problems. Today, he has stopped by to see your nurse for new prescriptions. Because he is
complaining of a headache, she checks his BP and then runs to find you because it is 220/112 mm Hg.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a
must not miss diagnosis? Given this di erential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

Mr. J’s BP clearly needs to be lowered, and the primary question is how quickly this needs to be
accomplished. In other words, is this a hypertensive emergency or hypertensive urgency? These syndromes
are defined by the degree of BP elevation and whether there is acute end organ damage.

A hypertensive emergency exists when there is severe BP elevation and acute target organ involvement:
acute neurologic syndromes (encephalopathy, cerebrovascular accident, intracerebral or subarachnoid
hemorrhage), acute aortic dissection, acute coronary syndrome, acute pulmonary edema, acute kidney
injury, severe preeclampsia/eclampsia, microangiopathic hemolytic anemia, or acute postoperative
hypertension.

In hypertensive urgency, there is severe BP elevation without any acute TOD. The exact definition of
“severe BP elevation” has not been established, but many experts use a cuto of > 180/110–120 mm Hg.
Common causes of hypertensive urgency and emergency include medication nonadherence, abrupt
cessation of clonidine, CKD, renovascular disease, drugs (cocaine, PCP), systemic lupus erythematosus,
eclampsia, and postoperative state; Cushing disease and pheochromocytoma are less common causes.

A hypertensive emergency is defined by the presence of TOD, not by the degree of BP

elevation.

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To some extent, the degree of the acute TOD in patients with very elevated BP depends on the time course
of the BP elevation. For example, normotensive women in whom acute hypertension develops from
eclampsia can have significant TOD at pressures of 160/100 mm Hg, whereas patients with chronic
hypertension can be asymptomatic at much higher pressures. So, despite his very elevated BP, it is quite
likely that Mr. J falls into the “hypertensive urgency” rather than the “hypertensive emergency” category.
Nevertheless, hypertensive emergency is always the “must not miss” diagnosis in such patients (Table 23-
10).

You tell the nurse to put Mr. J in an exam room. On further history, he has no shortness of breath, chest
pain, edema, abdominal pain, feelings of confusion, vomiting, or focal weakness or numbness. He
generally appears well and is clearly happy to have a new job. Physical exam confirms BP of 220/112 mm
Hg, pulse of 84 bpm, and RR of 16 breaths per minute. There is no papilledema. Lungs are clear, jugular
venous pressure is not elevated, there is an S4 and a 2/6 systolic ejection murmur without an S3, abdomen
is nontender, there is no peripheral edema, and neurologic exam is normal.

Is the clinical information su icient to make a diagnosis? If not, what other information do you
need?

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Table 23-10.
Diagnostic hypotheses for Mr. J.

Demographics, Risk Factors,

Diagnostic Hypotheses Important Tests
Symptoms and Signs

Leading Hypothesis

Hypertensive urgency Absence of hypertensive emergency

syndromes

Active Alternative—Must Not Miss

Hypertensive emergencies Acute Chest pain ECG

coronary syndrome Cardiac enzymes

Aortic dissection Chest, back pain Chest radiograph

Diastolic murmur Transesophageal
Absent pulses echocardiogram
Chest CT

Pulmonary edema Dyspnea Chest radiograph

Crackles
S3

Hypertensive encephalopathy Headache MRI

Nausea/vomiting
Delirium
Seizures
Coma
Papilledema

Acute kidney injury Nausea Serum creatinine

Fatigue

Leading Hypothesis: Hypertensive Urgency

Textbook Presentation

A patient with chronic hypertension has extremely high BP; by definition, patients have no symptoms or
signs of acute TOD.

Disease Highlights

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A. Hypertensive urgency or emergency occurs in about 1% of adults with hypertension; with urgency
occurring in three-quarters of these patients.

B. The most common presenting symptoms are headache (22%), epistaxis (17%), faintness (10%),
psychomotor agitation (10%), chest pain (9%), and dyspnea (9%).

Evidence-Based Diagnosis

A. Must rule out acute TOD through history, physical, and selected laboratory tests.

B. BP should be measured in both arms, and pulses palpated in both the upper and lower extremities; all
patients should have a complete cardiovascular and neurologic exam, including fundoscopic exam.

C. All patients should have a serum creatinine and urinalysis performed.

D. Patients with symptoms suggestive of myocardial ischemia or pulmonary edema should have an ECG,
chest radiograph, and cardiac enzymes.

E. Patients with neurologic signs or symptoms need a head CT scan and sometimes a brain MRI.

Treatment

A. In stable outpatients with chronically elevated BP, there is NOT an urgent need to reduce the BP, and it
is fine if it takes several days for the BP to be reduced.

B. There are several ways to approach treatment, depending on the overall condition of the patient,
whether the patient has been treated previously, and the ability of the patient to return for follow-up.

1. In patients who have stopped their medications, it is usually su icient just to restart them.

2. In previously untreated patients, options include

a. Starting 2 long-acting agents, such as a diuretic and either a calcium channel blocker or ACE
inhibitor

b. Beginning treatment with more rapid-acting agents, such as oral labetalol or clonidine, and then
transitioning to longer acting agents; patients can be observed for several hours to assess their
response to the short-acting agents.

C. Too rapid reduction of BP can lead to hypotension and cerebral hypoperfusion with stroke.

D. IV and sublingual medications can have unpredictable e ects on BP and should be avoided in
asymptomatic patients.

1. IV hydralazine causes a progressive and sometimes precipitous fall in BP 5–15 minutes a er

administration.

2. Although the circulating half-life of hydralazine is only 3 hours, the half time of its e ect on BP is 10
hours.

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3. Sublingual nifedipine causes completely unpredictable lowering of BP and should never be used.

Do not be in a hurry to normalize BP in patients without acute TOD!

MAKING A DIAGNOSIS

Mr. J’s serum creatinine is 1.4 mg/dL, unchanged from 1 year ago. His urinalysis is normal. Mr. J wants to
know if he can have a couple of acetaminophen tablets for his headache, get his prescriptions, and leave;
he has to pick up his son at school.

Have you crossed a diagnostic threshold for the leading hypothesis, hypertensive urgency?
Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative
diagnoses?

Alternative Diagnosis: Hypertensive Emergencies

Patients with hypertensive emergencies frequently present with chest pain (27%), dyspnea (22%), and
neurologic deficits (21%). Cerebral infarction is found in about 24% of patients, with about 22% having
pulmonary edema, 16% hypertensive encephalopathy, and 12% heart failure.

Acute coronary syndromes, aortic dissection, subarachnoid hemorrhage, and pulmonary edema are
discussed in other chapters. This section focuses on hypertensive encephalopathy.

Textbook Presentation

Patients present with the acute or subacute development of lethargy, confusion, headache, and visual
disturbances, sometimes followed by seizures (focal or generalized) and coma. The syndrome can occur
with or without proteinuria and retinopathy.

Disease Highlights

A. Cerebral blood flow is autoregulated within specific limits.

1. In normotensive people, cerebral blood flow is unchanged between mean arterial pressures (MAP)
of 60–120 mm Hg (MAP = [(2 × diastolic) + systolic]/3)

a. Cerebral vasoconstriction limits hyperperfusion up to a MAP of 180 mm Hg.

b. Above a MAP of 180 mm Hg, autoregulation is overwhelmed.

2. In hypertensive patients, cerebral blood flow can be maintained at MAPs of up to 200 mm Hg.

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a. Thought to be due to arteriolar thickening

b. Such patients also need higher MAPs to maintain adequate cerebral blood flow (ie, abrupt
lowering of the BP to a MAP of < 100–110 mm Hg can potentially lead to cerebral ischemia).

B. Failure of autoregulation leads to cerebral vasodilation, endothelial dysfunction, and cerebral edema.

C. The classic MRI finding in hypertensive encephalopathy is subcortical vasogenic edema.

1. Also called reversible posterior leukoencephalopathy syndrome (RPLS)

2. Generally in the posterior regions of the brain due to relatively sparse sympathetic innervation of
the vertebrobasilar territory leading to more disruption of autoregulatory mechanisms, increased
perfusion, and edema

3. Can also see changes in the brainstem and anterior brain

4. In 1 series, 92% of patients with RPLS presented with encephalopathy, 39% with visual symptoms,
and 53% with headache; 87% of patients had seizures.

5. Also seen with eclampsia and use of some immunosuppressive agents and cytotoxic drugs; in 1
series, 68% of patients with RPLS had hypertension, 11% eclampsia, 11% immunosuppressive use,
and 11% other causes

6. Reversible with treatment of hypertension or removal of inciting agent, with MRI findings resolving
in days to weeks; long-term antiepileptic therapy is not necessary.

Evidence-Based Diagnosis

A. Hypertensive encephalopathy is primarily a clinical diagnosis.

B. A head CT should be done to exclude intracranial hemorrhage (intracerebral or subarachnoid bleeding).

C. An MRI should be done to exclude acute ischemic stroke and to look for RPLS.

MRI is much more sensitive than CT (83% vs 16% sensitivity; specificity of both > 95%) for the
diagnosis of acute ischemic stroke.

Treatment

A. Hypertensive encephalopathy and other hypertensive emergencies should be treated in the ICU with
parenteral, titratable antihypertensive agents.

B. There is little evidence to guide the choice of agents; commonly used medications include labetalol,
esmolol, fenoldopam, clevidipine, nitroprusside, and nicardipine.

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C. Generally, the BP should be reduced by about 10% in the first hour, and by another 15% in the next 2–3
hours; patients can o en be transitioned to oral agents within 12–24 hours.

1. The BP should be reduced more quickly in acute aortic dissection, with a goal of < 120/80 mm Hg
within 20 minutes.

2. Neurology consultation should be obtained for guidance regarding BP lowering in the setting of
acute stroke.

CASE RESOLUTION

Mr. J has no signs or symptoms of stroke, intracranial hemorrhage, pulmonary edema, myocardial
ischemia, or aortic dissection. He has a headache, but he does not have other symptoms, such as lethargy
or confusion, to suggest hypertensive encephalopathy. His renal function is stable and his urinalysis is
normal. There is no need to perform any further testing at this point.

Mr. J’s previous regimen was hydrochlorothiazide, 25 mg; lisinopril 40 mg; and amlodipine, 10 mg. You
instruct him to fill his prescriptions a er he picks up his son at school, to take the amlodipine tonight, and
then to take all 3 medications in the morning. When he returns in 2 days, his BP is 160/100 mm Hg; 3 weeks
later it is 145/90 mm Hg.

REVIEW OF OTHER IMPORTANT DISEASES

Pheochromocytoma

Textbook Presentation

The classic presentation is a patient with attacks of paroxysmal hypertension, headache, palpitations, and
sweating occurring several times daily, weekly, or every few months. Patients generally have orthostatic
hypotension on physical exam.

Diseases Highlights

A. 95% of patients have headache, sweating, or palpitations.

B. 10% of pheochromocytomas are malignant and tend to have a less typical presentation.

C. 10–15% are familial (multiple endocrine neoplasia type 2, von Hippel-Lindau disease,
neurofibromatosis); these are more o en asymptomatic (and normotensive) than sporadic cases.

D. Table 23-11 lists symptoms, taken from a series of patients with pheochromocytoma, about half of
whom presented with paroxysmal hypertension and about half of whom had persistent hypertension.

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Table 23-11.
Symptoms of pheochromocytoma.

Patients with Pheochromocytoma and Patients with Pheochromocytoma and

Symptom
Paroxysmal Hypertension Persistent Hypertension

Severe headaches 92% 72%

Sweating 65% 69%

Palpitations and/or 73% 51%

tachycardia

Anxiety/panic 60% 28%

Tremulousness 51% 26%

Chest or 48% 28%

abdominal pain

Nausea ± vomiting 43% 26%

Evidence-Based Diagnosis

A. Pretest probability of 0.5% in hypertensive patients who have suggestive symptoms, and of 0.2% in
unselected hypertensive patients

B. Pretest probability of 4% in patients with incidentally discovered adrenal masses

C. Plasma free metanephrine is the single best test to rule out pheochromocytoma (Table 23-12).

1. Patients should fast overnight and be supine for 20 minutes prior to the blood draw.

2. Because ca eine and acetaminophen interfere with the assay, patients should avoid ca eine for 12
hours and acetaminophen for 5 days prior to testing.

3. The standard upper limit of normal for plasma metanephrines is 61 ng/L.

a. The overall (sporadic and hereditary cases) sensitivity at this cut o is 99% with a specificity of
89%.

b. A plasma metanephrine > 236 ng/L is 100% specific for the diagnosis of pheochromocytoma.

D. Patients with positive biochemical testing should undergo adrenal imaging.

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1. CT: sensitivity of 93–100% for detecting adrenal pheochromocytomas, 90% for extra-adrenal
tumors; specificity 50–70%

2. MRI: sensitivity 90%; specificity also 50–70%; better than CT for identifying vascular invasion

3. 131I-MIBG or positron emission tomography scanning is sometimes used when the biochemistry is
positive and both CT and MRI are negative.

Table 23-12.
Diagnostic tests for sporadic pheochromocytoma.1

Test Sensitivity Specificity LR+ LR-

Plasma free metanephrines 99% 82% 5.5 0.012

Plasma catecholamines 92% 72% 2.9 0.11

24-hour urine fractionated metanephrines 97% 45% 1.76 0.06

24-hour urine catecholamines 91% 75% 3.64 0.12

24-hour urine total metanephrines 88% 89% 8 0.13

24-hour urine vanillylmandelic acid level 77% 86% 5.5 0.26

1Test characteristics for the diagnosis in patients with hereditary pheochromocytoma are di erent and can be found
in (Data from Lenders JWM. JAMA. 2002;287:1427–34.)

Treatment

A. Surgery is the definitive treatment.

B. Must give both alpha- and beta-blocking agents preoperatively

1. The alpha-blocker opposes catecholamine-induced vasoconstriction.

2. The beta-blocker opposes the reflex tachycardia that occurs with alpha-blockade.

3. Unopposed beta-blockade causes inhibition of epinephrine-induced vasodilation, leading to

increased BP, le heart strain, and possibly heart failure.

4. Should be done in consultation with an endocrinologist because of the complexities of ensuring

adequate alpha-blockade

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Never give a patient with a pheochromocytoma a beta-blocker without first giving an

alpha-blocker.

C. 27–38% of patients have residual hypertension.

D. Patients with familial pheochromocytoma o en have multiple, bilateral tumors; the optimal approach
to therapy is not clear.

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Scientific Statement from the American Heart Association Professional Education Committee of the
Council for High Blood Pressure Research. Hypertension. 2008;51:1403–19.

Dworkin LD, Cooper CJ. Renal artery stenosis. N Engl J Med. 2009;361:1972–8.

Funder JW, Carey RM, Fardella C et al.; Endocrine Society. Case detection, diagnosis, and treatment of
patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol
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Jellinger PS, Smith DA, Mehta AE et al.; AACE Task Force for Management of Dyslipidemia and Prevention
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Lao D, Parasher PS, Cho KC, Yeghiazarians Y. Atherosclerotic renal artery stenosis—diagnosis and
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Lenders JWM, Pacak K, Walther MM et al. Biochemical diagnosis of pheochromocytoma. Which test is
best? JAMA. 2002;287:1427–34.

Manger WM, Gi ord RW. Pheochromocytoma. J Clin Hypertension. 2002;4:62–72.

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Rossi GP. A comprehensive review of the clinical aspects of primary aldosteronism. Nat Rev Endocrinol.
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The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH)
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