CHAPTER XXVII

SYSTEMIC HYPERTENSION

Definition: The Joint National Committee on the Detection, Evaluation, and Treatment of High
Blood Pressure has defined hypertension as indirect, sphygmomanometric levels of > 140 mm Hg
systolic, and/or > 90 mm Hg diastolic (table XXVII-1).

Table XXVII-1: Blood pressure classification (adults aged > 18, not taking antihypertensive drugs
and not acutely ill)

Systolic Diastolic
Category (mm Hg) (mm Hg)
Normal (no BP medications) <130 <85
High normal (borderline BP) 130–139 85–89

Hypertensive Average of 2 determinations/2 visits

Stage 1 (mild) 140–159 90–99

Stage 2 (moderate) 160–179 100–109
Stage 3 (severe) 180–209 110–119
Stage 4 (very severe) 210 120

(Adapted from Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The Fifth
Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch
Intern Med 1993; 153:154–183.)

General considerations:
1. Hypertension is a major cardiovascular risk factor that directly contributes to myocardial
infarction, cerebrovascular accidents, congestive heart failure, peripheral arterial insufficiency,
and premature mortality (Leavy & Larson , JAMA 1996).
2. Among reasons cited for office visits to American internists, hypertension is the most common,
and the most common indication for the use of prescription medication in the United States (Baum
D. Med. Care 1988).
3. Of all the known cardiovascular risk factors, hypertension is the most prevalent: 20% to 25% of
the population (in USA).

History:
1. The first report of direct blood pressure measurement dates from 1726 by Stephen Hales
(cannulation of a horse’s crural artery).
2. Richard Bright’s description (1827) of contracted kidneys and hypertrophied left ventricles and
the recognition that hypertension might be caused by factors other than kidney disease.
3. Riva-Rocci’s introduction of the sphygmomanometer cuff in 1896.
4. Korotkoff reported the auscultatory method of measuring arterial pressure in 1905.
5. In 1913, Janeway described 500 of his private-practice patients followed for 9 years, concluding,
“It does not seem to me that any very definite prognostic conclusions can be drawn from the
height of the blood pressure”.
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 6. Goldblatt’s description of the renal artery clip model (1934), inducing experimental
hypertension.
7. In 1939, Keith, Wagener, and Barker published their landmark study of survival curves of
four groups of hypertensive patients classified by eye ground patterns.
8. In 1960, Irving Page proposed the mosaic theory of hypertension: “a disease of regulation
in which abnormal regulatory systems fail to reduce blood pressure once it is elevated”.

Classification of systemic hypertension:

I. Primary “Essential” Hypertension ~ 90 % of cases
II. Secondary Hypertension (totally curable if the evolution is less than 5-8 years and the target
organs are not affected) ~ 10 % of cases.

PRIMARY (ESSENTIAL) HYPERTENSION

Definition: Hypertension that has no known cause (or we are unable to detect it). Positive diagnosis
must exclude secondary causes of hypertension.

Pathophysiology:
Since 1960 when Irving Page first describes it, the theory accepted worldwide today is the Mosaic
Theory that offers a way to combine diverse factors, from genetic and physiologic to emotional and
environmental.
No single cause has been discovered to explain essential hypertension. Many factors are certainly
or probably responsible which involve cardiac output and peripheral resistance. (Fig. XXVII-1)

BLOOD PRESSURE: Cardiac output X Peripheral resistance

The pathogenesis of essential hypertension is multifactorial.

1. Genetic Factors:
 Variation in blood pressure represents the combined effects of multiple genes, having
dominant transmission. Three gene mutations have been implicated in human hypertension:
(a) Glucocorticoid-remediable aldosteronism (from ectopic expression of aldosterone
synthetase enzymatic activity).
(b) Liddle’s syndrome (-subunit mutations of the amiloride-sensitive epithelial sodium
channel).
(c) Primary hypertension in some Caucasians (variants at the angiotensinogen locus ) (Lifton
1995)
 A strong family history (>2 first degree relatives with hypertension before age 55) predicts a
future occurrence of hypertension with a relative risk of 3.8 (Williams RR, Hunt SC, Hopkins PN, et
al. 1993)
2. Excessive Sodium Intake – proposed theories:
 Diets of more than 50 mEq sodium/day (~ 1/2 teaspoon (tsp) of salt/day, since 1 tsp of salt = 6
gm salt = 2.4 gm sodium = 104 mEq sodium = 104 mmol sodium) (20-50%).
 The sodium - potassium ratio intake. In primitive societies the incidence of hypertension was
rare, one of the possible explanation could be the low salt (10–30 mmol/dl) and high
potassium intakes.

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  “Intersalt “study (10,079 subjects from 32 countries) was unable to confirm a consistent
relationship between dietary NaCl intake and blood pressure in diverse settings. (Intersalt
Cooperative Research Group).

Fig. XXVII-1: Interaction among the genetic, environmental and physiological factors that
affect the blood pressure in health and in disease . (Adapted from Kaplan N.M. Clinical Hypertension,
Baltimore: Williams & Wilkins 1994)

3. Natriuresis and Renal Function:

 Normally, blood pressure elevation leads to a decrease in sodium reabsorption, which in turn
causes a diuresis and a fall in blood pressure, termed pressure natriuresis.
 Among hypertensives and prehypertensives, the kidney fails to control natriuresis. The cause
is unknown, but heredity may play a role.
 Reductions in filtration surface area from lower numbers of functioning nephrons and
intrarenally, prostaglandin function (especially prostaglandin E2 influencing natriuresis and
prostaglandin I2 modulating renin release) may serve as intermediary derangements (Romero
JC, Bentley MD, Textor SC, Know FG. 1989)

4. Renin-Angiotensin System:
 Renin (discovered in 1898) is a pressor hormone and a growth factor, secreted from the renal
juxtaglomerular apparatus in response to macular densa signals of lowered cytosolic calcium,
decreased renal arteriolar pressure, and/or increased renal - or -adrenergic nerve activity.

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  Renal ischemia leads to liberation of renin which converts angiotensinogen into angiotensin I
and then to angiotensin II (especially in the lung) which causes vasoconstriction and
stimulates liberation of aldosterone which leads in turn to salt and water retention.

Kininogen Angiotensinogen
Kalicrein Renin
Angiotensin I
Bradikinin

Angiotensin converting
enzyme

Angiotensin II
Angiotensin derived peptids
(III şi IV)

Inactive peptids

• Plasminogen tissular Endothelial cells

activator factor(t-PA) • PAI-1
• EDRF/NO • EDCF
• Prostacyclin • Endotelin

EDRF = endothelium - derived relaxing factor l, NO = nitric oxyde, PAI-1 = plasminogen activation inhibitor, EDCF =
endothelium - derived constricting factor

Fig. XXVII-2: Angiotensin converting enzyme activity (Adapted from Kang PM. Am Heart J. 1994;127.)

 Complete renin-angiotensin systems operate in the brain, reproductive tract, and heart and
play physiological roles in epithelial, fibroblast, and macrophage cell function. ( Johnson C.J.
1992)
 The principal effects of AII consist of (a) vasoconstriction that leads to elevated blood
pressure by inhibiting adenylate cyclase mediated through G proteins, particularly for the
kidney’s efferent arterioles; (b) volume retention via promoting aldosterone secretion by the
adrenal; and (c) vascular hypertrophy, especially in the heart, peripheral vessels, and renal
vasculature (Itoh H, Hukoyama M, Pratt RE, Gibbons GH, Dzau VJ. 1993.)
5. Sympathetic nervous system hyper-reactivity:

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  Sympathetic nervous system hyperactivity is mostly apparent in younger hypertensives, who
may exhibit tachycardia, vasoconstriction and an elevated cardiac output. Often, stress
activates the SNS, especially in those genetically or environmentally predisposed to respond
with increased levels of epinephrine, norepinephrine, and neuropeptide Y.
 Correlations between plasma catecholamines and blood pressure have generally been poor.
 Insensitivity of the baroreflexes may play a role in the genesis of adrenergic hyperactivity. In
hypertensive patients, the baroreceptors are “reset” so that higher pressures are required to
exert an influence toward lowering blood pressure.
 Sympathetic activation may also play a role in “labile” hypertension, characterized by marked
blood pressure fluctuations under differing, or even similar, circumstances.

6. Vascular Constriction and Vascular Remodeling and Hypertrophy:

 Systemic resistance vessel depends on complex interactions among smooth muscle
contractility, the vessels geometric design, vessel wall distensibility, and the distending
pressure.(Folkow B. 1990).
 The vascular tree acts like a Windkessel system (absorbs energy during systolic and releases it
during diastole).
 In hypertension, vessel wall compliance (the change in vessel diameter for a given change in
pressure) falls, predominantly among smaller, distal, resistance vessels, rather than large or
medium-sized vessels, and increases dramatically with age. ( McVeigh GE, Burns DE, Finkelstein
SM, et al. 1991).

7. Cell Membrane Alteration:

 Abnormal ionic fluxes across cell membranes potentially affect both vessel tone and
hypertrophy.
 Five sodium transport systems have potential involvement: (a) the Na+ channel; (b) Na+-H+
antiport/Na+-Li+ countertransport exchange; (c) Na+-K+-Cl- cotransport; (d) Na+-Ca++
exchange; and (e) Na+-K+ ATPase pump.
 Three reported defects in calcium transport have emerged, involving (a) the Ca++ pump; (b)
the Na+-Ca++ exchange; and (c) the dynamic release and sequestration of free Ca++ between
cytosol and mitochondria. (Adeoya SA, Norman RI, Bing RF. 1988).
 Increased intracellular Na+ could be accompanied by intracellular alkalinization, a recognized
stimulus for cell growth, and increased intracellular Ca++, a stimulus for vascular reactivity.

8. Endothelial dysfunction:
 The endothelinic system maintains the vascular integrity through a dual action of its
components:
 Dilation, vascular cells growth inhibition, anti-thrombotic effect, anti-inflammatory
action, anti-oxydant effect.
 Constriction, vascular cells growth stimulation, pro-thrombotic effect, pro-
inflammatory action, pro-oxydative effect.
 There are three types of endothelins (1, 2, 3) enzymatic synthesized from pro-endothelins
(endothelin converting enzyme 1, 2, 3, and chymase).
 Endothelins act on two types of receptors ETA and ETB:
 ETA receptors are localized on the smooth vascular cells, and have a special affinity
for ET1 (ET1> ET2> ET3). Stimulation of these receptors induces vasoconstriction and
cellular proliferation.

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  ETB receptors are especially located on endothelial cells (also on smooth vascular
cells), and make no affinity differences between the three types of endothelins.
Stimulation of these receptors induces NO and prostacyclin release, and inhibits
cellular apoptosis.

 Stimulating factors for endothelins synthesis: oxydative stress, hypoxia, cytokines, growth
factors, thrombine, LDL-cholesterol, glucose, obesity, estrogenic deficit, and cocaine abuse.
 Factors which inhibit endothelins synthesis: NO, prostacyclines, estrogens, and atrial
natriuretic factor.
 Endothelial system dysfunction is now the modern target for hypertension pathophysiology
research.

9. Vascular Hypertrophy. Some growth factors (at least seven) including endothelial-derived
factors and A II, can determine trophic influences for the vascular smooth muscle.

10. Atrial natriuretic factor (ANF):

 Normally is reducing systemic blood pressure, by:
 Increasing glomerular filtrate without increasing renal blood flow
 Relaxing preconstricted vasculature especially in the renal bed
 Suppressing renin levels and its secretion
 The hypotheses linking decreased levels or altered responsiveness of ANF to hypertension’s
pathogenesis was proposed, but it is still not conclusive.

11. Prostaglandins: -- play important roles in circulatory control and thrombosis, but their
implications in essential hypertension is less clear for the moment:
 Prostacyclin inhibits platelet aggregation, relaxes vascular smooth muscle, and promotes
natriuresis.
 PGE2 causes vasodilation
 PGF2a causes vasoconstriction.

12. Interleukins:
 Interleukin-1, may inhibit angiotensinogen synthesis
 Interleukin-6 may enhance the protein-producing messenger RNA transcription rate. (Printz
MP, Klett C. 1993)

13. Medullipin: (Christy IJ, Woods RL, Courneya CA, Denton KM, Anderson WP 1991)
 Secreted from renal medullary cells
 Requires activation by the hepatic cytochrome P-450 system for its effect
 Independent of renin-angiotensin or autonomic nervous function
 Acts as a counterbalance to angiotensin II.

DIAGNOSIS:

Primary “essential” hypertension is an exclusion diagnosis. First, secondary causes for

hypertension must be searched. Staging of systemic hypertension and prognosis are strongly
dependent on possible comorbidity, medication intake, and complications (see table XXVII-2).

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Initial history for hypertensive patients (table XXVII-2):

Sociodemographics: Age, sex, race, occupation, education, psychosocial issues

Symptoms of HTN complications:
Symptoms of secondary
HTN:
CV risk factors:
Complicating Comorbidity:
Medications:
TIA, CVA, angina, CHF, PVD, claudication
Episodic headaches, palpitations, sweating, weight loss
(pheochromocytoma), muscular weakness, cramps, paresthesia, and
polyuria (primary hyperaldosteronism), weight gain, acne, bruising,
hirsutism (Cushing’s syndrome), and lower-extremity claudication
(coarctation of aorta)
Dyslipidemia, diabetes mellitus, smoking, high salt intake, saturated
fat intake, stress, low activity level, alcohol abuse, gout; FH of
HTN, CAD (especially if < age 60), CVA, DM, dyslipidemia
Renal or hepatica dysfunction, COPD or asthma, obesity, gout
All including pressors (amphetamines, cocaine, appetite
suppressants, diet and cold capsules, nasal sprays), fluid retainers
(birth control pill, adrenal steroids, NSAIDs), and other
(cyclosporine, MAO inhibitors, erythropoietin, licorice, thyroid
hormones)

Table XXVII-2
CAD indicates coronary artery disease; CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease; CV =
cardiovascular; CVA = cerebrovascular accident; DM = diabetes mellitus; FH = family history; HTN = hypertension; MAO =
monoamine oxidase; NSAIDs = nonsteroidal anti-inflammatory drugs; PVD = peripheral vascular disease; TIA = transient ischemic
attack.

Exacerbating factors–exacerbate or precipitate hypertension in predisposed individuals.

1. Sedentary and obesity are associated with an increase in intravascular volume and an
appropriately high output. Weight reduction in the obese modestly lowers blood pressure.
2. Excessive use of alcohol (more than two drinks per day--40 g of ethanol)
 increasing plasma catecholamines;
 vasodilatation, but inactivates the action of antihypertensive mechanisms and drugs;
3. Cigarette smoking -- acute effect by increasing plasma norepinephrine and vasoconstriction
4. Age over 40 years (in a hypertensive family).
5. Prolonged stress.
6. Therapeutical drugs (see secondary hypertension etiology).

Clinical features:

I. Symptoms – usually there is a long asymptomatic period (“silent killer”)

1. Headache -- especially occipital, early in mornings (some patients are important
aspirin or antineuralgics consumers.
2. Dizziness – at movements made by the head (may also appear in an overdosed
patient, caused by orthostatic hypotension).
3. Sensory disturbances:
 Visual: blurred vision, foggy vision, “flying insects”. On effort (e.g.: cough)
temporary hemianopsy may also appear.
 Auditory: pulsations in the ear.
4. Cardiovascular complains:
 Palpitations.
 Dyspnea.
 Precordial stabbing – angina pectoris

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II. Physical examination (see table XXVII-3)
1. Increased intensity of 2nd heart sound in aortic area.
2. Mitral regurgitation murmur (mitral ring enlargement caused by left ventricle
dilatation and hypertrophy) – heart failure.
3. Tachycardia, tachyarrhythmia on effort (premature beats, atrial fibrillation, atrial
flutter).
4. Left ventricular gallop on effort (left ventricle failure)
5. Systemic hypertension – brachial artery blood pressure determinations:
 Both arms.
 Orthostatism and clinostatism.
 Repeated after 2 hours.
 One hour after smoking and 12 hours after alcohol intake.

* If diastolic blood pressure increases in orthostatism with more than 15 mm Hg, renovascular
hypertension is suspected (normally, in orthostatism, systolic pressure decreses and diastolic
pressure increases, but these variations are less than 10 mm Hg).

Table XXVII-3: Initial physical exam for hypertensive patients

1. Vital signs, including 2 BP determinations (averaged) both supine or sitting and standing,
separated by 2 minutes; notation and selection of “higher” arm if asymmetrical BPs; ankle-
brachial index or arm and leg BP.
2. Weight and height, calculation of BMI (weight in kg/height in m).
3. Funduscopic exam for retinopathy.
4. Neck exam for carotid artery pulsation and bruits, jugular venous distention, thyromegaly.
5. Cardiac and chest exam for heart size, murmurs, gallops, arrhythmias, and rales.
6. Abdominal exam for masses, bruits, abnormal aortic pulsations.
7. Extremity exam for peripheral vascular pulses, femoral bruits, edema, and discordance of
radial and femoral pulses.
8. Neurologic exam.
9. Check for stigmata of gout, dyslipidemia, thyroid dysfunction, Cushing’s syndrome,
neurofibromatosis.

Potential errors in blood pressure measurement:

Equipment:
1. Inaccurate or uncalibrated manometer.
2. Improper sphygmomanometer bladder size.
Patient preparation:
1. Not resting for 5 minutes in quiet, comfortable environment.
2. Drinking caffeine-containing beverage or smoking within 30 minutes.
Observer technique:
1. Not supporting arm or torso to decrease muscle artifact.
2. Not keeping arm position at heart level.
3. Not centering cuff bladder on brachial artery.
4. Not estimating SBP by palpating radial pulse before auscultation.
5. Not keeping eyes at level of mercury manometer.
6. Not consistently using Korotkoff Phase IV or Phase V sounds for diastolic blood pressure.
7. Inflating bladder too slowly or deflating it too fast.
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 8. Not measuring in both arms at first to establish symmetry.
9. Not completely deflating cuff and waiting 1-2 minutes before re-measurement.
General caveats:
1. Misinterpreting any auscultatory gap.
2. Not integrating distortion from any cardiac arrhythmias.
3. Ignoring potential observer errors: threshold bias from prior readings, preference for
particular numbers (digit preference) or rounding off.

Paraclinical investigations – implicates the “target organs” examinations, for functional or/and
morphological changes.

Initial tests -- to establish baseline levels and search for cardiovascular risk factors in hypertensive
patients:
Strongly recommended  Serum potassium, creatinine blood glucose
(preferably fasting), total and HDL-cholesterol,
urinalysis
Desirable but not essential  Complete blood count, uric acid, triglycerides,
electrocardiogram
Sometimes useful  Plasma renin/urinary sodium ratio, echocardiogram,
home or ambulatory blood pressure monitoring

Potentially useful in the future  Lipoprotein

I. BRAIN
1. Neurological examination
2. FUNDUSCOPIC examination – cerebral arteries appreciation by retinal arteries
examination:

KEITH – WAGENER – BARKER Funduscopic Classification

(KWB)

Grade I – normal aspect or narrowing of the arteriolar lumen (and

veins) (retinal angiopathy).

Fig.XXVII-3 : Grade I

Grade II:
– retinal angiopathy + arterio-venous crossing sign (Salus-
Guhn) (arteriovenous kinking):
 IIa: diminished venous caliber over the
crossing;
 IIb: arterioloconstriction and venodilatation;
 IIc: IIb + vessel deviation.
-- small caliber retinal arteries, having thick irregular
walls, with loss of transparency (“silver wiring”)
Fig. XXVII-4: Grade II
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Grade III – I + II + hemorrhages, exudates (old or new) Hypertensive
Grade IV – I + II + III + symmetric papillary edema. retinopathy

Fig. XXVII-6:
Grade IV
Fig. XXVII-5:
Grade III

II. HEART
Chest X-ray – left ventricle hypertrophy (or normal).
ECG:
 Stage I – normal.
 Stage II -- left ventricle hypertrophy (LVH)
 Stage III – various changes, other than LVH: arrhythmias, conduction
disturbances, ischemic changes.

III. KIDNEYS
1. Microhematuria.
2. Proteinuria.
3. Increased seric creatinine over 1.3 mg%.
4. Creatinine clearance under 80 ml/min.
5. Urinary density under 1020.

PRIMARY (ESSENTIAL) HYPERTENSION STAGING (WHO)

Stage I -- Systemic hypertension with non affected target organs (is allowed fundus gr. I)

Stage II
 Left ventricular hypertrophy.
 Fundus of the eye examination grade I or II.
 Mild proteinuria or slight decrease of creatinine clearance.
Stage III
 Fundus examination grade III or IV (hypertensive retinopathy).
 ECG changes others than LVH.
 Congestive heart failure.
 Impaired renal function: proteinuria, hematuria, casts, reduced creatinine clearance

Stage IV -- malignant hypertension (“accelerated”)

 Diastolic blood pressure > 130 mm Hg.
 Severe rapid progressive hypertension:
 Rapid renal failure
 Malignant nephrosclerosis

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  Survival time without treatment: maximum 2 years.
 High resistance to treatment.

Resistant or refractory hypertension is defined as failure to lower blood pressure to <140/90

mm Hg despite a regimen of three antihypertensive agents, may occur from factors related to the
prescribing clinician, the patient, the disease, or combinations of all three

* Differential diagnosis of refractory hypertension

1. Specific identifiable disorder (2° hypertension) (10%)
2. Exogenous substances (15%)
(a) Agents that raise blood pressure in susceptible person
(b) Agents that interfere with antihypertensive drug action
3. Complicating biological factors (5%)
4. Inappropriate or inadequate drug regimen (45%)
5. Noncompliance or partial compliance with regimen (25%)

COMPLICATIONS

I. Cardiac complications:
a. Hypertensive cardiopathy – LVH progressing to left ventricular failure (cardiac
asthma, arrhythmias, conduction disturbances).
b. Ischemic heart disease -- angina pectoris, acute myocardial infarction, arrhythmias,
sudden death.

II. Renal complications (the kidney may sometimes be the cause, but is mostly the victim of
systemic hypertension).
 Hypertensive nephrosclerosis with consecutive renal insufficiency
 Impaired renal function: proteinuria, hematuria, reduced creatinine clearance.

III. Nervous complications (produced by accelerated atherosclerosis, hemodynamic

traumatizations and ruptured aneurysms).
a. Cerebral or cerebro-meningeal hemorrhage -- sudden onset of hemiplegia or coma.
b. Hypertensive retinopathy.
c. Cerebral thrombosis – arise from atherosclerosis of large arteries (commonly the middle
cerebral and carotid): progressive onset + previous signs suggestive for atherosclerosis.
d. Hypertensive encephalopathy – cerebral edema (usually diastolic blood pressure > 130
mm Hg)
 Severe pulsatile headache.
 Photophobia.
 Hemianopsy
 Vomiting.
 Visual or speech defects.
 Convulsions.
 Coma.
e. Transient ischemic attacks (strokes) – transient palsies.

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IV. Other vascular complications
1. Obliterative arteriopathy of the lower limbs (acute or chronic).
2. Aortic dissecting aneurysm.
3. Vascular rupture (epistaxis, hematemesis, melena).

SECONNDARY HYPERTENSION

Definition: Systemic hypertension having a known cause.

Classification (etiology):

I. RENAL SYSTEMIC HYPERTENSION:

1. Renal Parenchymal Disease
 Acute and chronic glomerulonephritis.
 Chronic pyelonephritis.
 Congenital polycystic kidney.
 Renal tuberculosis.
 Reninoma (renin-secreting tumor).
 Small unilateral kidney.
 Diabetic glomerulosclerosis.
 Collagen diseases (SLE, SD, PAN).
 Drug-induced renal dysfunction (e.g., phenacetin-associated analgesic nephropathy).
 Other causes of chronic renal insufficiency (renal amyloidosis, gout nephropathy, IgA
nephropathy, etc.)
2. Renovascular (significant stenosis of one or both renal arteries)
 Congenital (renal artery dysplasia).
 Acquired (atherosclerotic disease or external compressions).

II. ENDOCRINOLOGIC SYSTEMIC HYPERTENSION

1. Suprarenal gland diseases:
 Hypersecretion of the cortical part -- Cushing’s Syndrome (glucocorticoid excess),
and Conn`s adenoma (primary hyperaldosteronism).
 Hypersecretion of the medullar part – Pheochromocytoma (catecholamine-secreting
tumor).
2. Thyroid gland disease – hyperthyroidism.
3. Parathyroid gland disease -- hyperparathyroidism.

III. CARDIOVASCULAR SYSTEMIC HYPERTENSION

1. Congenital: Coarctation of Aorta, 3rd degree atrioventricular block.
2. Acquired: Aortic insufficiency, 3rd degree atrioventricular block.
3. Hyperkinetic beta adrenergic syndrome:
 Males under 20 years of age.
 Tachycardia.
 Systolic hypertension (raised cardiac outflow, normal or decreased peripherial
resistance, hypervolemia).
 Elective medication: beta blockers.
4. Atherosclerotic systemic hypertension of the elderly (Coneway`s criteria):
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  Differential blood pressure > Diastolic blood pressure.
 Diastolic blood pressure < 100 mm Hg.
 Systolic blood pressure > 100 + age
 Age over 70 years.

IV. PHARMACOLOGIC SYSTEMIC HYPERTENSION

1. Vasoconstrictors:
 phenylephrine, pseudoephedrine, phenylpropanolamine;
 b-agonist bronchodilators, and other sympathetic amines;
 monoamine oxidase inhibitor cotreatment with tyramine-containing foods or
medications.
2. Volume expanders:
 glucocorticoids;
 estrogens (oral contraceptives);
 nonsteroidal anti-inflammatory agents that inhibit prostaglandins and thromboxane A2
via cyclo-oxygenase.
3. Miscellaneous:
 psychotropic drugs that interfere with sympatholytic antihypertensive agents;
 cyclosporine;
 erythropoietin.

V. PREGNANCY SYSTEMIC HYPERTENSION – positive diagnosis is made in the presence

of 2 of the following 3 signs: edema, proteinuria and hypertention (systolic BP with over 30
mm Hg the value before pregnancy but at least 150 mm Hg, and diastolic BP > 90 mm Hg).

VI. NEUROLOGICAL SYSTEMIC HYPERTENSION (increased intracranial tension)

1. Cerebral tumors (especially near the medulla and hypothalamus).
2. Meningitis, encephalitis.
3. Post-traumatic hematomas.

AORTIC COARCTATION
Definition: Coarctation of the aorta is a stenosis of the Stahel`s isthmus, situated immediately under
its emergence from the aorta of the left subclavicular artery, near the arterial canal – ductus
arteriosus, transformed into arterial ligament in adults.
History:
 In 1760, the disease was first described by Morgagni.
 First successful surgical operation – 1944, by Crafford-Nylin and Gross-Hufnagel.

Incidence: 0.5 – 1% of secondary hypertension.

Classification (Edwards):
1. Preductal aortic coarctation (infantile type): a) open duct; b) closed duct.
2. Postductal aortic coarctation (adult type).
3. Aortic coarctation along with anomalies of the left subclavicular artery or the aortic cross.
4. Aortic coarctation having atypical localization.

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 AORTA

COARCTATION

SUPERIOR EPIGASTRIC ARTERY

INTERCOSTAL
ARTERIES
INFERIOR EPIGASTRIC ARTERY

Fig. XXVII-7: Collateral circulation in coarctation

of aorta

Positive diagnosis:
Symptoms:
 Above coarctation (head, neck, upper limbs and superior half of the thorax).
1. Headaches (pulsatile), sweats, palpitations.
2. Increased pulsations (visible at the carotid arteries)
3. Hypervascularization.
 Below coarctation (inferior half of the thorax, abdomen and lower limbs):
1. Coldness, paraestesis.
2. Intermittent claudication.
Signs:
1. Symmetrical absence of the femoral pulse at the level of the Scarpa`s triangle (or
chronic diminished pulse).
2. Existence of a rich (palpable) collateral circulation (over 12 years of age):
 Intercostal – Suzman`s sign.
 Periscapular.
3. Hypertension in superior limbs and hypotension of the inferior limbs.
4. Left parasternal systolic ejection murmur in the 3rd intercostal space (+/- in the left
interscapulo-vertebral area), having a downwards radiation.
5. Visible pulse and fremitus in the jugular incision.

N.B !
Any young hypertensive patient with weak or absent femoral pulse must be suspected for aortic
coarctation !

Paraclinical investigations:
1. Chest X-ray:
 Direct features:
a. Disappearance of the “aortic button” (left superior arch of the heart) – “chimney-
like aspect”
b. Prominent left inferior arch of the heart (left ventricle hypertrophy).
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 c. “Index sign” – sometimes on the left margin of the heart may show a “3” like
image.
d. On a barium filled esophagus, 2 imprints (making the aspect of inverse “E”) may
be seen.
 Indirect features:
a. Ribs erosions (more frequently observed on the 3rd and 4th ribs, posteriorly).
2. Oscillography: decreased arterial pulse on the inferior limbs compared to the superior
limbs.
3. Angiography: precise location, form, stretching, and collateral circulation appreciation.
4. Pressure catheterism: high pressure above stenosis, and low pressure below stenosis.
5. ECG: Strain type left ventricular hypertrophy (T wave opposition).

Complications:
1. Cerebral hemorrhage.
2. Infective endocarditis.
3. Ruptured of the aortic coarctation causing sudden death.
4. Left ventricular failure.
5. Descending aortic dissection aneurysm.

RENOVASCULAR SYSTEMIC HYPERTENSION

Definition: Hypertension due to significant stenosis of the renal artery (or arteries).

Pathophysiology: Activation of the renin-angiotensin-aldosterone as a result of a compromise

arterial flow to either or both kidneys. Depending on the status and participation of the contralateral
kidney, the ischemic stimulus may elevate renin, promote fluid retention, or both. (E. Topol)

Classification of the renal artery lesions:

I. Dysplasia of the renal artery wall (McCormack and Harrison classification 1971).
1. Intimal fibroplasia 1% (concentric stenosis in the middle part of the artery).
2. Fibromuscular dysplasia of the media (25% of all renovascular
hypertension and occurs almost exclusively in younger patients, especially
females).
 medial fibroplasia – 70%
 perimedial fibroplasia.—20%
 medial hyperplasia
 medial dissection
3. Adventitial fibroplasia – very rare.
4. Periarterial fibroplasia.
II. Atherosclerotic disease -- 70% of the total all renovascular hypertension, usually
involves the proximal third of the renal artery +/- the ostium. Asymmetric stenosis.
III. Less common causes of renovascular hypertension include:
 Takayasu’s arteritis;
 polyarteritis nodosa;
 aneurysms of the renal artery;
 radiation fibrosis;
 thromboembolism (including cholesterol emboli);
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  extrinsic compression of the renal arteries by tumor;
 abdominal aortic coarctation..

Diagnosis:
1. Age: under 35 (white woman) = congenital; above 55 = atherosclerosis.
2. History: lumbar trauma, abdominal pain, coronary, cerebrovascular, or peripheral vascular
insufficiency.
3. Presentation: (a) recent-onset hypertension in a young white woman or (b) late onset or
exacerbation of hypertension in an older man.
4. Physical examination:
 Paraumbilical and lumbar stenotic murmurs (bruits) – 30-50% of cases.
 Raised diastolic blood pressure over 115 – 120 mm Hg, especially in the
orthostatic position.
5. Arteriography remains the gold standard in positive diagnosis:
 Narrowed arterial lumen (50% = surgical indication).
 Post-stenotic dilatation.
 Delayed blood flow in the affected kidney.
 Evidence of an increased collateral circulation (capsular, suprarenal, uretral).
 Pressure gradient (> 40 mm Hg, < 40 years of age = surgical indication).
6. Captopril scintigraphy (combines radionuclide scanning of the kidney (especially with
mercaptoacetyltriglycine) with captopril stimulation to enhance differences in renal blood
flow).
7. Intravenous pyelography (gives both morphological and functional informations).
8. Doppler ultrasound offer promising results but are not
9. Magnetic resonance technologies yet cost-effective alternatives
10. Blood tests:
 Hypokaliemia (+/- hypernatremia).
 Alkalosis.
 Mild azotemia and proteinuria.
 Plasma renin activity – very much increased (>3.2 ng/ml/min). If the ratio between
the renal veins is >1.5 = surgical indication).

PHEOCHROMOCYTOMA
Labb-Tinel Doumer syndrome (1922)

Definition: Adrenal medulla catecholamine-secreting tumor.

History: The first surgical resection was performed in 1927 – Mayo. High risk of accidents during
surgery.

General considerations:
 Frequency: 0.5 – 1% of total cases of systemic hypertension.
 Age: between 16 months and 82 years. Maximum incidence: 40 years. (25-55)
 Sex: increased incidence in females.
 Important family antecedents.
 “The rule of 10%” (pheochromocytoma is 10%):
1. Extra-adrenal.
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 2. Familial.
3. Occurs during childhood.
4. Malignant.

Pathology:
1. During embryological stages, there is a migration of pheochromoblast cells from the
neural crest towards periphery. These cells are absorbing chrome (Henle coloration),
transforming itself into pheochomocyte cells, that populates the suprarenal gland and the
sympathetic tissue:
 90% in the medullar part of the suprarenal gland (producing adrenaline and
noradrenaline), and
 10% in the paragangliomas (producing noradrenaline):
 Paravertebral sympathetic chains.
 Zuckerkandel organ (bifurcation of the aorta).
 Carotidian glomus.
 Aortic glomus (origin of the carotid arteries)
2. Large tumor (16 – 800 g), usually multiple, benign, but highly vascularised.
3. Malignant pheochromocytoma:
 Not having very high blood pressure values.
 Early metastasis on the hematogenous way: lymph nodes, liver, lungs.
4. The pheochromocytoma is frequently associated with other tumors:
 Rechlinghausen disease (braun spots + cutaneous tumors).
 Thyroidal cancer + hyperthyroidism = Sipple syndrome (MEN type 2)
 Uterus cancer, lung cancer.

Presentation – 4 types:
1. Severe hypertensive crisis (episodic hypertension) – 50 % of cases..
2. Permanent hypertension where a paroxistic crisis may occur.
3. Normotensive
4. Orthostatic hypotension.

Diagnosis:
Clinical supposition:
I. The classic triad (Thomas – Roth – Kvale) is accompanying the hypertension:
 episodic headache
 palpitations with or without tachycardia (tremors)
 inappropriate increased perspiration (obligatory symptom)
II. Adrenergic myocarditis:
 Arrhythmias.
 ECG repolarization changes (ST and T)
III. Metabolic disturbances:
 Hyperglycemia.
 Increased basal metabolism.
 Increased level of fatty acids in the blood.
IV. Renal disturbances:
 Mild azotemia.
 Urea clearance = normal.
V. Blood cells disturbances:
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  Leukocytosis.
 Polycytemia.
VI. Fever (intratumoral necrosis).
VII. Miscellaneous:
 Erytrocyanosis of the extremities.
 Vasomotor disturbances, flushing.
 Lumbar, or thoracic pain.
 Weight loss.
 Weight gain, vomiting, diarrhea.
 Unresponsiveness to appropriate triple drug therapy.
 Paroxysmal hypertension associated with clinical procedures.
 Hypertension developing after phenothiazine, tyramine, or tricyclic
medications.
 Pregnancy may unmask the disease, as the growing uterus applies pressure
on the adrenal gland.

Biochemical confirmation:
1. Increased level of vanillylmandelic acid, in urine. Normal dosage = 4-8 mg/24h. Over 20
mg/24h (up to 100 mg/24h) = pheochromocytoma.
2. Increased level of plasma methanephrine (x 3). Normal = 1.2 – 1.3 mg/day (more sensitive
than either serum catecholamines or urinary metanephrines for the diagnosis of
pheochromocytoma).
3. Increased level of plasma catecholamines (over 8 micrograms). In urine: over 100
micrograms.

Imaging -- localization:
1. Echography (large tumor).
2. Intravenous pyelography (renal ptosis + the tumor falls internally).
3. Computer tomography.
4. Selective arteriography (sometimes, the contrast substance can produce catecholamine
secretion overreaction = dangerous !).
5. Suprarenal phlebography.
6. Scanning by [131I] meta-iodobenzylguanidine (MIBG) uses a guanethidine analogue with
affinity for chromaffin tissue.

Diagnosis tests:

1. Oral clonidine suppression test (plasma catecholamine levels before and after clonidine 0.3 mg
orally) or overnight clonidine suppression test (clonidine 0.3 mg orally at 9 pm with overnight
urine collections). Clonidine serves to reduce central sympathetic outflow among those with
essential hypertension but leaves autonomous secretion unaffected.
2. The provocative tests (histamine, glucagon, tyramine) are used rarely or relegated only to the
small number of individuals with ambiguously mild elevations but strong clinical suspicion.
3. Phentolamine suppression test – 5 mg of phentolamine i.v. diminishes the blood pressure with
more than 35/25 mm Hg, in maximum 2 minutes, and lasts at least 15 minutes.

Differential diagnosis:
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 1. Hyperthyroidism (tachycardia, tremors, weight loss, perspiration – common for both
diseases).
2. Nervous asthenia.
3. Diabetes mellitus with hypertension.
4. Epilepsy.

Clinical forms -- predominance of:

1. Rhythm disturbances.
2. Metabolic disturbances.
3. Perspiration.
4. Hematological disturbances.
5. Malignant form.

CONN`S ADENOMA
(Primary hyperaldosteronism)

Definition: Mineralocorticoid excess produced by an adrenal adenoma.

Pathophysiology
1. Autonomous secretion of plasma aldosterone.
2. Aldosterone increases distal tubular sodium resorption and potassium secretion, increases
intravascular volume, and suppresses renin secretion.
3. Secreted in excess, aldosterone produces a volume-dependent hypertension and
hypokaliemia.

Classification of hyperaldosteronism:
I. Primary hyperaldosteronism
 Adenoma -- (60%–90% of the total) is benign, unilateral tumor of the
adrenal gland (aldosterone-producing adenoma, APA) Conn`s syndrome.
 Carcinoma of the adrenal gland.
 Bilateral hyperplasia of the adrenal gland -- usually congenital (malignant
hypertension) also named idiopathic hyperaldosteronism (IHA).
 Enzymatic deficiencies (11-OH-hydroxylase deficiency, 17-OH-
hydroxylase deficiency, and 11-OH-dehydrogenase deficiency syndromes)
II. Secondary hyperaldosteronism:
 Renal vasoconstriction.
 Vascular hypovolemia.:
1. Cirrhosis with ascites.
2. Nephrotic syndrome with edema.
3. Congestive heart failure with edema.

Pathology:
1. Small tumor (maximum weight ~ 30 g).
2. Encapsulated yellow tumor.

Clinical diagnosis:

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 1. General data:
 More common in women than in men, generally presenting in the third to sixth
decade.
 Mild, persistent hypertension, having few complications.
2. Hypertension symptoms:
 Long history of headache.
 Absence of edema.
3. Hypokalemia symptoms:
 Decreased muscular force (felt in ascension of stairs), early morning muscular
weakness (fatigue), accentuated on effort (unusual “muscular fever”).
 Paraestesia, periodic paralysis.
 Polyuria with nicturia.
 Neuro-muscular hyperexcitability.
4. No signs of neurological lesions.

Hypokalemia
Prominent U wave

Flat T + U wave

MILD SEVERE
Paraclinical diagnosis:

I. Metabolic effects of aldosterone excess:

1. Hypokalemia (K+ < 3.5 mEq/l) -- may reach panic values (< 2.8 mEq/l), especially after
diuretic therapy.
2. ECG characteristic for hypokalemia:
 Large “U” wave.
 P and T waves are flat (sometimes T+ U)
 Depressed ST segment.
 Arrhythmia (risk of ventricular fibrillation).
3. Hypernatremia.
4. Metabolic alkalosis.
5. Urinary biochemical features:
 Hyperkaliuria (> 30 mEq/l).
 Normal urinary Na+.
 Urinary density under 1024 mOsm/l.
 Urinary pH over 6 (alkaline urine).
6. Mild alteration of the renal function: mild proteinuria, with minor abnormal clearances.

II. Confirmation of inappropriately, autonomous high aldosterone secretion:

1. a 24-hour urinary collection for aldosterone -- the single best screening test for the
condition, after withdrawing all diuretics and ACE - inhibitors for > 2 weeks and all
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 aldosterone antagonists for > 6 weeks and repleting fluid status, sodium, and potassium to
normal levels, if necessary with 3 to 5 days of salt loading to ensure 24 - hour urinary
sodium of > 200 mEq/l. Normal urinary aldosterone level = 50 micrograms/24 h.
2. Increased plasma level of aldosterone. Normal value = 2-4 ng%. Increased salt intake diet
is not affecting the plasma aldosterone level.
3. Decreased, autonomous plasma renin activity (PRA). Normal value = 0.8-2.1 ng/ml/min.
4. Plasma aldosterone (PA) to plasma renin activity (PRA) ratio , if patients can be safely
withdrawn from antihypertensive medications > 2 weeks. A PA/PRA ratio >30 and a PA
>20 ng/ml may yield a sensitivity of 90%, a specificity of 91%, a positive predictive value
of 69%, and a negative predictive value of 98%.
5. Melby test: Antialdosteronic drug administration (Aldactone 4 x 100 mg/day, 4 weeks) is
normalizing the blood pressure, and the plasmatic kalium level.

III. Tumor localization (small tumor)

1. CT scans -- can detect adenomata of > 0.7 cm but  8% of the normal population may
have nonfunctioning, incidental adrenal adenomata.
2. MRI scanning offers no clear advantage comparing with CT scan.
3. Dexamethasone and Lugol’s solution pretreatment and (6-131) iodomethyl-19-
norcholesterol (NP-59) scanning may highlight a functioning mass while suppressing
surrounding adrenal tissue and protecting the thyroid. Unfortunately, scanning must
proceed over 2 to 5 days and carries only a 72% accuracy that is highly dependent on the
tumor’s size.
4. Adrenal gland arteriography.

Positive diagnosis:
1. Moderate hypertension.
2. High autonomous aldosterone level (in plasma and urine).
3. Low plasma renin activity.
4. Hypokaliemia and hyperkaliuria.

Differential diagnosis:
1. Essential hypertensive with low renin.
2. Drug induced hypertension (may have also hypokalemia).
3. Reninoma (Robertson-Kihara) – also a small renal tumor.
4. Idiopathic hyperaldosteronism (bilateral hyperplasia, IHA):
Orthostatic tests for APA versus IHA are based on two complementary features:
 (a) APA usually display autonomous aldosterone secretion, unaffected by
physiologic stimuli, such as standing, but exquisitely sensitive to the diurnal
variation in cortisol secretion.
 (b) IHA exhibit no particular diurnal variation but marked responsiveness to renin-
based stimuli like standing. Most critically, the change in plasma aldosterone from
8 am to noon after overnight recumbency must be interpreted in the context of the
concomitant changes in PRA and plasma cortisol. An increase in plasma cortisol
during the procedure invalidates the test because the procedure seeks to compare
the relative strength of two stimuli: orthostatic stimulation from standing versus
the physiologic fall in cortisol over the morning hours.

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 Secondary hypertension

Clues from Diagnostic tests

Condition History Physical Early lab Screening Definitive Comments
Renal disease Active urinary False
Urinary tract sediment Elevated 24-hour urinary reassurance
Renal infections Flank/abdominal creatinine protein [renal biopsy] with “normal”
parenchymal Diabetes mellitus mass Glycosuria Creatinine serum
disease Chronic analgesics Proteinuria clearance creatinine in
Anemia the elderly
Age <30,
especially female
Age >60,
Renovascular especially males Flank bruit Captopril renal scan Renal Split vein
hypertension New onset, rapid Peripheral Proteinuria [MRI] arteriography renins
course vascular no longer
Cardiovascular insufficiency required for
risk factors diagnosis
Family history of
vascular anomalies

Asymmetrical
pulses and Ankle: brachial index
blood pressure, Chest radiography ±
Coarctation of pulse delay notching of ribs Echocardiogram Aortography
the aorta arm: leg systolic
murmur or bruit

Vasoconstrictors
Drug Response Fluid retainers
Nephrotoxins

Abdominal mass Overnight

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 moon facies; dexamethasone 4-8 mg dexamethasone
Cushing’s Weight gain, acne, truncal obesity; Hyperglycemia suppression test (1 suppression test; CT or MRI scan
syndrome fluid retention, Striae, plethora, mg) CRH stimulation test
brushing Hirsuitism, 24-hour urinary
weakness free cortisol
Hypokalemia,
especially after 24-hour urinary Abdominal CT or MRI
Primary Weakness, potassium- aldosterone Adrenal vein sampling
hyperaldostero- paresthesia, wasting diuretics Orthostatic test Response to glucocorticoids
nism polyuria, tetany [diagnosis excluded Stimulated plasma
by potassium > 4 renin activity
mEq/I]

Paroxysmal
hypertension Spot urinary
Palpitations, metanephrine CT or MRI scan Provocative
headache, Orthostasis, Hyperglycemia 24-hour urinary 132I-MIBG tests
Pheo- sweating, fainting, tremor, posterior mediastinal metanephrine, total scan meta- no longer
chromocytoma weight loss perspiration mass on chest catecholamines, iodobenzylguan recommended
Procedure attacks Cardiomyopathy radiography VMA. Clonidine idine Tumor
Family history of suppression test [radiocholeste- palpation
multiple endocrine rolscan] in operating
neoplasm or room
neurofibromata

Nervousness, Tremor, goiter, Free thyroxine Thyroid uptake/scan

Hyperthyroidism Palpitations wide pulse Thyroid stimulating Antithyroid antibodies
Dysphagia, weight pressure, bruit, hormone
loss exophthalmos

Table XXVII-4. (modified from Topol E.: Cardiovascular Medicine Enhanced Multimedia Edition, Lippincott-Raven Publishers, 1998).

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