Secondary Hypertension (Parts 1 and 2)
by Norman M. Kaplan, MD, Professor of Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas
Secondary hypertension is
hypertension that can be ascribed to an identifiable cause. Up to 5-10% of the total
hypertensive population (2-5 million in the U.S. alone) have secondary hypertension,
emphasizing the importance of this condition. Indications for work-up include: history,
physical exam, and laboratory results suggesting a secondary cause; resistance to triple
drug therapy; BP worsening after a period of good control; accelerated or malignant
hypertension; and a negative family history of hypertension with diastolic BP > 110
mmHg. Clinical features, diagnostic tests, and treatment recommendations for the various
causes of secondary hypertension are described below.
A. RENAL PARENCHYMAL DISEASE |
Prevalence |
Renal parenchymal disease is the most common cause of secondary hypertension
(excluding obesity and alcohol abuse), and is responsible for 2-5% of all cases of
hypertension. |
Etiology |
Most commonly associated with chronic glomerulonephritis, hypertensive
nephrosclerosis, and diabetic nephropathy. Hypertension is primarily due to volume
overload. |
Diagnosis |
Renal
ultrasound (bilateral small scarred kidneys), renal biopsy. Laboratory findings include
azotemia, microalbuminuria, proteinuria, abnormal urinary sediment. |
| Treatment |
• Drug
therapy: Loop diuretics (may require multiple daily high doses) or metolazone
(effective as once-daily dosing). Nonresponders: Use of an ACE inhibitor, angiotensin
receptor blocker and/or calcium antagonist. If needed, follow with an alpha-blocker and/or
labetalol or a beta-blocker. Minoxidil is often useful when further therapy is required.
• Hemodialysis or renal transplantation may be required for hypertensive
control in end stage renal disease.
• Avoid nonsteroidal anti-inflammatory drugs, which inhibit the production of
vasodilatory renal prostaglandins. Also avoid potassium-sparing diuretics and potassium
supplements. |
B. RENOVASCULAR HYPERTENSION |
Prevalence |
Renovascular
hypertension is found in 1% of hypertensive patients and 20% of non-blacks with resistant
or accelerated-malignant hypertension. Less common in blacks. |
Etiology |
Atherosclerosis
is the cause in two-thirds of cases and is more common in older men and usually involves
the ostium and proximal third of the renal artery. Fibromuscular dysplasia is responsible
for the remaining one-third of cases and is more common in young females and often
bilateral. |
Presentation |
Suspect
the diagnosis in hypertensive patients with: Onset of hypertension < 30 years of age or
rapid onset after 50 years; resistance to 3-drug therapy; deterioration in renal function
after administration of ACE inhibitors or ARBs; uncontrolled hypertension after period of
good control; malignant hypertension; recurrent acute pulmonary edema; sudden worsening of
renal function in hypertensive patient; epigastric, subcostal or flank bruit; extensive
atherosclerosis elsewhere |
| Screen |
• Captopril
renography: Isotopic renography demonstrates a decrease in renal blood flow or GFR
by > 20% with a > 10% difference between the two sides. Renin response
may also be helpful: A positive test requires a stimulated plasma renin activity (PRA) of >
12 ng/ml/hr, an absolute increase in PRA > 10 ng/ml/hr, and a >
150% increase in PRA above baseline (> 400% if baseline below 3
ng/ml/hr). If possible, all antihypertensive agents should be withdrawn 3 days prior to
testing. After sitting for at least 30 minutes, venous blood for PRA is drawn at baseline
and 60 minutes after 25 mg of oral captopril (diluted in 10 ml of water).
• Renal duplex sonography is a useful screen if performed by experienced
sonographer.
• MRA angiography is useful, particularly in the presence of renal
insufficiency. |
| Diagnosis |
Renal arteriography
is needed to document the diagnosis. In patients with bilateral disease,
lateralization of renal vein renin predicts improvement in BP after revascularization in
80-85%. However, failure to lateralize has low predictive accuracy for the diagnosis. In
patients with unilateral disease, a positive captopril-challenge isotopic renogram is
usually adequate to confirm the functional significance of a lesion. |
Treatment |
(1)
Renal artery revascularization relieves hypertension in 60-85% of cases.
• Atherosclerotic disease: Surgery is the most reliable form of
therapy, but angioplasty with stenting may be as effective. If the lesion is short,
segmental, and unilateral, short-term balloon angioplasty results compare favorably with
surgical correction; restenosis, which may occur in up to 25% of cases, usually responds
to repeat dilatation, particularly with stenting. When plaque extends from the abdominal
aorta to involve the renal artery orifice, balloon angioplasty success and long-term
patency rates are diminished but are improved with stenting. Most agree that
revascularization is indicated for: poorly-controlled hypertension; renal function that
deteriorates on medical therapy; and for younger patients and those intolerant or
noncompliant with medical therapy.
• Fibromuscular dysplasia: Balloon angioplasty/stent is treatment of
choice (high success and low restenosis rates).
(2) Medical therapy:
ACE inhibitor, calcium antagonist, beta-blocker, or diuretic. ACE inhibitors are
very effective at controlling BP but may cause acute renal failure if bilateral renal
artery stenosis or unilateral renal artery stenosis of a solitary kidney is present or
develops. Even when BP is adequately controlled on medical therapy, renal dysfunction and
loss of renal mass may develop. Therefore, renal function and size should be followed
every 3-6 months. |
C. PRIMARY ALDOSTERONISM |
Prevalence |
Present
in < 1% of patients with hypertension, although reported to be more common when
patients are screened by plasma aldosterone-to-renin ratios (ARR) (Steroids
1995;60:35-41). |
Etiology |
Adrenal
adenoma (60%), bilateral adrenal hyperplasia (40%) in classical disease. BAH is more
common in early, normokalemic patients identified by AAR. |
Presentation |
Hypertension
with hypokalemia, which may first become evident during treatment with diuretics (75%
have serum potassiums < 3.5 mEq/L). Others manifestations include muscle pain, cramping
or weakness, polyuria, polydipsia, metabolic alkalosis, impaired carbohydrate tolerance,
multiple renal cysts. |
| Screen |
• Plasma
renin activity (PRA) < 1 ng/ml/hr and plasma aldosterone-to-renin ratio > 50
suggest the diagnosis. (Plasma aldosterone [PA] levels should be above normal since many
essential hypertensives have low renin levels, which would give a high ratio even with a
normal PA.)
• 24-hour urine potassium (UK) while patient is
hypokalemic, ingesting a normal sodium intake (urinary sodium excretion > 100 meq/day),
and not receiving supplemental potassium or diuretics. If UK is < 30
meq/day, primary aldosteronism is essentially excluded; if > 30 meq/day, continue
workup. |
| Diagnosis |
• A
highly abnormal plasma aldosterone-to-renin ratio (> 100) may be enough to proceed to
abdominal CT or MRI. Most also measure 24-hour urine for aldosterone and sodium after IV
or oral salt loads. To do this, discontinue diuretics and replenish normal body stores
and serum levels of potassium to within normal range (may take weeks to months). Then
administer either a high sodium diet for 5 days or IV normal saline (2 liters over 4
hours). Primary aldosteronism is diagnosed if either urinary aldosterone exceeds 14 ng/dL
on a high sodium diet, or if recumbent serum aldosterone exceeds 10 ng/dL following an IV
saline load.
• An abdominal CT or MRI should be obtained to distinguish bilateral adrenal
hyperplasia from adrenal adenoma. If nondiagnostic, an adrenal scintillation scan with
iodinated cholesterol derivative is often of value. If these tests continue to be
nondiagnostic, the diagnosis can be made by bilateral adrenal vein catheterization (less
than 2-fold difference in aldosterone suggests hyperplasia). |
| Treatment |
•
Bilateral adrenal hyperplasia: Potassium-sparing diuretic (spironolactone, amiloride
or triamterene) ± calcium antagonist.
• Adrenal adenoma: Preoperative therapy with spironolactone followed by surgical
resection. 75% of patients are cured. |
D. CUSHING'S SYNDROME |
Prevalence |
Present
in < 1% of patients with hypertension. |
Etiology |
Excessive
pituitary ACTH is responsible for 70% of cases, is usually caused by a pituitary adenoma,
and results in bilateral adrenal hyperplasia. Other causes include adrenal adenoma or
carcinoma (15%) and ACTH-producing extra-adrenal tumors (15%). |
Presentation |
Manifestations
include truncal obesity, moon facies, ecchymosis, muscle atrophy, edema, striae, acne,
hirsutism, osteoporosis, glucose intolerance, and hypokalemia. |
Screen |
•
24 hour urinary free cortisol levels > 100 mcg suggest the diagnosis.
• Overnight dexamethasone suppression test: 1 mg of dexamethasone at
midnight followed by plasma cortisol at 8:00 a.m. If level > 7 mcg/dL, proceed with
prolonged dexamethasone suppression test (see below). |
Diagnosis |
Measure
basal plasma ACTH levels and perform a prolonged dexamethasone suppression test:
Administer 0.5 mg every 6 hrs x 2 days followed by 2 mg every 6 hrs x 2 days. Measure
urinary free cortisol and plasma cortisol on the second day of each dose.
• Adrenal tumor: Failure to suppress on low or high dose; ACTH
undetectable.
• Ectopic ACTH syndrome: Failure to suppress on low or high dose; ACTH
very elevated.
• Cushing's disease (excess pituitary ACTH, bilateral adrenal
hyperplasia): Failure to suppress on low dose but suppressed to < 50% of control value
by high dose; ACTH normal to elevated. |
Treatment |
•
Pituitary adenoma: Transphenoidal microsurgery improves signs and symptoms in
80%. Heavy-particle irradiation also of value. Bilateral adrenalectomy is generally
reserved for disabling symptoms unresponsive to other therapy. Ketoconazole and mitotane
inhibit adrenal cortisol secretion.
• Ectopic ACTH syndrome: Remove tumor when feasible. Ketoconazole,
metapyrone, aminoglutethimide, alone or in combination.
• Adrenal adenoma or carcinoma: Surgical resection. Mitotane for
residual or nonresectable tumor.
• Drugs should not be considered primary therapy, although they may be
of adjunctive value (diuretic plus spironolactone). |
E. PHEOCHROMOCYTOMA |
| Prevalence |
Present in < 1% of
patients with hypertension. |
| Etiology |
More than 80% are
single, benign, norepinephrine-producing tumors of the adrenal medulla: 10% are
malignant, 10% bilateral, and 10% are familial (associated with multiple endocrine
neoplasia Type IIA [medullary carcinoma of thyroid, parathyroid hyperplasia] and IIB
[mucosal neuroma syndrome]). |
| Presentation |
Hypertension is
persistent in 50% and paroxysmal in 50%; a few patients are normotensive. May also
present with episodic palpitations, headache, sweating, orthostatic hypotension, weight
loss, and glucose intolerance. |
Screen |
•
Plasma metanephrine (Ann Intern Med 2001;134:315)
• 24 hour urinary total metanephrines > 1.3 mg. False positive tests
are much more likely if the patient is taking sympathomimetic drugs, MAO inhibitors (e.g.,
phenelzine, tranylcypromine), or labetalol. False negative results have been seen after
x-ray contrast media containing methylglucamine.
• Plasma catecholamines > 2000 pg/ml. Many acute illnesses (e.g., MI,
shock) and chronic disorders (e.g., depression, COPD, CHF) can elevate plasma
catecholamines and cause false-positive test results. If 500-2000 pg/ml, the clonidine
suppression test is used to make the diagnosis (see below). |
Diagnosis |
•
Clonidine suppression test: After resting for 30 minutes after placement of an
indwelling venous catheter, obtain basal plasma catecholamines; give 0.3 mg clonidine
orally and obtain repeat samples at 2 and 3 hours. Positive test: failure to suppress by
> 50%.
• Tumor localization: CT scan able to localize tumor in 90% of
cases (i.e., when tumor is > 1 cm in diameter). Others: I-MIBG [131] scan or selective
arteriography with regional catecholamine levels. |
Treatment |
•
Immediate treatment of severe Hypertension: Phentolamine (IV).
• Long-term therapy: Surgical resection is the treatment of choice. Pre-operative
alpha-receptor blockade (phenoxybenzamine or doxazosin until normotensive x 5-10 days)
is often recommended, but may not be needed (Urology 1999:161:764). May develop post-op
hypoglycemia ± hypotension. Long-term clinical follow-up is important to identify late
recurrences.
• If surgical resection is not possible, chronic medical therapy with phenoxybenzamine
(oral alpha-blocker) or alpha-methyl-tyrosine (oral inhibitor of catechol
synthesis) is recommended. |
F. COARCTATION OF THE AORTA |
Prevalence |
Present in 0.1-1% of
patients with hypertension. |
Etiology |
Congenital narrowing of the
aorta beyond origin of left subclavian artery, distal to insertion site of ligamentum
arteriosum. May involve long or short segments, and be partial or complete. |
Presentation |
May complain of cold feet
and leg claudication. Findings on physical exam include arm BP > leg BP, thrill in
suprasternal notch, systolic flow murmur best heard in left posterior thorax, and absent
femoral pulses in most. Chest x-ray may demonstrate rib notching (increased collateral
flow through intercostal arteries) and indentation of the aortic knob ("figure 3
sign"). One-third of patients have bicuspid aortic valves. Complications
include congestive heart failure, endocarditis, and stroke. |
Natural history |
Without corrective surgery,
80% ultimately die prematurely from complications of hypertension. In a series of 200
patients who died prior to the availability of surgical treatment, the majority of deaths
occurred in the 2nd-4th decades. Causes of death included cardiac (50%), cerebral
hemorrhage (13%; spontaneous or from ruptured cerebral aneurysm), and rupture of the aorta
(> 20%) (Am Heart J 1928;3:392,574). |
Diagnosis |
Aortography, transesophageal
echo with doppler, MRI |
Treatment |
• Surgical repair
or angioplasty is the treatment of choice. Transient worsening of hypertension may develop
in the post-op period but can usually be prevented by the prophylactic use of a
beta-blocker.
• Drug therapy: ACE inhibitor or calcium antagonist. |
G. ACROMEGALY |
Prevalence |
Present in < 0.1-0.2% of
patients with hypertension. |
Etiology |
Usually due to a
growth hormone-secreting pituitary adenoma. |
Presentation |
Soft tissue swelling,
extremity enlargement, joint pains, glucose intolerance, and macroglossia. Cardiovascular
manifestations include hypertension, cardiomegaly, premature coronary disease,
arrhythmias, cardiomyopathy, and heart failure (develops in 10-20%). |
Screen |
Increased levels of
insulin-like growth factor (somatomedin C). Once diagnosed, it is important to assess the
integrity of other pituitary hormones; if hypertension is present, exclude the presence of
a pheochromocytoma or an aldosterone-producing adenoma; if sinus tachycardia or atrial
fibrillation is present, exclude hyperthyroidism. |
Diagnosis |
Glucose suppression test:
Failure to suppress growth hormone levels to < 2 ng/ml 2 hours after oral
administration of 100 grams of glucose is indicative of acromegaly. |
Treatment |
Transphenoidal resection
of the tumor is the mainstay of therapy. Drug therapy (bromocriptine [dopaminergic
agonist], octreotride [long-acting somatostatin analog]) and radiation therapy are often
used as adjuncts. |
H. PRIMARY HYPERPARATHYROIDISM |
Prevalence |
Present in < 0.1-0.2% of
patients with hypertension. |
Etiology |
Solitary adenoma (85%),
hyperplasia of all 4 glands (10%; usually familial and occurs in association with multiple
endocrine neoplasia Types I and II), and carcinoma (<5%). |
Presentation |
Patients are frequently
asymptomatic: 10-20% of cases are first diagnosed after routine chemical screening. The
first manifestation may be hypercalcemia after initiating therapy with thiazide diuretics.
Other manifestations may include fatigue, weakness, renal symptoms in 50% (polyuria,
nocturia, renal stones, nephrocalcinosis), proximal muscle weakness, and/or nonspecific
joint and back symptoms. |
Diagnosis |
Elevated levels of serum
calcium and parathyroid hormone (note: hypercalcemia normally suppresses parathyroid
hormone levels). |
Treatment |
• Surgical
parathyroidectomy is the treatment of choice. Although hypertension may persist,
surgery generally halts the formation of renal stones and allows skeletal remineralization
in those with bone disease. Post-op hypocalcemia is not uncommon; acute treatment
with IV calcium and Long-term therapy with vitamin D and oral calcium may be needed.
• For elderly patients and those with mild elevations of serum calcium only,
optimal therapy is controversial (i.e., surgery vs. conservative medical follow-up). When
medical therapy is chosen, thiazide diuretics should be avoided (may further increase
serum calcium). |
I. DRUG-INDUCED HYPERTENSION |
Glucocorticoids |
Treat with diuretics ±
spironolactone; prevent by intermittent therapy (prednisone every other day) |
Licorice |
Present in some chewing
tobaccos. Treat with diuretics ± spironolactone. Hypertension should disappear after
licorice ingestion is stopped. |
Sympatho-
mimetics |
Present in diet
pills and street drugs. Treat with labetalol. |
NSAID's |
Mechanism: Inhibit
production of vasodilatory prostaglandins. Therapy: Substitute acetaminophen or increase
the dose of BP drug. |
Alcohol |
Etiology in up to 10% of
young males with hypertension. |
Oral contra-
ceptives (OCP) |
5% develop hypertension
within 5 years of use, which usually manifests as a small persistent increase in systolic
BP (5 mmHg) and diastolic BP (2 mmHg) and returns to baseline within 3 months of
discontinuation. All patients receiving OCP should have their BP checked after 3-6 months
of use. If BP is elevated, other forms of contraception should be considered. When medical
therapy is required, a diuretic-spironolactone combination is often effective. |
Cocaine,
amphetamines |
Cocaine stimulates the
release and inhibits neuronal re-uptake of norepinephrine. In addition to hypertension,
patients may present with arrhythmias, seizures, MI, dilated pupils, mental status changes
and stroke, usually within one hour of drug use. Acute renal failure from rhabdomyolysis
may also occur. Therapy: Phentolamine for hypertension and beta-blockers for
arrhythmias. Note: Nonselective beta-blockers may cause a paradoxical increase in BP
due to unopposed alpha-receptor simulation by excess catecholamines. |
Cyclosporine or
tacrolimus |
Therapy: Calcium antagonist,
labetalol or a central alpha-agonist. Drugs that increase cyclosporine levels, including
diltiazem, nicardipine and verapamil, may reduce costs of immunosuppression. |
 © 2009 Jones and Bartlett Publishers
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