Hypertension

2077CHAPTER 277

established, the rate of rise of blood pressure in the early morning

(blood pressure “surge”) may also predict a higher risk of cardiovascular events.

Home blood pressure and average 24-h ambulatory blood pressure

measurements are generally lower than clinic blood pressures. Recent

guidelines provide values of home and ambulatory blood pressure

monitoring that correspond to office-measured blood pressures.

Approximately 15–20% of patients with elevated office blood pressures

have normal ambulatory readings, a phenomenon termed “white coat

hypertension.” Long-term outcomes of individuals with white coat

hypertension are more similar to normotensive individuals than to

individuals with sustained hypertension (elevation of both office and

out-of-office blood pressures). In contrast, “masked hypertension”

(normal office blood pressure and elevated out-of-office blood pressure) is associated with a risk of cardiovascular disease and all-cause

mortality twice that of normotensive individuals, with a risk range

similar to that of patients with sustained hypertension. In populationbased surveys, the prevalence of masked hypertension varies from

10 to 30%.

CLINICAL DISORDERS OF HYPERTENSION

Depending on methods of patient ascertainment, ~80–95% of hypertensive patients are diagnosed as having primary, or “essential,”

hypertension (inclusive of patients with obesity and the metabolic

syndrome). In the remaining 5–20% of hypertensive patients, an

underlying disorder causing the elevation of blood pressure can be

identified (Tables 277-2 and 277-3). In individuals with “secondary”

TABLE 277-2 Systolic Hypertension with Wide Pulse Pressure

1. Decreased vascular compliance (arteriosclerosis)

2. Increased cardiac output

a. Aortic regurgitation

b. Thyrotoxicosis

c. Hyperkinetic heart syndrome

d. Fever

e. Arteriovenous fistula

f. Patent ductus arteriosus

TABLE 277-3 Secondary Causes of Systolic and Diastolic Hypertension

Renal Parenchymal diseases, renal cysts (including

polycystic kidney disease), renal tumors

(including renin-secreting tumors), obstructive

uropathy

Renovascular Arteriosclerotic, fibromuscular dysplasia

Adrenal Primary aldosteronism, Cushing’s syndrome,

17α-hydroxylase deficiency, 11β-hydroxylase

deficiency, 11-hydroxysteroid dehydrogenase

deficiency (licorice), pheochromocytoma

Aortic coarctation

Obstructive sleep apnea

Preeclampsia/eclampsia

Neurogenic Psychogenic, diencephalic syndrome, familial

dysautonomia, polyneuritis (acute porphyria, lead

poisoning), acute increased intracranial pressure,

acute spinal cord section

Miscellaneous endocrine Hypothyroidism, hyperthyroidism, hypercalcemia,

acromegaly

Medications High-dose estrogens, adrenal steroids,

decongestants, appetite suppressants,

amphetamines, cyclosporine, tricyclic

antidepressants, atypical antipsychotics,

monoamine oxidase inhibitors, erythropoietin,

nonsteroidal anti-inflammatory agents, alcohol,

herbal supplements, cocaine, others

Mendelian forms of

hypertension

See Table 277-4

hypertension, a specific mechanism for the blood pressure elevation

is often more apparent. Clues to secondary hypertension include

characteristic clinical features, severe or drug-resistant hypertension,

recent onset of hypertension, disproportionate target organ damage,

and younger age.

■ PRIMARY HYPERTENSION

Primary hypertension tends to be familial and is likely to be the consequence of an interaction between environmental and genetic factors. The prevalence of primary hypertension increases with age, and

individuals with relatively high blood pressures at younger ages are at

increased risk for the subsequent development of hypertension. It is

likely that primary hypertension represents a spectrum of disorders

with different underlying pathophysiologies. In the majority of patients

with established hypertension, peripheral resistance is increased and

cardiac output is normal or decreased; however, in younger patients

with mild or labile hypertension, cardiac output may be increased

and peripheral resistance may be normal. When plasma renin activity

(PRA) is plotted against 24-h sodium excretion, ~10–15% of hypertensive patients have high PRA, and 25% have low PRA. High-renin

patients may have a vasoconstrictor form of hypertension, whereas

low-renin patients may have volume-dependent hypertension. Compared to other U.S. populations, African Americans have a high prevalence of hypertension and hypertension-related cardiovascular disease

and renal morbidity and mortality. Hypertensive African Americans

tend to have low plasma renin and volume-dependent hypertension.

■ OBESITY AND THE METABOLIC SYNDROME

(See also Chap. 408) Sixty percent of hypertensive adults are >20%

overweight, and there is a well-documented association between obesity (body mass index >30 kg/m2

) and hypertension. Cross-sectional

studies document a direct linear correlation between body weight

(or body mass index) and blood pressure. Centrally located body fat

is a more important determinant of blood pressure elevation than is

peripheral body fat.

Hypertension and dyslipidemia frequently occur together and in

association with resistance to insulin-stimulated glucose uptake. This

clustering of risk factors is often, but not invariably, associated with

obesity, particularly abdominal obesity. Insulin resistance also is associated with an unfavorable imbalance in the endothelial production of

mediators that regulate platelet aggregation, coagulation, fibrinolysis,

and vessel tone. When these risk factors cluster, the risks for CHD,

stroke, diabetes, and cardiovascular disease mortality are increased

further.

Depending on the populations studied and the methodologies

for defining insulin resistance, ~25–50% of nonobese, nondiabetic

hypertensive persons are insulin resistant. The constellation of insulin

resistance, abdominal obesity, hypertension, and dyslipidemia has been

designated as the metabolic syndrome. First-degree relatives of patients

with primary hypertension are also insulin resistant, and hyperinsulinemia (a surrogate marker of insulin resistance) may predict the

eventual development of hypertension and cardiovascular disease. An

antinatriuretic effect of insulin may contribute to the development

of hypertension. Although the metabolic syndrome may in part be

heritable as a polygenic condition, the expression of the syndrome is

modified by environmental factors, such as degree of physical activity

and diet. Insulin sensitivity increases and blood pressure decreases in

response to weight loss. The recognition that cardiovascular disease

risk factors tend to cluster within individuals has important implications for the evaluation and treatment of hypertension. Evaluation

of both hypertensive patients and individuals at risk for developing

hypertension should include assessment of overall cardiovascular disease risk. Similarly, introduction of lifestyle modification strategies and

drug therapies should address overall risk and not focus exclusively on

hypertension.

■ RENAL PARENCHYMAL DISEASES

Virtually all disorders of the kidney may cause hypertension, and

renal disease is the most common cause of secondary hypertension.

2078 PART 6 Disorders of the Cardiovascular System

Hypertension is present in >80% of patients with chronic renal failure.

In general, hypertension is more severe in glomerular diseases than in

interstitial diseases such as chronic pyelonephritis. Conversely, hypertension may cause nephrosclerosis, and in some instances, it may be

difficult to determine whether hypertension or renal disease was the

initial disorder. Proteinuria >1000 mg/d and an active urine sediment

are indicative of primary renal disease. In either instance, the goals are

to control blood pressure and retard the rate of progression of renal

dysfunction.

■ RENOVASCULAR HYPERTENSION

Hypertension due to an occlusive lesion of a renal artery, renovascular hypertension, is a potentially curable form of hypertension. Two

groups of patients are at risk for this disorder: older arteriosclerotic

patients who have a plaque obstructing the renal artery, frequently

at its origin, and patients with fibromuscular dysplasia. Atherosclerosis accounts for the large majority of patients with renovascular

hypertension. Although fibromuscular dysplasia may occur at any

age, it has a strong predilection for young white women. The lesions

of fibromuscular dysplasia are frequently bilateral and, in contrast to

atherosclerotic renovascular disease, tend to affect more distal portions

of the renal artery.

Renovascular hypertension should be considered in patients with

other evidence of atherosclerotic vascular disease. Severe or refractory

hypertension, recent loss of hypertension control or recent onset of

moderately severe hypertension, carotid or femoral artery bruits, flash

pulmonary edema, and unexplained deterioration of renal function or

deterioration of renal function associated with an angiotensin-converting

enzyme inhibitor (ACEI) should raise the possibility of renovascular

hypertension. Approximately 50% of patients with renovascular hypertension have an abdominal or flank bruit, and the bruit is more likely to

be hemodynamically significant if it lateralizes or extends throughout

systole into diastole.

If renal artery stenosis is suspected and if the clinical condition

warrants an intervention such as percutaneous transluminal renal

angioplasty (PTRA), placement of a vascular endoprosthesis (stent),

or surgical renal revascularization, imaging studies should be the next

step in the evaluation. Doppler ultrasound of the renal arteries produces reliable estimates of renal blood flow and offers the opportunity

to track a lesion over time. Positive studies usually are confirmed at

angiography, whereas false-negative results occur frequently, particularly in obese patients. Gadolinium-contrast magnetic resonance

angiography offers clear images of the proximal renal artery but may

miss distal lesions. An advantage is the opportunity to image the renal

arteries with an agent that is not nephrotoxic. Contrast arteriography

remains the “gold standard” for evaluation and identification of renal

artery lesions.

Some degree of renal artery obstruction may be observed in almost

50% of patients with atherosclerotic disease, and there are several

approaches for evaluating the functional significance of such a lesion

to predict the effect of vascular repair on blood pressure control and

renal function. Functionally significant lesions generally occlude >70%

of the lumen of the affected renal artery. On angiography, the presence

of collateral vessels to the ischemic kidney suggests a functionally

significant lesion. A lateralizing renal vein renin ratio (ratio >1.5 of

affected side/contralateral side) has a 90% predictive value for a lesion

that would respond to vascular repair; however, the false-negative rate

for blood pressure control is 50–60%.

A decision concerning vascular repair versus medical therapy and

the type of repair procedure should be individualized. Several randomized clinical trials have found that PTRA with stent placement in

patients with arteriosclerotic renal artery stenosis offers no advantages

to medical therapy in controlling blood pressure, reducing cardiovascular events and mortality, or preserving kidney function. If blood

pressure is adequately controlled with medical therapy and renal function remains stable, there may be little impetus to pursue an extensive

evaluation for renal artery stenosis. Patients with long-standing hypertension, advanced renal insufficiency, or diabetes mellitus are less likely to

benefit from renal vascular repair. Patients with fibromuscular disease

have more favorable outcomes with vascular repair than do patients

with atherosclerotic lesions, presumably owing to their younger age,

shorter duration of hypertension, and less systemic disease. The most

effective medical therapies for renovascular hypertension include an

ACE inhibitor or an angiotensin II receptor blocker; however, these

agents decrease glomerular filtration rate in a stenotic kidney owing to

efferent renal arteriolar dilation. In the presence of bilateral renal artery

stenosis or renal artery stenosis to a solitary kidney, progressive renal

insufficiency may result from the use of these agents. Importantly, the

renal insufficiency is generally reversible after discontinuation of the

offending drug.

■ PRIMARY ALDOSTERONISM

Excess aldosterone production due to primary aldosteronism is a

potentially curable form of hypertension. In patients with primary

aldosteronism, increased aldosterone production is independent of the

renin-angiotensin system, and the consequences are sodium retention,

hypertension, hypokalemia, low PRA, cardiovascular disease, and kidney damage. The reported prevalence of this disorder varies from <2

to ~15% of hypertensive individuals. In part, this variation is related to

the intensity of screening and the criteria for establishing the diagnosis.

History and physical examination provide little information about

the diagnosis. The age at the time of diagnosis is generally the third

through fifth decade. Hypertension is usually mild to moderate but

occasionally may be severe; primary aldosteronism should be considered in all patients with refractory hypertension. Most patients are

asymptomatic; however, infrequently, polyuria, polydipsia, paresthesias, or muscle weakness may be present as a consequence of hypokalemic alkalosis. Although serum K+ is an insensitive screening test, in

hypertensive patients with unprovoked hypokalemia (i.e., unrelated to

diuretics, vomiting, or diarrhea), the prevalence of primary aldosteronism approaches 40–50%. In patients on diuretics, serum potassium

<3.1 mmol/L (<3.1 meq/L) also raises the possibility of primary

aldosteronism.

The ratio of plasma aldosterone (PA) to PRA (PA/PRA) is a useful

screening test. These measurements preferably are obtained in ambulatory patients in the morning. A ratio >30:1 in conjunction with a PA

concentration >555 pmol/L (>20 ng/dL) reportedly has a sensitivity of

90% and a specificity of 91% for an aldosterone-producing adenoma.

In a Mayo Clinic series, an aldosterone-producing adenoma subsequently was confirmed surgically in >90% of hypertensive patients

with a PA/PRA ratio ≥20 and a PA concentration ≥415 pmol/L

(≥15 ng/dL). There are, however, several caveats to interpreting the

ratio. The cutoff for a “high” ratio is laboratory- and assay-dependent.

Some antihypertensive agents may affect the ratio (e.g., aldosterone

antagonists, angiotensin receptor blockers [ARBs], and ACEIs may

increase renin; aldosterone antagonists may increase aldosterone).

Current recommendations are to withdraw aldosterone antagonists

for at least 4–6 weeks before obtaining these measurements. Because

aldosterone biosynthesis is potassium-dependent, hypokalemia should

be corrected with oral potassium supplements prior to screening. A

high ratio in the absence of an elevated PA level is considerably less

specific for primary aldosteronism. In patients with renal insufficiency, the ratio may also be elevated because of decreased aldosterone

clearance. In patients with an elevated PA/PRA ratio, the diagnosis of

primary aldosteronism can be confirmed by demonstrating failure to

suppress PA to any one of four suppression tests: oral sodium loading,

saline infusion, fludrocortisone, or captopril.

Several sporadic and familial adrenal abnormalities may culminate

in the syndrome of primary aldosteronism, and appropriate therapy

depends on the specific etiology. The two most common causes of sporadic primary aldosteronism are an aldosterone-producing adenoma

and bilateral adrenal hyperplasia. Together, they account for >90%

of all patients with primary aldosteronism. The tumor is most often

unilateral and measures <3 cm in diameter. Most of the remainder

of these patients have bilateral adrenocortical hyperplasia (idiopathic

hyperaldosteronism). An increasing number of somatic mutations,

including mutations in aldosterone-regulating genes, has been identified in adenomas and in idiopathic hyperaldosteronism. Rarely,

Hypertension

2079CHAPTER 277

primary aldosteronism may be caused by an adrenal carcinoma or an

ectopic malignancy, e.g., ovarian arrhenoblastoma. Functional differences in hormone secretion may assist in the diagnosis of adenoma

versus hyperplasia. Aldosterone biosynthesis is more responsive to

ACTH in patients with adenoma and more responsive to angiotensin

in patients with hyperplasia. Consequently, patients with adenoma

tend to have higher PA in the early morning that decreases during

the day, reflecting the diurnal rhythm of ACTH, whereas PA tends to

increase with upright posture in patients with hyperplasia, reflecting

the normal postural response of the renin-angiotensin-aldosterone

axis. However, there is overlap in the ability of these measurements to

discriminate between adenoma and hyperplasia. Rare familial forms

of primary aldosteronism include glucocorticoid-remediable primary

aldosteronism and familial aldosteronism types II and III. Familial

primary aldosteronism reflects a variety of germline mutations, and

genetic testing may assist in the diagnosis of these disorders.

Adrenal computed tomography (CT) should be carried out in all

patients diagnosed with primary aldosteronism. High-resolution CT may

identify tumors as small as 0.3 cm and is positive for an adrenal tumor

90% of the time. If the CT is not diagnostic, an adenoma may be detected

by adrenal scintigraphy with 6-β-[I131] iodomethyl-19-norcholesterol after

dexamethasone suppression (0.5 mg every 6 h for 7 days); however, this

technique has decreased sensitivity for adenomas <1.5 cm.

When carried out by an experienced radiologist, bilateral adrenal

venous sampling for measurement of PA is the most accurate means

of differentiating unilateral from bilateral forms of primary aldosteronism. A major difference in the aldosterone/cortisol ratio is indicative

of unilateral disease. The sensitivity and specificity of adrenal venous

sampling (95 and 100%, respectively) for detecting unilateral aldosterone hypersecretion are superior to those of adrenal CT; success rates

are 90–96%, and complication rates are <2.5%. One frequently used

protocol involves sampling for aldosterone and cortisol levels in

response to ACTH stimulation. An ipsilateral/contralateral aldosterone

ratio >4, with symmetric ACTH-stimulated cortisol levels, is indicative

of unilateral aldosterone production.

Hypertension generally is responsive to surgery in patients with

adenoma but not in patients with bilateral adrenal hyperplasia. For

patients with a unilateral adenoma, surgical treatment is generally

more effective than medical therapy. Unilateral adrenalectomy, often

done via a laparoscopic approach, is curative in 40–70% of patients

with an adenoma. Transient hypoaldosteronism may occur up to

3 months postoperatively, resulting in hyperkalemia, which should be

treated with potassium-wasting diuretics and with fludrocortisone, if

needed. Patients with bilateral hyperplasia should be treated medically.

The drug regimen for these patients, as well as for patients with an adenoma who are poor surgical candidates, should include an aldosterone

antagonist and, if necessary, other potassium-sparing diuretics.

Glucocorticoid-remediable hyperaldosteronism is a rare, monogenic

autosomal dominant disorder characterized by moderate to severe

hypertension, often occurring at an early age. These patients may have

a family history of hemorrhagic stroke at a young age. Hypokalemia is

usually mild or absent. Normally, angiotensin II stimulates aldosterone

production by the adrenal zona glomerulosa, whereas ACTH stimulates cortisol production in the zona fasciculata. Owing to a chimeric

gene on chromosome 8, ACTH also regulates aldosterone secretion

by the zona fasciculata in patients with glucocorticoid-remediable

hyperaldosteronism. The consequence is overproduction in the zona

fasciculata of both aldosterone and hybrid steroids (18-hydroxycortisol

and 18-oxocortisol) due to oxidation of cortisol. The diagnosis may be

established by urine excretion rates of these hybrid steroids that are

20–30 times normal or by direct genetic testing. Therapeutically, suppression of ACTH with low-dose glucocorticoids corrects the hyperaldosteronism, hypertension, and hypokalemia. Aldosterone antagonists

are also therapeutic options. Patients with familial aldosteronism types

II and III are treated with aldosterone antagonists or adrenalectomy.

■ CUSHING’S SYNDROME

(See also Chap. 386) Cushing’s syndrome is related to excess cortisol

production due either to excess ACTH secretion (from a pituitary

tumor or an ectopic tumor) or to ACTH-independent adrenal production of cortisol. Hypertension occurs in 75–80% of patients with

Cushing’s syndrome. The mechanism of hypertension may be related

to stimulation of mineralocorticoid receptors by cortisol and increased

secretion of other adrenal steroids. If clinically suspected based on

phenotypic characteristics, in patients not taking exogenous glucocorticoids, laboratory screening may be carried out with measurement of

24-h excretion rates of urine-free cortisol or an overnight dexamethasonesuppression test. Late night salivary cortisol is also a sensitive and

convenient screening test. Further endocrine and radiologic evaluation

is required to confirm the diagnosis and identify the specific etiology

of Cushing’s syndrome. Appropriate therapy depends on the etiology.

■ PHEOCHROMOCYTOMA

(See also Chap. 387) Catecholamine-secreting tumors are located

in the adrenal medulla (pheochromocytoma) or in extra-adrenal

paraganglion tissue (paraganglioma) and account for hypertension in

~0.05% of patients. If unrecognized, pheochromocytoma may result in

lethal cardiovascular consequences. Clinical manifestations, including

hypertension, are primarily related to increased circulating catecholamines, although some of these tumors may secrete a number of other

vasoactive substances. In a small percentage of patients, epinephrine is

the predominant catecholamine secreted by the tumor, and these

patients may present with hypotension rather than hypertension. The

initial suspicion of the diagnosis is based on symptoms and/or the

association of pheochromocytoma with other disorders (Table 277-4).

Approximately 20% of pheochromocytomas are familial with autosomal dominant inheritance. Inherited pheochromocytomas may be

associated with multiple endocrine neoplasia (MEN) type 2A and

type 2B, von Hippel-Lindau disease, and neurofibromatosis. Each of

these syndromes is related to specific germline mutations. Mutations

of succinate dehydrogenase genes are associated with paraganglioma

syndromes, generally characterized by head and neck paragangliomas.

Laboratory testing consists of measuring catecholamines in either

urine or plasma, e.g., 24-h urine fractionated metanephrine excretion

or plasma-free metanephrines under standardized conditions. The

urine measurement is less sensitive but more specific. The next step

would involve imaging of the abdomen and pelvis (CT or magnetic resonance imaging). Genetic screening is available for evaluating patients

and relatives suspected of harboring a pheochromocytoma associated

with a familial syndrome. Peripheral α-adrenergic antagonists may be

used to control blood pressure. Surgical excision is the definitive treatment of pheochromocytoma and results in cure in ~90% of patients.

■ MISCELLANEOUS CAUSES OF HYPERTENSION

Hypertension occurs in >50% of individuals with obstructive sleep

apnea. Hypertension appears to be due to sympathetic activation

caused by intermittent hypoxia and fragmented sleep. The severity of

hypertension correlates with the severity of sleep apnea. Approximately

70% of patients with obstructive sleep apnea are obese. Hypertension

related to obstructive sleep apnea also should be considered in patients

with drug-resistant hypertension and patients with a history of snoring. The diagnosis can be confirmed by polysomnography. In obese

patients, weight loss may alleviate or cure sleep apnea and related

hypertension. Continuous positive airway pressure (CPAP) and bilevel

positive airway pressure (BiPAP) administered during sleep are effective therapies for obstructive sleep apnea. Although CPAP and BiPAP

generally have only a modest effect on blood pressure, their use may

improve blood pressure responsiveness to antihypertensive agents.

Increasing evidence links other sleep-related disorders to hypertension,

including restless legs syndrome and sleep-related bruxism

Coarctation of the aorta is the most common congenital cardiovascular cause of hypertension (Chap. 269). The incidence is 1–8 per

1000 live births. It is usually sporadic but occurs in 35% of children

with Turner’s syndrome. Even when the anatomic lesion is surgically

corrected in infancy, up to 30% of patients develop subsequent hypertension and are at risk of accelerated coronary artery disease and

cerebrovascular events. Patients with less severe lesions may not be

diagnosed until young adulthood. Physical findings include diminished

2080 PART 6 Disorders of the Cardiovascular System

and delayed femoral pulses and a systolic pressure gradient between the

right arm and the legs and, depending on the location of the coarctation, between the right and left arms. A blowing systolic murmur may

be heard in the posterior left interscapular areas. The diagnosis may be

confirmed by thoracic and abdominal CT, angiogram, and transesophageal echocardiography. Therapeutic options include surgical repair

and balloon angioplasty, with or without placement of an intravascular

stent. Subsequently, many patients do not have a normal life expectancy but may have persistent hypertension, with death due to ischemic

heart disease, cerebral hemorrhage, or aortic aneurysm.

Several additional endocrine disorders, including thyroid diseases

and acromegaly, cause hypertension. Mild diastolic hypertension

may be a consequence of hypothyroidism, whereas hyperthyroidism

may result in systolic hypertension. Hypercalcemia of any etiology,

the most common being primary hyperparathyroidism, may result in

hypertension. Preeclampsia, a hypertensive disorder of pregnancy that

commonly presents after 20 weeks of gestation, may be a risk factor for

subsequent cardiovascular disease and stroke. Hypertension also may

be related to a number of prescribed or over-the-counter medications

and other substances.

MONOGENIC HYPERTENSION

In addition to glucocorticoid-remediable primary aldosteronism, a

number of rare forms of monogenic hypertension have been identified (Table 277–4). These disorders may be recognized by their

characteristic phenotypes, and in many instances, the diagnosis may

be confirmed by genetic analysis. Several inherited defects in adrenal

steroid biosynthesis and metabolism result in mineralocorticoidinduced hypertension and hypokalemia. In patients with a 17αhydroxylase deficiency, synthesis of sex hormones and cortisol is

decreased (Fig. 277-3). Consequently, these individuals do not mature

sexually; males may present with pseudohermaphroditism and females

with primary amenorrhea and absent secondary sexual characteristics. Because cortisol-induced negative feedback on pituitary ACTH

production is diminished, ACTH-stimulated adrenal steroid synthesis

proximal to the enzymatic block is increased. Hypertension and hypokalemia are consequences of increased synthesis of mineralocorticoids

proximal to the enzymatic block, particularly desoxycorticosterone.

Increased steroid production and, hence, hypertension may be treated

with low-dose glucocorticoids. An 11β-hydroxylase deficiency results

in a salt-retaining adrenogenital syndrome that occurs in 1 in 100,000

live births. This enzymatic defect results in decreased cortisol synthesis, increased synthesis of mineralocorticoids (e.g., desoxycorticosterone), and shunting of steroid biosynthesis into the androgen pathway.

In the severe form, the syndrome may present early in life, including

the newborn period, with virilization and ambiguous genitalia in

females and penile enlargement in males, or in older children as precocious puberty and short stature. Acne, hirsutism, and menstrual

irregularities may be the presenting features when the disorder is first

recognized in adolescence or early adulthood. Hypertension is less

common in the late-onset forms. Patients with an 11β-hydroxysteroid

dehydrogenase deficiency have an impaired capacity to metabolize cortisol to its inactive metabolite, cortisone, and hypertension is related to

activation of mineralocorticoid receptors by cortisol. This defect may

be inherited or acquired, due to licorice-containing glycyrrhizin acid.

The same substance is present in the paste of several brands of chewing

tobacco. The defect in Liddle’s syndrome (Chaps. 53 and 386) results

from constitutive activation of amiloride-sensitive ENaC on the distal

renal tubule, resulting in excess sodium reabsorption; the syndrome

is ameliorated by amiloride. Hypertension exacerbated in pregnancy

(Chap. 479) may be due to activation of the mineralocorticoid receptor

by progesterone.

TABLE 277-4 Rare Mendelian Forms of Hypertension

DISEASE PHENOTYPE GENETIC CAUSE

Glucocorticoid-remediable

hyperaldosteronism

Autosomal dominant

Absent or mild hypokalemia

Chimeric 11β-hydroxylase/aldosterone gene on

chromosome 8

17α-Hydroxylase deficiency Autosomal recessive

Males: pseudohermaphroditism

Females: primary amenorrhea, absent secondary sexual characteristics

Random mutations of the CYP17 gene on chromosome

10

11β-Hydroxylase deficiency Autosomal recessive

Masculinization

Mutations of the CYP11B1 gene on chromosome

8q21-q22

11β-Hydroxysteroid dehydrogenase

deficiency (apparent

mineralocorticoid excess syndrome)

Autosomal recessive

Hypokalemia, low renin, low aldosterone

Mutations in the 11β-hydroxysteroid dehydrogenase

gene

Liddle’s syndrome Autosomal dominant

Hypokalemia, low renin, low aldosterone

Mutation subunits of the epithelial sodium channel

SCNN1B and SCNN1C genes

Pseudohypoaldosteronism type II

(Gordon’s syndrome)

Autosomal dominant

Hyperkalemia, normal glomerular filtration rate

Linkage to chromosomes 1q31-q42 and 17p11-q21

Hypertension exacerbated in

pregnancy

Autosomal dominant

Severe hypertension in early pregnancy

Missense mutation with substitution of leucine for

serine at codon 810 (MRL810)

Polycystic kidney disease Autosomal dominant

Large cystic kidneys, renal failure, liver cysts, cerebral aneurysms,

valvular heart disease

Mutations in the PKD1 gene on chromosome 16 and

PKD2 gene on chromosome 4

Pheochromocytoma Autosomal dominant

(a) Multiple endocrine neoplasia, type 2A (a) Mutations in the RET protooncogene

Medullary thyroid carcinoma, hyperparathyroidism

(b) Multiple endocrine neoplasia, type 2B (b) Mutations in the RET protooncogene

 Medullary thyroid carcinoma, mucosal neuromas, thickened corneal

nerves, alimentary ganglioneuromatoses, marfanoid habitus

(c) von Hippel-Lindau disease (c) Mutations in the VHL tumor-suppressor gene

 Retinal angiomas, hemangioblastomas of the cerebellum and spinal

cord, renal cell carcinoma

(d) Neurofibromatosis type 1 (d) Mutations in the NF1 tumor-suppressor gene

Multiple neurofibromas, café-au-lait spots