Essential hypertension

KEY POINTS

* Hypertension contributes substantially to morbidity and mortality associated with renal failure, cardiovascular disease, and stroke.

* Cardiovascular risk factors and end-organ damage are used to identify risk groups among patients with hypertension and high-normal blood pressure.

* Clinical characteristics can identify those patients who have a high probability of an identifiable cause of hypertension.

Hypertension is arbitrarily defined as a diastolic blood pressure (DBP) of 90 mm Hg or higher, a systolic blood pressure (SBP) equal to or higher than 140 mm Hg, or both, on 3 separate occasions. It affects 24% of the population of the United States and is common among black (28%), white (24%), and Hispanic (14%) Americans. The prevalence of hypertension increases with age and is more than 70% among people 65 years and older. Among principal diagnoses given by family physicians for outpatient visits, only acute respiratory tract infection (7%) is more common than hypertension (6%). The annual direct medical cost of caring for hypertension exceeds $10 billion.

This article will discuss the pathophysiology and diagnosis of hypertension from an evidence-based perspective. An upcoming Applied Evidence article will cover treatment of hypertension and prognosis.

PATHOPHYSIOLOGY

Idiopathic, or essential, hypertension accounts for more than 95% of cases and appears to be caused by a complex interaction between genetic predisposition and environmental factors. The predisposition to essential hypertension is polygenic in origin and may find full expression when combined with environmental factors, such as obesity, low physical activity levels, high stress levels, high alcohol consumption, high dietary sodium, and low dietary potassium, calcium, and magnesium. The complex interaction of genetics and environment may affect sodium, catecholamines, the renin-angiotensin system, insulin, and cell membrane function, causing elevation of the blood pressure.

The more common identifiable causes of hypertension include chronic renal disease (2%-5%), renovascular disease--including renal artery atherosclerosis and fibromuscular dysplasia--(0.2%0-0.7%), Cushing syndrome (0.1%-0.6%), pheochromocytoma (0.04%-0.1%), and primary hyperaldosteronism (0.01%-0.30%). Although obesity, excessive alcohol consumption, oral contraceptive therapy, and sleep apnea may cause hypertension, they are not typically included as identifiable causes of hypertension. The prevalence of the latter conditions as identifiable causes of hypertension remains to be defined.-

DIAGNOSIS

The presence of hypertension must be confirmed by blood pressure measurements obtained with proper technique. The blood pressure of all patients 18 years and older should be measured at each health care visit because of the high prevalence of hypertension. Patients should be encouraged to abstain from nicotine and caffeine for at least 30 minutes before the measurement of the blood pressure. Measurement should be made with a mercury sphygmomanometer or a recently calibrated aneroid device. The bladder of the blood pressure cuff should encircle 80% of the arm. The pressure should be taken after at least 5 minutes of rest with the patient sitting, back supported, and arm bared and supported at heart level. The first sound heard (phase 1) is the SBP, and the last sound heard (phase 5) is the DBP. Two readings separated by 2 minutes should be averaged. Hypertension is present when an accurately measured blood pressure is high on 3 separate occasions.

A major consensus report, the Sixth Report of the Joint National Committee on Prevention Detection, Evaluation, and Treatment of High Blood Pressure,(11) designates 6 categories of blood pressure:

* Optimal -- SBP less than 120 mm; DBP less than 80 mm

* Normal -- SBP less than 130 mm; DBP less than 85 mm

* High normal -- SBP is 130 to 139 mm; DBP is 85 to 89 mm

* Stage 1 hypertension -- SBP is 140 to 159 mm; DBP is 90 to 99 mm

* Stage 2 hypertension -- SBP is 160 to 179 mm; DBP is 100 to 109 mm

* Stage 3 hypertension -- SBP is 180 mm or higher; DBP is 110 mm or higher

It is important to note that the recommended diagnostic evaluation is based on a consensus and should not be considered evidence-based. A complete history, physical examination, and limited diagnostic testing (urinalysis, complete blood count, potassium, sodium, fasting glucose, creatinine, total cholesterol, high-density cholesterol, and electrocardiogram) are recommended once the presence of hypertension has been confirmed. This evaluation has 3 purposes:

1. Identify other cardiovascular risk factors. Most patients with hypertension have multiple cardiovascular risk factors at the time of initial evaluation. Risk factors include smoking, hyperlipidemia, diabetes, age older than 60 years, sex (men or postmenopausal women), and family history of cardiovascular disease in a female relative before age 65 years or a male relative before 55 years.

2. Identify end-organ damage. Evidence of end-organ damage includes left ventricular hypertrophy, angina, previous myocardial infarction, previous angioplasty or coronary revascularization, heart failure, stroke or transient ischemic attack, nephropathy, peripheral arterial disease, and retinopathy.

3. Identify secondary causes of hypertension. Estimating the pretest probability of a secondary (identifiable) cause of hypertension is problematic, because referral bias is a major problem in hypertension prevalence studies; patients are typically included in these studies only after being referred to a study center by their primary care physician for resistant or difficult to control hypertension. On the basis of the best available estimates, it would be reasonable to assume that patients presenting to primary care physicians have a 5% probability of an identifiable cause of hypertension.

The diagnostic evaluation serves to identify other cardiovascular risk factors and end-organ damage in patients with high-normal blood pressure or hypertension. This information is used to identify 3 risk groups: Group A includes patients with no other cardiovascular risk factor, cardiovascular disease, or evidence of end-organ damage; group B includes patients who do not have cardiovascular disease or end-organ damage but have 1 or more of the major risk factors other than diabetes mellitus; and group C includes patients who have cardiovascular disease, other end-organ damage, or diabetes mellitus. The risk associated with hypertension and the intensity of recommended treatment increases progressively as a person moves from risk group A through risk group C.

The diagnostic evaluation may also reveal patients who are more likely to have an identifiable cause of hypertension. The probability of an identifiable cause of hypertension is increased by the onset of hypertension outside the normal age for essential hypertension (30-55 years), sudden onset or worsening of hypertension, stage 3 hypertension, and blood pressure that responds poorly to treatment. Elevated creatinine levels suggest hypertension caused by renal parenchymal disease. Abdominal or flank bruits, hypokalemia, or a significant rise in the serum creatinine level after an angiotensin-converting enzyme inhibitor is started suggests renovascular hypertension. Osteoporosis, truncal obesity, moon face, purple striae, muscle weakness, easy bruising, hirsutism, hyperglycemia, hypokalemia, and hyperlipidemia suggest Cushing syndrome. Labile hypertension, orthostatic hypotension, headache, palpitations, pallor, and diaphoresis suggests pheochromocytoma. Isolated hypokalemia may be caused by hyperaldosteronism.

Unfortunately, the accuracy of the history, physical examination, and preliminary diagnostic testing for patients presenting with hypertension has not been adequately studied. Therefore, estimating the pretest probability of a secondary cause of hypertension in a patient with specific clinical characteristics must be considered crude at best. The best available evidence is shown in Table 1.

DIAGNOSTIC STRATEGY

Patients whose initial history, physical, and laboratory evaluation suggest the possibility of a secondary cause of hypertension should undergo additional testing. The search for the secondary cause of hypertension should focus on chronic renal disease, renovascular hypertension, pheochromocytoma, Cushing syndrome, and primary aldosteronism, depending on the clinical scenario (Table 2).

Chronic renal disease will be evident from the blood urea nitrogen, creatinine, and the urinalysis results. The diagnostic approach to other causes of hypertension is more complicated.

Although renal artery stenosis is suggested by the presence of an abdominal or flank bruit, it is an insensitive test (sensitivity=65%; specificity=90%). It is useful when positive (positive likelihood ratio=6.5) but does not rule out renal artery stenosis when negative (negative likelihood ratio=0.4). A clinical decision rule has been developed and validated that integrates several findings from the history and physical examination. Software to implement this decision rule in clinical practice, using Palm or PocketPC hand-held computers, is available at no charge from the JFP Web site at www.jfponline.com (Figure 1).

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Duplex sonography is very accurate (sensitivity=98%; specificity=98%) when the study is adequate but is often nondiagnostic in obese patients. For these patients, magnetic resonance angiography (MRA) is better (sensitivity=93%; specificity=95%). Captopril renal scanning (CPS) is less sensitive and less specific than either sonography or MRA. Renal artery stenosis is confirmed by the highly accurate but more invasive reference standard test of conventional angiography.

Pheochromocytoma is rare even in the presence of suggestive symptoms (headache, palpitations, and excessive and inappropriate perspiration), but failure to identify this disease can have disastrous consequences. Therefore, patients who have suggestive signs and symptoms should be screened for pheochromocytoma. However, the standard for screening pheochromocytoma remains controversial. A 24-hour urinary metanephrine (cutoff point of [is greater than] 3.70 nmol/day) is highly sensitive and specific when done well, but urine collection is inconvenient and may be incomplete. Plasma metanephrines (metanephrine [is greater than] 0.66 nmol/L or normetanephrine [is greater than] 0.30 nmol/L) are easy to obtain, 100% sensitive, and may represent a good screening test for pheochromocytoma. Because they have limited specificity (85%), a positive plasma metanephrine should be confirmed by the 24-hour urinary metanephrine-to-creatinine ratio (cutoff point of [is greater than] 0.354; specificity=98%) before proceeding to anatomical localization of the tumor.

Two imaging studies are commonly used to localize pheochromocytomas. Metaiodobenzyl guanidine (MIBG) scintigraphy is more specific but less sensitive than computed tomography (CT). Relying on CT to guide surgery is less likely to miss tumors than MIBG scintigraphy (CT sensitivity = 100% vs MIBG=88%) but is more likely to result in unnecessary surgery because of the lower specificity (CT specificity = 50%; MIBG=89%0).

The 24-hour urinary free cortisol (cutoff point [is greater than] 90 [micro]g/day; sensitivity=100%; specificity=98%) is a useful screening test for Cushing syndrome. It is very sensitive, but false-positives may be seen in patients with depression and polycystic ovarian syndrome. The single-dose (1 mg) overnight dexamethasone suppression test is equally sensitive but is a little less specific than the 24-hour urinary cortisol. However, this test is relatively simple for patients. The patient takes 1 mg of dexamethasone at midnight, and the plasma cortisol level is drawn in the morning (cutoff point [is greater than] 100 nmol). The combined dexamethasone and corticotropin-releasing hormone (CRH) suppression test, which has both a sensitivity and a specificity of almost 100%, can be used to confirm the diagnosis of Cushing syndrome. However, it is a little more complicated for the patient. The patient takes 0.5 mg of dexamethasone at noon on the first day and repeats this dose every 6 hours for a total of 8 doses (ending at 6 AM on the third day). Two hours after the last dose the patient is given an intravenous bolus of CRH (1 [micro]g/kg), and 15 minutes later a plasma cortisol is drawn. A cortisol level greater than 38 nmol is the cutoff point for this test.

The coexistence of hypertension and spontaneous or diuretic-induced hypokalemia is strongly suggestive of primary aldosteronism. However, it is important to remember that many (if not most) patients with primary aldosteronism do not have hypokalemia. In the past, screening for primary aldosteronism was accomplished by measuring urinary aldosterone levels after oral or intravenous salt loading. The sensitivity of these tests is 90% to 95%, and they carry a risk of precipitous elevation of blood pressure due to volume expansion or hypokalemia. Measuring the plasma renin and aldosterone levels can be used to test for hyperaldosteronism. Various cut points and ratios have been suggested, but the plasma aldosterone-to-renin ratio (cutoff point [is greater than] 25) is currently the most useful screening test for hyperaldosteronism. For this test the patient is asked to rise at 6 AM and remain ambulatory for 2 hours, at which time the plasma aldosterone and renin levels are drawn. Beta-blockers and dihydropyridine calcium channel blockers must be stopped for 2 weeks, and spironolac-tone and loop diuretics must be stopped for 6 weeks before the test. Primary aldosteronism can be confirmed by the flu-drocortisone suppression test.

A diagnostic algorithm for hypertension evaluation is provided in Figure 2.

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ACKNOWLEDGMENTS

Special thanks to Kathleen Dosh, MS; Greg Tan, MD; and Mark Povich, DO, for help during the initial editing of this paper.

REFERENCES

1. Burt V, Whelton P, Rocella E, Brown C, Cutler J. Prevalence of hypertension in the US population: results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 1995; 25:305-13.

2. Barker W, Mullooly J, Linton K. Trends in hypertension prevalence, treatment, and control: in a well-defined older population. Hypertension 1998; 31:552-59.

3. Schappert S, Nelson C. National Ambulatory Medical Care Survey: 1995-96 summary. Vital Health Stat 1999; 142:1-122.

4. Stason W. Opportunities to improve cost-effectiveness of treatment of hypertension. Hypertension 1991; 18:1161-66.

5. Lander E, Schork N. Genetic dissection of complex traits. Science 1994; 265:2037-48.

6. Stevens V, Obarzanek E, Cook N, Lee I-M. Long-term weight loss and changes in blood pressure: results of the trials of hypertension prevention, phase II. Ann Intern Med 2001; 134:1-11.

7. Moore R, Levine D, Southard J, Entwisle G, Shapiro S. Alcohol consumption and blood pressure in the 1982 Maryland Hypertension Survey. Am J Hypertens 1990; 3:1-7.

8. Chasan-Taber L, Willett W, Manson J, et al. Prospective study of oral contraceptives and hypertension among women in the United States. Circulation 1996; 94:483-89.

9. Nieto F, Young T, Lind B, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study: Sleep Heart Health Study. JAMA 2000; 283:1829-36.

10. Reeves R. Does this patient have hypertension? How to measure blood pressure. JAMA 1995; 273:1211-18.

11. Joint National Committee on Prevention, Evaluation, and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med 1997; 157:2413-46.

12. Fuster V, Pearson T. 27th Bethesda conference: matching the intensity of risk factor management with the hazard for coronary disease events. September 14-15, 1995. J Am Coll Cardiol 1996; 27:957-1047.

13. Rudnick K, Sackett D, Hirst S, Holmes C. Hypertension in a family practice. Can Med Assoc J 1977; 117:492-97.

14. Sinclair A, Isles C, Brown I, Cameron H, Murray G, Robertson J. Secondary hypertension in a blood pressure clinic. Arch Intern Med 1987; 147:1289-93.

15. Anderson G, Blakeman N, Streeten D. The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens 1994; 12:609-15.

16. Tucker R, Labarthe D. Frequency of surgical treatment for hypertension in adults at the Mayo Clinic from 1973 through 1975. Mayo Clin Proc 1977; 52:549-55.

17. Gifford R. Evaluation of the hypertensive patient. Chest. 1973; 64:336-40.

18. Krjnen P, Jaarsveld B, Steyerberg E, Schalekamp M. A clinical prediction rule for renal artery stenosis. Ann Intern Med 1998; 129:705-11.

19. Berglund AS, Hulthen UL, Manhem P, Thorsson O, Wollmer P, Tornquist C. Metaiodobenzylguanidine (MIBG) scintigraphy and computed tomography (CT) in clinical practice: primary and secondary evaluation for localization of phaeochromocytomas. J Intern Med 2001; 249:247-51.

20. Yanovski J, Cutler G, Chrousos G, Nieman L. Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration: a new test to distinguish Cushing's syndrome from pseudo-Cushing's states. JAMA 1993; 269:2232-38.

21. Blumenfeld J, Sealey J, Schussel Y, Vaughan E. Diagnosis and treatment of primary aldosteronism. Ann Intern Med 1994; 121:877-85.

22. Fardella C, Lorena M, Gomez-Sanchez C, Cortes J. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metabol 2000; 85:1863-67.

23. Streeten D, Tomycz N, Anderson G. Reliability of screening methods for the diagnosis of primary aldosteronism. Am J Med 1979; 67:403-13.

24. Bravo E, Tarazi R, Dustan H, Fouad F. The changing clinical spectrum of primary aldosteronism. Am J Med 1983; 74:641-51.

25. Gordon R. Primary aldosteronism. J Endocrinol Invest 1995; 18:495-511.

26. Anderson G, Blakeman N, Streeten D. Prediction of renovascular hypertension. Am J Hypertens 1988; 1:301-04.

27. Manger W, Gifford R. Clinical and experimental pheochromocytoma. Cambridge, Mass: Blackwell Science; 1996.

28. Nugent C, Warner H, Dunn J, Tyler F. Probability theory in the diagnosis of Cushing's syndrome. J Clin Endocrinol Metabol 1964; 24:621-27.

29. Fishman L, Kuchel O, Liddle G, Michelakis A. Incidence of primary hyperaldosteronism in uncomplicated `essential' hypertension. JAMA 1968; 205:85-90.

30. Fenton S, Lyttle J, Pantridge J. Diagnosis and results of surgery in renovascular hypertension. Lancet 1966; 2:117-21.

31. de Haan M, Kouwenhoven M, Thelissen G, Koster D. Renovascular disease in patients with hypertension: detection with systolic and diastolic gating in three-dimensional, phase-contrast MR angiography. Radiology 1996; 198:449-56.

32. Olin J, Piedmonte M, Young J, DeAnna S. The utility of duplex ultrasound screening of renal arteries for diagnosing significant renal artery stenosis. Ann Intern Med 1995; 122:833-38.

33. Setaro J, Chen C, Hoffer P, Black H. Captopril renography in the diagnosis of renal artery stenosis and the prediction of improvement with revascularization: the Yale Vascular Center experience. Am J Hypertens 1991; 4:698S-705S.

34. Jacques W, Lenders M, Keiser H, Goldstein D. Plasma metanephrines in the diagnosis of pheochromocytoma. Ann Intern Med 1995; 123:101-09.

35. Heron E, Chatellier G, Billaud E, Foos E. The urinary metanephrine-to-creatinine ratio for the diagnosis of pheochromocytoma. Ann Intern Med 1996; 125:300-03.

36. Mengden T, Habmann P, Mullen J, Vetter W. Urinary free cortisol versus 17-hydroxysteroids: a comparative study of their diagnostic value in Cushing's syndrome. Clin Invest 1992; 70:545-48.

37. Montwill J, Igoe D, McKenna T. The overnight dexamethasone test is the procedure of choice in screening for Cushing's syndrome. Steroids 1994; 59:296-98.

38. Weinberger M, Fineberg N. The diagnosis of primary aldosteronism and separation of two major subtypes. Arch Intern Med 1993; 153:2125-29.

Each Applied Evidence review article considers a common presenting complaint or disease and summarizes the best available evidence for clinicians. The collected reviews are published online at www.jfponline.com. Explanations of the Levels of Evidence can be found at http://cebm.jr2.ox.ac.uk/docs/levels.html.

STEVEN A. DOSH, MD, MS Escanaba, Michigan

* From the OSF Medical Group. Reprint requests should be addressed to Steven A. Dosh, MD, MS, OSF Medical Group, 3409 Ludington, Escanaba, MI 49837. E-mail: doshstev@msu.edu.

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