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Prim Care Clin Office Pract 35 (2008) 489–500

Secondary Causes of Hypertension
Sandra J. Taler, MD
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA

Secondary hypertension is uncommon in traditional primary care practice, yet it may cause major morbidity for a subset of patients. Depending on the conditions included, it may affect 5% to 10% of hypertensive patients. Investigation of all to detect these few would be costly and impractical and may exaggerate the risk to some patients without benefit, particularly because some secondary causes may not be correctable and others may be potentially treatable but at substantial risk. Nevertheless, for the few with a treatable secondary cause, detection and correction may be highly rewarding, even life prolonging. Knowledge of key clinical clues to secondary hypertension is essential to select which patients should be evaluated further and to what extent. This article provides an overview of the range of secondary causes, including key clinical features and appropriate diagnostic and treatment options. Details on the merits of surgical and other invasive interventions are beyond the scope of this discussion, and the reader is encouraged to refer these patients for subspecialty consultation and management.

Definition and approach Secondary hypertension is the presence of a specific condition known to cause hypertension. This condition may be the sole cause for hypertension in an individual, or a contributing factor in a patient who already has primary hypertension. A classification of secondary causes is shown in Table 1. Renal parenchymal disease, commonly termed chronic kidney disease (CKD), is the most common secondary cause, but urinary outlet obstruction should be considered. Renovascular disease occurs in young women as fibromuscular dysplasia and in older individuals because of atherosclerotic renal artery stenosis. Endocrine causes include primary aldosteronism, pheochromocytoma,

E-mail address: taler.sandra@mayo.edu 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2008.06.001 primarycare.theclinics.com

as noted in 31% of a group of 104 patients enrolled in a resistant hypertension treatment trial [6]. even if feasible. For others.490 Table 1 Causes of secondary hypertension Renal Renovascular TALER Endocrine Other Renal parenchymal disease Ureteral or bladder outlet obstruction Renovascular hypertension Fibromuscular dysplasia Atherosclerotic disease Aortic coarctation Primary aldosteronism Pheochromocytoma Cushing’s disease Hypo. unusual clinical features or resistance to effective therapy triggers the search for secondary hypertension. it is best to avoid the use of complex diagnostic procedures. comorbidities. the author’s own experience suggests it may be more common. Although the reported prevalence is 5% to 18% in referral hypertension practices [3–5]. and thyroid or parathyroid abnormalities. reported prevalence rates vary widely depending on the extent of screening and the definitions used. does not resolve the hypertension. Is the issue whether fibromuscular renovascular disease is present and may be treated with endovascular intervention or whether bilateral atherosclerotic disease is present and threatening renal functional viability? Selection of testing may change considerably depending on the clinical question and the potential for modifying therapy as a result. Here. If the risks for intervention are prohibitive. some individuals can be treated to goal BP levels using lifestyle changes and medication. and long-term prognosis in addition to the efficacy of medical therapy. the specific clinical questions to be answered may direct the extent of testing to be undertaken. When making decisions regarding the extent of evaluation that is appropriate. Secondary hypertension may cause drug resistance. Further. obstructive sleep apnea (OSA) is an increasingly common problem and may comprise sympathetic nervous system activation [1] and a relative aldosterone excess state [2]. the provider must consider the patient’s age. these are balanced against the risks for leaving the condition undetected and the risks for potentially invasive treatment. In the current obesity epidemic. Because recent trends in primary hypertension management emphasize lifestyle changes and early initiation of drug treatment with limited . Even with secondary hypertension. which is related to increased severity of the blood pressure (BP) elevation or to the presence of underlying hormonal abnormalities. treatment of an identified secondary cause.or hyperthyroidism Hyperparathyroidism OSA cortisol excess. A patient’s response to medical treatment and tolerance of that treatment must also be considered. In most cases.

suggests excessive aldosterone production. Although rare. early diagnosis may provide an opportunity for cure that may be lost later as the hypertension persists over time. or unexpected laboratory findings (Table 2). such as obesity) merits a more aggressive evaluation. Declining renal function in an elderly patient presents a difficult dilemma in which it may be reasonable to pursue a more invasive evaluation in the hope of preventing the major morbidity of kidney failure. and thereby improve BP response to the prescribed antihypertensive medications. In this context. The development of acute renal failure with the introduction or dose increase of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker suggests the presence of severe bilateral renal artery stenosis. and snoring with daytime hypersomnolence (OSA). Other historical clues include a more severe or accelerated hypertension course and the absence of a family history of hypertension. The diagnosis of hypertension in a young person (younger than the age 30 years and especially without contributing features. urinary obstructive symptoms (obstructive uropathy). perhaps resulting in fewer in number and lower dosages. clues on physical examination. Clinical clues for secondary causes Secondary hypertension is more likely when there are atypical features of the patient’s history. the most common indication for secondary evaluation becomes the failure to achieve BP targets using escalating numbers and doses of medication [8]. Specific drug intolerances may be a clue to a secondary cause. many patients begin antihypertensive therapies without specific testing to exclude secondary causes. The overriding goal of additional testing is to evaluate and correct potential contributing causes. because the financial and medical costs of drug treatment are substantial over his or her lifetime. even if BP is well controlled. or the need for large amounts of potassium supplementation to maintain normokalemia. it is important to remember that most patients who have secondary hypertension do not attain complete resolution even if a cause is determined. For the patient unable to tolerate multiple attempts at medical therapy. whether primary or secondary. In this setting. Specific symptom constellations also merit further investigation. Although this discussion focuses on rare causes of hypertension that are potentially curable if properly identified and corrected. The rapid onset of pulmonary edema . If medical therapy fails. These include hypertensive spells and lability suggesting pheochromocytoma. the provider should then go back and expand the diagnostic testing to consider the presence of a secondary cause.SECONDARY CAUSES OF HYPERTENSION 491 laboratory investigation [7]. a secondary evaluation may also be appropriate. The development of hypokalemia that is disproportionate in severity to that anticipated. these features suggest that a potentially curable form of hypertension may be present. a progressive decline in renal function should prompt reconsideration of a secondary cause. In older patients.

multiple arterial bruits Large palpable kidneys Laboratory findings Hyperkalemia Hypokalemia Elevated serum creatinine Abnormal urinalysis Loss or blunting of nocturnal BP decrease Disproportionate target organ damage (cerebral lacunar infarcts. narrow pharynx with soft tissue crowding Abdominal systolic-diastolic bruit. orthostatism Prostatism Snoring. primary or secondary hyperaldosteronism Renal parenchymal disease. urinary obstruction. corticosteroid excess Pheochromocytoma Renovascular hypertension Pheochromocytoma Urinary obstruction OSA Renovascular hypertension Pheochromocytoma Cushing’s disease Aortic coarctation Thyroid disease OSA Renovascular hypertension Polycystic kidney disease Renal parenchymal disease. angiotensin-converting enzyme inhibitor. ARB Symptoms Spells. renal failure) Possible causes Any Any Any Any secondary secondary secondary secondary cause cause cause cause Primary or secondary hyperaldosteronism. left ventricular hypertrophy. Physical findings are infrequent and require additional studies to confirm a diagnosis. continuous murmur over back Goiter or thyroid nodule Large neck. angiotensin receptor blocker. urinary obstruction Renovascular hypertension. ARB. daytime hypersomnolence Flash pulmonary edema Physical examination signs ´ Cafe au lait spots. pigmented striae Thigh BP lower than brachial BP. neurofibromas Cervical fat pad.492 TALER Table 2 Atypical features suggesting secondary hypertension Historical Early age of onset Severe or accelerated course Absent family history of hypertension Resistant hypertension Specific drug intolerances Marked hypokalemia while taking a diuretic medication Worsening hypertension after beta-blockade Acute renal failure after initiation or dose increase of ACEI. moon facies. (‘‘flash pulmonary edema’’) in a patient who has normal cardiac function may indicate tight bilateral renal artery stenoses. the presence of these signs should point to the need for . lability. renovascular hypertension Renal parenchymal disease Any secondary cause Any secondary cause Abbreviations: ACEI. hypertensive retinopathy. Still.

even before a decline in renal function is evident. and Treatment of High Blood Pressure (JNC 7) [7]. pheochromocytoma. moon facies. Although full coverage of renal diseases and their treatment is beyond the scope of this review. The presence of target organ damage out of proportion to office BP levels suggests nocturnal hypertension and a potential secondary cause. and making earlier specialist referrals [10]. it is essential that the clinician recognize major types of renal disease in order to initiate early treatment and appropriate referral. and oropharyngeal examinations. cortisol. Further. Detection.SECONDARY CAUSES OF HYPERTENSION 493 further evaluation of the associated conditions (see Table 2). preliminary testing should include a noninvasive imaging study of the kidneys and renal arteries. An examination for secondary causes should include thorough skin. cervical fat pad and pigmented striae (Cushing’s disease). one should begin with a general evaluation encompassing multiple causes and then focus on contributing mechanisms based on abnormal test results. carotid or femoral bruits or an abdominal bruit (renovascular disease). Laboratory abnormalities relate primarily to reduced or elevated serum potassium levels or to evidence for decreased renal function. A recent movement to have clinical laboratories report an estimated glomerular filtration rate (eGFR) concurrent with serum creatinine measurements should assist practitioners in recognizing renal function impairment (CKD) earlier. and other causes. Hypertension may be a presenting sign of renal disease and may be severe. A basic classification of renal diseases is included in Table 3. Evaluation. including OSA (see Table 1). Secondary hypertension is associated with disturbances in circadian BP rhythm by ambulatory blood pressure monitoring (ABPM). thy´ roid. aggressive treatment of hypertension in this setting may delay progressive renal function decline. Renal parenchymal disease is the most common cause of secondary hypertension. paraganglioma). Secondary hypertension is traditionally classified by organ system into renal causes. for some. Beyond the basic laboratory tests advised by the seventh report of the Joint National Committee on Prevention. redundant pharyngeal soft tissues with airway crowding and large shirt collar size (OSA). left arm BP (aortic coarctation). it . cardiovascular. Specific features include cafe au lait spots or neurofibromas (eg. initiating renal protective measures. It is important to distinguish renal parenchymal disease from renovascular hypertension to direct further testing appropriately. and enlarged palpable kidneys (polycystic kidney disease). Diagnostic evaluation If secondary hypertension is suspected. along with hormonal screening for excess aldosterone. Further. and catecholamine states. Diabetic nephropathy is now the most common cause of end-stage renal disease. reduced thigh and. affecting 50% of those with diabetes over time [11]. endocrine causes. and thereby an increased risk for target organ damage [9].

Parenchymal renal disease is characterized by elevated serum creatinine and. often severe without urinary abnormalities. Renal outflow tract obstruction attributable to prostatic obstruction. venography Ultrasound. With slowly progressive renal diseases. urinary retention. Referral to a nephrologist for a renal biopsy may be necessary for definitive diagnosis. this merits further vascular imaging. in some settings. venous Renal mass or masses Hypertension. hypertension may occur later in the disease course related to reduced efficiency of sodium and water handling. and a negative urinary sediment test result suggest renal vascular disease. renal biopsy Ultrasound. a mass lesion. Renal ultrasound is a practical first imaging study to visualize the renal parenchyma and the collecting system. proteinuria. CT. for limitations). biopsy or resection incidental finding on imaging study. active urinary sediment. hematuria. ultrasound. a life-threatening sclerosis of the skin and connective tissues [12. Normal renal parenchymal imaging. the absence of hydronephrosis. MRI (see text for limitations). CT. MRI (see text Pain related to pressure from mass lesion.494 TALER Table 3 Broad classification of kidney diseases and appropriate testing options Renal parenchymal disease Manifestations Glomerular diseases Hypertension. proteinuria Reduced renal function with or without urinary abnormalities (casts) Painful hematuria. including interstitial diseases. especially cardiovascular disease. coupled with drug-resistant hypertension. decline in renal function if late or bilateral Edema. edema. CT imaging for nephrolithiasis. because most specialists would avoid the more invasive renal angiography unless other studies implicate significant and treatable arterial stenosis. Current concerns regarding the risk for nephrogenic systemic fibrosis (NSF). or complications of prior surgery should also be excluded before moving to invasive vascular imaging. The choice of modality is currently limited to computed tomography angiography (CTA) requiring iodinated contrast or magnetic resonance angiography (MRA) using gadolinium. ultrasound. nephrotic Ultrasound. renal biopsy Serologic testing. MRI (see text syndrome for limitations). overflow incontinence Confirmatory testing Serologic testing. may be asymptomatic carries risk for multiple medical comorbidities. Other glomerular diseases may also present with hypertension and proteinuria.13]. CT. urodynamic studies. have reversed prior selection algorithms to favor CTA in patients who have renal . urinary supersaturation testing Ultrasound. obstruction. including obstruction Vascular disease. cellular casts. arterial Vascular disease. arteriography Tubulointerstitial diseases Collecting system injury.

it is generally reversible if it occurs. The diagnosis is made by a 24-hour urine aldosterone level greater than 12 mg in the setting of salt loading. Spontaneous hypokalemia. In this form. More commonly. primary aldosteronism is reported in up to 20% of patients who have resistant hypertension [18. preferably drawn in the morning when production is greater. It is important to remember that a single positive ARR is not diagnostic. such that aldosterone is produced in relative excess [20]. In its classic form. The detection of an adrenal mass lesion may not correlate with the overproducing adrenal gland. Most specialists begin with concurrent measurements of plasma aldosterone and plasma renin activity. likely those with greater severity.19]. and adrenal vein sampling is needed to confirm laterality before adrenalectomy. percutaneous or.22]. surgical intervention may salvage critical renal function [15].5 ng/mL/h as the lowest threshold for renin measurement. screening should be considered early in the evaluation.17]. even in the setting of an aldosterone-producing adenoma. Adrenal imaging should be withheld unless inappropriate aldosterone production is confirmed. whereas NSF is irreversible and may be fatal. Primary hyperaldosteronism is increasingly recognized as a correctable cause for resistant hypertension. Chemokines in visceral fat may stimulate the renin angiotensin aldosterone system. demonstrating inappropriate aldosterone production in a sodium-replete state. . no distinct adenoma is identifiable. Using 0. primary aldosteronism refers to excess aldosterone secretion caused by an adrenal cortical adenoma. and for selected individuals. nor does a negative ARR exclude the diagnosis of primary aldosteronism. with large multicenter studies currently in progress [16. once considered a diagnostic requirement. An obese patient who has resistant hypertension may have a relative aldosterone excess but fall short of the classic criteria for primary aldosteronism. Whether renal revascularization is a superior method for treatment of renovascular hypertension remains unproved.SECONDARY CAUSES OF HYPERTENSION 495 insufficiency. Contrast agent–induced renal failure is uncommon and can be prevented in part by using preprocedural saline hydration and N-acetylcysteine [14]. Once regarded as rare. an aldosterone-to-renin ratio (ARR) of greater than 20 is considered a positive screen for primary aldosterone excess but not sufficient for diagnosis. This practice change further underscores the importance of careful consideration of the individual patient and the risk/benefit ratio of further testing before proceeding down this path. it has a different set point. For most patients. Significant renal vascular disease causing resistant hypertension or progressive renal dysfunction may respond well to renal revascularization. particularly in patients who have concurrent sympathetic activation from untreated sleep apnea [2]. a positive relation between angiotensin II and aldosterone remains. thus. although the sensitivity and specificity of this screen have not been well validated [21. but there is diffuse or nodular hyperplasia of both adrenal cortices. is reported in approximately 30% of cases. however. less commonly. Clinical features should guide the investigation of hormonal secondary causes.

particularly in settings in which the prevalence is low. hyperglycemia) or for those with an incidentally discovered adrenal mass. An overnight dexamethasone suppression test is used for screening and excludes cortisol excess if negative. 24-hour urinary metanephrine and catecholamine measurements are preferred to the more convenient plasma metanephrine measurement so as to provide adequate sensitivity with a lower rate of false-positive results. Fractionated plasma metanephrines have the highest sensitivity (97%) and are ideal for evaluation of hereditary pheochromocytoma states [23]. particularly those with orthostatic hypotension. For those with sporadic pheochromocytoma. sensitivities of plasma metanephrines or urinary measurements are comparable (96%).and then beta-receptor blockade before resection of the lesion. which may be particularly useful in patients who have hereditary pheochromocytoma and lack clinical signs or symptoms or who may harbor small tumors that release lower levels of catecholamines. particularly older hypertensive patients. which is more likely seen in clinical practice. amiloride may be effective. Bilateral adrenal hyperplasia should be treated medically with an aldosterone receptor antagonist. pigmented striae. For patients undergoing evaluation for sporadic pheochromocytoma. lateralizing aldosterone production supports the diagnosis of an independent aldosterone-producing adenoma. Directed testing of the adrenal cortisol axis is usually reserved for patients with clinical evidence of cortisol excess (eg. particularly if their BP is not controlled. such as spironolactone or eplerenone.496 TALER Once a diagnosis of primary aldosteronism is confirmed. Thus. Positive testing should result in referral to an endocrinologist for localization of the tumor and removal. as in the patient who has hypertension or an adrenal incidentaloma. Some specialists require successful response to an aldosterone receptor antagonist before adrenalectomy to ensure that the correct diagnosis has been made. the patient should be referred to an experienced endocrinologist for alpha. central obesity. Increasing age is associated with a greater likelihood of false-positive fractionated plasma metanephrine measurements. Epidemiologic evidence supports a link between OSA and hypertension. Pheochromocytoma is rare but should be considered in patients who have marked BP lability. Once a diagnosis is made. Potential mechanisms whereby OSA may contribute to hypertension include . or spells. tachycardia. but the urinary measurements more specific [24]. For patients intolerant to these agents. negative measurements of fractionated plasma metanephrines and 24-hour urinary total metanephrines with catecholamines are effective in ruling out the diagnosis of pheochromocytoma. Lower specificity (85%) means a lower likelihood of actually having pheochromocytoma. All patients who have hypertension should be evaluated for thyroid disease (hyperthyroid and hypothyroid states). The levels are unrelated to episodic catecholamine release or production of metabolites at sites remote from the tumor mass.

The odds ratio was graded with the severity of apneic frequency.SECONDARY CAUSES OF HYPERTENSION 497 sympathetic activation. the diagnosis of OSA conveyed a 4. In a recent case-control study of overweight or obese patients who had resistant hypertension. and effects on renal function. and adequacy of medical therapy. endothelial dysfunction. The key to detection is to consider the diagnosis in every patient but particularly in those who have obesity and resistant hypertension. Whether treatment of OSA with CPAP fully corrects the contribution to resistant hypertension is unclear [28. Less common secondary causes may present with subtle findings. The Wisconsin Sleep Cohort Study demonstrated an independent doseresponse relation between sleep-disordered breathing at baseline and development of new hypertension 4 years later [25]. and confirmatory testing. The diagnosis of OSA requires a high index of suspicion combined with direct questioning. long-term prognosis. risks for leaving the condition undetected.8-fold greater risk for resistant hypertension compared with body mass index (BMI)–matched subjects with treated and controlled hypertension [26]. The prevalence of resistant hypertension was directly related to the intensity of OSA by the apnea-hypopnea index. or other soft tissue redundancy. Role of ambulatory blood pressure monitoring As with the diagnosis of primary hypertension. Others have shown a correlation between plasma aldosterone concentration and OSA severity (apnea-hypopnea index) in subjects who have resistant hypertension but not in those who have OSA without resistant hypertension [27]. OSA-induced hypoxemia and increased upper airway resistance trigger a stress response manifested by chronically elevated circulating catecholamine levels [1]. the clinician must decide whether the condition has been sufficiently excluded in the individual patient or whether more definitive testing is indicated. hyperleptinemia. oxidative and inflammatory stress. tonsillar enlargement. patients show mild elevations in plasma and urinary metanephrines or catecholamine levels. insulin resistance. Such decisions should consider patient age. which are low enough not to suggest pheochromocytoma strongly but are higher than normal ranges. a focused examination. misdiagnosis of resistant hypertension and estimates of severity may occur in the treated patient . with a narrow oropharyngeal opening on direct oral examination as a result of crowding by a large uvula.29]. At each step in the pathway. in addition to the classic finding of a large neck (shirt collar size in a man). Characteristically. risks for intervention. and directed testing may be appropriate. impaired baroreflex function. elevated angiotensin II and aldosterone levels. The physical examination may suggest the diagnosis. Symptoms primarily relate to chronic fatigue with daytime hypersomnolence in permissive settings. Treatment of sleep apnea with continuous positive airway pressure (CPAP) often corrects the endocrine abnormalities and dramatically improves the fatigue symptoms.

the patient’s overall health status and prognosis. and balancing the risks for intervention against the risks for missing a diagnosis. volume overload). regimen simplification. This article begins with a discussion directed to the level of the internist or subspecialist physician with expertise in the selection and use of multiple agents for the treatment of hypertension. Referral patterns vary with regional expertise. using a 24-hour monitoring time [30] or an abbreviated method [31]. or when there are questions about the extent of intervention to pursue when BP remains uncontrolled. Renal parenchymal disease. When to refer patients for more specialized consultation Decisions on referral depend largely on the comfort and experience of the treating practitioner. Office or ‘‘white coat’’ hypertension may not extinguish with familiarity. when there are questions regarding selection of the most optimal studies. now termed CKD. Whether improvements in renal function may improve long-term survival merits . Before embarking on a full evaluation for secondary causes. endocrinologists (eg. renovascular hypertension. and sleep specialists for overnight polysomnography. because several types of secondary hypertension are associated with absence or even reversal of the normal nocturnal BP decrease. Selection of patients for testing incorporates historical and clinical clues. Cushing’s disease or posttransplant hypertension in the setting of exogenous corticosteroid use. referral and interpretation of adrenal imaging. is increasingly detected in an aging population. adrenal vein sampling). and primary aldosteronism [9]. renal parenchymal disease. previous treatment course. Summary The primary rationale for secondary hypertension evaluation is to achieve BP control more effectively and prevent morbidity and mortality related to the disease. ABPM may be justified. Decisions regarding the extent of secondary evaluation require consideration of the likelihood of diagnosis. and comorbidities. OSA. endocrine secondary causes. A blunted or absent nocturnal BP decrease is characteristic of secondary forms. Analysis of nocturnal readings may be of particular utility in this setting. pharmacists and pharmacologists (eg.498 TALER based on office BP measurements. Resources include nephrologists (eg. drug interactions. adherence). including renal parenchymal disease with reduced renal function. renovascular hypertension. Referral is advised when these risks seem prohibitive. Renovascular disease is increasingly associated with impaired renal function and may not improve after high-risk interventions. The use of multiple home readings is increasingly favored as a more cost-effective modality but does not provide circadian or nocturnal information.

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