Evaluation and Management of Secondary Hypertension

INTRODUCTION

Hypertension is the leading cause of cardiovascular morbidity and premature death worldwide. Global prevalence of hypertension was estimated to be approximately 31% in 2010, affecting over 1 billion persons worldwide.¹ Hypertension is typically described as essential, or primary, when there are no clearly discernible reasons for elevated blood pressure (BP) ≥130/80mmHg.² Secondary hypertension, or hypertension that can be attributed to another underlying cause, is less common than primary hypertension but also underrecognized. Secondary hypertension often affects younger patients and those with resistant or refractory hypertension. Identifying the underlying cause of secondary hypertension may lead to successful intervention with the potential to improve quality of life and reduce cardiovascular morbidity and mortality. Common secondary causes of hypertension include primary aldosteronism (PA), renovascular disease, chronic kidney disease (CKD), obstructive sleep apnea (OSA), and drug-induced or alcohol-induced hypertension. Rarer causes of secondary hypertension include catecholamine-secreting tumors (pheochromocytoma and paraganglioma), Cushing’s syndrome, hypo- and hyperthyroidism, coarctation of aorta, and hyperparathyroidism. In this review, we focus on identification and treatment of common causes of secondary hypertension and highlight the importance of obtaining a detailed history from the patient to facilitate appropriate diagnosis and treatment (Table 1).

Table 1.

Presentation, evaluation, and management of common causes of secondary hypertension

Cause of secondary hypertension	Common examples of clinical presentations	Evaluation	Management
Primary aldosteronism	Resistant hypertension Hypokalemia and hypertension Adrenal mass Family history of early age of onset of hypertension	Plasma aldosterone concentration and renin activity or direct renin concentration Confirmatory testing by hypertension specialists Adrenal vein sampling	Unilateral disease: surgical resection Bilateral disease: mineralocorticoid receptor antagonist therapy
Renovascular disease	Resistant hypertension Abrupt onset hypertension Sudden worsening of blood pressure control Early age of onset of hypertension	Abdominal CT angiography (ideally); alternatively renal Doppler ultrasound (operator-dependent) or magnetic resonance angiography	Medical optimization (preferred in atherosclerotic disease) Angioplasty with or without out stenting (preferred in fibromuscular dysplasia) Surgery (rare)
Obstructive sleep apnea	Resistant hypertension Witnessed apneic episodes while sleeping Daytime somnolence or fatigue	Polysomnography	Weight loss Continuous positive airway pressure
Prescription or non-prescription substances	Resistant hypertension	Careful medication reconciliation Assessment of history of substance use	Discontinuation of offending agent and initiation of alternative therapy, if appropriate

DISCUSSION

Primary Aldosteronism

Primary aldosteronism (PA) or Conn Syndrome is the commonest form of secondary hypertension and is amenable to treatment if diagnosed appropriately.³ Patients with PA have a significantly elevated risk of cardiovascular disease morbidity (including coronary heart disease, stroke, atrial fibrillation, left ventricular hypertrophy, heart failure, diabetes and metabolic syndrome) and mortality compared to age- and sex-matched patients with essential/primary hypertension, and this risk is independent of degree of blood pressure control.⁴ The elevated cardiovascular risk from PA is thought to be related to excessive stimulation of renal and extra-renal mineralocorticoid receptor (MR) activation often causing fibrosis, endothelial dysfunction, and target organ damage. Early recognition of PA is crucial because treatment reliably lowers blood pressure, reduces the number of antihypertensive medications needed, and improves cardiac and renal function.

While traditionally thought to be a rare form of hypertension that presents with severe hypertension with or without hypokalemia, recent evidence suggests that PA is present in up to 20% of patients with hypertension and is more common among those with greater severity of hypertension.^5-8 Nonetheless, screening for PA remains low and underutilized, even among patients with resistant hypertension.^9,10 PA is defined by autonomous and renin-independent, non-suppressible aldosterone production, which results in excessive mineralocorticoid receptor activation and thus increased sodium reabsorption, hypertension, hypokalemia, and elevated risk of adverse cardiovascular outcomes. Autonomous aldosterone hypersecretion may occur from aldosterone producing adenomas (APA), idiopathic (often bilateral) adrenal hyperplasia (IAH), or abnormal aldosterone producing cell clusters (APCCs) present within morphologically normal adrenal glands.⁵ Recent experimental and epidemiological studies have demonstrated a continuous spectrum of renin-independent autonomous hyperaldosteronism, ranging from subtle to overtly autonomous aldosteronism, and that occurs in all stages of hypertension and even in normotensive individuals.^6,11 Consensus is still emerging whether all patients with hypertension should be screened for PA, regardless of severity of hypertension.

Screening for PA in primary care is easy, inexpensive, and non-invasive. Furthermore, screening for PA can potentially identify patients with treatable forms of hypertension and modify cardiovascular risk. Current guidelines recommend screening for PA in patients with severe hypertension and/or hypertension with hypokalemia (spontaneous or diuretic-induced), particularly in those with resistant hypertension (defined as BP>130/80 despite being on three optimally dosed antihypertensive agents, of which one is a diuretic, or BP<130/80 with four antihypertensive agents), or associated with a family history of early-onset hypertension, stroke under the age of 40 years, first degree relative with PA, atrial fibrillation, sleep apnea, or adrenal incidentaloma.^2,5 Individuals who fall into these categories should have an aldosterone-to-renin ratio (ARR) measured, based on plasma aldosterone concentration and plasma renin activity (PRA) or direct renin concentration (DRC). Guidelines recommend drawing the blood tests for aldosterone and renin levels about 2 hours after waking up in the morning and with the patient in the seated position. Since hypokalemia suppresses aldosterone production, potassium levels should be corrected to normal prior to screening. Ideally, patients should have unrestricted salt intake before testing to ensure volume expansion, and mineralocorticoid receptor antagonists (such as spironolactone) should be withdrawn for at least 4 weeks prior to testing. It is not essential for patients to remain off-antihypertensive medications during testing, and is often not safe to withhold antihypertensive medications in patients with moderate or severe hypertension.^2,5 Some recommendations suggest temporarily replacing antihypertensive agents with verapamil, hydralazine or α-adrenergic blockers such as prazosin or doxazosin for the four weeks prior to testing, as these medications have minimal effects on plasma aldosterone or renin levels.⁵ When it is not reasonably safe or feasible to discontinue diuretics, renin-angiotensin aldosterone system (RAAS) inhibitors, or even mineralocorticoid receptor antagonists in patients with severe hypertension, testing is interpretable as long as renin levels are suppressed (which indicates volume expansion and therefore inhibition of endogenous feedback-driven aldosterone secretion).

ARR is a sensitive measure but not reliable by itself; it should be interpreted in the context of suppressed renin and elevated aldosterone levels. Patients with elevated ARR>20 along with elevated plasma aldosterone levels (>10 ng/dl) and suppressed renin levels (PRA <1 ng/ml/hr or DRC <10pg/ml) are considered to have positive screening for ‘biologically overt PA’ and then should undergo confirmatory testing for definitive diagnosis.^3,5 However, patients with spontaneous hypokalemia, suppressed renin, and PAC>20 ng/dl are considered to have unequivocal PA from screening alone and can proceed directly to subtype classification (i.e., to determine APA or unilateral IAH versus bilateral IAH).⁵ Familial hyperaldosteronism (FHA type I-IV) is a group of inherited PA disorders in patients with a significant family history of early onset hypertension and is associated with suppressed renin and elevated aldosterone levels but less elevated ARR compared to that seen with APA. FHA can be identified with genetic testing.

Patients with positive screening should be referred to PA hypertension specialty care (depending on the practice, this can be endocrinology, nephrology, or cardiology) to undergo confirmatory testing prior to subtype classification.⁵ While there is no gold standard for confirmatory testing, four testing procedures are currently in common use across the world and are considered equivalent: 1) oral sodium loading; 2) saline infusion; 3) fludrocortisone suppression test, which is more difficult to perform safely than the other options; and 4) captopril challenge test, which is prone to equivocal results.⁵ Most centers in the United States use oral sodium loading (>5g/day for 3 days or a 2-liter infusion of normal saline over 4 hours in a seated position) to induce volume expansion, which would normally suppress aldosterone production but does not do so in patients with autonomous aldosterone production. Adequate salt loading with the oral test is verified by 24-hour urine collection on the third day of salt loading: urine sodium levels should be >200 mmol/24-hours. A 24-hour urine aldosterone level >12 μg/24-hours after 3 days of oral salt loading or a serum aldosterone level >6 ng/dl after saline infusion confirms autonomous aldosterone production.

Subtype classification relies in non-invasive imaging with adrenal computed tomography (CT) along with invasive adrenal vein sampling performed by an experienced interventional radiologist.⁵ The initial adrenal CT can identify normal adrenal glands versus unilateral or bilateral macroadenoma (>1cm) or microadenomas (≤1cm) which present as hypodense nodules (<10 Hounsfield units, reflecting tissue that contains more lipid than water). It also excludes large masses (>4cm) that would be suspicious for adrenocortical carcinoma. CT is preferred over magnetic resonance imaging (MRI) because it is less expensive and has better resolution. Adrenal CT also anatomically delineates the mass and adrenal venous anatomy that is crucial for adrenal vein sampling (AVS). IAH may appear normal on CT scan or show nodular changes, and thus CT scan alone is insufficient to delineate unilateral from bilateral disease. AVS with lateralization of excessive aldosterone secretion is necessary to make that distinction so that treatment decisions can be made appropriately. Cosyntropin is often injected and cortisol and aldosterone levels are measure from each adrenal vein and compared to peripheral venous sampling. AVS is a technically challenging procedure that requires an experienced operator but is relatively safe.¹²

Depending on the PA subtype, unilateral laparoscopic adrenalectomy or mineralocorticoid receptor antagonist therapy can successfully treat and reverse hypertension, hypokalemia, and excess cardiovascular risk imposed by autonomous aldosterone secretion.^2,3,5 Surgery is more effective than medications in patients with unilateral hypersecreting adrenal adenoma or unilateral IAH, and is generally recommended unless the patient is unwilling or is not a surgical candidate. Patients with bilateral adrenal disease should be treated medically with a mineralocorticoid receptor antagonist both for blood pressure control and to protect against target organ damage from effects of aldosterone that are independent of blood pressure control. Spironolactone remains the preferred initial agent, and should be started at low doses 12.5-25mg daily and increased in 25mg increments every 4-8 days to a maximum of 100 mg daily (though doses up to 400mg daily have been used).^3,5 Side effects of spironolactone are dose-dependent and mainly in the form of gynecomastia and sexual dysfunction in men and menstrual irregularities and breast engorgement in women. Eplerenone, which is costlier and requires twice-daily dosing, can be an alternative to spironolactone when side effects occur. Patients should be monitored for hyperkalemia, especially in those with reduced kidney function.

Renovascular Disease

Renovascular disease (RVD), often referred to as renal artery stenosis, is an important and potentially correctable cause of secondary hypertension that occurs in about 5% of individuals with a diagnosis of hypertension, with higher prevalence among the elderly.^13,14 RVD results from reduced arterial blood flow to one or both kidneys leading to the over-activation of the RAAS. In most cases, RVD is either caused by atherosclerosis (90%) or fibromuscular dysplasia (FMD) (9%) of the renal arteries.¹⁵ Atherosclerotic RVD is commonly seen in patients age 50 or older, while FMD is more commonly seen in females less than 50 years of age.¹⁶ Less common causes of RVD, not specifically address in this review, include renal artery aneurysm, systemic vasculitis, arteriovenous fistula, Page kidney (e.g., due to trauma to the kidney), renin-secreting tumors, aortic coarctation, and extrinsic compression of the renal artery.¹⁷

Risk factors for atherosclerotic RVD include elevated low density lipoprotein level, low high density lipoprotein level, diabetes mellitus, hypertension, tobacco use, and the metabolic syndrome.¹⁸ Approximately 80-90% of patients with FMD are female.^19,20 The development of FMD is likely related to a combination of genetic and environmental factors.²¹ Environmental modifiers include female hormones, lifetime mechanical stress, and tobacco use. The genetic basis of FMD is incompletely understood. Genetic variants can be sporadic or familial, only a minority of patients (1.9-7.3%) with FMD report an affected family member.²⁰ Genetic screening for FMD is currently not supported nor are associated variants considered actionable by the American College of Medical Genetics.²²

Several clinical findings suggest renovascular disease as the underlying cause of hypertension. The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines suggest screening for renovascular disease among patients with 1) resistant hypertension; 2) abrupt onset hypertension; 3) hypertension that is increasingly difficult to control, especially in the context of flash pulmonary edema; and 4) early-onset hypertension (especially in females, given risk of FMD).² The 2018 European Society of Cardiology (ESC)/European Society of Hypertension (ESH) hypertension guidelines also describe signs and symptoms suggestive of RVD which include widespread atherosclerosis (especially peripheral arterial disease); diabetes; smoking; recurrent flash pulmonary edema; and abdominal bruit.²³ The ESH and the Society for Vascular Medicine (SVM) note that FMD should be considered in those with 1) onset of hypertension <30 years; 2) accelerated and/or malignant hypertension (>180/110); 3) drug resistance; 4) unilateral small kidney without causative urologic abnormality; 5) abdominal bruit in the absence of atherosclerotic risk factors; 6) suspected renal artery dissection; or 7) the presence of FMD in another artery.²⁴

Screening for RVD should be performed when patients have evidence of secondary hypertension without other obvious secondary causes, and when an intervention would likely be planned if a significant stenotic lesion is found. Testing is generally not performed in patients who are well-controlled with medical therapy. The gold standard for diagnosing RVD is renal angiogram. While renal angiogram is invasive and involves the use of radiocontrast dye, it allows for relatively precise measurement of flow gradients which can discern clinically significant lesions. Alternative modalities include renal Duplex Doppler ultrasound, magnetic resonance angiography (MRA), and CT angiography.² The choice of screening test is based on institutional factors (local expertise, availability) and patient factors (renal function, allergies, body habitus, preference).

Generally, non-invasive imaging is considered less reliable than renal angiogram for the diagnosis of FMD. Duplex Doppler ultrasound is widely available and inexpensive but technical expertise is center-dependent.²⁵ The ESH/SVM consensus group recommends CTA as the initial screening test when FMD is suspected, or MRA if CT angiography is contraindicated. Per the ESH/SVM, CT angiography is preferable to MRA for diagnosis of FMD because of superior spatial resolution and better discrimination of FMD from atherosclerotic RVD.²⁴

There are three treatment categories for RVD: 1) medical, 2) angioplasty with or without out stenting, and 3) surgical. Medical therapy is the first-line treatment in all cases of RVD. The ESC and AHA recommend angiotensin-converting enzyme inhibitor (ACEI), angiotensin-receptor blocker (ARB), or calcium channel blocker therapy, with a specific recommendation from the ESC to closely monitor estimated glomerular filtration rate (eGFR) and potassium upon initiation of an ACEI/ARB.^2,26 While ACEIs and ARBs are generally well tolerated, a fall in eGFR of >30% may prompt consideration of renal revascularization. Other important aspects of medical management of RVD include optimal management of hypercholesterolemia, diabetes mellitus, and obesity, tobacco cessation, and use of an antiplatelet agent.

The role of renal angioplasty with or without stenting remains controversial in atherosclerotic RVD but is accepted in FMD. Based on a 2014 Cochrane systematic review of eight randomized control trials involving 2,222 participants, angioplasty with or without stenting was not shown to be superior to medical therapy in atherosclerotic RVD.²⁷ Surgical treatment of renovascular disease is less common given the emphasis on medical therapy and the availability of percutaneous intervention. Generally, surgical revascularization or bypass is considered in patients with anatomically complex disease refractory to medical management or those undergoing vascular repair for other reasons.

Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is a breathing disorder where the upper airway recurrently collapses during sleep and induces intermittent hypoxemia.²⁸ Several studies have established a strong and consistent association between OSA and hypertension. In a systematic review and meta-analysis evaluating this association, Hou et al. examined twenty-six studies that included over 50,000 participants and demonstrated that OSA is significantly associated with both essential/primary and resistant hypertension.²⁹ Furthermore, episodes of apnea are significant predictors of both systolic and diastolic blood pressure; each episode of apnea per hour of sleep is associated with a 1% increased odds of hypertension.³⁰ A dose response relationship has been established, wherein the risk of hypertension increases linearly with increasing severity of OSA.^30,31 Furthermore, OSA has been found in over 80% of patients with resistant hypertension, ^32,33 with the highest prevalence among those with refractory hypertension.³⁴

The risk of acquiring OSA is influenced by several modifiable and unmodifiable risk factors. Unmodifiable risk factors include increased age, male sex, craniofacial anatomy, and family history of OSA. Modifiable risk factors include smoking, alcohol use, nasal congestion, and most commonly, obesity.^35,36 There is a strong, direct correlation between obesity and OSA; a 10% increase in body weight is associated with a sixfold increased risk of having OSA.³⁷

Screening for OSA should be considered in patients reporting sleep problems such as breathing pauses at night, snoring, and excessive daytime sleepiness or fatigue.³⁸ Screening for OSA should also be considered in individuals with known risk factors as well as those with comorbidities that may be attributed to OSA such as resistant hypertension, heart failure, arrythmias, coronary artery disease, and stroke as well as metabolic disorders including diabetes, glucose intolerance, and hyperlipidemia.^39-41 Several brief questionnaires are used for risk assessment such as the Berlin questionnaire or Epworth Sleepiness Scale, but the most accurate remains the STOP-Bang questionnaire.^42-44 Ultimately, the gold standard test to establish the diagnosis is laboratory-based polysomnography where both respiratory and sleep parameters are monitored.⁴⁵

Treatment of OSA carries several benefits, including improvement in blood pressure. Several treatment modalities are available including behavioral measures such as avoidance of tobacco and alcohol and adjusting sleep positioning, medical devices such as mandibular repositioning appliances, or surgical procedures such as uvulopalatopharyngoplasty or maxillomandibular advancement.³⁸ The mainstays of treatment, however, are continuous positive airway pressure (CPAP) and medically supervised weight loss. The use of CPAP for treatment of OSA is associated with improvement in blood pressure, with varying results depending on the severity of hypertension. In patients with moderate hypertension, the use of CPAP is associated with a modest decline in systolic blood pressure and diastolic blood pressure (mean decline 3mmHg/2mmHg, respectively) in addition to an improvement in blood pressure variability.^46-48 The antihypertensive effect of CPAP therapy is greater in patients with resistant hypertension (mean decline 6-7mmHg systolic blood pressure, 4-5mmHg diastolic blood pressure).^49,50 Data also supports that treatment of OSA with weight loss can have a significant effect on blood pressure. Surgical weight loss is associated with lower OSA severity and remission of hypertension in a subset of patients. ^51,52 The most robust improvement in blood pressure, however, can be achieved when CPAP is used in conjunction with weight loss. In a randomized control trial, Chirinos et al. assessed the antihypertensive effect of weight loss and CPAP use both alone and in combination. The authors found a reduction in systolic blood pressure of 6.8mmHg with weight loss, 3.0mmHg with CPAP use and 14.1mmHg in the dual intervention group.⁵³ This suggests that treatment of OSA with combined weight loss and CPAP can have a synergistic effect on blood pressure control.

Medication, Drug, and Alcohol-Induced Hypertension

Prescription medications, over-the-counter medications and supplements, illicit drugs, and alcohol are common causes of secondary hypertension.⁵⁴ A careful history is necessary to determine patients’ risks of hypertension due to prescribed or non-prescribed substances, including illicit drug use.^55,56 Serum or urine screening for toxins may be appropriate in some patients. Ideally, in patients with hypertension and particularly those with resistant hypertension, drugs that increase blood pressure should be discontinued in lieu of alternative agents that do not affect blood pressure.

Examples of drugs that can increase blood pressure are outlined in Table 2, including recommendations for addressing use of these agents and alternative therapies. Some examples are highlighted here. Drugs prescribed for psychiatric conditions including attention deficit hyperactivity disorder, depression, and psychosis are commonly associated with increased blood pressure. Providers should evaluate the appropriateness of recommending alternative approaches, such as behavioral therapy, or medications that do not generally affect blood pressure (e.g., selective serotonin reuptake inhibitors, aripiprazole, and ziprasidone).^2,57 Several chemotherapeutic agents increase blood pressure, including anti- vascular endothelial growth factor therapy, tyrosine kinase inhibitors, and alkylating agents. These medications should generally be continued, and their use should be accompanied by very close monitoring of blood pressure and anticipated escalation of antihypertensive therapy.⁵⁸ Of note, sudden withdrawal of centrally acting alpha-agonists, such as clonidine (commonly used as an antihypertensive medication) and tizanidine (increasingly used as a muscle relaxant) can result in severe rebound hypertension.^59,60 These medications should ideally be avoided in patients with hypertension due to this risk; if they are used, they should be tapered slowly upon cessation.

Table 2:

Prescription and non-prescription drugs that increase blood pressure and alternative approaches.

Drugs that increase blood pressure	Alternative approaches in patients with hypertension
Prescription drugs
Amphetamines	Recommend behavioral therapy73
Antidepressants including monoamine oxidase inhibitors, serotonin norepinephrine reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, and tricyclic antidepressants	Recommend alternative antidepressants including selective serotonin reuptake inhibitors54
Atypical antipsychotics including clozapine and olanzapine	Recommend alternative atypical antipsychotics such as aripiprazole and ziprasidone2,57
Immunosuppressing medications including cyclosporine and systemic corticosteroids	Recommend alternative immunosuppressing medications including tacrolimus and mycophenolate74
Estradiol-containing oral contraceptives	Recommend progestin-only contraceptives or alternative forms of contraception
Chemotherapeutic agents including anti- vascular endothelial growth factor therapy, tyrosine kinase inhibitors, and alkylating agents	Typically recommend close monitoring of blood pressure and escalation of antihypertensive therapy58
Sudden withdrawal of central-acting sympatholytic drugs such as clonidine and tizanidine	Recommend avoiding oral clonidine for treatment of hypertension whenever possible and tapering upon discontinuation;59 use cyclobenzaprine or other muscle relaxants instead of tizanidine60
Non-prescription drugs
Alcohol	Recommend limiting use to no more than one drink per day in women and two drinks per day in men2
Caffeine	Recommend limiting use to <300 mg/day2,75
Cocaine	Recommend abstinence
Methamphetamine	Recommend abstinence
Decongestants that include pseudoephedrine or phenylephrine	Decongestants such as antihistamines
Supplements such as ephedra and St. John’s wort	Recommend abstinence76
Non-steroidal anti-inflammatory drugs	Acetaminophen or topical non-steroidal agents

Non-steroidal anti-inflammatory drugs are associated with a modest increase in blood pressure, development of new onset hypertension, and worsening blood pressure control among patients already diagnosed with hypertension.^61-63 Some patients require escalation of antihypertensive therapy to counter these effects. Where possible, alternative agents should be used, particularly among patients with resistant hypertension. If non-steroidal anti-inflammatory agents are necessary, blood pressure should be closely monitoring and antihypertensive therapy should be escalated as needed, preferentially using non-RAAS-inhibiting agents.^64,65

Alcohol intake is associated with increased blood pressure and elevated risk of developing hypertension, particularly heavy alcohol intake of 3 or more standard drinks per day (>36 oz of beer, 15 oz of wine, or 4.5 ounces of spirits).^2,66 In the United States, excess alcohol intake is thought to contribute to up to 10% of cases of hypertension. Reduction of alcohol intake by about 50% among heavy drinkers lowers blood pressure by a mean of 5/4 mmHg in randomized controlled trials.^67,68 Current hypertension guidelines recommend that women drink no more than one standard drink and men drink no more than two standard drinks daily.²

Pheochromocytoma and Paraganglioma

Pheochromocytomas are rare catecholamine-secreting tumors of the adrenal gland. In approximately 10% of cases, these tumors occur in extra-adrenal locations that are derived from sympathetic/parasympathetic nerves, called paragangliomas. Pheochromocytomas occur in as few of 0.01% to 0.2% of patients with hypertension, with higher prevalence in those with resistant hypertension.⁶⁹ These tumors are often accompanied by paroxysmal hypertension and tachycardia as well as symptoms including piloerection, headache, and palpitations.⁷⁰ Thus, evaluation for pheochromocytoma is typically reserved for patients with paroxysmal hypertension and/or symptomatic hypertension. Testing for pheochromocytoma should include either plasma (preferable due to ease of assessment) or 24-hour urine metanephrines. These tests can be elevated in primary hypertension, obesity, and obstructive sleep apnea, but have high sensitivity and specificity for pheochromocytoma or paraganglioma at higher levels, typically 2.5 to 3-fold higher than the upper limit of normal.^69,71 Patients with significantly elevated metanephrines should undergo CT scan to localize the tumor (or alternatively, MRI), and metaiodobenzylguanidine scanning to evaluate for metastases.⁷⁰ Furthermore, since approximately one-third of cases are inherited, patients should undergo genetic testing. The mainstay of treatment for pheochromocytoma is surgical resection, where feasible, with pre-operative alpha-blockade to prevent blood pressure instability and post-operative monitoring for recurrence and metastases.⁷⁰

Additional Rare Causes of Secondary Hypertension

There are several additional rare causes of secondary hypertension that each occur in less than 1% of patients with hypertension, such as Cushing’s syndrome, hypothyroidism, hyperthyroidism, coarctation of the aorta, primary hyperparathyroidism, and acromegaly.^2,69 Given its relatively high prevalence in the general population, assessment for thyroid disease with a thyroid stimulating hormone test is generally recommended as part of the initial evaluation for hypertension; however, hypertension typically only occurs as a result of severe forms of thyroid disease, and merits treatment regardless of thyroid hormone levels.⁷² Similarly, primary hyperparathyroidism should be suspected in individuals with concomitant hypertension and hypercalcemia. Given their infrequency, patients should only be assessed for the remaining rare etiologies of secondary hypertension based on specific historical and examination findings. For example, Cushing’s syndrome occurs in less than 0.1% of patients with hypertension, and typically presents with systemic evidence of cortisol excess besides hypertension, including central obesity following rapid weight gain, hyperglycemia, proximal muscle weakness, striae, and hirsutism.

SUMMARY

Secondary hypertension is common among patients with hypertension and is often underrecognized. Furthermore, secondary hypertension can result in target organ damage independent of the effects of blood pressure alone, which can be mitigated with appropriate management. Patients with hypertension should be evaluated for risk factors for secondary hypertension and screened accordingly. In particular, patients with resistant hypertension should, at minimum, undergo testing for primary aldosteronism and screening for drugs that may induce hypertension, with further evaluation for renovascular hypertension and obstructive sleep apnea depending on their age, symptoms, and comorbidities. Rarer causes of secondary hypertension should be considered depending on the clinical picture. Given the high prevalence of hypertension in the general population, greater attention is needed to identify causes of secondary hypertension, which can be pivotal to improving blood pressure control and preventing cardiovascular events in these high-risk patients.

Key points:

1. Secondary hypertension is common in patients with hypertension, particularly those diagnosed with hypertension at a young age or with resistant hypertension

2. Secondary hypertension merits evaluation to prevent target organ damage but is often underrecognized

3. Appropriate evaluation of secondary hypertension is largely dependent on provider history-taking to determine necessary testing

Synopsis:

Hypertension is a major cause of cardiovascular morbidity and mortality globally. Many patients with hypertension have secondary causes of hypertension that merit further evaluation. For example, secondary hypertension can result in target organ damage to the heart, kidneys, and brain independent of the effects of blood pressure. Other causes benefit from targeted therapies to supplement first-line antihypertensive agents. However, secondary hypertension is often underrecognized. The goal of this review is to highlight optimal approaches to the diagnosis and management of common causes of secondary hypertension, including primary aldosteronism, renovascular hypertension, obstructive sleep apnea, and drug-induced hypertension.

CLINICAL CARE POINTS.

• Patients with hypertension can benefit from evaluation for secondary hypertension to reduce the risk of refractory hypertension and target organ damage independent of blood pressure control

• Patients with early age of onset of hypertension and resistant hypertension, in particular, should undergo evaluation for secondary hypertension

• Provider history-taking is critical to assessing patients for secondary hypertension, particularly identification of risk factors for secondary hypertension

• All patients with hypertension should be screened for use of prescription and non-prescription drugs that may increase blood pressure and whether alternative therapies may be appropriate