Adult Secondary Hypertension: What the Primary Care Provider Needs to Know

AUTHOR:
Jeffrey Thomas Budd, MD

AFFILIATION:
Department of Medicine, Division of General Internal Medicine, University of Florida College of Medicine, Gainesville, Florida

CITATION:
Budd JT. Adult secondary hypertension: what the primary care provider needs to know. Consultant. 2021;61(3):e1-e8. doi:10.25270/con.2020.09.00006

Received May 1, 2020. Accepted June 30, 2020. Published online September 9, 2020.

DISCLOSURES:
The authors report no relevant financial relationships.

CORRESPONDENCE:
Jeffrey Thomas Budd, MD, University of Florida College of Medicine, 1329 SW 16th St, Ste 5140, Gainesville, FL 32610 (buddjt@medicine.ufl.edu)

ABSTRACT: Although only a minority of patients with hypertension have secondary causes for it, identifying these patients is crucial, because treatment of the root cause may resolve or improve control of hypertension and improve long-term outcomes. Because primary care providers (PCPs) are the front line of screening for, diagnosis of, and management of hypertension, they have a vital responsibility to recognize clinical clues for secondary hypertension. Some of the important clues are treatment-resistant hypertension, onset of hypertension in a young adult, accelerated hypertension, and hypertension with unprovoked hypokalemia. Common causes of secondary hypertension are obstructive sleep apnea, renovascular disease, primary aldosteronism, renal parenchymal disease, and drugs. Some less-common causes include pheochromocytoma, Cushing syndrome, thyroid disease, hyperparathyroidism, and aortic coarctation. Each of these causes has suggestive symptoms and signs to prompt consideration and a diagnostic pathway.

KEYWORDS: Secondary hypertension, primary care, hypokalemia, obstructive sleep apnea, renovascular disease, primary aldosteronism, renal parenchymal disease, pheochromocytoma, Cushing syndrome, thyroid disease, hyperparathyroidism, aortic coarctation

Heart disease and stroke are the leading causes of death in the United States, and hypertension remains a prominent risk factor for both.¹ When defined as a pressure greater than 130/80 mm Hg, it is present in nearly half of the US adult population.² US health care costs associated with hypertension are more than $130 billion per year,³ and the prevalence of hypertension is predicted increase by 10% from 2010 to 2030.⁴ This rising prevalence at least partially may be a result of increasing rates of obesity.⁵

Most persons with hypertension have primary (essential or idiopathic) hypertension with no obvious secondary cause. The common risk factors for primary hypertension are obesity, insulin resistance, diabetes, aging, sedentary lifestyle, and family history.⁶ The pathogenesis of primary hypertension is complex, is incompletely understood, and appears to involve a combination of genetic and environmental factors.⁷ The predominant mechanisms seem to involve activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS).⁷

Secondary hypertension has causative underlying disorders and may represent 10% of all cases of hypertension^7,8 or nearly two-thirds of cases of resistant hypertension.⁹ The presence of secondary hypertension is important to identify, because in most cases treatment of the root cause can resolve or dramatically improve blood pressure and ultimately reduce cardiovascular risk.¹⁰

WHEN TO CONSIDER A SECONDARY CAUSE

A number of clinical findings suggest a higher likelihood of secondary hypertension and indicate a need to consider screening tests. These include (1) resistant hypertension, (2) abrupt onset of hypertension, (3) onset at an age less than 30 years, (3) disproportionate end-organ damage for the degree of hypertension, (4) accelerated or malignant hypertension, (5) onset of diastolic hypertension in a patient older than 65 years, and (6) unprovoked hypokalemia.¹⁰ Resistant hypertension is uncontrolled blood pressure despite the use of 3 antihypertensive medications (one of which must be a diuretic)^9,10 and may represent 20% to 30% of patients with hypertension.¹¹ The more common causes of secondary hypertension include obstructive sleep apnea (OSA), renovascular hypertension, renal parenchymal hypertension, primary aldosteronism (PA), and drugs.¹⁰ Less common causes are pheochromocytoma, Cushing syndrome, aortic coarctation, hyperthyroidism, hypothyroidism, congenital adrenal hyperplasia, and primary hyperparathyroidism.¹⁰ The accompanying Figure shows an approach to secondary hypertension. Tables 1 and 2 summarize clinical clues, indications to test, and diagnostic methods for some of these causes of secondary hypertension.

COMMON CAUSES OF SECONDARY HYPERTENSION

Obstructive Sleep Apnea

OSA is responsible for 64% of treatment-resistant hypertension cases and may be the most common cause for secondary hypertension.⁹ The prevalence of OSA is highest in patients with advanced age, male gender, and obesity.²⁰ An estimated 14% of all men and 5% of women have OSA.¹⁷ The prevalence correlates strongly with the degree of obesity. For example, less than 10% of men aged 30 to 50 years with a body mass index (BMI) below 25 kg/m² have OSA, but nearly 80% with a BMI greater than 40 kg/m² have OSA.²⁰ The incidence appears to be increasing, which is likely a direct result of escalating rates of obesity.^20,21

Common symptoms associated with OSA are nocturnal gasping, morning headaches, reported nocturnal apnea, excessive daytime sleepiness, and snoring.¹² Common signs are obesity, Mallampati scores of 3 or 4,¹² and a large neck circumference.^22,23 A number of clinical tools, questionnaires, and prediction algorithms are available (eg, Berlin Questionnaire, Epworth Sleepiness Scale, STOP-Bang Questionnaire, STOP Questionnaire) to predict the likelihood of OSA, but all seem to lack the specificity and accuracy to reliably diagnose it.^12,17 Instead, polysomnography or a home sleep study is required.¹⁷ Sleep studies are indicated only for patients at high risk for moderate or severe disease, because this population is most likely to benefit from treatment.¹⁷ These patients at risk can be identified clinically by a combination of excessive daytime fatigue with at least 2 of 3 additional findings of (1) habitual loud snoring (2) witnessed apnea, gasping or choking, or (3) diagnosed hypertension.¹⁷

The primary goal of treatment is to relieve airway obstruction during sleep, and first-line therapy remains positive airway pressure (PAP).²¹ Treatment with PAP has successfully reduced blood pressure in patients with previously treatment-resistant hypertension.^24,25 Oral appliances are second-line therapy for patients who are intolerant of PAP or who prefer alternative therapy.^21,26 Surprisingly, despite obesity being a critical risk factor for OSA, there is a lack of high-quality evidence that weight loss improves OSA.^21,27 Regardless, weight loss is a key component of therapy, not only because evidence (although weak) suggests improvement in symptoms and signs of OSA, but also because of multiple other potential health benefits.

Renovascular Hypertension

Renal artery stenosis is also a prominent cause of secondary hypertension. It may be responsible for 1% to 5% of all hypertension cases,²⁸ 2.4% of resistant hypertension cases,⁹ and 5% to 34% of secondary hypertension cases.¹⁰ Most renovascular disease is a result of atherosclerosis, followed by fibromuscular dysplasia and by very rare causes such as Takayasu arteritis.¹⁸ Atherosclerotic renal artery stenosis may be present in 0.5% of all persons older than age 65 years.²⁹ In patients with atherosclerotic renal artery stenosis, 67% also have heart disease, 25% have chronic kidney disease (CKD), and 91% have hypertension.²⁹ Clues to considering it are (1) onset of stage 2 hypertension after age 50 without a family history, (2) hypertension associated with renal insufficiency, especially if the renal function worsens with use of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), and (3) hypertension in advanced age with associated history of vascular disease.^18,30

Hypertension in renovascular disease is a result of reduced renal perfusion and subsequent activation of the RAAS.³⁰ Renal artery disease must produce at least 70% to 80% occlusion to cause a pressure gradient greater than 15 to 25 mm Hg needed for a clinically significant blood pressure increase.³⁰ Occlusions less than this are unlikely to be responsible for secondary hypertension and are not likely to benefit from intervention by opening the vessel.³⁰ The Society for Vascular Medicine recommends against screening for renal artery stenosis unless treatment-resistant hypertension is present along with abnormal renal function, because intervention with surgery or angioplasty would otherwise not be indicated.³¹ The diagnosis can be made by duplex ultrasonography, magnetic resonance angiography, or computed tomography (CT) angiography.¹⁸

Medical therapy is the first-line approach to atherosclerotic renovascular hypertension, and multiple antihypertensives are frequently required.^10,18 Treatment regimens with either an ACEI or an ARB are recommended to counteract the inappropriately overactivated RAAS.^10,18 ACEI use in renovascular disease results in reduced rates of mortality, myocardial infarction, stroke, hospitalization for congestive heart failure, and dialysis initiation.³² When severe bilateral stenosis or advanced CKD is present, initiating an ACEI or an ARB may induce acute renal failure (ARF), but the likelihood is low, and the ARF is typically reversible with discontinuing the ACEI or ARB.¹⁸ ACEI use in unilateral renovascular disease is associated with improved survival without affecting renal function.³³ An antiplatelet agent, high-intensity statin, smoking cessation, and diabetes control are also necessary components of treatment, as with other atherosclerotic disease.^10,18

Endovascular revascularization with angioplasty or stent placement for atherosclerotic renal artery stenosis is second-line therapy, because this has shown no clinical benefit in most cases over medication treatment alone.^10,34,35 Indications to consider revascularization are (1) nonatherosclerotic disease (such as fibromuscular dysplasia), (2) failed multidrug therapy for hypertension, (3) worsening renal function, or (4) intractable heart failure or recurrent flash pulmonary edema.¹⁰

Primary Aldosteronism

PA is associated with higher cardiovascular morbidity and mortality than essential hypertension at similar blood pressures.³⁶ It may be present in 6% of patients with moderate to severe hypertension,¹³ 17% to 23% of patients with treatment-resistant hypertension,¹³ and 8% to 20% of patients with secondary hypertension.¹⁰ It is often associated with adrenal adenomas, adrenal hyperplasia, or rare inherited endocrine diseases.¹³ In PA, the production of aldosterone becomes independent of the RAAS and inappropriately high.¹³ This excessive aldosterone suppresses plasma renin and causes sodium retention, increased potassium loss, and hypertension.¹³ Although hypokalemia and hypertension are classically associated with PA, most patients have a normal plasma potassium level. In fact, only 9% to 37% of patients with PA may be found to have hypokalemia.³⁷

Indications to screen for PA are (1) sustained pressures greater than 150/100 mm Hg, (2) treatment-resistant hypertension, (3) hypertension with spontaneous or diuretic-induced hypokalemia, (4) hypertension with the presence of an adrenal incidentaloma, (5) and hypertension with a family history of early-onset hypertension, stroke at a young age, or a first-degree family history of PA.¹³ The plasma aldosterone concentration (PAC, ng/dL) to plasma renin activity (PRA, ng/mL/h) ratio is used to screen for PA and is considered positive when greater than 30 with a PAC greater than or equal to 10 ng/dL.¹⁰ Ideally, medications that can affect this ratio—such as spironolactone, eplerenone, amiloride, triamterene, and products derived from natural licorice root—should be discontinued 4 weeks before measurement.¹³

Positive screening test results need to be followed by a confirmatory test except when either (1) spontaneous hyperkalemia is present, (2) the PRA is below detectible limits, or (3) the PAC is greater than 20 ng/dL.¹³ Any of 4 available confirmatory tests can be used, including an oral sodium loading test, saline infusion test, fludrocortisone suppression test, or a captopril challenge.¹³ After diagnosis of PA, an adrenal CT scan is recommended to detect adrenal hyperplasia, adrenal adenoma, or adrenocorticoid carcinoma.¹³ Genetic testing for glucocorticoid-remediable aldosteronism should be considered for onset of PA at age less than 20 years, a family history of PA, or family history of strokes at age less than 40 years.¹³ Unilateral adrenalectomy is first-line therapy after adrenal venous sampling confirms unilateral aldosterone-producing adenoma or hyperplasia.¹³ Mineralocorticoid receptor antagonists are indicated for bilateral disease or second-line therapy for unilateral disease.¹³

Renal Parenchymal Disease

Nearly all types of renal parenchymal disease are associated with hypertension, including glomerulonephritis, chronic pyelonephritis, polycystic kidney disease, diabetic nephropathy, hypertensive nephropathy, and obstructive uropathy.³⁸ Hypertension is present in approximately 80% of patients with stage 3 or greater CKD.³⁸ This prevalence correlates with the severity of renal disease as shown by 66% of patients having hypertension at a glomerular filtration rate (GFR) of 83 mL/min/1.73 m² but 95% at 12 mL/min/1.73 m².³⁹ Renal parenchymal disease may be responsible for 1.6% of treatment-resistant hypertension.⁹ Control of blood pressure in patients with renal disease is associated with improved outcomes.³⁸

The mechanisms by which renal disease causes hypertension are multiple and not completely known. Three potential mechanisms are (1) activation of the RAAS from reduced perfusion and structural kidney damage,³⁸ (2) reduced excretion and resulting retention of sodium from a decreasing GFR and RAAS activation,³⁸ and (3) activation of the sympathetic nervous system by chemosensitive nerve fibers in the kidneys.⁴⁰

ACEIs and ARBs are indicated for hypertension associated with renal parenchymal disease, because excessive RAAS activation is common.³⁸ Increases in creatinine up to 30% may result and are usually temporary and tolerable.³⁸ The ACEI or ARB should be discontinued if a greater increase in creatinine occurs, and a search should start for another compounding cause such as bilateral renal artery stenosis or hypovolemia.³⁸

Drugs

Multiple drug classes have been found to increase blood pressure, and these may be responsible for 2% to 4% of secondary hypertension cases.¹⁰ For a number of these drugs, the hypertensive effect can be inconsistent and can vary widely in the general population from little to no change in blood pressure to severe hypertension.¹¹ As a result of their widespread use, nonsteroidal anti-inflammatory drugs (NSAIDs) may be one of the more common classes to affect blood pressure control,¹¹ and they may increase the mean arterial pressure by an average of 5 mm Hg.⁴¹ NSAIDs also appear to partially impair the antihypertensive effects of diuretics, ACEIs, ARBs, and β-blockers.^11,41,42 In most patients, the effect of NSAIDs is not clinically significant, but elderly patients or those with CKD or diabetes may be at increased risk of fluid retention, increased blood pressure, and acute kidney injury.¹¹ Aspirin and cyclooxygenase 2 inhibitors seem to behave similarly to NSAIDs in terms of blood pressure outcomes.¹¹

Caffeine exposure in an infrequent user may result in a modest blood pressure rise for a few hours, but no meaningful blood pressure effect is seen in habitual caffeine users.⁴³ Alcohol in the form of beer, wine, or liquor at greater than 2 drinks per day is associated with blood pressure elevations.⁴⁴ Additional implicated drug classes are (1) sympathomimetic drugs such as decongestants, diet pills, and stimulants,¹¹ (2) estrogens, androgens, and oral contraceptives,^11,45 (3) systemic glucocorticoids,⁴⁶ and (4) drugs with mineralocorticoid activity such as natural licorice and ketoconazole.^45,46

UNCOMMON CAUSES OF SECONDARY HYPERTENSION

Pheochromocytoma

Pheochromocytomas are very uncommon catecholamine-secreting tumors. They may be present in less than 0.05% of all patients with hypertension¹⁹ and only 0.5% of patients with hypertension and suggestive symptoms.¹⁴ Although pheochromocytomas are rare, a high index of suspicion is needed, because early diagnosis and treatment mitigate the worrisome morbidity and mortality associated with them.⁴⁷ Clinical clues are hypertension with autonomic disturbances, panic attacks, adrenal incidentaloma, or familial diseases with a predisposition to pheochromoctyoma.¹⁴ Nearly 95% of patients with pheochromocytomas have sustained or paroxysmal hypertension associated with headaches, diaphoresis, and/or palpitations.¹⁹ The autonomic disturbances often manifest as orthostatic hypotension in an untreated patient with hypertension.¹⁹ Some of the familial diseases with increased risks of pheochromocytomas are multiple endocrine neoplasia type 2, von Hippel-Lindau syndrome, and neurofibromatosis type 2.¹⁹

The diagnosis of pheochromocytoma is made with plasma free-metanephrines testing (if available) or plasma catecholamines and 24-hour urine fractioned metanephrines testing.¹⁹ A pheochromocytoma is excluded with normal values or diagnosed with values more than 3 times normal.¹⁹ Urinary catecholamines, total metanephrines, and vanillylmandelic acid levels are less reliable.¹⁹ After diagnosis with biochemical determinants, imaging of the abdomen and pelvis is needed to locate the tumor, and for this, magnetic resonance imaging (MRI) seems to be more sensitive and specific than CT.¹⁹ If no tumor is found on this initial imaging, MRI or CT of the chest and neck with a whole-body ¹²³I-metaiodobenzylguanidine scintigraphy scan is needed.¹⁹

Surgical removal of the tumor can cure 90% of cases.¹⁴ Pretreatment first with α-adrenergic blockade and then possibly additional β-adrenergic blockade minimizes the risk of intraoperative hypertensive crisis and perioperative complications.⁴⁸ To prevent a hypertensive crisis from catecholamine stimulation of unopposed α receptors, α-adrenergic blockade begins before β-adrenergic blockade.⁴⁸ This pretreatment with phenoxybenzamine (α₁ and α₂ antagonist) or an α₁ antagonist such as prazosin ideally begins 1 to 2 weeks before surgery to stabilize blood pressure and pulse.^19,48 β antagonists are added if tachycardia or hypertension persists despite α blockade.⁴⁸

Cushing Syndrome

Cushing syndrome is a manifestation of excessive cortisol and is also very uncommon, with a prevalence of 39 to 79 cases per million.¹⁵ Suggestive clinical findings are treatment-resistant hypertension, hypertension or osteoporosis in a young adult, proximal muscle weakness, and wide purple-striae.¹⁵ Exogenous glucocorticoids need to be excluded before a workup.¹⁵ The diagnosis is made with positive results from any 2 of the following: (1) late-night salivary cortisol, (2) 24-hour urine free cortisol, or (3) dexamethasone suppression with a 1-mg overnight or a 2-mg 2-day test.¹⁵ After diagnosis, a plasma adrenocorticotropic hormone (ACTH) level distinguishes ACTH-dependent and ACTH-independent causes. Low or inappropriately normal ACTH values suggest ACTH independence from adrenal adenomas, carcinomas, or hyperplasia. Elevated ACTH levels suggest ACTH dependence from either a pituitary adenoma or hyperplasia (Cushing disease) or ectopic ACTH from small-cell lung cancers or neuroendocrine tumors.¹⁵

Aortic Coarctation

Aortic coarctation is found in 3 of 10,000 infants,⁴⁹ represents 4% to 7% of congenital heart disease cases, and is diagnosed most often before adulthood.⁵⁰ Symptoms are usually absent in an adult but when present may include headache, epistaxis, dizziness, palpitations, or claudication.¹⁶ Signs suggestive of aortic coarctation are a harsh systolic murmur at the sternal border and back or hypertension in the arms with diminished or absent femoral pulses.¹⁶ Two-thirds of patients older than 40 years with uncorrected aortic coarctation have heart failure, 75% die by the age of 40 years, and 90% die by the age of 60 years.¹⁶ Transthoracic echocardiography is a critical component of the diagnosis, and treatment is surgical.⁵¹

Thyroid Disease and Parathyroid Disease

Both hyperthyroidism and hypothyroidism can elevate blood pressure. Hyperthyroidism tends to cause systolic hypertension and widened pulse pressure by increased arterial stiffness, and this effect may be worsened in patients with pre-existing impaired arterial compliance, such as older adults with atherosclerotic disease.⁵² Hypothyroidism, on the other hand, tends to cause diastolic hypertension by impaired endothelial-derived vasorelaxation.⁵² Hyperparathyroidism appears to cause hypertension by a direct effect of parathyroid hormone in increasing renin secretion.

CONCLUSION

PCPs need to be aware of several key points about secondary hypertension. First, being alert to evidence of secondary hypertension is a necessary component of managing all hypertension cases, because managing the secondary causes leads to improved outcomes. Second, starting with a review of prescription medications, over-the-counter medications, and social history may identify drugs contributing to hypertension. Third, OSA is possibly the most common cause of secondary hypertension. Hypertensive patients with a combination of excessive daytime fatigue with habitual loud snoring and/or witnessed apnea, gasping, or choking may need further evaluation with a sleep study for diagnosis. Fourth, medical therapy, especially with an ACEI or ARB, is first line for renovascular hypertension. A diagnostic workup for renovascular disease is not necessary unless a patient would potentially benefit from surgery or angioplasty by having treatment-resistant hypertension with abnormal renal function, or if fibromuscular dysplasia is suspected in a young adult. Fifth, an ACEI or ARB is also indicated for treatment of hypertension associated with renal parenchymal disease. A mild, transient elevation in the creatinine level may occur when the ACEI or ARB is started, and more worrisome elevations in creatinine may suggest an additional compounding cause. Sixth, although hypertension with unprovoked hypokalemia suggests primary aldosteronism, most patients with primary aldosteronism actually have normal serum potassium levels. And, last, causes such as pheochromocytoma, Cushing syndrome, and aortic coarctation are very rare but are potentially devastating if the diagnosis is missed.

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