Hospital Medicine

Secondary Hypertension

Secondary Hypertension

I. Problem/Condition.

Secondary hypertension is simply high blood pressure due to a readily identifiable cause. The term is used to distinguish causes of hypertension wherein there is a clear disorder causing high blood pressure as opposed to essential hypertension, where the high blood pressure is presumed to be due to a complex interplay of other factors such as genetic, dietary, etc.

Definitions vary regarding whether or not medications are considered a cause of secondary hypertension, but drug-related hypertension is included here as a secondary cause insofar as removal of the offending agent can result in resolution of blood pressure. Similarly, drug intoxication and withdrawal states that are accompanied by changes in blood pressure are included here as well. Both are frequently encountered in the hospital.

Hospitalists and other inpatient providers have a unique advantage over outpatient providers in assessing causes of hypertension. Inpatient providers have the advantage of getting real time feedback on whether patients respond to medications administered under supervision in the hospital. This is particularly important as medication non-adherence is a common cause of elevated blood pressure.

In addition, inpatient evaluation allows providers to see many blood pressure readings per day and evaluate for labile hypertension.

In approaching secondary hypertension, providers need to identify those patients that may have a higher likelihood of having secondary hypertension (see clues below). Therefore, the key to diagnosis is not so much knowing the full differential diagnosis of the causes of secondary hypertension, but simply knowing when to look for it.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

  • Hypertension can be divided into simple categories: essential hypertension, drug-related, hormonal, nephrogenic, and other causes. Drug-induced causes can be further subdivided into hypertension due to acute drug intoxication, hypertension from chronic medications, or high blood pressure due to withdrawal of drugs.

  • Acute intoxication leading to hypertension can occur from ingestion of cocaine, methamphetamine, or MDMA (ecstasy). Herbal supplements such as ephedra or ma huang can also raise BP in higher doses.

  • Chronic medications can also raise blood pressure. Common categories of medications include oral contraceptives (OCPs), decongestants (with alpha agonist activity), NSAIDs (by altering renal blood flow), steroids (by a similar mechanism), EPO, and black licorice.

  • Withdrawal states that cause hypertension include withdrawal from any sedating medication or sedating drug of abuse. Common causes are withdrawal from alcohol, opiates, or benzodiazepines.

  • Hormonal causes of hypertension include hyperaldosteronism, hypo and hyperthyroidism, hyperparathyroidism (via increase in calcium), and Cushing’s syndrome (elevated cortisol).

  • Renal causes of hypertension can be subdivided into chronic kidney disease (CKD), acute glomerular diseases, and vascular causes.

  • Any disease state that leads to CKD will eventually cause hypertension via multiple mechanisms.

  • Acute glomerular diseases, such as lupus nephritis or post-infectious glomerulonephritis, often present with hypertension due to avid sodium retention and fluid overload.

  • Reno-vascular diseases that cause hypertension include acute changes in renal blood flow, such as vasculitis and scleroderma renal crisis. Chronic changes in renal blood flow that lead to hypertension include renal artery stenosis and fibromuscular dysplasia. In both conditions, low renal blood flow (RBF) leads to elevation in renin and aldosterone, causing sodium retention and plasma volume expansion.

  • Lastly, there are other causes of hypertension that are not easily categorized as drug-related, hormonal, or nephrogenic. Obstructive sleep apnea is a common cause of hypertension.

  • Other less common etiologies that could be considered are coarctation of the aorta, pheochromocytoma, and pseudo-pheochromocytoma (labile hypertension due to psychogenic causes, such as PTSD).

B. Describe a diagnostic approach/method to the patient with this problem.

While there are numerous causes of secondary hypertension, an inpatient provider should generally go looking for secondary causes when it might affect the inpatient stay. A patient with mildly elevated blood pressure, such as a systolic blood pressure of 150 mm Hg, could certainly have secondary hypertension, but this would be unlikely to affect the inpatient course regardless of the reason for admission. In contrast, when a patient presents with severe hypertension (systolic blood pressure over 180 mm Hg) or end-organ injury related to the hypertension (e.g. angina, acute kidney injury, etc.), a workup for the cause of hypertension during the inpatient stay may be necessary.

The above list discusses the numerous causes of secondary hypertension, but the diagnostic approach consists of looking primarily for those causes that will require immediate inpatient management. Therefore, the diagnostic approach recommended here is not comprehensive in identifying all causes of secondary hypertension, but highlights an approach to identifying those conditions that would likely affect inpatient management.

  1. Consider poorly controlled essential hypertension. It is important to remember that most cases of hypertension are not secondary hypertension. Perhaps 10% of patients with hypertension can be classified as secondary in nature. Presentation at a young age (less than 30), end-organ damage, or an acute increase in previously controlled blood pressure may be a clue for a secondary cause. Providers should first consider simply hard-to-control hypertension rather than undertake a workup for all patients with hypertension.

  2. Consider drug intoxication or withdrawal. While many medications affect blood pressure, consider those medications that could cause a profound increase. Stimulant use such as methamphetamine, cocaine, or bath salts may produce severe hypertension. Similarly, withdrawal from sedatives (such as alcohol or benzodiazepines) may also produce severe hypertension that may or may not be symptomatic.

    Review prior to admission medications for culprit medications that can raise blood pressure such as OCPs, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, and alpha-agonists. Discuss use of stimulants with the patient, such as cocaine and amphetamines. Consider a drug screen if unsure.

    Look for evidence of drug withdrawal (such as tachycardia, tremor, and tongue fasciculations in alcohol withdrawal).

  3. Consider nephrogenic causes. In cases of severe hypertension, all patients will require a metabolic panel. If the creatinine is elevated or if other clues suggest nephrotic syndrome (such as presence of edema on exam), a urinalysis would be recommended along with a urine protein-to-creatinine ratio.

    In addition to considering nephrotic syndrome, acute glomerulonephritis, and CKD as causes of severe hypertension, providers may consider reno-vascular diseases that may present with severe hypertension.

    • Renal artery stenosis and fibromuscular dysplasia are both disease states wherein RBF is impaired, leading to high renin release and high aldosterone state causing hypertension. Renal artery stenosis is common in elderly patients with atherosclerotic disease while fibromuscular dysplasia is more commonly seen in younger female patients. Renovascular hypertension is sometimes suggested when patients present with: acute kidney injury after institution of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blockers (ARBs), asymmetric kidneys on renal ultrasound, or flash pulmonary edema without a clear other etiology.

    • When considering renal artery stenosis or fibromuscular dysplasia, a renal ultrasound can be a useful initial test to assess kidney size and symmetry. As regional practice varies greatly regarding availability of other testing to confirm renal artery stenosis, nephrology consult would be warranted if this is suspected to guide further work-up. Fibromuscular dysplasia, by contrast, is best diagnosed by digital subtraction angiography.

  4. Consider hormonal causes. While hypothyroidism, hyperthyroidism and hyperparathyroidism can all elevate blood pressure, none of these conditions typically produces profound hypertension. Providers should consider hyperaldosteronism and Cushing’s syndrome in select patients with severe hypertension.

    Hyperaldosteronism should be considered in patients present with low potassium or metabolic alkalosis along with hypertension. It is important to remember however that hyperaldosteronism is one of the most common causes of secondary hypertension and metabolic derangements are not seen in all patients. Plasma renin activity and aldosterone concentration should be measured in suspected cases.

    Cushing’s syndrome (either due to adrenal adenoma or exogenous steroids) can cause hypertension and should be suspected when patients have characteristic exam findings such as moon face, buffalo hump, or hyperpigmentation. High cortisol levels also can cause other disease states that can be screened for when taking a past medical history. These include osteoporosis, glucose intolerance, obesity, easy bruising, and oligomenorrhea.

    In patients with suspected hypercortisolism, a 24-hour urine cortisol and a dexamethasone suppression test can be used as an initial screen. This should be done prior to imaging, as incidental adrenal adenomas are common with age.

  5. Consider less common diagnoses. Severe hypertension can also be due to multifactorial causes or other less common diseases such as aortic coarctation and pheochromocytoma. Consultation with a nephrologist may be considered in cases of severe hypertension without a cause identified by a basic workup.

    • Aortic coarctation is a congenital narrowing of the aorta which is often not diagnosed until adulthood. The area of narrowing most often occurs distal to the takeoff of the left subclavian, such that pulses may be symmetric and equal in the upper extremities. However, a delay in the femoral pulse or weakened blood pressure in the leg is suggestive of the diagnosis. It is more common in men than women and can be accompanied by other congenital heart disease such as VSD or bicuspid aortic valve. It should be suspected in a patient with asymmetric pulses, lower blood pressure in the legs, or cardiac auscultation findings consistent with bicuspid aortic valve. While there are suggestive findings on electrocardiography (EKG) and chest X-ray, aortic coarctation is usually diagnosed by echocardiogram.

    • Pheochromocytoma is an extremely rare cause of hypertension with an excess of catecholamines leading to labile hypertension. Patients sometimes have episodic hypertension with headaches and sweating. This triad is not seen in the majority of patients. Other associated symptoms include pallor, orthostasis, and polyuria/polydipsia with associated hyperglycemia. Plasma fractionated metanephrines can be measured as an initial sensitive screen for pheochromocytoma, although multiple different tests can be used for confirmation.

To summarize, the basic diagnostic work-up consists of the following:

  1. Consider the possibility of simply poorly controlled essential hypertension rather than a secondary cause.

  2. Review medical list, history of drug use, and consider a urine toxicology screen.

  3. Check urinalysis and metabolic panel (to look for CKD or AKI) and consider a urine protein-to-creatinine ratio in cases of suspected nephrotic syndrome.

  4. If the metabolic panel reveals alkalosis or hypokalemia, consider hyperaldosteronism.

  5. Consider less common causes such as renal artery stenosis, fibromuscular dysplasia, coarctation of the aorta, or pheochromocytoma.

  6. Consultation with nephrology is useful when considering imaging for renal artery stenosis or fibromuscular dysplasia or considering additional workup.

1. Historical information important in the diagnosis of this problem.

Because hypertension is among the most frequent diagnoses encountered by hospitalists, providers need to be aware of historical clues that may suggest a need to look further for secondary hypertension. As stated above, the challenge in evaluating for secondary hypertension is not how to screen but who to screen.

It is important to remember that most hypertension is essential hypertension (perhaps as high as 98%). Additionally, it is worth noting that many patients with high blood pressure during a hospitalization will later be diagnosed with neither essential hypertension nor secondary hypertension. High blood pressure during hospitalization can be due to a stress response, pain, drug intoxication or withdrawal or anxiety.

Secondary hypertension should be suspected in patients with the following historical features accompanying high blood pressure:

  • Very young age at onset (<20) or older age at onset (>55) with hypertension.

  • History of diaphoresis, headache, or palpitations (seen in pheochromocytoma).

  • History of edema, ascites, or anasarca (suggestive of nephrotic syndrome or glomerulonephritides).

Past medical history and family history clues to secondary hypertension include:

  • Wide variation in blood pressure during time of monitoring (seen in pheochromocytoma).

  • Past medical history of atherosclerotic disease (higher likelihood of renal artery stenosis).

  • Family history of kidney disease (thinking of CKD).

  • Lack of family history of hypertension (most patients with essential hypertension have family history of same diagnosis).

Secondary hypertension should also be considered in patients with certain clues at time of presentation to the hospital:

  • Acute renal failure after initiation of ACE-inhibitor (seen in reno-vascular hypertension).

  • Hypokalemia or metabolic alkalosis at presentation (seen in hyperaldosteronism).

As drugs are a common cause of elevated blood pressure, providers should additionally ask patients about potential culprit medications (including herbal supplements) and ask about illicit drug use that could predispose to blood pressure changes (cocaine, alcohol, methamphetamine).

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

  • On general examination, look for Cushingoid features such as moon face, buffalo hump and striae. Additionally, look for evidence of drug intoxication or withdrawal (agitation, pupillary changes, tremor).

  • On eye exam, funduscopic exam can point to longstanding hypertension, which can be useful when considering an acute presentation.

  • On cardiovascular exam, check blood pressure in both arms and compare pulses in carotid and femoral artery (if suspicious of coarctation of the aorta). Also comparing blood pressure in the arm and leg can be a more helpful comparison for aortic coarctation.

  • On abdominal exam, auscultate for a renal bruit (a specific, but insensitive indication of renal artery stenosis).

  • On extremity examination, look for leg edema (see in nephrotic syndrome, but also many other disease states such as acute glomerulonephritis with avid sodium retention).

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

A basic metabolic panel and urinalysis are the first key steps in diagnosis.

The metabolic panel can identify many causes of secondary hypertension. Elevated creatinine should prompt the provider to consider if acute or CKD is causing high blood pressure. If an abnormal creatinine is seen, a urinalysis can further help with sorting through whether the patient has acute kidney injury, CKD, or both. Importantly, patients with nephrotic syndrome and hypertension often have a normal creatinine at presentation, so a normal creatinine level should not lead a provider to not order a urinalysis.

Additionally, if hypokalemia or elevated bicarbonate is seen, the index of suspicion for hyperaldosteronism should increase. That said, it is important to remember that many patients with hyperaldosteronism do not have hypokalemia. If hyperaldosteronism is suspected, checking renin and aldosterone should be the initial screening test.

Lastly, if drug intoxication or abuse is considered as a possible cause of hypertension, a urine (or serum) drug screen can be useful for diagnosis.

Ordering a metabolic panel, urinalysis and renin/aldosterone is a simple and cost-effective initial lab work-up for the hypertensive patient in whom secondary hypertension is suspected. A urine toxicology screen can also be helpful in selected patients.

There are no routine imaging studies that should be done for diagnosis of secondary hypertension. While echocardiogram can be used to diagnose aortic coarctation, CT of the abdomen can identify some cases of adrenal adenoma or pheochromocytoma, and renal ultrasound can identify asymmetric kidneys suggestive of renal artery stenosis, none should be routinely ordered unless the history is suggestive of a particular diagnosis.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

  • Drug-related hypertension is best diagnosed by taking a concise history and aligning onset of high blood pressure with either initiation of medication or illicit drug, or withdrawal from medication or illicit drug. While a urine toxicology screen can identify various compounds, only the history will tell if the drug use can be clearly linked to the high blood pressure.

  • Renal causes of hypertension are best screened for by a metabolic panel and urinalysis.

  • Renin and aldosterone should also be measured when hyperaldosteronism are suspected. A ratio of aldosterone to renin of greater than 20 is suggestive of primary hyperaldosteronism.

  • Use of certain blood pressure agents can lead to false positive results with these blood tests (amiloride, spironolactone, triamterene, and beta-blockers). Confirmatory testing can be done by numerous methods wherein the goal is to suppress aldosterone, either through oral salt loading or saline infusion.

  • Renal artery stenosis or fibromuscular dysplasia can sometimes be identified by simple renal ultrasound, but confirmatory testing depends on available imaging.

  • Coarctation is most often diagnosed by transthoracic echocardiogram.

  • Pheochromocytoma is best screened for with plasma free metanephrines. 24-hour urine collection can also be used for diagnosis, but renal consultation may be warranted prior to ordering other labs.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Imaging tests can be over-utilized in the diagnosis if Cushing’s disease or primary hyperaldosteronism is being considered. While both of these disease states can be due to an active adrenal adenoma, non-functioning adrenal adenomas are quite common. It is prudent to not consider computed tomography (CT) of the abdomen until lab testing confirms either hypercortisolism or hyperaldosteronism. Both of these lab abnormalities should be confirmed before proceeding to imaging of any kind.

Similarly, renal imaging (via ultrasound) or other testing should be reserved for those patients with high suspicion of renal artery stenosis or fibromuscular dysplasia. Ultrasound is also an insensitive measurement for renal artery stenosis so the first step in diagnosis may be nephrology consultation rather than imaging if this diagnosis is suspected.

Testing for pheochromocytoma (such as with plasma free metanephrines) is somewhat overused insofar as this is a rare diagnosis and should only be considered once more common diagnoses are ruled out.

III. Management while the Diagnostic Process is Proceeding.

A. Management of secondary hypertension.

In the majority of cases, treating secondary hypertension initially does not differ from treating essential hypertension. In many cases, identifying a secondary cause of high blood pressure leads to tailored or simplified management of the blood pressure. That said, while the work-up is being undertaken, providers need not jump to treating a possible cause of secondary hypertension differently than they would treat essential hypertension.

Just as with patients with essential hypertension, the treatment parameters are similar for treating secondary hypertension, whether or not the patient presents with mildly elevated blood pressure or hypertensive emergency. There are a few select cases wherein the blood pressure lowering should be undertaken differently than in essential hypertension.

If pheochromocytoma is suspected, blood pressure should be lowered with alpha-blockers first (usually phenoxybenzamine). If cocaine ingestion is suspected, an agent that combines alpha and beta blockade is preferred (such as labetalol or carvedilol) for lowering blood pressure, although the risk of unopposed alpha activity may be more theoretical than of practical significance for management.

If drug withdrawal is suspected as the cause of the high blood pressure, management can be focused on treating the withdrawal, such as using benzodiazepines for alcohol withdrawal or clonidine for opiate withdrawal.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

None.

What’s the Evidence?

Brown, CA, Bouldin, MJ, Blackston, JW, Duddleston, DN, Shepherd, JM, Hicks, GS. "Hyperaldosteronism: the internist’s hypertensive disease". Am J Med Sci. vol. 324. 2002. pp. 227-31.

Drager, LF, Genta, PR, Pedrosa, RP, Nerbass, FB, Gonzaga, CC, Krieger, EM, Lorenzi-Filho, G. "Characteristics and predictors of obstructive sleep apnea in patients with systemic hypertension". Am J Cardiol. vol. 105. 2010. pp. 1135-9.

Grossman, E, Messerli, FH. "Drug-induced hypertension: an unappreciated cause of secondary hypertension". Am J Med. vol. 125. 2012. pp. 14-22.

Moser, M, Setaro, JF. "Resistant or Difficult-to-Control Hypertension". NEJM. vol. 355. 2006. pp. 385-392.

Parker, MG. "Resistant hypertension: Core Curriculum 2008". Am J Kidney Dis. vol. 52. 2008. pp. 796-802.

Pullalaveru, R, Akbar, G, Teehan, G. "Secondary hypertension, issues in diagnosis and treatment". Prim Care. vol. 41. December 2014. pp. 749-64.

(This article highlights some pitfalls in the diagnostic approach to secondary hypertension.)

Stabouli, S, Papakatsika, S, Kotsis, V. "Hypothyroidism and hypertension". Expert Rev Cardiovasc Ther.. vol. 8. 2010. pp. 1559-65.

Sukor, N. "Secondary hypertension: a condition not to be missed". Postgrad Med J. vol. 87. 2011. pp. 706-713.

Textor, SC. "Current approaches to renovascular hypertension". Med Clin North Am. vol. 93. 2009. pp. 717-32.

Trewet, CL, Ernst, ME. "Resistant hypertension: identifying causes and optimizing treatment regimens". South Med J. vol. 101. 2008. pp. 166-73.

White, WB, Turner, JR, Sica, D. "Detection, evaluation, and treatment of severe and resistant hypertension: proceedings from an American Society of Hypertension Interactive forum". J Am Soc Hypertens.. vol. 8. Oct 2014. pp. 743-57.

(This article reviews the distinction between secondary hypertension and resistant hypertension.)
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