Continuing Education Activity
Secondary hypertension is elevated blood pressure (BP), which is secondary to an identifiable cause. This activity outlines the causes, history, and physical examination findings, diagnostic tests, and management of secondary hypertension, giving particular importance to the role of interprofessional teamwork in managing such patients. It highlights all the clinical clues that can point towards a secondary cause of hypertension.
- Summarize the various causes of secondary hypertension.
- Describe the history and physical exam that can help identify the cause of secondary hypertension.
- Outline the various treatment and management options for secondary hypertension.
- Explain the interprofessional team strategies for improving patient evaluation and treatment in cases of secondary hypertension.
Hypertension affects about 30% of adults in the United States. Most cases are due to essential hypertension, i.e., hypertension without an identifiable cause. But, about 5 to 10% of cases of hypertension are due to secondary hypertension.
Secondary hypertension is elevated blood pressure (BP), which is secondary to an identifiable cause. Since its prevalence is relatively low, performing routine evaluations in every case of hypertension is not cost-effective and is also time-consuming. However, one must be aware of clinical clues that could suggest a secondary cause of hypertension. The clinical clues to look out for that could be suggestive of a secondary cause of hypertension are as follows:
- Resistant hypertension, i.e., persistent blood pressure greater than 140/90 mm Hg despite using three anti-hypertensives from different classes, that includes a diuretic, all at adequate doses.
- Increased lability or acute rise in blood pressure in a patient who had previously stable pressures.
- Hypertension that develops in non-black patients less than 30 years of age, who do not have any other risk factors for hypertension, e.g., obesity, family history, etc.
- Patients with severe hypertension (BP greater than 180/110 mm Hg) and patients with end-organ damage like acute kidney injury, neurological manifestations, flash pulmonary edema, hypertensive retinopathy, left ventricular hypertrophy, etc.
- Hypertension associated with electrolyte disorders like hypokalemia or metabolic alkalosis
- Age of onset of hypertension before puberty.
- Non-dipping or reverse dipping presents while monitoring 24-hour ambulatory blood pressure. Normally, the blood pressure at night is lower than the blood pressure during the day, i.e., there is a ‘dip’ in blood pressure at night. The absence of this ‘dip’ or ‘reverse dipping,’ i.e., ‘dip’ present during the day instead of at night can be suggestive of a secondary cause of hypertension.
The etiology of secondary hypertension is varied. The causes subdivide into the following four categories:
A. Renal causes: Among these, the major categories are renal parenchymal disease (which includes chronic kidney disease and polycystic kidney disease) and reno-vascular disease (which includes renal artery stenosis and fibromuscular dysplasia).
B. Endocrine causes: Primary aldosteronism, Cushing syndrome/disease, hyperthyroidism, hypothyroidism, hyperparathyroidism, pheochromocytoma including drug-mediated pheochromocytoma crisis, acromegaly, congenital adrenal hyperplasia.
C. Vascular: Coarctation of the aorta.
D. Other: Obstructive sleep apnea, drug-induced hypertension, pregnancy, scleroderma.
Drug-induced hypertension is a significant cause of secondary hypertension. Hence, it is essential to look at the patient's medication list. Following are the drugs that can cause hypertension:
- Non-steroidal anti-inflammatory drugs, acetaminophen, and aspirin are the commonest implicated drugs in the worsening of blood pressure control due to their widespread use
- Sodium-containing antacids
- Drugs used to treat attention-deficit/hyperactivity disorder(ADHD): Methylphenidate, amphetamine, dexmethylphenidate, and dextroamphetamine
- Anti-depressants: Monoamine oxidase inhibitors, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors
- Atypical antipsychotics like clozapine and olanzapine
- Decongestants that have phenylephrine or pseudoephedrine
- Appetite suppressants
- Herbal supplements like St John wort, ephedra, and yohimbine
- Systemic corticosteroids like dexamethasone, methylprednisolone, prednisone, prednisolone, and fludrocortisone
- Mineralocorticoids like carbenoxolone, licorice, 9-alpha fludrocortisone and ketoconazole
- Estrogens, androgens, and oral contraceptives
- Immunosuppressants like cyclosporine
- Chronic recombinant human erythropoietin
- Recreational drugs: cocaine, methamphetamine, MDMA, bath salts
- Nicotine, alcohol
- Chemotherapeutic agents like gemcitabine (which causes microvascular injury)
As stated above, about 5 to 10% of hypertension in adults results from secondary hypertension. The prevalence of secondary hypertension varies with age, being most prevalent at the extremes of age, accounting for 70 to 85 percent of hypertension cases in children less than 12 years of age, and approximately 17 percent of cases in adults age 65 and older. The prevalence of secondary hypertension is lowest amongst hypertensive patients who are 19 to 39 years of age at 5 percent. The prevalence in adolescents (12 to 18 years) is 10 to 15%.
History and Physical
Obtaining a complete history and performing a good physical exam is very important when trying to find the underlying cause of hypertension. The following history and physical exam findings point towards a specific cause of secondary hypertension:
- Snoring, obesity, and daytime sleepiness could be indicative of obstructive sleep apnea.
- History of renal insufficiency, atherosclerotic cardiovascular disease, edema may warrant further evaluation of chronic kidney disease (renal parenchymal disease).
- History of recurrent urinary tract infections, kidney stones, acute/chronic abdominal/flank pain, hematuria, progressive renal failure may point towards autosomal dominant polycystic kidney disease (renal parenchymal disease).
- A systolic/ diastolic abdominal bruit is audible in reno-vascular disease.
- Use of sympathomimetics, acute stress, perioperative setting, tachycardia could all be in the context of excess catecholamines.
- Decreased or delayed femoral pulses are seen in coarctation of the aorta.
- Weight gain, fatigue, weakness, hirsutism, amenorrhea, moon facies, dorsal hump, purple striae, and truncal obesity present in Cushing syndrome/disease.
- Paroxysmal hypertension, headaches, diaphoresis, palpitations, and tachycardia are features in pheochromocytoma.
- Fatigue, weight loss, hair loss, diastolic hypertension, and muscle weakness are seen in hypothyroidism.
- Heat intolerance, weight loss, palpitations, systolic hypertension, exophthalmos, tremor, and tachycardia will occur in hyperthyroidism.
- Kidney stones, osteoporosis, depression, lethargy, and muscle weakness present in hyperparathyroidism.
- Headaches, fatigue, visual problems, enlargement of the hands, feet, and tongue are features of acromegaly.
- Heartburn, Raynaud phenomenon, nail pitting on the exam may be suggestive of scleroderma.
Laboratory tests and imaging modalities also help in diagnosing secondary hypertension. Some of the findings on common tests that can create suspicion for an underlying cause of hypertension are as follows:
- Basic Metabolic Panel (BMP): Hypokalemia presents in primary hyperaldosteronism and Cushing syndrome/disease. Also seen on the BMP in primary hyperaldosteronism, is metabolic alkalosis and hypernatremia. Blood urea nitrogen (BUN) and creatinine become elevated in renal parenchymal disease.
- Complete blood count (CBC): Polycythemia can be present in obstructive sleep apnea.
- Urine analysis: Proteinuria can be a feature in renal parenchymal disease.
- Chest X-Ray in coarctation of aorta shows inferior rib notching and a figure of 3 sign (abnormality of the contour of the aorta).
Upon establishing suspicion for a particular cause based on history, physical exam findings, and common laboratory tests, certain tests can be used to specifically rule out or rule in a cause of secondary hypertension. They are as follows:
- Obstructive sleep apnea (OSA): Polysomnography (preferably in-laboratory polysomnography) is the diagnostic study of choice when there is a suspicion of obstructive sleep apnea.
- Primary hyperaldosteronism: A plasma aldosterone to renin ratio greater than 30, points towards a diagnosis of primary aldosteronism. A CT scan of the abdomen is also done to look for the presence of adenomas or hyperplasia of the adrenal glands.
- Renal parenchymal disease: A decreased creatinine clearance occurs in renal parenchymal disease. Renal ultrasonography can be further used to determine the cause for the decreased creatinine clearance. Multiple cysts demonstrate in polycystic kidney disease, and a small contracted kidney is a feature in chronic kidney disease. Genetic testing can also be useful in ADPKD.
- Reno-vascular disease: Magnetic resonance angiography/CT angiography/doppler of renal arteries can all be used to look for the presence of stenosis of the renal arteries. Other tests that can be useful are captopril-augmented radioisotopic renography and renal arteriography.
- Excess catecholamine use: If the patient is normotensive in the absence of high catecholamines, it rules out excess catecholamines as the cause.
- Coarctation of the aorta: Doppler or CT imaging of the aorta will show a narrowing of the aorta. Echocardiography is another modality of choice.
- Cushing syndrome/disease: Overnight 1 mg dexamethasone-suppression test and adrenocorticotropic hormone can help diagnose Cushing disease and syndrome.
- Pheochromocytoma: Urinary catecholamine metabolites (vanillylmandelic acid, metanephrines, normetanephrines) become elevated in pheochromocytoma.
- Hyper/hypothyroidism: Serum thyroid stimulating hormone, thyroxine, and triiodothyronine levels help diagnosing hyperthyroidism and hypothyroidism.
- Hyperparathyroidism: Serum calcium and parathyroid hormone levels help in the diagnosis of hyperparathyroidism.
- Acromegaly: Elevated growth hormone level can point towards acromegaly.
- Scleroderma/ scleroderma renal crisis: Thrombotic microangiopathy, autoantibodies against RNA polymerase III, positive antinuclear antibody (ANA) will present in scleroderma.
Treatment / Management
Management of secondary hypertension comprises adequate control of blood pressure with antihypertensive drugs and addressing the secondary causes mentioned above. This section briefly discusses the management of the more common causes of secondary hypertension, viz: renal parenchymal disease, renovascular hypertension, primary hyperaldosteronism, obstructive sleep apnea, drug-induced hypertension, and pregnancy.
A. Renal parenchymal disease:
Renal parenchymal disease-causing hypertension mainly involves chronic kidney disease (CKD) and autosomal dominant polycystic kidney disease (ADPKD).
i. Management of chronic kidney disease comprises treating the reversible causes responsible for causing CKD (e.g., treating hypovolemia with fluids, avoid nephrotoxin use, relieve urinary tract obstruction), and slowing the rate of progression of the disease. To slow the rate of progression, adequate blood pressure control, decreasing urine protein, glycemic control, lifestyle changes like dietary protein restriction, and smoking cessation help. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are the best anti-hypertensives to use in proteinuric CKD. Bicarbonate use in patients with chronic metabolic acidosis slows progression to end-stage renal disease.
ii. Patients with ADPKD eventually require renal replacement therapy. Before that stage reached, hypertension management is with anti-hypertensives: ACE inhibitors or ARBs and sodium restriction. Tolvaptan is an option in patients who are at high risk for progression to CKD. It decreases the rate of estimated glomerular filtration rate decline.
B. Renovascular hypertension:
Management of renovascular hypertension (i.e., renal artery stenosis from either atherosclerotic disease or fibromuscular dysplasia) divides into medical therapy and revascularization. Medical therapy involves the use of anti-hypertensives to control blood pressure and in the case of atherosclerotic disease, the use of antiplatelets, statins, diet, and lifestyle changes. ACE inhibitors and ARBs are the anti-hypertensives of choice. Other anti-hypertensives that are treatment options are calcium channel blockers and thiazide diuretics.
Revascularization is usually done by percutaneous angioplasty with stenting of the renal artery. Surgery (which frequently includes aorto-renal bypass or sometimes removal of the ‘pressor’ kidney) is only for patients with complex anatomy.
In the following patients, revascularization may be more beneficial than medical therapy alone:
- Patients with recurrent flash pulmonary edema
- Failure or intolerance to optimal medical treatment
- Refractory hypertension
- Unexplained, progressive, a decline in renal function,
- Recent initiation of dialysis in a patient with suspected renal artery stenosis
- An acute increase in creatinine after medical therapy and in patients with a renal resistive index of less than 80 mmHg on Doppler
C. Primary hyperaldosteronism:
Unilateral primary hyperaldosteronism (e.g., unilateral adrenal hyperplasia or aldosterone-producing adenoma) gets treated with unilateral laparoscopic adrenalectomy. If the patient is not a surgical candidate or a patient has bilateral adrenal disease, then medical management with a mineralocorticoid receptor antagonist is recommended- with spironolactone being the primary agent and eplerenone being the alternative.
D. Obstructive Sleep Apnea:
Continuous positive airway pressure (CPAP) therapy is the mainstay of treatment for OSA. To note, however, lifestyle modifications like weight loss, along with usage of CPAP have a synergistic effect on lowering blood pressure and are better than either intervention alone.
An alternative to CPAP is oral appliances, used in mild to moderate OSA, which are non-inferior to CPAP in the reduction of blood pressure and may even help with better compliance in patients. In patients refractory to the above treatment, few upper airway surgeries can be performed to help with symptoms and reduction in blood pressure, like uvulopalatopharyngoplasty (UPPP) in adults and tonsillectomy and adenoidectomy in children. Along with these, anti-hypertensive drugs also help, particularly the ones that modulate the renin-angiotensin system (ACE inhibitors, ARBs, aldosterone antagonists, and beta-blockers are the best options).
E. Drug-induced hypertension: In drug-induced hypertension, upon identification of the culprit drug, the management is to withhold it and look for improvement.
F. Pregnancy: Hypertension in pregnancy comprises chronic hypertension, gestational hypertension, pre-eclampsia, and eclampsia. Chronic hypertension is when hypertension occurs before pregnancy or before 20 weeks of gestation, whereas the other three occur after 20 weeks. Pre-eclampsia is associated with proteinuria, and eclampsia is associated with seizures.
Interventions for hypertension in pregnancy are lifestyle modifications and anti-hypertensives. The anti-hypertensives commonly used in pregnancy are labetalol, nifedipine, and methyldopa.
In cases of severe hypertension (severe preeclampsia, eclampsia, and HELLP syndrome), the standard of care is delivery, especially after 37 weeks of gestation. If an acute decrease in blood pressure is required, intravenous labetalol or intravenous hydralazine are options. Magnesium sulfate prevents seizures.
The differential diagnosis of secondary hypertension as stated above are chronic kidney disease, autosomal dominant polycystic kidney disease, renal artery stenosis, fibromuscular dysplasia, primary aldosteronism, Cushing syndrome/disease, hyperthyroidism, hypothyroidism, hyperparathyroidism, pheochromocytoma, acromegaly, congenital adrenal hyperplasia, coarctation of the aorta, obstructive sleep apnea, drug-induced hypertension, pregnancy, scleroderma.
The prognosis of secondary hypertension is good. With the treatment of the underlying condition, the blood pressure may decrease or even come back to normal.
The underlying medical condition that causes high blood pressure can be worsened by secondary hypertension. Some of the complications of secondary hypertension are atherosclerosis, aneurysm, heart failure, metabolic syndrome, chronic renal failure, and retinopathy.
Enhancing Healthcare Team Outcomes
The patient's primary care doctor and/or nurse practitioner may be the main person involved in diagnosing a secondary cause of hypertension. But an interprofessional team of specialists consisting of a nephrologist, cardiologist, endocrinologist, rheumatologist, and surgeons can help with diagnosing and managing the patient. Nurses also play an essential role in patient care, as do pharmacists. Hence, interprofessional communication and care coordination between physicians, nurses, and other health professionals is crucial to enhance patient outcomes. [Level 5]