Continuing Education Activity

Hypertension is the major risk factor for cardiovascular diseases, and in the contemporary era, more than 30% of the adult population is suffering from hypertension. Secondary hypertension is defined as elevated blood pressure (BP) secondary to an identifiable cause. This activity outlines the etiology of secondary hypertension and discusses the history, physical examination findings, diagnostic tests, and management of secondary hypertension. This activity also highlights the importance of interprofessional teamwork in managing such patients.

Objectives:

• 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.

Introduction

Hypertension is the major risk factor for cardiovascular diseases, and in the contemporary era, more than 30% of the adult population is suffering from hypertension.[1][2] Although essential hypertension (hypertension without an identifiable cause) is found as the main reason for hypertension, 10% of patients with hypertension are found to have secondary hypertension.[3]

Secondary hypertension is defined as elevated blood pressure (BP), secondary to an identifiable cause.[4] Since its prevalence is relatively low, performing routine evaluations in every case of hypertension is not cost-effective and is also time-consuming. However, identification of the etiology and pathophysiology of secondary hypertension is essential in selected groups of patients. It does not just guide towards the appropriate therapy, it may result in a complete cure of hypertension and elimination of antihypertensive therapy. It is important for healthcare professionals treating hypertension, to be aware of clinical clues that could suggest a secondary cause of hypertension.[5] The common clinical signs which warrant investigations for a secondary cause of hypertension may include;

• Resistant hypertension, i.e., persistent blood pressure greater than 140/90 mm Hg despite using optimal doses of at least three anti-hypertensive from different classes, that includes a diuretic.[6]

• An acute rise in blood pressure in a patient who had previously stable pressures.
• Hypertension develops in non-black patients before the age of 30 years, 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 patterns 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.[7]

Etiology

Myriads of etiologies have been reported for secondary hypertension, which may be classified into the following broad categories;[8][9]

Renal Parenchymal Disease

The renal parenchymal disease is the most common cause of secondary hypertension. It is a group of different renal disorders which may include diabetic nephropathy, glomerulonephritis, interstitial renal parenchymal diseases, and polycystic kidney diseases.[10] More than half of the patients with renal parenchymal diseases are found to have hypertension and the incidence of hypertension increases with the worsening of renal parenchymal disorders.[11] Development of hypertension has a negative effect on renal parenchymal disease and it accelerates the worsening of renal function and leads to end-stage renal diseases.[12]

Endocrine Disorders

Hypertension due to endocrine disorders is caused by increased secretion of hormones. The common endocrine disorders responsible for secondary hypertension include primary aldosteronism, pheochromocytoma, and Cushing`s syndrome, and primary aldosteronism is responsible for the majority of endocrine hypertension cases.[13] Acromegaly, primary hyperparathyroidism, and thyroid disorders are very rare causes of secondary hypertension.[14]

Renovascular Disorders

Hypertension due to renovascular disorders is a rare entity and occurs due to stenosis of the unilateral or bilateral renal arteries.[15] Atherosclerosis is the cause of renal artery stenosis in the elder population, while the younger population, especially females are found to have renal artery stenosis due to fibromuscular hyperplasia.[16]

Vascular Disorders

Coarctation of the aorta is the prime example of vascular disorders resulting in secondary hypertension in young adults.[17] The rare causes of secondary hypertension may include vasculitides of medium or large-sized arteries and arteriovenous fistula.[18]

Miscellaneous

Obstructive sleep apnea, polycystic ovarian syndrome, preeclampsia, and drugs may contribute to the etiology of secondary hypertension. In the presence of obstructive sleep apnea, the duration, as well as quality of sleep, is affected, which has been reported to increase the risk of hypertension.[19]

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.[20]

• Non-steroidal anti-inflammatory drugs are the most commonly 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)

Epidemiology

As stated above, up to 10% of adults with hypertension are found to have secondary hypertension. The prevalence of secondary hypertension varies with age and it is most prevalent at the extremes of age. It accounts for 70 to 85 percent of hypertension cases in children less than 12 years of age, and approximately 17 percent of cases in adults aged 65 and older.[21] The prevalence of secondary hypertension is lowest amongst hypertensive patients who are 19 to 39 years of age while its prevalence in adolescents (12 to 18 years) is 10 to 15%.[22]

Renal parenchymal diseases are responsible for secondary hypertension in 3-5% of the people diagnosed with hypertension. The incidence of secondary hypertension increases with worsening renal functions and more than 2/3 of the patients with advanced chronic kidney disease are found to have hypertension.[23] Primary aldosteronism is the main endocrine disorder leading to secondary hypertension and is found in as high as 5% of patients with hypertension.[24] Treatment of underlying endocrine abnormality usually results in the cure of hypertension. Renovascular hypertension accounts for 1% of the patients with hypertension and it has bimodal age distribution.[25]

Pathophysiology

Arterial blood pressure is determined by cardiac output and vascular compliance (systemic vascular resistance), therefore a high cardiac output and high systemic vascular resistance are the primary mechanisms of hypertension.[26] The factors responsible for secondary hypertension result in arterial hypertension by affecting the aforementioned determinants of blood pressure.

Renal parenchymal diseases lead to impaired renal function that results in intravascular volume expansion. While an inappropriate activation of the renin-angiotensin-aldosterone and sympathetic system is the other mechanism responsible for hypertension in renal parenchymal diseases.[27] Hypertension, on the other hand, leads to the worsening of the renal parenchymal disease and increases its progression to end-stage renal disease. The blood pressure in patients with advanced renal parenchymal disease is dependent on intravascular volume, that’s why fluid balance plays an essential role in controlling blood pressure in chronic kidney disease.

In endocrine disorders, different hormones are responsible for hypertension. In primary aldosteronism, higher levels of aldosterone result in volume expansion (by salt retention), while cortisol plays a similar role in Cushing`s syndrome.[28][29] Elevated serum levels of adrenaline and noradrenaline result in higher cardiac output as well as increased systemic vascular resistance, resulting in hypertension,  in patients with pheochromocytoma.[30] Increased systemic vascular resistance is the primary mechanism of hypertension in vascular disorders, while secondary hyperaldosteronism plays a major role in the development of hypertension in renal artery stenosis.[31]

History and Physical

Obtaining a complete history and performing a good physical exam is very important when trying to find the underlying cause of secondary hypertension. Development of hypertension in extremes of age accelerated end-organ dysfunction due to hypertension, resistant hypertension, and sudden rise in blood pressure in hypertensive individuals, who are stable on drug therapy, are classical features of secondary hypertension.[32][33][34] 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.[35]
• History of renal insufficiency, atherosclerotic cardiovascular disease, and edema may warrant further evaluation of chronic kidney disease (renal parenchymal disease).[36]
• History of recurrent urinary tract infections, kidney stones, acute/chronic abdominal/flank pain, hematuria, and progressive renal failure may point towards autosomal dominant polycystic kidney disease (renal parenchymal disease).[37]
• Worsening renal function with angiotensin-converting enzyme inhibitors (ACEi) and a systolic/ diastolic abdominal bruit point towards the reno-vascular disease.[38]
• Episodic hypertension, headache, and palpitation, associated with acute stress, in a perioperative setting, could be the signs of pheochromocytoma or paragangliomas.[39]
• Decreased or delayed femoral pulses, radio femoral delay, and differences in the blood pressure in the arms are seen in the coarctation of the aorta and vasculitic causes of secondary hypertension.[40]
• Weight gain, fatigue, weakness, hirsutism, amenorrhea, moon facies, dorsal hump, purple striae, and truncal obesity present in Cushing syndrome/disease.[41]
• 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.[42]
• Headaches, fatigue, visual problems, enlargement of the hands, feet, and tongue are features of acromegaly.
• Heartburn, Raynaud phenomenon, and nail pitting on the exam may be suggestive of scleroderma.

Evaluation

Investigations for the cause of secondary hypertension are determined by the history and clinical examination. Confirmatory laboratory and radiology investigations are individualized and preceded by the screening test. The contemporary guidelines recommend screening for secondary hypertension in patients with new-onset or uncontrolled hypertension, who have symptoms/signs consistent with the secondary causes of hypertension.[43] Patients with positive screening tests for one of the secondary causes of hypertension should go for the confirmatory test and it is reasonable to refer those patients to clinicians with special expertise.[43]

Renal Parenchymal Disease

The initial screening tests for renal parenchymal diseases include serum creatinine with estimated glomerular filtration rate (eGFR), urine detailed report, urinary protein/protein to creatinine ratio, and renal ultrasound.[44] A renal biopsy followed by histopathology is a gold-standard investigation, recommended for the diagnosis of specific conditions and pathophysiology of renal parenchymal diseases.[45][46] All patients with positive screening tests for renal parenchymal diseases should be referred to a nephrologist for the diagnosis and management of renal disorders.

Endocrine Disorders

Hypertension with hypokalemia is one of the characteristic features of primary aldosteronism, especially in those individuals with a family history of hypertension and cerebrovascular accidents at a young age. The plasma aldosterone/renin ratio is the preferred screening test for primary aldosteronism and it should be done at least four weeks after the withdrawal of aldosterone antagonists and after the correction of hypokalemia.[47] Measurement of 24-hour urine aldosterone level after oral sodium loading and plasma aldosterone level after intravenous saline infusion are the diagnostic tests for primary aldosteronism, while renal vein sampling can be done for selected patients. Adrenal imaging is recommended for the localization of the lesion.[48]

Screening for pheochromocytoma/paraganglioma is recommended in the presence of episodic hypertension, along with palpitations, headache, postural hypotension, and stigmata of neurofibromatosis. Measurement of urinary or plasma metanephrine is the recommended screening test for pheochromocytoma. While computed tomography or magnetic resonance imaging is recommended for the localization of the tumor.[39] An overnight dexamethasone suppression test is the preferred screening investigation for Cushing syndrome. While the confirmatory investigations include 24-hour urinary free cortisol and midnight salivary cortisol. Imaging modalities can be used for the localization of the lesion.[49]

Thyroid disorders are the rare causes of secondary hypertension, which can be diagnosed by measuring the thyroid stimulating hormone (TSH) and free T4/T3 levels.[50] Ultrasonography and biopsy are recommended in selected patients with suspected thyroid malignancies. Serum calcium level is the best screening test for hyperparathyroidism while the measurement of serum parathyroid hormone is recommended for the diagnosis of primary hyperparathyroidism.

Reno-vascular Hypertension

Renal artery stenosis is suspected when patients present with uncontrolled hypertension, have renal bruit, and develop deterioration of renal function after taking angiotensin-converting enzyme (ACE) inhibiting drugs. Ultrasound renal Doppler is the initial recommended test for the screening and diagnosis of renal artery stenosis. While computed tomographic angiogram (CTA) and magnetic resonance angiogram (MRA) can be considered in a selected group of patients, especially those with high suspicion of index, who have non-diagnostic ultrasound renal Doppler.[51] The bilateral, selective renal artery angiogram is rarely required for the diagnosis of renal artery stenosis in the contemporary era of advanced imaging.

Vascular and Other Causes of Hypertension

Coarctation of the aorta is the major contributor to secondary hypertension in this group and an echocardiogram is the best screening as well as a diagnostic test for the coarctation of the aorta. Computed tomographic aortogram (CTA) and magnetic resonance angiogram (MRA) is recommended for the diagnosis and confirmation of coarctation of the aorta as well as vasculitis.[52] Polysomnography (preferably in-laboratory polysomnography) is the diagnostic study of choice when there is a suspicion of obstructive sleep apnea. The clinical and laboratory findings consistent with scleroderma may include thrombotic microangiopathy, autoantibodies against RNA polymerase III, and positive antinuclear antibody (ANA).[53]

Treatment / Management

Management of secondary hypertension comprises adequate control of blood pressure with a healthy lifestyle and appropriate antihypertensive drugs and addressing the secondary causes mentioned above. It is recommended to refer these patients to clinicians with expertise, in order to treat the underlying cause of hypertension.[43] Identification of hypertension-inducing/provoking drugs is an essential part of management in patients with secondary hypertension. In this section, we will briefly discuss the management of the more common causes of secondary hypertension,

Renal Parenchymal Disease

The most common renal parenchymal diseases leading to secondary hypertension include diabetic nephropathy, chronic glomerulonephritis, glomerulosclerosis, and autosomal dominant polycystic kidney disease (ADPKD) and all these disorders result in chronic kidney disease (CKD).[54] Hypertension is found in more than 2/3 of the patients with CKD  and it accelerates its progression to end-stage renal diseases.[23] So it is imperative to achieve good hypertension control in this population.

Currently, there is no cure for chronic kidney disease and the main focus of the management is to treat the reversible causes responsible for the progression to advanced kidney disease.[55] Adequate blood pressure control is an essential component of management in CKD and contemporary guidelines recommend renin-angiotensin (RA) antagonists as the preferred drug therapy for the treatment of hypertension in CKD.[56] The RA-blocking drugs not only control hypertension but also prevent the progression of CKD, especially in patients with proteinuria.[57]

Renovascular Hypertension

Management of renovascular hypertension (renal artery stenosis) is divided into medical therapy and revascularization. Medical therapy involves the use of anti-hypertensive drugs to control blood pressure and in the case of atherosclerotic disease, the use of antiplatelets, statins, diet, and lifestyle changes.[58] ACE inhibitors and ARBs are the anti-hypertensive drugs of choice in patients with unilateral renal artery stenosis, however, these drugs are contraindicated in bilateral renal artery stenosis due to the risk of rapid renal dysfunction.[59] Other pharmacologic treatment options are calcium channel blockers and thiazide diuretics. Percutaneous revascularization is recommended along with medical therapy in selective patients, especially those with fibromuscular dysplasia. The combination of drug therapy and percutaneous revascularization has been reported to reduce blood pressure significantly and this strategy has long-term renoprotective effects in patients with fibromuscular dysplasia.[38]

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

Endocrine Hypertension

Unilateral primary aldosteronism (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 the bilateral adrenal disease, then medical management with a mineralocorticoid receptor antagonist is recommended and spironolactone is the drug of choice for primary aldosteronism.[47] For Cushing Syndrome or Cushing Disease, an open surgical or laparoscopic resection of the lesion/tumor is the treatment of choice,

The definite treatment of pheochromocytoma is surgical resection of the hormone-producing lesion, however preoperative alpha and beta-adrenergic blocking drugs are an essential part of pheochromocytoma management. It is recommended to start alpha-adrenergic blocking drugs first and then add beta blockers for the treatment of tachyarrhythmias.[60] Initiation of beta-adrenergic blocking drugs is not recommended alone/before the alpha-adrenergic blockade, as it results in hypertensive crisis due to the unopposed alpha-adrenergic effect. Pheochromocytoma crisis is treated with intravenous phentolamine followed by initiation of oral alpha-adrenergic blocking drugs.[61] The specific treatment of patients with hypothyroidism includes thyroid replacement therapy, while hyperthyroidism is treated with antithyroid drugs. The other treatment options are determined by the primary mechanism of thyroid disorders. The definite treatment of patients with hypertension due to acromegaly is transsphenoidal resection of the hormone-producing tumor.[62]

Vascular Hypertension

Coarctation of the aorta is the major cause of vascular hypertension in the younger population. The choice of antihypertensive drugs for this population depends on the other co-existing conditions, however, the definite treatment is the percutaneous or surgical correction of the coarctation. Correction of coarctation at an early age provides better long-term outcomes, but one-third of the patients remain hypertensive even after surgical correction of the coarctation of the aorta.[63]

Vasculitides of the large vessels (e.g Takayasu Arteritis) may also lead to hypertension due to a significant rise in systemic vascular resistance. Corticosteroids or other immunosuppressant agents along with antihypertensive drugs are recommended for the treatment of secondary hypertension due to vasculitides.[64]

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 the usage of CPAP have a synergistic effect on lowering blood pressure and are better than either intervention alone.[65] 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.[66] 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.[67]

Pregnancy-Related Hypertension

Interventions for hypertension in pregnancy are lifestyle modifications and anti-hypertensives. The anti-hypertensives commonly used in pregnancy are labetalol, nifedipine, and methyldopa. If an acute decrease in blood pressure is required, intravenous labetalol or intravenous hydralazine are options.[68] In cases of severe hypertension (severe preeclampsia, eclampsia, and HELLP syndrome), the standard of care is delivered, especially after 37 weeks of gestation.[69]

Differential Diagnosis

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. Detailed history and examination are imperative for the screening and early diagnosis of the underlying cause of secondary hypertension.[3]

Prognosis

Secondary hypertension is usually resistant to antihypertensive drugs if the underlying mechanism is not identified and treated appropriately. It may present with early end-organ dysfunction, hypertension crisis, and cardiovascular events at a younger age.[70] However, with early identification and treatment of the underlying cause, secondary hypertension has a favorable prognosis.[71]

Complications

Hypertension is the most prevalent non-communicable disease globally and it is a major risk factor for cardiovascular diseases, including coronary artery disease, cerebrovascular accidents, and peripheral arterial diseases.[72][73] The microvascular complication of hypertension includes chronic kidney disease and hypertensive retinopathy.[74] Hypertension also increases the risk of atrial fibrillation and heart failure, especially in the elder population.[75]

Secondary hypertension shares these complications with essential hypertension, however, a few complications are much more common in secondary hypertension. People with secondary hypertension commonly present with resistant hypertension, defined as uncontrolled hypertension on maximally tolerated doses of at least three antihypertensive drugs including a diuretic.[70] Secondary hypertension accelerates end-organ damage if not diagnosed and treated at the appropriate time and it significantly increases premature cardiovascular events.[4]

Consultations

The management of secondary hypertension requires a multidisciplinary approach. Patients with secondary hypertension should be referred to a clinician with expertise, in order to the appropriate treatment of the underlying cause. Consultation with the below-mentioned specialties is required for the management of these patients.

• Internal medicine
• Nephrology
• Cardiology
• Endocrinology
• Neurology
• Cardiac/Vascular surgery
• Rheumatology

Deterrence and Patient Education

Secondary hypertension is a potentially life-threatening condition, that accelerates cardiovascular complications and end-organ dysfunction. It is essential for the patients to identify the symptoms specific to the secondary causes of hypertension and consult their primary care physician in order to facilitate the early diagnosis and management of the primary cause. All patients on the treatment of hypertension should practice a healthy lifestyle, take the drugs properly and monitor their blood pressure regularly at home. They should notify their physician about new symptoms and a change in the blood, which may warrant evaluation of the secondary cause of hypertension.

Pearls and Other Issues

Secondary hypertension is found in 10% of the people diagnosed with hypertension and it is common in younger individuals. Secondary hypertension should be suspected in every individual with;

1. Signs and symptoms consistent with a secondary cause of hypertension
2. Hypertension diagnosed at the extremes of the age
3. Accelerated end-organ dysfunction
4. Resistant hypertension
5. An abrupt rise in blood pressure (in individuals with well-controlled hypertension)

Enhancing Healthcare Team Outcomes

People with secondary hypertension are commonly diagnosed incidentally or they present with resistant hypertension and end-organ dysfunction. The diagnosis and management of secondary hypertension require a multidisciplinary team and collaborative efforts. An inter-professional communication plays a key role in identifying the etiology of secondary hypertension and treating the condition effectively. A comprehensive team including a hypertension nurse, a primary care physician, a cardiologist, a nephrologist, a neurologist, an endocrinologist, a cardiovascular surgeon, and a rheumatologist, is of prime importance for the management of secondary hypertension. This collaborative effort is the key to improving the patient long-term outcomes of secondary hypertension and minimizing the economic burden on the healthcare system.