Secondary Hypertension

Question 1

Clinical Manifestations of Secondary Hypertension

Answer 1

a. The clinical features of secondary hypertension are, often times, indistinguishable to that of essential hypertension in the majority of cases
b. There are some clinical clues, however, that may suggest the presence of a secondary cause as outlined below:
i. Young age of onset (before 3rd decade)
ii. Sudden onset of hypertension
iii. Uncontrolled/refractory hypertension
iv. Hypokalemia in association with metabolic alkalosis (without the use of diuretics)
v. Features of a recognized underlying cause (i.e. hyperglycemia in the setting of Cushing’s syndrome)

Question 2

Causes of Secondary Hypertension

Answer 2

• Renal
• Endocrine
• Cardiovascular
• Drugs
• Inherited Causes

Question 3

Renal Causes

Answer 3

i. Renovascular hypertension
ii. Renal parenchymal hypertension

Question 4

Endocrine Causes

Answer 4

i. Primary hyperaldosteronism
ii. Cushing’s syndrome
iii. Pheochromocytoma
iv. Hyperreninism
v. Hypothyroidism
vi. Hyperparathyroidism

Question 5

Cardiovascular Causes

Answer 5

i. Obstructive sleep apnea
ii. Coarctation of the aorta

Question 6

Drugs

Answer 6

i. Glucocorticoids
ii. Nonsteroidal anti-inflammatory drugs
iii. Combined oral contraceptive medications
iv. Calcineurin inhibitors
v. Caffeine
vi. Pseudoephedrine
vii. Licorice (due to inhibition of 11-β hydroxysteroid dehydrogenase type 2 by glycerrhetinic acid)

Question 7

Inherited Causes

Answer 7

i. Glucocorticoid-remediable aldosteronism
ii. Syndrome of apparent mineralocorticoid excess (SAME)
iii. Liddle’s syndrome
iv. Gordon’s syndrome
v. Congenital adrenal hyperplasia

Question 8

Renovascular Hypertension Defined

Answer 8

Hypertension caused by renal artery stenosis (unilateral or bilateral).

i. The most common correctable cause of secondary hypertension

Question 9

Renovascular Hypertension Prevalence

Answer 9

Variable – depends on clinical circumstance

i. Less than 1% in mild to moderate hypertension
ii. 10-40% in patients with severe or refractory hypertension

Question 10

Renovascular Hypertension Etiology

Answer 10

i. Atherosclerosis - 75-90% of renovascular hypertension
1. Typically in patients > 50 years old who have cardiovascular risk factors (tobacco use, dyslipidemia, peripheral vascular disease)
ii. Fibromuscular dysplasia (FMD) – 10-25% of renovascular hypertension
1. Nonatherosclerotic, noninflammatory vascular disease presenting between the ages of 30-50 years old
2. Women > men
iii. Other
1. Aortic/renal dissection
2. Takayasu’s arteritis
3. Thrombotic/cholesterol emboli
4. Post-transplant renal artery stenosis (TRAS)
5. Post radiation

Question 11

Renovascular Hypertension Pathophysiology

Answer 11

i. Reduced renal perfusion pressure resulting from stenosis of the arterial vasculature in one of both kidneys
ii. Decrease in renal perfusion pressure activates the renin-angiotensin-aldosterone system (RAAS)
iii. Angiotensin II stimulation causes the following that results in sustained hypertension:
1. Increase in sympathetic nervous system activity
2. Vasoconstriction
3. Anti-diuretic hormone release (water retention)
4. Aldosterone release from the adrenal gland (sodium retention)

Question 12

Renovascular Hypertension Clinical Features

Answer 12

i. History
1. Onset of hypertension in the 3rd-5th decade (FMD), >55 years old for atherosclerotic disease
2. Sudden onset of uncontrolled hypertension in a previously well controlled patient
3. Accelerated or malignant hypertension (hypertension in association with end-organ damage)
4. Intermittent pulmonary edema with normal cardiac function
ii. Investigations
1. Epigastric bruit (not always present)
2. Acute, unexplained rise in serum creatinine induced by ACE inhibitor or angiotensin receptor blocker
3. Asymmetric renal size on imaging (affected kidney is smaller)

Question 13

Renovascular Hypertension Diagnosis

Answer 13

1. Physical findings (abdominal bruit) – nonspecific
2. Laboratory – elevated plasma renin activity and plasma aldosterone concentration
3. Magnetic Resonance Angiography (MRA)
   a. Highly sensitive and specific and noninvasive making this test the screening tool of choice in most centers
   b. Contraindicated in patients with GFR <30ml/min (contrast agent – gadolinium associated with nephrogenic systemic fibrosis)
4. Computed tomography (CT) spiral angiography with contrast
   a. High sensitivity and specificity but risk of contrast-induced nephrotoxicity in patients with impaired GFR
5. Duplex doppler ultrasonography
   a. Moderate sensitivity and specificity – time consuming and highly operator dependent
   b. Advantage is no exposure to contrast agents
   c. Diagnostic test of choice for FMD
6. Conventional renal arteriography
   a. Gold standard diagnostic investigation for renal artery stenosis
   b. Used typically when planning intervention (surgery or stent placement) otherwise exposes patient to risk of contrast-induced nephrotoxicity, cholesterol embolization, and damage to the renal or femoral arteries

Question 14

Renovascular Hypertension Treatment

Answer 14

1. All patients with renovascular disease should be on appropriate antihypertensive and lipid lowering therapy
2. Patients with FMD should initially trial ACE inhibitor or angiotensin receptor blocker therapy (ARB)
   a. If remain hypertensive, treatment of choice is revascularization with percutaneous transluminal angioplasty (PTA).
3. Patients with atherosclerotic disease are treated with aggressive medical therapy including ACE inhibitor or ARB, lipid lowering medications, and antiplatelet therapy
   a. Recent meta-analysis (2009) showed no benefit of PTA over medical therapy
   b. Revascularization with stent placement is reserved for those who have uncontrolled HTN on multiagent therapy or rapid rise in serum creatinine with parenchymal loss

Question 15

Renal Parenchymal Hypertension

Answer 15

a. Common feature in acute (typically glomerular and vascular disorders) and chronic kidney disease (CKD)
b. Acute glomerular disease, pathogenesis is related to volume overload and suppression of RAAS whereas in acute vascular disease, hypertension results from ischemia-induced activation of RAAS
c. CKD – pathogenesis of hypertension is multifactorial including volume expansion via sodium and water retention, activation of the sympathetic nervous system, RAAS activation, contribution from secondary hyperparathyroidism (intracellular calcium mediating vasoconstriction), and endothelial dysfunction
i. Treatment includes ACE inhibitor/ARB (has been shown to slow decline in GFR in proteinuric diseases), diuretic for volume removal, and if a 3rd agent is needed, calcium channel blocker
1. ACE inhibitors/ARB may cause an initial fall in GFR; however, an increase in serum creatinine ~ 30-35% is tolerated and should not precipitate discontinuation of therapy

Question 16

Primary Hyperaldosteronism Prevalence

Answer 16

The most common cause of hypertension due to an endocrinopathy with prevalence ~0.5-2% (5-12% in referral centers)

Question 17

Primary Hyperaldosteronism Etiology

Answer 17

i. Adrenal adenoma
ii. Bilateral adrenal hyperplasia
iii. Adrenal carcinoma (rare)

Question 18

Primary Hyperaldosteronism Clinical Presentation

Answer 18

Mineralocorticoid excess should be suspected in any patient with the triad of hypertension, unexplained hypokalemia, and metabolic alkalosis (although a significant number of patient are normokalemic)

Question 19

Primary Hyperaldosteronism Diagnosis

Answer 19

i. Plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio
1. Morning ambulatory blood sample – a ratio of > 30-50 and PAC of > 15 (i.e. PRA 0.6 and PAC 30 = ratio of 50) is suggestive of primary hyperaldosteronism
2. Aldosterone antagonists such as spironolactone or eplerenone need to be discontinued for at least 6 weeks prior to testing, remainder of antihypertensive medications should not pose a problem
ii. Confirmatory testing
1. Sodium loading with 3 days of a high sodium diet (~5g day/90meq day) followed by 24h urine collection for aldosterone (sodium and creatinine should be measured to ensure appropriate sodium load and accurate urine collection). Aldosterone > 14µg confirms primary hyperaldosteronism
2. OR 2L isotonic saline administration over 4 hours in recumbent position. Plasma aldosterone level should fall 10ng/dL is a positive result
iii. Subtype classification – once diagnosis of primary hyperaldosteronism is confirmed, a unilateral adenoma, or rarely carcinoma needs to be distinguished from bilateral adrenal hyperplasia
1. CT abdomen – sensitivity and specificity are only moderate (false positive and false negatives – i.e. may detect a nonfunctioning adenoma when patient actually has bilateral hyperplasia)
2. Adrenal vein sampling – predictive for successful unilateral adrenalectomy.
a. A > 5x increase in plasma aldosterone concentration compared with the contralateral side should be demonstrated on the side of the adenoma
b. Problem – very few centers in the US can do this test successfully

Question 20

Primary Hyperaldosteronism Treatment

Answer 20

i. If confirmation of functional unilateral adenoma, laparoscopic surgical removal can be performed
1. Patients should be pretreated for 3-4 weeks with aldosterone antagonist (spironolactone or eplerenone)
ii. If bilateral adrenal hyperplasia, then treatment with spironolactone or eplerenone indefinitely

Question 21

Cushing’s Syndrome Definition

Answer 21

A clinical condition resulting from excess effects of either exogenous or endogenous glucocorticoids

Question 22

Cushing’s Syndrome Etiology

Answer 22

i. Exogenous glucocorticoid administration
ii. Endogenous glucocorticoid excess
1. Pituitary secretory adenoma (Cushing’s disease)
2. Ectopic ACTH production
3. Adrenal adenoma

Question 23

Cushing’s Syndrome Clinical Features

Answer 23

i. Centripetal obesity – fat deposition in the face, neck, trunk, and abdomen
ii. “Moon facies” –fat accumulation in the cheeks and temporal fossa
iii. Skin atrophy and abdominal striae – broad purple streaks due to fragile skin (underlying venous blood flow in the dermis)
iv. Acne and hirsutism (increased hair on the upper lip and chin) due to androgen excess
v. Proximal muscle weakness
vi. Hypertension
vii. Glucose intolerance

Question 24

Cushing’s Syndrome Diagnosis

Answer 24

i. 24 hour urinary cortisol excretion (positive is 3x upper limit of normal)
1. Can have false positives in polycystic ovarian syndrome
ii. Late evening salivary cortisol (elevated in Cushing’s)
iii. Low dose dexamethasone suppression test
1. Dexamethasone substitutes for endogenous cortisol in suppressing ACTH release leading to suppression of cortisol secretion/reduction in serum cortisol level
2. A 1-mg dose of Dexamethasone is taken at midnight, plasma cortisol is measured at 8 am (<50 nmol/L is normal)
iv. Diagnosis is confirmed when 2 of the above tests are unequivocally abnormal

Question 25

Cushing’s Syndrome Imaging

Answer 25

i. MRI with thin cuts through the sella turcica to identify a pituitary/ACTH adenoma (Cushing’s disease)
ii. CT
1. Chest - ectopic ACTH production from tumor (typically lung cancer)
2. Abdomen – adrenal gland from cortisol-secreting tumor

Question 26

Cushing’s Syndrome Treatment

Answer 26

i. Cushing’s disease/pituitary adenoma
1. Transphenoidal resection
2. Pituitary irradiation
ii. Adrenal tumors – adrenalectomy
iii. Ectopic ACTH – removal of tumor

Question 27

Pheochromocytoma Definition

Answer 27

Catecholamine-secreting tumors that arise from chromaffin cells of the adrenal medulla and the sympathetic ganglia (the latter are referred to as catecholamine-secreting paragangliomas or extra-adrenal pheochromocytomas)

Question 28

Pheochromocytoma Clinical Features

Answer 28

i. Classic Triad: Episodic headache, sweating, and tachycardia in addition to hypertension
ii. Symptoms may be precipitated by triggers such as tyramine-containing foods (cheese, wine), pain, trauma, drugs (clonidine, MAO inhibitors, opiates, anesthesia)

Question 29

Pheochromocytoma Diagnosis

Answer 29

i. 24 hour fractionated urinary metanephrines and catecholamines (norepinephrine, epinephrine, dopamine, and normetanaphrine)
1. High sensitivity and specificity (~98% respectively)
ii. Fractionated plasma metanephrines
1. High sensitivity (96-100%) but specificity low (85-89%)
2. More attractive due to simplicity (hard to accurately collect 24h urine)
3. Should be used first-line when suspicion or pretest probability high

Question 30

Pheochromocytoma Imaging

Answer 30

i. CT or MRI of the abdomen and pelvis detects almost all sporadic tumors (most are 3cm or larger in diameter)
1. Sensitivity high (98-100%) but only 70% specific due to high prevalence of adrenal “incidentalomas” (benign cortical adenomas that are nonfunctional)
ii. MIBG scinitigraphy – if CT or MRI is negative following a positive biochemical test, then 123-I-metaiodobenzylguanidine (MIBG) scan can be performed (a radioisotope of a norepinephrine analogue) to detect the tumor or multiple tumors

Question 31

Pheochromocytoma Treatment

Answer 31

i. Surgical removal of the tumor
1. Blood pressure control is needed prior to surgical intervention
2. Alpha antagonists are first-line
a. Phenoxybenzamine (long-acting, nonspecific alpha-blocking agent) – typically started ~ 7-10 days prior to surgery
b. Phentolamine is a shorter acting nonspecific alpha-blocking agent
3. Beta blockers – after adequate alpha blockade is achieved (helps to control tachycardia)
a. Do NOT start beta blockers prior to adequate alpha blockade
b. Can result in unopposed alpha stimulation 4. If an additional agent is needed, dihydropyridine calcium channel blocker – nifedipine is used
5. Acute hypertensive crisis – can occur with surgical resection due to endotracheal intubation/anesthesia induction, manipulation of the adrenal gland
a. Treat with parenteral nitroprusside, phentolamine, or nicardipine

Question 32

Obstructive Sleep Apnea Definition

Answer 32

i. Obstructive apneas, hypopneas (abnormal reduction of airflow), or respiratory effort related arousals during sleep
ii. Daytime sleepiness, fatigue or poor concentration
iii. Signs of disturbed sleep including snoring, restlessness, or resuscitative snorts

Question 33

Obstructive Sleep Apnea Pathophysiology

Answer 33

i. Association of obesity, obstructive sleep apnea (OSA) and hypertension has long been established
ii. Apneic syndrome itself is thought to contribute directly to hypertension
1. Abnormalities of sympathetic nervous function and vascular reactivity

Question 34

Obstructive Sleep Apnea Clinical Features

Answer 34

i. Approximately 30-80% of patients with essential hypertension have OSA and about 50% of patients with OSA have hypertension
ii. Manifestations include daytime hypersomnolence, morning headache, snoring or witnessed apneic episodes, poor concentration

Question 35

Obstructive Sleep Apnea Diagnosis

Answer 35

i. Polysomography (sleep study) is g

Question 36

Obstructive Sleep Apnea Treatment

Answer 36

i. Weight loss, avoidance of alcohol, and sedating medications (benzodiazepines, antihistamines) – depresses the central nervous system and exacerbates OSA
ii. Continuous positive airway pressure (CPAP) splints the upper airway open
iii. Oral appliances – mandibular advancement splints are designed to protrude the mandible forward or hold the tongue in a more anterior position
iv. Surgical therapy – uvulopalatopharyngoplasty (UPPP)
1. Reserved for those who have a surgically correctable obstructing lesion