SECONDARY CAUSES OF HYPERTENSION Flashcards
Indications for Evaluation of Secondary HTN
Drug-resistant HTN
Indications for Evaluation of Secondary HTN
Refractory HTN:
Failure to achieve goal blood pressure (i.e., <140/90 mm Hg), despite being treated by a HTN specialist over at least three visits over a 6-month period or longer
Refractory HTN patients tend to have higher heart rate (81 vs. 70) compared to those who are controlled, despite being on more β-blocker use. Sympathetic dysregulation is thought to play a role.
Specific Causes of Secondary HTN
Top three causes: renal parenchymal disease, aldosteronism, renal artery disease.
Specific Causes of Secondary HTN
Obesity
Proposed contributing factors: hyperleptinemia, hyperinsulinemia, endothelial dysfunction, sympathetic nervous system (SNS) activation, kidney injury, fructose ingestion, hyperaldosteronism driven by circulating oxidized fatty acids (linoleic acid) or uric acid, concurrent obstructive sleep apnea (OSA)
Specific Causes of Secondary HTN
Obesity
Fructose gets phosphorylated rapidly intracellularly leading to → local adenosine triphosphate depletion and uric acid generation → uric acid–induced endothelial dysfunction, SNS activation.
Specific Causes of Secondary HTN
Obesity
OSA:
OSA occurs in 30% of patients with HTN and up to 70% to 90% of patients with drug resistant HTN.
The association between OSA and HTN is dependent on OSA severity and presence of obesity. Association is not significant in individuals with BMI < 25 kg/m2 (National health and Evaluation Survey).
Specific Causes of Secondary HTN
Obesity
OSA:
Signs and symptoms to consider OSA in hypertensive patients: snoring, gasping/choking, daytime somnolence particularly with associated functional impairment (e.g., “sleeping on the job”).
Specific Causes of Secondary HTN
Obesity
OSA:
Physical risks: older men (>50 years old), “crowded” oropharynx, large neck circumference (>50 cm or >20 inches)
Specific Causes of Secondary HTN
Obesity
OSA:
Treatment with continuous positive airway pressure (CPAP) ventilation:
Improves BP control with use >4 hours in young patients (2 to 5 mm Hg reduction)
Recommended for symptomatic patients
Specific Causes of Secondary HTN
Obesity
OSA:
β-blockers are most effective antihypertensive agent in OSA due to sympathetic overactivity.
Specific Causes of Secondary HTN
Obesity
OSA:
Renal denervation improves office BP (average reduction of 34/13 mm Hg), but no significant effect on ambulatory BP (average reduction of 8 mm Hg) in small case series involving 10 patients.
Bariatric surgery versus lifestyle modifications/medical therapy
greater weight loss, greater BP reduction, lower antihypertensive drug requirement with bariatric surgery compared with lifestyle modifications/medical therapy alone, even in patients without morbid obesity
Neurogenic HTN
Cerebral blood flow = cerebral perfusion pressure/cerebrovascular resistance, where
Cerebral perfusion pressure = MAP − ICP and should be >60 mm Hg.
Neurogenic HTN
HTN after stroke:
Contributing factors: cushing reflex, catecholamine and cortisol release, lesion involving brain stem or hypothalamus, nonspecific response, acute stress.
Neurogenic HTN
HTN after stroke:
BP management per American Heart/American Stroke Associations:
For stroke patients receiving thrombolytic therapy:
Before thrombolytics: lower BP if SBP > 185 mm Hg or DBP > 110 mm Hg.
After thrombolytics: lower BP if SBP > 180 mm Hg or DBP > 105 mm Hg.
Neurogenic HTN
HTN after stroke:
Nonthrombolytic therapy stroke patients:
Antihypertensive medications should be withheld unless SBP > 220 mm Hg or DBP > 120 mm Hg.
When indicated, lowering BP by ~15% is reasonable.
Neurogenic HTN
HTN after stroke:
For acute cerebral hemorrhage:
If SBP > 200 mm Hg or MAP > 150 mm Hg, consider aggressive BP reduction (goal MAP 130 mm Hg if increased ICP, otherwise MAP 110 mm Hg).
If SBP > 180 mm Hg or MAP > 130 mm Hg plus evidence of or suspicion for elevated ICP, consider monitoring of ICP and reducing BP to keep cerebral perfusion pressure > 60 mm Hg.
If SBP > 180 mm Hg or MAP > 130 mm Hg and no evidence of or suspicion of elevated ICP, consider modest reduction of BP (e.g., MAP of 110 mm Hg or target BP of 160/90 mm Hg).
Most common agents used: IV labetalol and nicardipine
Antihypertensive agent selection in acute cerebrovascular hypertension
LABETALOL
Effect on Cerebral Blood Flow: Neutral
Effect on Intracranial Pressure: Neutral
Comments: Do not affect Cerebral Autoregulation
Antihypertensive agent selection in acute cerebrovascular hypertension
ESMOLOL
Effect on Cerebral Blood Flow: Neutral
Effect on Intracranial Pressure: Neutral
Comments: Concensus guidelines suggest IV Labetalol and Nicardipine as first line agents in acute hypertensive phase of stroke. This one is Contraindicated if bradycardic. May be used in the setting of cerebral ischemia or increased ICP.
Antihypertensive agent selection in acute cerebrovascular hypertension
NICARDIPINE
Effect on Cerebral Blood Flow: Neutral
Effect on Intracranial Pressure: May Increase
Comments: Long duration of action. Variabe effect on Cerebral Autoregulation. May be used in patients with acute ICH and SAH. Nimodipine is routinely used in patients with SAH, has been shown to improve outcome, presumably from a neuroprotective effect. Nifedipine is not recommended due to potential for hypotension.
Antihypertensive agent selection in acute cerebrovascular hypertension
HYDRALAZINE
Effect on Cerebral Blood Flow: May cause both Cerebral and arterial venodilation.
Effect on Intracranial Pressure: May increase ICP. May be used in patients with small to moderate-sized ICH or SAH if no ICP.
Comments: May be used when Beta-Blockers are contraindicated (e.g., bradycardia)
Antihypertensive agent selection in acute cerebrovascular hypertension
SODIUM NITROPRUSSIDE
Effect on Cerebral Blood Flow: May cause both Cerebral and arterial venodilation.
Effect on Intracranial Pressure: May increase ICP. May be used in patients with small to moderate-sized ICH or SAH if no ICP.
Comments: There is a concern for cyanide toxicity, reduced platelet aggregation. Cerebral steal possible in pts with cerebral ischemia
Antihypertensive agent selection in acute cerebrovascular hypertension
NITROGLYCERIN
Effect on Cerebral Blood Flow: May cause both Cerebral and arterial venodilation.
Effect on Intracranial Pressure: May increase ICP. May be used in patients with small to moderate-sized ICH or SAH if no ICP.
Comments: There is a concern for cyanide toxicity, reduced platelet aggregation. Cerebral steal possible in pts with cerebral ischemia
Antihypertensive agent selection in acute cerebrovascular hypertension
ENALAPRILAT
Effect on Cerebral Blood Flow: Neutral
Effect on Intracranial Pressure: —
Comments: Long duration of action.
Neurogenic HTN
HTN after carotid endarterectomy and endovascular procedures (e.g., angioplasty, stenting
Contributing factors: carotid baroreceptor impairment after surgical manipulation, elevated catecholamine levels, activation of trigeminovascular axon reflex
Neurogenic HTN
HTN after carotid endarterectomy and endovascular procedures (e.g., angioplasty, stenting
Carotid hyperperfusion syndrome following carotid endarterectomy:
Occurs during first week after surgery
Cerebral hyperperfusion is defined as having a postoperative increase in cerebral flow of >100% compared with preoperative flow on the ipsilateral side.
Ipsilateral symptoms: pulsatile headaches, seizures, intracranial hemorrhage, cerebral edema
Contralateral symptoms: neurological deficits
Neurogenic HTN
HTN after carotid endarterectomy and endovascular procedures (e.g., angioplasty, stenting
Management:
Continuous intra- and postoperative BP monitoring
Strict BP control with SBP < 120 mm Hg
Preferred agents: intravenous labetalol or clonidine
AVOID: vasodilators such as nitroglycerin, sodium nitroprusside
Neurogenic HTN
HTN after spinal cord injury affecting the sixth or above the sixth thoracic spinal nerve (autonomic dysreflexia):
Defined as SBP > 20% from baseline with associated change in heart rate (brady- to tachycardia), and at least one of the following: headache, facial flushing, blurry vision, stuffy nose, sweating, piloerection. Flush sweaty skin above lesion levels is due to brain stem parasympathetic activation.
Neurogenic HTN
HTN after spinal cord injury affecting the sixth or above the sixth thoracic spinal nerve (autonomic dysreflexia):
Occurs in up to 70% of patients with spinal injury affecting the sixth thoracic spinal nerve or higher level
Occurs in up to 90% of pregnant women during labor and delivery. Use of epidural or spinal anesthesia may reduce risk.
Neurogenic HTN
HTN after spinal cord injury affecting the sixth or above the sixth thoracic spinal nerve (autonomic dysreflexia):
Pathophysiology:
Immediately following spinal injury: loss of supraspinal sympathetic control leading to initial period of muscle flaccidity and “spinal shock,” clinically evident as bradycardia and hypotension
Neurogenic HTN
HTN after spinal cord injury affecting the sixth or above the sixth thoracic spinal nerve (autonomic dysreflexia):
Pathophysiology:
Weeks to months following injury: extrajunctional sprouting of α-receptors, denervation hypersensitivity, impaired presynaptic uptake of norepinephrine, and derangement of spinal glutamatergic neurons
Neurogenic HTN
HTN after spinal cord injury affecting the sixth or above the sixth thoracic spinal nerve (autonomic dysreflexia):
Pathophysiology:
Noxious stimuli below neurologic level of the lesion triggers a spinal reflex arc that results in increased sympathetic tone and HTN.
Neurogenic HTN
HTN after spinal cord injury affecting the sixth or above the sixth thoracic spinal nerve (autonomic dysreflexia):
Pathophysiology:
Common noxious stimuli are from urinary overdistention and fecal impaction. Others: sympathomimetic medications and sildenafil citrate used for sperm retrieval
Neurogenic HTN
HTN after spinal cord injury affecting the sixth or above the sixth thoracic spinal nerve (autonomic dysreflexia):
Management:
Preventive measures: good bowel, bladder, and skin care
Treatment:
Position patient upright to precipitate orthostatic BP.
Remove noxious stimuli (e.g., tight clothing, devices, fecal disimpaction, bladder catheterization as applicable).
Medications: select fast-acting, short-lived agents for persistent SBP elevation > 150 mm Hg. Consider other noxious stimuli, hospitalization if no resolution.
Parenchymal kidney disease
is the most common cause of secondary HTN
Simple renal cysts and HTN
Association thought to be due to cyst compression on adjacent renal parenchyma resulting in focal ischemia and activation of the renin–angiotensin–aldosterone system.
Simple renal cysts and HTN
Association with HTN is strengthened with increased number of cysts (≥2) and increased cystic size > 1.4 to 2.0 cm.
Simple renal cysts and HTN
Management:
Cyst decompression anecdotal reports of reducing BP.
Use of RAAS blockers may be beneficial.
Proteinuria and HTN
Proteinuria with loss of plasminogen in urine, leads to the formation of plasmin by tubular urokinase-like plasminogen activator. Plasmin directly stimulates the distal tubular sodium epithelial channel ENaC and sodium reabsorption (thus HTN) via the proteolytic cleavage of ENaC extracellular α- and γ-subunits.
Proteinuria and HTN
Potential role of amiloride or triamterene as preferred agent in the management of edema and salt sensitivity in patients with proteinuria and HTN.
Renovascular HTN
Clinical manifestations:
Clinical manifestations:
Activation of renin–angiotensin–aldosterone system: seen in early phase in bilateral renal artery stenosis, but sustained in unilateral disease
Paroxysmal symptoms due to SNS activation
Loss of nocturnal BP dipping
Renovascular HTN
Clinical manifestations:
Accelerated end-organ damage: left ventricular hypertrophy, microvascular disease, renal fibrosis
Abdominal systolic–diastolic bruits, sensitivity 39% to 63%, specificity 90% to 99%
Slow progression of renovascular HTN is thought to be associated with an adaptive response to tissue hypoxia thereby minimizing structural damage.
Renovascular HTN
Diagnostic studies:
Contrast angiography: gold standard: provides both structural and functional information; Risks: procedure-related vascular injury, contrast-induced AKI (CI-AKI).
Spiral computed tomographic angiography: good images of vessels; Risks: CI-AKI
Renovascular HTN
Magnetic resonance angiography with gadolinium: good structural and functional images of vessels; Risks: nephrogenic systemic fibrosis if gadolinium is used in patients with eGFR < 30 mL/min/1.73 m2; Other disadvantages: high interobserver variability; limited sensitivity for mid and distal vascular lesions associated with FMD. A lternative MRI contrast in patients with eGFR < 30 mL/min/1.73 m2: Feraheme
Renovascular HTN
Captopril renography (renal nuclear scan): provides information on renal blood flow (uptake/appearance of isotope [MAG3] phase) and filtration (excretory phase), hence information on size and excretory capacity of kidney. Delayed excretory phase following captopril administration suggests significant role of AII in maintaining GFR. Advantage: high negative predictive value, that is negative test essentially rules out clinically significant renal artery stenosis.
Renovascular HTN
Renal arterial Doppler (ultrasonography): most effective for detection of lesions in proximal main renal artery (thus likely not great study for fibromuscular dysplasia [FMD] where lesions are typically more distal). Advantages: inexpensive, readily available; Disadvantages: no functional information.
Renovascular HTN
Renal vein renin measurements: used to predict BP response to renal revascularization: a ratio > 1.5 (stenotic kidney):1.0 (nonstenotic kidney), predicts good BP response in > 90% of patients. However, nonlateralization may also have good response in ~50%.
Renovascular HTN
HTN occurs in the presence of a critical stenosis (e.g., >70% to 80%); Stenotic lesions < 60 % typically do not lead to clinically significant reduction in renal arterial flow to induce systemic activation of vasopressors to cause HTN.
Renovascular HTN
Unilateral stenosis
Unilateral stenosis (one-clip, two-kidney HTN model): one stenosed (experimental clipping of one renal artery) + one normal kidney
Renovascular HTN
Unilateral stenosis
Stenosed “clipped” kidney has reduced renal perfusion pressure → stimulation of neuronal NO synthase and cyclooxygenase 2 in macula densa → release of renin from juxtaglomerular apparatus → activation of RAAS, (i.e., increased angiotensin II (AII) and aldosterone) → systemic BP increases to restore renal perfusion pressure, increased sodium retention.
Renovascular HTN
Unilateral stenosis
Normal contralateral kidney undergoes pressure natriuresis to restore sodium and volume balance, thus counteracts the stenosed kidney’s attempt to improve its own perfusion → continued RAAS activation by stenosed kidney → angiotensin II-dependent HTN; aldosterone-induced renal K+ and H+ secretion in the contralateral kidney, hence hypokalemia and metabolic alkalosis.
Renovascular HTN
Unilateral stenosis
Long-term HTN also attributes to activation of SNS, impairment of NO generation, endothelin release, and hypertensive microvascular injury in the normal contralateral kidney.
Renovascular HTN
Unilateral stenosis
Clinical implication of RAAS activation in unilateral renal artery stenosis:
RAAS inhibition: reduces BP, enhances lateralization of diagnostic testing, reduces GFR in stenotic kidney.
Renovascular HTN
Unilateral stenosis
Common clinical conditions equivalent to one-clip, two-kidney HTN (unilateral stenosis):
Unilateral FMD
Unilateral renal atherosclerotic disease
Unilateral renal artery aneurysm, dissection, embolism, thrombosis, traumatic occlusion, vasospasm
Unilateral renal arteriovenous fistula
Aortic dissection affecting renal ostium
“Page” kidney (perinephric compression, i.e., large capsular hematoma, perinephric fibrosis)
Extrinsic compression (e.g., tumor) on one renal artery
Aortic stent occluding origin of renal artery
Renovascular HTN
Bilateral renal artery stenosis
Bilateral renal artery stenosis (one-clip, one-kidney HTN) or (two-clip, two-kidney HTN model):
Entire kidney mass is exposed to reduced pressures from site of stenosis.
There is no “normal nonstenotic kidney.”
Renovascular HTN
Bilateral renal artery stenosis
Initial activation of SNS, RAAS leads to sodium and water retention. Since there is no “normal kidney” to excrete the sodium and volume retained, volume overload eventually develops which leads to inhibition of RAAS.
HTN is not RAAS-dependent, but volume-dependent.
Renovascular HTN
Bilateral renal artery stenosis
Clinical implications:
Patients can be salt-sensitive → easy development of “flash pulmonary edema,” following a high dietary salt load
Diuretics may be effective in lowering BP.
Renovascular HTN
Bilateral renal artery stenosis
Use of RAAS inhibition:
Only lowers BP after euvolemia has been achieved (i.e., RAAS activation only occurs after negative feedback from volume expansion has been removed).
May significantly lower GFR and cause kidney failure.
Renovascular HTN
Bilateral renal artery stenosis
Since RAAS is inhibited due to volume expansion, patients with bilateral renal stenosis or equivalent (see conditions below), typically do not develop hypokalemia and metabolic alkalosis. In fact, the opposite, hyperkalemia and metabolic acidosis, may be present.
Renovascular HTN
Bilateral renal artery stenosis
Clinical conditions equivalent to one-clip, one-kidney HTN model:
Bilateral arterial stenosis or stenosis of solitary kidney
Significant coarctation of aorta or any flow-limiting lesions (e.g., atheroembolic disease, aneurysms, extrinsic mass compression) of suprarenal abdominal aorta
Renal artery vasculitis
Congenital vascular anomalies
Renovascular HTN
Fibromuscular dysplasia
Nonatherosclerotic arteriopathy affecting large and medium-sized arteries, typically mid to distal renal artery beyond the first 2 cm from aorta.
Renovascular HTN
Fibromuscular dysplasia
Epidemiology:
Prevalence of clinically significant renovascular FMD is 4/1,000, cerebrovascular involvement 1/1,000 (may present with carotid flow abnormalities, stroke); may be up to 3% to 6% in normotensive individual.
Familial presentation in 10%, thought to be autosomal dominant.
Renovascular HTN
Fibromuscular dysplasia
Clinical manifestations:
Commonly seen in young (15 to 50 years old) females with early-onset HTN.
Renovascular HTN
Fibromuscular dysplasia
Associated conditions: Marfan and Ehlers–Danlos syndromes, tuberous sclerosis, cystic medial necrosis, coarctation of aorta, Alport syndrome, renal agenesis or dysgenesis, α1-antitrypsin deficiency, medullary sponge kidney, PHEO, infantile myofibromatosis, ergotamine preparation, methysergide, cigarette smoking, collagen III glomerulopathy, atherosclerotic renovascular disease.
Renovascular HTN
Fibromuscular dysplasia
Lesions are characterized by disruptions of vascular wall components with abnormal collagen deposition in bands, ± disruption of elastic membrane.
Renovascular HTN
Fibromuscular dysplasia
FMD typically occurs in the middle or distal portions of renal artery or branch vessels and may present with aneurysms, occlusion, dissection, arteriovenous fistulas, or thrombosis.
Renovascular HTN
Fibromuscular dysplasia
FMD types:
Medial (85% to 100%) > intimal (<10%) > adventitial (<1%)
Media and perimedial fibroplasia classically have “string of beads” appearance. Medial hyperplasia may only present as smooth stenosis of artery.
Initimal and adventitial fibroplasia present as smooth stenotic segments or diffuse attenuation of vessel lumen.
Renovascular HTN
Fibromuscular dysplasia
Natural history:
Progression of disease slows down with age.
Rarely causes ischemic kidney failure, but associated thrombosis or dissection of affected renal vessel may lead to renal infarction.
Renovascular HTN
Fibromuscular dysplasia
Management of FMD + HTN: percutaneous transluminal renal angioplasty (PTRA) versus surgical revascularization:
PTRA:
Higher chance of BP lowering following PTRA in younger patients or those with lower pre-PTRA BP, shorter duration of HTN, and positive captopril test.
If restenosis occurs, repeat PTRA may be performed as needed.
Renovascular HTN
Atherosclerotic renal artery stenosis
Surgical revascularization:
If aneurysmal dilations > 1.5 cm in diameter
Covered stent grafts may also be used in renal artery aneurysms.
Renovascular HTN
Atherosclerotic renal artery stenosis
Atherosclerotic plaque formed from the first 1 to 2 cm of renal artery or from aorta extending into renal ostium (more proximal involvement compared with FMD).
Renovascular HTN
Atherosclerotic renal artery stenosis
Epidemiology:
Seen in 10% to 40% of patients undergoing coronary angiography
Similar prevalence in African Americans and Caucasians in one study cohort involving 870 patients > 65 years old
Autopsy series: prevalence of 4% to 20%; 25% to 30% in those >60 years old, 40% to 60% in those >75 years old
Estimated to contribute to decline in kidney function in 15% to 22% of patients with end-stage kidney disease
Renovascular HTN
Atherosclerotic renal artery stenosis
Clues to presence of ischemic renal disease due to atherosclerosis:
Asymmetry of kidney size
Recent kidney function deterioration
AKI following use of ACEI or ARB due to acute reduction in intraglomerular filtration pressure (due to loss of AII-dependent efferent vasoconstriction to maintain intraglomerular filtration pressure)
Renovascular HTN
Atherosclerotic renal artery stenosis
Clues to presence of ischemic renal disease due to atherosclerosis cont’d:
AKI following acute systemic BP reduction with any other hypertensive agents
Presence of flash pulmonary edema, more common in bilateral compared with unilateral stenosis
Consider renal stenosis in patients with known or at increased risks for atherosclerotic disease and unexplained kidney injury
Renovascular HTN
Atherosclerotic renal artery stenosis
NOTE: Most patients with renovascular HTN do not develop AKI with ACEI/ARB because
In unilateral renal artery stenosis, the normal contralateral kidney may still have adequate function to mask any reduced filtration pressure in the affected kidney by ACEI/ARB.
Renovascular HTN
Atherosclerotic renal artery stenosis
Most patients with renovascular HTN do not develop AKI with ACEI/ARB because:
In bilateral RAS, AII is suppressed due to sodium retention. Hence, ACEI/ARB does not directly reduce glomerular filtration pressure.
Those with AKI with ACEI/ARB tend to have other additional source(s) contributing to reduced renal perfusion, for example, volume depletion, cardiac decompensation.
Renovascular HTN
Atherosclerotic renal artery stenosis
Management of atherosclerotic renal artery stenosis:
Medical therapy:
RAAS inhibition as safely tolerated (SCr increases less than 20% to 30% from baseline is acceptable).
Use of other agents as needed to control BP: CCB, diuretics, etc.
Daily aspirin
Statin as tolerated particularly if hyperlipidemia and/or CKD and >50 years old
Smoking cessation if applicable
Renovascular HTN
Atherosclerotic renal artery stenosis
Invasive therapy:
No evidence of renal or cardiovascular benefits with invasive therapy if stable kidney function and BP
Renovascular HTN
Atherosclerotic renal artery stenosis
Cardiovascular outcomes of renal atherosclerotic lesions (CORAL) trial: comparative trial for renal artery stenting versus best medical therapy involving 947 patients with uncontrolled HTN and atherosclerotic renal artery stenosis, BP > 155 mm Hg while on >2 BP medications
Average SBP was 2.3 mm Hg lower in the stent group throughout the trial (median follow-up 3.6 years).
No difference in incidence of cardiovascular or renal death, myocardial infarction, hospitalization for congestive heart failure, stroke, progressive CKD, or need for renal replacement therapy
Renovascular HTN
Atherosclerotic renal artery stenosis
Meta-analysis of five RCT involving 1,159 patients comparing percutaneous renal artery revascularization (with or without stenting) versus medical therapy on future occurrence of nonfatal myocardial infarction: Renal revascularization did not affect risk of nonfatal MI.
Renovascular HTN
Atherosclerotic renal artery stenosis
However, invasive therapy may be considered in younger viable (low comorbidities) patients with:
Rapidly progressive disease (i.e., AKI with RAAS inhibition or achievement of BP control)
Failure to appropriate medical therapy
Unexplained acute heart failure, “flash pulmonary edema”
Renovascular HTN
Atherosclerotic renal artery stenosis
Renal artery stenting versus surgical revascularization:
Surgical revascularization is reserved for patients with technically challenging vascular lesions or associated aortic disease.
Renovascular HTN
Atherosclerotic renal artery stenosis
Intervention being considered: concurrent renal revascularization and use of anti-inflammatory therapies or agents that can alter mitochondrial function to reduce the generation of reactive oxygen species and/or ATP depletion during reperfusion.
Renovascular HTN
Atherosclerotic renal artery stenosis
Contraindications to invasive therapy: advanced kidney disease (e.g. SCr > 3 to 4 mg/dL, kidney length < 8 cm), poor surgical candidate, or low life-expectancy.
Renovascular HTN
Atherosclerotic renal artery stenosis
Atherosclerotic renal artery stenosis typically affects the proximal 1 to 2 cm of the renal artery from aorta, FMD involves the distal 1/2 to 1/3 of the renal artery, and polyarteritis nodosa involves multiple aneurysmal dilatations within the kidneys
Endocrine causes of HTN
Endocrine causes of HTN: from pituitary → thyroid → parathyroid → adrenals
Endocrine causes of HTN
Pituitary: acromegaly
Pituitary tumor producing excessive circulating growth hormone (GH). Other GH-producing tumors: pancreatic, hypothalamic, breast, bronchial malignancies
More common in women and older patients
Endocrine causes of HTN
acromegaly
Pathogenesis:
Sodium retention with inappropriately normal to only minimally low renin and aldosterone levels and normal atrial natriuretic peptide.
Others: GH–induced vascular hypertrophy with decreased vascular compliance, increased SNS, associated hyperthyroidism.
Endocrine causes of HTN
acromegaly
Clinical manifestations: skull, hands, feet enlargement, excessive sweating, carpal tunnel syndrome, sexual dysfunction, diabetes mellitus, thyromegaly, thyrotoxicosis, headaches, visual field defects
Endocrine causes of HTN
acromegaly
Diagnosis:
Elevated plasma GH, especially in response to an oral glucose tolerance test
Others: plasma insulin-like growth factor I, lateral skull X-ray (thickened skull vault, enlarged frontal sinuses), MRI of pituitary fossa
Endocrine causes of HTN
acromegaly
Management:
Tumor-specific:
Transphenoidal adenomectomy is treatment of choice if no contraindication
Tumor radiation
Dopaminergic agents: bromocriptine and cabergoline, octreotide
HTN: diuretics as primary agent, addition of others as needed
Endocrine causes of HTN
Pituitary: Cushing syndrome
Pituitary: Cushing syndrome (pituitary adenoma producing excess adrenocorticotropic hormone (ACTH); other sources of excess ACTH secretion: adrenal tumors, bronchogenic carcinoma.
Endocrine causes of HTN
Pituitary: Cushing syndrome
Pathogenesis:
Increased cardiac output and peripheral vascular resistance
Concurrent production of mineralocorticoids
Cortisol inhibition of NO
Increased sensitivity to catecholamines, AII, and β-adrenergic stimulation
Blunted response to atrial natriuretic peptide
Endocrine causes of HTN
Pituitary: Cushing syndrome
Diagnosis:
24-hour urine free cortisol
Dexamethasone suppression test
Low dose (1 mg) at midnight
High dose (partially suppresses ACTH from pituitary tumors but not with ectopic ACTH)
Corticotropin-releasing hormone test.
Imaging studies: CT or MRI of pituitary, adrenals, thorax/abdomen/pelvis
Simultaneous bilateral inferior petrosal sinus sampling for ACTH measurements
Endocrine causes of HTN
Pituitary: Cushing syndrome
Management:
Cushing disease: resection of pituitary adenoma
Cushing syndrome:
Unilateral adrenalectomy if adrenal adenoma
Adrenal carcinoma is associated with poor survival
Antihypertensive medications: consider potassium-sparing diuretics
Endocrine causes of HTN
Thyroid
Hypothyroidism-associated HTN:
Sodium retention
Increased peripheral vascular resistance; 30% of patients have diastolic HTN
Underdamping of swings in SNS activity
Endocrine causes of HTN
Thyroid
Hyperthyroidism-induced HTN:
Pathogenesis:
Increased cardiac output, heart rate, myocardium contractility. (Peripheral vascular resistance tends to be reduced.)
Expanded blood volume
Increased RAS activity but not SNS
Classic presentation: high pulse pressure HTN, ISH
Endocrine causes of HTN
Parathyroid
Parathyroid: Hyperparathyroidism-induced HTN is thought to be due to increased peripheral vascular resistance, presumably due to hypercalcemia
Endocrine causes of HTN
Adrenals
PHEO
PHEO:
90% arise from adrenals, 10% extra-adrenal (paraganglioma, PGL).
Most are benign; 10% metastasize to regional lymph nodes
Common hormones produced: norepinephrine, epinephrine, dopamine
Malignant disease or large tumor mass may have very high dopamine levels.
Endocrine causes of HTN
Adrenals
PHEO
Sporadic disease:
Often focal, unilateral involvement
Up to 14% have somatic mutations
Endocrine causes of HTN
Adrenals
PHEO
Familial disease:
Typically multifocal, bilateral, extra-adrenal disease, age < 50 years old, may be associated with germ line mutations (most are autosomal dominant)
Endocrine causes of HTN
Adrenals
PHEO
RET gene: multiple endocrine neoplasia type 2 (MEN 2):
MEN 2a: medullary thyroid carcinoma, hyperparathyroidism, cutaneous lichen amyloid
MEN 2b: medullary thyroid carcinoma, multiple neuromas, marfanoid habitus
Mostly epinephrine secretion
Paroxysmal symptoms
Endocrine causes of HTN
Adrenals
PHEO
von Hippel–Lindau gene: von Hippel–Lindau syndrome
Syndrome with retinal and CNS hemangioblastomas, renal cell carcinoma, pancreatic, endolymphatic sac, epididymal tumors
Predominant noradrenergic secretory pattern
Can present primarily with asymptomatic HTN due to downregulation of α-adrenoceptors
Endocrine causes of HTN
Adrenals
PHEO
Neurofibromatosis type 1 gene:
Neurofibromatosis type 1 (a.k.a. von Recklinghausen disease): neurofibromas, café-au-lait spots
Mostly epinephrine secretion
Paroxysmal symptoms
Endocrine causes of HTN
Adrenals
PHEO
Genes encoding the B and D subunits of mitochondrial succinate dehydrogenase (SDHB, SDHB): familial PGLs (head and neck) and PHEOs; no secretory activity; no symptoms related to catecholamines, but space-occupying effect
Endocrine causes of HTN
Adrenals
PHEO
Hypoxia induced factor -2α (HIF-2α), somatic mutation: multiple duodenal somatostatinomas, polycythemia
Endocrine causes of HTN
Adrenals
PHEO
Common clinical manifestations of PHEOs:
Classic: paroxysmal HTN, headaches, diaphoresis, palpitations, anxiety, chest/abdominal pain, nausea/vomiting, dyspnea, pallor
Severe HTN with trauma, delivery, or sudden onset
Subclinical
Endocrine causes of HTN
Adrenals
PHEO
Physical examination: 2/3 labile HTN, 1/3 persistent HTN; reciprocal changes in BP and heart rate may occur with predominantly norepinephrine secreting tumors; postural hypotension; low-grade fevers, tachycardia, skin may be cool, mottled appearing.
Endocrine causes of HTN
Adrenals
PHEO
Diagnosis:
Plasma free metanephrines and normetanephrines greater than four- to fivefold of normal → positive test. High sensitivity
If positive plasma study, obtain urine metanephrines and normetanephrines. High sensitivity and high specificity
Endocrine causes of HTN
Adrenals
PHEO
Glucagon stimulation:
Indicated if equivocal plasma study
Administer 2 mg glucagon IV bolus. Positive test: greater than threefold increase in baseline levels of catecholamines within 1 to 2 minutes
Endocrine causes of HTN
Adrenals
PHEO
Clonidine suppression test:
Indicated if equivocal plasma study
Administer 0.3 mg clonidine. Positive test: failure to reduce plasma catecholamines to >50% from baseline
Endocrine causes of HTN
Adrenals
PHEO
Imaging studies:
MRI or CT: abdomen/pelvis if no family history; neck to pelvis if family history or suspicion for genetic disease
If negative, consider metaiodobenzylguanidine (MIBG) scan, indium In111-labeled octreotide scan, plasma-free metanephrines coupled with vena caval sampling, or positron emission tomography (PET) scan.
MIBG has high sensitivity (83% to 100%) and specificity (95% to 100%) in sporadic PHEO.
MIBG has been suggested to be inferior to PET in the evaluation of PHEO/PGL in familial and metastatic disease.
Endocrine causes of HTN
Adrenals
PHEO
Management:
BP control:
α-adrenergic blockers (phenoxybenzamine [usually not well tolerated due to orthostatic hypotension]), doxazosin, terazosin
CCB
Add β-blockers if tachycardia or arrhythmias after full α-adrenergic inhibition. Consider agents with both α- and β-inhibition (e.g., carvedilol, labetalol).
Endocrine causes of HTN
Adrenals
PHEO
Surgical removal:
Preoperative preparation: BP control weeks prior to surgery
Intraoperative BP management options: phentolamine, sodium nitroprusside, and magnesium sulfate
Postoperative management: monitor for hypoglycemia and hypotension
Endocrine causes of HTN
Adrenals
PHEO
Long-term management:
BP control if persistent HTN
If malignant PHEO, use both α- and β-adrenergic blockers as needed for symptoms, radiation therapy for bone metastatic disease, and chemotherapy (cyclophosphamide, vincristine, and dacarbazine). Median survival ~5 years.
Endocrine causes of HTN
Adrenals
PHEO
Follow-up (life-long):
Adrenal PHEO < 5 cm and no suspected hereditary syndrome: biochemical screening at 1 year, then every other year thereafter
PHEO > 5 cm or hereditary syndromes, multifocal PGL: biochemical evaluation after 6 months following surgery, then yearly thereafter with periodic imaging study
For patients with biochemically silent disease: periodic imaging study
Endocrine causes of HTN
Adrenals
Adrenal incidentaloma/hyperplasia/adenoma/carcinoma:
Screening aldosterone/renin ratio (ARR):
ARR > 30 and aldosterone levels > 20 ng/dL
Sensitivity 90%, specificity 91%, positive predictive value 69%
Endocrine causes of HTN
Adrenals
Factors affecting ratio:
False negative ARR due to increased renin: dietary salt restriction, malignant or renovascular HTN, diuretics (including spironolactone, eplerenone), dihydropyridine calcium channel blockers, ACEI/ARB, selective serotonin reuptake inhibitors
False positive ARR due to suppressed renin: β-blockers, α-methyldopa, clonidine, NSAIDS. False positives may also occur in patients with renal dysfunction and older age.
Optimization of ARR measurements: normalize serum potassium levels prior to measuring ARR.
Avoid use of medications that can affect ARR if clinically safe.
Endocrine causes of HTN
Adrenals
Prevalence of high ARR is 16% to 20% in patients with HTN.
Prevalence of confirmed primary aldosteronism is 4.5% to 9.5%
Endocrine causes of HTN
Adrenals
Confirmatory testing following positive ARR:
IV salt loading: 2 L NS over 4 hours (recumbent) → (+) if plasma aldosterone > 10 ng/dL (<6 ng/dL in normal subjects)
Oral salt loading: 2 g NaCl tablets t.i.d. × 3 days and potassium supplement → (+) if 24-hour urine aldosterone > 14 g/24-hour (UNa should also be >200 mEq to assess compliance with Na load)
Endocrine causes of HTN
Adrenals
Fludrocortisone-suppression test: fludrocortisone acetate 0.1 mg q6h with high salt diet (3 mmol/kg/d) × 4 days and potassium supplement → (+) if plasma aldosterone > 5 ng/dL and PRA < 1.0 ng/mL/h.
Endocrine causes of HTN
Adrenals
Imaging studies:
CT/MRI imaging with adrenal cuts: Adrenal carcinoma is more likely with increasing size; 2% of masses up to 4 cm, 6% of masses from 4 to 6 cm, 25% of masses > 6 cm are malignant.
Endocrine causes of HTN
Adrenals
Adrenal venous sampling (AVS) for lateralization of aldosterone levels should be considered in good candidates for adrenalectomy (young, non-obese patients with limited end-organ damage and short duration of HTN and hypokalemia) to confirm the correct side of the hyperfunctioning gland prior to removal. NOTE: AVS for lateralization of aldosteronism should be measured along with a selectivity index (adrenal vein to inferior vena cava cortisol ratio > 5:1) to indicate successful adrenal vein catheterization. A low selectivity index may indicate erroneous blood sampling from a vein other than the adrenal vein, which may give a falsely low aldosterone level, thus falsely negative lateralization test.
Endocrine causes of HTN
Adrenals
Long-term effects of hyperaldosteronism:
German registry compared mortality rates of 300 patients with primary aldosteronism (either surgically or medically managed) to 600 hypertensive patients and 600 normotensive controls over a 16-year follow-up revealed:
No difference in mortality among the three groups.
Cardiovascular deaths were higher for patients with primary hyperaldosteronism (50%) compared to those with essential (38%) or normotensive controls (35%).
Unadjusted analyses suggested better outcomes with adrenalectomy versus medical therapy, but not on multivariate analyses, thought to be due to healthier patient selection for adrenalectomy.
Endocrine causes of HTN
Adrenals
Management:
Medical intervention:
MRA: aldosterone antognists spironolactone or eplerenone
Aldosterone synthase activity blocker LC1699 versus eplerenone: eplerenone more effective in reducing BP and improving hypokalemia. LC1699, however, reduces, whereas eplerenone increases aldosterone levels. Long-term effects of elevated aldosterone levels are not known.
Endocrine causes of HTN
Adrenals
Surgical versus medical intervention:
Better cardiovascular mortality with surgical intervention than MRA is questioned by patient selection for surgery versus MRA.
Nonetheless, adrenalectomy may still be considered in younger patients with short disease duration and minimal or no evidence of end-organ damage.
Acute intermittent porphyria:
Rare autosomal dominant disorder with deficiency of porphobilinogen deaminase affecting heme production and associated with increased porphobilinogens
Acute intermittent porphyria:
Clinical Manifestations
Clinical manifestations:
Intermittent severe colicky abdominal pain, constipation, dystonic bladder with urinary retention/incontinence, dark urine, autonomic dysfunction with increased circulating catecholamine levels resulting in HTN, tachycardia, sweating, restless and tremors, peripheral neuropathy, proximal muscle weakness, neuropsychiatric disorders, SIADH with hyponatremia. Skin rash is not a typical manifestation compared to other forms of porphyria.
Attacks may be brought on by infections, hormonal or dietary changes, drugs.
Acute intermittent porphyria:
Diagnosis and Management
Diagnosis: elevated urinary porphobilinogens (urine spot test)
Management:
Mild attacks: high-dose oral glucose (400 g/d) or intravenous dextrose 10% solution
Severe attacks, severe neurologic symptoms: hematin (hemin) 3 to 4 mg/kg/d for 4 days
Pain control with narcotics as needed
Laxatives, softeners for constipation, particularly if narcotics are used
Gabapentin for seizures
