Hipertensi Sekunder

01Pathophysiology

Secondary hypertension means blood pressure elevation driven by a discrete, identifiable mechanism rather than the multifactorial process behind essential (primary) hypertension. Understanding why each cause raises blood pressure is the key to answering vignette questions correctly, because the test expects you to connect the mechanism to the presentation and to the appropriate workup.

Renovascular hypertension is driven by reduced perfusion to one or both kidneys. When the renal artery is narrowed (by atherosclerosis in older patients or fibromuscular dysplasia in young women), the juxtaglomerular apparatus senses decreased perfusion pressure and responds by increasing renin secretion. Renin converts angiotensinogen to angiotensin I, which is then converted to angiotensin II, a potent vasoconstrictor that also stimulates aldosterone release. The result is sodium and water retention plus systemic vasoconstriction. This is why these patients develop hypertension that is often refractory to standard therapy and why ACE inhibitors can precipitate acute kidney injury in bilateral renal artery stenosis: you are removing the angiotensin II-mediated efferent arteriolar tone that was maintaining glomerular filtration in an already underperfused kidney.

Primary aldosteronism (Conn syndrome when caused by an adrenal adenoma, or bilateral adrenal hyperplasia) produces excess aldosterone independent of the renin-angiotensin system. Aldosterone acts on the principal cells of the collecting duct, upregulating ENaC (epithelial sodium channels) and ROMK potassium channels. The net effect is aggressive sodium reabsorption (expanding plasma volume and raising BP) and potassium excretion (causing hypokalemia). Because aldosterone production is autonomous, renin is suppressed by the volume expansion, yielding the hallmark elevated aldosterone-to-renin ratio.

Pheochromocytoma arises from chromaffin cells of the adrenal medulla (or extra-adrenal paraganglia). These tumors secrete catecholamines (epinephrine and norepinephrine) in an episodic or sustained pattern. Catecholamine surges activate alpha-1 receptors (vasoconstriction, elevated BP) and beta-1 receptors (tachycardia, increased contractility). This explains the classic triad of episodic headache, diaphoresis, and palpitations accompanied by severe hypertensive spikes. Sustained catecholamine excess can cause a catecholamine cardiomyopathy.

Cushing syndrome involves chronic glucocorticoid excess. Cortisol at high concentrations can activate the mineralocorticoid receptor (cortisol and aldosterone share structural similarity; normally 11-beta-hydroxysteroid dehydrogenase type 2 inactivates cortisol in the kidney, but this enzyme is overwhelmed when cortisol is excessive). This causes sodium retention and volume expansion. Cortisol also potentiates the vasoconstrictive effects of catecholamines and angiotensin II. The patient develops hypertension alongside the recognizable cushingoid phenotype.

Coarctation of the aorta is a structural narrowing, usually just distal to the left subclavian artery at the ligamentum arteriosum. The narrowing creates a mechanical obstruction: the upper body receives blood at high pressure (upper extremity hypertension) while the lower body is relatively underperfused (weak femoral pulses, lower BP in legs). The kidneys, receiving reduced perfusion pressure, activate the RAAS, perpetuating hypertension. This is why coarctation should be suspected in any young patient with upper extremity hypertension and a radio-femoral pulse delay.

Obstructive sleep apnea (OSA) raises blood pressure through repeated nocturnal hypoxemia and hypercapnia, which trigger sympathetic nervous system activation, oxidative stress, and endothelial dysfunction. The intermittent surges in sympathetic tone persist into the daytime, producing sustained hypertension that is classically resistant to pharmacologic therapy and frequently has a non-dipping pattern on ambulatory BP monitoring (meaning BP does not fall appropriately during sleep).

Renal parenchymal disease (chronic glomerulonephritis, diabetic nephropathy, polycystic kidney disease) causes hypertension through impaired sodium excretion and volume expansion, as well as activation of the RAAS due to intrarenal ischemia from damaged nephrons.

Thyroid disorders contribute through distinct pathways. Hyperthyroidism increases cardiac output and heart rate (predominantly systolic hypertension with a wide pulse pressure). Hypothyroidism increases systemic vascular resistance (predominantly diastolic hypertension).

02Classification and Clinical Manifestation

03Diagnostic Workup

The approach to diagnosing secondary hypertension is not to screen every hypertensive patient for every cause. The exam tests whether you can identify clinical clues in the vignette that should prompt further workup.

When to suspect secondary hypertension:
The test will present a patient with one or more red flags: onset before age 30 or after age 55, hypertension that is resistant despite three appropriate agents (one being a diuretic), abrupt onset or sudden worsening, unprovoked hypokalemia, a relevant physical finding (bruit, pulse delay, cushingoid habitus), or end-organ damage disproportionate to the duration of known hypertension.

Renovascular disease workup: When the vignette describes an older smoker with resistant HTN plus an abdominal bruit or acute kidney injury after starting an ACE inhibitor, the next step is imaging of the renal arteries. Duplex ultrasonography is noninvasive but operator-dependent. CTA or MRA are commonly used as the initial imaging study. If intervention is planned, conventional catheter angiography is definitive. A critically tested point: in a young woman with severe hypertension and no other risk factors, think fibromuscular dysplasia and image the renal arteries.

Primary aldosteronism workup: This is a two-step process that the exam loves to test. Step one is screening with the aldosterone-to-renin ratio (ARR). An ARR > 30 with an absolute aldosterone > 15 ng/dL is considered positive. Step two is confirmatory testing (oral salt loading or IV saline infusion; failure to suppress aldosterone confirms autonomous production). Step three is subtype differentiation: a CT of the adrenals may show an adenoma, but CT alone is unreliable for distinguishing adenoma from hyperplasia, so adrenal vein sampling is the gold standard for determining lateralization before recommending surgery.

Pheochromocytoma workup: The best initial biochemical test is plasma-free metanephrines due to their high sensitivity (approaching 99%). A 24-hour urine collection for metanephrines and catecholamines is an acceptable alternative. Once biochemical evidence is confirmed, CT or MRI of the abdomen is used for localization. MRI is preferred if there is concern for paraganglioma or metastatic disease. An MIBG (iodine-131-metaiodobenzylguanidine) scan is reserved for cases where imaging is equivocal or extra-adrenal/metastatic disease is suspected. A tested pearl: never biopsy a suspected pheochromocytoma without alpha-blockade, as manipulation can provoke a catecholamine crisis.

Cushing syndrome workup: Three acceptable screening tests exist. The exam expects you to know that at least two positive screening tests are typically needed before proceeding. Once hypercortisolism is confirmed, measure ACTH to determine whether the source is ACTH-dependent (pituitary adenoma, ectopic ACTH) or ACTH-independent (adrenal tumor, exogenous steroids). A high-dose dexamethasone suppression test helps distinguish pituitary from ectopic ACTH sources: pituitary adenomas typically suppress with high-dose dexamethasone, while ectopic sources do not.

04Management and Treatment

The overarching principle tested is: identify and treat the cause, not just the blood pressure.

For pheochromocytoma, management sequencing is one of the most commonly tested points in all of secondary hypertension. The rule is alpha-blockade before beta-blockade. Phenoxybenzamine (a non-selective, irreversible alpha-blocker) is started at 10 mg twice daily and titrated upward over 10 to 14 days until the patient has orthostatic hypotension (a sign of adequate blockade). Only after adequate alpha-blockade (typically 2-3 days before surgery) is a beta-blocker (propranolol or atenolol) added for reflex tachycardia. If you give a beta-blocker first, you eliminate the beta-2 mediated vasodilation in skeletal muscle, leaving alpha-mediated vasoconstriction completely unopposed, which can precipitate a life-threatening hypertensive crisis. Volume expansion with a liberal salt diet and IV normal saline is also performed preoperatively to counteract the chronic volume-contracted state caused by sustained catecholamine-mediated vasoconstriction.

For primary aldosteronism, the management depends entirely on subtype. A unilateral aldosterone-producing adenoma is treated with laparoscopic adrenalectomy, which is curative in most patients. Bilateral adrenal hyperplasia is treated medically because removing both adrenals would create permanent adrenal insufficiency. Spironolactone at 25 to 100 mg daily is the drug of choice. Eplerenone (50 mg once or twice daily) is the alternative when patients develop anti-androgenic side effects from spironolactone (gynecomastia, erectile dysfunction, menstrual irregularities), since eplerenone is selective for the mineralocorticoid receptor.

For renovascular hypertension, the management paradigm has shifted. The CORAL trial demonstrated that for atherosclerotic renal artery stenosis, renal artery stenting added no benefit over optimal medical therapy (ACE inhibitor/ARB, statin, antiplatelet agent) for most patients. Stenting is now reserved for patients with recurrent flash pulmonary edema, refractory hypertension despite maximal medical therapy, or progressive decline in renal function. In contrast, fibromuscular dysplasia responds very well to percutaneous transluminal angioplasty without stenting, with high cure or significant improvement rates.

For Cushing syndrome, always rule out exogenous glucocorticoid use first, as this is the most common cause. If endogenous, the treatment is surgical: transsphenoidal resection for pituitary adenomas (Cushing disease), adrenalectomy for adrenal tumors. Post-surgical adrenal insufficiency is expected because the contralateral adrenal gland is atrophied from chronic suppression; patients require glucocorticoid replacement tapering over months.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The single most common way students get secondary hypertension questions wrong is by failing to recognize the clinical clue that triggers a secondary workup in the first place. The vignette will embed one or two red flags (a young patient, unexplained hypokalemia, episodic spells, an abdominal bruit, a creatinine bump after starting an ACE inhibitor) into an otherwise routine-looking hypertension stem. Students who skim past these details will default to "essential hypertension" and choose a generic antihypertensive, missing the diagnosis entirely. The core competency being tested is pattern recognition: can you match the clinical clue to the correct secondary cause and then select the appropriate next diagnostic step?

The second major trap involves management sequencing errors in pheochromocytoma. Every year, students select a beta-blocker as the initial agent for a patient with paroxysmal hypertension and the classic triad. The answer is always alpha-blockade first. If a vignette describes a patient already on an alpha-blocker who still has tachycardia, then and only then is a beta-blocker the correct next step.

A third common error is in primary aldosteronism workup. Students often jump from a positive screening ARR directly to CT imaging and then to surgery. The exam expects you to know that a confirmatory test (salt loading) is needed after screening, and that a CT alone cannot reliably distinguish an adenoma from hyperplasia. Adrenal vein sampling is required to lateralize the source before recommending unilateral adrenalectomy.

For renovascular hypertension, the trap is assuming that stenting is always the answer for renal artery stenosis. Post-CORAL trial, the correct answer for atherosclerotic RAS is usually optimized medical therapy unless there is a compelling indication for revascularization (flash pulmonary edema, refractory HTN, progressive renal decline). For FMD, however, angioplasty remains the treatment of choice.

Finally, do not forget the vignette where a patient's creatinine rises significantly after starting an ACE inhibitor or ARB. This is a classic signal for bilateral renal artery stenosis (or stenosis in a solitary functioning kidney). The next step is to stop the ACE inhibitor/ARB and image the renal arteries, not to simply switch to another antihypertensive class.