Secondary Hypertension: Diagnostic Approach and Management
Learning Objectives
By the end of this handout, students will be able to:
- Identify clinical features that suggest secondary hypertension and determine when to pursue testing
- Understand the pathophysiology of primary aldosteronism, renovascular disease, pheochromocytoma, Cushing syndrome, and other secondary causes
- Apply diagnostic algorithms for each major cause, including screening tests and confirmatory studies
- Interpret tests appropriately: Aldosterone-renin ratio, renin measurements, imaging, suppression testing
- Manage refractory hypertension and identify candidates for intervention (revascularization, adrenalectomy, etc.)
- Recognize syndromic presentations and order appropriate testing in context
I. Overview: When to Suspect Secondary Hypertension
Epidemiology
- Essential (primary) hypertension: 90–95% of hypertension cases
- Secondary hypertension: 5–10% overall; up to 30% in resistant/refractory cases
- Most common secondary causes: CKD, primary aldosteronism, renovascular disease, pheochromocytoma, Cushing syndrome
Clinical Clues Suggesting Secondary Hypertension
| Finding | Consider |
|---|---|
| Age <30 or >50 with sudden HTN onset | Renovascular disease, pheochromocytoma, Cushing syndrome |
| Resistant HTN (uncontrolled on ≥3 agents) | Primary aldosteronism, pheochromocytoma, Cushing, OSA, CKD |
| Acute HTN crisis with symptoms | Pheochromocytoma, Cushing, renovascular disease, preeclampsia |
| Hypokalemia (unprovoked or on diuretics) | Primary aldosteronism, Cushing, hypomagnesemia |
| Flash pulmonary edema | Renovascular disease (bilateral or in single kidney) |
| Abdominal bruit on exam | Renovascular disease (fibromuscular dysplasia or atherosclerotic) |
| Family history of early HTN or strokes | Renovascular disease, genetic forms (rarely: monogenic HTN) |
| Palpitations, headaches, sweating spells | Pheochromocytoma, hyperthyroidism |
| Proximal weakness, moon facies, striae | Cushing syndrome |
| Sleep apnea symptoms (snoring, daytime somnolence) | OSA-related HTN |
| Medication-induced | NSAIDs, oral contraceptives, decongestants, anesthetics |
II. Primary Aldosteronism (Hyperaldosteronism)
Definition & Epidemiology
Primary aldosteronism (PA) is autonomous aldosterone secretion from the adrenal cortex independent of the renin-angiotensin system.
- Prevalence: 5–15% of hypertensive patients; up to 20% of resistant HTN
- Most common secondary cause of hypertension in developed countries
- Often overlooked: Many patients remain undiagnosed for years
Pathophysiology
Normal physiology (renin-angiotensin-aldosterone axis): 1. Low renal perfusion or hypovolemia → juxtaglomerular cells → ↑ renin release 2. Renin → angiotensinogen → angiotensin I (inactive) 3. ACE → angiotensin II (active) 4. Angiotensin II → aldosterone secretion from zona glomerulosa 5. Aldosterone → Na+ reabsorption (ENaC channels), K+ excretion 6. ↑ Intravascular volume → BP ↑ → feedback suppression of renin (negative feedback)
In primary aldosteronism: - Aldosterone secretion becomes autonomous (not suppressed by normal renin feedback) - Renin is suppressed (from volume expansion caused by excessive aldosterone-driven Na+ reabsorption) - Characterized by: ↑ Aldosterone + ↓ Renin (reverse of normal) - Classic presentation: HTN + hypokalemia + metabolic alkalosis
Forms of Primary Aldosteronism
1. Aldosterone-Producing Adenoma (APA) — “Conn’s Syndrome” (35–40%) - Single adenoma (unilateral), usually small (<2 cm) - Autonomously secretes aldosterone (ACTH-independent) - Presentation: Often younger patients (30–50s), more severe HTN - Prognosis: Surgically curable (adrenalectomy normalizes BP in 30–60%) - Genetic basis in ~40%: KCNJ5 mutations (potassium channel), CYP11B2 mutations, CACNA1D
2. Bilateral Idiopathic Adrenal Hyperplasia (IHA) — “Idiopathic Hyperaldosteronism” (60–65%) - Bilateral adrenal tissue hyperplasia (diffuse or nodular) - No identifiable adenoma on imaging - Presentation: Often older, less severe HTN than APA - Prognosis: Not surgically curable; requires medical management (MRA: spironolactone, eplerenone) - Genetic basis unclear; possibly polygenic or acquired (chronic ACTH stimulation)
3. Familial Hyperaldosteronism Type I (FH-I) — Glucocorticoid-Remediable Aldosteronism (GRA) — RARE (1%) - Genetic chimera: CYP11β1/CYP11β2 gene fusion → aldosterone regulated by ACTH (not renin) - Autosomal dominant inheritance - Presentation: Very early-onset HTN (teens–20s), hypokalemia, metabolic alkalosis - Unique finding: Aldosterone secretion suppressed by dexamethasone (ACTH-suppressed) - Molecular test: Genetic analysis for chimeric gene or long-range PCR - Treatment: Low-dose glucocorticoid (dexamethasone) or amiloride (K+-sparing diuretic)
4. Familial Hyperaldosteronism Type II & III (FH-II, FH-III) — VERY RARE - Genetic basis unclear or identified (CLCN2 for FH-II) - Autosomal dominant - Present with APA-like or IHA-like features
Diagnostic Algorithm for Primary Aldosteronism
Step 1: Screening (Case Detection)
Indications for screening: - Resistant hypertension (≥3 agents) - Hypertension + hypokalemia (spontaneous or diuretic-induced) - HTN + adrenal incidentaloma - Hypertension + family history of early stroke/HTN - All newly diagnosed HTN patients (PA is common; some advocate universal screening)
Screening test: Aldosterone-Renin Ratio (ARR)
| Measurement | Unit | Interpretation |
|---|---|---|
| Plasma renin activity (PRA) | ng/mL/hour | Suppressed in PA |
| Plasma aldosterone concentration (PAC) | ng/dL | Elevated in PA |
| ARR = PAC / PRA | (ng/dL) / (ng/mL/h) | ARR >20–30 suggests PA (threshold varies by lab) |
Conditions for accurate ARR: - OFF diuretics for 4–6 weeks (if possible; diuretics raise renin, lower ARR sensitivity) - OFF ACE-I/ARB for 2+ weeks (raise renin, lower ARR) - OFF β-blockers for 1–2 weeks (can suppress renin) - Avoid NSAIDs, licorice, phenylephrine (affect renin/aldosterone) - Patient sitting upright for 5 min before blood draw (standing raises renin) - Morning blood draw (aldosterone and renin follow circadian rhythm) - Normokalemia (if hypokalemic, correct first; hypokalemia suppresses aldosterone)
ARR interpretation: - ARR >20–30: Suggests PA (exact cutoff varies by lab; check your institution’s reference range) - ARR <10: PA unlikely - ARR 10–20: Borderline; repeat or consider confirmatory testing
Step 2: Confirmatory Testing
If ARR elevated, confirm with suppression/stimulation tests:
A. Saline Suppression Test (Gold Standard)
- Protocol: IV normal saline 0.9%, 500 mL/hour × 4 hours (total 2 L)
- Measure: PAC at baseline and end of infusion; PRA optional
- Interpretation:
- PAC remains >5 ng/dL after saline: Confirms PA (aldosterone not suppressed by volume expansion)
- PAC <4 ng/dL after saline: PA excluded
- PAC 4–5 ng/dL: Borderline (repeat or use other test)
B. Oral Sodium Suppression Test
- Protocol: High-sodium diet (200+ mEq Na/day) × 3 days; measure 24-h urine sodium and plasma aldosterone on day 3
- Interpretation:
- PAC >5 ng/dL + 24-h urine Na >200 mEq: Confirms PA
- More physiologic than IV saline but slower, patient-dependent
C. Captopril Challenge Test
- Protocol: Baseline PAC/PRA, then captopril 25 mg PO; repeat labs 60 min later
- Interpretation:
- Lack of PRA increase (remains <1 ng/mL/h) + PAC remains elevated: Suggests PA
- Less specific than saline suppression; mostly historical
Step 3: Subtype Differentiation (APA vs. IHA)
After confirming PA, distinguish APA (surgically curable) from IHA (medical management) with:
A. Imaging (CT or MRI of adrenals) - Look for: Unilateral nodule/adenoma vs. bilateral hyperplasia - APA: Usually single nodule, <1.5 cm, may not be visible if very small - IHA: Bilateral diffuse or micronodular hyperplasia, or apparently normal - Caveat: ~30% of PA from adenoma are NOT visible on imaging; aldosterone/renin ratio and clinical context guide subtyping
B. Adrenal Venous Sampling (AVS) — GOLD STANDARD for lateralization
Indication: If CT suggests unilateral adenoma (to confirm), or if subtype unclear and surgery being considered.
Protocol: - Bilateral adrenal vein catheterization - Draw blood from each adrenal vein + IVC for PAC and cortisol - Measure aldosterone-to-cortisol ratio in each adrenal vein
Interpretation (Selectivity Criteria): - Selectivity Index = (Adrenal Aldosterone / Adrenal Cortisol) / (IVC Aldosterone / IVC Cortisol) - Selectivity Index >2 (or >4 with ACTH stimulation) = adequate sampling - Lateralization: Aldosterone ratio (high-to-low adrenal side) >4 (or >3 with ACTH stim) = unilateral secretion (APA) - No lateralization: Bilateral secretion (IHA)
C. Genetic Testing - If FH-I suspected (very early onset, family history, dexamethasone-suppressible): Test for CYP11β1/CYP11β2 chimera - KCNJ5, CYP11B2, CACNA1D mutations for APA (research/specialized centers)
Management of Primary Aldosteronism
Medical Management (First-line or for IHA)
Mineralocorticoid Receptor Antagonists (MRAs):
| Agent | Dose Range | Mechanism | Notes |
|---|---|---|---|
| Spironolactone | 12.5–50 mg daily | Non-selective MRA (also androgen antagonist) | Gynecomastia, sexual dysfunction common; long onset (weeks) |
| Eplerenone | 50–100 mg daily | Selective for MR; fewer endocrine side effects | Better tolerance; more expensive; less potent than spironolactone |
| Finerenone | 10–20 mg daily | Non-steroidal MRA (newer) | Renal and CV protective effects; emerging data |
Expected BP reduction: 10–20 mmHg with MRA monotherapy; often combined with other agents.
Additional agents: - ACE-I or ARB: Adds 5–10 mmHg reduction; protects kidney; often combined with MRA - Dihydropyridine calcium channel blocker (amlodipine, nifedipine): Synergistic with MRA - Thiazide diuretic: Can be used cautiously with MRA (monitor K+) - Amiloride or triamterene: K+-sparing diuretics; alternative if MRA not tolerated; less effective than MRA
Monitoring on MRA: - Potassium levels: Check baseline, 1–2 weeks after initiation, then periodically (risk of hyperkalemia) - Creatinine/eGFR: Baseline, then periodically (MRA can worsen renal function if not carefully dosed) - Aldosterone-renin ratio: May normalize with suppressed aldosterone
Surgical Management (For APA)
Indications: - Confirmed APA (adenoma) with: - Young age (<50, ideally) - Good surgical candidate (no major comorbidities) - Desire to normalize BP (avoid lifelong MRA) - Successful AVS lateralization
Procedure: Laparoscopic adrenalectomy (minimally invasive)
Expected outcomes: - 60–70% of patients achieve BP normalization (off all antihypertensive meds) - 20–30% achieve partial BP improvement (reduced medications) - Cure best if younger, shorter duration of HTN, smaller adenoma
Preparation: - Alpha-blockade first: Start phentolamine or doxazosin before surgery to prevent intraoperative hypertensive crisis - Continue MRA until surgery (maintains K+ balance)
Complications: - Acute adrenal insufficiency if bilateral adrenals damaged (rare with unilateral adrenalectomy) - Recurrent HTN if incomplete tumor resection or if IHA (not APA) wrongly operated on
Special Case: FH-I (GRA)
- Medical management: Low-dose dexamethasone (0.5 mg nightly) suppresses ACTH, normalizes aldosterone, controls BP
- Alternative: Amiloride 5–10 mg daily (K+-sparing diuretic)
- No surgical benefit (ACTH-driven, not tumor)
III. Renovascular Hypertension
Definition & Epidemiology
Hypertension caused by renal artery stenosis (RAS) leading to activation of the renin-angiotensin system.
- Prevalence: 1–2% of general hypertensive population; 10–15% of resistant HTN; up to 25% in acute coronary syndrome
- Hemodynamically significant RAS (>60% stenosis): In ~20% of patients found to have any RAS on imaging
Types of Renal Artery Stenosis
1. Atherosclerotic RAS (ARAS) — 90% of cases - Fibrous plaque in renal artery (usually proximal 1/3) - Associated atherosclerosis elsewhere (CAD, cerebrovascular disease, peripheral arterial disease) - Demographics: Older patients (>50), smoking history, dyslipidemia, male predominance - Natural history: Progressive stenosis in many; ~25% develop total occlusion over 5 years if untreated - Risk: Atheroemboli during intervention (angiography, angioplasty)
2. Fibromuscular Dysplasia (FMD) — 10% of cases - Medial fibroplasia (85%): “String of pearls” appearance, multiple segmental stenoses - Intimal fibroplasia (5%): Young patients, rapid progression - Adventitial fibroplasia (5%): Rare; affects outer arterial layers - Demographics: Young to middle-aged women (F:M = 5:1), no atherosclerosis risk factors - Natural history: May be stable over years; rarely progresses to total occlusion - Associated conditions: Connective tissue disorders (Ehlers-Danlos, Marfan), fibromuscular dysplasia in other vascular beds - Better intervention outcomes than atherosclerotic RAS (balloon angioplasty often curative; PCI/stent less often needed)
Pathophysiology of Renovascular HTN
Mechanism (Goldblatt two-kidney, one-clip model): 1. Renal artery stenosis → ↓ renal perfusion pressure 2. Juxtaglomerular cells sense ↓ perfusion → ↑ renin release 3. Renin → angiotensin II (via ACE) 4. Angiotensin II effects: - Systemic: Vasoconstriction, sympathetic activation → ↑ BP - Renal: Efferent arteriole vasoconstriction → maintains GFR in stenotic kidney (initially) 5. Untreated: Progressive renal fibrosis; non-stenotic kidney may develop secondary HTN-related glomerulosclerosis
Clinical consequence: “Flash” pulmonary edema can occur in bilateral RAS or RAS to solitary kidney (from sudden pressure drop across stenosis causing renal ischemia).
Clinical Presentation
Classic features: - HTN with atherosclerotic risk factors (smoking, old age, dyslipidemia) - Abdominal or flank bruit on exam - Hypomagnesemia (can accompany renovascular disease; unknown mechanism) - Acute kidney injury after starting ACE-I/ARB (paradoxically)
“Flash pulmonary edema”: - Acute dyspnea, orthopnea, crackles on lung exam - Often without significant systemic HTN at moment - Mechanism: Renal ischemia → ↑ renin → angiotensin II-driven efferent arteriole vasoconstriction → acute ↓ GFR → fluid retention → pulmonary edema - Classic scenario: Elderly patient with atherosclerotic RAS, often bilateral or in single kidney
Diagnostic Approach
Step 1: Screening
Indications for RAS workup: - Resistant HTN (≥3 agents) + age >55 - Sudden HTN onset (any age) - HTN + flash pulmonary edema - HTN + abdominal bruit - Acute kidney injury after starting ACE-I/ARB - Unexplained progressive renal insufficiency - Peripheral arterial disease (high prevalence of concurrent RAS) - Young woman with HTN (FMD)
Step 2: Imaging Modalities
| Modality | Sensitivity/Specificity | Pros | Cons | Radiation |
|---|---|---|---|---|
| Doppler ultrasound | 85/92% (operator-dependent) | Non-invasive, no contrast, cheap | Difficult in obesity, aortic disease | None |
| CT angiography (CTA) | 94/90% | Excellent spatial resolution, fast | Iodinated contrast (nephrotoxicity risk), radiation | Yes |
| MR angiography (MRA) | 90/95% | Excellent for vessel anatomy, no radiation | Gadolinium (NSF risk in eGFR <30), expensive | No |
| Captopril renography | 85/85% | Functional (renin-mediated), no contrast | Slow (requires time), mostly historical | Yes |
| Renal artery angiography | Gold standard | Direct visualization, ability to intervene | Invasive, contrast nephropathy risk, atheroemboli | Yes |
Clinical approach: - First-line: CTA or MRA (excellent sensitivity/specificity, good for treatment planning) - If eGFR <30: MRA preferred (gadolinium caution <30) or Doppler ultrasound - If contrast allergy: MRA or Doppler - If imaging shows stenosis: Angiography reserved for when intervention planned
Step 3: Functional Testing (Captopril Renography) — Mostly Historical
- Protocol: Baseline and post-captopril nuclear renography
- Interpretation: ACE-I causes ↓ efferent arteriole vasoconstriction → ↓ GFR in stenotic kidney → asymmetric perfusion pattern
- Largely replaced by newer imaging but can provide functional correlation if needed
Management of Renovascular Hypertension
Medical Management (First-line for most)
ACE-I or ARB: - Mechanism: Block angiotensin II effects (both systemic and efferent vasoconstriction) - Effect: Normalize BP in many patients (partial angiotensin II-dependent HTN) - Caution: In bilateral RAS or RAS to single kidney, ACE-I/ARB can precipitate acute kidney injury (loss of efferent vasoconstriction-maintained GFR) - Monitor creatinine closely; expect small rise initially - If Cr rises >30% from baseline, reassess (may need intervention or discontinuation)
Additional agents: - Calcium channel blockers (dihydropyridines like amlodipine) - Thiazide diuretics - Beta-blockers (for CAD if present)
Medical management alone is appropriate if: - HTN controlled on ≤2 agents - Stable renal function - No evidence of recurrent fluid overload/flash pulmonary edema - Patient preference to avoid intervention
Percutaneous Transluminal Angioplasty (PTA) and Stenting
PTA (balloon angioplasty): - Superior results in fibromuscular dysplasia (~90% success, durable) - Less durable in atherosclerotic RAS (restenosis 30–40% at 1 year)
Stenting (preferred for ARAS): - Better patency rates than PTA alone in atherosclerotic disease - But evidence for superiority over medical management alone is limited - ASTRAL trial (2009): Stent + medical vs. medical alone showed NO difference in renal function decline or BP control in most patients - Exception: Flash pulmonary edema, recurrent fluid overload (stenting may help) - Complications: Atheroemboli (blue toe syndrome), access site complications, in-stent restenosis, contrast nephropathy
Indications for intervention (PTA or stenting): - Definite: Recurrent flash pulmonary edema, rapidly declining renal function attributable to RAS - Probable: HTN refractory to medical therapy + hemodynamically significant stenosis + good LVEF - Consider: Young patient with FMD (better durability with PTA) - Avoid: Asymptomatic stenosis with stable HTN and renal function (medical therapy sufficient)
Surgical Revascularization (Rare)
- Indications: Failed PTA, complex anatomy, need for concurrent surgery
- Options: Aortorenal bypass, endarterectomy
- Morbidity higher than PTA; reserved for select cases
Special Scenario: Flash Pulmonary Edema from Bilateral RAS
Pathophysiology: - Bilateral stenoses or single-kidney RAS → renal ischemia in both kidneys - ↑ Renin-angiotensin activation → systemic and renal vasoconstriction - Acute oliguria → rapid volume accumulation → pulmonary edema despite HTN sometimes not severe
Management: - ACE-I/ARB caution: May worsen hyperkalemia and reduce GFR (but often needed for systemic BP control) - Diuretics: Aggressive; loop diuretics often required - Intervention (PTA ± stent): Often necessary to restore renal perfusion, reduce renin-angiotensin drive - Renal replacement therapy: If acute kidney injury severe
IV. Pheochromocytoma and Paraganglioma
Definition & Epidemiology
Pheochromocytoma is a neuroendocrine tumor arising from chromaffin cells of the adrenal medulla, secreting catecholamines (epinephrine, norepinephrine) causing episodic HTN, tachycardia, and headaches.
- Prevalence: 0.1–0.5% of hypertensive patients; 5–15% if HTN is paroxysmal/resistant
- Incidence: 1–4 per million per year
- Age of onset: Typically 30–50 years
- Rule of 10s (older data, now outdated):
- 10% bilateral (adrenal medulla)
- 10% extra-adrenal (paraganglioma)
- 10% malignant
- 10% familial
- Modern data: ~30–40% have germline mutations; ~10% bilateral; ~5% malignant
Genetic Syndromes Associated with Pheochromocytoma
| Syndrome | Gene | Tumor Risk | Associated Features |
|---|---|---|---|
| Multiple Endocrine Neoplasia 2 (MEN2) | RET | 50% | Medullary thyroid cancer, primary hyperparathyroidism |
| Neurofibromatosis Type 1 (NF1) | NF1 | 1–5% | Café-au-lait spots, optic nerve glioma, scoliosis |
| Familial Paraganglioma Syndromes | SDHx (B, C, D, E) | Variable | Extra-adrenal tumors, malignancy risk |
| Von Hippel-Lindau (VHL) | VHL | 10–20% | Hemangioblastomas, RCC, pancreatic cysts |
Recommendation: Screen family members if pheochromocytoma diagnosed, especially if <40 years old or familial syndrome suspected.
Pathophysiology
Catecholamine excess effects:
| Mechanism | Effect | Manifestation |
|---|---|---|
| α1-adrenergic (vasoconstriction) | Systemic vasoconstriction | HTN, particularly systolic; tachycardia |
| α2-adrenergic | Presynaptic inhibition | Often blunted in pheochromocytoma (less relevant) |
| β1-adrenergic (cardiac) | ↑ HR, contractility, renin | Tachycardia, palpitations, tremor |
| β2-adrenergic (vasodilation) | Peripheral vasodilation, metabolic effects | Hyperglycemia, hypokalemia (with sympathetic stimulation shift) |
Result of episodic catecholamine surge: - Sudden severe HTN (SBP 160–200+) - Intense headache (migraine-like) - Profuse diaphoresis (sweating) - Palpitations and tachycardia - Tremor, anxiety, sense of impending doom - Episodes last 15 min – 1 hour, then resolve spontaneously
Clinical Presentation
Classic triad: 1. Episodic headache 2. Diaphoresis (sweating) 3. Palpitations
Additional findings: - HTN: Often sustained with episodic spikes; some patients normotensive between episodes - Anxiety, panic attacks: Can mimic panic disorder - Pallor alternating with flushing - Orthostatic hypotension: Between episodes (catecholamine depletion) - Weight loss: From hypermetabolic state - Hyperglycemia: From catecholamine-mediated insulin suppression
Red flags for pheochromocytoma: - Young age + resistant HTN - Episodic symptoms with normal BP between episodes - Family history of pheochromocytoma or genetic syndrome - Adrenal incidentaloma + HTN symptoms
Diagnostic Approach
Step 1: Biochemical Screening
First-line test: 24-hour urine catecholamines or metanephrines
| Test | Interpretation | Advantages |
|---|---|---|
| 24-h urine free catecholamines | Epinephrine + norepinephrine | Most specific but less sensitive |
| 24-h urine metanephrines | O-methylated catecholamine metabolites | Most sensitive (95%); preferred initial test |
| Plasma free metanephrines | Measured in supine position | Very sensitive; may be more convenient than 24-h urine |
Diagnostic criteria: - Urine metanephrines >2x upper limit of normal: Suggestive of pheochromocytoma (sensitivity ~97%) - Normal urine metanephrines: Pheochromocytoma unlikely (but not ruled out if testing done during asymptomatic phase)
Conditions affecting test validity: - Foods: Caffeine, chocolate, bananas, citrus (contain catecholamines/tyramine) — avoid 48 hours before test - Medications: Decongestants (phenylephrine), tricyclic antidepressants, some antibiotics — hold 2 weeks if possible - Stress: Physical or emotional stress can elevate catecholamines; retest if elevated and low suspicion
Repeat testing: - If borderline elevation and low clinical suspicion, repeat in 1–2 weeks - If markedly elevated (>4x ULN), pheochromocytoma very likely
Step 2: Imaging
Once biochemistry confirmed, localize tumor:
A. CT Abdomen/Pelvis - First-line localization - Sensitivity ~95% for adrenal masses >1 cm - Look for bilateral adrenal masses (MEN2, NF1) - Look for extra-adrenal tumors (paragangliomas, typically along aorta or at organ junctions)
B. MRI Abdomen/Pelvis - Alternative if CT contraindicated or inconclusive - Excellent soft-tissue contrast - Similar sensitivity to CT
C. I-123 Metaiodobenzylguanidine (MIBG) Scintigraphy - Functional imaging; uptake by catecholamine storage vesicles - Indications: Extra-adrenal tumor suspected, metastatic disease suspected, familial syndrome - Better sensitivity for paragangliomas and metastases than CT/MRI
D. Positron Emission Tomography (PET) — F-18 FDOPA or F-18 FDG - Research/specialized centers - Useful for localizing occult tumors, assessing malignancy
E. Whole-body imaging with MIBG or PET if malignancy risk (SDH mutations, extra-adrenal location, large size, high plasma metanephrines)
Management
Alpha-Blockade (Essential Before Any Intervention)
Why: Pheochromocytoma release of catecholamines can cause hypertensive crisis if unopposed (α-effects cause vasoconstriction). Must block α-effects first, then add β-blockade if tachycardia develops.
Alpha-blockers:
| Agent | Dose | Onset | Notes |
|---|---|---|---|
| Phentolamine | 5 mg IV (emergency only) | Immediate | For acute hypertensive crisis; short duration |
| Phenoxybenzamine | 10–20 mg PO BID–TID (up to 60+ mg) | Days | Non-selective α-antagonist; most durable; long half-life |
| Doxazosin | 1–8 mg daily | Days | Selective α1-antagonist; shorter acting; less ideal |
| Prazosin | 1–5 mg TID | Days | Selective α1; similar to doxazosin |
Target: - Titrate to normalization of BP (goal <140/90) - Also achieves volume expansion (catecholamine-induced hypovolemia corrected) - Continue for ≥7–10 days before surgery to allow volume equilibration
Beta-Blockade (After Alpha-Blockade)
When to add: If tachycardia develops after alpha-blockade or ongoing palpitations
Agents: - Propranolol 10–40 mg TID (non-selective β-antagonist) - Labetalol 100–400 mg TID (combined α and β; can be used alone but less ideal)
Critical point: NEVER start β-blockade without α-blockade first (unopposed α-effects → hypertensive crisis, stroke, MI)
Surgical Management (Adrenalectomy or Tumor Resection)
Timing: After ≥1 week of adequate alpha-blockade (ideally 2–3 weeks)
Surgical approach: - Adrenalectomy (laparoscopic or open) for adrenal pheochromocytoma - Resection of paraganglioma for extra-adrenal tumor - Monitor for intraoperative catecholamine surge (can be life-threatening; anesthesist vigilance essential)
Success rate: Cures 95%+ of nonmalignant pheochromocytomas; BP often normalizes.
Medical Management (If Surgery Not Possible or Malignant)
- Long-acting α-blocker: Phenoxybenzamine (as above) or doxazosin
- Additional agents: Calcium channel blocker (nifedipine) for HTN control
- Chemotherapy: For malignant pheochromocytoma (SDCT: streptozotocin + doxorubicin + cisplatin)
- I-131 MIBG: Radionuclide therapy for metastatic disease (limited utility)
V. Cushing Syndrome
Definition & Epidemiology
Hypertension from excessive glucocorticoid exposure, either endogenous (pituitary adenoma, adrenal tumor) or exogenous (medication).
- Prevalence of endogenous Cushing: 1–2 per million (rare)
- HTN prevalence in Cushing: 60–80%
- Exogenous Cushing (from steroids): Most common form of iatrogenic Cushing; much more common
Pathophysiology
Glucocorticoid effects on HTN: 1. Increased angiotensinogen production → renin-angiotensin activation 2. Enhanced vascular responsiveness to catecholamines (permissive effect) 3. Salt retention (via mineralocorticoid receptor activation; cortisol has ~1% activity at MR despite selective receptor; high cortisol overcomes selectivity) 4. Impaired vasodilation (suppression of NO production) 5. Sympathetic nervous system activation
Result: Hypertension in 60–80% of Cushing patients.
Clinical Presentation (Endogenous Cushing)
Classic features (“central obesity”): - Proximal muscle weakness (quadriceps, deltoid atrophy) - Central weight gain (dorsocervical fat pad/“buffalo hump,” supraclavicular fullness, truncal obesity with relatively thin extremities) - Moon facies (facial plethora, roundness) - Purple striae (depressed, violaceous stretch marks, typically >1 cm wide) - Easy bruising (collagen weakness) - Skin atrophy (paper-thin, transparent) - Hirsutism and acne (androgen excess from ACTH) - Hypokalemic metabolic alkalosis (salt retention, K+ wasting) - Hypertension (present in 60–80%)
Psychiatric features: - Depression, mood lability, anxiety, psychosis
Other manifestations: - Osteoporosis, pathologic fractures - Immunosuppression (recurrent infections) - Hyperglycemia, diabetes - Hypogonadism
Diagnostic Approach (Endogenous Cushing)
Step 1: Screening for Cushing (Confirm HTN from Cushing)
Cushing should be suspected if: - HTN + suggestive clinical features (proximal weakness, striae, easy bruising, facial plethora) - Resistant HTN + metabolic abnormalities (hypokalemia, hyperglycemia)
Screening tests:
| Test | Method | Interpretation |
|---|---|---|
| 24-h urinary free cortisol (UFC) | Urine collection | UFC >4x ULN highly suggestive; sensitivity ~95% |
| Late-night salivary cortisol | Saliva at 11 PM | Should be <1.8 ng/dL; elevated in Cushing |
| Low-dose dexamethasone suppression test | Dexamethasone 1 mg at 11 PM, measure 8 AM cortisol | Normal <1.8 ng/dL; cortisol remains elevated in Cushing |
| Morning plasma ACTH | Blood draw 8–9 AM | ACTH <5 pIU/mL suggests adrenal cause; high ACTH suggests pituitary or ectopic |
If screening positive (elevated UFC or suppressed cortisol on dex):
Step 2: Source Localization
Measure morning ACTH:
If ACTH-dependent Cushing (ACTH >10 pIU/mL): - Could be pituitary adenoma or ectopic ACTH secretion - High-dose dexamethasone suppression test: Dexamethasone 8 mg, measure cortisol - Cortisol suppresses >50%: Pituitary adenoma (Cushing’s disease) - Cortisol does NOT suppress: Ectopic ACTH (carcinoid, small cell lung cancer, pheochromocytoma) - Pituitary MRI: Look for adenoma; ectopic imaging if imaging unrevealing
If ACTH-independent (ACTH <5 pIU/mL): - Autonomous adrenal secretion - Adrenal imaging (CT/MRI): Look for adenoma or carcinoma - Adrenal biopsy if imaging shows bilateral disease
VI. Other Secondary Causes of Hypertension
Thyroid Disease
Hyperthyroidism: - ↑ Sympathetic sensitivity to catecholamines - ↑ Cardiac output, ↑ HR - Widened pulse pressure - Management: Treat thyroid; beta-blockers for symptom control
Hypothyroidism: - Usually ↑ diastolic BP (decreased CO, increased SVR) - Management: Thyroid hormone replacement
Hyperparathyroidism
- PTH → ↑ serum calcium
- Hypercalcemia → vascular smooth muscle contraction, volume expansion
- Prevalence of HTN in hyperparathyroidism: 30–50%
- Management: Parathyroidectomy if indicated for hypercalcemia
Obstructive Sleep Apnea (OSA)
- Most common secondary cause of resistant HTN
- Hypoxia-induced sympathetic activation
- Multiple arousals → blood pressure surges nightly
- Management: CPAP (positive airway pressure) therapy; effective BP reduction
Oral Contraceptives and Estrogen Therapy
- Angiotensinogen ↑, renin-substrate ↑ → renin-angiotensin activation
- HTN incidence: 3–5% of users
- Risk factors: Age >35, smoking, prior HTN
- Management: Switch to progestin-only or non-hormonal contraception; lower estrogen doses
NSAIDs and Decongestants
- NSAIDs: Inhibit renal prostaglandin synthesis → fluid retention, HTN
- Sympathomimetics (phenylephrine, pseudoephedrine): Direct vasoconstriction
- Management: Discontinue or use alternative
Coarctation of the Aorta
- Narrowing of descending aorta (usually left of ductus arteriosus)
- Upper body HTN, lower body hypotension
- Clinical clue: Rib notching on chest X-ray (erosions from intercostal arteries)
- Diagnosis: CTA, MRA, echo
- Management: Surgical repair or percutaneous stenting
VII. Clinical Pearls
ARR >20–30 is screening positive for primary aldosteronism; confirm with suppression test before pursuing imaging/AVS.
Renovascular HTN can present with flash pulmonary edema without severe systemic hypertension; think of this diagnosis in elderly patients with acute pulmonary edema and renal disease.
ACE-I/ARB can worsen renal function in bilateral RAS or single-kidney RAS; monitor Cr carefully when initiating, but don’t reflexively discontinue if small rise.
Pheochromocytoma: ALWAYS alpha-block before beta-block to avoid unopposed α-adrenergic crisis.
Pheochromocytoma can mimic panic disorder; high clinical suspicion (episodic symptoms) warrants biochemical testing even in psychiatric patients.
Cushing syndrome can present with “resistant HTN” but should have clinical clues (proximal weakness, striae, easy bruising); screen with 24-h UFC.
OSA is the most common secondary cause of resistant HTN in modern practice; ask all resistant HTN patients about snoring, witnessed apneas, daytime somnolence.
Young women with hypertension should be screened for fibromuscular dysplasia (RAS) if HTN is severe or medication-resistant; FMD has excellent outcomes with PTA.
FH-I (GRA) is dexamethasone-suppressible — a unique form where low-dose dexamethasone, not MRA, is the treatment.
All patients with adrenal pheochromocytoma should be screened for familial syndrome (RET, NF1, VHL, SDH) if <40 years or family history present; affects counseling and follow-up.
VIII. Practice Questions
Question 1: A 45-year-old man with resistant hypertension (on amlodipine, lisinopril, and spironolactone) has labs: K 3.1 mEq/L (normal), Na 140 mEq/L, eGFR 82, BP 160/100 in office. ARR on diuretics is 32 (nl <10). What is the next step?
- Increase spironolactone dose immediately
- Confirm ARR by repeating OFF diuretics; if elevated, proceed to confirmatory testing
- Order adrenal CT for adenoma
- Start eplerenone in addition to spironolactone
Correct Answer: B Explanation: ARR is falsely elevated while on diuretics (diuretics raise renin, lower aldosterone ratio interpretation). The ARR should be rechecked OFF diuretics (ideally hold ≥4–6 weeks) to accurately assess. Only if off-diuretic ARR is elevated should confirmatory testing (saline suppression) proceed. Jumping to imaging without confirming PA would be premature.
Question 2: A 68-year-old man with COPD, smoking history, and resistant hypertension presents with acute pulmonary edema. He is on lisinopril and amlodipine. Creatinine rose from 1.2 to 1.8 mg/dL over 3 months. Abdominal exam reveals a faint bruit. CXR shows pulmonary edema with normal heart size. What is the MOST likely diagnosis?
- Acute heart failure from hypertensive cardiomyopathy
- Acute coronary syndrome causing cardiogenic shock
- Bilateral renal artery stenosis causing “flash” pulmonary edema from renal ischemia
- Acute interstitial pneumonia
Correct Answer: C Explanation: The classic triad is: resistant HTN + acute pulmonary edema (often without marked systemic HTN at moment) + progressive renal insufficiency + abdominal bruit (RAS) = flash pulmonary edema from bilateral RAS. The mechanism is renal ischemia → renin-angiotensin activation → systemic HTN + renal vasoconstriction → oliguria → volume overload → pulmonary edema. Creatinine worsening with ACE-I supports this (loss of efferent vasoconstriction). Need imaging (CTA/MRA) and consideration of intervention.
Question 3: A 35-year-old woman presents with episodic severe headaches (bilateral, throbbing), profuse diaphoresis, and palpitations lasting 20–30 minutes, then resolving completely. BP in clinic today 148/92 but during episode “very high” per patient. Two 24-hour urine catecholamine collections show normal epinephrine and norepinephrine. 24-hour urine metanephrines are elevated at 1.8x ULN (reference <0.9 μmol/day). What should you do?
- Reassure patient; pheochromocytoma ruled out because catecholamines normal
- Repeat 24-h urine metanephrines; pheochromocytoma remains in differential if again elevated
- Start phentolamine for symptomatic management; if symptoms improve, diagnose pheochromocytoma
- Order adrenal imaging now; proceed to CT/MRI
Correct Answer: B Explanation: Urine metanephrines are more sensitive than urine catecholamines for pheochromocytoma detection (95% vs. 80–85% sensitivity). The elevated metanephrines warrant repeat testing to confirm. If repeat is again elevated (especially >2x ULN), imaging is justified. If repeat is normal and clinical suspicion remains high, testing during an episode or extended monitoring might help. Phentolamine acutely for symptom management is reasonable, but alpha-blockade is permanent therapy, not diagnostic.
IX. References
Funder, J.W., et al. (2016). “The Management of Endocrine Disorders of the Adrenal Cortex.” J Clin Endocrinol Metab. 2016;101(10):3552–3563.
Endocrine Society Clinical Practice Guideline for Primary Aldosteronism (2016) https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2015-4818
Lim, P.O., et al. (1999). “Renal Artery Stenosis in Hypertensive Patients: Prevalence and Risk Factors.” J Hum Hypertens. 1999;13(4):215–224.
Endocrine Society Clinical Practice Guideline for Pheochromocytoma and Paraganglioma (2014) https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2014-1498
Lenders, J.W., et al. (2014). “Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline.” J Clin Endocrinol Metab. 2014;99(6):1915–1942.
KDIGO Blood Pressure Management in CKD (2021) https://kdigo.org/wp-content/uploads/2021/10/KDIGO-BP-Guideline_Final_08242021.pdf
ASTRAL Investigators. (2009). “Revascularization versus Medical Therapy for Renal-Artery Stenosis.” N Engl J Med. 2009;361(20):1953–1962.
Neumann, H.P., et al. (2009). “Pheochromocytoma in the Era of Genomic Biomarkers.” J Clin Endocrinol Metab. 2019;104(11):5841–5856.
Mulatero, P., et al. (2013). “Increased Diagnosis of Primary Aldosteronism with a Simplified Screening and Confirmatory Testing Algorithm.” Hypertension. 2013;61(2):463–470.
Blakely, R.D., et al. (2018). “Catecholamine System and Hypertension.” Circ Res. 2018;122(11):1515–1524.
End of Handout
Last updated: 2026-02-12 | For medical students and residents in nephrology, cardiology, and internal medicine
Clinical Resources
- Clinical Review: Hypertension Management Patient Bp Monitoring Guide — Comprehensive clinical review with PubMed references
- Clinical Review: Renovascular Hypertension Review — Comprehensive clinical review with PubMed references
- Clinical Review: Hypertension Management Report — Comprehensive clinical review with PubMed references