Endocrine

Pheochromocytoma: diagnosis and perioperative management

Clinical Overview and When to Suspect Pheochromocytoma

— Rare: 0.2–0.6% of hypertensive adults, but cause of secondary HTN in ~5% of incidentally found adrenal masses

— Peak incidence 4th–5th decade; ~40% are hereditary (much higher than older "10% rule")

— Classic "10% rule" (10% bilateral, extra-adrenal, malignant, pediatric, familial, normotensive) is outdated — modern data: up to 40% germline mutations, 15–20% extra-adrenal, malignancy risk varies by genotype (SDHB highest)

— Resistant hypertension (≥3 agents including diuretic) plus paroxysms

— Classic triad: episodic headache + palpitations + diaphoresis with HTN (specificity ~90%)

— Adrenal incidentaloma on CT/MRI — must screen all

— Hypertensive crisis triggered by anesthesia, surgery, contrast, β-blockade alone, tyramine, or certain drugs (metoclopramide, glucagon, TCAs)

— Known hereditary syndrome: MEN2A/2B (RET), VHL, NF1, SDHx mutations, familial paraganglioma

— Unexplained orthostatic hypotension in a hypertensive patient (volume-contracted from chronic catecholamines)

Board pearl: A young patient with hypertensive crisis after induction of anesthesia or after starting a non-selective β-blocker (unopposed α effect) should prompt immediate consideration of pheochromocytoma — this is a classic Step 3 trigger and the wrong answer is "increase β-blocker." Always screen every adrenal incidentaloma for pheochromocytoma regardless of symptoms because silent tumors can decompensate intraoperatively.

Definition: Catecholamine-secreting tumor arising from chromaffin cells of the adrenal medulla (pheochromocytoma) or extra-adrenal sympathetic/parasympathetic ganglia (paraganglioma). Together often abbreviated PPGL.

Epidemiology:

When to suspect on Step 3:

Pathophysiology drives the exam: sustained or episodic catecholamine release → α1 vasoconstriction, β1 inotropy/chronotropy, β2 metabolic effects → HTN, tachycardia, hyperglycemia, weight loss, hypermetabolic state.

Presentation Patterns and Key History

— Abrupt onset headache (throbbing, ~90%), palpitations (~70%), diaphoresis (~60%) — triad present together in ~40% but each alone is common

— Duration minutes to 1 hour; frequency variable (daily to monthly)

— Triggers: bending, exercise, micturition (bladder paragangliomas), abdominal palpation, anesthesia induction, IV contrast, surgery, certain foods (tyramine), medications

— Sustained HTN (~50%), paroxysmal HTN with normotension between (~30%), normotensive (~10–15%, especially dopamine-secreting tumors), or alternating HTN/hypotension

— Orthostatic hypotension despite supine HTN is a clue (volume contraction + desensitized receptors)

— Weight loss, heat intolerance, anxiety/panic-like attacks, tremor, pallor (not flushing — flushing favors carcinoid)

— Hyperglycemia/new-onset diabetes from β2-mediated insulin suppression

— Constipation (α-mediated decreased GI motility)

— Cardiomyopathy: dilated, Takotsubo, or hypertrophic patterns

— β-blocker monotherapy → unopposed α → crisis

— Metoclopramide, droperidol, glucagon, IV contrast, anesthetics (halothane, ketamine, succinylcholine), TCAs, MAOIs, sympathomimetics, opioids (morphine, histamine release)

— Tyramine-rich foods (aged cheese, wine) if MAOI-like state

Key distinction: Pheochromocytoma "spells" produce pallor and HTN, while carcinoid syndrome produces flushing and diarrhea, and panic attacks rarely cause significant blood pressure elevation (>180/120). Anxiety with sustained severe HTN should never be dismissed without biochemical screening.

Step 3 management: When taking the history, always ask about prior anesthesia reactions and family history of endocrine tumors — a positive family screen mandates germline testing referral after biochemical confirmation.

Classic paroxysmal pattern ("spells"):

Hypertension patterns:

Systemic/metabolic clues:

Drug/exposure history (essential):

Family history: MEN2 (medullary thyroid CA, hyperparathyroidism), VHL (hemangioblastomas, RCC, retinal angiomas), NF1 (café-au-lait, neurofibromas), familial paraganglioma (SDHx), early-onset HTN in relatives, sudden death

Physical Exam Findings and Hemodynamic Assessment

— HTN often >180/110 during spells; wide pulse pressure

— Tachycardia, sometimes reflex bradycardia from extreme α-mediated HTN

— Orthostatic hypotension in a hypertensive patient is highly suggestive (volume depletion)

— Hyperthermia during paroxysms from thermogenesis

— Thin, anxious, diaphoretic, pale (not flushed)

— Tremor, mydriasis during attack

— Tachycardia, S4 from LVH, displaced PMI if cardiomyopathy

— Murmurs uncommon unless coexistent valvular disease

— Signs of heart failure (rales, JVD, edema) if catecholamine cardiomyopathy

— Usually unremarkable; palpation may provoke a hypertensive paroxysm — avoid deep palpation if suspected

— Bruit rare; flank mass uncommon (most tumors <5 cm at diagnosis)

— MEN2: marfanoid habitus, mucosal neuromas on lips/tongue, thickened corneal nerves (MEN2B); thyroid nodule (medullary CA)

— VHL: retinal hemangioblastomas on funduscopy

— NF1: ≥6 café-au-lait macules (>15 mm adult), axillary/inguinal freckling, Lisch nodules, cutaneous neurofibromas

— Neck mass at carotid bifurcation → carotid body paraganglioma

— Document supine and standing BP/HR — orthostatic drop guides volume repletion preoperatively

— Continuous telemetry if hospitalized for crisis

— Echo to assess LV function before surgery (catecholamine cardiomyopathy may be reversible)

Board pearl: Funduscopic exam showing retinal hemangioblastomas in a patient with HTN spells points to VHL syndrome — order genetic testing and screen for renal cell carcinoma, pancreatic neuroendocrine tumors, and CNS hemangioblastomas.

Step 3 management: Avoid abdominal palpation in suspected pheochromocytoma during initial exam; if a paroxysm is provoked, do not give β-blocker first — give IV phentolamine or nicardipine, then α-blockade before any β-agent.

Vital signs:

General appearance:

Cardiovascular:

Abdomen:

Syndromic stigmata (always look):

Hemodynamic assessment for management:

Diagnostic Workup — Initial Biochemical Testing

— Both have sensitivity >95%; plasma slightly more sensitive, urine slightly more specific

— Choose based on pretest probability:

— High pretest probability (syndromic, adrenal mass, prior PPGL, classic spells): plasma free metanephrines preferred

— Lower pretest probability (resistant HTN screen): 24-hr urine metanephrines + creatinine to verify collection

— Metanephrines are produced continuously inside chromaffin tumor cells by COMT, independent of episodic catecholamine release

— Catecholamines have short half-life and may be normal between spells

— Plasma: supine for ≥30 min before draw, fasting, no caffeine/nicotine, IV access placed ≥20 min prior

— Discontinue interfering drugs when feasible:

— TCAs, SNRIs, MAOIs, levodopa, sympathomimetics, buspirone, acetaminophen (assay-dependent), labetalol (assay interference)

— Hold ≥2 weeks before testing if possible

— Plasma metanephrines >3–4× upper limit of normal → near-100% specific, proceed directly to imaging

— Mild elevation (1–3× ULN) → repeat or proceed to clonidine suppression test

— Normal levels essentially exclude PPGL (NPV >99%)

— CBC, BMP (look for hyperglycemia, hypokalemia), calcium (MEN2 hyperparathyroidism), calcitonin (MEN2 MTC), HbA1c

— ECG: LVH, strain, T-wave inversions, QT prolongation, occasional infarct pattern

Key distinction: VMA (vanillylmandelic acid) is an outdated, low-sensitivity test — do not choose it on Step 3. The correct screening test is plasma free or urinary fractionated metanephrines.

Board pearl: False positives are common with TCAs and physical stress (acute illness, ICU); always re-check in stable outpatient conditions before proceeding to expensive imaging.

First-line test: plasma free metanephrines OR 24-hour urinary fractionated metanephrines and catecholamines

Why metanephrines (not catecholamines)?

Proper collection technique (testable):

Interpretation:

Adjunct labs:

Diagnostic Workup — Imaging and Confirmatory Studies

— CT abdomen/pelvis with contrast is first-line: sensitivity 85–95%; pheochromocytomas typically >10 HU on unenhanced CT, heterogeneous, with delayed contrast washout (<50% absolute, <40% relative at 10 min) — opposite of lipid-rich adenoma

— MRI abdomen preferred in: pregnancy, children, allergy to iodinated contrast, suspected paraganglioma (better for skull base/neck), or follow-up to limit radiation in hereditary cases

— Classic: T2 hyperintense "light bulb" lesion (though only ~65% sensitive)

— ¹²³I-MIBG scintigraphy: historically standard; useful to confirm functionality and detect metastases; limited sensitivity for SDHx-related paragangliomas

— ⁶⁸Ga-DOTATATE PET/CT: now preferred for metastatic disease, SDHB-related paraganglioma, head/neck PGL — superior sensitivity (>90%)

— ¹⁸F-FDG PET: useful for metastatic SDHB tumors

— Clonidine suppression test: 0.3 mg PO; failure of plasma normetanephrine to suppress by ≥40% (or remain elevated) confirms pheochromocytoma

— Used rarely now given high specificity of plasma metanephrines >3× ULN

— Especially if <45 years, bilateral, multifocal, extra-adrenal, malignant, or syndromic features

— Panel includes: RET, VHL, NF1, SDHA/B/C/D/AF2, TMEM127, MAX, FH

— SDHB carries highest malignancy risk (~30–70%)

Step 3 management: Confirm biochemically first, image second, refer for genetic counseling third — never order MIBG before metanephrines.

Board pearl: An adrenal mass with HU >10 on unenhanced CT and slow contrast washout in a patient with HTN spells = pheochromocytoma until proven otherwise; do not biopsy — biopsy can trigger fatal hypertensive crisis.

Imaging step — only after biochemical confirmation (avoid imaging-first to prevent chasing nonfunctional incidentalomas):

Functional imaging (when to add):

When biochemistry is borderline:

Genetic testing — recommended in ALL patients with confirmed PPGL (per Endocrine Society):

Staging if malignant features: bone scan or FDG-PET, chest CT

Risk Stratification and Management Logic

— BP <130/80 seated, <90/45 standing (mild orthostasis acceptable)

— HR 60–70 seated, 70–80 standing

— No ST-T changes on ECG for ≥1 week

— ≤1 PVC every 5 minutes

— Adequate volume expansion (liberalize sodium and fluids in last few days)

— Higher risk: SDHB mutation, extra-adrenal location, size >5 cm, necrosis, vascular invasion

— No reliable histologic marker — only metastasis to non-chromaffin sites (bone, liver, lung, lymph node) defines malignancy

— MEN2: address pheochromocytoma before thyroidectomy for medullary thyroid cancer to prevent intraoperative crisis

— Bilateral adrenal tumors (MEN2, VHL): consider cortical-sparing adrenalectomy to preserve glucocorticoid function

Step 3 management: The single most common wrong answer on Step 3 is "proceed to surgery now" in a newly diagnosed patient — the correct sequence is biochemistry → imaging → α-blockade → β-blockade → volume repletion → surgery.

Board pearl: In MEN2 with both medullary thyroid carcinoma and pheochromocytoma, always resect the pheochromocytoma first — the adrenergic surge from thyroid surgery would be fatal.

Definitive treatment is surgical resection (laparoscopic adrenalectomy for most adrenal pheochromocytomas; open for large >6–8 cm, invasive, or malignant tumors).

Critical principle: NEVER operate without adequate preoperative medical preparation. Unprepared resection has historical mortality up to 50% from intraoperative hypertensive crisis, arrhythmia, or post-resection refractory hypotension.

Preoperative preparation goals (Roizen criteria):

Timeline: 10–14 days of α-blockade minimum before surgery; longer (4–6 weeks) if cardiomyopathy.

Risk stratification for malignancy (PASS, GAPP scoring used clinically; not memorized for boards):

Multidisciplinary team: endocrinology, endocrine surgery, anesthesiology with cardiac/critical care expertise, genetic counselor.

Multifocal/hereditary disease:

Pharmacotherapy — Preoperative α- and β-Blockade

— Phenoxybenzamine (non-selective, irreversible, long-acting): first-line at most centers

— Start 10 mg BID; titrate by 10–20 mg every 2–3 days to target BP and mild orthostasis

— Typical final dose 20–100 mg/day

— Side effects: orthostatic hypotension, reflex tachycardia, nasal congestion, fatigue, retrograde ejaculation

— Selective α1-blockers (doxazosin, prazosin, terazosin): alternative

— Doxazosin 2–8 mg daily; advantages: less reflex tachycardia, less postop hypotension, cheaper, available

— Preferred in some centers and for normotensive/mildly symptomatic patients

— Indications: reflex tachycardia (HR >100), arrhythmias, or β-mediated symptoms

— Propranolol 10–40 mg TID or metoprolol or atenolol

— NEVER start β-blocker first — unopposed α stimulation precipitates hypertensive crisis, pulmonary edema, and death

— Calcium channel blockers (amlodipine, nicardipine) — useful add-on, especially in patients intolerant of α-blockade or with coronary spasm

— Metyrosine (α-methyl-paratyrosine, tyrosine hydroxylase inhibitor): blocks catecholamine synthesis; reserved for refractory cases, metastatic disease, or large tumors; expensive, causes sedation and extrapyramidal effects

— IV phentolamine (α-blocker) 1–5 mg bolus, or

— IV nicardipine infusion, or nitroprusside for refractory cases

— Avoid labetalol monotherapy (β > α effect causes paradoxical worsening)

Board pearl: The Step 3 stem describing crisis after β-blocker initiation tests the α-before-β rule — always.

Step 1: α-blockade (start 10–14 days preop)

Step 2: β-blockade — ONLY after adequate α-blockade (typically 2–3 days before surgery)

Step 3: High-sodium diet (>5 g/day) and IV fluids 1–2 days preop to expand contracted intravascular volume and prevent post-resection hypotension

Adjuncts when BP not controlled:

Hypertensive crisis acute management:

Intraoperative and Postoperative Management

— Continue α-blocker on the morning of surgery

— Ensure adequate hydration with IV crystalloid the night before

— Arterial line, central venous access, large-bore IVs, type and cross

— Avoid drugs that release histamine or catecholamines: morphine, atracurium, succinylcholine (controversial), ketamine, ephedrine, droperidol, metoclopramide

— Preferred agents: propofol, etomidate, fentanyl, rocuronium, sevoflurane, isoflurane

— Tumor manipulation phase: expect surges → manage with IV phentolamine, nicardipine, nitroprusside, magnesium sulfate

— Tachyarrhythmias: IV esmolol (short-acting β1) once α-blocked

— After venous ligation: abrupt catecholamine withdrawal → hypotension; treat with volume + vasopressin or norepinephrine (phenylephrine may be ineffective due to receptor downregulation)

— Laparoscopic transabdominal or posterior retroperitoneal adrenalectomy: standard for tumors <6–8 cm

— Open adrenalectomy: large, invasive, or malignant tumors, or extra-adrenal paragangliomas in difficult locations

— Cortical-sparing adrenalectomy for bilateral disease (MEN2, VHL) to preserve adrenal function and avoid lifelong steroid dependence

— ICU for 24 hours; watch for hypotension, hypoglycemia (rebound hyperinsulinemia from loss of β2 suppression), and adrenal insufficiency (if bilateral or cortical injury)

— Monitor glucose q1–2h for 24h

— Continue volume support; α-blocker is stopped postop

— Recheck plasma or urinary metanephrines at 2–6 weeks to confirm biochemical cure

— Chronic α-blockade ± metyrosine

— ¹³¹I-MIBG therapy or peptide receptor radionuclide therapy (¹⁷⁷Lu-DOTATATE)

— Systemic chemo (CVD: cyclophosphamide, vincristine, dacarbazine) or sunitinib for progressive disease

CCS pearl: Post-resection hypotension responds best to volume + norepinephrine/vasopressin, not phenylephrine — order CVP monitoring and serial glucose checks.

Preoperative day:

Intraoperative considerations:

Surgical approach:

Postoperative monitoring:

For metastatic/unresectable disease:

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher prevalence of incidentally discovered adrenal masses; ~5% are pheochromocytomas

— Often have sustained HTN rather than paroxysmal pattern

— Comorbid CAD, HFrEF, cerebrovascular disease increase perioperative risk

— Catecholamine cardiomyopathy more common and may mimic acute coronary syndrome or Takotsubo

— Slower titration of α-blockade; greater risk of falls from orthostasis — start doxazosin 1–2 mg, uptitrate every 3–4 days

— Preoperative cardiac assessment with echo and stress testing as indicated; revascularize significant CAD before adrenalectomy when feasible

— Preoperative preparation may extend to 3–4 weeks to optimize volume and cardiac status

— Plasma metanephrines preferred over 24-hr urine (urine creatinine-corrected results unreliable)

— Reference ranges may shift slightly upward in CKD; interpret with caution

— Avoid iodinated contrast if eGFR <30 → use MRI with caution (gadolinium avoided in eGFR <30 or on dialysis; use macrocyclic agents if essential)

— Dose adjustments: atenolol (renally cleared) — prefer metoprolol or propranolol

— Phenoxybenzamine and doxazosin do not require renal dose adjustment but accumulate clinically — monitor BP closely

— Phenoxybenzamine hepatically metabolized; use lower doses in cirrhosis

— Propranolol hepatically cleared — reduce dose

— Metanephrine assays unaffected

— Acetaminophen interference: matters more than hepatic clearance — discontinue before testing

— Plasma free metanephrines the test of choice; collect before dialysis session

— Volume management for surgery is delicate — coordinate with nephrology for perioperative dialysis schedule

Step 3 management: In the elderly with new resistant HTN, palpitations, and an adrenal mass, do not skip biochemical screening assuming "essential HTN" — workup is cost-effective and prevents perioperative catastrophe during unrelated surgeries.

Board pearl: Atenolol in CKD accumulates and causes bradycardia; switch to metoprolol succinate when eGFR <30.

Elderly patients (>65 years):

Renal impairment (CKD):

Hepatic impairment:

Dialysis patients:

Special Populations — Pregnancy, Pediatrics, and Hereditary Syndromes

— Rare (~1 in 50,000) but maternal mortality up to 50% if undiagnosed (~0–5% with proper preparation)

— Mimics preeclampsia, but pheochromocytoma lacks proteinuria and often presents before 20 weeks

— Diagnosis: plasma free metanephrines (pregnancy does not significantly alter)

— Imaging: MRI without gadolinium is preferred; avoid CT

— Management:

— Phenoxybenzamine is first-line (crosses placenta — risk of neonatal hypotension/respiratory depression, but benefits outweigh risks); doxazosin is alternative

— β-blocker (labetalol, metoprolol) only after α-blockade

— Avoid methyldopa, hydralazine monotherapy, magnesium (can interact)

— Timing of surgery:

— <24 weeks: consider laparoscopic adrenalectomy in 2nd trimester after α-blockade

— >24 weeks: medical management until fetal maturity, then planned cesarean delivery with concurrent or staged adrenalectomy

— Avoid vaginal delivery (uterine contractions trigger crisis)

— Higher proportion are hereditary (~80%), bilateral, and extra-adrenal

— Strong association with VHL, SDHB, NF1, MEN2

— Presents with sustained (not paroxysmal) HTN, headache, visual changes, weight loss, polyuria

— Same preparation principles, weight-based dosing

— MEN2 (RET): annual plasma metanephrines starting age 11 (MEN2B) or 16 (MEN2A); calcitonin, calcium

— VHL: annual plasma metanephrines starting age 5; renal/CNS imaging; ophtho exam

— NF1: screen only if hypertensive (lower lifetime risk ~5%)

— SDHB carriers: annual biochemistry + every 2-year whole-body MRI starting age 6–10

— All first-degree relatives of mutation carriers should undergo genetic testing and counseling

Board pearl: Pheochromocytoma in pregnancy + no proteinuria + BP labile + before 20 weeks distinguishes from preeclampsia — get plasma metanephrines.

Step 3 management: Refer every confirmed PPGL patient to genetic counseling regardless of age or family history.

Pregnancy:

Pediatrics:

Hereditary syndromes — surveillance:

Complications and Adverse Outcomes

— Hypertensive crisis: sudden severe BP elevation with end-organ damage — encephalopathy, stroke (ischemic or hemorrhagic), aortic dissection, MI, acute pulmonary edema

— Catecholamine cardiomyopathy: dilated, Takotsubo (apical ballooning), or rarely hypertrophic; often reversible after tumor removal in weeks to months

— Arrhythmias: sinus tachycardia, AF, VT, VF; QT prolongation

— Acute MI: from coronary vasospasm or oxygen demand-supply mismatch — angiography may show normal coronaries

— Shock: paradoxically, severe vasoconstriction → end-organ hypoperfusion despite HTN ("pheochromocytoma multisystem crisis")

— Hyperglycemia and new-onset diabetes (β2-mediated insulin suppression + glycogenolysis) — usually resolves after resection

— Hypercalcemia (rare, paraneoplastic PTHrP or MEN2-associated hyperparathyroidism)

— Lactic acidosis during crisis

— PRES (posterior reversible encephalopathy syndrome) from severe HTN

— Ischemic or hemorrhagic stroke

— Seizures from hypertensive encephalopathy

— Acute kidney injury from severe HTN, renal artery vasospasm, or rhabdomyolysis

— Chronic CKD from prolonged uncontrolled HTN

— Intraoperative hypertensive crisis, arrhythmia, MI, stroke

— Post-resection refractory hypotension and hypoglycemia

— Adrenal insufficiency after bilateral adrenalectomy → lifelong glucocorticoid + mineralocorticoid replacement

— Recurrence ~5–15% over 10 years (higher with SDHB, paraganglioma, large tumors)

— Metastatic disease (bone, liver, lung, lymph nodes); 5-year survival 50–80%

— Second primary tumors in hereditary syndromes

Board pearl: Apical ballooning on echo + HTN spells = consider catecholamine-induced (or pheo-induced) Takotsubo — screen with plasma metanephrines before attributing to emotional stress.

Step 3 management: Post-bilateral adrenalectomy patients need lifelong hydrocortisone + fludrocortisone plus a MedicAlert bracelet and stress-dose teaching.

Cardiovascular:

Metabolic:

Neurologic:

Renal:

Perioperative:

Long-term:

When to Escalate Care — ICU, Consults, and Triage

— Hypertensive emergency with end-organ damage (encephalopathy, ACS, dissection, pulmonary edema, AKI, PRES)

— Hemodynamic instability (alternating HTN/hypotension, shock)

— Catecholamine cardiomyopathy with HF or arrhythmia

— Multisystem crisis: hyperthermia, lactic acidosis, mental status changes — mortality >50% without aggressive care

— Postoperative day 0–1 for all pheochromocytoma resections (standard of care)

— Admit to ICU; continuous telemetry, arterial line, foley

— IV access × 2 large bore; CVC if shock or vasopressor anticipated

— First-line IV: phentolamine 1–5 mg bolus q5–10 min OR nicardipine infusion 5–15 mg/hr OR nitroprusside (limit duration due to cyanide)

— Add IV esmolol or metoprolol only after α-blockade for tachycardia/arrhythmia

— IV magnesium sulfate adjunct (vasodilates, antiarrhythmic, blocks catecholamine release)

— Aggressive crystalloid hydration

— Labs: troponin, BNP, lactate, BMP, glucose; ECG q6h; echo within 24h

— Endocrinology and endocrine surgery consults immediately

— Endocrinology: all confirmed cases for medical preparation

— Endocrine/adrenal surgery: ideally high-volume center (>20 adrenalectomies/year)

— Cardiology: if cardiomyopathy, arrhythmia, or CAD

— Anesthesiology: preop evaluation 1–2 weeks before surgery

— Genetics: all confirmed cases per Endocrine Society

— Maternal-fetal medicine: pregnancy cases

— Transfer to tertiary center if local team lacks experience with PPGL surgery — outcomes are volume-dependent

— Do not transfer during active crisis — stabilize first

— Stable BP/HR on titrated α-blocker

— No end-organ damage

— Reliable patient with follow-up arranged

CCS pearl: Order plasma metanephrines, CT abdomen with contrast, ECG, troponin, BNP, echo, and endocrinology + surgery + anesthesiology consults on day 1 — do not start β-blocker yet.

Immediate ICU admission indicators:

Acute crisis management algorithm (CCS-style orders):

Consults:

Transfer criteria:

Outpatient management appropriate when:

Key Differentials — Same-Category (Endocrine/Adrenergic) Causes

— HTN with hypokalemia, metabolic alkalosis, suppressed renin, elevated aldosterone

— No paroxysms, no catecholamine symptoms

— Aldosterone-to-renin ratio (ARR) >20–30 with aldo >15 ng/dL screens positive

— HTN with central obesity, striae, easy bruising, proximal weakness, glucose intolerance

— Screen: 24-hr urine cortisol, late-night salivary cortisol, low-dose dex suppression

— Tachycardia, tremor, weight loss, heat intolerance, anxiety — mimics pheo

— But wide pulse pressure with systolic HTN, warm moist skin, lid lag, goiter

— TSH suppressed, free T4/T3 elevated

— Flushing (not pallor), diarrhea, wheezing, right-sided heart valve disease

— 5-HIAA urine elevated

— Flushing, urticaria, hypotension during episodes (not HTN), tryptase elevated

— HTN with hypokalemia, very high renin and aldosterone

— HTN, glucose intolerance, organomegaly, classic facial features; IGF-1 elevated

— Clonidine withdrawal: rebound HTN, tachycardia, diaphoresis — closely mimics pheo

— Alcohol/benzodiazepine withdrawal

— Severe paroxysmal HTN with normal metanephrines; psychosocial trigger; treated with combined α/β-blockade + behavioral therapy

Key distinction: Carcinoid = flushing + diarrhea; pheochromocytoma = pallor + HTN. Hyperaldosteronism = HTN + hypokalemia, no spells. Clonidine withdrawal mimics pheo perfectly — always ask about recent medication changes.

Board pearl: A patient with HTN spells and a thyroid nodule needs both plasma metanephrines AND calcitonin to evaluate for MEN2A before any thyroid surgery.

Primary hyperaldosteronism (Conn syndrome):

Cushing syndrome:

Hyperthyroidism (Graves, toxic nodular goiter):

Carcinoid syndrome:

Mastocytosis / mast cell activation:

Renin-secreting tumor (juxtaglomerular cell tumor):

Acromegaly:

Withdrawal syndromes:

Pseudopheochromocytoma:

Key Differentials — Other-Category (Non-Endocrine) Causes

— Palpitations, sweating, dyspnea, fear of dying

— BP usually <160/100; metanephrines normal

— Responds to SSRI/CBT

— Step 3 trap: don't anchor on panic in a patient with BP >200/120

— Sustained HTN without true paroxysms; common

— Ambulatory BP monitoring discriminates

— Cocaine, amphetamines, MDMA, PCP — toxicology screen

— Sympathomimetic decongestants (pseudoephedrine, phenylephrine)

— MAOI + tyramine reaction

— Tyrosine-kinase inhibitors (sunitinib), bevacizumab, calcineurin inhibitors, oral contraceptives, NSAIDs, glucocorticoids

— Stimulant ADHD meds

— Resistant HTN, daytime sleepiness, snoring; STOP-BANG screening; polysomnography

— Fibromuscular dysplasia (young women) or atherosclerotic renal artery stenosis (older)

— Abdominal bruit, sudden HTN, asymmetric kidneys; renal Doppler

— Young patient, upper-extremity HTN, weak femoral pulses, rib notching on CXR

— Spinal cord injury at T6 or above; triggered by bladder distention, constipation; sudden HTN, bradycardia, headache, sweating above lesion

— Tetany, perioral tingling; ABG shows respiratory alkalosis

Step 3 management: In resistant HTN, screen for secondary causes systematically: plasma metanephrines (pheo), aldosterone-renin ratio (Conn), cortisol (Cushing), TSH (thyroid), renal Doppler (renovascular), sleep study (OSA), urine drug screen, and detailed med review.

Board pearl: A spinal cord injury patient with sudden HTN headache is autonomic dysreflexia — sit them up, remove the trigger (Foley check, disimpaction), and use IV nitroprusside or nifedipine; not pheochromocytoma.

Panic disorder / anxiety:

Essential hypertension with labile readings:

White coat / masked HTN:

Drug-induced HTN:

Obstructive sleep apnea:

Renovascular hypertension:

Coarctation of the aorta:

Autonomic dysreflexia:

Hyperventilation/pheo-mimic anxiety:

Migraine with autonomic features

Secondary Prevention, Discharge Medications, and Long-Term Plan

— Discontinue α-blocker typically on POD 0–1 (no longer needed once tumor removed)

— Antihypertensive regimen if residual HTN: standard JNC/AHA approach (ACEi/ARB, CCB, thiazide)

— Glucose monitoring: hyperglycemia usually resolves but may persist if longstanding

— If bilateral adrenalectomy: hydrocortisone 15–25 mg/day (split AM/PM dose) + fludrocortisone 0.05–0.2 mg daily

— Stress-dose steroid teaching: triple oral dose for fever/illness; IM hydrocortisone 100 mg for vomiting/inability to take PO; emergency MedicAlert bracelet

— Plasma free metanephrines or 24-hr urine fractionated metanephrines at 2–6 weeks postop

— Normalization confirms biochemical cure

— Persistently elevated → residual or metastatic disease → DOTATATE PET, further surgery, or systemic therapy

— Annual plasma free metanephrines for at least 10 years; some recommend lifelong

— Higher risk groups (SDHB, paraganglioma, hereditary, young, large tumor): lifelong annual biochemistry + periodic imaging

— Recurrence rate ~5–15% at 10 years overall, higher with hereditary disease

— Genetic counseling for family members

— Cascade testing of first-degree relatives

— Syndrome-specific surveillance (MTC for MEN2, RCC for VHL, etc.)

— Statin if ASCVD risk warrants

— Lifestyle: weight, exercise, sodium reduction, smoking cessation

— Aspirin per primary/secondary prevention guidelines

Step 3 management: Order plasma metanephrines at 4 weeks as the first follow-up step; if normal, transition to annual surveillance for life and refer to genetic counseling if not already done.

Board pearl: Recurrence is not rare — never tell a patient they are "cured forever" after resection; lifelong annual biochemical screening is standard.

Postoperative discharge medications:

Biochemical confirmation of cure:

Long-term surveillance (lifelong):

Hereditary patients:

Cardiovascular risk reduction:

Follow-Up, Monitoring Parameters, and Counseling

— Postop week 1–2: wound check, BP check, glucose check, review pathology

— Week 4–6: first plasma/urine metanephrines to confirm biochemical remission

— Month 3: BP optimization, medication reconciliation

— Month 6: imaging if any biochemical concern; otherwise clinical

— Annual visits lifelong: plasma metanephrines, BP, HR, glucose/HbA1c, weight, symptom review

— Imaging (CT/MRI or DOTATATE PET) every 1–2 years for high-risk patients (SDHB, paraganglioma, hereditary, young, multifocal), every 3–5 years for sporadic resected disease

— BP target <130/80 (general AHA/ACC); some recurrence patients need multidrug regimens

— Plasma metanephrines: any rise above ULN warrants imaging

— In bilateral adrenalectomy: morning cortisol periodically; electrolytes, renin, BP for mineralocorticoid replacement adequacy

— Echo at 3–6 months if catecholamine cardiomyopathy at baseline — most recover EF to normal

— Recognize warning signs of recurrence: return of spells, new HTN, palpitations, sweating

— Medication adherence and side effect awareness

— Hereditary disease implications — family screening, reproductive counseling, preimplantation genetic diagnosis options for SDHB carriers

— Pregnancy planning: confirm biochemical remission and counsel about recurrence risk during gestation

— Avoid triggering medications: high-dose decongestants, MAOIs without coordination, stimulants

— Cardiac rehab if catecholamine cardiomyopathy or postop deconditioning

— Psychological support: many patients have anxiety from years of misdiagnosed spells; brief CBT helpful

— Endocrine support group / patient advocacy resources (Pheo Para Alliance)

Step 3 management: At every annual visit, document BP, HR, weight, HbA1c, plasma metanephrines, and screen for new symptoms; refer back to surgery if any biochemical abnormality.

Board pearl: Catecholamine cardiomyopathy EF typically recovers fully within 3–6 months after successful resection — repeat echo before declaring chronic HFrEF.

Follow-up cadence:

Monitoring parameters:

Patient counseling:

Rehabilitation:

Ethical, Legal, and Patient Safety Considerations

— Discuss perioperative mortality (~1–3% at high-volume centers, higher elsewhere), risk of intraoperative hypertensive crisis, post-resection hypotension, hypoglycemia, adrenal insufficiency, and recurrence

— For bilateral or planned cortical-sparing surgery: lifelong steroid dependence and Addisonian crisis risk

— Discuss alternative surgical approaches (laparoscopic vs open, cortical-sparing vs total)

— All confirmed PPGL patients should be offered germline testing per Endocrine Society 2014

— Pre-test counseling required: implications for insurability (GINA protects health insurance and employment but NOT life, disability, or long-term care insurance), family member implications, psychological impact

— Pediatric testing: balance early surveillance benefit against autonomy — generally test at age that surveillance would begin

— Cascade testing of family members requires consent and may create family tension

— Handoff from medical preparation to operating room: explicit communication of which drugs are safe and which to avoid (anesthesia checklist)

— Discharge handoff: ensure patient knows when α-blocker was stopped, what to do if HTN returns, who to contact

— Transition-of-care risk: a patient on phenoxybenzamine for unexplained HTN seen in a new ER without records may be given β-blocker → crisis. Provide patient with wallet card listing diagnosis and drug warnings

— Adverse events (e.g., intraoperative crisis, wrong-site surgery, medication error) require disclosure per institutional policy and patient safety standards (Joint Commission)

— Genetic findings: physician has a duty to inform the patient; the patient (not physician) typically informs family members, though some jurisdictions allow physician outreach with consent

— Patients in hypertensive encephalopathy lack capacity — use surrogate decision-maker for emergent treatment

— Refer to high-volume centers (>20 adrenalectomies/year) — value-based care and outcomes favor centralization

Step 3 management: Provide every PPGL patient with a MedicAlert bracelet and wallet card listing diagnosis, surgical status, and dangerous drugs (β-blocker monotherapy, metoclopramide, glucagon, certain anesthetics) — this is a tested transition-of-care safety intervention.

Informed consent for adrenalectomy:

Genetic testing — ethical considerations:

Patient safety in care transitions:

Mandatory reporting and disclosure:

Capacity and decision-making:

Health systems:

High-Yield Associations and Rapid-Fire Clinical Facts

— MEN2A: RET — MTC + pheo + primary hyperparathyroidism

— MEN2B: RET — MTC + pheo + mucosal neuromas + marfanoid habitus

— VHL: hemangioblastomas + RCC + pheo + pancreatic NETs

— NF1: café-au-lait + neurofibromas + Lisch nodules + pheo (5%)

— SDHB: highest malignancy risk; paragangliomas

— SDHD: parent-of-origin (paternal) inheritance

Board pearl: Bladder paraganglioma → spells with micturition and painless hematuria — cystoscopy plus metanephrines.

"Rule of 10s" — outdated: modern data: ~40% hereditary, ~15–20% extra-adrenal, malignancy varies (highest with SDHB).

Classic triad: episodic headache + palpitations + diaphoresis with HTN; specificity ~90%, sensitivity ~40%.

First test: plasma free or 24-hr urinary fractionated metanephrines (NOT VMA, NOT catecholamines alone).

Imaging after biochemistry: CT abdomen with contrast first; MRI if pregnant, child, or paraganglioma suspected.

CT features: HU >10 unenhanced, heterogeneous, slow washout (<50% absolute), often >3 cm.

MRI features: "Light bulb" T2 hyperintensity (only ~65% sensitive).

Functional imaging: ⁶⁸Ga-DOTATATE PET superior to MIBG for metastatic, SDHB, head/neck PGL.

Genetic testing: offer to ALL confirmed PPGL patients.

Hereditary syndromes:

Drugs to avoid in unprepared pheo: β-blockers as monotherapy, metoclopramide, droperidol, glucagon, ephedrine, ketamine, morphine, TCAs, MAOIs, halothane, succinylcholine (controversial), histamine releasers.

Preop preparation: 10–14 days α-blockade (phenoxybenzamine or doxazosin) → β-blocker if tachycardic → high salt + fluids → surgery.

Surgery first in MEN2: pheochromocytoma before thyroidectomy.

Post-resection hypotension: treat with volume + norepinephrine/vasopressin (not phenylephrine).

Biopsy contraindicated: never biopsy a suspected pheo.

Bilateral adrenalectomy: lifelong glucocorticoid + mineralocorticoid replacement; consider cortical-sparing.

Recurrence: 5–15% at 10 years; lifelong annual surveillance.

Carney triad: gastric GIST + pulmonary chondroma + paraganglioma (young women).

Carney-Stratakis dyad: GIST + paraganglioma (SDHx).

Board Question Stem Patterns

Board pearl: Whenever a stem starts a β-blocker on a patient with paroxysmal HTN and the BP gets worse — the answer is always pheochromocytoma.

Step 3 management: Recognize the trigger drug (β-blocker, metoclopramide, glucagon, contrast, anesthetic) → suspect pheo → confirm biochemically → α-blockade before β-blockade → surgery at high-volume center.

Stem 1 — Anesthesia crisis: "A 38-year-old undergoes elective cholecystectomy. After induction with halothane, BP rises to 240/130, HR 160, develops pulmonary edema..." → Answer: IV phentolamine, postpone surgery, screen with plasma metanephrines. Distractor: increase β-blocker (wrong).

Stem 2 — β-blocker first: "Resistant HTN treated with propranolol; develops severe headache, sweating, BP 220/130..." → Diagnosis: pheochromocytoma with unopposed α stimulation. Next step: stop propranolol, give phentolamine, start α-blockade with phenoxybenzamine, then resume β-blocker.

Stem 3 — Adrenal incidentaloma: "55-year-old with right adrenal mass found on CT for back pain; mass 4 cm, HU 25, washout 30%..." → Next step: plasma free metanephrines (and cortisol screening + ARR).

Stem 4 — MEN2: "Young patient with thyroid nodule, neck pain, calcium 11.2, BP 180/110, palpitations..." → MEN2A. Next step: plasma metanephrines and calcitonin before any surgery; resect pheo before thyroid.

Stem 5 — Pregnancy: "28-year-old at 18 weeks gestation, BP 200/120, no proteinuria, severe headaches..." → Pheo (not preeclampsia). Test: plasma metanephrines + MRI without gadolinium. Treat: phenoxybenzamine then labetalol.

Stem 6 — Family screening: "Father had pheo, son age 12 with HTN..." → Likely hereditary (VHL or MEN2). Genetic testing + plasma metanephrines.

Stem 7 — Post-resection hypotension: "Adrenalectomy completed, BP drops to 70/40 after tumor venous ligation..." → Treat: IV crystalloid + norepinephrine or vasopressin; check glucose (hypoglycemia common).

Stem 8 — Pseudopheochromocytoma: "Severe paroxysmal HTN, multiple negative metanephrines, anxious patient..." → Combined α/β-blockade + CBT.

Stem 9 — Bladder paraganglioma: "Spells during micturition + hematuria" → urinary catecholamines, cystoscopy, MRI pelvis.

Stem 10 — SDHB: "Young patient, extra-adrenal abdominal mass, bone metastases..." → SDHB paraganglioma; ⁶⁸Ga-DOTATATE PET; metyrosine + α-blockade + consider ¹³¹I-MIBG or ¹⁷⁷Lu-DOTATATE.

One-Line Recap

Pheochromocytoma is a catecholamine-secreting tumor diagnosed by elevated plasma free or 24-hour urinary fractionated metanephrines followed by CT/MRI, managed with at least 10–14 days of α-blockade (phenoxybenzamine or doxazosin) before β-blockade, volume repletion, and laparoscopic adrenalectomy at a high-volume center, with lifelong annual biochemical surveillance and genetic counseling for all patients.

Board pearl: The unifying Step 3 theme is sequence — biochemistry before imaging, α before β, preparation before surgery, surveillance forever — and the unifying patient safety theme is the MedicAlert bracelet + wallet card warning future clinicians about danger drugs.

Step 3 management: Any patient with resistant HTN, paroxysmal spells, adrenal incidentaloma, or a hereditary syndrome (MEN2, VHL, NF1, SDHx) deserves plasma free metanephrines today — the test is cheap, the disease is curable, and the missed diagnosis is lethal under anesthesia.

Diagnosis: plasma or urinary metanephrines first → CT abdomen with contrast → ⁶⁸Ga-DOTATATE PET for metastatic/SDHB/paraganglioma → germline genetic testing in every confirmed case.

Preop preparation: α-blockade 10–14 days (phenoxybenzamine 10 mg BID titrated, or doxazosin) → β-blocker only after α-blockade if tachycardic → high-sodium diet + IV fluids → target Roizen criteria.

Never: start a β-blocker before α-blockade, biopsy a suspected pheo, give metoclopramide/glucagon/ephedrine unprepared, or operate without preparation. In MEN2, always resect pheochromocytoma before thyroidectomy.

Postop: confirm biochemical cure at 4–6 weeks, manage post-resection hypotension with volume + norepinephrine/vasopressin, monitor glucose, replace steroids if bilateral adrenalectomy, and commit to lifelong annual plasma metanephrines given 5–15% recurrence risk.