Phaeochromocytoma is a catecholamine-secreting tumor arising from chromaffin cells of the adrenal medulla, causing episodic or sustained hypertension along with the classic triad of headache, sweating, and palpitations.

Phaeochromocytoma

2. Epidemiology

Feature	Detail
Incidence	~0.8 per 100,000/year ^[3]
Proportion of HTN	< 0.2% of all hypertensive patients ^[3]
Age	Any age, but peak in 4th–5th decades (30–50 years) ^[3]
Sex	M:F = 1:1 ^[3]
Presentation	~60% discovered incidentally on imaging (adrenal incidentaloma) ^[2]
Familial	Up to 30–40% have a germline mutation (historically quoted as 10%, but modern genetic testing has revised this upward)

10% Rule	Meaning
10% familial	(actually closer to 30–40% with modern genetic testing)
10% bilateral	(higher if familial, e.g. MEN2 up to 50% bilateral)
10% extra-adrenal	(paraganglioma)
10% malignant	(now reclassified — see below)
10% secrete adrenaline/dopamine	(cf. 90% secrete noradrenaline predominantly)
10% in children
10% not associated with HTN
10% recurrence after surgery

Exam Pearl

The "10% rule" is a classic exam favourite. However, be aware that the 10% familial figure is outdated — current data show that up to 30–40% of PPGLs harbour germline mutations. The Endocrine Society now recommends genetic testing for all patients with PPGL.

3. Anatomy and Function of the Adrenal Medulla

The biosynthetic pathway in chromaffin cells is almost identical to that in sympathetic neurone terminals, with one additional step ^[3]:

Tyrosine
  ↓ (Tyrosine hydroxylase — rate-limiting step)
DOPA (dihydroxyphenylalanine)
  ↓ (DOPA decarboxylase)
Dopamine
  ↓ (Dopamine β-hydroxylase)
Noradrenaline
  ↓ (Phenylethanolamine-N-methyltransferase / PNMT — ONLY in adrenal medulla, cortisol-dependent)
Adrenaline

Catecholamine	Receptor Profile	Source	Major Action
Noradrenaline	α₁ + β₁ (no significant β₂)	Major circulating catecholamine at rest; 95% from peripheral sympathetic nerve endings, 5% from adrenal medulla	↑BP (vasoconstriction via α₁), modest ↑HR (β₁)
Adrenaline	β₁ + β₂ (little α₁)	Represents true adrenal medullary secretion	↑CO (β₁), bronchodilation + vasodilation (β₂), little direct effect on BP at physiological doses
Dopamine	Varying (D₁, D₂, α, β at high concentrations)	Released during intense medullary activity; majority of circulating dopamine is of renal origin	Renal vasodilation (low dose), ↑CO (moderate dose), vasoconstriction (high dose)

Receptor	Location	Effect
α₁	Vascular smooth muscle, pupil dilator	Vasoconstriction → ↑SVR → ↑BP; mydriasis
α₂	Presynaptic nerve terminals	Negative feedback → ↓noradrenaline release
β₁	Heart (SA node, AV node, myocardium)	↑HR (chronotropy), ↑contractility (inotropy), ↑conduction (dromotropy)
β₂	Bronchial smooth muscle, vascular smooth muscle (skeletal muscle beds), liver, uterus	Bronchodilation, vasodilation, glycogenolysis, relaxation of uterus
β₃	Adipose tissue	Lipolysis, thermogenesis

4. Aetiology

All are autosomal dominant inheritance:

Syndrome	Gene	Associated Features	Phaeo Characteristics
MEN2A	RET proto-oncogene (tyrosine kinase receptor)	Medullary thyroid carcinoma + Phaeochromocytoma + Parathyroid hyperplasia ^[1]	Bilateral in 50–80%; almost always adrenal; often adrenaline-predominant
MEN2B	RET proto-oncogene	Medullary thyroid carcinoma + Phaeochromocytoma + Mucosal neuromas/intestinal ganglioneuromatosis ^[1]	Similar to MEN2A; Marfanoid habitus
Von Hippel-Lindau (VHL) disease	VHL gene (3p25)	Clear cell RCC (40%), renal cysts (75%), cerebellar haemangioblastoma, retinal angiomas, epididymal/pancreatic cysts ^[5]	Often bilateral; extra-adrenal in ~30%; noradrenaline-predominant
Neurofibromatosis type 1 (NF1)	NF1 gene (17q11.2)	Café-au-lait macules, neurofibromas, axillary freckling, Lisch nodules, optic glioma ^[6]	Usually unilateral adrenal; ~2% of NF1 patients develop phaeo
Familial paraganglioma syndromes	SDHx genes (SDHA, SDHB, SDHC, SDHD) — succinate dehydrogenase subunits	Paragangliomas (head/neck + sympathetic chain)	SDHB mutations carry highest malignancy risk (up to 30–40%)
Carney triad	SDH gene mutation ^[2]	GIST + pulmonary chondroma + paragangliomas	Rare; usually in young women

MEN Syndromes — Table

Type	Gene	Components	Mnemonic
MEN1	MEN1 (menin)	Pancreatic endocrine tumour + Pituitary adenoma (prolactinoma) + Parathyroid hyperplasia	"3 P's"
MEN2A	RET	Medullary thyroid CA + Phaeochromocytoma + Parathyroid hyperplasia
MEN2B	RET	Medullary thyroid CA + Phaeochromocytoma + Mucosal neuromas

Clinical Pearl — Screen for phaeo before thyroidectomy in MEN2

In MEN2 patients presenting with medullary thyroid carcinoma, you MUST screen for and exclude phaeochromocytoma before performing thyroidectomy. Operating on an undiagnosed phaeo can trigger a fatal catecholamine crisis during anaesthesia induction.

Location	Percentage
Para-aortic (including Organ of Zuckerkandl*)	75%
Urinary bladder	10%
Thorax (posterior mediastinum)	10%
Skull base / neck / pelvis	5%

*The Organ of Zuckerkandl is the largest collection of extra-adrenal chromaffin tissue, located at the aortic bifurcation near the origin of the inferior mesenteric artery. It is the most common site of extra-adrenal phaeochromocytoma (sympathetic paraganglioma).

5. Pathophysiology

Effect	Mechanism
Hyperglycaemia	β₂ stimulation → hepatic glycogenolysis + gluconeogenesis; α₂ stimulation → inhibition of insulin secretion from pancreatic β-cells
Weight loss	↑basal metabolic rate from sustained catecholamine-driven thermogenesis; lipolysis via β₃ receptors
Lactic acidosis	Excessive vasoconstriction → tissue hypoperfusion → anaerobic metabolism
Hypercalcaemia	Rare; may be due to PTHrP secretion by the tumour, or co-existing hyperparathyroidism (MEN2A)

Manifestation	Mechanism
Catecholamine cardiomyopathy	Direct myocardial toxicity from chronic catecholamine exposure → contraction band necrosis, myocardial fibrosis → dilated cardiomyopathy ^[4]
Takotsubo-like cardiomyopathy	Catecholamine-mediated stunning of the myocardium → transient apical ballooning
Arrhythmias	β₁ stimulation → ↑automaticity, ↑conduction velocity; can cause sinus tachycardia, SVT, VT, VF
Acute pulmonary oedema (APO)	From acute LV failure during catecholamine surge; or from flash pulmonary oedema due to acute ↑afterload ^[2]

6. Classification

Classification	Description
Phaeochromocytoma	Adrenal medulla (80–85%)
Paraganglioma	Extra-adrenal chromaffin tissue (15–20%)

Type	Description
Functional (secretory)	Produce catecholamines → clinical symptoms; most phaeochromocytomas and sympathetic paragangliomas
Non-functional (non-secretory)	Parasympathetic paragangliomas (head/neck) are typically non-functional

Phenotype	Predominant Secretion	Typical Associations
Adrenergic	Adrenaline (± noradrenaline)	MEN2, NF1
Noradrenergic	Noradrenaline	VHL, SDHx, sporadic
Dopaminergic	Dopamine	SDHx (SDHB); may present with fewer classic symptoms; more likely malignant

7. Clinical Features

Symptom	Pathophysiological Basis
Paroxysmal headache (60–90%)	Acute ↑BP from catecholamine surges → cerebral vasoconstriction/vasodilation → throbbing headache. Part of the "classic triad" ^[2]
Sweating / diaphoresis (55–75%)	Generalised sympathetic activation → eccrine sweat gland stimulation via α₁ and muscarinic receptors. Part of the "classic triad" ^[2]
Palpitations (50–70%)	β₁ stimulation → ↑HR and ↑force of contraction → patient perceives the heart beating forcefully/rapidly. Part of the "classic triad" ^[2]
Anxiety / panic	Catecholamine excess mimics the fight-or-flight response → sense of impending doom, nervousness, tremor. Can mimic panic disorder ^[7]
Tremor	β₂ stimulation of skeletal muscle → fine resting tremor (same mechanism as salbutamol-induced tremor)
Chest pain	↑myocardial oxygen demand (↑HR, ↑contractility) in setting of coronary vasoconstriction (α₁) → supply-demand mismatch. Can also be from catecholamine-induced coronary spasm
Dyspnoea	From acute LV failure / pulmonary oedema during catecholamine surges, or from chronic catecholamine cardiomyopathy
Nausea / vomiting / abdominal pain	Sympathetic activation → ↓GI motility + mesenteric vasoconstriction; also direct effect of catecholamines on the chemoreceptor trigger zone
Constipation	α and β adrenergic stimulation → ↓GI motility (sympathetic inhibition of peristalsis)
Weight loss	↑basal metabolic rate from chronic catecholamine-driven thermogenesis + lipolysis
Visual disturbance	Hypertensive retinopathy during severe hypertensive episodes
Flushing (uncommon; pallor more typical)	Some adrenaline-predominant tumours → transient β₂-mediated vasodilation → flushing; but the majority cause pallor from α₁-mediated vasoconstriction

The Classic Triad

Paroxysmal headache + sweating + palpitations — this triad has a sensitivity of ~90% and specificity of ~94% for phaeochromocytoma in hypertensive patients. If all three are present with paroxysmal hypertension, the positive predictive value is very high.

Sign	Pathophysiological Basis
Hypertension — sustained (50%) or paroxysmal (30%)	α₁ → vasoconstriction → ↑SVR; β₁ → ↑CO. May be severe (> 200/120). Some patients have apparently treatment-resistant hypertension ^[2]
Postural (orthostatic) hypotension	Chronic catecholamine excess → ↓plasma volume (pressure natriuresis) + α-receptor downregulation → blunted baroreceptor reflex on standing ^[2]
Tachycardia	β₁ stimulation → ↑SA node firing rate
Pallor (not flushing!)	α₁-mediated cutaneous vasoconstriction ^[2]
Diaphoresis (visible sweating)	Generalised sympathetic-driven sweating
Tremor	β₂ stimulation of skeletal muscle
Dilated pupils (mydriasis)	α₁ stimulation of the pupil dilator muscle (sympathetic mydriasis)
Hypertensive retinopathy	Chronic/acute severe hypertension → arteriolar damage → haemorrhages, exudates, papilloedema
Fever / low-grade temperature	↑metabolic rate + impaired heat dissipation from cutaneous vasoconstriction
Hyperglycaemia (may present as new-onset diabetes)	β₂ → glycogenolysis + gluconeogenesis; α₂ → ↓insulin secretion
Signs of associated syndromes (see below)	Must examine for café-au-lait spots (NF1), retinal angiomas (VHL), Marfanoid habitus / mucosal neuromas (MEN2B), thyroid nodules (MEN2 → MTC)

Presentation	Frequency	Details
Incidental discovery	~60% ^[2]	Found on cross-sectional imaging (CT/MRI) for unrelated reasons → "adrenal incidentaloma" ^[8]
Classic symptomatic	~30%	Triad of headache + sweating + palpitations ± paroxysmal HTN
Phaeochromocytoma crisis	Rare but life-threatening	APO, ICH, malignant arrhythmia ^[2]

Syndrome	Key Examination Findings
MEN2A	Thyroid nodule (MTC), hypercalcaemia (hyperparathyroidism), family history
MEN2B	Mucosal neuromas (lips, tongue), Marfanoid habitus, thyroid nodule (MTC), intestinal ganglioneuromatosis (constipation)
VHL	Retinal angiomas (fundoscopy), cerebellar haemangioblastoma (ataxia), renal masses (RCC), pancreatic cysts
NF1	≥6 café-au-lait macules, axillary/inguinal freckling (Crowe sign), neurofibromas, Lisch nodules (iris), optic glioma
SDHx (Carney-Stratakis / familial paraganglioma)	Head/neck paragangliomas, GIST

High Yield Summary

Definition: Phaeochromocytoma = catecholamine-secreting tumour from chromaffin cells of adrenal medulla; paraganglioma = extra-adrenal chromaffin tumour.

Epidemiology: Rare (0.8/100k/yr), < 0.2% of HTN, peak 4th–5th decade, M=F. The "10% rule" is classic but outdated — 30–40% are now known to be familial.

Anatomy: Adrenal medulla from neural crest. Dual blood supply — corticomedullary portal system exposes medullary cells to cortisol → induces PNMT → explains why adrenal tumours produce adrenaline but extra-adrenal do not.

Aetiology: Sporadic (60–70%), familial (30–40%) — MEN2 (RET), VHL, NF1, SDHx, Carney triad. SDHB carries highest malignancy risk. All PPGL patients should undergo genetic testing.

Pathophysiology: Excess catecholamines → α₁ (vasoconstriction → HTN, pallor) + β₁ (↑HR, ↑contractility → palpitations) + β₂ (glycogenolysis, tremor) + metabolic effects (hyperglycaemia, weight loss). Chronic catecholamine excess → volume depletion + receptor downregulation → orthostatic hypotension.

Classic triad: Paroxysmal headache + sweating + palpitations (sensitivity ~90%, specificity ~94% in HTN patients).

5 Ps: Pressure, Pain, Palpitation, Perspiration, Pallor.

Crisis triggers: Tumour palpation, anaesthesia, drugs (TCAs, metoclopramide, β-blockers without α-block), contrast, tyramine-rich foods.

Red flags for screening: Young-onset HTN, treatment-resistant HTN, paroxysmal HTN + orthostatic hypotension, adrenal incidentaloma, family history of MEN2/VHL/NF1/SDHx.

Never give β-blockers without prior α-blockade → unopposed α stimulation → hypertensive crisis.

Metanephrines: Plasma free metanephrines are the best screening test because COMT within chromaffin cells constitutively converts catecholamines to metanephrines regardless of episodic secretion.

Active Recall - Phaeochromocytoma (Definition, Epidemiology, Anatomy, Aetiology, Pathophysiology, Clinical Features)

Differential Diagnosis of Phaeochromocytoma

The differential diagnosis of phaeochromocytoma is essentially the differential diagnosis of its presenting features — namely, paroxysmal hypertension, episodic sympathetic-type symptoms (headache, sweating, palpitations, pallor), and/or an adrenal incidentaloma. Let's approach this systematically from first principles.

This is the classic phaeo presentation. The question is: what else causes paroxysmal blood pressure surges with headache, sweating, palpitations, and pallor?

Differential	Key Distinguishing Features	Why It Mimics Phaeo
Essential (primary) hypertension	Most common cause of HTN (> 90%); usually sustained, not paroxysmal; no orthostatic hypotension; normal metanephrines	Does not truly mimic phaeo, but is so common that most hypertensive patients being screened will have this
Panic disorder / anxiety disorders ^[7]	Episodic palpitations, sweating, tremor, chest tightness, sense of doom; BUT associated with flushing (not pallor), no true sustained HTN between episodes, normal metanephrines; symptoms often triggered by psychological stressors not physical ones	Catecholamine-like fight-or-flight response from central sympathetic activation; but the BP rise is modest and there is no true catecholamine excess
Thyrotoxicosis	Persistent (not episodic) symptoms: heat intolerance, weight loss, tremor, diarrhoea, lid lag/retraction, goitre; predominantly systolic HTN with wide pulse pressure	↑β-adrenergic sensitivity from thyroid hormone excess causes tachycardia, sweating, tremor — but not usually episodic ^[3]
Hypoglycaemia	Sweating, palpitations, tremor, anxiety; but a/w neuroglycopenic symptoms (confusion, seizures); relieved by glucose; usually in context of diabetes treatment or insulinoma	Sympathoadrenal counter-regulatory response to low glucose mimics catecholamine excess; tends to be episodic and more likely to mimic phobic disorder or panic disorder ^[7]
Renovascular hypertension / renal artery stenosis	Resistant HTN, abdominal bruit, flash pulmonary oedema, worsening renal function on ACEi/ARB ^[4]	Can cause severe HTN via RAAS activation but lacks the episodic sympathetic symptoms
Primary aldosteronism (Conn's syndrome)	Resistant HTN + hypokalaemia + metabolic alkalosis; muscle cramps, weakness; differentiated by plasma aldosterone-to-renin ratio (ARR) ^[4]	Causes secondary HTN but without paroxysmal catecholamine-type symptoms
Cushing's syndrome	Central obesity, moon face, buffalo hump, striae, proximal myopathy, hyperglycaemia; screened by overnight 1mg dexamethasone suppression test ^[4]^[9]	Cortisol excess causes HTN via mineralocorticoid activity and ↑vascular sensitivity to catecholamines; can co-exist with phaeo in rare cases
Drug-induced hypertensive crises	History of substance use: cocaine, amphetamines, MAOIs + tyramine, sympathomimetics, decongestants, TCAs; abrupt clonidine/methyldopa withdrawal ^[4]	Exogenous sympathomimetic stimulation causes identical catecholamine-excess symptoms; always take a thorough drug history
Obstructive sleep apnoea (OSA)	Resistant HTN, obesity, snoring, daytime somnolence; nocturnal BP surges; screened by polysomnography ^[4]	Intermittent hypoxia → sympathetic activation → nocturnal HTN surges
Coarctation of the aorta	Young HTN (< 30y), upper limb > lower limb BP, radiofemoral delay, continuous murmur over chest/back ^[4]	Mechanical obstruction causes upper body HTN; but no episodic symptoms
Autonomic dysreflexia	Only in spinal cord injury above T6; paroxysmal HTN triggered by bladder distension, bowel impaction; flushing above level of lesion, pallor below	Uninhibited sympathetic discharge below the level of spinal cord lesion
Carcinoid syndrome	Episodic flushing (not pallor), diarrhoea, wheezing, right heart valve disease; screened by 24h urine 5-HIAA	Serotonin and other vasoactive substances cause episodic vasomotor symptoms — but carcinoid causes flushing whereas phaeo causes pallor ^[3]
Baroreflex failure	History of neck surgery/radiation (e.g. carotid endarterectomy, radical neck dissection); volatile BP with both severe HTN and hypotension	Damage to baroreceptors → loss of buffering capacity → wide BP swings with sympathetic surges

Phaeo vs Panic: A Classic DDx Trap

Both conditions cause episodic palpitations, sweating, and a sense of doom. The key differences: (1) Pallor in phaeo vs flushing in panic (α₁ vasoconstriction vs anxiety-mediated vasodilation). (2) Severe hypertension during attacks in phaeo (often > 200 systolic) vs modest or normal BP in panic. (3) Postural hypotension between attacks in phaeo (volume depletion + receptor downregulation) — not a feature of panic disorder. (4) Normal plasma/urine metanephrines exclude phaeo. Panic attacks can occur as a result of phaeochromocytoma ^[7] — so always consider biochemical screening in atypical or refractory panic presentations, especially with concurrent hypertension.

This is explicitly highlighted in the senior notes and is a high-yield differential:

Condition	Sweating?	Flushing?	Key Distinguishing Points
Oestrogen/testosterone deficiency (e.g. menopause, castration)	Yes	Yes (hot flushes)	Typical age/context; hormone levels confirm; responsive to HRT
Carcinoid syndrome	Possible	Yes (flushing, diarrhoea, wheeze)	Episodic flushing + diarrhoea + wheezing; 24h urine 5-HIAA elevated; right-sided valve disease
Phaeochromocytoma	Yes	No — sweats but does NOT flush	Pallor (not flushing) due to α₁-mediated vasoconstriction; elevated plasma/urine metanephrines
Thyrotoxicosis	Yes	Possible	Not usually episodic — symptoms are persistent; check TFTs
Systemic mastocytosis	Yes	Yes (histamine release)	Urticaria pigmentosa, anaphylaxis; elevated serum tryptase
Allergy	Possible	Yes	Identifiable trigger; associated urticaria/angioedema; IgE-mediated

Key Distinction: Sweating WITHOUT Flushing = Think Phaeo

Phaeochromocytoma causes pallor during attacks (α₁-mediated vasoconstriction), NOT flushing. If a patient has episodic sweating with flushing, think menopause, carcinoid, or mastocytosis instead. This is a classic distinguishing feature ^[3].

When a phaeochromocytoma is discovered incidentally on imaging (which accounts for ~60% of cases ^[2]), the differential is that of any adrenal mass:

Cause	Approximate Frequency	Key Features
Non-functioning adenoma	85%	Lipid-rich (< 10 HU on unenhanced CT), homogeneous, well-defined, < 4 cm
Subclinical Cushing's (cortisol-secreting adenoma)	5–10%	Mild autonomous cortisol secretion; abnormal 1mg DST; may have subtle Cushingoid features
Phaeochromocytoma	~5%	Lipid-poor ( > 10 HU), ↑vascularity, heterogeneous, may be large; MUST exclude before biopsy ^[8]
Primary aldosteronism (Conn's adenoma)	~1% (if hypertensive)	HTN + hypokalaemia; ↑aldosterone, ↓renin
Adrenocortical carcinoma	~2% (higher if > 4 cm)	Large ( > 4 cm), heterogeneous, irregular margins, delayed contrast washout, calcification; may secrete androgens/cortisol
Metastasis (from lung, breast, melanoma, renal, etc.)	~2–5%	History of known primary malignancy; bilateral in 50%; biopsy may be indicated only after excluding phaeo
Others	Rare	Myelolipoma (fat-containing, pathognomonic on CT), ganglioneuroma, haemorrhage, cyst, granuloma (TB, sarcoid)

Never Biopsy an Adrenal Mass Without Excluding Phaeo First

Biopsy is NOT for primary adrenal tumours — especially avoid if phaeochromocytoma is possible ^[8]. Biopsy of an undiagnosed phaeo can trigger a fatal catecholamine crisis. Additionally, histology cannot reliably distinguish benign from malignant primary adrenal tumours. Always check plasma/urine metanephrines before any adrenal biopsy.

Phaeochromocytoma is one cause within the broader differential of secondary hypertension. The mnemonic DANCER helps organise this:

Letter	Cause	Screen When	Screen By
D	Drugs (OCP, NSAIDs, steroids, sympathomimetics, cocaine, amphetamines, TCA, cyclosporine) ^[4]	Always — take a thorough drug history	Drug history
A	Apnoea (obstructive sleep apnoea)	Resistant HTN + obesity + snoring + daytime sleepiness	Polysomnography
N	Neurological (↑ICP, stress, autonomic dysfunction)	Clinically indicated	Clinical evaluation
C	Coarctation of aorta	Young HTN < 30y, radiofemoral delay, UL > LL BP	Echocardiogram, CTA/MRA thorax
E	Endocrine	Clinically indicated	See below
R	Renal (parenchymal disease, renal artery stenosis)	Abnormal urinalysis, renal bruit, worsening renal function on ACEi	Renal USG, duplex USG, MRA

Endocrine causes further broken down ^[4]:

Thyroid: hyperthyroidism (systolic HTN), hypothyroidism (diastolic HTN)
Adrenal: Cushing's syndrome, Conn's syndrome, phaeochromocytoma
Parathyroid: hyperparathyroidism (hypercalcaemia → HTN)
Others: pre-eclampsia, acromegaly

Cause	Prevalence Among HTN	Screen By ^[4]
Primary aldosteronism	8–20%	Plasma ARR → salt loading test
Renal artery stenosis	5–34%	Renal duplex USG → MRA → CT abdomen
Renal parenchymal disease	1–2%	Renal USG → renal biopsy
OSA	25–50%	Polysomnography
Coarctation of aorta	0.1%	Echocardiogram → CTA/MRA
Phaeochromocytoma / paraganglioma	0.1–0.6%	24h urine fractionated metanephrines → plasma metanephrines ^[4]
Cushing's syndrome	< 0.1%	Overnight 1mg DST

Feature	Phaeochromocytoma	Panic Disorder	Thyrotoxicosis	Carcinoid	Menopause
Episodic	Yes	Yes	No (persistent)	Yes	Yes
HTN	Severe, paroxysmal	Mild/absent	Systolic (wide PP)	Usually absent	Usually absent
Pallor vs Flush	Pallor	Flushing	Flushing	Flushing	Flushing
Sweating	Profuse	Present	Present	Variable	Present
Orthostatic hypotension	Yes (characteristic)	No	No	No	No
Screening test	Metanephrines	Clinical/psychometric	TFTs	24h urine 5-HIAA	FSH/oestradiol

High Yield Summary

The DDx of phaeochromocytoma is the DDx of paroxysmal sympathetic symptoms + hypertension:

Most important mimics: Panic disorder, thyrotoxicosis, drug-induced HTN crisis, hypoglycaemia
Episodic sweating DDx ^[3]: Menopause, carcinoid (flushing + diarrhoea + wheeze), phaeo (sweats but does NOT flush), thyrotoxicosis (not episodic), systemic mastocytosis, allergy
Key distinguisher: Phaeo = pallor (α₁ vasoconstriction); most other causes = flushing
Adrenal incidentaloma DDx ^[8]: Non-functioning adenoma (85%), subclinical Cushing's, phaeo, Conn's, adrenal carcinoma, metastasis — always exclude phaeo before biopsy
Secondary HTN framework (DANCER) ^[4]: Drugs, Apnoea, Neurological, Coarctation, Endocrine (thyroid, adrenal — Cushing's/Conn's/phaeo, parathyroid), Renal
Screening indications ^[3]: compatible symptoms, atypical HTN (young/resistant/paroxysmal), genetic syndrome risk (MEN2/VHL/NF1), adrenal incidentaloma with CT > 10 HU, pressor response during procedures, idiopathic DCMP
Screening test: 24h urine fractionated metanephrines (Sens 98%, Spec 98%) or plasma fractionated metanephrines (Sens 96–100%, Spec 85–89%) ^[3]

Active Recall - Phaeochromocytoma Differential Diagnosis

References

^[2] Senior notes: maxim.md (Phaeochromocytoma — Definitions, Clinical features, 5 Ps, 10% rule) ^[3] Senior notes: Ryan Ho Endocrine.pdf (Section 3.4 Phaeochromocytoma — Clinical features, DDx of episodic sweating/flushing, indications for screening, diagnosis) ^[4] Senior notes: Ryan Ho Cardiology.pdf (p177–178 — Secondary HTN workup, DANCER mnemonic, screening table for 2° HTN causes) ^[7] Senior notes: Ryan Ho Psychiatry.pdf (p175, p179 — Phaeochromocytoma mimicking panic disorder/anxiety; panic DDx includes phaeo, hyperthyroidism, hyperPTH) ^[8] Senior notes: Ryan Ho Fundamentals.pdf (p438 — Adrenal incidentaloma DDx and approach; contraindication to biopsy without excluding phaeo) ^[9] Senior notes: Ryan Ho Chemical Path.pdf (p29 — Diagnosis of Cushing's syndrome, DST)

Diagnostic Criteria, Algorithm and Investigations for Phaeochromocytoma

10.2 Pre-Analytical Considerations — Before You Even Order the Test

This is a step many students overlook, but it is critical for accurate interpretation.

Stop drugs affecting catecholamine secretion before testing ^[3]:

Drug Class	Mechanism of Interference	Action
Tricyclic antidepressants (TCAs)	Block noradrenaline reuptake → ↑plasma normetanephrine	Stop ≥1 week before testing ^[2]
α-agonists (e.g. clonidine, methyldopa)	Interfere with catecholamine metabolism	Stop before testing
Levodopa	Precursor of dopamine → converted to catecholamines	Stop before testing
Amphetamines, cocaine	Sympathomimetics → ↑catecholamine release	Stop before testing
MAO inhibitors	Block catecholamine degradation → ↑levels	Stop before testing
Paracetamol (acetaminophen)	Analytical interference with some HPLC-based metanephrine assays	Avoid for 48h before some lab assays
Caffeine, nicotine, alcohol	Sympathetic stimulation → modest ↑catecholamines	Avoid on testing day

Condition	Mechanism
Stress (acute illness, surgery, pain)	Physiological sympathetic activation → ↑catecholamines
Obstructive sleep apnoea	Nocturnal hypoxia → sympathetic surges → ↑catecholamines ^[2]
Heart failure	Chronic sympathetic activation
Renal failure	↓Clearance of metanephrines (for urine tests); also ↑sympathetic tone

Exam Pearl — False Positives

The most common reason for a false-positive metanephrine result is failure to stop interfering medications and not controlling for physiological stress. Always check the drug history and testing conditions before interpreting results.

10.3 Biochemical Diagnosis — The First Step

The principle: prove the tumour is making excess catecholamines/metanephrines before looking for it on imaging.

Result	Interpretation	Next Step
Metanephrines > 2× ULN	Highly suggestive of phaeochromocytoma ^[2]	Proceed directly to imaging for localisation
Metanephrines 1–2× ULN	Borderline — could be phaeo or false positive	Repeat testing under ideal conditions (supine, no interfering drugs, no stress); consider clonidine suppression test
Metanephrines normal	Effectively excludes phaeo (negative predictive value > 99% for plasma free metanephrines)	No further workup unless clinical suspicion remains very high

10.4 Other Biochemical Investigations

10.5 Imaging for Localisation — The Second Step

Golden rule: Only image AFTER biochemical confirmation. The purpose of imaging is to locate the tumour for surgical planning, not to make the diagnosis.

Modality	Key Points
CT abdomen	Can usually identify adrenal + intra-abdominal extra-adrenal phaeochromocytomas ^[3]
	Detection rate: Sensitivity 98–100%, Specificity 70% in sporadic phaeochromocytoma ^[3]
	Findings: > 20 HU high attenuation, ↑vascularity, delayed contrast washout ^[3]
	Typically heterogeneous, well-vascularised, may contain areas of necrosis/haemorrhage
	IV iodinated contrast may induce a pressor crisis ^[3] → consider preparation with complete adrenoceptor blockade, e.g. phenoxybenzamine
	However: low-osmolar contrast is safe even without alpha/beta blockade ^[2] (modern non-ionic contrast agents have negligible risk)
MRI abdomen	Preferred in: children, pregnant women, patients with contrast allergy, SDHx carriers needing lifelong surveillance (to minimise cumulative radiation)
	T2-weighted hyperintense ("light bulb sign") ^[3] — phaeochromocytomas appear very bright on T2W MRI due to their high water content and vascularity
	No radiation exposure; similar sensitivity to CT

Why are phaeochromocytomas bright on T2-weighted MRI?

The tumour has a very high water content (large extracellular fluid component, areas of haemorrhage and necrosis, rich vascularity). Water has a long T2 relaxation time → appears hyperintense (bright) on T2-weighted sequences. This "light bulb" appearance, while not pathognomonic (cysts, some carcinomas can also be T2-bright), is highly suggestive in the right clinical context.

CT findings distinguishing phaeo from benign adenoma ^[3]^[8]:

Feature	Benign Adenoma	Phaeochromocytoma
Unenhanced CT attenuation	< 10 HU (lipid-rich)	> 20 HU (lipid-poor)
Contrast enhancement	Rapid washout (> 60% at 15 min)	Delayed contrast washout
Vascularity	Low	↑Vascularity
Homogeneity	Homogeneous	Often heterogeneous (necrosis, haemorrhage)
Size	Usually < 3 cm	Variable; often > 3 cm

Radiopharmaceutical: ¹²³I-MIBG (or ¹³¹I-MIBG)
Principle: MIBG is an analogue of norepinephrine ^[2]^[10] → taken up by norepinephrine-secreting cells (chromaffin cells) via the noradrenaline transporter (uptake-1 mechanism) → scintigraphy reveals adrenomedullary images 24–48 hours after injection ^[3]
Physiological distribution (organs supplied by sympathetic nervous system + excretion routes) ^[10]:
- Liver and spleen
- Myocardium
- Salivary glands and thyroid
- Normal adrenals
- Other organs (nasal mucosa, bladder, colon)
Thyroid blockade should be used as radioiodine in ¹³¹I-MIBG may localise to the thyroid and destroy glandular tissue (e.g. Lugol's solution) ^[10]

Feature	Detail
Sensitivity	~85–90% for adrenal phaeo; lower (~60%) for paraganglioma and metastatic disease
Specificity	~95–100% — very high (MIBG is specifically taken up by chromaffin tissue)
Indications	Negative initial CT/MRI abdomen, > 10 cm adrenal tumour (↑risk of metastases), paraganglioma (↑risk of multifocal or metastatic tumour) ^[3]
Clinical indications (from nuclear medicine) ^[10]	Diagnosis of phaeochromocytoma, neuroblastoma or other APUD cell tumours; staging and follow-up; detection of metastasis and recurrent disease; plan for MIBG therapy

When Do You Need MIBG Beyond CT/MRI?

CT/MRI is excellent for finding the primary adrenal tumour (~98% sensitivity). You need functional imaging (MIBG or PET) when: (1) CT/MRI is negative but biochemistry is strongly positive (the tumour may be extra-adrenal or occult), (2) the tumour is very large ( > 10 cm) raising concern for metastatic disease, or (3) the tumour is a paraganglioma which has a higher risk of being multifocal or metastatic ^[3].

Tracer	Mechanism	Indication
⁶⁸Ga-DOTATATE PET/CT	Binds to somatostatin receptors (SSTR2) on neuroendocrine tumour cells	For malignant/metastatic disease ^[3]; superior to MIBG for detecting metastatic PPGL; now considered best functional imaging for SDHx-related tumours
¹⁸F-FDG PET/CT	Detects ↑glucose metabolism in metabolically active tumours	For malignant disease ^[3]; useful when MIBG-negative; high sensitivity for SDHx-mutated (aggressive) tumours
¹⁸F-FDOPA PET/CT	Analogue of DOPA — taken up by catecholamine-synthesising cells	High sensitivity for head/neck paragangliomas; not universally available

Investigation	What It Measures	Sensitivity	Specificity	Key Points
24h urine fractionated metanephrines	Metanephrine + normetanephrine in urine	98%	98%	Best combined Sens/Spec; abnormal if > 2× ULN ^[2]^[3]
Plasma free metanephrines	Free metanephrine + normetanephrine in plasma	96–100%	85–89%	Highest sensitivity; preferred in CRF ^[2]^[3]; needs supine sampling with indwelling catheter
24h urine catecholamines	Adrenaline, noradrenaline, dopamine	~85%	~90%	Adjunct; episodic secretion may cause false negatives
24h urine VMA	Vanillylmandelic acid	~64%	~95%	Now superseded as less accurate ^[3]
Clonidine suppression test	Plasma normetanephrine/noradrenaline post-clonidine	~97%	~100%	For borderline cases; failure to suppress = autonomous secretion
Serum chromogranin A	Chromogranin A	Variable	Low	Useful tumour marker for metastatic disease ^[3]; elevated by PPIs
CT abdomen	Anatomical localisation	98–100%	70%	> 20 HU, ↑vascularity, delayed washout ^[3]; IV contrast may induce crisis ^[3]
MRI abdomen	Anatomical localisation	~98%	~70%	T2W hyperintense ^[3]; preferred in children/pregnancy
¹²³I-MIBG scan	Functional — NE analogue uptake by chromaffin tissue	~85–90%	~95–100%	Indications: negative CT/MRI, > 10 cm tumour, paraganglioma ^[3]; need thyroid blockade ^[10]
⁶⁸Ga-DOTATATE PET/CT	Somatostatin receptor binding	~90–100%	~90–95%	For metastatic disease ^[3]; best for SDHx-related PPGL
¹⁸F-FDG PET/CT	Glucose metabolism	~85%	~80%	For malignant disease ^[3]; high sensitivity for aggressive tumours
Genetic testing	Germline mutations	—	—	Indicated if: syndromic features, FHx, age < 50 ^[3]

10.8 Special Considerations

Historically, IV iodinated contrast was considered high-risk for triggering pressor crises in phaeo patients ^[3]
Modern low-osmolar non-ionic contrast agents are considered safe even without alpha/beta blockade ^[2]
However, if using ionic or high-osmolar contrast (now rare), alpha-blockade should be established first ^[3]

High Yield Summary

Diagnosis of phaeochromocytoma is a two-step process: (1) Biochemical confirmation, then (2) Anatomical/functional localisation.

Step 1 — Biochemistry:

First-line: 24h urine fractionated metanephrines (Sens 98%, Spec 98%) or plasma free metanephrines (Sens 96–100%, Spec 85–89%) ^[3]
Abnormal if > 2× ULN ^[2] → proceed to imaging
Borderline (1–2× ULN) → repeat under ideal conditions or perform clonidine suppression test
Stop interfering drugs ≥1 week before (TCAs, α-agonists, levodopa, amphetamines) ^[2]^[3]
Plasma metanephrines preferred in CRF ^[2]
24h urine VMA is now superseded as less accurate ^[3]
Biopsy is NOT required — high risk of hypertensive crisis and haematoma ^[2]

Step 2 — Localisation:

CT/MRI abdomen first-line (Sens 98–100%, Spec 70%): > 20 HU, ↑vascularity, delayed washout, T2W hyperintense ^[3]
MIBG scan: NE analogue uptake; indications: negative CT/MRI, > 10 cm tumour, paraganglioma ^[3]
⁶⁸Ga-DOTATATE or ¹⁸F-FDG PET/CT for metastatic disease ^[3]

Additional:

Serum chromogranin A for metastatic disease ^[3]
Genetic testing if: syndromic features, FHx, age < 50, bilateral/multifocal/extra-adrenal/metastatic ^[3]
Annual metanephrine screening from age 11–16 in genetic syndrome carriers ^[3]

Active Recall - Phaeochromocytoma Diagnosis

References

^[2] Senior notes: maxim.md (Phaeochromocytoma — Investigations, biopsy contraindication, false positives, MIBG, PET-CT) ^[3] Senior notes: Ryan Ho Endocrine.pdf (Section 3.4 — Diagnosis: urine/plasma metanephrines performance, CT/MRI findings, MIBG indications, PET/CT for metastatic disease, chromogranin A, genetic testing indications, MEN2 screening) ^[8] Senior notes: Ryan Ho Fundamentals.pdf (p438 — Adrenal incidentaloma approach, CT attenuation > 10 HU, biopsy contraindication) ^[9] Senior notes: Ryan Ho Chemical Path.pdf (p29 — Diagnostic function tests, DST for Cushing's) ^[10] Senior notes: Ryan Ho Diagnostic Radiology.pdf (p71 — MIBG scan principle, clinical indications, physiological distribution, thyroid blockade; p79 — Adrenal venous sampling)

Management of Phaeochromocytoma

11.3 Pre-Operative Medical Preparation

This is the most critical phase of management. The purpose is to prevent intra-operative catecholamine crisis — because during surgery, tumour manipulation causes massive catecholamine release into the circulation, which can cause fatal arrhythmia, hypertensive crisis, stroke, or APO.

Why α-blockade first?

The dominant haemodynamic effect of catecholamine excess is α₁-mediated vasoconstriction → ↑SVR → severe hypertension. You must antagonise this before doing anything else.

Drug	Mechanism	Dosing	Key Points
Phenoxybenzamine	Non-competitive (irreversible) α-blocker ^[3]	Start 10 mg BD, titrate up every 2–3 days to 20–40 mg BD (max ~1 mg/kg/day)	Preferred over competitive α-blockers (e.g. terazosin) ^[3] because irreversible binding means it cannot be displaced by the massive catecholamine surges during tumour manipulation; side effect: stuffy nose (nasal mucosal vasodilation), postural hypotension, reflex tachycardia ^[2]
Doxazosin / Prazosin / Terazosin	Competitive (reversible) selective α₁-blockers	Doxazosin: 2–8 mg daily	Alternative; shorter acting; can be displaced by catecholamine surges → less reliable peri-operatively, but fewer side effects (less reflex tachycardia, less nasal congestion)
Dihydropyridine CCBs (e.g. nifedipine, amlodipine)	Block L-type Ca²⁺ channels in vascular smooth muscle → vasodilation	As per standard dosing	Alternative to alpha-blockers ^[3]; useful as add-on therapy if BP not controlled with α-blocker alone; can be used as monotherapy if α-blockers not tolerated

Why is Phenoxybenzamine Non-Competitive and Why Does That Matter?

"Non-competitive" means phenoxybenzamine forms a covalent bond with the α-adrenergic receptor — it binds irreversibly and cannot be displaced, even by massive catecholamine surges. During tumour manipulation at surgery, the catecholamine levels can spike to hundreds of times normal. A competitive blocker (like doxazosin) can be overwhelmed by this flood of catecholamines because they compete for the same receptor binding site. Phenoxybenzamine cannot be overcome — this is why it's the traditional gold-standard for peri-operative α-blockade ^[3].

Adequate α-blockade is indicated by a postural BP drop ^[3] — this tells you that the α₁ receptors are sufficiently blocked such that the normal vasoconstriction on standing is impaired.

Target of pre-operative preparation ^[2]:

BP < 130/80 mmHg seated (some guidelines say < 140/90)
HR 60–70 bpm seated
Postural hypotension present (but SBP standing > 80 mmHg)
No ST-segment changes on ECG for > 1 week

Why β-blockade?

Once α-blockade is established, the patient often develops reflex tachycardia (because α-blockade → vasodilation → baroreceptor-mediated ↑sympathetic drive → β₁ stimulation → ↑HR). Also, the catecholamine excess itself directly stimulates β₁ receptors. β-blockade controls this.

ALWAYS initiate α-blockade before β-blockade ^[3]. β-blockade alone will cause unopposed α-adrenergic activity → exacerbate HTN ^[3].

Drug	Mechanism	Dosing	Key Points
Propranolol	Non-selective β-blocker (β₁ + β₂)	20–40 mg TDS, start 2–3 days pre-operatively ^[2]	Classic choice; controls both HR and catecholamine-induced arrhythmias
Atenolol / Metoprolol	Selective β₁-blocker	Standard dosing	Alternative; less bronchospasm risk (relevant if asthma)
Labetalol	Combined α₁ + β-blocker (β:α ratio ~7:1)	See crisis section below	NOT ideal as sole pre-operative agent because the β:α ratio is heavily β-dominant → may not provide adequate α-blockade; some authorities avoid it for routine pre-op preparation

Common Exam Mistake

Never give a β-blocker without prior α-blockade in phaeo. If you block β₂-mediated vasodilation (in skeletal muscle beds) without blocking α₁-mediated vasoconstriction, you get unopposed vasoconstriction → hypertensive crisis. This is one of the most tested concepts in phaeo management. The mnemonic is: "A before B" — α before β.

11.4 Surgical Therapy — The Definitive Treatment

Surgery is the only curative treatment for phaeochromocytoma. The goal is complete tumour removal.

Approach	Indication	Details
Laparoscopic adrenalectomy	First-line ^[2]; for tumours < 6 cm	Laparoscopic, robotic with retroperitoneal or transabdominal approach ^[3]; lateral decubitus, ipsilateral side up; minimally invasive → faster recovery, less pain
Open adrenalectomy	If large tumour ( > 6 cm) or suspected malignancy ^[2]	Allows wider exposure for potential invasion into surrounding structures; en bloc resection possible
Cortical-sparing (partial) adrenalectomy	Bilateral phaeo (e.g. MEN2, VHL)	Aims to preserve some adrenal cortex to avoid lifelong glucocorticoid + mineralocorticoid replacement; higher recurrence risk (~10%) but avoids adrenal insufficiency

This is where your pre-operative preparation is tested. Even with optimal α/β-blockade, tumour manipulation releases catecholamines.

Consideration	Rationale
Meticulous monitoring: A-line, CVP, Foley catheter	Risk of unstable haemodynamics ^[2]; need continuous beat-to-beat BP monitoring (arterial line), central venous pressure for volume status, and urinary output monitoring
Communicate with experienced anaesthetist	Inform about possible HTN crisis during intubation; inform before mobilisation/ligation of tumour; medications on standby ^[2]
Medications on standby ^[2]	Nitroprusside (for acute HTN), phentolamine (α-blocker for acute HTN), adrenaline/noradrenaline (for hypotension after tumour removal), esmolol (ultra-short-acting β-blocker for tachyarrhythmia)
Gentle manipulation of lesion ^[2]	Minimise catecholamine discharge from the tumour
Dissect and control adrenal vein first ^[2]	Ligating the venous drainage before further tumour manipulation prevents catecholamine washout into the systemic circulation — this is a key surgical principle

Potential intra-operative complications ^[2]:

Hypertensive crisis: during intubation, tumour manipulation → treat with IV phentolamine or nitroprusside
Hypotension: after tumour ligation/removal (sudden loss of catecholamine drive + residual α-blockade + volume depletion) → treat with IV fluids + vasopressors (noradrenaline/adrenaline)
Arrhythmias: catecholamine-induced → esmolol, lidocaine
Injury to surrounding structures ^[2]:
- Right adrenalectomy: IVC, right lobe of liver
- Left adrenalectomy: pancreatic tail, spleen

Post-operative ICU monitoring for specific complications ^[2]:

Complication	Mechanism	Management
Cardiac arrhythmia	Residual catecholamine effects; electrolyte shifts	Continuous cardiac monitoring; antiarrhythmics as needed
Hypotension	Drug effect ^[2] — residual α-blockade (phenoxybenzamine has a half-life of ~24 hours) + sudden removal of catecholamine-driven vasoconstriction + pre-existing intravascular volume depletion	Aggressive IV fluid resuscitation; vasopressors (noradrenaline) if needed; this is why pre-op volume expansion is so important
Hypoglycaemia	Rebound hyperinsulinaemia ^[2] — during catecholamine excess, α₂ stimulation suppresses insulin secretion from pancreatic β-cells; once the tumour is removed, the α₂ suppression is released → insulin secretion rebounds → hypoglycaemia; simultaneously, β₂-driven glycogenolysis ceases	Monitor blood glucose (H'stix) closely post-operatively ^[3]; IV dextrose infusion if needed
Adrenal insufficiency	If bilateral adrenalectomy performed (e.g. in MEN2 with bilateral phaeo) → loss of cortisol and aldosterone production	IV hydrocortisone upon removal of adrenal gland ^[2]; lifelong glucocorticoid ± mineralocorticoid replacement

Post-Op Monitoring Triad: BP + HR + Blood Sugar

After phaeo surgery, the three things that can go wrong immediately are: (1) Hypotension (loss of catecholamine drive), (2) Arrhythmia (residual catecholamine effect), (3) Hypoglycaemia (rebound insulin secretion). That's why post-op monitoring focuses on BP, HR, and H'stix ^[3]. Always monitor in ICU for at least 24–48 hours.

11.6 Management of Phaeochromocytoma Crisis [3][4]

Phaeochromocytoma crisis is classified as a hypertensive emergency (when accompanied by target organ damage) or hypertensive urgency ^[3]^[4].

Compelling indications for acute BP control include: aortic dissection, phaeochromocytoma crisis, eclampsia or severe pre-eclampsia ^[4].

Step	Action	Rationale
1	ICU admission with IABP monitoring ^[3]	Need continuous beat-to-beat BP monitoring for rapid titration of antihypertensives
2	IV Phentolamine: 0.5–5 mg IV bolus, then 2–20 μg/kg/h infusion ^[3]	Phentolamine is a competitive α-blocker with rapid onset (1–2 min IV); directly antagonises catecholamine-mediated vasoconstriction; short duration of action allows rapid titration
3	IV Nitroprusside: 0.3–8 μg/kg/min infusion ^[3]	Direct vasodilator (releases NO → vascular smooth muscle relaxation); especially good for acute LV failure ^[4]; rapid onset of action
4	Volume repletion to prevent hypotension after antihypertensives ^[3]	Once vasoconstriction is reversed, the underlying hypovolaemia is unmasked → risk of severe hypotension
5	β-blockade AFTER α-blockade ^[3]: Propranolol for tachycardia; Labetalol infusion at 1–2 mg/min (max 200 mg)	Controls reflex/catecholamine-driven tachycardia; labetalol provides combined α + β block (but ONLY after adequate α-blockade established)

BP targets in hypertensive emergency ^[4]:

Aim ≤ 25% ↓BP in the first hour
Then to 160/110 in the next 2–6 hours
Then cautiously to normal during the next 24–48 hours
In compelling indications (aortic dissection, phaeo crisis): aim SBP < 140 in the first hour

Additional agents for crisis ^[4]:

Drug	Route	Indication
Phentolamine: 5–10 mg IV bolus, repeat 10–20 min PRN ^[4]	IV bolus	For catecholamine crisis — rapid, short-acting α-blockade
Nicardipine	IV infusion 5–15 mg/h	Alternative vasodilator; does not cause reflex tachycardia as much as nitroprusside
Magnesium sulphate	IV	Adjunct; ↓catecholamine release from medulla + direct vasodilation + antiarrhythmic

Nitroprusside Safety

Nitroprusside is metabolised to cyanide → do NOT give for > 48 hours (risk of thiocyanide/cyanide intoxication) ^[4]. Protect from light by wrapping the infusion bag/syringe; discard after every 12 hours ^[4]. It is also contraindicated in pregnancy ^[4].

Histologically and biochemically indistinguishable from benign disease, defined by metastasis ^[2].

Modality	Detail
Surgical excision (tumour debulking)	To control catecholamine excess ^[2]; cytoreductive surgery even if not curative — reduces catecholamine burden → ↓symptoms and crisis risk
¹³¹I-MIBG therapy	Therapeutic doses of MIBG (typically ¹³¹I-labelled) delivered to chromaffin tissue; response rate ~30–40%; requires thyroid blockade
Chemotherapy	CVD regimen (cyclophosphamide + vincristine + dacarbazine); partial response in ~40%; reserved for progressive metastatic disease
Tyrosine kinase inhibitors	Sunitinib; some evidence of benefit in progressive metastatic PPGL
Peptide receptor radionuclide therapy (PRRT)	¹⁷⁷Lu-DOTATATE for SSTR-positive metastatic PPGL; emerging evidence of efficacy
Palliative α/β-blockade	Lifelong medical management of catecholamine excess when surgical cure is not possible
Metyrosine	Inhibits catecholamine synthesis ^[3]; adjunct for symptom control in metastatic disease

Prognosis: 5-year survival 95% for benign, 40% for malignant ^[3].

Lifelong yearly screening for recurrent, metastatic, or metachronous tumour ^[2]:

Modality	Detail
Urine/plasma metanephrines	Annual measurement — confirms biochemical cure and screens for recurrence
Chromogranin A	Not useful for primary diagnosis but useful for monitoring metastatic disease burden ^[2]
Imaging	CT/MRI as clinically indicated; periodic surveillance in genetic syndrome carriers
Genetic testing and counselling	If not done at diagnosis, should be performed; screen first-degree relatives ^[2]

Monitoring schedule (Endocrine Society guidelines):

Plasma or urine metanephrines at 2–6 weeks post-op to confirm biochemical cure
Then annually for at least 10 years (lifelong if hereditary or malignant)
Some guidelines recommend lifelong surveillance for all patients given the 10% recurrence rate

11.9 Special Scenarios

Phase	Treatment	Indication	Contraindication/Caution
Pre-op Step 1	α-blockade (phenoxybenzamine)	All phaeo patients pre-surgery	Caution: postural hypotension, reflex tachycardia, nasal congestion
Pre-op Step 2	β-blockade (propranolol)	After adequate α-blockade for residual tachycardia	NEVER before α-blockade → unopposed α → hypertensive crisis
Pre-op Step 3	Volume expansion (high-Na diet + fluids)	All patients — reverse catecholamine-induced volume depletion	Start on 2nd–3rd day of α-blockade
Pre-op (adjunct)	Metyrosine	Refractory BP/HR despite α/β-blockade	Sedation, EPS, crystalluria
Pre-op (adjunct)	Dihydropyridine CCB	Alternative/add-on to α-blocker	Standard CCB cautions
Surgery	Laparoscopic adrenalectomy	First-line for < 6 cm tumours	Not for > 6 cm or suspected malignancy
Surgery	Open adrenalectomy	> 6 cm, suspected malignancy, local invasion	Greater morbidity
Surgery	Cortical-sparing adrenalectomy	Bilateral phaeo (MEN2/VHL)	Higher recurrence risk (~10%)
Crisis	IV phentolamine + nitroprusside	Hypertensive emergency from phaeo crisis	Nitroprusside: avoid > 48h, avoid in pregnancy
Crisis	Volume repletion	Prevent hypotension after vasoconstriction reversed	—
Metastatic	Debulking surgery, ¹³¹I-MIBG therapy, CVD chemo, PRRT, TKIs	Progressive metastatic PPGL	Palliative intent in most cases
Post-op	ICU monitoring: BP, HR, H'stix	All patients post-adrenalectomy for phaeo	Watch for hypotension, hypoglycaemia, arrhythmia
Long-term	Annual metanephrines, genetic testing	All patients — lifelong	—

High Yield Summary

Management of phaeochromocytoma follows a strict sequence: Medical preparation → Surgery → Post-op monitoring → Lifelong follow-up.

Pre-operative preparation (7–14 days minimum, up to 4 weeks):

Step 1: α-blockade FIRST — phenoxybenzamine (non-competitive, irreversible); adequate blockade = postural BP drop ^[3]
Step 2: β-blockade SECOND — propranolol; NEVER before α-blockade (unopposed α → crisis) ^[3]
Step 3: Volume expansion — high-Na diet ( > 5 g/day) + fluids from day 2–3 of α-blockade ^[3]
Target: BP < 130/80 seated, HR 60–70 ^[2]
Alternative agents: dihydropyridine CCB, metyrosine ^[3]

Surgery:

Laparoscopic adrenalectomy — first-line for < 6 cm ^[2]
Open if > 6 cm or malignant ^[2]
Intra-op: A-line, CVP, Foley; dissect adrenal vein first; have phentolamine/nitroprusside/adrenaline on standby ^[2]

Post-op:

ICU monitoring for: hypotension (loss of catecholamine drive), hypoglycaemia (rebound hyperinsulinaemia), arrhythmia ^[2]^[3]

Crisis:

ICU + IABP monitoring; IV phentolamine + nitroprusside; volume repletion; β-blockade only after α-blockade ^[3]

Long-term:

Lifelong annual metanephrines; chromogranin A for metastatic disease; genetic testing and counselling ^[2]

Prognosis: 5-year survival 95% benign, 40% malignant ^[3]

Active Recall - Phaeochromocytoma Management

References

^[2] Senior notes: maxim.md (Phaeochromocytoma — Management: alpha/beta blockade sequence, pre-op targets, intra-op considerations, post-op complications, adrenalectomy approach and indications, malignant phaeo, follow-up) ^[3] Senior notes: Ryan Ho Endocrine.pdf (Section 3.4 — Management: phenoxybenzamine as non-competitive alpha-blocker, alpha before beta rationale, CCB/metyrosine alternatives, 7–14 days pre-op, surgical route, post-op complications, prognosis, crisis management with phentolamine/nitroprusside/labetalol, volume repletion, MEN2 screening protocol) ^[4] Senior notes: Ryan Ho Cardiology.pdf (p182–183 — Hypertensive emergency/urgency: BP targets, phentolamine for catecholamine crisis, nitroprusside precautions, labetalol dosing, compelling indications for acute BP control) ^[9] Senior notes: Ryan Ho Chemical Path.pdf (p34 — Glucagon test contraindication in phaeochromocytoma: risk of hypertensive crisis)

Complications of Phaeochromocytoma

Complications of phaeochromocytoma can be organised into three temporal categories: (1) complications of the disease itself (from chronic/acute catecholamine excess), (2) peri-operative complications (related to surgery), and (3) long-term complications (recurrence, metastasis). Understanding each complication from first principles — i.e. tracing it back to catecholamine receptor pharmacology — makes them logical and memorable rather than a list to memorise.

12.1 Complications of the Disease (Catecholamine Excess)

These are the consequences of uncontrolled catecholamine overproduction. They affect virtually every organ system because adrenergic receptors are ubiquitous.

Complication	Pathophysiology	Clinical Significance
Hypertensive crisis	Massive α₁-mediated vasoconstriction → extreme ↑SVR → BP may exceed 250/150 mmHg	Can precipitate any of the complications below; classified as a hypertensive emergency when accompanied by target organ damage ^[3]^[4]
Acute pulmonary oedema (APO) ^[2]^[3]	Two mechanisms: (1) Afterload crisis — acute ↑SVR from α₁ stimulation → ↑LV wall stress → LV fails to eject → pulmonary congestion. (2) Direct catecholamine cardiotoxicity → acute LV systolic dysfunction. Both lead to ↑pulmonary capillary pressure → fluid transudation into alveoli	Life-threatening; may be the presenting feature of phaeo; part of phaeochromocytoma crisis ^[2]
Myocardial infarction (MI) ^[3]	(1) ↑Myocardial oxygen demand: β₁ → ↑HR + ↑contractility. (2) ↓Myocardial oxygen supply: α₁ → coronary vasoconstriction/spasm. (3) Demand-supply mismatch → myocardial ischaemia/infarction. May also cause plaque rupture from haemodynamic stress	Can occur even in patients with angiographically normal coronary arteries (vasospasm-mediated)
Catecholamine cardiomyopathy ^[3]^[11]	Chronic exposure to high catecholamine levels → direct myocardial toxicity: contraction band necrosis → myocyte death → replacement fibrosis → progressive LV dilatation with ↓systolic function → dilated cardiomyopathy (DCMP)	Phaeochromocytoma is listed as an endocrine cause of DCMP ^[11]; importantly, this is potentially reversible after tumour removal — a rare "curable" cause of cardiomyopathy
Takotsubo-like (stress) cardiomyopathy	Acute catecholamine surge → myocardial stunning → transient apical/mid-ventricular ballooning with severe LV dysfunction	Reversible over days–weeks; can be the presenting feature; differentiated from ACS by characteristic echo/MRI pattern and coronary angiography
Cardiac arrhythmias ^[2]	β₁ stimulation → ↑automaticity of SA node, atrial and ventricular myocytes; ↑conduction velocity through AV node; shortened refractory period. Catecholamines also cause intracellular Ca²⁺ overload → triggered activity (delayed afterdepolarisations)	Sinus tachycardia (most common), SVT, AF, VT, VF; arrhythmia may cause sudden cardiac death

Catecholamine Cardiomyopathy — A Reversible Cause of Heart Failure

One of the most important points clinically: phaeochromocytoma can present as unexplained dilated cardiomyopathy, especially in younger patients. This is why idiopathic DCMP is listed as an indication for screening for phaeochromocytoma ^[3]. The good news is that after successful tumour removal, LV function can recover substantially or completely over weeks to months — making this a rare curable cause of heart failure ^[11].

Complication	Pathophysiology
Stroke (ischaemic or haemorrhagic) ^[3]	Hypertensive intracranial haemorrhage (ICH): severe ↑BP → rupture of small penetrating arteries (especially lenticulostriate arteries in the basal ganglia). Ischaemic stroke: either from artery-to-artery embolism from hypertension-accelerated atherosclerosis, or from catecholamine-induced cerebral vasospasm
Hypertensive encephalopathy ^[4]	Severe ↑BP exceeds the upper limit of cerebral autoregulation → breakthrough hyperperfusion → cerebral oedema → headache, confusion, visual disturbance, seizures, coma
Hypertensive retinopathy ^[3]	Chronic/acute severe HTN → arteriolar damage in the retina → haemorrhages, hard/soft exudates, papilloedema (grade 3–4 changes). Can cause acute visual loss

Complication	Pathophysiology
Glucose intolerance / diabetes mellitus ^[3]	β₂ stimulation → hepatic glycogenolysis + gluconeogenesis; α₂ stimulation → suppression of insulin secretion from pancreatic β-cells. Chronic catecholamine excess → sustained hyperglycaemia → may present as new-onset DM. Typically resolves after tumour removal
Lactic acidosis	Severe vasoconstriction (α₁) → tissue hypoperfusion → anaerobic metabolism → lactic acid accumulation. Exacerbated during hypertensive crises
Weight loss ^[3]	Chronically ↑metabolic rate from catecholamine-driven thermogenesis (β₃ in brown adipose tissue, β₁/β₂ general metabolic stimulation) + lipolysis

Phaeochromocytoma crisis: HTN or ↓BP with hyperthermia, altered mentation, multiorgan dysfunction ^[3]

This is the syndrome of catastrophic, uncontrolled catecholamine release leading to:

Manifestation	Mechanism
APO ^[2]	Acute LV failure from afterload crisis + direct cardiotoxicity
ICH ^[2]	Rupture of cerebral arteries from extreme BP elevation
Malignant arrhythmia / sudden cardiac death	Catecholamine-induced VT/VF
Hyperthermia	Massively ↑metabolic rate + impaired heat dissipation from cutaneous vasoconstriction
Multiorgan failure	Severe vasoconstriction → global tissue ischaemia → hepatic, renal, and intestinal failure
Hypotension / cardiovascular collapse	Paradoxically, severe crisis can lead to circulatory collapse: catecholamine-induced cardiomyopathy → ↓CO; or desensitisation of adrenergic receptors ("catecholamine storm burnout")

Triggers for crisis were discussed in the management section: tumour manipulation, anaesthesia, certain drugs (TCAs, β-blockers without α-blockade, metoclopramide, IV contrast), glucagon ^[9].

Phaeo Crisis Can Present with Hypotension, Not Just Hypertension

Students often assume phaeo crisis = extreme hypertension only. In reality, the crisis can present with profound hypotension and shock — from catecholamine cardiomyopathy causing acute LV failure, or from catecholamine receptor desensitisation. This is a particularly dangerous presentation because the usual reflex is to give vasopressors, which may worsen the situation. Recognition requires a high index of suspicion.

Complication	Mechanism
Anxiety disorder / panic-like attacks ^[7]	Catecholamine excess directly mimics the fight-or-flight response → sense of impending doom, tremor, palpitations, sweating. Phaeochromocytoma and hypoglycaemia tend to be associated with episodic anxiety and are more likely to mimic a phobic disorder or panic disorder ^[7]
Misdiagnosis as psychiatric illness	Patients with undiagnosed phaeo may be labelled as having panic disorder, generalised anxiety disorder, or somatoform disorder for years before the organic cause is identified

These complications arise during and immediately after adrenalectomy for phaeochromocytoma.

Complication	Mechanism	Prevention/Management
Haemodynamic instability (phaeochromocytoma) ^[2]	Tumour manipulation → massive catecholamine release → extreme ↑BP and HR	Adequate pre-op α/β-blockade for ≥ 7–14 days; dissect and control adrenal vein first ^[2]; gentle tumour handling; IV phentolamine/nitroprusside on standby
Intra-operative hypertensive crisis	As above — can occur even with optimal preparation; intubation is a high-risk moment	A-line monitoring; rapid titration of IV phentolamine or nitroprusside; communicate with anaesthetist before every critical surgical step ^[2]
Intra-operative hypotension	After adrenal vein ligation and tumour devascularisation → abrupt ↓catecholamine input → vasodilation + residual α-blockade + pre-existing volume depletion	Pre-op volume expansion (high-Na diet); IV fluid boluses; vasopressors (noradrenaline, vasopressin) on standby
Arrhythmias	Catecholamine surges during manipulation → VT, VF, SVT	Esmolol (ultra-short-acting β₁ blocker); lidocaine for VT; defibrillator on standby
Injury to surrounding structures ^[2]	Anatomical proximity during adrenalectomy
Right adrenalectomy: IVC, right lobe of liver ^[2]	Right adrenal gland sits in close proximity to the IVC posteriorly and the right hepatic lobe anteriorly	Careful surgical technique; vascular surgeon on standby for IVC injury
Left adrenalectomy: pancreatic tail, spleen ^[2]	Left adrenal gland is related to the pancreatic tail and splenic hilum	Careful dissection; risk of pancreatitis or splenectomy

Complication	Mechanism	Management
Hypotension ^[2]^[3]	Drug effect (residual α-blockade from phenoxybenzamine, which has a long half-life of ~24h) ^[2] + sudden loss of catecholamine drive after tumour removal + pre-existing intravascular volume depletion (despite pre-op expansion)	Monitor BP closely post-op ^[3]; aggressive IV fluid resuscitation; vasopressors (noradrenaline) if refractory; pre-op volume expansion is the best prevention
Hypoglycaemia ^[2]^[3]	Rebound hyperinsulinaemia ^[2]: during catecholamine excess, α₂ stimulation suppresses pancreatic β-cell insulin secretion; tumour removal abruptly releases this suppression → insulin surges. Simultaneously, β₂-driven hepatic glycogenolysis ceases → glucose production drops while insulin secretion rises	Monitor H'stix closely post-op ^[3]; IV dextrose (D10W or D50W) infusion; may require glucose monitoring Q1–2h for 24–48 hours
Cardiac arrhythmia ^[2]	Residual catecholamine effects (catecholamines already in the circulation have a finite clearance time); also electrolyte shifts from fluid resuscitation (hypokalaemia)	Continuous cardiac monitoring in ICU; correct electrolytes; antiarrhythmics as needed
Adrenal insufficiency ^[2]	Occurs specifically after bilateral adrenalectomy (e.g. bilateral phaeo in MEN2/VHL): loss of both adrenal cortices → no cortisol or aldosterone production. Can also occur (rarely) after unilateral adrenalectomy if the contralateral adrenal has been suppressed	IV hydrocortisone upon removal of adrenal gland ^[2]; lifelong glucocorticoid ± mineralocorticoid replacement if bilateral; educate patient about sick-day rules and MedicAlert bracelet

Complication	Detail
Hypertension (renal artery injury) ^[2]	Surgical damage to the renal artery or its branches during adrenalectomy → renal artery stenosis → activation of RAAS → renovascular hypertension
Persistent hypertension	~25% of patients remain hypertensive after successful phaeo resection — usually because of co-existing essential hypertension, or chronic renovascular damage from years of catecholamine-induced HTN

12.3 Long-Term Complications and Prognosis

Because phaeochromocytoma is part of several hereditary syndromes, patients may develop complications from the other components of these syndromes:

Syndrome	Related Complications
MEN2A/2B	Medullary thyroid carcinoma (aggressive, may metastasise); hyperparathyroidism with hypercalcaemia (MEN2A); intestinal ganglioneuromatosis causing chronic constipation/megacolon (MEN2B)
VHL	Clear cell RCC (40% of VHL patients); cerebellar haemangioblastoma (ataxia, hydrocephalus); retinal angiomas (visual loss)
NF1	Malignant peripheral nerve sheath tumours (MPNST); optic glioma; skeletal abnormalities
SDHx	Head and neck paragangliomas (cranial nerve palsies); highest risk of metastatic PPGL (SDHB)

References

^[2] Senior notes: maxim.md (Phaeochromocytoma — Post-operative complications: arrhythmia, hypotension, hypoglycaemia; adrenalectomy complications: haemodynamic instability, injury to IVC/liver/pancreas/spleen, adrenal insufficiency; late: hypertension from renal artery injury; malignant phaeo: defined by metastasis, indistinguishable histologically; lifelong screening) ^[3] Senior notes: Ryan Ho Endocrine.pdf (Section 3.4 — Clinical features: HTN complications including LV failure, MI, cardiomyopathy, stroke, hypertensive retinopathy; phaeo crisis definition; metabolic effects; post-op complications: HTN crisis, hypotension, rebound hypoglycaemia; malignancy rate 8.3–13%, 3x risk in females; prognosis 95% vs 40% 5-year survival) ^[4] Senior notes: Ryan Ho Cardiology.pdf (p182 — Hypertensive emergency: compelling indications include phaeo crisis; target organ damage: ICH, APO, HTN encephalopathy) ^[7] Senior notes: Ryan Ho Psychiatry.pdf (p175, p179 — Phaeochromocytoma mimicking panic disorder; episodic anxiety) ^[9] Senior notes: Ryan Ho Chemical Path.pdf (p34 — Glucagon test: risk of hypertensive crisis in phaeochromocytoma) ^[11] Senior notes: Ryan Ho Cardiology.pdf (p169 — DCMP aetiology: endocrine causes including phaeochromocytoma)