• The majority of phaeochromocytomas are sporadic with no identifiable genetic mutation ^[2].

Up to 40% of PPGLs have an identifiable germline mutation ^[2][3]. This is one of the highest rates of hereditary predisposition among all tumours.

• The adrenal glands (also called suprarenal glands) sit on top of the kidneys in the retroperitoneum.
• Each gland has two functionally distinct parts:
  • Cortex (outer): produces steroids (mineralocorticoids, glucocorticoids, androgens) — from mesoderm
  • Medulla (inner): produces catecholamines — from neural crest (ectoderm)

• The adrenal medulla is essentially a modified sympathetic ganglion.
• Chromaffin cells are the functional cells of the adrenal medulla. They are the equivalent of post-ganglionic sympathetic neurons, but instead of sending axons to target organs, they secrete catecholamines directly into the bloodstream (i.e. they function as neuroendocrine cells).
• They are innervated by preganglionic sympathetic fibres from the greater splanchnic nerve (T5–T9).
• When stimulated by acetylcholine (from preganglionic neurons), chromaffin cells release catecholamines via exocytosis.

The catecholamine synthesis pathway (from the amino acid tyrosine):

Tyrosine → [Tyrosine hydroxylase (rate-limiting)] → DOPA → [DOPA decarboxylase] → Dopamine
→ [Dopamine β-hydroxylase] → Noradrenaline (norepinephrine)
→ [PNMT*] → Adrenaline (epinephrine)

*PNMT = Phenylethanolamine N-methyltransferase (found almost exclusively in the adrenal medulla, induced by cortisol from the adrenal cortex — this is why adrenaline is mainly produced in the adrenal medulla, not in extra-adrenal chromaffin tissue).

Key point: Extra-adrenal paragangliomas tend to secrete noradrenaline (and sometimes dopamine) but not adrenaline, because they lack PNMT (which requires cortisol exposure). Adrenal phaeochromocytomas can secrete both adrenaline and noradrenaline ^[2][3].

Catecholamines are metabolised by two key enzymes:

1. COMT (catechol-O-methyltransferase): converts noradrenaline → normetanephrine, adrenaline → metanephrine
2. MAO (monoamine oxidase): further metabolises metanephrines → vanillylmandelic acid (VMA)

The key metabolites we measure diagnostically are: ^[1][2]

• Plasma free metanephrines (metanephrine + normetanephrine) — most sensitive
• 24-hour urinary fractionated metanephrines (metanephrine + normetanephrine) — traditional gold standard
• 24-hour urinary catecholamines (adrenaline, noradrenaline, dopamine)
• Urinary VMA — older, less sensitive and specific (historically important)

Understanding receptor physiology is critical for understanding both the clinical features and the pharmacological management:

In Hong Kong, the most commonly encountered scenarios in clinical practice and exams:

• Sporadic phaeochromocytoma presenting as secondary hypertension in a young patient ^[4][6]
• Adrenal incidentaloma found on imaging done for another reason — must exclude phaeochromocytoma before any biopsy or intervention ^[2][7]
• Part of MEN2 workup — important in surgical/endocrine setting

Endocrine causes of secondary hypertension (as framed in the GC lecture) include ^[4][6]:

• Conn syndrome (primary aldosteronism)
• Cushing syndrome
• Phaeochromocytoma
• Acromegaly
• Obesity / OSA
• Renovascular causes (renal artery stenosis)
• Coarctation of the aorta

The pathophysiology of phaeochromocytoma centres on unregulated, excessive catecholamine secretion:

1. Tumour chromaffin cells synthesise and store catecholamines in secretory granules
2. Release is autonomous and may be:
   • Continuous (sustained hypertension — ~50% of cases)
   • Episodic/paroxysmal (triggered by physical activity, postural change, abdominal palpation, anaesthesia induction, tyramine-rich foods, certain drugs) — the classic "attacks"
   • Mixed (sustained with paroxysmal spikes)
3. The released catecholamines exert effects via α and β adrenergic receptors throughout the body

Key pathophysiological consequences:

Why does phaeochromocytoma cause such dramatic clinical presentations?

• Catecholamines in supraphysiological concentrations activate multiple organ systems simultaneously
• The episodic nature of secretion means the body cannot adapt (unlike essential hypertension where baroreceptor resetting occurs gradually)
• Phaeochromocytoma crisis can manifest as acute pulmonary oedema (APO), intracranial haemorrhage (ICH), hypertensive encephalopathy, or multi-organ dysfunction — these represent end-organ damage from massive catecholamine surges ^[2]

Catecholamine cardiomyopathy:

• Chronic catecholamine excess is directly cardiotoxic (contraction band necrosis, myocardial fibrosis)
• Can present as dilated cardiomyopathy (DCM) or Takotsubo-like cardiomyopathy
• This is reversible after tumour removal in many cases

The organ of Zuckerkandl is a collection of chromaffin tissue at the aortic bifurcation near the origin of the inferior mesenteric artery — a classic extra-adrenal site ^[2].

Indications for screening for phaeochromocytoma ^[3]:

In the GC lecture on secondary hypertension, phaeochromocytoma is listed alongside Conn syndrome, Cushing syndrome, acromegaly, obesity/OSA, renovascular causes, and coarctation of the aorta as important endocrine/secondary causes of hypertension to screen for ^[4][6].

1. "Phaeochromocytoma is a great mimic" — it can mimic anxiety disorders, thyrotoxicosis, carcinoid syndrome, menopause (hot flushes vs. pallor), essential hypertension, panic disorder, or drug-induced states
2. Biopsy of a suspected phaeochromocytoma is CONTRAINDICATED — manipulation of the tumour risks a massive catecholamine surge and hypertensive crisis/haemorrhage ^[2]
3. Always rule out phaeochromocytoma BEFORE adrenal surgery or biopsy — perioperative catecholamine storm can be fatal
4. Consider phaeochromocytoma in any patient with: labile/resistant hypertension, young-onset HTN, HTN with postural drop, hypertensive crisis during anaesthesia, unexplained cardiomyopathy, or hyperadrenergic spells

Beware of drug and dietary interference with biochemical testing: β-blockers, methyldopa, TCAs, MAO inhibitors, sympathomimetics, and tyramine-rich foods can cause false-positive results on urinary catecholamine/metanephrine testing ^[1]. Patients should ideally stop interfering medications 1–2 weeks before testing.

The differential of episodic sweating and/or flushing (as listed in the senior notes ^[3]):

• Oestrogen/testosterone deficiency (e.g. menopause, castration)
• Carcinoid syndrome (flushing, diarrhoea, wheeze)
• Phaeochromocytoma (sweat but do NOT flush)
• Thyrotoxicosis (not usually episodic)
• Systemic mastocytosis (histamine release)
• Allergy

Phaeochromocytoma is listed as a metabolic cause of palpitations, alongside thyrotoxicosis, hypoglycaemia, and electrolyte disturbances ^[8].

From the Endocrine Data Interpretation notes ^[4]: "Sky high plasma metanephrine levels → phaeochromocytoma". In the context of an adrenal incidentaloma workup, markedly elevated metanephrines essentially clinch the biochemical diagnosis.

Beware of drug and dietary interference ^[1][13]:

Preparation before urine collection ^[13]:

• Avoid dietary intake of caffeine, chocolate, and bananas before the test
• Avoid usage of drugs such as methyldopa, labetalol, sotalol which can create false positive results
• Urine specimen should be kept refrigerated during collection till hospital

• Rationale: Clonidine is a central α₂-agonist → reduces sympathetic outflow → in normal individuals, plasma catecholamines/normetanephrines fall after clonidine administration. In phaeochromocytoma, catecholamine release is autonomous (not under sympathetic control) → levels do not suppress.
• Protocol: Measure baseline plasma catecholamines/normetanephrines → administer oral clonidine (300 µg) → remeasure at 3 hours.
• Positive result (supports phaeo): Plasma normetanephrine fails to suppress to < 40% of baseline, or remains above the upper reference limit.
• Indication: Used when biochemical results are borderline/equivocal and clinical suspicion persists.

From the paediatric notes ^[13]:

GC Lecture Slide ^[14]: "Imaging modality. CT rather than MRI is recommended. This is due to the superior spatial resolution of CT in thorax, abdomen, and pelvis. Sensitivity for CT in these areas is 88-100%. For skull base lesions, MRI is better (Sn 90-95%)."

Functional imaging is used when:

• Anatomical imaging is negative despite positive biochemistry (suggesting extra-adrenal or small tumour)
• Large adrenal tumour (> 10 cm) with ↑ risk of metastatic disease ^[3]
• Known/suspected paraganglioma (↑ risk of multifocal or metastatic tumour) ^[3]
• Staging for malignant phaeochromocytoma (detecting metastases)

GC Lecture Slide ^[14]: "18F-FDG-PET is preferred over 131I-MIBG SPECT because MIBG-SPECT is unable to detect some SDHx-related tumours."

Important to initiate an alpha-blockade FIRST with phenoxybenzamine ^[1]. ALWAYS initiate α-blockade before β-blockade ^[3].

Why α-blockade first?

This is one of the most important pharmacological principles in endocrine surgery, and it is asked repeatedly in exams:

• Catecholamines act on both α and β receptors
• If you give a β-blocker first, you block the vasodilatory β₂ effect in skeletal muscle vasculature → this leaves α₁-mediated vasoconstriction completely unopposed → paradoxical SEVERE hypertensive crisis ^[1][3][15]
• By blocking α₁ first, you eliminate vasoconstriction. Only then can you safely add β-blockade to control tachycardia without fear of unopposed α-agonism.

Why is volume expansion needed?

Chronic catecholamine excess causes:

1. Sustained α₁-mediated venoconstriction → reduced venous capacitance → blood is squeezed out of the venous reservoir
2. Pressure natriuresis from chronic hypertension → sodium and water loss
3. The net result: significant intravascular volume contraction despite hypertension

When α-blockade is initiated, the vasculature dilates → the now-inadequate blood volume is spread across a much larger vascular bed → risk of profound hypotension.

Management ^[3]:

• ↑ Salt intake (> 5 g/day) and liberal fluid intake to reverse catecholamine-induced intravascular volume contraction
• This is especially important to prevent postoperative hypotension — when the tumour is removed, catecholamine levels drop abruptly → α-blockade + sudden loss of vasoconstriction + depleted volume = severe hypotension
• Start volume expansion when α-blockade is initiated; continue through to surgery

Then beta-blockade with propranolol ^[1]. β-blockade alone will cause unopposed α-adrenergic activity → exacerbate HTN ^[3].

Indications: Tachycardia (HR > 80–100 at rest), arrhythmias, angina-type symptoms — all of which are driven by β₁ stimulation.

Timing: β-blockade is typically started 2–3 days after α-blockade, once the postural drop confirms adequate α-receptor coverage.

The combined α/β-blockade must be maintained for at least 7–14 days before surgery ^[3].

Adrenalectomy preoperative preparation for phaeochromocytoma: alpha blockade → beta blockade → fluid replacement ^[11].

The intraoperative period is the most haemodynamically dangerous time — the anaesthesia and surgical teams must be prepared for extreme BP swings:

Postoperative complications ^[3]: HTN crisis, hypotension, rebound hypoglycaemia → monitor BP, HR, H'stix closely postop

Phaeochromocytoma crisis is classified as a hypertensive urgency/emergency ^[3][10]:

Compelling indications for acute BP control include aortic dissection, phaeochromocytoma crisis, eclampsia or severe pre-eclampsia ^[10].

Malignant phaeochromocytoma (defined by metastasis to non-chromaffin tissue) has a poor prognosis: 5-year survival ~40% (compared with 95% for benign disease) ^[3].

• Chronic medical management with α-blockade ± β-blockade ± CCBs ± metyrosine
• Aim: symptom control and prevention of catecholamine-related complications (HTN, cardiomyopathy)
• Regular biochemical and imaging surveillance

• Extremely dangerous: maternal mortality historically ~17% if undiagnosed
• Medical management: Phenoxybenzamine (crosses placenta but acceptable) → then β-blockade if needed; MgSO₄ is an excellent adjunct (safe in pregnancy, also treats pre-eclampsia)
• Timing of surgery: If diagnosed in 1st/2nd trimester → laparoscopic adrenalectomy during 2nd trimester; if diagnosed in 3rd trimester → α/β-blockade → deliver by elective C-section → then adrenalectomy
• Avoid: Vaginal delivery (bearing down → tumour compression → crisis); metoclopramide (can trigger catecholamine release)

Postoperative complications ^[3]: HTN crisis, hypotension, rebound hypoglycaemia → monitor BP, HR, H'stix closely postop.

Since ~40% of phaeochromocytomas are hereditary, patients may develop complications from the associated genetic syndrome rather than from the phaeochromocytoma itself:

Neuroendocrine tumour with serious and potentially lethal cardiovascular complications due to effects of secreted catecholamines ^[16]