Adrenal — Study Notes

Adrenal Gland

Cortex → GFR
- G: Aldosterone
- F: Cortisol
- R: Androgens
Medulla → Catecholamines

Most abundant cortical product: Androgens

Hypercortisolism / Cushing's Syndrome

Causes (3 groups)

Category	%	Notes
Exogenous	most common in Western world	iatrogenic steroid use
ACTH-dependent (endogenous)	85%	Cushing disease (pituitary, 80%), ectopic ACTH (bronchial carcinoid, SCLC), ectopic CRH (rare)
ACTH-independent (endogenous)	15%	adrenal pathology — adenoma, ACC, bilateral hyperplasia

Clinical Features

Central obesity, moon facies, buffalo hump, facial plethora
Striae, easy bruising, proximal muscle weakness, hirsutism
HTN, dyslipidemia, insulin resistance
Urological:
- ED + low libido (hypogonadotropic hypogonadism — common in men)
- Urolithiasis in up to 50% ( most common presentation )

Diagnosis (Screening — 3 tests)

Low-dose dexamethasone suppression test
Late-night salivary cortisol
24-hour urinary free cortisol
Preferred in pregnancy

Localising the Source

➡ Confirm hypercortisolism → measure serum ACTH

Low ACTH → adrenal source → CT abdomen
- Normal adrenals → exogenous steroids
High ACTH → pituitary vs ectopic ( need further testing )

High-Dose Dexamethasone Test

>50% suppression → Pituitary adenoma
<50% suppression → Ectopic ACTH

- Gold standard: inferior petrosal sinus sampling after CRH stimulation

Management

ACTH-independent ➡ ipsilateral adrenalectomy
Cushing disease ➡ trans-sphenoidal resection (preferred first-line)
- Failed pituitary surgery ➡ bilateral adrenalectomy + lifelong gluco-/mineralocorticoid replacement
Ectopic ACTH ➡ resect primary (only 10% resectable); unresectable → bilateral adrenalectomy
Bridging meds (enzyme blockers): mitotane, metyrapone, ketoconazole, aminoglutethimide, etomidate, trilostane

Hyperaldosteronism

RAAS Recap

Renin triggers: low perfusion, ↑ renal sympathetic activity, low Na at macula densa
Angiotensin II = most potent stimulator of aldosterone
Other stimulators: ↑ K⁺, ↓ Na⁺, ACTH (weak)
Aldosterone ➡ ↑ Na/H₂O reabsorption + ↑ K⁺ secretion in distal nephron

RAAS Pathway

Renin → Liver → Angiotensin I → Lung (ACE) → Angiotensin II → Adrenal → Aldosterone

Classification

	Renin	Aldosterone
Primary	suppressed	↑
Secondary	↑ (driver)	↑

Secondary causes: renal artery stenosis, hypovolemia (CHF/cirrhosis), FMD, JG cell tumour

Primary Hyperaldosteronism —

Normokalemia in 50% (only 9–37% hypokalemic at diagnosis)
No hypernatremia (Na reabsorption iso-osmotic with water)

Screening Indications (9)

Unexplained hypokalemia (spontaneous or diuretic-induced)
HTN + hypokalemia
Adrenal incidentaloma + HTN
Resistant HTN (≥3 agents)
Early-onset HTN (<20 yrs) or stroke (<50 yrs)
Severe HTN (≥160/110)
Considering secondary HTN (pheo, renovascular)
End-organ damage disproportionate to HTN
Family hx of primary aldosteronism

Diagnosis

Aldosterone-to-renin ratio (ARR) — screen between 8–10 AM
- ARR >20–30 + aldosterone >15 ng/mL = positive screen
Stop spironolactone 6 weeks before screening
Confirmatory: sodium loading test , Fludrocortisone suppression (oral or IV) — aldosterone fails to suppress
Imaging: cross-sectional CT — adenoma = unilateral, <10 HU, non-enhancing
Adrenal vein sampling (AVS) required for lateralisation
- Exceptions (skip AVS):
  - <40 yrs with clear unilateral adenoma + normal contralateral
  - Suspected ACC

When to Do Adrenal Venous Sampling?

Bilateral
Micronodular < 1cm
Normal adrenal imaging
Unilateral Adrenal nodule >1 cm AND age more than 40 years

Management

➡ Surgically correctable (4): adenoma, unilateral hyperplasia, ectopic tumour, ACC

➡ Not surgically correctable (4): bilateral hyperplasia, familial types I/II/III

Surgical: laparoscopic adrenalectomy (small tumours)
- Open if ACC suspected
Medical: spironolactone or eplerenone (MRA) — start 1–2 wks pre-op, especially if on long-term ACEi

Pheochromocytoma

Background

Chromaffin cell tumour of adrenal medulla
~⅓ familial | 1–25% extra-adrenal (= paraganglioma)
Extra-adrenal sites: Organ of Zuckerkandl (aortic bifurcation), sympathetic chain, perivesical
Malignancy = clinical metastases only (no pathologic criteria)
Rule of 10s (classic, imperfect): 10% bilateral, 10% extra-adrenal, 10% malignant, 10% familial, 10% paediatric

Hereditary Syndromes

VHL (all types, type 2 more)
MEN 2
SDHB
Familial pheos: nearly always bilateral, more often malignant

Clinical Features

Classic triad: headache, episodic sweating, tachycardia
Other: anxiety, palpitations, pallor, abdominal/chest pain, tremor, weight loss, flushing

Labs

Plasma free metanephrines — highest sensitivity (use if high index of suspicion)

For screening ( high sensitivity )
24-hr urinary fractionated metanephrines + catecholamines

For confirmatory ( high specificity )
Hold before test:
- Acetaminophen (5 days — cross-reactivity)
- TCAs
- Phenoxybenzamine
Clonidine suppression test — distinguishes pheo from essential HTN when catecholamines mildly ↑
- Essential HTN ➡ NE drops; pheo ➡ no drop

Imaging

Modality	Finding
Unenhanced CT	>10 HU (mean ~35)
Contrast CT	Often >100 HU, washout <50%
MRI T2	High signal ("light bulb" sign — not specific or sensitive enough alone)
¹²³I-MIBG	NE analogue; high spec, low sens
¹⁸F-FDG PET	Gold standard for staging — superior to MIBG, especially for mets

Functional imaging (MIBG/PET) can be omitted if solitary adrenal mass + biochemical pheo on cross-sectional imaging
Do for tumours >5 cm to rule out mets pre-op

Pre-op Management (4 pillars)

Cardiology / anaesthesia consult + ECG + echo
IV volume repletion (most important; admit day before)
α-blockade THEN β-blockade
Monitored bed / ICU post-op

α-Blockade

Phenoxybenzamine — irreversible non-selective α-blocker
- Start 7–14 days pre-op
- 10 mg BID → titrate by 10–20 mg q2–3 days → up to 1 mg/kg
- Hold morning of surgery (prevents prolonged hypotension)
- May cause reflex tachycardia ➡ add β-blocker
Doxazosin / prazosin / terazosin (selective α₁) — avoid need for β-blocker
Phentolamine — short-acting α-blocker for acute crisis
Metyrosine — if phenoxybenzamine fails (blocks tyrosine → L-dopa)

β-Blockade

Never before α-blockade (unopposed α causes hypertensive crisis)
Indications: SBP <100, tachycardia (true or reflex)
Selective β₁ preferred: atenolol, metoprolol

Calcium Channel Blockers

Alternative for normotensive patients with paroxysmal HTN
2 wks pre-op sufficient

Intra-op + Post-op

Ligate adrenal vein early + minimal tumour manipulation
Thermal injury alone can trigger catecholamine release
Notify anaesthesia at adrenal vein ligation
Post-op: hypotension common (loss of tonic vasoconstriction)
➡ Aggressive fluids + phenylephrine
Watch for hypoglycaemia (rebound hyperinsulinaemia after α₂ withdrawal)
ICU admit overnight

Follow-up

Repeat metanephrines ~2 wks post-op
Annual biochemical follow-up — lifelong
10-yr recurrence rate up to 16%
Persistent HTN at 2–3 mo ➡ recheck plasma metanephrines ➡ MIBG if positive

Special Scenarios

Hereditary (MEN 2 / VHL) — low malignancy + high bilateral risk
- ➡ Partial cortical-sparing adrenalectomy (avoid lifelong replacement)
Malignant pheo ➡ surgical metastasectomy if resectable + α/β-blockade + metyrosine; palliative
- Chemo if MIBG-negative or MIBG therapy failed
Pregnancy (late term) ➡ phenoxybenzamine until fetal maturity ➡ C-section + tumour resection in one operation (no vaginal delivery)

Adrenal Insufficiency

Classification

	Cause	Aldosterone	Skin
Primary (Addison's)	Autoimmune adrenalitis (Western world)	Deficient	Hyperpigmentation
Secondary	Pituitary/hypothalamic failure	Preserved (zona glomerulosa ACTH-independent)	Normal

Clinical

Anorexia, abdominal pain, weakness, weight loss, fatigue
Hypotension, salt craving
Hyperpigmentation only in primary

Diagnosis

Morning serum cortisol + ACTH (+ aldosterone/renin if primary suspected)
Confirm: ACTH stimulation (cortrosyn) test

Management

Replace cortisol + mineralocorticoid (if primary)
Post-op adrenal crisis:
- At risk: prior contralateral nephrectomy + current contralateral renal/adrenal surgery
- ➡ Check old op notes + imaging for adrenal tissue
- Treatment: 2 mg dexamethasone or 100 mg hydrocortisone

Adrenal Cortical Carcinoma (ACC)

Background

Avg 10–12 cm at presentation
Most are functional — most common hormone secreted = cortisol

Genetic Syndromes (6)

Li-Fraumeni
Beckwith-Wiedemann
Lynch
Carney complex
MEN-1
McCune-Albright

Risk of Malignancy by Size

Size	Malignancy risk
<4 cm	5%
>4 cm	10%
>6 cm	25%

➡ Resect masses >4–6 cm unless clearly benign

Imaging (CT — 5 features)

Irregular borders
Heterogeneous enhancement
Mean ~39 HU (vs adenoma 8 HU)
Calcifications
Necrotic / cystic degeneration

MRI

T1: isointense to liver/spleen
T2: intermediate–high signal
Marked gadolinium uptake

Biopsy

Not recommended pre-op (seeding risk)
Cannot reliably distinguish adenoma vs carcinoma histologically
➡ Useful only for suspected metastasis to adrenal from known primary

Pathology — Modified Weiss (5)

Necrosis
Abnormal mitoses
Cytoplasm (clear cells ≤25%)
Capsular invasion
Mitotic rate >5/50 HPF

➡ Score = 2×(mitotic rate) + 2×(clear cells) + abnormal mitoses + necrosis + capsular invasion → ≥3 = malignant

Management

Surgical resection = mainstay (open, no-touch technique)
Mitotane = most common chemotherapeutic agent
- Inhibits P450scc, 11β-OHase, 18-OHase, 3β-HSD
Multimodal: surgery + RT + chemo

Prognosis

Recurrence 60–80% despite resection
Margin status = most important predictor of overall survival
Other OS predictors: size, nodal status, mets

Adrenal Metastases

>50% of newly discovered adrenal lesions in patients with prior malignancy = metastatic
Still need metabolic workup
Adrenal insufficiency only with bilateral + bulky (>4 cm) disease

Benign Adrenal Tumours

Adenoma

Most common primary adrenal tumour
93% metabolically silent
Goal of workup ➡ differentiate non-functional benign adenoma from functional or malignant lesion
Non-functional + <4 cm ➡ surveillance
Functional ➡ adrenalectomy

Myelolipoma

Benign, metabolically silent, contains fat + bone marrow
CT: −30 to −140 HU
Resect only if symptomatic

Adrenal Cysts

4 types: pseudocyst, endothelial, epithelial, parasitic
7% of cysts associated with malignancy (all pseudocysts) — observe with caution
Routine endocrine workup mandatory despite usually benign

Incidental Adrenal Mass

Definition

Adrenal lesion >1 cm on imaging done for non-adrenal reasons

Workup —

Labs (3):

LD-DST or 24-hr urine cortisol → rule out hypercortisolism
24-hr urinary metanephrines/catecholamines → rule out pheo
ARR → if hypertensive, rule out hyperaldosteronism

Imaging (1):

Unenhanced CT first
- <10 HU ➡ adenoma (sens ~70%, spec 98%)
- ≥10 HU ➡ adrenal protocol CT with washout

Adrenal Washout CT (3 phases)

Non-contrast → enhanced (1 min) → delayed (15 min)
Absolute washout >60% = adenoma
- (Enhanced − delayed) / (Enhanced − unenhanced) × 100
Relative washout >40% = adenoma
- (Enhanced − delayed) / Enhanced × 100
If less than 60 or 40 need further evaluation

Pheo / Malignant Features on Imaging (5)

Size >3 cm
Heterogeneous texture
↑ vascularity
Attenuation >10 HU unenhanced
↓ contrast washout at 10–15 min

MRI

Chemical-shift useful for adenomas
CT washout > chemical-shift MRI (gold standard)

Indications for Adrenalectomy:

Size ≥4 cm (except myelolipoma)
- >6 cm = malignant until proven otherwise
Growth >1 cm on follow-up
Any imaging suspicious for malignancy regardless of size
Adrenal hyperfunction (functional adenoma, pheo, aldosteronoma, ACC)
Symptomatic / large cyst or myelolipoma
Isolated adrenal metastasis (multidisciplinary)
During RCC surgery if:
- Adrenal abnormal / obscured by large renal tumour
- Vein thrombus to adrenal vein level

Adrenal Mass Algorithm (Traffic-Light System)

A. Imaging Feature

Lipid-rich → Green
Lipid-poor → Purple

B. Size

<4 cm → Green
≥4 cm → Purple

C. Metabolic Work-up

Silent → Green
Subclinical → Purple
Functional → Red

Management Rules

All Green → No follow-up
One Purple → Follow-up
Two Purple OR One Red → Surgical resection

Partial Adrenalectomy

Total adrenalectomy = gold standard for functioning/malignant tumours
Indications for partial (3):
- Bilateral adrenal tumours
- Solitary adrenal gland
- Familial syndromes (VHL, MEN 2A, familial pheo)
Amount of tissue needed to preserve function — unknown
Bilateral adrenalectomy ➡ lifelong replacement + ↓ QOL + Addisonian crisis risk