- HPA axis: hypothalamus releases CRH → anterior pituitary releases ACTH → adrenal cortex makes glucocorticoids and androgens; cortisol peaks AM, nadir ~11 PM.
- Without ACTH, all of the adrenal cortex atrophies except the zona glomerulosa (aldosterone-producing) — the only region that doesn't atrophy with pituitary failure.
- Stress is the most important variable modulating HPA axis activity.
- Causes of Cushing's: exogenous (most common in Western world) vs. ACTH-dependent endogenous (85%, of which pituitary/Cushing disease ≈80%) vs. ACTH-independent endogenous (15%); ectopic ACTH is nearly always malignant — bronchial carcinoid, small cell lung, less often pheo.
- LD-DST: sensitivity 85–90%, specificity 95–99%; false-positive up to 50% in women on OCPs (raised cortisol-binding globulin); cannot rule out exogenous steroid use.
- 24-hour urinary free cortisol may miss subclinical Cushing — Endocrine Society recommends against it for incidentaloma metabolic workup.
- After confirming hypercortisolism, serum ACTH distinguishes ACTH-independent (low) from ACTH-dependent (high); inferior petrosal sinus sampling after CRH is the gold standard for distinguishing Cushing disease from ectopic ACTH.
- Aldosterone is stimulated by angiotensin II (most potent), elevated K⁺/decreased Na⁺, and ACTH; inhibited by ANP.
- Primary hyperaldosteronism causes: bilateral hyperplasia 60%, aldosterone-producing adenoma 35%, unilateral hyperplasia 2%, ACC <1%, ectopic <1%, familial types I–III each <1%.
- Only 9–37% of newly diagnosed primary aldosteronism patients are hypokalemic; normokalemia occurs in up to 50%.
- ARR screening: PAC > 15 ng/mL with ARR > 20; stop spironolactone/eplerenone for ~6 weeks before testing; liberalize salt intake.
- Surgically correctable hyperaldosteronism: aldosterone-producing adenoma, unilateral hyperplasia, ectopic aldosterone-secreting tumor, aldosterone-producing ACC. Non-correctable: bilateral hyperplasia, familial types I/II/III (medical therapy with spironolactone/eplerenone).
- AVS required for lateralization in primary aldo — exceptions: patient <40 years with clear unilateral adenoma and normal contralateral gland, or suspected ACC.
- Pheochromocytoma: ~1/3 familial; 1–25% extra-adrenal (paraganglioma) — organ of Zuckerkandl, sympathetic chain, perivesical; ≈5% of incidental adrenal masses are pheo.
- Malignant pheo can only be defined by clinical metastases — no agreed pathologic criterion; histology shows zellballen.
- VHL pheos predominantly produce norepinephrine; MEN2 and NF1 predominantly produce epinephrine; familial pheos are almost always bilateral and more frequently malignant.
- PNMT (norepi → epi) is localized to the adrenal medulla (plus brain and organ of Zuckerkandl), making the adrenal medulla the source of systemic epinephrine.
- Plasma fractionated metanephrines used in high index of suspicion; 24-hour urinary fractionated metanephrines/catecholamines for low index (2011 CUA); 2019 AUA Update favors plasma free metanephrines for initial screening.
- Stop acetaminophen ≥5 days, TCAs, and phenoxybenzamine before metanephrine testing; β-blockers can cause false positive but are only stopped on repeat testing.
- 18F-FDG PET is the gold standard imaging for definitive staging of pheo; MIBG has high specificity but low sensitivity.
- On unenhanced CT, pheo is typically >10 HU (mean ≈35 HU), >100 HU on contrast, and does NOT wash out; benign adrenal lesions wash out >50% on delayed imaging.
- Preoperative α-blockade with phenoxybenzamine for 7–14 days; β-blockade should never be started before α-blockade due to risk of unopposed α1 stimulation and hypertensive crisis.
- Post-op ICU monitoring for pheo: watch for hypotension (loss of tonic vasoconstriction, lingering phenoxybenzamine effect) and rebound hyperinsulinemia → hypoglycemia.
- 10-year pheo recurrence rate up to 16%; lifelong annual biochemical follow-up is mandatory.
- Primary adrenal insufficiency (Addison's disease) most commonly caused by autoimmune adrenalitis in the Western world; mineralocorticoid deficiency present only in primary AI (zona glomerulosa is preserved in secondary AI).
- Suspected post-operative adrenal crisis: consider 2 mg dexamethasone or 100 mg hydrocortisone.
- ACC syndromes: Li-Fraumeni, Beckwith-Wiedemann, Lynch, Carney complex, MEN-1, McCune-Albright; most ACCs are functional at presentation and cortisol is the most common hormone secreted.
- Risk of malignancy by size: <4 cm ≈5%, >4 cm ≈10%, >6 cm ≈25% — resect adrenal masses >4–6 cm.
- Modified Weiss criteria for ACC: necrosis, abnormal mitoses, clear cells ≤25%, capsular invasion, mitotic rate >5/50 hpf — score ≥3 suggests malignancy.
- Mitotane (oral DDT derivative) is the most commonly used chemotherapy for ACC; inhibits multiple adrenal cortex enzymes including P450scc, 11β-hydroxylase, 18-hydroxylase.
- Margin status is the most important factor for overall survival in ACC; recurrence rate after surgery 60–80%.
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50% of newly discovered adrenal lesions in patients with prior malignancy are metastatic; bulky bilateral disease (>4 cm) needed to produce biochemical adrenal insufficiency.
- Adenoma is the most common primary adrenal tumour; 93% are metabolically silent; <2% of initially non-functional adenomas later gain function.
- Myelolipoma: pathognomonic CT enhancement -30 to -140 HU; NIH consensus regards it as an exception to mandatory metabolic workup.
- 7% of adrenal cysts are associated with malignancy — all of these were pseudocysts.
- Incidental adrenal mass = lesion >1 cm discovered on imaging not done for primary adrenal disease; ≈20% are potential surgical lesions.
- Workup of incidental adrenal mass (excluding myelolipomas, hemorrhages, cysts) per 2011 CUA: LD-DST or 24-h urinary cortisol + 24-h urinary metanephrines/catecholamines ± ARR (in hypertensive patients).
- Unenhanced CT <10 HU is diagnostic of adrenal adenoma (sens ≈70%, spec ≈98%); ≈30% of adenomas are "lipid-poor" with >10 HU and need contrast washout assessment.
- Adenoma washout on CT: absolute washout >60% or relative washout >40%; RCC and HCC mets may mimic lipid-poor adenoma washout.
- Always exclude pheochromocytoma before adrenal biopsy to avoid life-threatening hemorrhage and hypertensive crisis.
- Right adrenal vein is short and drains into the posterior segment of the IVC; left adrenal vein joins the inferior phrenic vein and enters the cranial aspect of the left renal vein.
- In bilateral adrenalectomy, do the left side first as it is more difficult.
- Absolute contraindications to laparoscopic adrenalectomy: local recurrence of previously resected adrenal mass, and invasive ACC with invasion of neighboring organs / renal artery / vena cava.
- Posterior lumbodorsal approach should not be used for large tumors or ACC; flank approach allows easier conversion to transperitoneal.
- Pheo surgery principles: early ligation of the main adrenal vein, minimal gland manipulation, notify anesthesia at the time of vein ligation.
- Partial adrenalectomy indications: bilateral adrenal tumors, solitary adrenal gland, and familial syndromes (VHL, familial pheo, MEN-IIA).
- Bilateral adrenalectomy = lifelong adrenal replacement therapy; risk of Nelson-Salassa syndrome 8–29% from progressive pituitary adenoma growth.
- Hereditary pheo (MEN-2, VHL) — low malignant potential but high bilateral risk — favors cortical-sparing partial adrenalectomy to avoid lifelong steroid replacement.
- Thermal ablation options for adrenal tumors: RFA (60–100 °C protein denaturation), cryoablation (rupture from freeze–thaw, iceball visible on CT), microwave ablation (water dipole oscillation, larger volumes, can treat cystic lesions).