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ADRENAL GLAND - Comprehensive Study Notes (Topics 2-6)

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TOPIC 2: Basic Adrenal Anatomy, Histology & Overview

Historical Background

• Eustachius gave the first anatomic description of the adrenals in 1563
• Cuvier described the cortex-medulla division in 1805
• Thomas Addison described adrenal insufficiency in 1855
• Harvey Cushing described his syndrome in 1932 (11 patients with moon facies, truncal obesity, hypertension)
• Aldosterone was identified in 1952; Conn's syndrome described in 1955

Embryology

• The fetal cortex is functional by 8 weeks and produces fetal steroids, but involutes after birth - adrenal weight decreases in first 3 postpartum months
• The definitive cortex forms the adult cortex over the first 3 years of life
• Because the cortex originates near the gonads, ectopic adrenocortical tissue can be found in the ovaries, spermatic cord, and testes
• Neural crest cells migrate to form the medulla; most extra-adrenal neural tissue regresses, but the organ of Zuckerkandl (near the aortic bifurcation/inferior mesenteric artery origin) is the largest persistent remnant

Adult Anatomy

• Right adrenal: pyramidal shape, sits above the right kidney; right adrenal vein drains directly into the inferior vena cava (short and wide - high risk of hemorrhage during surgery)
• Left adrenal: semilunar/crescentic shape; left adrenal vein drains into the left renal vein
• Arterial supply: three sources - superior suprarenal artery (from inferior phrenic), middle suprarenal (directly from aorta), inferior suprarenal (from renal artery)
• Weight: each gland ~4-5 g in adults

Histology - The Three Zones of the Cortex

• The medulla contains chromaffin cells (modified postganglionic sympathetic neurons) that produce catecholamines: epinephrine (~80%) and norepinephrine (~20%)
• Medullary cells stain brown with chromate salts - the "chromaffin reaction"

Adrenal Physiology Overview

• Cortisol: zona fasciculata secretes up to 20 mg/day; follows a circadian rhythm - peak in morning, nadir at ~11 PM
• HPA Axis: Hypothalamus → CRH → Anterior pituitary → ACTH → Adrenal cortex → Cortisol → negative feedback
• ACTH is cleaved from the precursor molecule pro-opiomelanocortin (POMC)
• Without ACTH, all cortical cells except mineralocorticoid-producing zona glomerulosa undergo apoptosis

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TOPIC 3: Adrenal Cortex - Cushing Syndrome

Definition & Epidemiology

• Cushing syndrome: hypercortisolism from excessive glucocorticoid production
• Incidence: 2-5 per million per year (rare)
• Most common cause today: exogenous/iatrogenic (prescribed corticosteroids)

Causes - Classification

Clinical Features

• Hyperpigmentation suggests ectopic ACTH (very high circulating ACTH levels stimulate melanocortin receptors)
• Children: obesity + stunted growth (growth suppression distinguishes it from simple obesity)

Diagnostic Workup

• Overnight low-dose DST: 1 mg dexamethasone at 11 PM → cortisol at 8 AM. Normal suppresses to <3 μg/dL (or <1.8 μg/dL by strict criteria)
• 24-hour urinary free cortisol: sensitivity 95-100%, specificity 98%; <100 μg/day rules out hypercortisolism
• Late-night salivary cortisol: reflects loss of diurnal rhythm; increasingly used

• Plasma ACTH levels (normal 10-100 pg/mL):
  • Cushing's disease: 15-500 pg/mL (elevated)
  • Ectopic ACTH: >1000 pg/mL (markedly elevated)
  • Adrenal tumor: <5 pg/mL (suppressed)

• High-dose DST (2 mg q6h x 8 doses, or 8 mg overnight): pituitary adenoma usually suppresses; ectopic ACTH does not
• CRH stimulation test: pituitary adenoma responds (ACTH rises); ectopic ACTH does not
• MRI pituitary for Cushing's disease
• CT adrenal for adrenal cause
• Petrosal sinus sampling: gold standard to distinguish pituitary vs. ectopic when imaging inconclusive

Treatment

• Cushing's disease: trans-sphenoidal pituitary surgery (first line)
• Adrenal adenoma: laparoscopic adrenalectomy (adrenal-dependent disease)
• Bilateral adrenal disease / ectopic ACTH not resectable: bilateral adrenalectomy
• Medical bridging: metyrapone, ketoconazole, aminoglutethimide, etomidate (block steroidogenesis); mitotane
• Prognosis: life expectancy reduced; cardiovascular risk persists even after normalization of cortisol

Subclinical Cushing Syndrome

• Occurs in ~8% of adrenal incidentalomas
• No overt clinical features, but subtle cortisol excess (loss of diurnal variation, resistance to dexamethasone suppression)
• Risk: postoperative adrenal crisis due to unrecognized contralateral adrenal suppression

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TOPIC 4: Adrenal Cortical Insufficiency (Addison's Disease)

Classification

Primary vs. Secondary: Key Differences

Clinical Features of Primary Adrenal Insufficiency

• Chronic: fatigue, weakness, anorexia, weight loss, nausea, hyperpigmentation (buccal mucosa, scars, creases), salt craving, postural hypotension
• Electrolytes: hyponatremia, hyperkalemia, mild acidosis (from aldosterone deficiency)
• Adrenal crisis (acute): severe hypotension/shock, vomiting, abdominal pain, fever, hypoglycemia - precipitated by stress (infection, trauma, surgery)

Diagnosis

• 8 AM cortisol: <3 μg/dL is diagnostic; >18 μg/dL excludes
• ACTH stimulation test (cosyntropin test): give 250 μg synthetic ACTH IV; cortisol should rise to >18 μg/dL. Failure confirms adrenal insufficiency
• Plasma ACTH: elevated in primary, low in secondary
• Anti-21-hydroxylase antibodies: positive in ~90% of autoimmune Addison's

Treatment

• Chronic replacement:
  • Hydrocortisone 15-25 mg/day (split doses; higher in morning to mimic diurnal rhythm)
  • Fludrocortisone 0.05-0.2 mg/day (mineralocorticoid replacement - only needed in primary)
  • DHEA replacement in some patients (especially women, for well-being/libido)
• Sick day rules: double/triple hydrocortisone dose during illness
• Adrenal crisis: IV hydrocortisone 100 mg bolus → 50-100 mg q6-8h + aggressive IV fluids (normal saline + dextrose)

Congenital Adrenal Hyperplasia (CAH)

• Autosomal recessive deficiency of steroidogenic enzymes
• Most common: 21-hydroxylase deficiency (~90%) → cannot make cortisol → excess ACTH → adrenal hyperplasia + excess androgens
• Classic forms: salt-wasting (severe, neonatal crisis) and simple virilizing
• Results in female pseudohermaphroditism (virilization of 46,XX females)

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TOPIC 5: Neoplasms of the Adrenal Cortex

Adrenal Adenoma

• Benign, usually functioning (Conn's or Cushing's) or non-functioning
• Imaging (CT): homogeneous, well-encapsulated, smooth margins, <10 Hounsfield units (lipid-rich), low attenuation
• MRI: low signal intensity T2-weighted relative to liver (mass-to-liver ratio <1.4)
• Most are <4 cm; carcinoma accounts for only 2% of lesions <4 cm

Adrenocortical Carcinoma (ACC)

• Rare, highly aggressive malignancy
• Incidence: ~1-2 per million per year
• Most present with large tumors (median 10-12 cm at diagnosis)
• ~60% are functioning - most commonly excess cortisol ± androgens (Cushing + virilization is a suspicious combination)

• Size >6 cm (~25% malignancy risk; but carcinomas occur in smaller lesions too)
• CT attenuation >18 Hounsfield units (lipid-poor)
• Inhomogeneous, irregular borders, local invasion, lymphadenopathy
• MRI T2: moderate-high signal intensity (mass-to-liver ratio 1.2-2.8)
• Slow washout of contrast on delayed CT imaging

• Stage I: <5 cm, no invasion
• Stage II: >5 cm, no invasion
• Stage III: local invasion or nodal disease
• Stage IV: distant metastases

• Complete surgical resection (open adrenalectomy preferred for ACC - wide margins needed)
• Mitotane (adrenolytic agent): adjuvant treatment; also used for unresectable/metastatic disease
• Additional chemotherapy: EDP-M regimen (etoposide, doxorubicin, cisplatin + mitotane)
• Prognosis is poor: 5-year survival ~15-35% overall

Adrenal Incidentaloma

• Adrenal mass found incidentally on imaging performed for another reason
• Prevalence increases with age (~5% of abdominal CT scans)
• Mandatory workup for ALL incidentalomas (except obvious cysts, hemorrhage, myelolipoma, diffuse mets):
  1. Overnight 1 mg DST (rule out subclinical Cushing)
  2. 24-hour urine catecholamines/metanephrines OR plasma metanephrines (rule out pheochromocytoma - must exclude before any procedure)
  3. Aldosterone/renin ratio if hypertensive (rule out Conn's)
  4. 17-ketosteroids if sex steroid excess suspected

• Functioning tumor (any hormone excess)
• Size >4-6 cm (increased malignancy risk)
• Growth >1 cm on follow-up imaging

Primary Aldosteronism (Conn's Syndrome)

• Most common cause of secondary hypertension (3-13% of hypertensive patients in primary care; up to 30% at referral centers)
• Characterized by autonomous aldosterone production → suppressed renin → hypertension + hypokalemia (though hypokalemia absent in ~50%)
• Subtypes: unilateral adrenal adenoma (~35-40%) vs. bilateral idiopathic hyperplasia (~60%)
• Diagnosis: aldosterone-to-renin ratio (ARR) as screening test
• Treatment: adenoma → laparoscopic adrenalectomy; bilateral hyperplasia → mineralocorticoid antagonist (spironolactone/eplerenone)

Adrenal Myelolipoma

• Benign, non-functioning lesion
• Composed of hematopoietic tissue + mature adipose tissue
• Characteristic CT appearance: fat attenuation (negative Hounsfield units)
• Usually requires no treatment; surgery if symptomatic or large

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TOPIC 6: Adrenal Medullary Neoplasms

Pheochromocytoma

Definition & Epidemiology

• Catecholamine-secreting tumor arising from chromaffin cells of the adrenal medulla
• Estimated incidence: 2-8 cases per million per year
• Found in 0.2-0.6% of hypertensive patients (1.7% of hypertensive children)
• Paraganglioma: same tumor type arising from extra-adrenal chromaffin tissue (sympathetic paraganglia)

The "10% Rule" (classic, now updated)

Familial Syndromes Involving Pheochromocytoma

Clinical Features

• Classic triad: episodic headache, diaphoresis (sweating), and hypertension (sustained or paroxysmal)
• Present in 95% of cases in some large series
• Other: palpitations, pallor, anxiety, weight loss, hyperglycemia
• Hypertensive crisis can be fatal and may be precipitated by surgery, anesthesia, contrast dye, certain medications (beta-blockers, TCA, metoclopramide)
• May present as: heart failure, cardiomyopathy, stroke, or incidentaloma

Diagnosis

• Plasma free metanephrines (normetanephrine + metanephrine): highest sensitivity (~99%); test of choice for screening
• 24-hour urine catecholamines + metanephrines + VMA: good sensitivity, widely available
• Combination of plasma + urine tests maximizes accuracy

• CT abdomen/pelvis: first-line imaging; 90-95% sensitivity for adrenal pheo
• MRI: preferred in children, pregnancy, known metastases; pheochromocytoma is characteristically very bright on T2 (mass-to-liver ratio >3)
• MIBG scan (metaiodobenzylguanidine): functional imaging; useful for extra-adrenal, metastatic, and recurrent disease
• PET scan (FDOPA or FDG-PET): increasingly used for metastatic/familial disease

Preoperative Preparation (CRITICAL)

• Alpha-blockade FIRST (phenoxybenzamine 10-40 mg/day, titrated over 7-14 days; or prazosin/doxazosin)
• Beta-blockade only AFTER adequate alpha-blockade (to control tachycardia) - NEVER give beta-blocker first (risks unopposed alpha causing hypertensive crisis)
• Liberal salt and fluid intake to expand contracted intravascular volume
• Delay surgery 7-14 days after localization to normalize BP, heart rate, and volume
• Metyrosine (tyrosine hydroxylase inhibitor) for very large tumors or non-surgical candidates

Surgery

• Laparoscopic adrenalectomy: preferred for small, benign-appearing adrenal pheochromocytomas
• Open approach: for large tumors, suspected malignancy, or paragangliomas in difficult locations
• Intraoperative risks: severe hypertension during tumor manipulation, severe hypotension after ligation of adrenal vein
• Postoperative: monitor for hypotension, hypoglycemia, adrenal insufficiency

Follow-up

• Repeat biochemical testing 4-6 weeks postop (to confirm complete resection)
• Long-term annual follow-up (recurrence, metachronous tumors, especially in familial cases)
• Genetic testing recommended for all patients - especially for SDHB (high malignancy risk), VHL, RET, NF1

Malignant Pheochromocytoma

• Defined by presence of metastases (not histologic features alone) in sites where chromaffin tissue is normally absent (bone, liver, lung, lymph nodes)

• 10% are malignant at diagnosis; SDHB mutation is the strongest predictor

• Treatment: surgery + MIBG therapy, sunitinib, CVD chemotherapy (cyclophosphamide-vincristine-dacarbazine)
• Prognosis: highly variable; 5-year survival ~50% for malignant disease

Neuroblastoma

• Most common extracranial solid tumor of childhood
• Arises from neural crest cells (same as pheochromocytoma) - can arise in the adrenal medulla or anywhere along the sympathetic chain
• Secretes catecholamines (mostly norepinephrine + dopamine) but rarely causes hypertension
• Presents with abdominal mass, opsoclonus-myoclonus, skin nodules ("blueberry muffin"), bone pain, orbital ecchymosis ("raccoon eyes")
• Biochemical marker: elevated urine VMA and HVA (vanillylmandelic acid and homovanillic acid)
• Genetics: MYCN amplification (poor prognosis), chromosome 1p deletion
• Treatment: surgery, chemotherapy, radiation, differentiation therapy (retinoic acid), MIBG therapy

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