Adrenal Pathology — Cortex and Medulla

Adrenocortical Structure and Steroidogenesis

• The adrenal cortex comprises three functional zones: zona glomerulosa (outer; aldosterone synthesis via 18-hydroxylase), zona fasciculata (middle; cortisol synthesis via 17α-hydroxylase and 11β-hydroxylase), and zona reticularis (inner; androgen synthesis via 17,20-lyase)
• Steroidogenesis requires P450scc (side-chain cleavage enzyme; P450c11a) to convert cholesterol to pregnenolone; subsequent hydroxylation and oxidation steps generate each hormone class
• ACTH stimulates cortisol and androgens via cAMP-PKA pathway; angiotensin II and serum potassium stimulate aldosterone
• Negative feedback: cortisol suppresses ACTH at anterior pituitary and hypothalamus, preventing excessive glucocorticoid synthesis

Primary Adrenal Insufficiency (Addison Disease)

• Destruction or dysfunction of >90% of adrenal cortex results in inability to synthesize all three hormone classes
• Causes include autoimmune destruction (most common in developed countries; lymphocytic infiltration with anti-21-hydroxylase antibodies), tuberculosis (most common worldwide; caseous necrosis), adrenoleukodystrophy (X-linked; very long-chain fatty acid accumulation), adrenomyeloneuropathy, fungal infection (histoplasmosis, coccidioidomycosis), metastatic malignancy, sepsis, anticoagulation-induced hemorrhage
• Deficient cortisol permits unopposed ACTH stimulation; deficient aldosterone causes sodium wasting and hyperkalemia
• ACTH accumulates and melanocyte-stimulating hormone (MSH) from POMC increases, causing hyperpigmentation

Cushing Syndrome (Cortisol Excess)

• ACTH-dependent (80%): Pituitary adenoma (Cushing disease; 70%) or ectopic ACTH production (small cell lung cancer, carcinoid tumors; 15%)
• ACTH-independent (20%): Primary adrenocortical pathology—adrenocortical adenoma (most common), carcinoma, or primary bilateral macronodular adrenocortical hyperplasia (PBMAH)
• Cortisol inhibits ACTH in normal physiology; ACTH-producing tumors escape this feedback, causing persistent glucocorticoid synthesis
• Chronic cortisol excess suppresses immune function, causes protein catabolism (muscle weakness, skin striae), redistributes fat (central obesity, buffalo hump), promotes hepatic gluconeogenesis (hyperglycemia), and enhances mineralocorticoid activity (hypertension)

Primary Aldosteronism (Conn Syndrome)

• Bilateral adrenocortical hyperplasia (60-70%; zona glomerulosa hyperplasia)
• Solitary aldosterone-producing adenoma (APA) (30-40%; often <2 cm, lipid-rich)
• Somatic mutations in ion channel genes (KCNJ5, CACNA1D, ATP1A1, ATP2B3) cause autonomous aldosterone secretion independent of renin-angiotensin system
• Excess aldosterone promotes renal sodium reabsorption (hypertension, volume expansion) and potassium excretion (hypokalemia)
• Metabolic alkalosis develops from hydrogen ion loss accompanying kaliuresis

Adrenocortical Adenoma and Carcinoma

• Adenomas are benign, lipid-rich tumors; most are hormonally silent (incidentalomas)
• Carcinomas are rare (1-2 per million), highly aggressive, often produce multiple hormones (cortisol and androgens), and demonstrate mitotic activity, necrosis, capsular invasion, and vascular invasion
• Weiss criteria (≥3 features predict malignancy): high mitotic rate (>5/50 hpf), atypical mitosis, >25% tumor necrosis, diffuse architecture, capsular invasion, sinusoidal invasion, broad bands of hyalinization, cellular atypia, mitochondrial atypia
• Hereditary associations: Li-Fraumeni syndrome (TP53 mutation; adrenocortical carcinoma in children), Beckwith-Wiedemann syndrome, familial adenomatous polyposis (FAP)

Congenital Adrenal Hyperplasia (CAH)

• Autosomal recessive enzyme deficiencies block steroidogenesis, causing:
• 21-hydroxylase deficiency (90%; most common): prevents cortisol and aldosterone synthesis; accumulated precursors shunt to androgen pathway, causing virilization in females and salt-wasting in some
• 11β-hydroxylase deficiency (5%): deoxycorticosterone accumulates, causing hypertension and hypokalemia; androgens elevated
• 3β-hydroxysteroid dehydrogenase and 17α-hydroxylase deficiencies: rare; cause variable virilization patterns
• In utero androgen exposure causes virilization of external genitalia in genetic females (clitoromegaly, labial fusion)
• ACTH stimulation causes adrenal hyperplasia as gland attempts to overcome enzymatic block

Pheochromocytoma

• Neuroendocrine tumor arising from chromaffin cells of adrenal medulla (90%); extra-adrenal tumors are paragangliomas
• Catecholamine excess (epinephrine, norepinephrine, dopamine) causes paroxysmal hypertension, tachycardia, palpitations, and diaphoresis from α- and β-adrenergic overstimulation
• Rule of 10s: 10% bilateral, 10% extra-adrenal, 10% malignant, 10% familial (associated with MEN2A/2B, neurofibromatosis type 1 (NF1), and familial paraganglioma syndromes)
• Tumor cells contain chromaffin granules (electron-dense on EM) and stain positive for chromogranin A and synaptophysin

Neuroblastoma

• Malignant tumor of developing sympathetic nervous system; arises from primitive neural crest precursors
• Most common extracranial malignancy in children; often presents with metastatic disease (bone, bone marrow, liver)
• Produces catecholamines and metabolites (vanillylmandelic acid [VMA], homovanillic acid [HVA])
• Molecular basis involves MYCN amplification (associated with aggressive, stage 4 disease), 1p deletion, and 11q deletion (poor prognosis)
• Spontaneous maturation to benign ganglioneuroma can occur (favorable prognostic feature)

Adrenoleukodystrophy (ALD)

• X-linked disorder of very long-chain fatty acid (VLCFA) metabolism; deficient ABCD1 peroxisomal transporter
• Cerebral form: demyelination and progressive neurological decline; often fatal in childhood
• Adrenomyeloneuropathy (AMN): slower progression with spinal cord and peripheral nerve involvement
• Addison-only phenotype: adrenal insufficiency without neurological manifestation
• VLCFAs accumulate in adrenocortical tissue (often in lipid-laden macrophages), causing fibrosis and atrophy

Primary Adrenal Insufficiency (Addison Disease)

• Autoimmune adrenalitis (most common in developed nations; 60-70%): organ-specific autoimmune destruction, often associated with other autoimmune endocrinopathies (Hashimoto thyroiditis, type 1 diabetes mellitus, Graves disease)
• Tuberculosis (most common worldwide; 20-30%): caseating granulomatous infiltration with subsequent fibrosis
• Adrenoleukodystrophy (X-linked metabolic disorder; 1% of primary AI in US): accumulation of very long-chain fatty acids
• Metastatic malignancy (lung cancer, breast cancer, lymphoma)
• Fungal infections (histoplasmosis, coccidioidomycosis, blastomycosis, cryptococcosis; endemic regions)
• HIV-related opportunistic infections (CMV, mycobacterial infection, tuberculosis)
• Adrenal hemorrhage: sepsis (meningococcemia; Waterhouse-Friderichsen syndrome), anticoagulation, trauma
• Medications: mitotane (adrenolytic agent), etomidate, ketoconazole (enzyme inhibitors)
• Autoimmune polyendocrine syndrome (APS) type 1: AIRE gene mutations; adrenal insufficiency in ~70%

Cushing Syndrome

• Pituitary adenoma (Cushing disease): ACTH-secreting corticotropinoma; accounts for 70% of ACTH-dependent cases
• Ectopic ACTH production (15% of Cushing syndrome): small cell lung cancer (most common), bronchial carcinoid, thymic carcinoid, gastrin-secreting tumors, pheochromocytoma
• Adrenocortical adenoma: hormone-secreting benign tumor; cortisol-producing (usually >2 cm)
• Adrenocortical carcinoma: aggressive malignancy; often produces multiple hormones
• Bilateral adrenocortical hyperplasia: diffuse expansion of both glands responding to excessive ACTH
• Primary bilateral macronodular hyperplasia (PBMAH): large nodules bilaterally; often from somatic activating mutations or aberrant G-protein coupled receptor expression
• Exogenous glucocorticoid administration: iatrogenic; most common "cause" of Cushing syndrome clinically

Primary Aldosteronism (Conn Syndrome)

• Bilateral idiopathic hyperaldosteronism (IHA) (60-70%): bilateral adrenocortical hyperplasia; zona glomerulosa expansion
• Aldosterone-producing adenoma (APA) (30-40%): usually <4 cm, lipid-rich, often located in zona glomerulosa
• Familial hyperaldosteronism type 1 (FH-I/glucocorticoid-remediable aldosteronism; GRA): autosomal dominant; chimeric CYP11B1/CYP11B2 gene fusion
• Familial hyperaldosteronism type II (FH-II): autosomal dominant; mutations in KCNJ5, CACNA1D, ATP1A1, ATP2B3
• Aldosterone-producing carcinoma: rare, aggressive
• Secondary aldosteronism: occurs with volume depletion, renal artery stenosis, heart failure, liver cirrhosis (activated renin-angiotensin system)

Congenital Adrenal Hyperplasia (CAH)

• 21-hydroxylase deficiency (CYP21A2 mutations) (90%): autosomal recessive; accounts for 90% of CAH cases
• Classic salt-wasting form: severe deficiency; hyponatremia, hyperkalemia, metabolic acidosis in infancy
• Classic simple virilizing form: partial deficiency; normal electrolytes, virilization in females
• Non-classic form: late-onset or mild enzyme deficiency; presents in adulthood with hirsutism, alopecia
• 11β-hydroxylase deficiency (CYP11B1 mutations) (5%): second most common; causes hypertension and hypokalemia
• 3β-hydroxysteroid dehydrogenase deficiency (<1%): autosomal recessive; mild virilization
• 17α-hydroxylase deficiency (<1%): causes hypertension, hypokalemia, absent virilization (shunts to mineralocorticoid pathway)
• Lipoid CAH (StAR protein deficiency): severe; no steroid synthesis; female external genitalia despite XY genotype
• P450 oxidoreductase deficiency: rare; variable presentation

Pheochromocytoma

• Sporadic (70%): somatic mutations; SDHA/SDHB most common (~35%)
• Hereditary syndromes (30%):
• MEN2A (RET proto-oncogene; ~50% develop pheochromocytoma)
• MEN2B (RET mutations; ~50% develop pheochromocytoma)
• Neurofibromatosis type 1 (NF1) (NEUROFIBROMIN; 1-5% develop pheochromocytoma)
• Familial paraganglioma syndromes (SDH mutations: SDHA, SDHB, SDHD, SDHAF2)
• Risk factors for malignancy: extra-adrenal location (paraganglioma), SDHB mutations, large tumor size (>4-5 cm), high mitotic rate

Neuroblastoma

• Age <5 years at diagnosis (most common pediatric malignancy outside CNS)
• Hereditary predisposition: ALK mutations, PHOX2B mutations, family history
• MYCN amplification: worse prognosis
• Segmental chromosome abnormalities: 1p deletion, 11q deletion (high-risk)
• Diploid DNA content and near-tetraploid ploidy: favorable prognostic features (hyperdiploidy)

Adrenoleukodystrophy

• X-linked inheritance (ABCD1 gene mutations; males predominantly affected)
• Female carriers: variable manifestations depending on X-inactivation patterns
• Age of onset: cerebral form typically 4-8 years; adrenomyeloneuropathy 20-30 years

Primary Adrenal Insufficiency (Addison Disease)

• Hyperpigmentation: diffuse, including oral mucosa and palmar creases; due to ACTH-stimulated MSH production (ACTH cleaved from POMC)
• Fatigue and weakness: from cortisol deficiency; nonspecific but progressive
• Hypotension and syncope: from cortisol and aldosterone deficiency; orthostatic hypotension common
• Gastrointestinal symptoms: nausea, vomiting, anorexia, abdominal pain, diarrhea; may mimic acute abdomen
• Hyponatremia and hyperkalemia: from aldosterone deficiency (sodium wasting, potassium retention); can cause lethal arrhythmias
• Metabolic acidosis: from hyperkalemia and renal tubular dysfunction
• Fever: during acute crisis; paradoxically may be present despite severe infection
• Acute adrenal crisis: life-threatening; presents with cardiovascular collapse, severe hyponatremia, shock; triggered by infection, trauma, surgery, or abrupt corticosteroid withdrawal
• Laboratory findings: low cortisol (<3 μg/dL at 8 AM), elevated ACTH (>100 pg/mL), elevated eosinophils, mild anemia, hyponatremia, hyperkalemia

Cushing Syndrome

• Central obesity (truncal) with **

Cushing syndrome — screen, then localize (Endocrine Society Clinical Practice Guideline)

• Step 1, exclude exogenous steroids, then obtain any two of: late-night salivary cortisol, 1 mg overnight dexamethasone suppression test (failure to suppress morning cortisol below ~1.8 μg/dL is abnormal), or 24-hour urinary free cortisol. Dexamethasone is used because it does not cross-react in cortisol immunoassays.
• Step 2, measure plasma ACTH: suppressed ACTH = ACTH-independent (adrenal) disease → adrenal CT. Normal/elevated ACTH = pituitary or ectopic → pituitary MRI.
• Step 3, distinguish pituitary from ectopic: high-dose (8 mg) dexamethasone suppresses a corticotroph adenoma but not ectopic ACTH; CRH stimulation raises ACTH in Cushing disease only. Inferior petrosal sinus sampling is the reference standard when imaging is equivocal, using a central-to-peripheral ACTH gradient.

Primary adrenal insufficiency

• 8 AM cortisol with simultaneous ACTH: low cortisol with markedly elevated ACTH is diagnostic; the confirmatory test is the cosyntropin (250 μg) stimulation test, in which cortisol fails to rise to roughly 18 μg/dL.
• Etiology work-up: anti-21-hydroxylase antibodies first; if negative, adrenal CT (TB, hemorrhage, metastasis) and, in males, very long-chain fatty acids for adrenoleukodystrophy. High renin with low aldosterone confirms mineralocorticoid loss.

Primary aldosteronism (Endocrine Society)

• Aldosterone-to-renin ratio with an elevated plasma aldosterone and suppressed renin is the screening test; withdraw MRAs beforehand.
• Confirm autonomy with saline infusion, oral sodium loading, fludrocortisone suppression, or captopril challenge — aldosterone fails to suppress. Then adrenal CT plus adrenal venous sampling to lateralize before any adrenalectomy.

Medullary and pediatric disease

• Pheochromocytoma: plasma free metanephrines or 24-hour fractionated urinary metanephrines first; image (CT/MRI) only after biochemical confirmation. Functional imaging (MIBG, DOTATATE PET) for metastatic or extra-adrenal disease; germline testing is recommended for all patients.
• Neuroblastoma: urinary HVA and VMA, cross-sectional imaging showing a calcified suprarenal mass that crosses midline and encases vessels, MIBG scan, and bone marrow biopsies; risk assignment uses the INRG staging/risk classification with MYCN status.
• CAH: markedly elevated 17-hydroxyprogesterone (newborn screen), confirmed by ACTH stimulation testing; 11β-hydroxylase deficiency shows elevated 11-deoxycortisol and deoxycorticosterone.
• Incidentaloma: unenhanced CT attenuation ≤10 HU indicates a lipid-rich adenoma; all require pheochromocytoma and cortisol screening before any intervention.

Adrenal crisis — treat before confirming (Endocrine Society)

• Immediate glucocorticoid: hydrocortisone 100 mg IV bolus followed by continuous or divided dosing; at this dose it also supplies mineralocorticoid activity.
• Volume resuscitation: isotonic saline with dextrose for hypotension and hypoglycemia. If the diagnosis is unconfirmed, dexamethasone may be given because it does not interfere with the cortisol assay.
• Chronic replacement: weight-based hydrocortisone in divided doses plus fludrocortisone; teach sick-day rules (double/triple dosing) and provide parenteral hydrocortisone and a medical alert bracelet. Abrupt steroid withdrawal is contraindicated.

Cushing syndrome (Endocrine Society treatment guideline)

• Surgery is first-line: transsphenoidal resection for Cushing disease; laparoscopic adrenalectomy for a unilateral cortisol-secreting adenoma; resection of an ectopic ACTH source.
• Medical therapy when surgery fails or is delayed: steroidogenesis inhibitors (osilodrostat, metyrapone, ketoconazole; etomidate for parenteral control), pituitary-directed agents (pasireotide, cabergoline), or the glucocorticoid-receptor antagonist mifepristone for associated hyperglycemia — mifepristone is contraindicated in pregnancy.
• Bilateral adrenalectomy is a last resort and mandates lifelong replacement.
• Adrenocortical carcinoma: open en bloc resection by an experienced surgeon, adjuvant mitotane, with platinum-based chemotherapy for advanced disease.

Primary aldosteronism

• Unilateral disease confirmed by venous sampling → laparoscopic adrenalectomy. Bilateral hyperplasia → mineralocorticoid receptor antagonist, spironolactone (switch to eplerenone for gynecomastia). Glucocorticoid-remediable aldosteronism responds to low-dose glucocorticoid.

Pheochromocytoma (Endocrine Society)

• Alpha blockade first — phenoxybenzamine or a selective agent such as doxazosin — for one to two weeks, with liberal sodium and fluid intake to re-expand the contracted plasma volume.
• Beta blockade only after adequate alpha blockade, for reflex tachycardia. Giving a beta blocker first is contraindicated: unopposed α-mediated vasoconstriction precipitates hypertensive crisis.
• Definitive therapy is laparoscopic adrenalectomy; intraoperative surges are managed with phentolamine or nitroprusside. Never biopsy a suspected pheochromocytoma.

Pediatric and congenital disease

• CAH: hydrocortisone (avoiding potent long-acting steroids in growing children) plus fludrocortisone and sodium chloride supplementation in salt-wasters, with stress dosing (Endocrine Society).
• Neuroblastoma: risk-adapted Children's Oncology Group therapy — observation or surgery alone for low-risk/stage MS, and induction chemotherapy, resection, myeloablative therapy with autologous stem cell rescue, radiation, then anti-GD2 immunotherapy (dinutuximab) with isotretinoin for high-risk disease.

Emergencies

• Acute adrenal crisis: cortisol deficiency removes permissive support for catecholamine vasoconstriction while aldosterone loss depletes volume → refractory hypotension, hyponatremia, hyperkalemia, hypoglycemia. Signaled by shock unresponsive to fluids and pressors in a patient with hyperpigmentation or recent steroid withdrawal.
• Hyperkalemic arrhythmia: peaked T waves widening to a sine-wave pattern.
• Catecholamine hypertensive crisis: precipitated by beta blockade before alpha blockade, tumor manipulation, or contrast/anesthetic induction; may cause stroke, aortic dissection, or catecholamine (Takotsubo-like) cardiomyopathy with acute pulmonary edema.
• Salt-wasting crisis in classic 21-hydroxylase deficiency: a vomiting, dehydrated neonate in week 1–3 of life with hyponatremia and hyperkalemia.
• Epidural spinal cord compression from a dumbbell paraspinal neuroblastoma extending through neural foramina.

Complications of the disease

• Cortisol excess: osteoporosis with vertebral compression fractures, avascular necrosis, diabetes, proximal myopathy, poor wound healing, opportunistic infection (including Pneumocystis), psychosis, and a hypercoagulable state raising perioperative VTE risk.
• Aldosterone excess: myocardial and vascular fibrosis producing LVH, atrial fibrillation, stroke, and CKD out of proportion to the blood pressure — the reason primary aldosteronism must be identified rather than simply treated as essential hypertension.
• Neuroblastoma paraneoplastic syndromes: opsoclonus-myoclonus ("dancing eyes-dancing feet") and VIP-mediated secretory diarrhea with hypokalemia.
• CAH: virilization and short adult stature from premature epiphyseal fusion, testicular adrenal rest tumors, and subfertility.

Complications of treatment

• Post-adrenalectomy or post-transsphenoidal adrenal insufficiency: chronic cortisol excess suppresses the contralateral gland and the corticotroph axis; replacement is required until recovery.
• Nelson syndrome: after bilateral adrenalectomy, loss of feedback allows corticotroph adenoma growth with intense hyperpigmentation and visual field loss.
• Post-resection hypotension and hypoglycemia after pheochromocytoma removal — abrupt catecholamine withdrawal in a vasodilated, chronically volume-contracted patient, with rebound hyperinsulinemia.
• Post-adrenalectomy hyperkalemia in primary aldosteronism from a chronically suppressed contralateral zona glomerulosa; spironolactone causes gynecomastia and hyperkalemia.
• Drug toxicities: mitotane-induced adrenal insufficiency and neurotoxicity; ketoconazole hepatotoxicity; steroidogenesis inhibitors causing precursor-driven hypokalemia, hypertension, and hirsutism; dinutuximab neuropathic pain and capillary leak; supraphysiologic hydrocortisone producing iatrogenic Cushing syndrome.

• Hyperpigmentation localizes the lesion: it occurs only in primary adrenal insufficiency, where POMC-derived ACTH/MSH is elevated. Secondary (pituitary) insufficiency spares aldosterone, so there is no hyperkalemia and no hyperpigmentation — the most common distractor in adrenal insufficiency stems.
• Suspected pheochromocytoma? Biochemistry before imaging, alpha before beta. The single best next step is plasma free or urinary fractionated metanephrines, not a CT and never a biopsy. Starting a beta blocker first causes unopposed α-vasoconstriction and hypertensive crisis.
• Resistant hypertension with spontaneous or diuretic-induced hypokalemia and metabolic alkalosis = primary aldosteronism; check the aldosterone-to-renin ratio. Adrenal venous sampling, not CT alone, decides who gets an adrenalectomy, because nonfunctioning incidentalomas are common.
• Dexamethasone is the steroid used in Cushing testing because it does not cross-react in cortisol immunoassays — and it is also the steroid of choice when treating a suspected crisis before the cosyntropin test is done.
• The CAH triad by enzyme: 21-hydroxylase → ↑17-OHP, salt wasting, hypotension, virilization; 11β-hydroxylase → hypertension (deoxycorticosterone) with virilization; 17α-hydroxylase → hypertension without virilization and absent secondary sexual development.
• Neuroblastoma versus Wilms tumor: neuroblastoma is a calcified suprarenal mass that crosses the midline and encases vessels, with elevated HVA/VMA, Homer-Wright rosettes, small round blue cells, and MYCN amplification as the key adverse prognostic marker; Wilms tumor displaces rather than crosses and presents with hematuria.
• The association examiners love: pheochromocytoma in MEN2A/2B, von Hippel-Lindau, NF1, and SDH-mutation paraganglioma syndromes — in MEN2, exclude and treat the pheochromocytoma before thyroid or parathyroid surgery.
• Buzzword pairings: Waterhouse-Friderichsen syndrome (meningococcemia, bilateral adrenal hemorrhage), Nelson syndrome (post-bilateral-adrenalectomy corticotroph adenoma), Weiss criteria (adrenocortical carcinoma), and a young male with Addison disease plus neurologic decline → check very long-chain fatty acids for adrenoleukodystrophy.