Hypo- and hyperfunctions and tumors of the adrenal gland

1. Adrenal Anatomy

• Cortex:
  • Zona glomerulosa → mineralocorticoids (aldosterone)
  • Zona fasciculata → glucocorticoids (cortisol)
  • Zona reticularis → androgens
• Medulla → catecholamines (chromaffin cells).
• Mnemonic: GFR → “Salt, Sugar, Sex”.

2. Adrenocortical Hypofunction

• Destruction of > 90 % of gland required for clinical insufficiency.

A) Primary Acute Adrenal Insufficiency

• Waterhouse-Friderichsen syndrome:
  • Caused by N. meningitidis sepsis (or other bacteria).
  • Hypovolemia → vasoconstriction → bilateral adrenal hemorrhage/necrosis → acute adrenal failure → death.
• Sudden withdrawal of long-term corticosteroid therapy.
• Stress in patients with underlying chronic adrenal insufficiency (Addisonian crisis).

B) Primary Chronic Adrenal Insufficiency (Addison Disease)

• Progressive destruction of adrenal cortex (> 90 %).
• Chronic deficiency of glucocorticoids ± mineralocorticoids.
• #1 cause = autoimmune adrenalitis.
• Other causes: TB, metastases (breast, lung), amyloidosis, hemorrhage, fungi (histoplasmosis).

Symptoms

• Hyperpigmentation (↑ ACTH → ↑ MSH from POMC).
• Hyperkalemia, hyponatremia, hypoglycemia.
• Weakness, fatigue, weight loss, hypotension.

C) Secondary Adrenal Insufficiency

• Hypothalamic/pituitary disorder → ↓ ACTH.
• Cortical atrophy.
• NO hyperpigmentation (low ACTH/MSH).
• Aldosterone preserved (RAAS-driven) → no hyperkalemia.

3. Adrenocortical Hyperfunction

A) Conn Syndrome (Hyperaldosteronism)

• Aldosterone overproduction → ↑ Na⁺ + H₂O reabsorption + ↑ K⁺/H⁺ secretion.
• → HTN + hypokalemia + metabolic alkalosis.

Primary hyperaldosteronism (Conn)

• High aldosterone, LOW plasma renin activity (PRA) (suppressed by feedback).
• Causes:
  • Aldosterone-producing adenoma (Conn syndrome; solitary + encapsulated).
  • Idiopathic bilateral hyperplasia.
• Tx: surgical adenomectomy / spironolactone.

Secondary hyperaldosteronism

• HIGH PRA → ↑ aldosterone.
• Causes: ↓ renal perfusion (renal artery stenosis), arterial hypovolemia + edema (CHF, cirrhosis, nephrotic), pregnancy.

B) Cushing Syndrome (Hypercortisolism)

• Zona fasciculata → cortisol excess.
• Most common cause = exogenous corticosteroid administration.
• Endogenous causes:
  1. Pituitary ACTH adenoma = Cushing disease (#1 endogenous; ↑ ACTH).
  2. Primary adrenal lesion (adenoma, carcinoma, hyperplasia) → ↑ cortisol + ↓ ACTH.
  3. Ectopic ACTH by non-endocrine neoplasms (small cell lung carcinoma, carcinoid).

Morphology

• Pituitary: Crooke hyaline change — intermediate keratin filaments accumulate in cytoplasm → lighter color.
• Adrenal:
  • Cortical atrophy (exogenous / adrenal lesion).
  • Diffuse or nodular hyperplasia (ACTH-dependent).
  • Adenoma: yellow, encapsulated.
  • Carcinoma: non-encapsulated, anaplastic; atrophy of surrounding gland.

Clinical features

• Central obesity (moon face, buffalo hump).
• HTN.
• Skin: purple/livid striae (abdominal), thin skin, easy bruising, hirsutism.
• Osteoporosis.
• Mental disturbances, hyperglycemia, immunosuppression.

C) Adrenogenital Syndrome (Congenital Adrenal Hyperplasia, CAH)

• Zona reticularis → excess androgens.
• Autosomal recessive; hereditary enzyme defects in adrenal steroid biosynthesis.
• ↓ Cortisol → ↑ ACTH → adrenal hyperplasia → ↑ cortisol precursors → channeled into androgen synthesis.

21β-Hydroxylase deficiency (most common, ~90 %)

• No cortisol, no aldosterone (salt wasting).
• Excessive androgens.
• Female: masculinization (virilization), ambiguous genitalia, early adrenarche, hirsutism, amenorrhea.
• Male: enlargement of external genitalia, reduced spermatogenesis.
• Salt-wasting crisis in neonates: hypotension, hyperkalemia, hyponatremia.

11β-Hydroxylase deficiency

• Androgen overproduction + cortisol deficiency.
• ↑ 11-deoxycorticosterone (mineralocorticoid activity) → Na⁺/H₂O retention + hypokalemia + HTN.

4. Adrenal Medulla Tumors

A) Pheochromocytoma

• Benign neoplasm of chromaffin cells → ↑ catecholamines (epi/norepi) → HTN.
• “Rule of 10s”:
  • 10 % bilateral
  • 10 % familial (MEN-2, NF1, VHL)
  • 10 % malignant
  • 10 % extra-adrenal (organ of Zuckerkandl, bladder)
  • 10 % in children
  • 10 % calcify

Morphology

• Well-circumscribed, yellowish-brown.
• Small lesion or large with hemorrhage, necrosis, cystic.
• Histology:
  • Chromaffin cells + supporting (sustentacular) cells; pleomorphic.
  • “Zellballen” (cell balls) with rich vascular network.
  • Chromogranin A⁺ on IHC.

Clinical features

• HTN (paroxysmal or sustained) with 5 P’s:
  • Pressure (HTN)
  • Pain (headache)
  • Perspiration (sweating)
  • Palpitations (tachycardia)
  • Pallor
• Risk: MI, HF, renal injury, hypertensive encephalopathy.
• Diagnosis: urinary free catecholamines + metabolites (VMA, metanephrines).
• Treatment: surgery AFTER α-blockade (phenoxybenzamine) then β-blockade — never β-block first (unopposed α → hypertensive crisis).

B) Neuroblastoma

• 2nd most common childhood malignant tumor (after ALL).
• Most common solid extracranial cancer in kids.
• From neural crest cells of sympathetic ganglia + adrenal medulla.
• Peak age 1–2 yr; often palpable abdominal mass.
• Features: spontaneous regression, spontaneous/therapy-induced maturation.

Morphology

• 40 % in adrenal medulla; rest along sympathetic chain.
• Soft, sharply demarcated, fibrous capsule; calcification, hemorrhage, necrosis.
• Histology: small, dark nuclei + little cytoplasm + poorly defined borders.
• Homer-Wright pseudorosettes: tumor cells concentrically around central neuropil.

Maturation spectrum

• Neuroblastoma → ganglioneuroblastoma → ganglioneuroma (good prognosis).
• Ganglioneuroma = only mature ganglion cells (benign).

Clinical course

• Mets to liver, lung, bone, skin via blood + lymph.
• Neonates: skin mets → blue discoloration (“blueberry muffin”).
• < 2 yr: protuberant belly, fever, weight loss.

• 2 yr: hepatomegaly, ascites, bone pain.

• Markers: ↑ urinary VMA / HVA.

Prognosis

• Better in < 18 months.
• Stage (1–4), stromal-rich better than stromal-poor, low mitotic activity, calcification → better.
• N-myc amplification (~25 %) = unfavorable prognosis.

5. Adrenal Cortex Tumors

Adenomas

• Non-functional (incidental) or functional:
  • Glucocorticoid → Cushing.
  • Mineralocorticoid → Conn.
  • Androgen → adrenogenital syndrome.
• Yellowish, small.
• Surgical removal corrects HTN (Conn adenoma).

Carcinomas

• Rare, large, invasive.
• Necrosis, hemorrhage, cystic changes.
• Invade vessels, distant mets → poor prognosis.

Metastasis

• Usually from lung.
• Bilateral adrenal tumor → check for small cell lung carcinoma.

6. Summary Table

Condition	Hormone	Key feature
Addison disease	↓ cortisol + aldosterone	Autoimmune, hyperpigmentation, hyperkalemia/hyponatremia/hypoglycemia
Waterhouse-Friderichsen	Acute adrenal failure	N. meningitidis → bilateral adrenal hemorrhage
Conn syndrome	↑ aldosterone	HTN + hypokalemia + alkalosis; ↓ PRA
Cushing syndrome	↑ cortisol	Exogenous #1; endogenous → pituitary (Cushing disease) / adrenal / ectopic (SCLC); moon face + buffalo hump + purple striae
CAH (21β-OH)	↑ androgens, ↓ cortisol/aldo	Salt wasting + virilization (#1 CAH)
Pheochromocytoma	↑ catecholamines	Rule of 10s, 5 P’s, ↑ VMA + metanephrines, α-block before surgery
Neuroblastoma	↑ catecholamines	#2 childhood cancer; Homer-Wright rosettes; N-myc; < 18 mo better

💡 High-yield: Cortex zones: GFR → Salt/Sugar/Sex. Addison = autoimmune, ↓ cortisol/aldo, hyperpigmentation (↑ ACTH/MSH), hyperkalemia/hyponatremia. Waterhouse-Friderichsen = meningococcal sepsis → bilateral adrenal hemorrhage. Conn = primary hyperaldosteronism: HTN + hypokalemia + ↓ PRA. Cushing: #1 exogenous; endogenous: pituitary adenoma (Cushing disease), adrenal tumor, ectopic ACTH (SCLC); moon face + buffalo hump + purple striae + DM + osteoporosis. CAH 21β-OH deficiency (#1) = salt wasting + virilization. Pheochromocytoma = Rule of 10s, 5 P’s, VMA + metanephrines, α-block before β-block + surgery; MEN-2. Neuroblastoma = #2 childhood malignancy, < 2 yr, Homer-Wright rosettes, N-myc amplification = poor prognosis.