Pathophysiology

Pathophysiology

I-21. Pathogenesis of Cushing's syndrome; symptoms & diagnosis

クッシング症候群の発症機序・症状・診断

Glucocorticoid Physiology (recap)

  • Glucocorticoids (zona fasciculata): anti-inflammatory/immunosuppressive; ↑hepatic gluconeogenesis/glycogenolysis, ↑muscle protein catabolism, ↑adipose lipolysis, ↑insulin resistance → ↑glucose; permissive SNS effect (maintains CO/BP); ↑GFR; inhibits bone formation; CNS arousal; fetal surfactant.
  • Mineralocorticoids: ↑Na⁺/water reabsorption, ↑K⁺/H⁺ secretion.

Types of Cushing’s Syndrome

Caused by glucocorticoid (cortisol) overproduction:

  • ACTH-dependent (bilateral adrenal hyperplasia):
    • Pituitary adenoma producing ACTH = Cushing’s disease (~70%).
    • Ectopic ACTH-producing tumor (~15%).
  • ACTH-independent:
    • Cortisol-producing adrenal adenoma/carcinoma.
    • Iatrogenic (chronic glucocorticoid therapy — most common; taper gradually).

Leading Symptoms

  • Central obesity (visceral fat) → moon face, buffalo hump.
  • Hypertension; thin fragile skin, livid striae, stretch marks, acne, hirsutism.
  • Muscle weakness/fatigue; frequent fractures (osteoporosis); childhood growth failure.
  • Infections (immunosuppression); psychiatric and menstrual disorders.

Metabolic Abnormalities

  • Lipid: central obesity (cortisol → pre-adipocyte differentiation + orexigenic effect); thin limb subcutaneous fat (lipolysis via GH/epinephrine permissiveness); dyslipidemia (FFA → liver → ↑TAG/VLDL/LDL).
  • Carbohydrate: insulin resistance + hyperglycemia (↑gluconeogenesis, ↓muscle/adipose glucose uptake, visceral obesity).
  • Protein: proteolysis → muscle weakness, ↓connective tissue (skin symptoms), ↑hepatic gluconeogenesis.

Organ/System Pathomechanisms

  • Renal: Na⁺/water retention (hypervolemia), ↑K⁺ excretion (hypokalemia) — excess cortisol saturates 11β-HSD2 (which normally inactivates cortisol→cortisone) → cortisol activates mineralocorticoid receptors.
  • Circulatory: acts as a metabolic syndrome (obesity, dyslipidemia, insulin resistance, hypertension) → ↑CV morbidity.
  • Hypertension: ↑CO + TPR (permissive SYM); Na⁺ retention (mineralocorticoid receptor).
  • Vascular: ↑vasoconstriction (↑catecholamine sensitivity), ↓vasodilation (↓NO via ROS); accelerated atherosclerosis (potentiates ANGII → ROS, inflammation, SMC hypertrophy/fibrosis).
  • Skin: thinning, striae, fragility (proteolysis, ↓collagen); delayed wound healing/fungal infections (immunosuppression); hirsutism/acne (androgens).
  • Muscle: myopathy/atrophy (proteolysis + hypokalemia-induced hyperpolarization).
  • Bone: osteoporosis/fractures (↑osteoclast, ↓osteoblast, ↓osteoprotegerin); childhood growth delay.
  • Nervous: anxiety, irritability, sleep disturbance. Reproductive: amenorrhea, ↓spermatogenesis, infertility (androgens ↓GnRH/FSH/LH). Immune: ↑infection susceptibility.

Diagnosis

  • Labs: hyperglycemia (↓glucose tolerance), dyslipidemia (↑TAG/LDL), hypokalemia, high plasma cortisol with no circadian rhythm.
  • Dexamethasone (DEXA) test localizes the cause:
    1. Cortisol suppressed by low-dose DEXA → no Cushing’s.
    2. Not suppressed → measure ACTH:
      • Low ACTH → adrenocortical adenoma.
      • High ACTH → use high-dose DEXA: ≥50% suppression → pituitary adenoma (Cushing’s disease); <50% → ectopic ACTH syndrome.
  • Treatment: mainly surgical; slow withdrawal of medication.

一問一答

▶What causes Cushing's syndrome?

Glucocorticoid (cortisol) overproduction — either ACTH-dependent (pituitary or ectopic) or ACTH-independent (adrenal tumor or iatrogenic).

▶What is Cushing's disease specifically?

ACTH-dependent Cushing's syndrome caused by an ACTH-producing pituitary adenoma (~70%), leading to bilateral adrenal hyperplasia.

▶What is the most common cause of Cushing's syndrome overall?

Iatrogenic (chronic glucocorticoid therapy), which is ACTH-independent and must be tapered gradually.

▶What are the leading clinical features of Cushing's syndrome?

Central (visceral) obesity → moon face, buffalo hump; hypertension; thin fragile skin with livid striae; acne, hirsutism; muscle weakness; osteoporosis/fractures; infections; and psychiatric/menstrual disorders.

▶Why does Cushing's cause central obesity but thin limbs?

Cortisol promotes pre-adipocyte differentiation and appetite (visceral fat gain), while permitting GH/epinephrine-driven lipolysis in the limbs (subcutaneous fat loss).

▶Why does Cushing's syndrome cause hyperglycemia?

Insulin resistance plus increased gluconeogenesis, decreased muscle/adipose glucose uptake, and visceral obesity.

▶Why does Cushing's cause muscle weakness and skin thinning?

Cortisol-driven proteolysis breaks down muscle and connective tissue (↓collagen), causing weakness, thin fragile skin, and striae.

▶Why does Cushing's cause hypokalemia and Na+/water retention?

Excess cortisol saturates 11β-HSD2 (which normally inactivates cortisol to cortisone), so cortisol activates mineralocorticoid receptors → Na+/water retention and ↑K+ excretion.

▶Why is Cushing's syndrome hypertensive?

Increased cardiac output and TPR (permissive sympathetic effect) plus Na+ retention via mineralocorticoid receptor activation.

▶How does Cushing's syndrome accelerate atherosclerosis?

Increased vasoconstriction (↑catecholamine sensitivity), decreased NO (ROS), and potentiation of ANGII → ROS, inflammation, and SMC hypertrophy/fibrosis; it behaves like a metabolic syndrome.

▶Why does Cushing's syndrome cause osteoporosis?

Increased osteoclast activity, decreased osteoblast activity, and decreased osteoprotegerin → bone loss and fractures (plus childhood growth delay).

▶Why do Cushing's patients have increased infection risk and poor wound healing?

Glucocorticoid immunosuppression delays wound healing and predisposes to infections (including fungal).

▶Why does Cushing's cause hirsutism, acne, and reproductive disorders?

Excess adrenal androgens cause hirsutism/acne and suppress GnRH/FSH/LH → amenorrhea, decreased spermatogenesis, and infertility.

▶What laboratory findings support Cushing's syndrome?

Hyperglycemia (↓glucose tolerance), dyslipidemia (↑TAG/LDL), hypokalemia, and high plasma cortisol with loss of circadian rhythm.

▶What does the low-dose dexamethasone test show in Cushing's?

If cortisol is suppressed by low-dose DEXA, there is no Cushing's; if not suppressed, Cushing's is present and ACTH is measured next.

▶After a non-suppressed low-dose DEXA test, how does ACTH localize the cause?

Low ACTH → adrenocortical adenoma. High ACTH → do high-dose DEXA: ≥50% suppression → pituitary adenoma (Cushing's disease); <50% → ectopic ACTH syndrome.

▶What is the treatment of Cushing's syndrome?

Mainly surgical; for iatrogenic cases, gradual (slow) withdrawal of medication.

▶Why does Cushing's cause dyslipidemia?

Lipolysis releases free fatty acids to the liver → increased TAG/VLDL/LDL production.

▶What are the ACTH-independent causes of Cushing's syndrome?

A cortisol-producing adrenal adenoma/carcinoma and iatrogenic chronic glucocorticoid therapy.

▶Why does Cushing's cause neuropsychiatric symptoms?

Excess cortisol affects the CNS, causing anxiety, irritability, and sleep disturbance.