Cushing's Syndrome - Complete Notes Explained

Definition

Etiopathogenesis (Causes)

a) Exogenous Corticosteroids (Drugs) - MOST COMMON overall

• Patient is given steroids for treatment of another disease (e.g., asthma, autoimmune disease)
• The exogenous cortisol feeds back negatively on the pituitary, suppressing ACTH production
• Result: decreased ACTH + bilateral adrenal atrophy (both adrenal glands shrink because they receive no ACTH stimulation)

b) Adrenal Cushing's Syndrome (ACTH-independent, ~20-30% of endogenous cases)

• Caused by a primary adrenal adenoma (most common adrenal cause), adrenal hyperplasia, or carcinoma
• The adrenal tumor produces cortisol autonomously, without needing ACTH
• This autonomously produced cortisol suppresses the pituitary via negative feedback
• Result: decreased ACTH + atrophy of the uninvolved adrenal gland (the opposite gland shrinks)
• Key exam distinction: ACTH is LOW, cortisol is HIGH

c) Pituitary Cushing's Disease (~60-70% of endogenous cases)

• Caused by an ACTH-secreting pituitary adenoma (almost always a microadenoma, too small to cause mass effects)
• The excess ACTH drives both adrenal glands to overproduce cortisol
• Result: bilateral adrenal hyperplasia (both glands enlarge)
• ACTH is HIGH, cortisol is HIGH
• 4x more common in women, peak age 20-40 years
• This is specifically called "Cushing's disease" - the term "disease" is reserved for the pituitary adenoma subtype

d) Paraneoplastic (Ectopic) ACTH Secretion (~10-15% of endogenous cases)

• A non-pituitary tumor produces ACTH ectopically
• Most common cause: Carcinoid tumor > Small cell carcinoma of the lung
  • (Your notes say carcinoid > SCLC; Robbins states SCLC is most common, but carcinoid is more frequently associated with the classic full syndrome because SCLC progresses too fast)
• Other tumors: medullary thyroid carcinoma, pancreatic neuroendocrine tumors
• Result: bilateral adrenal hyperplasia (same mechanism as pituitary - excess ACTH drives both glands)
• ACTH is HIGH (often very high), cortisol is HIGH

Summary Table: ACTH Levels and Adrenal Morphology

Clinical Features

1. Fat Redistribution (Lipid Effects)

• Cortisol increases lipid mobilization and catabolism in the extremities
• But high insulin (from cortisol-driven hyperglycemia) promotes fat storage centrally
• Results in:
  • Moon facies - round, puffy face
  • Buffalo hump - fat pad on upper back/posterior neck
  • Truncal obesity - central fat accumulation
  • Thin arms and legs - peripheral fat loss + muscle wasting

2. Glucose / Metabolic Effects

• Cortisol increases hepatic gluconeogenesis and causes insulin resistance
• Results in:
  • Secondary diabetes (hyperglycemia, glycosuria, polydipsia)
  • Hypokalemic metabolic alkalosis - cortisol has mild mineralocorticoid activity, causing renal K+ loss

3. Protein Catabolism (Negative Nitrogen Balance)

• Cortisol breaks down muscle protein to provide amino acids for gluconeogenesis
• Results in:
  • Proximal muscle weakness (type II myofiber atrophy) - the patient cannot climb stairs or rise from a chair
  • Thin extremities
• Impaired collagen synthesis causes:
  • Violaceous (purple) abdominal striae - skin tears because collagen is deficient
  • Thin, fragile skin - bruises easily
  • Poor wound healing

4. Water and Electrolyte Disturbance

• Dependent edema - fluid retention from mineralocorticoid-like effects
• Hypertension - sodium and water retention raises blood pressure

5. Plethora (from your second image)

• Excess cortisol causes degradation and atrophy of the epidermis and underlying connective tissue
• This leads to thinning of the skin and facial plethora (a reddish-flushed appearance on the face, because the thin skin reveals the underlying blood vessels)

6. Hirsutism (from your first image)

• In ACTH-excess states (pituitary or ectopic), the excess ACTH stimulates all three zones of the adrenal cortex:
  • Zona glomerulosa -> aldosterone
  • Zona fasciculata -> cortisol
  • Zona reticularis -> androgens
• Excess adrenal androgens cause hirsutism (male-pattern hair growth in females)
• Also causes menstrual irregularities and acne

7. Other Features

• Osteoporosis - cortisol reduces calcium absorption from the gut, increases renal calcium loss, and directly suppresses osteoblasts -> bone resorption and fractures
• Immune suppression - cortisol suppresses lymphocytes and inflammatory mediators -> increased infection risk
• Psychiatric features - mood swings, depression, psychosis
• Skin hyperpigmentation - only in ACTH-excess causes (pituitary and ectopic), because ACTH is derived from the same POMC precursor as melanocyte-stimulating hormone (MSH)

Key Exam Mnemonics

• C - Central obesity, Collagen loss (striae)
• U - Urinary free cortisol elevated
• S - Striae, Skin thinning
• H - Hypertension, Hirsutism, Hyperglycemia
• I - Immune suppression, Infections
• N - Nitrogen balance negative (muscle wasting)
• G - Gluconeogenesis increased
• S - Secondary diabetes, Suppressed ACTH (in adrenal/exogenous types)