CUSHING SYNDROME—CLINICAL FINDINGS

Definition

• Cushing syndrome: A symptom complex from prolonged exposure to supraphysiologic glucocorticoids.
  • Exogenous (Iatrogenic): Due to administration of synthetic glucocorticoids (most common overall).
  • Endogenous (Spontaneous): Rare; due to ACTH hypersecretion (ACTH-dependent) or primary adrenal hypersecretion (ACTH-independent).

Clinical Approach

1. Recognize signs/symptoms of Cushing syndrome.
2. Confirm endogenous hypercortisolism biochemically.
3. Identify the underlying cause (e.g., pituitary, ectopic ACTH, adrenal).
4. Definitive Cure (surgical or otherwise).

Common Signs and Symptoms

• Weight Gain with Central (Centripetal) Obesity
  • Fat deposition in face (“moon face,” temporal fossae, cheeks), supraclavicular areas, dorsocervical region (“buffalo hump”).
• Skin Changes
  • Easy bruising (ecchymoses).
  • Thin, fragile skin (“cigarette paper” skin) with visible subcutaneous vessels.
  • Poor wound healing.
  • Red-purple wide striae (>1 cm), often on abdomen, flanks, axilla, breasts, hips, inner thighs.
  • Hyperpigmentation (only in markedly increased ACTH).
• Hair and Muscle
  • Scalp hair thinning.
  • Proximal muscle weakness (thin extremities).
• Neuropsychiatric
  • Emotional lability, depression, insomnia, restlessness, irritability.
• Androgen Excess (in women)
  • Hirsutism, acne, possible scalp hair recession.
• Cardiovascular and Metabolic
  • Hypertension.
  • Osteopenia/osteoporosis, vertebral compression fractures, low back pain.
  • Glucose intolerance, diabetes mellitus (insulin resistance).
  • Renal lithiasis.
  • Hyperlipidemia.
  • Increased risk of opportunistic & fungal infections.
  • Menstrual dysfunction (oligomenorrhea, amenorrhea), infertility.
• Children: May show obesity + growth retardation.

Additional Clues

• Gradual Onset: Compare current appearance to old photos.
• Nonspecific Signs: Obesity, HTN, glucose intolerance, menstrual irregularities are common in general population.
• Characteristic Features: Supraclavicular fat pads, wide purple striae, proximal myopathy.
• Weakness: Difficulty climbing stairs, rising from a chair without arms.
• ACTH-Dependent Cases: Often more androgen excess (e.g., hirsutism) in women, hyperpigmentation if ACTH is very high.
• Laboratory Findings:
  • Hyperglycemia, Hyperlipidemia.
  • Hypokalemia (if cortisol has mineralocorticoid activity).
  • Leukocytosis with lymphopenia, possible albuminuria.
  • Severe HTN and profound hypokalemia more typical with ectopic ACTH or adrenal carcinoma.
  • Osteoporosis on bone density scans.
• Prognosis: Untreated Cushing syndrome can be fatal.

TESTS USED IN THE DIAGNOSIS OF CUSHING SYNDROME

General Strategy

1. Case-Detection Testing (screening).
2. Confirmatory Testing (to establish autonomous hypercortisolism).
3. Subtype Testing (to pinpoint the cause).

1. Case-Detection Tests

1. 24-hour Urinary Free Cortisol (UFC)
   • Measures free cortisol excretion; normal or slightly elevated results do not exclude cyclical hypercortisolism.
   • Multiple collections may be needed (10–15% false negatives).
   • Elevated by alcoholism, depression, severe illness, high urine volume.
   • Upper limit of normal is ~45 μg (124 nmol) by tandem mass spec.
2. Late-Night (11 pm) Salivary Cortisol
   • Loss of normal diurnal rhythm (cortisol should be low at night).
   • ~92% sensitivity.
3. Serum Cortisol Diurnal Pattern
   • Loss of normal morning/evening differential supports Cushing’s.
4. Overnight 1-mg Dexamethasone Suppression Test (DST)
   • 1 mg dexamethasone at 11 pm → measure 8 am serum cortisol.
   • Healthy individuals suppress <1.8 μg/dL (50 nmol/L).
   • False positives: Estrogen therapy (↑CBG), pregnancy, obesity, certain drugs (enzyme inducers), severe stress, depression, etc.

2. Confirmatory Testing

• Not required if very high UFC (e.g., >200 μg/24 h or >552 nmol/24 h) plus strong clinical picture.
• 2-Day Low-Dose DST
  • 0.5 mg dexamethasone q6h for 48 hours → measure UFC.
  • UFC >10 μg/24 h (28 nmol/24 h) = diagnostic.
  • Sensitivity ~79%, specificity ~74%.
• If suspicion is high, normal suppression with low-dose DST does not exclude mild pituitary disease.

3. Subtype Testing

• Performed only after confirming Cushing syndrome.
• Plasma ACTH: Distinguishes ACTH-dependent (normal-high) vs. ACTH-independent (undetectable).
• Pituitary MRI (with gadolinium) if ACTH-dependent.
  • Lesions ≥4 mm with typical presentation often confirm pituitary cause; no further studies needed.
  • If lesion <4 mm or normal pituitary MRI (~50% of pituitary Cushing’s), consider inferior petrosal sinus sampling (IPSS).
• Adrenal CT if ACTH-independent to identify adenoma, carcinoma, macronodular hyperplasia, or PPNAD.

CUSHING SYNDROME: PATHOPHYSIOLOGY

Mechanisms

1. ACTH-Dependent Cushing Syndrome
   • Bilateral Adrenal Hyperplasia due to ACTH excess.
   • Pituitary Adenoma (Cushing disease) most common endogenous cause.
   • Ectopic ACTH (small cell lung cancer, bronchial carcinoid, medullary thyroid carcinoma, thymic carcinoid, pancreatic NET, pheochromocytoma).
   • Ectopic CRH (rare).
2. ACTH-Independent Cushing Syndrome
   • Adrenal Adenoma or Carcinoma (unilateral).
   • Adrenal Macronodular Hyperplasia (AIMAH).
   • Primary Pigmented Nodular Adrenocortical Disease (PPNAD).

Clinical Variation by Etiology

• Ectopic ACTH or Adrenal Carcinoma: Marked androgen excess → severe hirsutism, acne, possibly severe HTN/hypokalemia.
• Slow Onset (e.g., Pituitary microadenoma, AIMAH, PPNAD): Gradual central obesity, osteoporosis, proximal myopathy.
• Very High ACTH: Skin hyperpigmentation (ectopic ACTH, pituitary macroadenoma).

ACTH-Dependent

1. Pituitary-Dependent (Cushing Disease)
   • ~70% of endogenous cases.
   • 95% are microadenomas (≤10 mm); half invisible on MRI.
   • Bilateral adrenal hyperplasia → mild to moderate adrenal enlargement (6–12 g each).
   • Excess cortisol ± moderate androgen elevations (DHEA-S mildly ↑).
   • Pituitary histology: ACTH-staining adenoma cells + Crooke hyaline change in non-tumorous corticotrophs.
   • Selective transsphenoidal surgery = treatment of choice.
2. Ectopic ACTH Syndrome
   • Marked hypercortisolism + bilateral large adrenal glands (>12 g each).
   • Common source: Bronchial carcinoid (others: SCLC, MTC, thymic carcinoid, pancreatic NET, pheochromocytoma).
   • Commonly severe: HTN, hypokalemia, hyperpigmentation if ACTH is extremely high.
   • Definitive therapy: Surgical resection of ectopic tumor if possible, else bilateral adrenalectomy.
3. Ectopic CRH Syndrome
   • Rare. CRH secreted by ectopic tumor → pituitary hyperplasia → excess ACTH.

ACTH-Independent

1. Adrenal Adenoma
   • Usually secretes only cortisol, leading to suppressed ACTH and contralateral gland atrophy.
   • Typically ≥2.5 cm for clinical hypercortisolism.
   • Mild androgen elevation is uncommon.
   • Unilateral laparoscopic adrenalectomy = curative approach.
2. Adrenal Carcinoma
   • May produce cortisol ± androgen ± mineralocorticoid.
   • Often large (5–20 cm), can metastasize to LN, liver, lungs.
   • DHEA-S often very high.
   • Open en bloc resection if possible, though recurrences are common. 5-year survival ~30%.
3. AIMAH (ACTH-Independent Macronodular Adrenal Hyperplasia)
   • Bilateral massive nodular adrenal enlargement (each 100–500 g).
   • Often ectopic or overexpressed receptors (GIP, β-adrenergic, vasopressin, LH, etc.) leading to cortisol secretion.
   • Typically mild, slowly progressive.
   • Bilateral adrenalectomy often needed if symptomatic hypercortisolism.
4. PPNAD (Primary Pigmented Nodular Adrenocortical Disease)
   • May be sporadic or familial (Carney complex).
   • Multiple pigmented nodules in both glands; normal or slightly enlarged weight.
   • Slow, mild hypercortisolism, often cyclical.
   • Low ACTH, low DHEA-S, paradoxical ↑cortisol with dex suppression.
   • Bilateral laparoscopic adrenalectomy = curative.

PRIMARY PIGMENTED NODULAR ADRENOCORTICAL DISEASE (PPNAD)

Overview

• Rare ACTH-independent Cushing syndrome with multiple, pigmented, autonomously functioning nodules.
• Presents with mild hypercortisolism, frequent osteoporosis, possibly cyclical cortisol secretion.

Clinical Features

• Young patients (<30 years).
• Central obesity, HTN, glucose intolerance, proximal muscle weakness, menstrual disruption.
• Marked osteoporosis out of proportion to mild Cushing’s.
• Paradoxical ↑UFC during dexamethasone suppression.

Adrenal Morphology

• Adrenals often normal size or mildly enlarged (4–15 g).
• Multiple pigmented nodules (1 mm to 3 cm) with lipofuscin.
• Surrounded by atrophic cortex.

Association with Carney Complex

• ~50% have Carney complex:
  • Spotty skin pigmentation (lentigines, blue nevi), myxomas (atrial, cutaneous, mammary), testicular large-cell Sertoli tumors, GH-secreting pituitary adenomas, melanotic schwannomas.
• Familial in ~60% of Carney complex; autosomal dominant inheritance for most.
• Genes: PRKAR1A (MC), PDE11A, MYH8, others.

Management

• Bilateral laparoscopic adrenalectomy cures hypercortisolism.
• Genetic counseling if Carney complex suspected.