Cushing’s Syndrome

Sub-section: Adrenal Section: Endocrine

Definition and Incidence

• Cushing’s Syndrome
  • Disorder characterised by a no. of signs and symptoms, caused by long term effects of elevated glucocorticoid levels
• Cushing’s Disease
  • Glucocorticoid excess caused by an ACTH-secreting Pituitary Adenoma

Clinical Presentation

• Symptoms
  • Central obesity
  • Buffalo hump
  • Moon faces
    • Facial Plethora ****
    • Reddening due to thin skin
  • Striae****
  • Hirsutism
  • Loss of libido
  • Menstrual irregularity
  • Depression/psychosis
  • Proximal myopathy****
  • Easy bruising****
• Signs
  • Diabetes Mellitus
  • Osteoporosis
  • Hypertension (> 70%)
  • Hypokalaemia

Aetiology

• Most common cause is exogenous steroid use
• Endogenous Cushing’s syndrome is rare (F > M)
  • ACTH-Dependent (80%)
    • Pituitary-related (Cushing’s disease) (70%)
    • Ectopic (10%)
      • E.g. NET’s, Bronchogenic Carcinoid, Medullary Thyroid, Phaeo, or Small Cell Lung Ca
  • ACTH-Independent (15-20%)
    • Primary adrenal Cushing syndrome
      • Adenoma (90%)
      • Carcinoma (10%)
      • Bilateral micronodular/ macronodular Hyperplasia (<1%)

Diagnosis

• Screening tests
  • 24hr Urinary Free Cortisol
    • Reflects average cortisol levels
    • Levels > 4x normal - diagnostic of Cushing’s
    • Less sensitive at diagnosing subclinical Cushing’s
    • Do at least 2 measurements, may need 3
  • Late-night Salivary Cortisol
    • Cushing’s syndrome shows loss of normal circadian rhythm of cortisol secretion
    • Resting midnight plasma cortisol > 50nmol/L is 100% sensitive for Cushing’s
    • Salivary results closely correlated to plasma
    • High sensitivity and specificity for Cushing’s (> 92%)
    • Need to do in low stress environment
      • Hence: At home
  • Low Dose Dexamethasone Suppression Test
    • Exploits loss of negative feedback loop for cortisol
    • 1-2mg dexamethasone, given at midnight
    • Should suppress cortisol level taken at 9am following am
    • If cortisol > 50nmol/L the following am
      • Sensitivity for Cushing’s 95%
      • Specificity 80%
    • Some units may do 2mg/day, 48hr testing
      • Gives higher specificity
• Establishing a cause
  • Corticotropin dependent or ACTH-independent disease
    • High ACTH = ACTH-dependent

      • 20 pg/mL, 4.4 pmol/L

    • Low ACTH = ACTH-independent
      • <5 pg/mL (1.1 pmol/L
    • Intermediate
      • Repeat testing
  • ACTH-dependent
    • Pituitary vs ectopic
      • Noninvasive biochemical testing with
        • CRH (if available) or desmopressin (DDAVP) stimulation test
          • Both stimulate ACTH
          • Increases in ACTH and cortisol is consistent with pituitary adenoma
        • High dose dexamethasone suppression
          • Pituitary tumours retain some negative feedback control and ectopic source does not
          • Give single dose 8mg dexamethasone, or 2mg QID for 48hrs
            • If cortisol level drops to < 50% baseline
            • Suggests Pituitary Cushing’s
          • If no significant drop - Ectopic cause (or Adrenal cause, but will have already ruled this out with prior investigations)
      • Imaging
        • MRI
      • Invasive testing
        • Bilateral Inferior Petrosal Sinus Sampling
          • To differentiate pituitary Cushing’s from ectopic if dexamethasone suppression test equivocal
          • Invasive
            • Catheter measures ACTH in each Petrosal Sinus and peripheral ACTH levels
              • Central-to-peripheral ACTH gradient
      • Further Investigations of Ectopic ACTH Dependent Cushing’s
        • Basic tumour markers
          • Urinary 5-HIAA
          • Serum Calcitonin
          • Chromogranin A
          • Other GI neuroendocrine hormones as indicated
          • CT neck/chest/abdo/pelvis
          • Somatostatin receptor scintigraphy
  • ACTH Independent
    • Adrenal) Cushing’s
    • Next step is Localisation
      • CT is the initial modality of choice
        • Will see adenoma, carcinoma, and macronodular hyperplasia
        • Won’t see micronodular hyperplasia
        • NB: Overlap in appearances of adrenal adenoma and carcinoma on cross sectional imaging
      • Risk of malignancy increased if
        • High attenuation
        • Irregular outline
        • Delayed contrast washout
        • Heterogenous

        • 4cm in size

      • If concerned about malignancy:
        • MRI with Gadolinium can help to differentiate
        • High water content of carcinoma c.f. adenoma

Management

• Peri- and Post-op glucocorticoid administration
  • Essential
  • Initial high dose with taper post-op
    • Some units withhold initially post-op
      • To assess cortisol levels, ? biochemical cure
    • Beware of Adrenal Crisis – Endocrinologist should manage
• Surgery
  • Primary adrenal Cushing’s syndrome
  • Cushing’s disease
  • Ectopic ACTH independent Cushing’s syndrome

Surgical Management of Primary Adrenal Cushing’s

• Unilateral Adrenalectomy

  • 90% effective, but resolution of symptoms takes months-to-years

  • Failure could be due to missed or recurrent malignant disease
• Perform in specialised center
  • High risk of infections, Skin injury, Fractures, Hyperglycaemia
  • DVT risk increased (up to 5%) so use clexane

Surgical Management of Cushing’s Disease (Pituitary)

• Initial approach
  • Pituitary microsurgery for Cushing’s disease
  • Trans-nasal, trans-sphenoidal approach
• If fails, consider:
  • Re-operation
  • Danger of causing pan-hypopituitarism
• Radiation
  • If fail
• Bilateral Adrenalectomy
  • Will need lifelong glucocorticoids and mineralocorticoid supplementation

Management Ectopic Cushing’s Syndrome

• Treatment of primary tumour is preferable
  • But not always possible
• Controlling symptoms paramount if removing primary not possible
  • Ketoconazole inhibits cortisol production
  • Bilateral Adrenalectomy best way to achieve symptom palliation
    • Even in patients with limited life expectancy
    • Esp. if laparoscopic