Adrenal Hyperfunction - Cushing Syndrome

Diagnosis

Indications for Testing

• Resistant diabetes
• Refractory hypertension
• Multiple signs/symptoms of Cushing syndrome after ruling out metabolic syndrome or polycystic ovarian syndrome (PCOS)
• Do not test patients who have hypercortisolism secondary to administration of glucocorticoids (oral, inhaled, injections, topical)

Laboratory Testing

• Initial testing (Nieman, Endocrine Society, 2008; National Comprehensive Cancer Network [NCCN], 2018)
  • Salivary cortisol (collected between 2300 hours and 0000 hours) – at least two measurements
    • Reflects circadian nadir so elevations are more relevant
    • Samples are stable over time
    • Cutoff values are test and age specific
    • Counsel individual to collect on quiet, restful evening
  • 24-hour urine free cortisol (UFC) – at least two measurements
    • 24-hour urine collection – random measurements not recommended
    • Urinary cortisol levels >3 x upper limit of normal are unequivocal and confirm diagnosis
    • Results not affected by taking oral estrogen
  • Dexamethasone suppression testing (DST) – overnight and 2-day tests are available
    • Does not interfere with cortisol tests
    • Other glucocorticoids will influence cortisol levels and must be discontinued prior to testing
      • Other hormones that may interfere with cortisol testing – exogenous testosterone, Nature-Throid, estrogens (eg, birth control), megestrol acetate
      • Estrogen-containing drugs should be withdrawn for 6 weeks prior to testing
    • Low-dose (1 mg) DST
      • Patient should take 1 mg dexamethasone between 2300 hours and 0000 hours – should suppress adrenocorticotropic hormone (ACTH) production if hypothalamic-pituitary-adrenal axis (HPA) is normal
      • Serum or urine should be collected between 0800 and 0900 hours and tested for free cortisol
        • ACTH collected at same time may be helpful in case of positive test
      • Dexamethasone is measured to confirm administration and normal metabolism
    • 2-day, 2 mg test – may be used to confirm that ACTH can be suppressed if overnight, low-dose test is equivocal
      • Administer 0.5 mg every 6 hours starting at 0800 for 2 days for a total of eight doses (2 mg)
      • Collect serum for cortisol 2-6 hours after last dose administered
      • Collecting ACTH at same time will assist with etiology in case of positive test
      • Collect dexamethasone to confirm administration and normal metabolism
      • Urinary corticosteroid excretion on day two of dexamethasone administration has been used (compare to baseline day urinary corticosteroid excretion)
        • Not currently recommended, but literature often cites concentrations
    • To confirm elevated results – repeat either of the DST tests or the cortisol tests
      • If high suspicion remains – use high-dose dexamethasone (8 mg) overnight test
        • Similar protocol to low-dose overnight dexamethasone suppression test
        • Negative suppression testing – suggests etiology other than Cushing syndrome
• Follow-up testing (Nieman, Endocrine Society, 2008; NCCN, 2018)
  • Endocrinology referral
  • Serum ACTH in conjunction with suppression tests – aid in determining whether disease is adrenal, pituitary, or ectopic ACTH based
    • Suppressed ACTH (<10 pg/mL) – suggests etiology is ACTH independent and pathology is adrenal (adenoma, carcinoma)
      • Refer to Imaging Studies
    • High ACTH (>20 pg/mL) – suggests ectopic ACTH
      • Refer to Imaging Studies
    • Intermediate ACTH (10 pg/mL – 20 pg/mL) – likely Cushing syndrome and magnetic resonance imaging (MRI) should be done to visualize tumor
      • ACTH-producing tumors are often not visualized (microadenoma)
      • Bilateral inferior petrosal sinus sampling is indicated  – testing is technically difficult and should only be performed in a high-volume center (Pappachan, 2017)
        • Petrosal ACTH to serum ACTH ratio is measured before and after corticotropin stimulation
        • Absence of change in gradient – suggestive of ectopic ACTH-producing tumor
        • Significant increase in pre- and poststimulation – expected in Cushing syndrome
• Mechanisms of potential interference with test evaluation when diagnosing Cushing syndrome and selected drugs that may cause these effects (Nieman, Endocrine Society, 2008)
  • CYP3A4 and dexamethasone metabolism
    • Accelerate dexamethasone metabolism by induction of CYP3A4
      • Phenobarbital
      • Phenytoin
      • Carbamazepine
      • Primidone
      • Rifampin
      • Rifapentine
      • Ethosuximide
      • Pioglitazone
    • Impair dexamethasone metabolism by inhibition of CYP3A4
      • Aprepitant/fosaprepitant
      • Itraconazole
      • Ritonavir
      • Fluoxetine
      • Diltiazem
      • Cimetidine
  • Increase cortisol-binding globulin, therefore falsely elevate cortisol results
    • Estrogens
    • Mitotane
  • Increase urine free cortisol results
    • Carbamazepine – increase
    • Fenofibrate – increase if measured by high-performance liquid chromatography (HPLC)
    • Some synthetic glucocorticoids – immunoassays
  • Drugs that inhibit 11β-HSD2 – licorice, carbenoxolone​

Histopathology

• Definitive solid tumor diagnosis requires biopsy and pathologist examination
• Useful immunohistochemical stains may include ACTH by immunohistochemistry
• For detailed descriptions, refer to ARUP’s Immunohistochemistry Stain Offerings

Imaging Studies

• MRI pituitary with inferior bilateral petrosal sampling of ACTH – differentiate between Cushing syndrome and ectopic source (if necessary)
  • If ACTH is low – MRI of adrenal glands
  • If ACTH >20 pg/mL – search for ectopic ACTH-secreting tumor
• Computed tomography (CT) adrenal protocol or MRI adrenals – identify unilateral/bilateral tumor or hyperplasia

Prognosis

• Untreated Cushing syndrome – associated with excess morbidity/mortality secondary to cardiovascular disease
• If tumor is benign and removed – mortality associated with comorbid diseases developed in association with tumor may normalize
• Malignant tumors producing ACTH have a poor prognosis

Differential Diagnosis

• Obesity/metabolic syndrome
• Type 2 diabetes mellitus
• PCOS
• Depression
• Hypertension
• Malignancy associated with ectopic ACTH production – most common are small cell lung cancer, thymoma, medullary carcinoma of the thyroid

Monitoring

• Following definitive treatment (surgery of adrenals or pituitary, medical adrenal suppression, radiation therapy), consider monitoring (Nieman, Endocrine Society, 2015)
  • Cortisol – for hypocortisolism or hypercortisolism
  • Pituitary hormone (refer to Hypopituitarism)
  • Serum sodium – 5-14 days following transsphenoidal surgery

Background

Epidemiology

• Incidence – 2-3/100,000 (Nieman, Endocrine Society, 2008)
• Age – uncommon in children; peaks in 20s-50s
• Sex – M<F, 1:4-6

Etiology

• Endogenous
  • Pituitary (Cushing syndrome)
    • Hyperplasia
    • Adenoma, often microadenoma
  • Adrenal
    • Adenoma
    • Carcinoma
      • Most are sporadic tumors
      • Hereditary syndromes (eg, Li-Fraumeni) may present as carcinoma
    • Ectopic production of ACTH – tumors (carcinoid, small cell lung cancer)
  • Exogenous – glucocorticoid administration
• Genetics (Lacroix, 2015)
  • Pituitary adenoma – USP8, MEN1, CDKNB/p27Kip1, AIP, DICER1
    • Ectopic ACTH secretion – RET, MEN1
    • Bilateral macronodular adrenal hyperplasia – ARMC5, MEN1, FH, GNAS1, PDE11A, PDE88, MC2R, PRKACA
    • Adrenal adenoma – PRKACA, CTNNB1, GNAS1, PRKAR1A
    • Primary pigmented nodular adrenocortical disease – PRKAR1A, PDE11A, PDE8B, PRKACA

Pathophysiology

• Corticotropin-releasing hormone (CRH) in the hypothalamus stimulates release of ACTH from the pituitary gland
• ACTH acts on the adrenal glands to produce cortisol
• Most endogenous cases are caused by hypersecretion of pituitary ACTH or ectopic production of ACTH from nonpituitary source

Clinical Presentation

• Centripetal obesity, moon facies, buffalo hump, hirsutism, reddish-purple striae
• Hypertension
• Menstrual abnormalities (eg, amenorrhea)
• Irritability, impaired memory
• Osteoporosis
• Fatigue, weakness
• Proximal myopathy
• Impaired glucose tolerance