Complications and Comorbidities> Endocrine>

DEFINITION

• Hormonal disorder caused by prolonged exposure to high levels of glucocorticoids 
• May be due to exogenous glucocorticoids (more common) or endogenous hypercortisolemia
• Cushing's syndrome due to an ACTH-secreting pituitary adenoma is referred to as Cushing's disease.
• Excess glucocorticoids, endogenous or exogenous, exert a powerful hyperglycemic effect

EPIDEMIOLOGY

• Overt Cushing's incidence in general population: 2.4 cases per 1 million persons per year with standardized mortality ratio of 3.8 for affected persons in Spain (Etxabe)
• Occult Cushing's prevalence in diabetes: 2-5% of overweight or obese, poorly-controlled type 2 diabetes patients (Catargi)
• Approximately 25% of overweight, type-2 diabetes patients have impaired morning cortisol suppression after a low-dose overnight dexamethasone suppression test (Catargi)
• Most common hormonal abnormality in patients with adrenal incidentaloma.

DIAGNOSIS

• Detailed history to assess for any use of exogenous glucocorticoids (oral, topical, injection, inhaled).
• CYP3A4 inhibitors (especially ritonavir) inhibit glucocorticoid clearance causing Cushing's with concurrent inhaled and injection steroid use.
• Screening: late night salivary cortisol x 2, 24-hour urine free cortisol (UFC) x 2, low-dose dexamethasone suppression test (after 1mg dexamethasone at 11pm, normal 8AM cortisol < 1.8 mcg/dL)
• At least two clearly abnormal (e.g. UFC > 3 times upper limit of normal) tests using different test methods needed to establish diagnosis.
• False positive dexamethasone suppression test seen with increased cortisol binding globulin (e.g., estrogen-containing OCPs).
• After diagnosis of hypercortisolism, serum ACTH < 5 pg/ml (1.1pmol/L) suggests ACTH-independent disease and next step is CT or MRI adrenal imaging.
• Low or suppressed ACTH suggests ACTH-independent: usually adrenal adenoma, adrenal carcinoma or bilateral adrenal hyperplasia
• Normal or elevated ACTH suggests ACTH dependent; usually due to pituitary ACTH-secreting tumor (Cushing's disease), less commonly ectopic ACTH-secreting tumor (e.g. bronchial carcinoid tumor)
• Pituitary vs ectopic ACTH: MRI pituitary (>6mm less likely incidentaloma), high-dose 8mg dexamethasone test (pituitary tumors more likely to suppress), CRH stimulation (pituitary tumors more likely to stimulate), presence of hypokalemia (more likely with ectopic), degree of ACTH elevation (may be greater with ectopic), age (ectopic less likely in young patients), inferior petrosal sinus sampling (most direct test). Detection of ectopic ACTH-secreting tumors may involve CT, MRI, PET, or octreotide scintigraphy.
• Pseudo-Cushing's: patients with marked obesity, glucose intolerance, severe depression, or alcoholism may have non-specific manifestations of Cushing's and mildly elevated cortisol (1-3 times upper limit of normal).

SIGNS AND SYMPTOMS

• Common: centripetal obesity, facial plethora, hyperglycemia, hypertension, mood lability, easy bruisability, oligo/amenorrhea, hirsutism/acne (ACTH-dependent)
• More specific: broad (> 1cm) purple striae, proximal muscle weakness
• Other: bone loss, fracture, kidney stones, polydipsia, polyuria
• Ectopic ACTH: more severe hypertension, hypokalemia, hyperpigmentation
• Adrenal carcinoma: virilization (temporal balding, clitoromegaly, deepening voice) seen in Cushing's due to co-secretion of androgens
• Pseudo-Cushing's: unlikely to have skin (bruising, thinning) or muscle (proximal weakness, atrophy) manifestations

CLINICAL TREATMENT

• Exogenous Cushing's: discontinue glucocorticoid therapy if possible.
• Cushing's disease: 1st line: transphenoidal pituitary surgery; 2nd line: pituitary irradiation; Definitive/3rd line: bilateral total adrenalectomy requiring lifelong glucocorticoid and mineralocorticoid replacement therapy and monitoring for Nelson's syndrome (rapid enlargement of residual pituitary adenoma).
• Ectopic ACTH: surgical excision of tumor if possible. Non-resectable tumors treated with adrenal enzyme inhibitor (e.g. ketoconazole, metyrapone), medical adrenalectomy (mitotane), or bilateral surgical adrenalectomy.
• ACTH-independent adrenal adenomas: unilateral adrenalectomy generally curative
• ACTH-independent bilateral adrenal hyperplasia: most cases treated with bilateral adrenalectomy
• Adrenal carcinoma: surgery and mitotane for resectable disease; mitotane and chemotherapy for advanced, unresectable disease; adrenal enzyme inhibitors for persistent hypercortisolemia
• Pseudo-Cushing's: treat primary disease (i.e. depression, diabetes)
• Hyperglycemia management in Cushing's syndrome likely similar to exogenous steroid-induced hyperglycemia.

FOLLOW UP

• Physiologic glucocorticoid replacement until recovery of endogenous adrenal function, which may take many months.
• Follow cortisol levels, not ACTH, for evidence of cure
• Late relapse common after apparent surgical cure of Cushing's disease. Long-term periodic assessment of the hypothalamic-pituitary-adrenal axis required.
• Hyperglycemia, hypertension, and osteoporosis improve but often partially persist after effective therapy for Cushing's.

EXPERT COMMENTS

• Although testing for Cushing's not recommended in all patients with diabetes, screening is recommended for those with specific findings (myopathy, thin skin, bruising) or accumulation of new features over time.
• Pseudo-Cushing's more common than Cushing's syndrome in diabetes and requires no specific treatment except for usual diabetes management.
• Incidental pituitary and adrenal tumors are common in the general population. Imaging studies should only be performed in patients after confirming hypercortisolism.
• Late-night salivary cortisol testing is a widely available, easy to perform, sensitive and specific screening test for Cushing's syndrome.
• 24-hour urine free cortisol or 1mg overnight dexamethasone suppression are reasonable alternative screening tests which may be more widely available in the primary care setting.
• In patients with clinically suspected Cushing's and equivocal screening test results, repeat testing after several months is advisable.

Basis for Recommendations

• Nieman LK, Biller BM, Findling JW, et al.; The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline.; J Clin Endocrinol Metab; 2008; Vol. 93; pp. 1526-40;
  ISSN: 0021-972X;
  PUBMED: 18334580
  Rating: Basis for recommendation
  Comments:Most recent Endocrine Society consensus guidelines on diagnosis of Cushing's syndrome.
  
  

REFERENCES

RELATED MODULES

• Hyperosmolar Hyperglycemic State