John B. Eifler, MD
Michael S. Cookson, MD
BASICS
DESCRIPTION
• Cushing disease is hypercortisolism due to an ACTH-secreting pituitary adenoma
• Cushing syndrome is the cluster of symptoms attributable to hypercortisolism
• Pituitary adenomas account for 70% of patients with endogenously elevated cortisol (15% primary adrenal tumor, 15% ectopic ACTH production)
• Iatrogenic supplementation of glucocorticoids is the most common cause of hypercortisolism
EPIDEMIOLOGY
Incidence
N/A
Prevalence
• Cushing disease: 1.2–2.4 per million
• Cushing syndrome 4–5× more common in women than men
• In diabetics, prevalence 2–5%
RISK FACTORS
• Iatrogenic exposure to glucocorticoids
– Includes steroid creams or nasal sprays
Genetics
• Associated with MEN-1, Carney complex
• GNAS1 gene mutation (McCune-Albright syndrome)
PATHOPHYSIOLOGY
• Elevated serum levels of cortisol, either from exogenous intake or endogenous production
• Hypothalamus-pituitary-adrenal physiology
– ACTH (anterior pituitary), stimulates cortisol production in zona fasciculate of adrenal cortex
– ACTH release governed by CRH (hypothalamus)
– Cortisol—feedback regulation of CRH/ACTH production
• Cushing syndrome causes:
– Exogenous intake (most common)
– Cushing disease (70% of endogenous Cushing)
– Adrenal adenoma/carcinoma (10% of endogenous Cushing)
– Ectopic ACTH producer (10%): Neuroendocrine tumor (small-cell lung cancer, thymoma, ovarian tumors)
– Other: ACTH-independent macronodular adrenal hyperplasia, ectopic CRH production
ASSOCIATED CONDITIONS
• Pituitary tumor
• Steroid administration
• Adrenal adenoma/carcinoma
GENERAL PREVENTION
Diligent management of glucocorticoid administration
DIAGNOSIS
HISTORY
• Progressive weight gain
• Fatigue
• Proximal limb weakness
• Skin abnormalities: Easy bruisability, and striae
• Abnormal menses/decreased libido
• Impotence
• New-onset hypertension/diabetes
• Frequent infections
• Osteopenia/osteoporosis
• Visual disturbances due to pituitary impinging optic nerves
PHYSICAL EXAM
• Obesity/weight gain (80%)
• Thin skin with striae (70%)
• Moon facies (75%)
• Buffalo hump (50%)
• Hypertension (75%)
• Truncal obesity (50%)
• Amenorrhea (60%)
• Loss of visual fields
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• CBC, serum glucose, electrolytes, lipids
– Hyperglycemia, hypokalemia, neutrophilia, lymphopenia, hyperlipidemia consistent with Cushing
• Initial screen: Late-night salivary cortisol and 24-hr urinary free cortisol. (Note: Establishes hypercortisolemia, not etiology)
– Elevated late-night salivary cortisol: In Cushing syndrome, diurnal variation of cortisol levels is lost → high levels of cortisol suggest Cushing syndrome
– 24-hr urinary free cortisol × 3 samples: Sensitivity 90–97%, specificity 85–96%
• Second-line tests: Late-night serum cortisol, low-dose DST
• Determining etiology of hypercortisolemia
– Plasma ACTH concentration
Elevated in Cushing disease/ectopic tumor
Decreased in adrenal adenoma/carcinoma, nodular adrenal hyperplasia, steroid use
– High dose DST
May distinguish pituitary from ectopic ACTH-secreting tumor (failure to suppress cortisol suggests ectopic tumor)
– Inferior petrosal vein sampling: Higher sensitivity and specificity than high-dose DST
Imaging
• Brain MRI if pituitary lesion suspected
• CT abdomen/pelvis adrenal protocol for ACTH-independent hypercortisolism to evaluate for adrenal adenoma/carcinoma
Diagnostic Procedures/Surgery
Inferior petrosal vein sampling to diagnose and localize pituitary adenoma
Pathologic Findings
• Pituitary adenoma
• Adrenal adenoma/carcinoma
• Micronodular/macronodular adrenal hyperplasia
DIFFERENTIAL DIAGNOSIS
• Alcoholism (pseudo-Cushing)
• Anorexia nervosa
• Bulimia
• Depression
• Hypertension
• Obesity
• Polycystic ovarian syndrome
TREATMENT
GENERAL MEASURES
• Multidisciplinary approach: Endocrinologist, neurosurgeon, adrenal surgeon
• Surgical therapy is the mainstay of treatment
MEDICATION
First Line
• Medical therapy only indicated when surgery not possible
– Ketoconazole: Considered medical treatment of choice; not FDA approved for this indication.
Inhibits cytochrome p450
200–400 mg 2 or 3 times a day
Side effects: Reversible hepatotoxicity, headache, sedation, nausea, and vomiting.
Reduced androgen production may lead to gynecomastia, decreased libido, and impotence in males
– Mitotane: Suppresses cortisol production by inhibiting 11β-hydroxylase
Primarily used for adrenocortical carcinoma
0.5 g start, gradually increase to 2–3 g/d
– Metyrapone: Inhibits 11β-hydroxylase
500–750 mg 3 or 4 times a day
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Cushing disease:
– Trans-sphenoidal resection of pituitary adenoma: Gold standard
Cure in 60–80% of patients
– Bilateral adrenalectomy if disease refractory to pituitary surgery or if life-threatening hypercortisolism
• Ectopic ACTH-secreting tumor: Surgical resection
– Bilateral adrenalectomy reserved for unresectable disease
• Ipsilateral adrenalectomy for primary cortisol-secreting adrenal masses
ADDITIONAL TREATMENT
Radiation Therapy
Pituitary irradiation effective in 15% of refractory cases—not considered primary therapy
Additional Therapies
N/A
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Prognosis good for adrenal adenoma or Cushing disease, worse for adrenocortical carcinoma
• Prognosis for ectopic ACTH-producing tumors typically poor
COMPLICATIONS
• Bilateral adrenalectomy
– Adrenal insufficiency
– Osteoporosis
– Increased infection risk
– Nelson syndrome (pituitary adenoma)
FOLLOW-UP
Patient Monitoring
• Postoperative monitoring for adrenal insufficiency
• Pre- and postoperative management is complex and should be coordinated by endocrinologist
• Post operative hydorcortisone replacement with prolonged wean to allow pituitary adrenal axis to recalibrate
• After primary treatment (pituitary surgery), any new-onset symptoms → reevaluation
Patient Resources
NIH Medline Plus. http://www.nlm.nih.gov/medlineplus/ency/article/000410.htm. Accessed December 2013.
REFERENCES
1. Nieman LK, Ilias I. Evaluation and treatment of Cushing’s syndrome. Am J Med. 2005;118:1340–1346.
2. 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;93:1526–1540.
3. Raff H, Findling JW. A physiologic approach to diagnosis of the Cushing syndrome. Ann Intern Med. 2003;138(12):980–991.
ADDITIONAL READING
• Aggarwal S, Yadav K, Sharma AP, et al. Laparoscopic bilateral transperitoneal adrenalectomy for Cushing syndrome: Surgical challenges and lessons learnt. Surg Laparosc Endosc Percutan Tech. 2013;23(3):324–328.
• Lake MG, Krook LS, Cruz SV. Pituitary adenomas: An overview. Am Fam Physician. 2013;88(5):319–327.
See Also (Topic, Algorithm, Media)
• Adrenal Adenoma
• Adrenal Cortical carcinoma
• Adrenal Mass
• Cushing Syndrome Algorithm 
• Nelson Syndrome
CODES
ICD9
255.0 Cushing’s syndrome
ICD10
• E24.0 Pituitary-dependent Cushing’s disease
• E24.8 Other Cushing’s syndrome
• E24.9 Cushing’s syndrome, unspecified
CLINICAL/SURGICAL PEARLS
• Initial diagnostic studies for suspected Cushing syndrome include late-night salivary cortisol and 24-hr urinary free cortisol.
• Most common cause of endogenous Cushing syndrome is a pituitary adenoma.
• Muscle weakness +/− skin hyperpigmentation after bilateral adrenalectomy may be due to pituitary adenoma (Nelson syndrome).