Cushing Syndrome (Hypercortisolism)

Essentials of Diagnosis

• Central obesity, muscle wasting, thin skin, psychological changes, hirsutism, purple striae

• Osteoporosis, hypertension, poor wound healing

• Hyperglycemia, leukocytosis, lymphocytopenia, hypokalemia, glycosuria

• Elevated serum cortisol and urinary free cortisol. Lack of normal suppression by dexamethasone

General Considerations

• Cushing "syndrome" refers to manifestations of excessive corticosteroids

  • Commonly due to supraphysiologic doses of corticosteroid drugs

  • Rarely due to excessive spontaneous corticosteroid production

  • ~68% of such cases are due to ACTH hypersecretion by a pituitary adenoma (so-called Cushing "disease"), which is usually small and benign

  • ~25% are due to excessive autonomous secretion of cortisol

  • Cortisol secretion is independent of ACTH, and plasma ACTH levels are usually low or low-normal

  • ~7% are due to nonpituitary ACTH-secreting neuroendocrine neoplasms that produce ectopic ACTH

  • ~15% are due to ACTH from a source that cannot be initially located

  • May result from excessive ingestion of gamma-hydroxybutyric acid; resolves when drug is stopped

• Impaired glucose tolerance from insulin resistance

Demographics

• Spontaneous Cushing syndrome is rare: 2.6 new cases yearly per million population in the United States

• ACTH-secreting pituitary adenoma (Cushing "disease") > 3 times more common in women than men

Symptoms and Signs

• Fatigue and reduced endurance

• Central obesity with plethoric "moon face," "buffalo hump," supraclavicular fat pads, protuberant abdomen, and thin extremities

• Muscle atrophy causes weakness, with difficulty standing up from a seated position or climbing stairs

• Oligomenorrhea or amenorrhea in women (or erectile dysfunction in men)

• Backache, headache

• Hypertension

• Osteoporosis or avascular bone necrosis

• Skin

  • Acne

  • Superficial skin infections

  • Purple striae (especially around the thighs, breasts, and abdomen)

  • Easy bruising, impaired wound healing

• Thirst and polyuria (with or without glycosuria); renal calculi

• Glaucoma

• Unusual bacterial or fungal infections occur more commonly

• Mental symptoms range from diminished concentration to increased mood lability to psychosis

• Increased susceptibility to opportunistic infections

Differential Diagnosis

• Chronic alcoholism (alcoholic pseudo-Cushing syndrome)

• Diabetes mellitus

• Depression (may have hypercortisolism)

• Osteoporosis due to other cause

• Obesity due to other cause

• Primary hyperaldosteronism

• Anorexia nervosa (high urine free cortisol)

• Striae distensae ("stress marks") seen in adolescence and in pregnancy

• Lipodystrophy from antiretroviral agents

Laboratory Tests

• Hyperglycemia

• Leukocytosis; relative granulocytosis and lymphopenia

• Hypokalemia (not hypernatremia), particularly with ectopic ACTH secretion

• Easiest screening test involves dexamethasone suppression test

  • 1 mg is given orally at 11 PM and serum is collected for cortisol determination at 8 AM the next morning

  • Cortisol level < 1.8 mcg/dL (50 nmol/L, high-performance liquid chromatography [HPLC] assay) excludes Cushing syndrome with some certainty

• If hypercortisolism is not excluded, measure 24-hour urine for free cortisol and creatinine

  • High 24-hour urine free cortisol (or free cortisol to creatinine ratio of > 95 mcg cortisol/g creatinine) helps confirm hypercortisolism

  • Misleadingly high urine free cortisol occurs with high fluid intake

• Midnight serum cortisol levels >7.5 mcg/dL (200 nmol/L) are indicative of Cushing syndrome; patient takes nothing by mouth for 3 hours and has an intravenous line established in advance for blood draw

• If hypercortisolism is confirmed

  • Plasma ACTH below ~6 pg/mL with a low serum DHEAS indicates probable adrenal tumor

  • High or normal ACTH indicates pituitary or ectopic tumor

  • Blood for ACTH assay must be collected in a plastic tube, placed on ice, and processed quickly to avoid falsely low results

Imaging Studies

• In ~50% of cases of ACTH-dependent Cushing syndrome, MRI of the pituitary shows an adenoma

• CT scanning

  • CT scan of chest and abdomen can help locate source of ectopic ACTH production--in lungs (carcinoid or small-cell carcinomas), thymus, pancreas, or adrenals

  • CT scan of adrenals can localize an adrenal tumor in most cases of non-ACTH-dependent Cushing syndrome

  • However, it fails to detect the source of ACTH in about 34% of patients with ectopic ACTH secretion

• When CT scan fails to detect the source, the most sensitive scanning techniques are

  • Whole-body imaging with ⁶⁸Ga-somatostatin receptor-PET/CT (⁶⁸Ga-DOTATOTATE-PET/CT) (82%)

  • Whole-body imaging with ¹⁸F-DOPA-PET/CT (58%)

Diagnostic Procedures

• If pituitary MRI is normal or shows incidental irregularity, selective inferior petrosal venous sampling for ACTH is performed (with corticotropin-releasing hormone stimulation) where available to confirm pituitary ACTH source, distinguishing it from an occult nonpituitary tumor secreting ACTH

• In patients with ACTH-dependent Cushing syndrome

  • Chest masses may be the source of ACTH

  • However, opportunistic infections are common

  • Therefore, it is prudent to biopsy a chest mass to confirm the pathologic diagnosis prior to resection

Medications

• Spironolactone, eplerenone, and dihydroperidine calcium channel blockers used for mineralocorticoid hypertension

• Flutamide for women with hyperandrogenism

• Cabergoline, 0.5–3.5 mg orally twice weekly

  • Reduced hypercortisolemia in 40% of patients in one small study

• Pasireotide LAR (60 mg intramuscularly every 28 days) or octreotide LAR (30–40 mg intramuscularly every 28 days)

  • Slows progression of the malignancy and

  • Reduces ACTH secretion in up to half such patients

• Ketoconazole

  • Inhibits adrenal steroidogenesis when given in doses of about 200 mg orally every 6 hours

  • However, it is marginally effective and can cause liver toxicity

• Metyrapone

  • Can suppress hypercortisolism

  • Required median daily dose: 1250–1500 mg/day orally in divided doses

  • May be combined with ketoconazole

  • May be used for patients with secretory adrenocortical carcinoma whose hypercortisolism is not fully controlled with mitotane

• Mitotane for adrenocortical carcinoma

  • Initial dosage: 0.5 g twice daily with meals and increasing to 1 g twice daily within 2 weeks

  • Doses are adjusted every 2–3 weeks to reach serum levels of 14–20 mcg/mL

  • However, only about half the patients can tolerate mitotane levels above 14 mcg/mL due to side effects, including

    • CNS depression

    • Lethargy

    • Hypercholesterolemia

    • Hypocalcemia

    • Hepatotoxicity

    • Leukopenia

    • Hypertension

    • Nausea

    • Rash

  • Can cause hypogonadism

  • Can suppress TSH and cause hypothyroidism

  • Often causes primary adrenal insufficiency

• Combined chemotherapy with etoposide, doxorubicin, cisplatin and mitotane (EDP-M) appears to be the most effective regimen for recurrent or metastatic adrenocortical carcinoma

• Replacement hydrocortisone or prednisone

  • Should be started when mitotane doses reach 2 g daily

  • Replacement dose of oral hydrocortisone starts at 15 mg in the morning and 10 mg in the afternoon but must often be doubled or tripled because mitotane increases cortisol metabolism and cortisol binding globulin levels; the latter can artifactually raise serum cortisol levels

Surgery

• Selective transsphenoidal resection of pituitary adenoma is indicated in Cushing disease, after which remainder of pituitary usually returns to normal function

  • However, corticotrophs require 6–36 months to recover normal function

  • Thus, hydrocortisone replacement is required temporarily

  • Remission rates range from 65% to 90%

  • For patients with persistent or recurrent Cushing disease, repeat transsphenoidal pituitary surgery may be warranted if the recurrent tumor is visible and deemed resectable

• Bilateral laparoscopic adrenalectomy is usually best option particularly for patients with very severe disease, since it renders an immediate remission in a condition with significant morbidity and mortality

• Laparoscopic resection for benign adrenal adenomas

  • May be done if they are < 6 cm in diameter

  • Because the contralateral adrenal is suppressed, postoperative hydrocortisone replacement is required until recovery

  • Surgical resection of ectopic ACTH-secreting tumors

Therapeutic Procedures

• Stereotactic pituitary radiosurgery (gamma knife)

  • An option for patients with ACTH-secreting pituitary tumors that persist or recur after pituitary surgery

  • Normalizes urine free cortisol in 70% of patients within 17 months

• Conventional radiation therapy cures 23%

• Pituitary radiosurgery can also be used to treat Nelson syndrome, the progressive enlargement of ACTH-secreting pituitary tumors following bilateral adrenalectomy

Complications

• Complications of hypertension or diabetes mellitus

• Increased susceptibility to infections

• Nephrolithiasis

• Depression, dementia, psychosis

• Following bilateral adrenalectomy for Cushing disease, progressive enlargement of pituitary adenoma may cause local effects (eg, visual field impairment) and hyperpigmentation (Nelson syndrome)

• "Cortisol withdrawal syndrome," even when given replacement corticosteroids for adrenal insufficiency; manifestations include

  • Hypotension

  • Nausea

  • Fatigue

  • Arthralgias

  • Myalgias

  • Pruritus

  • Flaking skin

Prognosis

• Following successful therapy for Cushing syndrome, secondary adrenal insufficiency occurs and requires long-term glucocorticoid replacement

• Five years after successful surgery, secondary hypoadrenalism resolves in about

  • 58% of patients with pituitary Cushing disease

  • 82% of those with ectopic ACTH

  • 38% of those who had an adrenal tumor

• Although manifestations regress with time, patients may have residual cognitive or psychiatric impairment, muscle weakness, osteoporosis, and sequelae from vertebral fractures

• Younger patients have a better chance for recovery and children with short stature may have catch-up growth following cure

• Patients with failed pituitary surgery may require pituitary radiation therapy, which has its own morbidity

• Patients with Cushing syndrome due to benign adrenal adenoma have

  • 5-year survival rate of 95%

  • 10-year survival rate of 90% following successful adrenalectomy

• Patients with Cushing disease from pituitary adenoma have similar survival if pituitary surgery is successful

• Transsphenoidal surgery fails in ~10–20%

• Despite complete remission after transsphenoidal surgery, ~15–20% of pituitary adenoma recur over 10 years

• Laparoscopic bilateral laparoscopic adrenalectomy

  • May be required

  • Recurrence of hypercortisolism may occur as a result of growth of adrenal remnant stimulated by high ACTH levels

• Prognosis with ectopic ACTH-producing tumors depends on aggressiveness and stage of tumor

• Patients with ACTH of unknown source have

  • 5-year survival rate of 65%

  • 10-year survival rate of 55%

• 5-year survival rates in patients with adrenocortical carcinoma

  • Stage 1: 81%

  • Stage 2: 61%

  • Stage 3: 50%

  • Stage 4: 13%

When to Refer

• If abnormal dexamethasone suppression test

When to Admit

• For transsphenoidal hypophysectomy, adrenalectomy, resection of ectopic ACTH-secreting tumor