Cushing Disease and Cushing Syndrome – Causes, Symptoms, Diagnosis, Treatment and Ongoing care

Basics

Description

  • Clinical abnormalities associated with chronic exposure to excessive amounts of cortisol (the major adrenocorticoid)
  • Cushing disease is defined as glucocorticoid excess due to excessive adrenocorticotropic hormone (ACTH) secretion from a pituitary tumor. This is the most common cause of primary Cushing syndrome.
  • Cushing syndrome is defined as excessive corticosteroid exposure from exogenous sources (medications) or endogenous sources (pituitary, adrenal, pulmonary, etc., or tumor)
  • System(s) affected: Endocrine/Metabolic; Musculoskeletal; Skin/Exocrine; Cardiovascular; Neuropsychiatric

Pediatric Considerations

  • Rare in infancy and childhood
  • Most cases in children <8 years are a result of malignant adrenal tumors.

Pregnancy Considerations

Pregnancy may exacerbate disease.

Epidemiology

Incidence

Uncommon: 0.7–2.4 per million per year

Prevalence

In difficult-to-control diabetic patients with obesity and hypertension, prevalence has been reported at 2–5%.

Risk Factors

  • Predominant sex: Female > Male (slightly). Cushing syndrome is equally prevalent in both sexes.
  • Pituitary tumor
  • Adrenal mass
  • Neuroendocrine tumor (e.g., bronchial carcinoid)
  • Prolonged use of corticosteroids

Genetics

  • Multiple endocrine neoplasia type I
  • Carney complex (an inherited multiple neoplasia syndrome)
  • McCune-Albright syndrome (mutation of GNAS1 gene)

General Prevention

Avoid corticosteroid exposure when possible.

Pathophysiology

  • Disease: Pituitary tumor causing excess ACTH (corticotropin)
  • Syndrome: Excessive corticosteroid exposure from exogenous sources (medications) or endogenous sources (pituitary, adrenal, pulmonary, etc., or tumor)

Etiology

  • Exogenous glucocorticoids or ACTH
  • Endogenous ACTH-dependent hypercortisolism (80–85%):
    • ACTH-secreting pituitary tumor: 70%
    • Ectopic ACTH production (e.g., small-cell carcinoma of lung, bronchial carcinoid): 20%
  • Endogenous ACTH-independent hypercortisolism: 15–20%:
    • Adrenal adenoma
    • Adrenal carcinoma
    • Macronodular or micronodular hyperplasia

Cushing, Cushing Syndrome, Adrenocorticotropic hormone, Pregnancy, Endocrine Disorders, small cell carcinoma, pituitary tumor, adrenal tumors, hypercortisolism, adrenocorticotropic hormone, endocrine neoplasia,

Diagnosis

History

  • Weight gain: 95% (1)[B]
  • Decreased libido: 90%
  • Menstrual irregularity: 80%
  • Hirsutism: 75%
  • Depression/emotional lability: 50–80%
  • Easy bruising: 65%
  • Proximal muscle weakness: 60%
  • Diabetes or glucose intolerance: 60%

Physical Exam

  • Obesity: 95%
  • Facial plethora: 90%
  • Moon face (facial adiposity): 90%
  • Thin skin: 85%
  • Hypertension: 75%
  • Skeletal growth retardation in children (epiphyseal plates remain open): 70–80%
  • Purple striae on the skin
  • Increased adipose tissue in neck and trunk
  • Acne

Diagnostic Tests & Interpretation

Lab

Initial lab tests

  • For initial evaluation, order either late-night salivary cortisol or 24-hour urinary-free cortisol. In normal circadian rhythm, cortisol secretion is highest in the morning and lowest between 11 PM and midnight. The nadir of serum cortisol is maintained in pseudo-Cushing (e.g., obesity, alcoholism, depression), but not in Cushing syndrome.
  • Elevated late-night salivary cortisol provides sensitivity and specificity >90–95% (2,3)[B]. (Contact local lab for instructions to obtain this test.)
  • 24-hour urinary-free cortisol level: Obtain ≥3 samples to rule out intermittent hypercortisolism if results are normal and suspicion is high. Also measure 24-hour urinary creatinine excretion to verify adequacy of collection. Results may be falsely low if glomerular filtration rate <30 mL/min. Overall sensitivity and specificity varies, but has been reported to be 90–97% and 85–96%, respectively (2)[B].
  • Midnight plasma cortisol: Try to obtain samples on 3 consecutive nights. A late evening serum cortisol >7.5 µg/dL has a sensitivity of 96% and a specificity of 100% (4)[B].
  • Persistently elevated serum cortisol implies Cushing syndrome; nadir of serum cortisol is maintained in obese patients, but not in those with Cushing.
  • Low-dose dexamethasone suppression testing is no longer used as 1st-line testing. Dexamethasone 1 mg is given between 11 PM and midnight, and fasting plasma cortisol is measured between 8 and 9 AM the following morning. A serum cortisol level below 1.8 µg/dL excludes Cushing syndrome, but specificity is limited. The presence of pseudo-Cushing states (depression, obesity, etc.), hepatic or renal disease, or any drug that induces cytochrome P-450 enzymes may cause a false result.
  • High-dose dexamethasone suppression testing: This test is used to distinguish between an ACTH-secreting pituitary tumor and an ectopic ACTH-secreting tumor. 0.5 mg dexamethasone is given q.6h for 8 doses, with serum cortisol measured at 2 and 6 hours after last dose. Sensitivity 79%, specificity 74%.

Alert

  • Antiepileptic drugs, progesterone, oral contraceptives, rifampin, and spironolactone may cause a false-positive dexamethasone suppression test.
  • Corticotropin-releasing hormone (CRH) after dexamethasone: This test is used to distinguish Cushing syndrome from pseudo-Cushing syndrome. Dexamethasone 0.5 mg is given q.6h for 48 hours starting at noon. CRH (1 µg/Kg) is given 2 hours after the last dose of dexamethasone. Plasma cortisol is >1.4 µg/dL 15 minutes after CRH in patients with Cushing syndrome but not in those with pseudo-Cushing (5)[B].

Imaging

Initial approach

Support Tipsdiscover.com's development and hosting
  • Chest radiograph
  • Lumbar spine radiograph:
    • Osteoporosis is common
  • Pituitary MRI scan if pituitary tumor suspected
  • Abdominal CT scan if adrenal disease suspected
  • Chest CT scan if ectopic ACTH secretion is suspected and inferior petrosal sinus sampling rules out pituitary source (6)[C]
  • Octreotide scintigraphy to look for occult ACTH-secreting tumor

Diagnostic Procedures/Surgery

  • Diagnostic procedure depends on circumstances and clinical judgment
  • Inferior petrosal sinus sampling with CRH stimulation if ACTH-dependent tumor suspected (6)[C]

Pathological Findings

  • Thyroid function suppressed
  • Hypertension
  • Dyslipidemia
  • Polycystic ovarian syndrome/hyperandrogenism
  • Oligomenorrhea/hypogonadism
  • Myopathy/cutaneous wasting
  • Neuropsychiatric problems
  • Nodular adrenal disease
  • Hypercoagulable state
  • Osteoporosis
  • Nephrolithiasis
  • Growth hormone reduced

Differential Diagnosis

  • Obesity
  • Diabetes mellitus
  • Hypertension
  • Metabolic syndrome X
  • Polycystic ovarian disease
  • Hypercortisolism secondary to alcoholism (pseudo-Cushing)

Treatment

Medication

  • Drugs are not usually effective as the primary long-term treatment, and are used primarily either in preparation for surgery or as adjunctive treatment after surgery, pituitary radiotherapy, or both.
  • Metyrapone, ketoconazole, and mitotane can all be used to lower cortisol by directly inhibiting synthesis and secretion in the adrenal gland. As initial treatment, remission rates up to 85% (6,7)[C].

Surgery/Other Procedures

  • Tumor-specific surgery:
    • Trans-sphenoidal surgery for Cushing disease offers selective microadenectomy of the ACTH-producing adenoma, leaving the remaining pituitary intact (remission rate 60–80%).
    • For Cushing syndrome, resection of the ACTH-producing tumor is optimal treatment.
  • Adrenal surgery:
    • For unilateral adrenal adenomas, laparoscopic surgery is treatment of choice.
    • For patients with Cushing disease, bilateral laparoscopic adrenalectomy is used more often, especially when the disease is severe or because of patient preference.
    • Pituitary radiotherapy can be used to treat persistent hypercortisolism after trans-sphenoidal surgery.

Ongoing Care

Patient Education

  • Comprehensive teaching to help patient cope with lifelong treatment may be needed, including:
    • Diet and monitoring weight daily
    • Early treatment of infections
    • Emotional lability prevention
  • Refer to National Adrenal Disease Foundation: NADF 505 Northern Blvd. Great Neck, NY 11021; (516) 407-4992

Prognosis

  • Generally chronic course with cyclic exacerbations and rare remissions
  • Guardedly favorable prognosis with surgery
  • 20% long-term recurrence rate after surgery; more frequent following surgery for benign adrenal tumors:
    • Poor with small cell carcinoma of the lung producing ectopic hormone; neuroendocrine tumors (bronchial carcinoid) have much better prognosis (4)[C]

Complications

  • Osteoporosis
  • Increased susceptibility to infections
  • Metastases of malignant tumors
  • Increased cardiovascular risk even after treatment
  • Lifelong glucocorticoid dependence following treatment with bilateral adrenalectomy
  • Nelson syndrome (pituitary tumor) after treatment with bilateral adrenalectomy

References

1. Newell-Price J, Bertagna X, Grossman AB, et al. Cushing’s syndrome. Lancet. 2006;367:1605–17.

2. Putignano P, et al. Midnight salivary cortisol versus urinary free and midnight serum cortisol as screening tests for Cushing’s syndrome. J Clin Endocrinol Metabol. 88(9):4153–7.

3. Yaneva M, Mosnier-Pudar H, Dugué MA et al. Midnight salivary cortisol for the initial diagnosis of Cushing’s syndrome of various causes. J Clin Endocrinol Metab. 2004;89:3345–51.

4. Isidori AM, et al. The ectopic adrenocorticotropin syndrome: Clinical features, diagnosis, management and long term follow up. J Clin Endocrinol Metabol. 2006;91(2):371–7.

5. Yanovski JA, Cutler GB, Chrousos GP et al. Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing’s syndrome from pseudo-Cushing’s states. JAMA. 1993;269:2232–8.

6. Findling JF, et al. Cushing’s syndrome: Important issues in diagnosis and management. J Clin Endocrinol Metabol. 2006;10:3746–53.

7. Nieman LK, Ilias I. Evaluation and treatment of Cushing’s syndrome. Am J Med. 2005;118:1340–6.

Additional Reading

See Also (Topic, Algorithm, Electronic Media Element)

Algorithm: Cushing Syndrome

Codes

ICD9

255.0 Cushing’s syndrome

Snomed

  • 47270006 Hypercortisolism (disorder)
  • 190502001 Pituitary-dependent Cushing’s disease (disorder)

Clinical Pearls

  • Cushing disease is due to excessive ACTH secretion from a pituitary tumor, resulting in corticosteroid excess.
  • Cushing syndrome is due to excessive corticosteroid exposure from exogenous sources (medications) or endogenous sources (pituitary, adrenal, pulmonary, etc. or tumor).

About the author

Many tips are based on recent research, while others were known in ancient times. But they have all been proven to be effective. So keep this website close at hand and make the advice it offers a part of your daily life.