A. Introduction

1. Results from lengthy exposure to excessive concentrations of circulating free glucocorticoids
2. Usually caused by overproduction of Cortisol
   1. Cortisol is the major glucocorticoid produced by adrenal cortex
   2. Produced in the fasciculata (mid) zone of the adrenal cortex
   3. Cortisol is produced at baseline and simulated by ACTH (see below)
3. ACTH (adrenocorticotropic hormone, corticotropin)
   1. Normally produced by anterior pituitary in response to CRH
   2. CRH (corticotropin releasing hormone) is normally made in the hypothalamus
   3. CRH binds to pituitary corticotrophs and induce pro-opiomelanocortin (POMC) synthesis
   4. POMC is a precursor polypeptide cleaved to ACTH, ß-endorphin and ß-MSH (lipoprotein)
   5. Normally, high serum levels of cortisol negatively regulate CRH and ACTH synthesis
4. Epidemiology
   1. Incidence is 0.7-2.4 per million population per year
   2. In obese patients with type 2 diabetes mellitus, may be present in ~2%
   3. Incompletely controlled Cushing's syndrome have ~5X increased mortality risk
   4. Cushing's Syndrome is divided into corticotropin-dependent and -independent classes
   5. Corticotropin-dependent form accounts for ~85% of cases of Cushing's Syndrome
   6. Adrenal tumors causing Cushing's syndrome account for ~50% in pregnancy [11]

B. Etiology

1. Corticotropin-Dependent Cushing's Syndrome
   1. Cushing's Disease (Pituitary Adenoma): 70% of all Cushing's Syndrome
   2. Ectopic ACTH Syndrome: 10%, equal female to male
   3. Unknown source of ACTH: 5%, 5X more common in female
2. Corticotropin-Independent Cushing's Syndrome (~15% overall)
   1. Adrenal Adenoma: 10% [11]
   2. Adrenal Carcinoma ~5%
   3. Bilateral Adrenal Hyperplasia / Macronodular Hyperplasia <2%
   4. Carny Complex (primary pigmented nodular adrenal disease) <2%
   5. McCune Albright Syndrome <2%
3. Most common cause of Cushing's Syndrome is Pituitary Adenoma
   1. Accounts for ~70% of Cushing's Syndrome
   2. Originally called Cushing's Disease
   3. 3.5X more common in women
   4. Most are microadenomas (<1cm) consisting primarily of autonomous corticotrophs
   5. Macroadenomas and pituitary carcinomas are much less common
4. Ectopic ACTH Production
   1. Small Cell Lung CA - most common cause
   2. Ovarian carcinoma
   3. Carcinoids - bronchial, thymic, pancreatic
   4. Neuroendocrine derived pulmonary tumorlets [3]
   5. Equally found in men and women
5. Adrenal Adenoma and Carcinoma
   1. ~4X more common in women than men
   2. High rate of ß-catenin mutations, particularly in adenomas
   3. Allelic or imprinting loss of chromosome 11p15 in carcinomas, not adenomas
   4. This leads to increases in insulin like growth factor II and reduced p27/kip
6. Carney Complex [4,7,8]
   1. Also called LAMB or NAME Syndrome
   2. Primary pigmented nodular adrenocortical disease (PPNAD)
   3. Bilateral micronodular adrenal disorder often with hypercortisolism
   4. Associated multiple endocrine and non-endocrine cancers
   5. These include skin lentigines, cardiac myxomas, and various other tumors
   6. ~50% of cases due to mutations in PRKAR1 alpha gene on chromosome 17q2
   7. PRKAR1a encodes regulatory subunit of R1alpha of cAMP-dependent protein kinase A
   8. Lifelong surveillance for complications is required
7. McCune-Albright Syndrome
   1. Hereditary polyostotic fibrous dysplasia with precocious puberty
   2. Chushing's syndrome, hyperprolactinemia, gigantism, multinodular goiter may be found

C. Signs and Symptoms [1]

1. Weight Gain 95%
2. Facial Plethora 90%
3. Rounded Face 90%
4. Decreased Libido 90%
5. Thin Skin 85%
6. Mentrual Irregularity 80%
7. Reduced linear growth in children 75%
8. Hypertension 75%
9. Hirsutism 75%
10. Depression / Emotional Lability 70%
11. Easy Bruising / Poor Wound Healing 65%
12. Hyperglycemia / Diabetes Mellitus 60%
13. Weakness 60%
14. Osteopenia / Osteoporosis / Fracture 50%
15. Kidney Stones 50%
16. Less Common
    1. Buffalo Hump
    2. Abdominal Striae
    3. Edema, usually truncal
    4. Frequent infections (immunosuppression)
17. Subclinical hypercortisolism may be a cause of "idiopathic" osteoporosis [12]

D. Diagnostic Criteria [6]
[Figure]: "Evaluation for Cushing's Syndrome"

1. Cortisol Levels
   1. Plasma Cortisol - relatively insensitive but fairly specific if other causes ruled out
   2. Nighttime salivary cortisol level is simplest test [5]
   3. Urine free cortisol level (24 hour urine collection) is not as accurate as originally believed
   4. Urine 17-hydroxycortisone (17-hydroxysteroid, 17-OHS) is usually measured also
2. Initial Evaluation
   [Figure]: "Steroid Synthesis"
   1. Salivary cortisol level (see below)
   2. 24 hour urine free cortisol (normal 20-40µg/d) and 17-OHS (normal 2-6mg/d) levels
   3. Plasma AM cortisol (normal 190-690 nmol/L) is also useful
3. Salivary Cortisol Level [5]
   1. Nighttime specimen showed sensitivity 93%, specificity 100%
   2. Special sampling tubes required
   3. Normal persons have late night salivary cortisol <3-4 mmol/L (<0.11-0.15µg/dL)
   4. Levels >7.0 nmol/L (>0.25µg/dL) are diagnostic of Cushing's Syndrome
   5. Levels 3-7 nnmol/L require additional biochemical confirmation
4. High Dose Dexamethasone Suppression Test (DST)
   1. Give 2mg dexamethasone po qid for 2 days
   2. Typically, pituitary tumors are suppressed, whereas ACTH secreting tumors are not
   3. >70% drop in 17-OHS on day 2 suggests Pituitary Disease
   4. <50% drop in 17-OHS on day 2 suggests Adrenal or Ectopic Disease
   5. Measurement of urine free cortisol during this test is extremely sensitive also
5. Low Dose DST with 1mg dexamethasone is no longer recommended [5]

E. Determination of Etiology [5]

1. Once Cushing's Syndrome established, must determine source (pituitary, adrenal or ectopic)
2. Plasma ACTHH Test is Performed
   1. Level is typically high for pituitary causes or ectopic ACTH production
   2. Level is low or low normal in adrenal or ectopic steroid production
   3. ACTH level low indictaes ACTH-independent Cushing's Syndrome --> do adrenal CT scan
   4. Normal or elevated ACTH level suggests ACTH dependent Cushing's Syndrome
   5. Radiographic imaging is next step after determination of ACTH level
3. Radiographic Evaluation
   1. MRI with Gadolinium for evaluation of pituitary gland (+ in 10% of general population)
   2. CT scan with intravenous and oral contrast for adrenal evaluation
   3. Note that a large proportion of general population have adrenal and pituitary anomalies
   4. Solitary <1cm adrenal adenomas occur in ~5% of general population (of no significance)
4. Metyrapone
   1. Blocks 11ß-hydroxylase causing increased production of steroids
   2. GIve 750mg q4 hours x 6 doses
   3. Measure 24-hour urinary 17-OHS and plasma 11-deoxycortisol
   4. Normally, have mild increase in steroid production (due to lack of feedback inhibition)
   5. Patients with pituitary overproductin of ACTH have >70% increase 17-OHS and/or >400X increase 11-deoxycortisol
5. CRH stimulation test
   1. Useful to distinguish between Cushing's and Pseudo-Cushing's Syndromes
   2. Also useful for distinguishing between Ectopic and Pituitary ACTH production
   3. Combination with petrosal sinus or internal jugular sampling
6. Somatostatin Analog Nuclear Scintography
   1. Somatostatin binds to most ACTH producing tumors
   2. Also useful for localizing carcinoid tumors
7. Invasive Diagnostics [9]
   1. Adrenal vein sampling (selective)
   2. Inferior petrosal sinus sampling for ACTH
   3. Internal jugular ACTH sampling was correct in 80% cases and less invasive than petrosal sinus sampling
   4. CRH stimulation is often required for correctly diagnosing pituitary adenomas [9]

F. Differential Diagnosis

1. Corticotropin Independent
   1. Adrenal adenoma
   2. Adrenal hyperplasia
   3. Adrenal carcinoma
   4. Carney Complex (PPNAD)
2. Corticotropin Dependent
   1. Cushing's Disease - pituitary adenoma / carcinoma
   2. Ectopic adrenocorticotropin production - usually carcinoma (such as small cell lung cancer)
   3. Carcinoids
   4. Ectopic CRH
   5. Autonomous macronodular adrenal hyperplasia
   6. Iatrogenic: treatment with corticotropin or its analogs
3. Pseudo-Cushing's State
   1. Major Depression
   2. Alcoholism - Long term, active alcoholism and withdrawal from EtOH intoxication
4. Miscellaneous
   1. Physiological stressful conditions: surgery, severe illness
   2. Anorexia and Bulimia
   3. Glucocorticoid receptor resistance
   4. Severe Obesity

G. Treatment

1. Directed at underlying cause
2. Adrenal mass - removal is strongly recommended
3. Pituitary Adenoma
   1. Transphenoidal Surgery - directed adenectomy
   2. Pituitary Irradiation
   3. Trans-sphenoidal adenomectomy has 99% 5 year and 93% 10 year survival rates [10]
   4. Replacement of other pituitary hormones may be required after surgery
4. Ectopic Production - anti-neoplastic therapy usually needed
5. Ketoconazole can be used in patients with incomplete reduction in hypercortisolemia

References

1. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. 2006. Lancet. 367(9522):1605
2. Boscaro M, Barzon L, Fallo F, Sonino N. 2001. Lancet. 357(9258):783
3. Arioglu E, Doppman J, Gomes M, et al. 1998. NEJM. 339(13):883 (Case Report)
4. Stratakis CA, Sarlis N, Kirchner LS, et al. 1999. Ann Intern Med. 131(8):585
5. Raff H and Findling JW. 2003. Ann Intern Med. 138(12):980
6. Bornstein SR, Stratakis CA, Chrousos GP. 1999. Ann Intern Med. 130(9):759
7. Basson CT and Aretz HT. 2002. NEJM. 346(15):1152 (Case Record)
8. Edwards RJ, Moss T, Sandeman DR. 2003. Lancet. 362(9395):1541 (Case Report)
9. Doppman JL, Oldfield EH, Nieman LK. 1998. Ann Intern Med. 128(1):33
10. Swearingen B, Biller BMK, Barker FG II, et al. 1999. Ann Intern Med. 130(10):821
11. Klibanski A, Stephen AE, Greene MF, et al. 2006. NEJM. 355(21):2237 (Case Record)
12. Chiodini I, Mascia ML, Muscarella S, et al. 2007. Ann Intern Med. 147(8):541