Updated: 9/9/2020

Cushing Syndrome / Disease

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Snapshot
  • A 61-year-old obese man with well-controlled hypertension on a diuretic, hyperlipidemia, diabetes and current smoker (35 pack-year history) presents to his primary care physician for fatigue. He also notes that he has been having increasing cough, shortness of breath, and poor appetite. On evaluation, he is found to be hypertensive reaching 190/110 mmHg and noted to have facial flushing, purple abdominal striae, and a buffalo hump.
Introduction
  • Clinical definition
    • a condition that refers to the manifestations of chronic hypercortisolism
    • 2 broad categories
      • exogenous
        • iatrogenic exogenous glucocorticoid administration (reviewed separately)
      • endogenous
        • pituitary adrenocorticotropic hormone (ACTH) overproduction (Cushing disease)
        • adrenal glucocorticoid overproduction
        • ectopic ACTH overproduction
  • Epidemiology
    • demographics
      • 5:1 female-to-male ratio for adrenal or pituitary source
        • peak age 25-50 years of age
      • male predominance for ectopic source secondary to lung cancer
        • peak age 70-80 years of age
  • Etiology and classification
    • ACTH-dependent (ACTH is elevated)
      • etiologies
        • pituitary overproduction: 
          • ACTH-secreting tumor (usually an adenoma)
        • ectopic production: 
          • ACTH-secreting malignancy of a neuroendocrine origin such as small-cell lung cancer
    • ACTH-independent (ACTH is normal or low)
      • cortisol overproduction --> negative feedback --> lowers ACTH --> atrophy of normal adrenal tissue
      • etiologies
        • exogenous intake (usually patients prescribed systemic glucocorticoids for inflammatory conditions)
          • most common cause of Cushing's syndrome
          • may cause bilateral adrenal hypertrophy
        • adrenal overproduction (by adrenal adenoma, carcinoma or nodular hyperplasia)
          • may cause atrophy of the contralateral adrenal gland (imaging may show one adrenal gland enlarged by a tumor and one atrophied adrenal gland) 
  • Associated conditions
    • multiple endocrine neoplasia type 1 (ACTH-secreting pituitary adenoma, though most are prolactin-secreting adenomas)
Presentation
  • Symptoms 
    • depression and psychological changes
    • oligomenorrhea
    • decreased libido
    • proximal muscle weakness
    • acne
    • excessive hair growth
    • symptoms of diabetes (polydipsia and polyuria)
    • weight gain
  • Physical exam
    • hypertension 
    • central obesity
    • muscle wasting
    • thin skin that easily bruises
    • purple striae
    • hirsutism
    • moon facies
    • buffalo hump
    • hyperpigmentation if high ACTH
Studies
  • Diagnostic testing
    • diagnostic approach
      • medication review to rule out exogenous etiology
      • initial screening tests are very sensitive
        • if normal, rules out the diagnosis
        • if abnormal, does not determine etiology of Cushing
      • to determine etiology, follow up with ACTH level, high-dose dexamethasone suppression, corticotropin-releasing hormone (CRH) stimulation, and imaging
      • ancillary lab studies to evaluate for associated imbalances
    • studies
      • overnight low-dose dexamethasone suppression test
        • initial screening
        • very sensitive
      • cortisol (initial screening)
        • 24-hour urinary free cortisol (more sensitive, but logistically difficult to collect)
        • serum morning cortisol level (more convenient)
      • serum morning ACTH-level 
      • high-dose dexamethasone suppression test
        • performed after the diagnosis of Cushing syndrome is made, to distinguish between pituitary (Cushing disease) and non-pituitary causes 
        • determines if pituitary or ectopic
      • corticotropin-releasing hormone (CRH) stimulation test
        • determines if pituitary or ectopic
      • ancillary
        • chemistry panel 
          • associated metabolic alkalosis, hypokalemia, and hyperglycemia
        • lipid panel
          • associated hyperlipidemia
        • complete blood count
          • associated leukocytosis
      • chemistries
        • hypokalemia and metabolic alkalosis from mineralocorticoid activity 
    • imaging 
      • adrenal computed tomography (CT) scan or magnetic resonance imaging (MRI)  
        • evaluate for adrenal tumor as possible etiology of low ACTH Cushing syndrome
      • chest and/or abdominal CT
        • evaluate for ectopic ACTH-producing tumor
  • Diagnostic criteria
    • overnight low-dose dexamethasone suppression test 
      • if serum cortisol is < 5 ug/dL, Cushing can be excluded
      • if serum cortisol is > 5 ug/dL, Cushing is diagnosed
    • 24-hour urinary free cortisol
      • greater than 3x the normal value is consistent with diagnosis
    • ACTH level 
      • ↓ serum ACTH ( < 5 pg/mL) is consistent with iatrogenic Cushing and adrenal Cushing
      • ↑ serum ACTH (< 5 pg/mL) is consistent with pituitary or ectopic Cushing
    • high-dose dexamethasone suppression test 
      • > 50% suppression is consistent with pituitary Cushing disease
      • < 50% suppression is consistent with ectopic Cushing
    • corticotropin-releasing hormone (CRH) stimulation test
      • ↑ ACTH and cortisol is consistent with pituitary Cushing disease
      • no response is consistent with ectopic Cushing
    • imaging
      • identified adrenal, chest, or abdominal neoplasm
Differential
  • Pseudo-Cushing syndrome
    • distinguishing factor
      • hypercortisolemia is secondary to other factors and when resolved, Cushingoid features resolve as well
      • examples include obesity, polycystic ovarian syndrome, diabetes, and chronic alcoholism
Treatment
  • Management approach
    • resectable lesions
      • localize lesion with subsequent resection
      • may require temporary postoperative glucocorticoid replacement for HPA axis suppression from chronic hypercortisolemia
    • nonresectable lesions
      • ketoconazole and metyrapone
        • blocks cortisol production
      • mifepristone
        • blocks the cortisol receptor
      • pasireotide or cabergoline
        • somatostatin analog
  • Pituitary Cushing
    • transsphenoidal adenomectomy of the pituitary
    • may require replacement of other lost functions
  • Adrenal Cushing
    • adrenalectomy
      • if bilateral, requires lifelong glucocorticoid and mineralocorticoid replacement
  • Ectopic Cushing
    • treat the underlying neuroendocrine tumor, may consist of surgical resection, chemotherapy, radiation, and other targeted therapies
  • Hypertension
    • eplerenone and spironolactone (potassium sparing diuretics) 
Complications
  • Panhypopituitarism, if large pituitary adenoma
  • Adrenal insufficiency, if bilateral adenectomy is performed
  • Nelson syndrome, if bilateral adenectomy is performed
  • Death, if a malignant lesion
 

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(M2.EC.17.4830) A 65-year-old obese man presents to his primary care clinic feeling weak. He was in the military and stationed in Vietnam in his youth. His current weakness gradually worsened to the point that he had to call his son to help him stand to get on the ambulance. He smokes a pack of cigarettes every day and drinks a bottle of vodka a week. He has been admitted for alcohol withdrawal multiple times and has been occasionally taking thiamine, folic acid, and naltrexone. He denies taking steroids. His temperature is 98°F (36.7°C), blood pressure is 170/90 mmHg, pulse is 75/min, and respirations are 20/min. He is obese with a significant pannus. Hepatomegaly is not appreciable. Abdominal striae are present. His workup is notable for the following:

Serum:
Na+: 142 mEq/L
Cl-: 102 mEq/L
K+: 3.9 mEq/L
HCO3-: 25 mEq/L
BUN: 24 mg/dL
Glucose: 292 mg/dL
Creatinine: 1.5 mg/dL
Ca2+: 10.1 mg/dL
AST: 7 U/L
ALT: 14 U/L
24-hour urinary cortisol: 400 µg (reference range < 300 µg)
Serum cortisol: 45 pg/mL (reference range < 15 pg/mL)

A 48-hour high dose dexamethasone suppression trial shows that his serum cortisol levels partially decrease to 25 pg/mL and his adrenocorticotropin-releasing hormone (ACTH) level decreases from 10 to 6 pg/mL (reference range > 5 pg/mL). What is the best next step in management?
Tested Concept

QID: 109472
1

CT of the chest

12%

(17/147)

2

MRI of the adrenal glands

31%

(46/147)

3

MRI of the pituitary gland

49%

(72/147)

4

Low-dose dexamethasone therapy for 3 months

5%

(7/147)

5

High-dose dexamethasone therapy for 3 months

1%

(2/147)

M 6 C

Select Answer to see Preferred Response

(M2.EC.17.4828) A 25-year-old woman presents to her physician with a four month history of fatigue and weakness. The weakness has been progressive to the point where she cannot climb stairs and stand from a sitting position. She has only had one menstrual period in the last four months and has never been pregnant. She smokes a pack of cigarettes every day and does not take any medications. Her temperature is 98°F (36.7°C), blood pressure is 160/100 mmHg, pulse is 70/min, and respirations are 15/min. She is obese with a significant pannus. Abdominal striae are present. Her laboratory workup is notable for the following:

Serum:
Na+: 142 mEq/L
Cl-: 102 mEq/L
K+: 3.9 mEq/L
HCO3-: 25 mEq/L
BUN: 20 mg/dL
Glucose: 314 mg/dL
Creatinine: 1.1 mg/dL
Ca2+: 10.1 mg/dL
AST: 9 U/L
ALT: 8 U/L
24-hour urinary cortisol: 470 µg (< 300 µg)
Serum cortisol 30 µg/mL (5-23 µg/dL)
Serum adrenocorticotropin-releasing hormone (ACTH) 2 pg/mL (> 5 pg/mL)

A 48-hour high dose dexamethasone suppression trial shows that her serum cortisol levels do not decrease. What is the best next step in management?
Tested Concept

QID: 109470
1

MRI of the adrenal glands

47%

(24/51)

2

MRI of the chest

31%

(16/51)

3

MRI of the pituitary gland

4%

(2/51)

4

Low dose dexamethasone suppression test

2%

(1/51)

5

Inferior petrosal sinus sampling

12%

(6/51)

M 6 C

Select Answer to see Preferred Response

(M2.EC.14.33) A 69-year-old man presents with granulomatosis with polyangiitis diagnosed about 8 months ago. He was treated appropriately and states that his symptoms are well controlled. He is presenting today for a general follow up visit. His temperature is 99.0°F (37.2°C), blood pressure is 184/104 mmHg, pulse is 88/min, respirations are 12/min, and oxygen saturation is 98% on room air. His physical examination is notable for the findings in Figures A and B. Which of the following would be found in this patient on serum laboratory studies? Tested Concept

QID: 104307
FIGURES:
1

Hyperkalemia and metabolic acidosis

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2

Hyperkalemia and metabolic alkalosis

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3

Hypokalemia and metabolic acidosis

91%

(10/11)

4

Hypokalemia and metabolic alkalosis

9%

(1/11)

5

Hypokalemia and normal acid-base status

0%

(0/11)

M 6 E

Select Answer to see Preferred Response

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