Cushing's Disease

Aka: Cushing's Disease, Cushing's Syndrome, Cushing Disease, Cushings Disease, Cushing Syndrome

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II. Definitions

  1. Cushings Syndrome
    1. Chronic Glucocorticoid excess
  2. Cushing Disease
    1. ACTH Secreting pituitary tumors
    2. Named for Harvey Cushing, who first described the condition in 1932
  3. Hypercortisolism
    1. Glucocorticoid excess
    2. May represent up to 2 to 5% of poorly controlled type diabetes cases with Hypertension
    3. Functional hypercortisolism also occurs in pregnancy

III. Epidemiology

  1. Incidence: 1-3 cases per million/year (U.S.)
  2. Prevalence: 40-79 cases per million (worldwide)
  3. Gender: More common in women (3:1)
  4. Peak age
    1. Mean Age: 41 years
    2. Women: 50 to 60 years old
    3. Children account for 10% of cases/year

IV. Causes: Hypercortisolism

  1. Exogenous Cushings Syndrome (Iatrogenic, most common)
    1. Corticosteroid therapy
  2. Endogenous - ACTH Dependent Cushings Syndrome (80% of Endogenous Cushings Syndrome)
    1. Central Cause (75 to 80% of cases of ACTH dependent Cushings)
      1. Pituitary Adenoma (Cushing's Disease)
    2. Ectopic ACTH Syndrome - Malignancy (15 to 20% of ACTH dependent Cushings)
      1. Small Cell Carcinoma of the lung
      2. Neuroendocrine tumors (pancreatic, thymic, pulmonary Carcinoid)
      3. Gastrinoma
      4. Medullary Thyroid Cancer
      5. Pheochromocytoma
      6. Corticotropin Releasing Hormone Tumors (<1%)
  3. Endogenous - ACTH Independent (Adrenal) Cushings Syndrome (15 to 20% of Endogenous Cushings Syndrome)
    1. Unilateral Adrenal Adenoma (90% of ACTH Independent Cushings)
    2. Primary Bilateral Macronodular Adrenal Hyperplasia (2%)
    3. Primary Pigmented Nodular Adrenal Hyperplasia (2%)
    4. McCune-Albright Syndrome (2%)
    5. Adrenal Malignancy (1%)
  4. Pseudo-Cushings Syndrome (Non-neoplastic Physiologic Hypercortisolism via Hypothalamic-Pituitary Axis Activation)
    1. Obesity
    2. Major Depression
    3. Alcoholism
    4. Obstructive Sleep Apnea
    5. Diabetes Mellitus (poorly controlled)
    6. Polycystic Ovary Syndrome
    7. Emotional stress
    8. Pregnancy
    9. Anorexia Nervosa
    10. Malnutrition
    11. Excessive Exercise
    12. Glucocorticoid resistance or elevated Corticosteroid binding globulin

V. Precautions

  1. Delayed diagnosis is common (often 3 to 6 years after initial symptoms, and multiple medical providers seen)
  2. Avoid screening all patients with Obesity or Hypertension, as low yield without other findings
    1. See screening indications below

VI. History

  1. Exogenous Corticosteroids (esp. prolonged use, higher dose)
  2. Pseudo-Cushing Syndrome associated conditions (see above)
  3. Change in overall appearance
  4. Frequent Skin Infections (esp. fungal)

VII. Symptoms

  1. Mood Disorder (depression, anxiety, irritability)
    1. Personality changes (often with relationship problems)
    2. Work performance often impacted
  2. Easy Bruising
  3. Weakness
  4. Weight gain
  5. Amenorrhea
  6. Back pain

VIII. Signs

  1. General
    1. Weight gain (70 to 95%)
    2. Childhood growth curve changes (decreased height growth, increased weight)
    3. Truncal Obesity or Abdominal Obesity (90%)
    4. Glucose Intolerance (80%) or Insulin Resistance (20 to 47%)
    5. Round face or Moon facies (80-90%)
    6. Plethoric face (70 to 90%)
  2. Protein wasting
    1. Thin skin (premature, age <40 years)
    2. Wide (>1 cm), purple abdominal and thigh striae (65%)
    3. Easy Bruising and slow healing
    4. Muscle wasting (esp. leg atrophy)
  3. Musculoskeletal
    1. Osteoporosis or Osteopenia (55%)
    2. Supraclavicular fat pad development (also in temporal and dorsocervical regions)
    3. Buffalo hump or Thoracic kyphosis (50%)
    4. Myopathy
      1. Proximal Muscle Weakness (weakness on climbing stairs or rising from chair)
      2. Muscle atrophy (60 to 80%)
  4. Cardiopulmonary
    1. Hypertension (85% when Cushing Disease is caused by tumors, 20% when iatrogenic)
    2. Peripheral Edema
    3. Hyperlipidemia (70%)
    4. Pulmonary Embolism (4%)
      1. Hypercoagulable state related to decreased Fibrinolysis and activated coagulation
    5. Complications include Left Ventricular Hypertrophy, Dilated Cardiomyopathy, coronary disease
  5. Neurologic
    1. Cognition, Memory, language and Executive Function decreased (70 to 85%)
    2. Associated with increased Cerebrovascular Accident risk
    3. Pituitary mass effect findings (Visual Field Deficits, anterior Hypopituitarism)
  6. Hyperandrogenism
    1. Hirsutism (70%)
    2. Hypertrichosis (esp. forehead)
    3. Irregular Menses (e.g. Amenorrhea)
    4. Acne (20 to 35%)
    5. Alopecia (75%)
    6. Hyperpigmentation (e.g. perioral, buccal, vaginal)
    7. Hypogonadism (including Delayed Puberty)
    8. Abnormal Uterine Bleeding
    9. Infertility
  7. MIscellaneous
    1. Nephrolithiasis (20 to 50%)
    2. Sleep disorder (60%)

IX. Labs

  1. Complete Blood Count
    1. Leukocytosis with Neutrophilia (and relative decrease in Lymphocytes, Eosinophils, Monocytes, Basophils)
  2. Comprehensive metabolic panel
    1. Hypernatremia
    2. Hypokalemia
    3. Hyperglycemia
    4. Elevated Liver Function Tests
  3. Lipid panel
    1. Hypertriglyceridemia
    2. Hypercholesterolemia

X. Imaging

  1. ACTH Dependent Cushings with normal or high ACTH
    1. CT or MRI Cone down Sella Turcica
      1. Pituitary Adenoma >6 mm (Cushing Disease)
    2. Whole Body CT (with petrosal sinus sampling or CRH /Desmopressin test)
      1. Indicated if Sella Turcica negative for Pituitary Adenoma >6 mm
      2. Evaluate for ectopic ACTH Secreting tumor
  2. ACTH Independent Cushings with low ACTH
    1. CT or MRI Abdomen
      1. Adrenal Adenoma

XI. Differential Diagnosis

  1. See Causes above

XII. Diagnosis

  1. Screening Indications
    1. Weight gain and central fat redistribution (Abdomen, face)
      1. However Obesity alone does not increase Cushing Syndrome likelihood
    2. Multiple signs and symptoms consistent with Cushing Syndrome (as above)
    3. Premature onset of related conditions (Uncontrolled Hypertension, Osteoporosis)
    4. Pediatric growth restriction (decreased height growth, increased weight)
    5. Adrenal Adenoma incidentally found on imaging
  2. Screening Protocol
    1. Step 1: Exclude Exclude exogenous Corticosteroids (oral, inhaled, intraarticular or topical)
    2. Step 2: Initial Cushing Syndrome Screening Tests
      1. Perform one of the following first-line tests
        1. 24-hour Urinary Free Cortisol level (>= 2 samples)
        2. Late Night Salivary Cortisol (>=2 samples)
        3. Low dose Dexamethasone Suppression Test (1 mg)
      2. Positive results with two different tests
        1. Go to Step 3
      3. Normal results with 2 different tests AND low pretest probability
        1. Cushing Syndrome unlikely
        2. Consider cyclic Cushing Syndrome with repeat later testing
      4. Discordant or normal results AND high pretest probability
        1. Endocrinology Consultation
        2. Consider pseudo-Cushing Syndrome (see causes above)
        3. Consider second-line tests
          1. Dexamethasone/CRH Test (preferred)
          2. Desmopressin/CRH Test
    3. Step 3: Cushing Syndrome Confirmed - Differentiate ACTH Dependence
      1. Refer to Endocrinology
      2. Obtain morning ACTH on 2 different days
      3. ACTH Low: ACTH Independent (Adrenal) Cushings Syndrome
        1. Obtain Adrenal CT or MRI
        2. Identify unilateral or bilateral Adrenal Adenoma
      4. ACTH High or Normal: ACTH Dependent Cushings Syndrome
        1. Go to Step 4
    4. Step 4: ACTH Dependent Cushings Syndrome - Differentiate Source
      1. Obtain Pituitary MRI (3 Tesla preferred, as 1.5 Tesla misses 50% of cases)
      2. Pituitary Adenoma >=6 mm
        1. Cushing Disease diagnosis
      3. No Pituitary Adenoma (or <6 mm)
        1. Go to Step 5 (ectopic source)
    5. Step 5: Ectopic ACTH Syndrome - Identify Source/Malignancy
      1. Obtain whole body AND 1 of the following tests
        1. Inferior Petrosal Sinus Sampling (preferred for tumors <6 mm, avoid if >10 mm)
        2. Corticotropin Releasing Hormone (CRH)/Desmopressin Test
      2. Negative whole body CT AND pituitary gradient (or positive CRH/Desmopressin)
        1. Presumed Cushing Disease (Pituitary Adenoma source)
      3. Positive whole body CT AND no pituitary gradient (or negative CRH/Desmopressin)
        1. Ectopic ACTH syndrome
  3. Screening Tests
    1. General
      1. Performd at least 2 of the following tests (two negative tests excludes Cushing Syndrome)
      2. Urinary and Salivary tests should be performed twice due to variability in samples
    2. 24-hour Urinary Free Cortisol level (preferred first line test)
      1. However, often normal in adrenal hypercortisolism (use Dexamethasone suppression instead)
      2. Perform urinary Cortisol at least twice due to variability (discrepant in 50% of samples)
      3. Measures Urine 17-Ketosteroid Excretion and Urine 17-Hydroxysteroid Excretion
    3. Serum Cortisol
      1. Obtain at 8 am
    4. Low dose Dexamethasone Suppression Test (1 mg)
      1. Preferred test if adrenal tumor suspected or Night Shift Worker (altered circadian rhythm)
      2. Dexamethasone 1 mg at 11 pm
      3. Plasma Cortisol in following 8 AM
      4. Efficacy
        1. High Test Sensitivity
        2. Strong Negative Predictive Value
    5. Late Night Salivary Cortisol testing
      1. Often normal in adrenal hypercortisolism
      2. Perform Salivary Cortisol twice due to variability in 50% of samples
      3. Efficacy
        1. High Test Sensitivity
        2. Highest Test Specificity
  4. Distinguish between pituitary, adrenal or ectopic cause
    1. Plasma ACTH (preferred)
    2. High dose Dexamethasone Suppression Test (8 mg)

XIII. Management

  1. Endocrinology Referral
  2. Exogenous Cushing Syndrome (Iatrogenic Cushing Syndrome, most common cause)
    1. Stop Corticosteroids or decrease dose
    2. Change Corticosteroid dosing to every other day with drug holiday
  3. Endogenous Cushing Syndrome
    1. Transphenoidal surgery to excise Pituitary Adenoma (Cushing Disease)
      1. Preferred first-line management
      2. Associated with 65 to 90% remission rate for microadenomas (65% for macroadenomas)
    2. Laparoscopic Adrenalectomy
      1. Unilateral adrenalectomy (requires temporary post-operative adrenal replacement therapy)
        1. Unilateral Adrenal Adenoma
        2. Cancerous lesions (open adrenalectomy)
      2. Bilateral adrenalectomy (requires subsequent lifelong adrenal replacement therapy)
        1. Primary bilateral macronodular adrenalectomy
        2. Primary pigmented nodular adrenal disease
    3. Alternatives to Surgical Management (and adjunctive in refractory cases)
      1. Pituitary Radiation Therapy
        1. Indicated in post-operative persistent or recurrent hypercortisolism
        2. Indicated as adjunctive management in aggressive tumor growth
        3. Risk of Hypopituitarism
      2. Medications (lower efficacy, difficult titration, high adverse effects)
        1. Adrenal Steroidogenesis Inhibition (first-line)
          1. Ketoconazole 400 to 1600 mg/day (risk of hepatotoxicity, QT Prolongation)
          2. Metyrapone 500 to 600 mg/day (risk of Hirsutism, Hypokalemia)
          3. Other agents: Mitotane, Osilodrostat
        2. Central Inhibition of ACTH Secretion (e.g. pasireotide, Cabergoline)
        3. Glucocorticoid Receptor Blockade (e.g. Mifepristone)
  4. General Measures
    1. Manage comorbidities (e.g. Hypertension, Diabetes Mellitus, Obesity)
    2. Lifelong, yearly monitoring of hypothalamic-pituitary axis
    3. Encourage Healthy Diet, regular Exercise and weight loss
      1. Improves self image, mood, sleep

XIV. Complications

  1. Decreased quality of life
  2. Hypertension
  3. Mood Disorders (e.g. Major Depression)
  4. Cognitive disorders (with impact on work/school performance)
  5. Muscle atrophy
  6. Osteoporosis
  7. Type 2 Diabetes Mellitus
  8. Cardiovascular events (RR 4.5)
  9. Venous Thromboembolism (RR 10)
  10. Infections
  11. Childhood Growth Delay and Obesity

XV. Prognosis

  1. Mortality
    1. Untreated cases are ultimately fatal
    2. Overall mortality (RR 5)
      1. Mortality rate 10%
      2. Mortality is not significantly decreased after treatment
  2. Recurrence Rates: 5 to 35%
    1. Half of recurrences occur within 5 years of surgery

XVI. Resources

  1. Cushings Disease (StatPearls)
    1. https://www.ncbi.nlm.nih.gov/books/NBK448184/

XVII. References

  1. Castinetti (2012) Orphanet J Rare Dis 7:41 +PMID: 22710101 [PubMed]
  2. Maness (2024) Am Fam Physician 110(3): 270-80 [PubMed]
  3. Magiakou (2006) Best Pract Res Clin Endocrinol Metab 20(3): 467-82 [PubMed]
  4. Orth (1995) N Engl J Med 332:791-803 [PubMed]

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