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Common and differentiating features of glucocorticoid withdrawal syndrome and glucocorticoid-induced adrenal insufficiency

Common and differentiating features of glucocorticoid withdrawal syndrome and glucocorticoid-induced adrenal insufficiency
  Glucocorticoid-induced adrenal insufficiency Glucocorticoid withdrawal syndrome
Timing relative to glucocorticoid dose

When taking physiologic or subphysiologic glucocorticoid doses*

or

When there is an increased glucocorticoid requirement beyond the exogenous dose (eg, serious infection, trauma)

 At any point while decreasing the glucocorticoid dose, while the glucocorticoid dose is supraphysiologic*
Symptoms
  • May be asymptomatic
  • Fatigue and general malaise
  • Nausea and/or abdominal pain
  • Arthralgias and/or myalgias
  • Dizziness
  • Fatigue and general malaise
  • Nausea
  • Arthralgias and/or myalgias
  • Sleep disturbances
  • Mood changes
Clinical signs
  • May have none
  • Weight loss or, in growing children, failure to gain weight
  • Hypotension and orthostasis
  • Hyponatremia
  • Hypoglycemia
  • May have none
  • Cushingoid features (eg, progressive weight gain, facial rounding, striae)
Approach to laboratory testing
  • HPA axisΔ: Initially low ACTH (if measured) and cortisol; later in recovery, normal to elevated ACTH and low cortisol
  • Hyponatremia
  • Hypoglycemia
  • HPA axisΔ: Not typically tested, but usually undetectable or low ACTH (if measured) and cortisol
  • Hyperglycemia in some cases
To be used with UpToDate content on discontinuing systemic glucocorticoid therapy in adults and children. For additional information on the signs and symptoms of other forms of adrenal insufficiency, refer to UpToDate topics on clinical features of adrenal insufficiency in adults and children.

ACTH: adrenocorticotropic hormone; AI: adrenal insufficiency; HPA: hypothalamic-pituitary-adrenal.

* In adults and older adolescents, a physiologic dose is approximately 5 to 7.5 mg/day of prednisone, 0.25 to 0.5 mg/day of dexamethasone, or 15 to 25 mg/day of hydrocortisone. In children who have not completed growth, a physiologic dose (based on body surface area) is approximately 2 to 2.5 mg/m2/day of prednisone, 0.25 to 0.5 mg/m2/day of dexamethasone, or 8 to 10 mg/m2/day of hydrocortisone.

¶ Hyponatremia in glucocorticoid-induced AI is related to decreased free water clearance rather than aldosterone deficiency, which is the cause of hyponatremia in primary AI (Addison disease). As a result, patients with glucocorticoid-induced AI do not typically develop the hyperkalemia, metabolic acidosis, and profound dehydration that occurs in primary AI (eg, Addison disease). Please refer to the UpToDate topic on primary AI for more information.

Δ Testing involves omitting the glucocorticoid dose on the morning of the test and measuring an endogenous cortisol level at approximately 7 to 9 AM. For more information, refer to UpToDate content on the diagnosis of adrenal insufficiency. For more information, refer to UpToDate content on the diagnosis of adrenal insufficiency.

Adapted from: Beuschlein F, Else T, Bancos I, et al. European Society of Endocrinology and Endocrine Society joint clinical guideline: Diagnosis and therapy of glucocorticoid-induced adrenal insufficiency. J Clin Endocrinol Metab 2024; 109:1657.
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