DOI: 10.1097/MPH.0b013e318223feb6

,  

,  

PMID: 21792034

Issn Print: 1077-4114

Publication Date: 2011/08/01


Print

Reducing the Risk for Adrenal Insufficiency in Those Treated for ALL: Tapering Glucocorticoids Before Abrupt Discontinuation

Eric I. Felner

    loading  Checking for direct PDF access through Ovid

Excerpt

In this issue of the journal, Vestergaard et al1 carried out a retrospective study in children with leukemia to evaluate the effect of glucocorticoid tapering before its discontinuation. They examined adrenal function in children treated for leukemia and reviewed all previous studies from the past 30 years.2–11 Virtually, every therapeutic protocol for children with acute lymphoblastic leukemia (ALL) glucocorticoid therapy is part of the chemotherapeutic regimen. This study provides compelling evidence that the majority of these children will develop adrenal insufficiency after completing chemotherapeutic induction therapy. They emphasize the need to test adrenal function in all children treated for leukemia who develop a significant stressful event after the completion of induction therapy. Those who experience a stressful event (ie, hypotension, infection, etc.) and have biochemical evidence of adrenal insufficiency should be treated with glucocorticoid replacement therapy. This study also supports the concept that in patients receiving supraphysiologic doses of glucocorticoids for a prolonged period of time, a glucocorticoid-tapering regimen before abrupt discontinuation should be used. There are several methods of tapering glucocorticoids. I generally recommend a taper from the supraphysiologic chemotherapeutic dose immediately to physiologic hydrocortisone (approximately 10 mg/m2/d delivered 3 times a day) for 2 weeks, followed by a 25% weekly reduction over the next 4 weeks before discontinuation.
Cortisol production in both children and adults is approximately 6 to 10 mg/m2/d, with a mean early morning plasma baseline level of 7 to 22 mcg/dL.12 However, during periods of stress, including illness, trauma, anesthesia, or surgery, cortisol requirements (60 to 100 mg/m2/d) and levels (2 to 3× baseline) are substantially elevated above baseline.13
Cortisol is the most potent glucocorticoid produced by the human adrenal. It is synthesized from cholesterol and secreted from the adrenal zona fasciculata. Its production is stimulated by pituitary adrenocorticotropic hormone (ACTH) that is regulated by hypothalamic corticotropin releasing factor (CRF). Secretions of ACTH and CRF are inhibited by high cortisol levels in a negative feedback loop. Cortisol acts through specific intracellular receptors and affects numerous physiologic systems, including immune function, glucose counter regulation, vascular tone, and bone metabolism. Cortisol production has an ACTH-dependent circadian rhythm with a peak level in the early morning and a nadir at night. The factor controlling this rhythm is not completely understood and can be disrupted by a number of physical and psychological conditions. ACTH and cortisol are secreted independent of circadian rhythm in response to physical and psychological stress.14,15 Owing to the normal circadian variation in cortisol, distinguishing normal from abnormally low levels can be difficult. Therefore, adrenal gland stimulation testing should be performed, as it is the best method to effectively determine if adrenal insufficiency has developed.
The symptoms of cortisol deficiency—fatigue, weakness, listlessness, orthostatic dizziness, weight loss, and anorexia—are frequently nonspecific and usually occur insidiously. Some patients initially present with gastrointestinal symptoms, including: abdominal cramps, nausea, vomiting, and diarrhea. In others, the cortisol insufficiency may be misdiagnosed as depression or anorexia nervosa.14,15 The clinical manifestations of underproduction or inappropriate action of glucocorticoids may be life threatening. It results from either primary adrenal failure or secondary adrenal disease due to impairment of the hypothalamic-pituitary-adrenal (HPA) axis.14–16
There are multiple causes for both primary and secondary adrenal insufficiency. In children, the most common primary causes include: autoimmune adrenalitis, infectious diseases, congenital adrenal hyperplasia, adrenoleukodystrophy, and adrenal hemorrhage. Causes of secondary adrenal insufficiency usually involve abnormalities involving the hypothalamus or pituitary gland.14 The most common cause is suppression of the HPA axis by exogenous glucocorticoid treatment.14–17 It is well documented in the literature that prolonged administration of exogenous glucocorticoid (>7 d) at supraphysiologic doses (>10 mg/m2/d) suppresses both production and secretion of CRF.

Related Topics

    loading  Loading Related Articles