Review article
Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself

https://doi.org/10.1016/j.ejim.2013.05.014Get rights and content

Highlights

  • Glucocorticoid-induced adrenal insufficiency is a serious clinical problem.

  • The prevalence might be 50–100% initially and 2–3% after several months.

  • Neither dose nor duration of glucocorticoid treatment can predict the risk.

  • There is an individual variation in adrenal function after glucocorticoid withdrawal.

  • More awareness and research is urgently needed.

Abstract

Glucocorticoid therapy is widely used, but withdrawal from glucocorticoids comes with a potential life-threatening risk of adrenal insufficiency. Recent case reports document that adrenal crisis after glucocorticoid withdrawal remains a serious problem in clinical practice. Partly due to difficulties in inter-study comparison the true prevalence of glucocorticoid-induced adrenal insufficiency is unknown, but it might be somewhere between 46 and 100% 24 h after glucocorticoid withdrawal, 26–49% after approximately one week, and some patients show prolonged suppression lasting months to years. Adrenal insufficiency might therefore be underdiagnosed in clinical practice.

Clinical data do not permit accurate estimates of a lower limit of glucocorticoid dose and duration of treatment, where adrenal insufficiency will not occur. Due to individual variation, neither the glucocorticoid dose nor the duration of treatment can be used reliably to predict adrenal function after glucocorticoid withdrawal. Also the recovery rate of the adrenal glands shows individual variation, which may be why there is currently insufficient evidence to prove the efficacy and safety of different withdrawal regimens.

Whether a patient with an insufficient response to an adrenal stimulating test develops clinically significant adrenal insufficiency depends on the presence of stress and resulting glucocorticoid demand and it is thus totally unpredictable and can change relative fast. Adrenal insufficiency should therefore always be taken seriously. Individual variation in hypothalamic–pituitary–adrenal axis function might be due to differences in glucocorticoid sensitivity and might be genetic.

Further awareness of the potential side effect of withdrawal of glucocorticoid and further research are urgently needed.

Introduction

Glucocorticoids are used in the treatment of a large number of patients suffering from various inflammatory and neoplastic diseases as well as in organ transplantation. The drug is used with great effect, but also with a large number of side effects. While the common and feared side effects such as osteoporosis, diabetes mellitus, hypertension, elevated lipids, depression etc. are well known, glucocorticoid-induced adrenal insufficiency is less recognized although it is one of the more dangerous adverse effects that renders the patient unable to produce a sufficient stress–response. Identification of patients with glucocorticoid-induced adrenal insufficiency is crucial, since an acute adrenal crisis with life threatening hypotension and hypoglycemia is preventable, if the condition is properly and timely recognized and the patient is given supplemental glucocorticoids before or early in the course of stress. If the diagnosis is missed, the critically ill patient may die, and several fatal cases [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11] due to glucocorticoid-induced adrenal insufficiency have been described. Recent case reports of shock or other severe symptoms of adrenal crises in patients treated with glucocorticoids (Table 1) showed that this adverse effect is still a serious problem in clinical practice.

The aim of this review is to challenge and question the “safe regimens” used in glucocorticoid withdrawal and instead focus on the uncertainty of the treatment induced suppression of adrenal function.

Section snippets

Prevalence and diagnosis of adrenal insufficiency after glucocorticoids

Treatment with supraphysiologic doses of glucocorticoids will suppress the hypothalamic–pituitary–adrenal axis (HPA axis) (Fig. 1). In fact, suppression has been shown to occur even at physiologic doses of exogenous steroid due to its suppression of endogenous secretion of corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH). Suppression of endogenous ACTH is known to result in adrenocortical hypoplasia or even atrophy [8]. When glucocorticoid therapy is discontinued

Unpredictable adrenal function

Although prolonged suppression of adrenal function might be more likely to follow large doses and long duration of glucocorticoid treatment, the recovery of HPA axis function seems to display a considerable individuality [26]. It has been shown that neither the total dose, the highest dose of prednisone, nor the duration of therapy was the significant predictor of HPA axis recovery [35]. During a suppressed period the adrenal glands might be able to produce a sufficient amount of steroids for

Are test results clinically relevant?

It has been questioned whether the reduced responses found by HPA-axis testing were clinically relevant, or whether the actual risk of adrenal insufficiency was overestimated [17], [37], [51]. Several studies testing the prevalence of glucocorticoid-induced adrenal insufficiency have assessed the symptoms among patients with an insufficient test result and found either some [26], [55] or all [53] insufficient patients to have classical symptoms or clinical signs of adrenal insufficiency.

It has

Glucocorticoid therapy and withdrawal

Attempts have been made to make glucocorticoid therapy and withdrawal safer by using the lowest possible dose, shortest possible duration of therapy, alternate day administration, locally applied glucocorticoids, tapering of the dose and perioperative coverage. All these improvements have made glucocorticoid withdrawal safer, but none of the improvements have made it possible to draw a line that ensures “safe”.

One example of an unfortunate use of the word safe, with respect to withdrawal from

Management of patients withdrawing glucocorticoids

Many clinicians consider glucocorticoid-induced adrenal insufficiency a very rare adverse effect. Due to lack of focus on the problem, clinicians can easily be less aware of it and forget to inform the patients of the potential risk and to do the appropriate follow-up in each individual patient.

The solution cannot be to run adrenal stimulation tests in all patients withdrawing glucocorticoids, nor should prolonging glucocorticoid tapering in general be standard for all patients as it increases

Substantial inter-individual variation

The individual variation in HPA axis function after glucocorticoid withdrawal may be caused by individual variation in sensitivity towards glucocorticoids. It has been shown that the response to a dexamethasone suppression test in healthy volunteers before a 14 days high dose prednisone course could predict adrenal function after prednisone withdrawal. It was found that the risk of suppressed adrenal function 7 days after prednisone treatment had stopped was increased in those individuals, who

Learning points

  • The true prevalence of glucocorticoid-induced adrenal insufficiency is unknown — it might be around 50–100% initially, 25–50% after a few weeks and around 2–3% after several months and might therefore be underdiagnosed among clinicians.

  • Neither dose nor duration of glucocorticoid treatment can predict a patient's risk of developing glucocorticoid-induced adrenal insufficiency.

  • Low dose and short duration of glucocorticoid treatment do not rule out adrenal insufficiency.

  • There is insufficient

Grant support

None.

Conflict of interests

The authors state that they have no conflicts of interest.

Acknowledgement

This study was supported by the Eva Maduras Foundation.

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