Review article Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself Stina Dinsen a , Bo Baslund c , Marianne Klose a , Aase Krogh Rasmussen a , Lennart Friis-Hansen b , Linda Hilsted b , Ulla Feldt-Rasmussen a, ⁎ a Department of Medical Endocrinology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark b Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark c Department of Rheumatology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark abstract article info Article history: Received 3 April 2013 Received in revised form 20 May 2013 Accepted 24 May 2013 Available online xxxx Keywords: Glucocorticoid-induced adrenal insufficiency Glucocorticoid withdrawal Adrenal insufficiency Glucocorticoids 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 glucocor- ticoid withdrawal remains a serious problem in clinical practice. Partly due to difficulties in inter-study compar- ison 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 treat- ment, 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 with- drawal. 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. © 2013 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine. 1. Introduction Glucocorticoids are used in the treatment of a large number of pa- tients 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, ele- vated 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 [1–11] 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 regi- mens” used in glucocorticoid withdrawal and instead focus on the uncer- tainty of the treatment induced suppression of adrenal function. 2. Prevalence and diagnosis of adrenal insufficiency after glucocorticoids Treatment with supraphysiologic doses of glucocorticoids will sup- press the hypothalamic–pituitary–adrenal axis (HPA axis) (Fig. 1). In fact, suppression has been shown to occur even at physiologic doses European Journal of Internal Medicine xxx (2013) xxx–xxx ⁎ Corresponding author at: Department of Medical Endocrinology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel.: + 45 35452337, + 45 35451023; fax: + 45 35452240. E-mail address: ufeldt@rh.dk (U. Feldt-Rasmussen). EJINME-02527; No of Pages 7 0953-6205/$ – see front matter © 2013 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine. http://dx.doi.org/10.1016/j.ejim.2013.05.014 Contents lists available at SciVerse ScienceDirect European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim Please cite this article as: Dinsen S, et al, Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself, Eur J Intern Med (2013), http://dx.doi.org/10.1016/j.ejim.2013.05.014