Exogenous Cushing's Syndrome and Glucocorticoid Withdrawal

Hopkins, Rachel; Leinung, Matthew C.

doi:10.1016/j.ecl.2005.01.013

Cited by 188 publications

(159 citation statements)

References 48 publications

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“…Sudden, and often inadvertent, withdrawal of steroids can lead to adrenal crisis. Hence, a detailed drug history is 24 Concomitant use of steroids with itraconazole 25 or ritonavir 26 (which inhibit hepatic CYP3A metabolism of steroids) can increase this risk. Generally, longer duration, higher dosages, and oral and intraarticular preparations increase the risk of adrenal suppression.…”

Section: Risk Factorsmentioning

confidence: 99%

Adrenal Crisis: Still a Deadly Event in the 21st Century

Puar

Stikkelbroeck

Smans

et al. 2016

The American Journal of Medicine

144

140

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Adrenal crisis is a life-threatening medical emergency, associated with a high mortality unless it is appropriately recognized and early treatment is rendered. Despite it being a treatable condition for almost 70 years, failure of adequate preventive measures or delayed treatment has often led to unnecessary deaths. Gastrointestinal illness is the most common precipitant for an adrenal crisis. Although most patients are educated about "sick day rules," patients, and physicians too, are often reluctant to increase their glucocorticoid doses or switch to parenteral injections, and thereby fail to avert the rapid deterioration of the patients' condition. Therefore, more can be done to prevent an adrenal crisis, as well as to ensure that adequate acute medical care is instituted after a crisis has occurred. There is generally a paucity of studies on adrenal crisis. Hence, we will review the current literature, while also focusing on the incidence, presentation, treatment, prevention strategies, and latest recommendations in terms of steroid dosing in stress situations.

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Section: Risk Factorsmentioning

confidence: 99%

Adrenal Crisis: Still a Deadly Event in the 21st Century

Puar

Stikkelbroeck

Smans

et al. 2016

The American Journal of Medicine

144

140

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“…2 The normal physiological release of glucocorticoid occurs via both circadian and high-frequency pulsations, with these stimulations determining the release of glucocorticoid receptor-mediated transcripts. This phenomenon has been referred to as gene pulsations.…”

Section: Discussionmentioning

confidence: 99%

Iatrogenic Cushing Syndrome and Secondary Adrenal Insufficiency Related to Concomitant Triamcinolone and Ritonavir Administration

Song

Schroeder

Bush

2013

J Int Assoc Provid AIDS Care

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Triamcinolone is a long-acting glucocorticoid medication that can be responsible for transient suppression of the hypothalamicpituitary-adrenal (HPA) axis. This physiologic alteration may persist for weeks after repeated or even single localized injection of this agent. However, when this glucocorticoid agent is given to patients receiving the HIV protease inhibitor (PI) ritonavir (RTV), inhibition of their shared cytochrome P450 3A4 degradation pathway leads to an increased bioavailability of triamcinolone, with subsequent heightening and prolongation of the glucocorticoid serum levels. In those instances, iatrogenic Cushing syndrome may ensue. The authors encountered such an event in an HIV-infected patient on chronic treatment with an antiretroviral regimen containing RTV. The patient's clinical presentation and laboratory investigations confirmed a diagnosis of Cushing syndrome and secondary adrenal insufficiency. This was believed to have occurred in close association following cervical vertebral column facet joint injections with triamcinolone acetonide for cephalagia deemed related to cervical spine disease. The discontinuation of the RTV-boosted PI therapy alone, promoting the clearance of the elevated triamcinolone serum levels and restoration of HPA homeostasis, proved successful in this patient. For this case, the authors review the published English medical literature relating to this uncommon phenomenon.

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“…Some manifestations of glucocorticoid excess occur quickly (hours/days), for example psychiatric effects and increased appetite, whereas a cushingoid appearance, glucose intolerance or osteoporosis may take longer to develop (weeks/months). 13 In our cohort, changes in appearance (weight gain, striae, proximal myopathy) and fatigue were the commonest presenting features; however, presentations can vary significantly. [6][7][8][9][10][11] Although glucocorticoid treatment courses of less than 3 weeks duration often will not lead to HPA axis suppression, at relatively high doses, significant HPA suppression can occur in as little as 5 days.…”

Section: Features and Timing Of Ics And Saimentioning

confidence: 99%

mentioning

confidence: 99%

Iatrogenic Cushing’s syndrome due to drug interaction between glucocorticoids and the ritonavir or cobicistat containing HIV therapies

et al. 2016

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Ritonavir and cobicistat, used as pharmacokinetic enhancers in combination with some antiretrovirals (ARVs) for the treatment of HIV, are potent inhibitors of the CYP3A4 isoenzyme. Most glucocorticoids are metabolised via the CYP3A4 pathway and iatrogenic Cushing's syndrome (ICS), with possible secondary adrenal insufficiency (SAI), is a recognised complication following co-administration with ritonavir or cobicistat. A structured approach for identifying and managing potentially affected individuals has not been established. We systematically identified patients with ICS/SAI and found substantial heterogeneity in clinical practice across three large London HIV centres. While this significant drug interaction and its complications are now well-recognised, it is apparent that there is no standardised approach to management or guidance for the general physician. Here we describe the management of ICS/SAI in our current practice, review the available evidence and suggest practice recommendations. KEYWORDS : Adrenal insuffi ciency , cobicistat , Cushing's syndrome , HIV , ritonavir IntroductionRitonavir and cobicistat are pharmacokinetic enhancers used in the treatment of HIV infection. They are extremely potent inhibitors of cytochrome P450 3A4 (CYP3A4) activity. Ritonavir, originally developed as an antiretroviral, is used ABSTRACT Iatrogenic Cushing's syndrome due to drug interaction between glucocorticoids and the ritonavir or cobicistat containing HIV therapies at sub-therapeutic doses, in combination with HIV protease inhibitors (PIs), to significantly increase their concentrations and allow less frequent and lower dosing.1 Cobicistat was developed more recently and is similar in structure. It is used in combination with PIs or elvitegravir (an integrase inhibitor) 2 but has no antiretroviral activity itself. 3 The downside of this pharmacokinetic manipulation is the significant potential for interactions with CYP3A4 substrates, leading to side effects. CYP3A4 is the dominant isoenzyme of the hepatic cytochrome P450 system and is the primary metabolic step for the degradation of endogenous and most prescribed corticosteroids. The metabolism of these can therefore be decreased by inhibitors such as ritonavir/cobicistat. 4 Subsequent increases in exogenous corticosteroid plasma concentrations and half-life can lead to iatrogenic Cushing's syndrome (ICS) 5 and, at supraphysiological levels, to suppression of adrenocorticotropic hormone (ACTH) and endogenous corticosteroid secretion, potentially resulting in secondary adrenal insufficiency (SAI). There is abundant evidence highlighting this issue. 1,[6][7][8][9][10][11] However, a structured approach to identify and manage potentially affected individuals has not been established. We aim to summarise the current management of ICS/SAI in three large HIV patient cohorts, review the available literature and develop practice recommendations. Of note, cobicistat became available after the evaluation period covered; however, all advice for ritonavir is applicable to i...

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Exogenous Cushing's Syndrome and Glucocorticoid Withdrawal

Cited by 188 publications

References 48 publications

Adrenal Crisis: Still a Deadly Event in the 21st Century

Adrenal Crisis: Still a Deadly Event in the 21st Century

Iatrogenic Cushing Syndrome and Secondary Adrenal Insufficiency Related to Concomitant Triamcinolone and Ritonavir Administration

Iatrogenic Cushing’s syndrome due to drug interaction between glucocorticoids and the ritonavir or cobicistat containing HIV therapies

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