Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0036
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 4394-4398
Copyright © 2005 by The Endocrine Society
Iatrogenic Cushing’s Syndrome with Osteoporosis and Secondary Adrenal Failure in Human Immunodeficiency Virus-Infected Patients Receiving Inhaled Corticosteroids and Ritonavir-Boosted Protease Inhibitors: Six Cases
Katherine Samaras,
Sarah Pett,
Andrew Gowers,
Marilyn McMurchie and
David A. Cooper
Department of Endocrinology (K.S.), St. Vincent’s Hospital and St. Vincent’s Clinic; Immunology and Infectious Diseases Unit (S.P., D.A.C.), St. Vincent’s Hospital; National Centre for HIV Epidemiology and Clinical Research (S.P., D.A.C.), University of New South Wales; and Holdsworth House General Practice (A.G.), Darlinghurst, New South Wales 2010, Australia; and 407 Doctors General Practice (M.M.), Surry Hills, New South Wales 2010, Australia
Address all correspondence and requests for reprints to: Dr. Katherine Samaras, MBBS, FRACP, Ph.D., Diabetes and Obesity Group, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales, 2010, Australia. E-mail: k.samaras{at}garvan.org.au.
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Abstract
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Ritonavir, a protease inhibitor (PI), is a potent inhibitor of cytochrome P450 3A4. This pharmacological effect, even at low doses (
200 mg/d), is used to "boost" levels of other PIs in the treatment of HIV infection and facilitate once or twice daily dosing with reduced pill burden. Six patients with preexisting HIV-lipodystrophy developed symptomatic Cushing’s syndrome when treated with inhaled fluticasone at varying doses for asthma while concurrently treated with low-dose ritonavir-boosted PI antiretroviral therapy (ART) regimens for HIV infection. There was evidence of adrenal suppression in all patients on stimulation studies. After the withdrawal of inhaled fluticasone, four patients became symptomatic of hypocortisolism, and three required oral corticosteroid support for several months. Other complications included evidence of osteoporosis (n = 3), crush fractures (n = 1), and exacerbation of preexisting type 2 diabetes mellitus (n = 1). In part, the diagnosis of fluticasone-induced Cushing’s syndrome was delayed because all patients had preexisting body composition changes of ART-associated lipodystrophy, masking the Cushing’s features. Practitioners should be aware of the impact on the adrenal axis of coadministration of PI-based ART regimens with inhaled corticosteroids and the potential for exacerbating or even inducing other metabolic conditions, such as osteoporosis or diabetes.
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Introduction
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RITONAVIR, A PROTEASE inhibitor (PI) used in the treatment of HIV infection, is an extremely potent inhibitor of cytochrome P450 3A4 activity. The combination of small (boosting) doses of ritonavir (200 mg/d) with other PIs leads to significant increases in dosing area under the curve (AUC) of the second PI, an advantageous drug-drug interaction that reduces pill burden and increases dosing intervals, thereby facilitating adherence to antiretroviral therapy (ART) (1, 2). Although the clinical benefits from exploiting this effect on P450 3A4 are obvious and are being used elsewhere (e.g. transplant medicine) with other inhibitors, a caveat of this pharmacological manipulation is the potential for significant harmful side effects and interactions involving ritonavir and other drugs, even when low-dose ritonavir is used (www.mims.com.au). Importantly, the metabolism of commonly used drugs may be affected. This case series highlights the severity of a drug interaction between low-dose ritonavir and inhaled corticosteroids, perhaps more prevalent in HIV medicine than previously recognized, because the presence of lipodystrophy may mask the clinical detection of iatrogenic Cushing’s syndrome.
Current guidelines for asthma treatment (3) recommend the use of inhaled corticosteroids for suppression of airway inflammation. Fluticasone is only one of several inhaled synthetic corticosteroids available. Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after inhaled dosing, due to extensive first pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the liver and gut (4). Fluticasone is highly lipophilic with a large volume of distribution (250 liters) (4). In healthy volunteers on low doses of both ritonavir (200 mg/d) and fluticasone nasal spray (200 µg/d), there was a significant increase in the AUC for fluticasone and a significant decrease (86%) in plasma cortisol AUC within 7 d (5). In these experiments, serum cortisol AUC over 24 h was determined by the trapezoid method (GlaxoSmithKline Australia, personal communication, February 2005). The manufacturers currently do not recommend the coadministration of inhaled fluticasone with ritonavir, unless the benefits outweigh the risk. Moreover, an addendum to the product information for both ritonavir and fluticasone was issued in February 2004 (GlaxoSmithKline and Abbott Laboratories, personal communication, March 2004) that reiterated this warning and emphasized the potential for Cushing’s syndrome and adrenal suppression when ritonavir and inhaled fluticasone were coadministered. These effects are not limited to ritonavir, because similar effects have been seen with other PIs and other drugs inhibiting P450 3A4 (e.g. macrolide antibiotics and some azoles) when coadministered with fluticasone and other 17-OH sterols (i.e. beclamethasone and budesonide) (6, 7, 8, 9).
There have been relatively few reports of iatrogenic Cushing’s syndrome associated with the either the coadministration of high-dose (800–1200 mg/d) (7, 10, 11) or low-dose (200 mg/d) (12, 13) ritonavir with inhaled or nasal fluticasone. We report six cases of ritonavir-inhaled fluticasone-induced Cushing’s syndrome in HIV-infected patients with HIV-lipodystrophy (Table 1
). The phenotype was severe, causing biochemical adrenal suppression in all cases and symptoms of adrenal failure after withdrawal of fluticasone in four cases, with prolonged adrenal recovery necessitating oral corticosteroid support. Osteoporosis was present in four cases; one case had crush fractures. There was a significant decline in glycemic control in one patient with preexisting type 2 diabetes within days of commencing inhaled fluticasone. In part, the diagnosis of iatrogenic Cushing’s syndrome was masked or delayed because all the patients reported preexisting body composition changes commonly observed in ART-associated lipodystrophy, i.e. limb fat and facial fat loss accompanied by increased truncal fat. Each patient gave consent for anonymous details to be presented.
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Case 1
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A 43-yr-old man receiving ART including ritonavir (Table 1
) presented for assessment and treatment of osteoporosis on a background of mild HIV-lipodystrophy. He had asthma, which was treated with inhaled fluticasone/salmeterol 250/50 µg twice a day (b.i.d.) (Accuhaler device) for approximately 2 yr before presentation. Presentation followed multiple rib fractures, sustained by an unremarkable embrace. Hypertension had been present for 5 yr. Bone mineral density (BMD) readings by dual energy x-ray absorptiometry (Lunar Expert, General Electric, Madison, WI) showed disproportionately low density in the lumbar spine: L2–L4, 0.94 g/cm2, 2.5 SD below young normal; femoral density, 0.94 g/cm2, 1.2 SD below young normal. The patient described central weight gain, a ravenous appetite, facial plethora, an acneiform facial rash, muscle wasting, weakness, easy bruising, irritability, a withdrawn and depressed mood, and abdominal stretch marks; the onset followed commencement of inhaled fluticasone. Clinically, facial plethora, central obesity, a mild buffalo hump, and prominent abdominal striae were evident (Fig. 1). Investigations demonstrated normal calcium, 25-hydroxy vitamin D, parathyroid hormone, osteocalcin, and serum electrophoretogram. The urinary N-telopeptide was markedly elevated at 205 nM/mM [reference range (RR), 16–51]. The 24-h urinary free cortisol was 11 nmol/24 h (RR, 70–430). A diagnosis of Cushing’s syndrome secondary to fluticasone was made, and fluticasone ceased. The patient developed symptoms of extreme fatigue and depression approximately 1 wk later. A random cortisol at 1300 h was 22 nmol/liter; a short synacthen test (SST) demonstrated significant adrenal suppression (Table 2). Low-dose oral corticosteroid support was commenced (prednisolone 2.5 mg/d). Subsequent early morning cortisol levels remained low: 254 and 308 nmol/liter, 1 and 3 months after fluticasone cessation. Prednisolone was gradually weaned over 5 months. At 5 months after fluticasone cessation, the early morning cortisol was 371 nmol/liter. There was resolution of the buffalo hump and facial plethora by 5 months; however, central obesity remained. The striae, while evident, were pale.
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FIG. 1. Case 1. Cushingoid features in a 43-yr-old man after approximately 2 yr of inhaled fluticasone.
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TABLE 2. SST for six patients with HIV-lipodystrophy and inhaled fluticasone-induced Cushing’s syndrome with subsequent adrenal suppression
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Case 2
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A 43-yr-old man receiving ritonavir-boosted ART (Table 1) for 2 yr had commenced inhaled fluticasone 250 µg b.i.d. contemporaneously. He developed an acneiform facial rash 1–2 months later, followed by body fat changes (increased truncal and abdominal fat), facial plethora, muscle wasting, and depressive symptoms. Fluticasone was ceased by the respiratory physician approximately 22 months after its commencement, and over the ensuing 2 months the patient reported rapid weight loss, severe fatigue, anorexia, severe myalgias and arthralgias, cognitive impairment, and worsening of depression. The patient was also receiving ketoconazole for a fungal nail infection. Shortly after fluticasone cessation, the early morning cortisol was 27 nmol/liter; a SST demonstrated adrenal suppression (Table 2). At endocrine review, 3 months after fluticasone withdrawal, features of hypocortisolism were evident with severe wasting and a postural blood pressure drop. Review of the patient’s photographs before the cessation of fluticasone demonstrated Cushingoid facies and central obesity, physical features significantly different to those at presentation. Ketoconazole was ceased, because it was considered a contributor to adrenal suppression; however, a second SST performed 2 wk after cessation of ketoconazole (14 wk after fluticasone cessation) showed ongoing adrenal suppression. Due to the severity of the patient’s symptoms, low-dose corticosteroid support was initiated (prednisolone 3 mg mane). An early morning cortisol 4.5 months after fluticasone cessation was 150 nmol/liter; 6 months after fluticasone cessation, it was 277 nmol/liter. A BMD scan (Lunar Expert) demonstrated disproportionately severe lumbar osteoporosis: lumbar spine (L2–L4), 0.81 g/cm2, 3.6 SD below young normal; femoral density, 0.92 g/cm2, 1.3 SD below young normal.
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Case 3
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A 53-yr-old man receiving ritonavir-boosted ART (Table 1) with severe peripheral lipodystrophy and mild central obesity had received combined fluticasone/salmeterol 500/50 µg b.i.d. (Accuhaler device) for the previous 2 yr. Shortly after commencing asthma therapy, he noted an increase in facial fat ("chipmunk cheeks"), facial plethora, and bruising. The patient had also received rosiglitazone (as part of a drug trial), although the onset of the facial swelling predated rosiglitazone commencement. The patient had been off rosiglitazone for at least 6 months before presentation. At diagnosis of the Cushing’s syndrome, the serum cortisol was undetectable (<30 nmol/liter at 1500 h), and the 24-h urinary free cortisol was 80 nmol/d. After cessation of inhaled fluticasone, the patient developed nausea, headaches, weight loss, fatigue, postural presyncope, and arthralgias. A SST performed 1 month later demonstrated a low baseline cortisol but adequate response to maximal ACTH stimulation (Table 2). Symptoms of hypoadrenalism persisted at reassessment 4 months after fluticasone cessation, although the clinical features had resolved by this time. The morning cortisol and ACTH levels at that time were consistent with a degree of adrenal unresponsiveness: the morning cortisol was 536 nmol/liter, with an elevated ACTH of 14.9 pmol/liter (RR < 12.0). Six months after fluticasone cessation, a second SST demonstrated a persistent defect in cortisol metabolism: a low morning baseline cortisol but vigorous responses to ACTH stimulation (Table 2). A total body BMD (Lunar Expert) was 1.03 g/cm2, 2.4 SD below young normal.
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Case 4
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A 49-yr-old man receiving ritonavir-boosted ART for 6 months (Table 1) with moderately severe asthma was treated with a budesonide inhaler (200 µg b.i.d.) and intermittent oral corticosteroids for asthma exacerbations. After a respiratory review, he was commenced on inhaled fluticasone/salmeterol 500/50 µg b.i.d. An asthma exacerbation 1 month later required a 10-d reducing course of oral prednisolone (starting dose, 80 mg/d). Three days after oral corticosteroids cessation, he experienced presyncope and fatigue and reported coincidental abdominal distension and facial swelling. Clinical examination confirmed a "moon face," marked increase in abdominal girth, and newly diagnosed hypertension. The patient subsequently ceased his PI-based regimen and switched to an efavirenz-based regimen while remaining on the inhaled fluticasone. The patient experienced worsening lethargy and weakness; a SST demonstrated adrenal suppression (Table 2). The patient was given low-dose prednisolone (5 mg mane) replacement, and a repeat SST 2 months later showed a normal cortisol profile. Over the next few months, there was a gradual resolution of the moon face and abdominal distension, but the patient remained hypertensive. Bone densitometry shortly after the development of Cushing’s syndrome showed a lumbar spine reading of 0.97 g/cm2, 2.3 SD below young normal; femoral density 0.77 g/cm2, 2.5 SD below young normal, with little change over the subsequent year.
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Case 5
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A 43-yr-old man receiving ART including ritonavir (Table 1) commenced inhaled fluticasone 250 µg b.i.d. for asthma, 2 months before presentation. Within 6 wk, he noted severe muscle cramping and body composition changes with upper abdominal obesity and increasing facial fatness. Inhaled fluticasone was ceased 1 wk before presentation, after the detection of undetectable serum cortisol levels (<30 nmol/liter). Clinically, typical Cushingoid features were evident with facial plethora, moon face, abdominal obesity, and thin skin with bruising. Low-dose prednisolone was commenced (2.5 mg) on cessation of fluticasone. An SST 1 wk later showed adrenal suppression (Table 2). Clinical features were still evident 2 months later.
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Case 6
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A 51-yr-old man receiving ART (Table 1) with severe HIV-lipodystrophy presented for a usual 3-month review of type 2 diabetes mellitus, diagnosed 6 yr previously. Type 2 diabetes mellitus was stable and well controlled on gliperimide 1 mg mane and rosiglitazone 4 mg mane; glycosylated hemoglobin 4 months before presentation was 7.0%. The patient developed a respiratory infection with bronchospasm and was commenced on fluticasone 500 µg b.i.d. 2 months before presentation. He developed significant deterioration in his glucose levels, with postprandial readings up to 20 mmol/liter, despite increasing the gliperimide to 4 mg. He reported muscle cramps with weakness and wasting, significant mood perturbations with irritability and euphoria, and abdominal bloating. Clinically, there was facial plethora and significant facial changes: on a background of marked facial lipodystrophy, there was new facial puffiness in the submandibular and retroauricular region. Abdominal bloating was more marked than previously. A midday cortisol was undetectable, and inhaled fluticasone was ceased. The patient had few symptoms of adrenal insufficiency, apart from mild fatigue and dizziness that resolved over the subsequent few days. An 0800-h cortisol 2 months later was 393 nmol/liter, and his glycemic control was restored (glycosylated hemoglobin, 6.8%). Clinical features had resolved by 4 months.
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Discussion
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These six cases, seen in relatively rapid succession in clinical practice, highlight drug interactions between medications used for the treatment of HIV infection and those for other common conditions such as asthma. Four of these cases represent the first reports of osteoporosis (with fractures in one patient) after iatrogenic Cushing’s syndrome due to the ritonavir-fluticasone drug interaction (although low BMD can be found in HIV disease and lipodystrophy). The frequent clinical phenotype of lipodystrophy in antiretroviral-treated HIV-infected individuals may mask or hinder the clinical detection of Cushing’s syndrome in this patient group, where central abdominal fat accumulation or thinning limbs may be attributed to lipodystrophy. Whether lipodystrophy predisposes patients receiving ritonavir to fluticasone-induced Cushing’s syndrome is not known. Fluticasone is highly lipophilic, so it is possible that patients with severe lipodystrophy may have higher circulating fluticasone levels, because these patients would have a lesser capacity to partition fluticasone out of the circulation into body fat. If this hypothesis is correct, patients with more severe lipodystrophy may develop Cushing’s syndrome on inhaled fluticasone more quickly than those with more body fat, as evidenced in cases 2, 3, 4, and 6. Prospective studies would be useful in this regard.
A further clinical difficulty in diagnosis is the inability of standard diagnostic techniques (24-h urine free cortisol) to detect this syndrome. Low urinary free cortisol levels or suppressed early morning cortisol levels, a consequence of adrenal suppression, would be indicative; however, the wide reference range of morning cortisol levels provides a significant hurdle, unless levels are very suppressed. More recently, declines in dehydroepiandrosterone sulfate after the initiation of inhaled steroids have been recommended as an early index of adrenal suppression (14). Although there are no widely accepted guidelines for the early detection of adrenal suppression after instigation of inhaled corticosteroids, such would hold significant clinical utility.
These six cases demonstrate the severity of the syndrome including significant disturbance of mood, osteoporosis, and adrenal insufficiency requiring supportive treatment after fluticasone withdrawal. The rate of recovery from adrenal suppression secondary to fluticasone is not known. At the time of writing, partial or significant adrenal suppression persisted in five of the six patients. It is possible, given the highly lipophilic nature of the fluticasone, that slow leaching of fluticasone into the circulation from fat stores may perpetuate the adrenal suppression. If this hypothesis is correct, patients with greater body fat mass may be expected to have longer adrenal suppression.
Osteoporosis in HIV-infected patients using ART is relatively common and has been related to a number of factors including duration and type of ART (15). These cases illustrate that drugs, particularly inhaled corticosteroids, require special consideration in the setting of HIV infection, where there is already an increased risk of accelerated bone mineral loss. Because bone density scans before the commencement of inhaled steroids are not available for all of these individuals and osteoporosis is frequently seen in HIV infection ± lipodystrophy, we cannot attribute the osteoporosis solely to inhaled steroids. However, it is noteworthy that disproportionately lower lumbar spine readings were found in patients 1 and 2, a pattern typical of steroid-induced osteoporosis. Apart from ritonavir-fluticasone interactions, there may also be individual susceptibility to reduced cytochrome P450 3A4 metabolism of fluticasone (16). One case of iatrogenic Cushing’s syndrome in a non-HIV-infected adult patient with asthma receiving standard doses of fluticasone has been described (17) and growth retardation and low bone mass have been documented in children using fluticasone (6).
In summary, iatrogenic Cushing’s syndrome induced by inhaled fluticasone in PI-treated patients can be associated with severe metabolic consequences, including postwithdrawal hypoadrenalism and (possibly) osteoporosis, even after relatively short-term therapy (<2 yr). The Cushingoid body composition changes in these case reports were initially attributed to the body shape changes of HIV-lipodystrophy, which possibly delayed the diagnosis of Cushing’s syndrome. PI therapy in HIV-infected patients with asthma should be considered a relative contraindication to fluticasone use. If no other alternative is available, use of the lowest dose of fluticasone with careful clinical monitoring might be the best compromise. However, if practitioners undertake to coadminister both drugs, patients must be appropriately warned of the inherent dangers. In many cases, patients may not consider the use of sprays—including nasal corticosteroids available over the counter without prescription in some countries—as "medication" and fail to report their use. In this situation, clinicians would be unlikely to suspect the diagnosis. The ability to measure circulating fluticasone levels, with the assumption that these levels accurately predict effects on the adrenal axis, would be a useful tool in guiding regimens in clinical practice.
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Footnotes
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First Published Online March 8, 2005
Abbreviations: ART, Antiretroviral therapy; AUC, area under the curve; b.i.d., twice a day; BMD, bone mineral density; PI, protease inhibitor; RR, reference range; SST, short synacthen test.
Received January 6, 2005.
Accepted March 1, 2005.
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Abstract
Introduction
