Iatrogenic Cushing’s syndrome with inhaled steroid plus antidepressant drugs
© Celik et al.; licensee BioMed Central Ltd. 2012
Received: 25 July 2012
Accepted: 25 July 2012
Published: 29 August 2012
Current guidelines recommend the use of inhaled corticosteroids (ICS) for suppression of airway inflammation in patients with asthma. Although it is well known that ICS cause dose-related adrenocortical suppression, it is less known that they can lead to iatrogenic Cushing’s syndrome (CS). Fluticasone propionate (FP) is an ICS more potent than beclomethasone and budesonide. FP is metabolized as mediated by cytochrome P450 3A4 in the liver and the gut. Systemic bioactivity of FP can increase with the use of drugs that affect the cytochrome P450. Herein, we report the rapid development of iatrogenic CS in a patient receiving paroxetine and mirtazepine for 12 weeks in addition to inhaled FP.
Inhaled corticosteroids (ICS) are widely accepted as the first line of treatment for the suppression of airway inflammation of asthma [1, 2]. Although it is well known that ICS cause dose-related adrenocortical suppression, it is less known that they can lead to iatrogenic Cushing’s syndrome (CS) [3–5]. Fluticasone propionate (FP) is the most potent inhaled corticosteroid and is highly lipophilic with a large volume of distribution. Low plasma concentrations of FP are achieved after inhaled dosing due to first-pass metabolism and high systemic clearance, mediated by cytochrome P450 3A4 in the liver and the gut . Systemic bioactivity of FP depends on: glucocorticoid potency, dose, duration of therapy, individual glucocoticoid receptor sensitivity, and drug combinations. Previously, iatrogenic CS was recognized after prolonged high dose use of FP in a female patient . The literature presents many reports of iatrogenic CS with osteoporosis and secondary adrenal failure in Human Immunodeficiency Virus (HIV)-infected patients receiving ICS and ritonavir .
Paroxetine and mirtazepine are antidepressant drugs that inhibit cytochrome P450 and, consequently, decrease the clearance of corticosteroids. Paroxetine is highly metabolized with cytochrome P450- dependent CYP2D6. There is a moderate effect on other P450 enzymes. Although mirtazepine is a weak competitive inhibitor of CYP 1A2, 2D6 and 3A4, it is known that there have been no clinical effects on cytochrome P450 to date .
Herein, we report for the first time the rapid development of iatrogenic CS in a patient who has been taking paroxetine and mirtazepine, in addition to inhaled FP, for 12 weeks.
The initial laboratory results in pat i ent with Iatrogenic Cushing’s syndrome
Results (normal range)
Results (normal range)
: 1 pg/mL (0–46)
: 3.7 gr/dL (3.2-4.8)
: 0.8 μg/dL (5–25)
: 41U/L (0–45)
Urinary free cortisol
: 60 μg /day (20–70)
: 9 μg/dL (35–430)
: 42U/L (45–129)
: 15ng/dL (20–90)
: 9 mg/dL (8.6-10)
: 2.34ng/dl (0.8-1.58)
: 2.9mg/dL (2.1-4)
: 1.44mIU/L (0.4-4)
: 232mg/dL (50–200)
: 104mg/dL (74–106)
: 21mg/dL (19–50)
: 0.6mg/dL (0.7-1.3)
: 139 mg/dL(5–130)
: 143mEq/L (135–145)
: < 3mg/L (0–5)
: 3.2 mEq/L (3.5-5.5)
: 9 mm/sa (5–25)
: 7700/mm3 (4600–10.000)
: 13 gr/dL(12–17)
: 38% (37–50)
: 133000/mm 3 (150–450)
: 2.67 L (2.83)
: 97% (83)
: 6.16L/sec (6.59)
: 4.51L/sec (3.83)
After consultation with a thoracic diseases specialist, the patient was reassessed for asthma. Respiratory function tests were as follows: FEV1: 2.67, FEV1/FVC: 97, PEF: 6.16, MEF25-75: 4.51. FP was changed to salbutamol sulphate as needed for a re-evaluation of the diagnosis.
The patient developed symptoms of extreme fatigue, anorexia, and myalgia after cessation of FP. Hydrocortisone (20 mg /day for 2 months, po), at gradually decreasing doses, was started for evaluation of the hypothalamic-pituitary-adrenal axis. Two months after withdrawal of FP, the patient felt that her clinical appearance was better, but there was still evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression.
A case of clinical CS secondary to increased systemic concentration of FP due to cytochrome P450 inhibition has been described. The condition of the patient was associated with subsequent adrenal insufficiency related to the suppression of pituitary-adrenal axis.
FP undergoes very high first-pass hepatic metabolism, mediated by cytochrome P450 3A4, and it is also very lipophilic, resulting in much higher tissue levels, longer plasma half-life and greater glucocorticoid receptor affinity than other ICSs such as beclomethasone and budenoside . Recently, HPA axis suppression related to ICS is thought to be due to systemic absorption through the lungs rather than oral absorption via ingested corticosteroids after inhalation . A recent retrospective study  aimed at estimating the incidence of adrenal insufficiency in users of inhaled corticosteroids reported 46 cases (involving fluticasone, budesonide, or beclomethasone). Eleven patients treated with fluticasone and four with budesonide were concomitantly treated with an enzymatic inhibitor: itraconazole (six cases), ritonavir (five cases), verapamil (two cases), and diltiazem (two cases). Although the use of ICS in the long-term management of asthma is recommended, it is advised that the lowest effective dose of ICS be used to prevent systemic side effects [1, 12].
A recent meta-analysis showed that FP had minimal effects on adrenal function when prescribed within the therapeutic range of 50–500 μg/day to patients with asthma . It was demonstrated that age, being a normal volunteer inhaler technique and compliance, plays a role in determining the systemic effects of ICS. In spite of this, Paton J et al. reported that clinical adrenal insufficiency was particularly associated with high doses (> 400 μg/day) of inhaled FP in children with asthma . Wilson AM et al. demonstrated that high doses of inhaled FP alone were associated with adrenal suppression and CS features with use over 2 years in a female asthmatic patient. Inhaled FP was changed to budenoside, then her cushingoid features improved and HPA also returned to normal . Recently Matos AC et al. presented a 22- year-old man with adrenal insufficiency and a cushingoid habitus who was receiving 250 μg FP and salmeterol 50 μg two blisters, twice a day for four years . These cases confirms that HPA axis suppression with features of Cushing’s syndrome occurs at commonly used, and licensed, doses of ICS.
Some important drugs that inhibit cytochrome P450 dependent CYP3A4 and CYP2D6
Antiarrhythmics (Flecainide, Propafenone, etc.)
Antiarrhythmics (Amiodarone, Lidocaine, Propafenone, etc.)
Beta blockers (Carvedilol, Metoprolol, etc..)
Anti-histamines (Astemizole, Chlorpheniramine)
Neuroleptics (Haloperidol, Risperidone, Clozapine, etc.)
Anti-cancer (Tamoxifen, Vinblastine)
Opiates (Dextromethorphan, Codeine, Tramadol, etc.)
Benzodiazepines (Midozalam, Diazepam, Alprazolam, etc.)
SSRI (Fluoxetine, Paroxetine, Fluvoxamine, etc.)
HIV-protease inh (Ritonavir, Indinavir, etc.)
Tricyclic antidepressants (Amitriptyline, Desipramine, Imipramine, Nortriptyline, etc.)
HMG CoA reductaseinh (Atorvastatin, Lovastatine, Simvastatin)
Hormones (Cortisol, Progesterone, Testosterone, steroids)
Calcium channel blocker (Diltiazem, Verapamil, Nitrendipin)
Macrolides (Erythromycin, Clarithromycin)
Others (Ketoconazole, Itraconazole, Lidocaine, Cocaine,…etc)
Paroxetine and mirtazepine are antidepressant drugs that inhibit cytochrome P450, and, consequently, decrease the clearance of corticosteroids. Although it is known that paroxetine is highly metabolized with cytochrome P450-dependent CYP2D6, mirtazepine has not known to have clinical effects on cytochrome P450 to date . However, it should be verified with research and observations. It was thought that our patient had developed clinical CS secondary to increased systemic concentration of FP due to cytochrome P450 inhibition by antidepressants. In addition to the CS development, biochemical results of the patient showed low cortisol, ACTH, testosterone, DHEAS (Dehydroepiandrosterone sulfate) levels, and hypokalemia. Moreover, she had impaired fasting glucose. Recently, declines in DHEAS after the initiation of ICS have been recommended as an early index of adrenal suppression . Significantly low DHEAS levels (9 μg/dl) were found in this patient. These findings may provide significant clinical utility for the early detection of adrenal suppression after ICS therapy.
In conclusion, to the best of our knowledge, this is the first report of a patient with iatrogenic CS receiving FP and antidepressants. Both thoracic diseases specialists and general practitioners should be aware of the risk of iatrogenic CS due to serious drug interactions with FP.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
- Williams SG, Schmidt DK, Redd SC, Storms W: National Asthma Education and Prevention Program. Key clinical activities for quality asthma care. Recommendations of the National Asthma Education and Prevention Program. MMWR Recomm Rep. 2003, 52: 1-8.PubMedGoogle Scholar
- Gonzalez-Barcala FJ, Aboal J, Valdes L, Carreira JM, Alvarez-Dobaño JM, Puga A, Garcia-Sanz MT, Takkouche B: Trends in adult asthma hospitalization: gender-age effect. Multidiscip Resp Med. 2011, 6: 82-86.View ArticleGoogle Scholar
- Wilson AM, Blumsohn A, Jung RT, Lipworth BJ: Asthma and Cushing’s syndrome. Chest. 2000, 117: 593-594. 10.1378/chest.117.2.593.View ArticlePubMedGoogle Scholar
- Paton J, Jardine E, McNeil E, Beaton S, Galloway P, Young D, Donaldson M: Adrenal responses to low dose synthetic ACTH (Synacthen) in children receiving high dose inhaled fluticasone. Arch Dis Child. 2006, 91: 808-813. 10.1136/adc.2005.087247.PubMed CentralView ArticlePubMedGoogle Scholar
- Sim D, Griffiths A, Armstrong D, Clarke C, Rodda C, Freezer N: Adrenal suppression from high dose inhaled fluticasone propionate in children with asthma. Eur Respir J. 2003, 21: 633-636. 10.1183/09031936.03.00306302.View ArticlePubMedGoogle Scholar
- Möllmann H, Wagner M, Meibohm B, Hochhaus G, Barth J, Stöckmann R, Krieg M, Weisser H, Falcoz C, Derendorf H: Pharmacokinetic and pharmacodynamic evaluation of fluticasone propionate after inhaled administration. Eur J Clin Pharmacol. 1998, 53: 459-467. 10.1007/s002280050407.View ArticlePubMedGoogle Scholar
- Samaras K, Pett S, Gowers A, McMurchie M, Cooper DA: 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. J Clin Endocrinol Metab. 2005, 90: 4394-4398. 10.1210/jc.2005-0036.View ArticlePubMedGoogle Scholar
- Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI: Drug interactions with newer antidepressants: role of human cytochromes P450. J Clin Psychiatry. 1998, 59 (Suppl.15): 19-27.PubMedGoogle Scholar
- Pedersen S, O’Byrne P: A comparison of the efficacy and safety of inhaled corticosteroids in asthma. Allergy. 1997, 52 (39 Suppl): 1-34.View ArticlePubMedGoogle Scholar
- Matos AC, Srirangalingam U, Barry T, Grossman AB: Cushing’s syndrome with low levels of serum cortisol: the role of inhaled steroids. Clin Med. 2011, 11: 404-405.View ArticlePubMedGoogle Scholar
- Molimard M, Girodet PO, Pollet C, Fourrier-Réglat A, Daveluy A, Haramburu F, Fayon M, Tabarin A: Inhaled corticosteroids and adrenal insufficiency: prevalence and clinical presentation. Drug Saf. 2008, 31: 769-774. 10.2165/00002018-200831090-00005.View ArticlePubMedGoogle Scholar
- Leone FT, Fish JE, Szefler SJ, West SL: Systematic review of the evidence regarding potential complications of inhaled corticosteroid use in asthma: collaboration of American College of Chest Physicians, American Academy of Allergy, Asthma, and Immunology, and American College of Allergy, Asthma, and Immunology. Chest. 2003, 124: 2329-2340. 10.1378/chest.124.6.2329.View ArticlePubMedGoogle Scholar
- Masoli M, Weatherall M, Holt S, Schirtcliffe P, Beasley R: Inhaled fluticasone propionate and adrenal effects in adults asthma: systemic review and meta-analysis. Eur Respir J. 2006, 28: 960-967. 10.1183/09031936.06.00119305.View ArticlePubMedGoogle Scholar
- Woods DR, Arun CS, Corris PA, Perros P: Cushing’s syndrome without excess cortisol. BMJ. 2006, 332: 469-470. 10.1136/bmj.332.7539.469.PubMed CentralView ArticlePubMedGoogle Scholar
- Hoover WC, Britton LJ, Gardner J, Jackson T, Gutierrez H: Rapid onset of iatrogenic adrenal insufficiency in a patient with cystic fibrosis-related liver disease treated with inhaled corticosteroids and a moderate CYP3A4 inhibitor. Ann Pharmacother. 2011, 45: e38-10.1345/aph.1Q103.View ArticlePubMedGoogle Scholar
- Main KM, Skov M, Sillesen IB, Dige-Petersen H, Müller J, Koch C, Lanng S: Cushing's syndrome due to pharmacological interaction in a cystic fibrosis patient. Acta Paediatr. 2002, 91: 1008-1011. 10.1111/j.1651-2227.2002.tb02894.x.View ArticlePubMedGoogle Scholar
- Kannisto S, Laatikainen A, Taivainen A, Savolainen K, Tukiainen H, Voutilainen R: Serum dehydroepiandrosterone sulfate concentrations as an indicator adrenocortical suppression during inhaled steroid therapy in adult asthmatic patients. Eur J Endocrinol. 2004, 150: 687-690. 10.1530/eje.0.1500687.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.