Cushing's syndrome

A female patient was treated with high-dose inhaled fluticasone propionate for her asthma. Over 2 years, she developed features of Cushing's syndrome with proximal myopathy, osteopenia, hypertension, depressive psychosis, and cushingoid appearance. She had biochemical evidence of marked adrenal suppression with a 9:00 AM serum cortisol of 20 nmol/L that returned to normal (315 mol/L) after her therapy was changed to budenoside, 0.8 mg/d. Her appearance, mental state, and myopathy also improved with no loss of asthma control. This ease illustrates the potential for developing clinically relevant adverse effects of inhaled corticosteroids when given at licensed doses.

(CHEST 2000; 117:593-594)

Key words: adrenal suppression; Cushing's syndrome; fluticasone propionate; osteoporosis

Inhaled glucocorticoids are widely accepted as first-line preventative anti-inflammatory therapy for the treatment of asthma. This is based on the principle of delivering a relatively low nominal dose of topically active glucocorticoid to achieve a high local concentration within the airway, while at the same time minimizing systemic bioactivity. Although it is recognized that inhaled glucocorticoids cause dose-related adrenocortical suppression, it is less well known that they may be a cause of overt cushingoid presentation. The etiology of systemic bioactivity is multifactorial, depending on the glucocorticoid potency, dose, duration of therapy, inhaler delivery device, and individual patient's glucocorticoid-receptor sensitivity. The following case illustrates the severity of systemic glucocorticoid activity in a susceptible patient and how this may pose a potential diagnostic problem.

CASE REPORT

A 59-year-old female patient with chronic severe asthma was first seen in the chest clinic in March 1995 with deterioration in her asthma control, having intermittently taken inhaled beclomethasone. Her [FEV.sub.1] at that time was 41% of predicted normal. She was prescribed inhaled fluticasone propionate at a nominal dosage of 1 mg/d (1 mg ex-valve equivalent to 0.88 mg ex-actuator dose) via a Volumatic spacer (Glaxo Wellcome; Middlesex, UK) plus an inhaled long-acting [[Beta].sub.2]-agonist (salmeterol) and slow-release oral theophylline bid. The same physician increased the dosage of fluticasone propionate to 2 mg/d (2 mg ex-valve equivalent to 1.76 mg ex-actuator) at a subsequent visit, and she was then discharged from the clinic to be followed up by her general practitioner ([FEV.sub.1] of 52% predicted at that time).

She was next seen in hospital [is greater than] 2 years later (August 1997), when she was referred to the metabolic bone clinic (A.B.) because of back pain thought to be due to osteoporosis. She had received two tapering courses of prednisolone (1-week duration of each) for her asthma and had been taking inhaled fluticasone propionate, 2 mg/d (1.76 mg ex-actuator), over the previous 3 years. At that time, she was noted to have a markedly cushingoid appearance, with a moon-shaped face, hirsutism, kyphosis, and widespread bruising. She was also hypertensive (BP, 180/110 mm Hg) and had proximal muscle weakness and a depressive psychosis. Osteopenia was evident on both thoracic and lumbar radiographs, with a wedge fracture of the fifth thoracic vertebrae. Bone densitometry showed evidence of significant osteopenia (left ultra-distal radius Z score, 2.02; T score, 1.39; 67% of expected for age; and mid-distal radius Z score, 1.39; T score, 3.06; 85% of expected for age), as assessed by dual energy x-ray absorptiometry. She was therefore prescribed oral cyclical etidronate.

As it was considered that her degree of cushingoid appearance could not be explained by her inhaled corticosteroid therapy, she was referred to an endocrinologist (R.T.J.), who arranged further tests to evaluate her adrenocortical function. Her results showed a lack of normal diurnal variation in serum cortisol: 9:00 AM cortisol of 20 nmol/L (lower limit of normal, 190 nmol/L) and a 12:00 midnight cortisol of 13 nmol/L. Her 24-h urinary free cortisol excretion was less than the lower limit of the reference range ([is less than] 60 nmol/24 h). A dexamethasone suppression test (dexamethasone, 1 mg, at 11:00 PM) as performed that showed a postsuppression 9:00 AM serum cortisol concentration of [is less than] 20 nmol/L.

After consultation with another chest physician (B.J.L.), it was considered that inhaled fluticasone propionate was probably responsible for her condition. Fluticasone propionate was changed to budenoside, 0.8 mg/d, via a dry powder inhaler (Turbuhaler; Astra Pharmaceuticals; Herts, UK) and her salmeterol was changed to an oral leukotriene receptor antagonist (montelukast). Her cushingoid features markedly improved as did her muscle weakness, and her mental state returned to normal. When repeated in May 1998, her 9:00 AM serum cortisol had also returned to normal, with serial values of 315 nmol/L and 308 nmol/L, as did her 24-h urinary free cortisol excretion (100 nmol/24 h). Despite reducing the total daily dose of inhaled corticosteroids, she had improved diurnal asthma control of symptoms, peak flow, and [FEV.sub.1] (66% of predicted normal). She remained hypertensive and was treated with an angiotensinreceptor antagonist (losartan).

This case illustrates the potential for inhaled glucocorticoids to cause overt secondary Cushing's syndrome. Indeed, primary Cushing's syndrome was considered to be the most likely diagnosis at first presentation. Hence, a 24-h urinary cortisol collection and a dexamethasone suppression test were initially performed to establish the diagnosis. Dynamic stimulation testing with tetracosactrin (adrenocorticotropic hormone) was not performed, as tetracosactin is contraindicated in the UK for use in asthmatic subjects because of occasional reports of anaphylactic reactions.

There are other reported eases of children and adults with cushingoid features and adrenal suppression due to inhaled fluticasone.[1,2] However, our ease also showed documented evidence of osteoporosis as well as having a depressive psychosis. There has also been a reported ease of an acute addisonian crisis on withdrawal of budesonide in a 38-year-old man[3] and on withdrawal of beclomethasone dipropionate in a 7-year-old girl.[4]

Had our patient received prolonged courses of oral prednisolone, this could have accounted for the systemic effects observed. However, she only received two tapering courses of oral prednisolone for 1 week each. In a study by Webb and Clark,[5] it was shown that short courses of prednisolone do not cause long-term adverse effects because (after 3 weeks of prednisolone, 40 mg/d) both early-morning cortisol and response to dynamic stimulation with cosyntropin, 250 [micro]g, recovered after 3 days.

Fluticasone propionate is the most potent of the available glucocorticoids for inhalation. A recent meta-analysis of 22 studies[6] showed fluticasone to exhibit significantly steeper dose-related adrenal suppression compared to beclomethasone (2.1-fold), budesonide (2.5-fold), or triamcinolone acetonide (3.6-fold). These effects are due to the particular pharmacologic and pharmacokinetic properties of fluticasone resulting in more prolonged drug retention at receptors, in blood, and in systemic tissues.

Our ease highlights the importance of following asthma management guidelines in terms of stepping down to the lowest effective maintenance dose of inhaled corticosteroid, particularly with higher potency corticosteroids such as fluticasone propionate.

REFERENCES

[1] Zimmerman B, Gold M, Wherrett D, et al. Adrenal suppression in two patients with asthma treated with low doses of inhaled steroid fluticasone propionate. J Allergy Clin Immunol 1998; 101:425-426

[2] Duplantier JE, Nelson RP, Morelli AR, et al. Hypothalamicpituitary-adrenal axis suppression associated with the use of inhaled fluticasone propionate. J Allergy Clin Immunol 1998; 102:699-700

[3] Wong J, Black P. Acute adrenal insufficiency associated with high dose inhaled steroids [letter]. Br Med J 1992; 304:1415

[4] Zwaan CM, Odink RJH, Delemarre-van de Wall HA, et al. Acute adrenal insufficiency after discontinuation of inhaled corticosteroid therapy. Lancet 1992; 340:1289-1290

[5] Webb J, Clark TJH. Recovery of plasma corticotrophin and cortisol levels after a three-week course of prednisolone. Thorax 1981; 36:22-24

[6] Lipworth BJ, Wilson AM. Dose response to inhaled corticosteroids: benefits and risks. Semin Respir Crit Care Med 1998;19:625-646

(*) From the Departments of Clinical Pharmacology and Therapeutics (Drs. Wilson and Lipworth), Biochemical Medicine (Dr. Blumsohn), and Medicine (Dr. Jung), Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK. Manuscript received May 17, 1999; revision accepted September 8, 1999.

Correspondence to: Brian J. Lipworth, MD, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY; e-mail: b.j.lipworth@dundee.ac.uk

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