How to manage a patient with suspected Cushing's syndrome, hypertension, and osteoporosis, on ibuprofen and inhaled fluticasone/umeclidinium/vilanterol, with daily alcohol use?

Management of Suspected Cushing's Syndrome with Hypertension and Osteoporosis

Immediately discontinue the inhaled fluticasone/umeclidinium/vilanterol as this is the most likely cause of iatrogenic Cushing's syndrome in this patient, and switch to a lower-potency inhaled corticosteroid or non-steroidal asthma therapy. 1, 2

Critical First Step: Rule Out Exogenous Glucocorticoid Exposure

• The elevated late-night salivary cortisol (290 ng/dL) and elevated ACTH (78 pg/mL) in a patient using inhaled fluticasone strongly suggests iatrogenic Cushing's syndrome from exogenous glucocorticoid exposure 3, 4
• Inhaled fluticasone propionate at licensed doses can cause clinically significant Cushing's syndrome with proximal myopathy, osteoporosis, hypertension, and cushingoid features, with documented cases showing complete adrenal suppression 1
• The combination of inhaled corticosteroids with certain medications (itraconazole, ritonavazir) can precipitate severe iatrogenic Cushing's syndrome, though this patient's alcohol use (2-3 glasses daily) may also affect cortisol metabolism 2
• Stop all exogenous glucocorticoids if medically feasible before pursuing workup for endogenous Cushing's syndrome 3

Immediate Management Priorities

Address Life-Threatening Complications

Initiate thromboprophylaxis immediately given the 10-fold increased risk of venous thromboembolism in Cushing's syndrome, particularly with hypertension (174/109 mmHg) as an additional risk factor 3

• The incidence of venous thromboembolic events is more than 10-fold higher in endogenous Cushing's syndrome versus healthy population, with an odds ratio of 18 3
• Extended thromboprophylaxis to 30 days post-intervention decreases postoperative VTE incidence 3
• Hypercoagulability persists in the first few months after cortisol normalization 3

Manage Severe Hypertension

Target blood pressure control with antihypertensive therapy while addressing the underlying hypercortisolism, as cardiovascular events are a primary cause of the 4.1 to 16-fold increased mortality in active Cushing's disease 3

• Discontinue ibuprofen immediately as NSAIDs can exacerbate hypertension and interact negatively with the hypercortisolemic state 3
• Structural cardiovascular changes including left ventricular hypertrophy and increased atherosclerotic plaque formation improve with cortisol normalization but may not fully resolve 3

Address Osteoporosis and Fracture Risk

Initiate bisphosphonate therapy with vitamin D and calcium supplementation immediately, as vertebral fractures occur in 30-50% of Cushing's patients and fractures may occur even with normal or osteopenic bone mineral density 3

• Conventional osteoporosis treatments induce more rapid BMD improvement than cortisol normalization alone 3
• Fracture risk persists even after hypercortisolism resolution, with men at higher risk than women 3
• Skeletal fragility is an early complication and fractures may be the first clinical manifestation 3

Counsel on Alcohol Cessation

Strongly recommend cessation of the 2-3 glasses of wine daily, as alcohol can interfere with cortisol metabolism and exacerbate hypertension, osteoporosis, and muscle wasting 3

Diagnostic Approach After Stopping Exogenous Glucocorticoids

If Hypercortisolism Persists After Discontinuing Inhaled Fluticasone

Repeat screening tests 4-6 weeks after stopping exogenous glucocorticoids: obtain 2-3 collections of 24-hour urinary free cortisol (UFC) and at least 2 late-night salivary cortisol measurements on consecutive days 3

• Multiple LNSC measurements are particularly useful and may be easier for patient collection 3
• UFC should be averaged over 2-3 collections for confirmation 3
• The elevated ACTH (78 pg/mL) suggests ACTH-dependent disease if endogenous Cushing's is confirmed 3

Localization Studies if Endogenous Cushing's Confirmed

Obtain pituitary MRI with gadolinium to evaluate for Cushing's disease, as ACTH-dependent disease accounts for 60-70% of endogenous Cushing's syndrome 4, 5

• If pituitary lesion ≥10 mm is detected and dynamic testing is consistent with Cushing's disease, inferior petrosal sinus sampling (IPSS) is not necessary 3
• All patients with lesions <6 mm should have IPSS; expert opinions differ for tumors 6-9 mm but the majority recommend IPSS in this range 3
• Consider whole-body CT scan if ectopic ACTH syndrome is suspected (though less likely given the clinical presentation) 3

Medical Therapy If Endogenous Cushing's Disease Confirmed

First-Line Medical Therapy Options

If surgery is not immediately feasible or fails to achieve remission, initiate osilodrostat as first-line medical therapy given its highest efficacy (86% UFC normalization) among adrenal steroidogenesis inhibitors 3

• Osilodrostat: 2-7 mg twice daily, maximum 30 mg twice daily, with rapid UFC decrease 3
• Alternative options include ketoconazole 400-1200 mg/day (approximately 65% UFC normalization) or metyrapone 500 mg/day to 6 g/day (approximately 70% UFC normalization with rapid onset) 3
• Monitor for adrenal insufficiency, hypokalemia, and QTc prolongation with osilodrostat 3

Monitoring Treatment Response

Measure UFC and morning cortisol every 2-4 weeks during dose titration, along with weight, blood pressure, and glycemic control 3

• Morning cortisol values are especially pertinent if taking higher medication doses in the evening 3
• Consider switching therapy if cortisol levels remain persistently elevated after 2-3 months on maximum tolerated doses 3
• Combination therapy (e.g., ketoconazole plus metyrapone) should be considered if monotherapy provides partial but insufficient cortisol reduction 3, 6

Common Pitfalls to Avoid

• Never pursue extensive workup for endogenous Cushing's syndrome without first ruling out and stopping exogenous glucocorticoid exposure 3, 4
• Do not delay thromboprophylaxis—VTE risk remains elevated even after cortisol normalization 3
• Do not wait to treat osteoporosis—fractures occur even with normal BMD and bone loss may not fully reverse 3
• Do not use UFC alone to diagnose adrenal insufficiency during medical therapy monitoring—use morning cortisol or LNSC 3
• Monitor liver function tests regularly with ketoconazole, but mild stable elevations do not require discontinuation 3