How to evaluate and manage a patient with weakness, fatigue, obesity, hypertension, and diabetes suspected of having Cushing's syndrome?

Evaluation and Management of Suspected Cushing's Syndrome

In a patient presenting with weakness, fatigue, obesity, hypertension, and diabetes, you should immediately screen for Cushing's syndrome using 2-3 first-line biochemical tests: 1-mg overnight dexamethasone suppression test, 24-hour urinary free cortisol, and/or late-night salivary cortisol. 1, 2

Clinical Recognition

The constellation of symptoms in this patient—central obesity, hypertension, diabetes, weakness, and fatigue—represents classic features that should trigger suspicion for Cushing's syndrome 3. The ACC/AHA guidelines specifically list "central obesity, facial rounding, easy bruisability" as historical features favoring secondary hypertension from Cushing's syndrome 3.

Key Physical Examination Findings to Assess

Look specifically for these distinctive features during physical examination 3:

• Purple striae (>1 cm wide, violaceous)
• Facial plethora and moon facies
• Dorsocervical and supraclavicular fat pads (buffalo hump)
• Proximal muscle weakness (difficulty rising from chair without using arms)
• Thin, atrophic skin with easy bruising
• Acanthosis nigricans (insulin resistance marker)
• Hirsutism in women

The presence of proximal myopathy and wide purple striae are particularly specific for Cushing's syndrome 3, 4, 2.

Diagnostic Testing Algorithm

Initial Screening Tests

The Endocrine Society recommends starting with 2-3 of the following screening tests 1, 2:

1. 1-mg overnight dexamethasone suppression test (DST): Give 1 mg dexamethasone at 11 PM, measure serum cortisol at 8 AM the next morning. Morning cortisol <1.8 μg/dL (<50 nmol/L) excludes Cushing's syndrome 1, 2

2. 24-hour urinary free cortisol (UFC): Reflects integrated tissue exposure to cortisol over 24 hours; elevated levels indicate hypercortisolism 2

3. Late-night salivary cortisol (LNSC): Measures loss of normal circadian rhythm; can be collected at home and mailed to laboratory 2

Important Testing Caveats

• Drug interactions: Some medications interfere with the DST, particularly those affecting CYP3A4 metabolism 2
• False positives: Antibody-based immunoassays can cross-react with cortisone and other metabolites; liquid chromatography with tandem mass spectrometry is more specific 2
• Cyclic Cushing's: May produce false-negative results; repeat testing if clinical suspicion remains high 2
• UFC collection: Ensure complete 24-hour collection with appropriate total volume 2

Baseline Laboratory Evaluation

Obtain the following tests to assess comorbidities and complications 3:

• Fasting blood glucose and hemoglobin A1c
• Complete metabolic panel (assess for hypokalemia from mineralocorticoid excess)
• Lipid profile
• Serum creatinine with eGFR
• Serum potassium (hypokalemia suggests mineralocorticoid activity)
• Thyroid-stimulating hormone
• Electrocardiogram

Management of Hypertension in Suspected/Confirmed Cushing's Syndrome

Antihypertensive Selection

Spironolactone or eplerenone should be the first-line antihypertensive agent because these mineralocorticoid receptor antagonists block the mechanism by which excess cortisol causes hypertension 1, 5. The American Heart Association specifically recommends this approach as "the most sensible strategy" for hypertension in Cushing's syndrome 1.

Additional considerations for blood pressure management 5:

• Renin-angiotensin system inhibitors (ACE inhibitors or ARBs) are recommended based on pathophysiology
• Conventional antihypertensives alone (ACE inhibitors, ARBs, calcium channel blockers) may not achieve blood pressure targets without addressing the underlying hypercortisolism 1
• Hypokalemia correction is essential, as it contributes to arrhythmias (especially atrial fibrillation) and worsens hypertension 3

Definitive Treatment Approach

Surgical Management

Surgery is the first-line definitive treatment to remove the source of cortisol production (pituitary adenoma, adrenal tumor, or ectopic ACTH-producing tumor) 3, 1. This addresses the root cause and prevents long-term cardiovascular mortality, which is the primary cause of death in Cushing's syndrome 5, 6.

Medical Management

Medical therapy with steroidogenesis inhibitors is reserved for 3, 1:

• Non-surgical candidates
• Bridge to surgery to reduce perioperative risk
• Persistent disease after failed surgery

Available agents include 3:

• Ketoconazole or levoketoconazole (monitor liver function and QTc interval)
• Metyrapone
• Pasireotide LAR (high risk for hyperglycemia—use cautiously in diabetics)
• Mifepristone (for hyperglycemia associated with Cushing's syndrome)

Cardiovascular Risk Management

Thromboprophylaxis Considerations

Cushing's syndrome creates a hypercoagulable state 3:

• Consider prophylactic anticoagulation for patients with severe hypercortisolism, history of VTE, poor mobility, or current estrogen use
• Low molecular weight heparin is preferred over oral anticoagulants perioperatively
• Early ambulation and compression stockings for all patients

Long-term Cardiovascular Monitoring

Evaluate and treat according to high cardiovascular risk guidelines 3. Patients with Cushing's syndrome have increased mortality primarily from cardiovascular causes driven by the metabolic syndrome constellation 5, 6, 7:

• Hypertension (multifactorial pathogenesis)
• Diabetes and insulin resistance
• Dyslipidemia
• Visceral obesity
• Prothrombotic state

Critical point: Metabolic syndrome features can persist long after cortisol normalization, requiring continued aggressive management of cardiovascular risk factors 7.

Prevalence Context

While traditionally considered rare (10-15 per million), studies of patients with diabetes, obesity, and hypertension have found unexpectedly high prevalence of Cushing's syndrome in these populations 4. This supports aggressive screening in patients presenting with this clinical triad plus weakness and fatigue.