What are the appropriate steps to manage and treat an adult patient with elevated cortisol levels, potentially due to steroid use or underlying medical conditions such as obesity or diabetes?

Management of Elevated Cortisol Levels in Adults

The first critical step is to measure ACTH levels to distinguish between ACTH-dependent causes (pituitary tumors, ectopic ACTH production) and ACTH-independent causes (primary adrenal pathology), as this fundamentally determines the treatment pathway, with surgical resection being definitive treatment for most cases and medical management with adrenal steroidogenesis inhibitors serving as first-line pharmacotherapy when surgery is not feasible. 1

Initial Diagnostic Approach

Measure ACTH levels immediately to categorize the hypercortisolism:

• Elevated ACTH: Indicates pituitary tumors (Cushing's disease) or ectopic ACTH production 1
• Low or undetectable ACTH: Indicates primary adrenal pathology (adenoma, carcinoma, or exogenous steroid use) 1

Important Context for Obesity and Diabetes

While you mention obesity and diabetes as potential underlying conditions, recognize that:

• The prevalence of true Cushing's syndrome in patients with type 2 diabetes ranges from 0.6-9.3%, with false positive screening rates of 3.7-21% 2
• In obese patients, CS prevalence is generally around 1% 2
• Clinical stigmata of Cushing's syndrome (proximal muscle weakness, wide purple striae, easy bruising, facial plethora) combined with typical comorbidities are the strongest predictors of true CS 2
• Elevated cortisol in obesity/diabetes may reflect stress-related HPA axis dysregulation rather than autonomous hypercortisolism 3, 4

Treatment Algorithm Based on Etiology

For ACTH-Independent Disease (Adrenal Source)

Surgical Management:

• Laparoscopic adrenalectomy is the treatment of choice for benign adrenal adenoma 1
• For malignant adrenal tumors, open adrenalectomy with removal of adjacent lymph nodes is required, potentially including en bloc resection of liver, kidney, pancreas, spleen, or diaphragm 1
• Mandatory postoperative corticosteroid supplementation until HPA axis recovery (typically several months) 1

For ACTH-Dependent Disease (Cushing's Disease)

Medical Management is First-Line When Surgery Not Feasible:

Severity-Based Treatment Selection

For Mild Disease:

• Ketoconazole 400-1200 mg/day achieves UFC normalization in approximately 64% of patients 1
• Monitor liver function tests regularly due to hepatotoxicity risk 1
• Alternative: Osilodrostat (recently approved, rapid response, no hepatotoxicity or hypogonadism concerns) 1
• Metyrapone can be used but requires more frequent dosing 5

For Moderate-to-Severe Disease:

• Metyrapone provides rapid cortisol control within hours 5, 1
• Peak plasma concentration occurs approximately 1 hour after oral administration 6
• Terminal elimination half-life is 1.9 hours for metyrapone and 4 hours for active metabolite metyrapol 6
• Often combined with ketoconazole to maximize adrenal blockade or allow lower doses of both drugs 5, 1

For Very Severe/Life-Threatening Hypercortisolism:

• Combination therapy with multiple steroidogenesis inhibitors 5
• If unresponsive to optimized medical therapy, bilateral adrenalectomy should be considered to avoid worsening outcomes 5
• Etomidate can be used if hospitalized and unable to take oral medications 5

Rational Combination Therapy Regimens

Ketoconazole + Metyrapone is the most commonly used combination to maximize adrenal blockade 5, 1

• Allows lower doses of both drugs, reducing individual toxicities 5
• Monitor for overlapping toxicities and drug-drug interactions 1

Alternative combinations:

• Ketoconazole + osilodrostat 1
• Steroidogenesis inhibitor + tumor-targeting agent (e.g., ketoconazole + cabergoline if visible tumor present) 5

Critical Monitoring Parameters

Biochemical Monitoring:

• Measure urinary free cortisol (UFC) regularly to assess treatment response 1
• Multiple serial tests of both UFC and late-night salivary cortisol 5
• Exception: Cortisol measurements are not reliable when using mifepristone 5

Clinical Monitoring:

• Assess improvement in phenotype, weight, hypertension, glucose metabolism, and quality of life 1
• Monitor for signs of adrenal insufficiency (nausea, vomiting, abdominal pain, hypotension) 6

Tumor Surveillance:

• Monitor ACTH levels with adrenal-targeting agents 1
• Perform MRI 6-12 months after initiating treatment, then every few years 1
• If progressive tumor growth occurs, suspend medical treatment and reassess management 1

Special Considerations for Exogenous Steroid Use

If hypercortisolism is iatrogenic from steroid therapy:

• Gradual taper is essential to allow HPA axis recovery
• Patients on long-term or high-dose corticosteroids require vitamin D and calcium supplementation for osteoporosis prevention 5
• Monitor for diabetes mellitus development 5
• Consider stress-dose coverage during illness or procedures until HPA axis recovers

Critical Safety Warnings

Risk of Acute Adrenal Insufficiency:

• Metyrapone can induce acute adrenal insufficiency 6
• Patients should be counseled on symptoms: nausea, vomiting, abdominal pain, hypotension 6
• Immediate treatment with hydrocortisone, IV saline, and glucose is essential if overdose or acute insufficiency occurs 6

Drug-Specific Precautions:

• Metyrapone may cause dizziness and sedation; advise patients not to drive until effects pass 6
• Patients with cirrhosis may have impaired response to metyrapone 6
• Ketoconazole requires regular liver function monitoring 1

When to Escalate Care

Consider bilateral adrenalectomy if:

• Medical therapy fails to control severe hypercortisolism despite optimized combinations 5
• Progressive tumor growth on imaging despite medical management 1
• Life-threatening complications of hypercortisolism develop 5