What diagnostic tests and treatment options are recommended for a patient suspected of having Cushing's disease with a rash on the bilateral arms?

Diagnostic Approach for Cushing's Disease

For patients with suspected Cushing's disease, the recommended diagnostic workup includes a stepwise approach starting with screening tests to confirm hypercortisolism, followed by tests to determine the source of excess cortisol production, with particular attention to any skin manifestations including rashes on bilateral arms. 1

Initial Screening Tests for Hypercortisolism

When clinical suspicion for Cushing's syndrome exists, the following first-line screening tests should be ordered:

1. Late night salivary cortisol (LNSC) - At least 2 measurements on consecutive days

   • Easiest for patient collection
   • High sensitivity (95%) and specificity (100%) 1

2. 24-hour urinary free cortisol (UFC) - Average of 2-3 collections

   • Elevated levels indicate Cushing's syndrome
   • Values >193 nmol/24h (>70 μg/m²) are diagnostic 1

3. Overnight 1mg dexamethasone suppression test (DST)

   • Failure to suppress cortisol to <50 nmol/L (<1.8 μg/dL) suggests Cushing's syndrome
   • Consider measuring dexamethasone level along with cortisol to improve test interpretability 1

Determining the Source of Hypercortisolism

After confirming hypercortisolism, determine the cause with:

1. Plasma ACTH measurement

   • Normal/elevated ACTH (>1.1 pmol/L or >5 ng/L): ACTH-dependent Cushing's (pituitary or ectopic source)
   • Suppressed ACTH: ACTH-independent Cushing's (adrenal source) 1

2. For ACTH-dependent cases:

   • Pituitary MRI with contrast to detect pituitary adenoma
   • CRH stimulation test - ≥20% increase in cortisol suggests pituitary source 1
   • Bilateral inferior petrosal sinus sampling (IPSS) - Required for:
     • Lesions <6mm on MRI
     • Equivocal MRI findings
     • Discordant biochemical results 1

3. For ACTH-independent cases:

   • Adrenal CT or MRI to identify adrenal adenoma or carcinoma 1

Evaluation of Skin Manifestations

The presence of a rash on bilateral arms should be carefully evaluated as it may be:

1. A manifestation of hypercortisolism - Cushing's syndrome can cause skin changes including:

   • Thinned, fragile skin
   • Easy bruising
   • Livid (purplish) striae
   • Acne
   • Fungal infections 1, 2

2. An unrelated dermatological condition requiring separate evaluation

Diagnostic Pitfalls to Avoid

• False positives in screening tests can occur with:

  • Severe obesity
  • Uncontrolled diabetes
  • Pregnancy
  • Polycystic ovary syndrome
  • Depression
  • Alcoholism 1

• Cyclic Cushing's syndrome may be missed if testing occurs during periods of normal cortisol production - repeat testing may be necessary 1, 2

• Medications that can interfere with dexamethasone metabolism (e.g., estrogen-containing oral contraceptives) may cause false positive DST results 1

Treatment Considerations

If Cushing's disease is confirmed:

1. First-line treatment: Transsphenoidal surgery to remove pituitary adenoma 1

2. Medical therapy options when surgery is not possible or unsuccessful:

   • Ketoconazole (400-1200 mg/day)
   • Osilodrostat (2-7 mg/day)
   • Metyrapone (500 mg/day to 6 g/day) - inhibits 11-beta-hydroxylation in adrenal cortex 1, 3

3. Radiation therapy for persistent or recurrent disease 1

By following this systematic diagnostic approach, Cushing's disease can be accurately diagnosed and appropriate treatment initiated to reduce morbidity and mortality associated with chronic hypercortisolism.