Immediate Workup for ACTH-Dependent Cushing Syndrome
This patient requires immediate 24-hour urinary free cortisol collection to confirm true hypercortisolism, followed by pituitary MRI and likely bilateral inferior petrosal sinus sampling (BIPSS), as the combination of elevated cortisol (29 mcg/dL) with normal (detectable) ACTH definitively indicates ACTH-dependent Cushing syndrome—not a primary psychiatric disorder. 1
Why This Is ACTH-Dependent Cushing Syndrome
The biochemical pattern is diagnostic:
- Elevated morning cortisol with detectable/normal ACTH rules out primary adrenal causes (which would suppress ACTH to undetectable levels) and confirms ACTH-dependent hypercortisolism 1, 2
- Normal ACTH in the setting of hypercortisolism indicates either pituitary adenoma (Cushing disease) or ectopic ACTH production from tumors in lung, thyroid, pancreas, or bowel 1, 2
Clinical Presentation Matches Cushing Syndrome
Her symptoms are entirely consistent with hypercortisolism, not primary psychiatric disease:
- Significant unintentional weight loss occurs in 20% of Cushing syndrome patients despite classic teaching of weight gain 1
- Persistent anxiety and cognitive impairment are direct manifestations of hypercortisolism, not treatment-refractory psychiatric illness 1
- Paresthesias may represent hypercortisolism-induced proximal muscle weakness and myopathy 1
- Impaired fasting glucose (116 mg/dL) and mild inflammatory markers (ESR 29, CRP 15) are consistent with hypercortisolism-induced hyperglycemia and inflammation 1
Algorithmic Diagnostic Workup
Step 1: Confirm True Hypercortisolism
- Obtain 24-hour urinary free cortisol immediately to distinguish true hypercortisolism from stress-related elevation 1, 2
Step 2: Localize ACTH Source
- Order pituitary MRI with sellar cuts protocol as the first imaging study (sensitivity 63% for detecting pituitary adenomas) 1, 2
- If MRI is negative or equivocal, proceed directly to BIPSS, which is the gold standard with 95% diagnostic accuracy 1, 2
- Central-to-peripheral ACTH ratio ≥2:1 before CRH/desmopressin and ≥3:1 after stimulation confirms pituitary Cushing disease 1, 2
Step 3: If Ectopic Source Suspected
- Obtain chest/abdominal/pelvic CT or whole-body PET/CT to locate ectopic tumors (detection rate 80%) 1, 2
Treatment Based on Source
For Pituitary Cushing Disease (Most Likely)
- Transsphenoidal surgical resection is first-line treatment when adenoma is identified (80% success rate) 1, 2
- Postoperative corticosteroid supplementation is mandatory until HPA axis recovery 1, 2
- Ketoconazole 400-1200 mg/day is preferred medical therapy if surgery is delayed or unsuccessful (70% response rate, relatively tolerable side effects) 1, 2
For Ectopic ACTH Production
- Surgical removal of ectopic tumor if possible 2
- Bilateral laparoscopic adrenalectomy if tumor is unresectable 2
- Medical management with ketoconazole or mitotane 2
Critical Monitoring During Workup
- Screen for hypertension, hypokalemia, and hyperglycemia (present in 50% of cases) 1
- Monitor for adrenal crisis risk during BIPSS procedure (10% risk) 1
- Follow-up imaging and biomarkers every 3-6 months if treatment is delayed 1, 2
- Consider supplementing B12 to >400 pg/mL (current level 385 pg/mL) to address potential contribution to paresthesias (50% response rate) 1
Critical Pitfalls to Avoid
- Do not attribute symptoms to primary psychiatric disease when objective evidence of hypercortisolism exists (causes 6-month diagnostic delay) 1
- Do not rely solely on pituitary MRI, as 37% of pituitary adenomas are not visible on imaging, requiring BIPSS for diagnosis 1
- Do not delay workup for "psychiatric stabilization", as untreated Cushing syndrome causes progressive morbidity with 10% mortality 1
- Do not confuse pseudo-Cushing states (depression, alcoholism, obesity) with true Cushing syndrome (20% misdiagnosis rate) 1, 2
Regarding Her Psychiatric Medications
Her persistent anxiety despite multiple SSRI trials (Prozac, Lexapro) and adjunctive agents (Depakote, Buspar, Adderall, Lybalvi) strongly suggests that the anxiety is a manifestation of untreated hypercortisolism, not treatment-refractory psychiatric illness 1. The cognitive impairment following polypharmacy discontinuation likely represents unmasking of cortisol-induced cognitive dysfunction rather than medication withdrawal effects.