Why was an adrenal etiology considered when the Adrenocorticotropic hormone (ACTH) level was not suppressed, suggesting a pituitary or ectopic source?

Understanding ACTH Levels in Cushing Syndrome Diagnosis

Non-suppressed ACTH levels indicate a pituitary or ectopic source of Cushing syndrome, not an adrenal etiology. 1

Differential Diagnosis Based on ACTH Levels

• ACTH-dependent Cushing syndrome (non-suppressed ACTH) indicates either:
  • Cushing disease (pituitary source) - most common cause
  • Ectopic ACTH syndrome - from tumors outside the pituitary 1
• ACTH-independent Cushing syndrome (suppressed ACTH) indicates:
  • Adrenal source (adenoma, carcinoma, or bilateral hyperplasia) 1

Diagnostic Algorithm for ACTH-Dependent Cushing Syndrome

1. Measure morning plasma ACTH levels:

   • Detectable ACTH (>5 ng/l or >1.1 pmol/l) confirms ACTH-dependent Cushing syndrome 1
   • Low or undetectable ACTH would suggest adrenal etiology 1

2. Dynamic testing to differentiate pituitary from ectopic source:

   • CRH stimulation test: >20% increase in cortisol suggests pituitary source 1
   • Desmopressin stimulation: increased ACTH and cortisol suggests pituitary source 1
   • High-dose dexamethasone suppression test (less accurate but still used in some centers) 1

3. Imaging studies:

   • Pituitary MRI (preferably 3T) for suspected Cushing disease 2
   • Neck-to-pelvis thin-slice CT if ectopic ACTH syndrome is suspected 1
   • 68Ga-DOTATATE PET/CT for localizing ectopic ACTH-secreting tumors (65% detection rate) 1, 2

4. Bilateral inferior petrosal sinus sampling (BIPSS):

   • Gold standard to differentiate pituitary from ectopic source 1
   • Central-to-peripheral ACTH gradient ≥2 before or ≥3 after CRH/desmopressin stimulation confirms pituitary source 1
   • Gradient <2 before or <3 after stimulation suggests ectopic source 1

Important Clinical Considerations

• No single test is 100% accurate for differentiating pituitary from ectopic ACTH sources; results may be discordant in up to one-third of patients 1

• BIPSS indications:

  • Pituitary lesions <6 mm on MRI
  • Negative or equivocal MRI
  • Discordant biochemical and imaging findings 2

• BIPSS not necessary when:

  • Pituitary tumor ≥10 mm is detected on MRI and dynamic testing results are consistent with Cushing disease 1
  • For tumors 6-9 mm, opinions differ but most recommend BIPSS 1

• Common pitfalls in diagnosis:

  • Well-differentiated neuroendocrine tumors may express receptors similar to pituitary tumors, leading to false-positive results on dynamic testing 1
  • Incidental non-functioning pituitary adenomas can coexist with ectopic ACTH sources 3
  • Ectopic pituitary adenomas (outside the sella) can secrete ACTH and cause Cushing syndrome 4, 3

• Clinical features that suggest ectopic source:

  • Male gender with very high UFC levels
  • Profound hypokalemia 1
  • Rapid onset of symptoms 3

Conclusion

The distinction between pituitary and ectopic sources of ACTH-dependent Cushing syndrome requires careful interpretation of biochemical testing and imaging. Non-suppressed ACTH levels definitively rule out an adrenal etiology and point toward either a pituitary or ectopic source. 1