Can a liver granuloma be a source of ectopic Adrenocorticotropic Hormone (ACTH) production in a patient with a normal pituitary Magnetic Resonance Imaging (MRI) and adrenal Computed Tomography (CT) scan, but a positive Dexamethasone Suppression Test (DST)?

From the Guidelines

Yes, a liver granuloma can potentially be a source of ectopic Adrenocorticotropic Hormone (ACTH) production in a patient with a normal pituitary Magnetic Resonance Imaging (MRI) and adrenal Computed Tomography (CT) scan, but a positive Dexamethasone Suppression Test (DST). Ectopic ACTH syndrome accounts for approximately 10-20% of Cushing's syndrome cases, and while bronchial carcinoids and small cell lung cancers are the most common sources, hepatic neuroendocrine tumors or granulomas can occasionally secrete ACTH 1. For this patient, further evaluation should include a chest and abdominal CT with contrast, octreotide scintigraphy, or a gallium-68 DOTATATE PET scan to better visualize neuroendocrine tissue.

Diagnostic Approach

• Bilateral inferior petrosal sinus sampling (BIPSS) would be essential to confirm the ectopic source by demonstrating lack of central-to-peripheral ACTH gradient 1.
• The use of 68Ga-DOTATATE PET scan can be useful in guiding clinical management, as it can localize about 65% of ectopic ACTH-secreting neuroendocrine tumors, including those not seen or not definitively identified on cross-sectional imaging 1.
• A combination of three or four tests, specifically CRH and desmopressin stimulation plus MRI, followed by whole-body CT if diagnosis is equivocal, can correctly diagnose Cushing's disease in approximately half of patients, potentially eliminating the need for IPSS 1.

Treatment Approach

• If the liver granuloma is confirmed as the ACTH source, surgical resection would be the first-line treatment if feasible.
• If surgery isn't possible, medical therapy with steroidogenesis inhibitors like ketoconazole or metyrapone can help control cortisol levels.
• The patient should be monitored regularly with 24-hour urinary free cortisol measurements and clinical assessment of Cushing's symptoms.

Key Considerations

• The diagnosis and management of Cushing's syndrome require a thorough investigation, especially when common sources have been ruled out 1.
• The use of novel screening and diagnostic modalities, such as 68Ga-DOTATATE PET scan, can improve the accuracy of diagnosis and guide clinical management 1.

From the Research

Ectopic Adrenocorticotropic Hormone (ACTH) Production

• Ectopic ACTH syndrome is a rare cause of Cushing's syndrome, accounting for a small proportion of all cases 2.
• The syndrome can be caused by various tumors, including neuroendocrine tumors, carcinoids, and small cell lung cancer, which secrete ACTH or corticotropin-releasing hormone (CRH) 3, 4, 2.
• The diagnosis of ectopic ACTH syndrome can be challenging, and a high degree of clinical suspicion is required, along with concordance between biochemical, imaging, and pathology findings 4.

Liver Granuloma as a Source of Ectopic ACTH Production

• There is no direct evidence in the provided studies to suggest that a liver granuloma can be a source of ectopic ACTH production.
• However, the studies do highlight the importance of considering rare and unusual sources of ectopic ACTH production, including thymic neuroendocrine tumors and pancreatic neuroendocrine tumors 5, 4.
• In patients with ectopic Cushing's syndrome, a systematic approach considering all potential sources of ACTH production is crucial to avoid misdiagnosis 3, 5.

Diagnostic Challenges

• The diagnosis of ectopic ACTH syndrome can be difficult, especially in cases where the source of ACTH production is occult or not easily localized 5, 2.
• Inferior petrosal sinus sampling for ACTH after ovine-CRH stimulation can help establish the diagnosis in over 90% of cases 2.
• Molecular imaging with gallium-68 somatostatin receptor-targeted positron emission tomography (PET)/CT and fluorine-18 fluorodeoxyglucose PET/CT can also be useful in localizing the source of ectopic ACTH production 5.