Spurious Plasma Adrenocorticotropic Hormone Level in a Patient With Adrenal Cushing Syndrome

Background Endogenous Cushing syndrome results from excessive cortisol production by the adrenal glands and is characterized by the loss of circadian rhythm of cortisol secretion and negative feedback regulation of the hypothalamic-pituitary-adrenal axis. This condition is broadly subtyped into adrenocorticotropic hormone (ACTH)–dependent and ACTH-independent types based on ACTH measurement. A plasma ACTH level <5 pg/mL suggests ACTH-independent Cushing syndrome (adrenal source), while a level >15 pg/mL suggests ACTH-dependent Cushing syndrome (pituitary or ectopic source). A certain immunoassay platform (Immulite 1000 [Siemens AG]) has a known positive ACTH bias, so a patient with ACTH-independent Cushing syndrome may be falsely labeled as having ACTH-dependent disease. This misclassification can lead to unnecessary investigations and interventions such as pituitary imaging, inferior petrosal sinus sampling, and even pituitary surgery. Case Report A 41-year-old male with a history of right open adrenalectomy presented for evaluation of recent-onset abdominal distension, weight gain, facial fullness, and fatigue. He also had newly diagnosed diabetes and hypertension. Physical examination revealed facial fullness with plethora, centripetal obesity, and dilated abdominal veins. Biochemical evaluation revealed endogenous Cushing syndrome (late-night serum cortisol of 30.9 μg/dL, late-night salivary cortisol of 3.42 μg/dL, and overnight dexamethasone suppression test cortisol of 30.5 μg/dL), with hypokalemia (3.2 mmol/L) and grossly elevated dehydroepiandrosterone sulphate (2,857 μg/dL). Plasma ACTH as measured by the Immulite 1000 was unsuppressed (17.2 pg/mL) in the face of hypercortisolism, indicating ACTH dependence. Because of the patient9s history and the known positive bias of plasma ACTH measurements from the immunoassay platform used for the assay, abdominal and thoracic imaging was performed, revealing multiple metastatic deposits in the liver and lungs. The left adrenal gland was atrophic, confirming that ACTH was truly suppressed. A diagnosis of metastatic adrenocortical carcinoma with adrenal Cushing syndrome was considered, and a chemotherapy regimen comprising etoposide, doxorubicin, and cisplatin was initiated. Ketoconazole was added later to control hypercortisolism. The patient took ketoconazole for 1 month and was then lost to follow-up. Conclusion Spurious plasma ACTH measurements can occur with the Immulite 1000 and falsely indicate ACTH-dependent Cushing syndrome. Consequently, the clinical context must be carefully considered when evaluating patients with hypothalamic-pituitary-adrenal axis disorders.