The Importance of Early Diagnosis of Cushing Disease

Endogenous Cushing syndrome (CS) is an underdiagnosed endocrinologic disorder with an estimated incidence of 0.2-5 per million people per year. CS may present with variable clinical manifestations resulting from excess and continuous secretion of cortisol. Early recognition is key to preventing CS-associated high morbidity and mortality when untreated. Hypercortisolemia may be independent or dependent on the adrenocorticotropic hormone (ACTH) being ACTH-secreting pituitary adenoma, also known as Cushing disease (CD), the most common cause of the latter. Trans-sphenoidal surgery (TSS) is the treatment of choice for CD, though alternative therapies are often needed considering CD high recurrence rate.

Case Description :

A 47-year-old Hispanic woman with a history of obesity, diabetes mellitus, hyperlipidemia, and hypertension presented with a three-month history of hypokalemia episodes, proximal muscle weakness, and facial swelling. Endogenous CS was suspected. Work-up revealed a basal cortisol level of 70.7 ug/dL after a low-dose dexamethasone suppression test. CS was further confirmed with a 24-hour urinary free cortisol level of 3,630 mcg/24h. ACTH and dehydroepiandrosterone-sulfate (DHEA-S) levels of 251 pg/mL and 2005 ug/dL, respectively, were highly indicative of ACTH-dependent CS. The high-dose dexamethasone suppression test resulted in more than 50% reduction in plasma cortisol, suggesting CD. Pituitary magnetic resonance imaging (MRI) revealed a macroadenoma of the pituitary gland of 11 x 9.9 x 8.2 mm with extension into the left cavernous sinus. The patient underwent inferior petrosal sinus sampling (IPSS) which confirmed CD. Subsequently, tumor resection via endoscopic TSS was performed, and cytopathology tested positive for ACTH with a Ki-67 index of 10-15%. The immediate postoperative biochemical response showed a basal cortisol level of 14.5 ug/dL and an ACTH level of 66.5 pg/mL.

Discussion :

CS diagnosis may be difficult in the absence of overt clinical manifestations, particularly, as symptoms overlap with other systemic conditions, such as diabetes mellitus, obesity, and hypertension. CS diagnosis requires a biochemical confirmation of hypercortisolism. Differentiating CD from ectopic ACTH syndrome (EAS) is a greater challenge, and involves dynamic testing, imaging studies, and occasionally invasive testing. CD is usually identified via pituitary MRI and bilateral IPSS. CD accounts for 70% of ACTH-dependent CS carrying a mortality rate of 50% in 5 years if untreated. CD carries a high recurrence rate, and long-term biochemical remission is difficult to achieve despite apparent successful initial surgical intervention. For this reason, further interventions such as pituitary radiation, bilateral adrenalectomy, and cortisol-lowering pharmacologic management must be considered. Possible predictor factors of recurrence include undetectable adenoma on preoperative MRI, high immunopositivity for Ki-67 ( >3%), tumor invasion beyond the sella, and elevated postoperative ACTH. Tumor size appears to have a clear impact on remission rate although it does not have a direct correlation with disease recurrence.