Kolin Hoff, MDAssistant Professor of Clinical Medicine
Hospital of the University of Pennsylvania
The patient in this case is most interesting for representing the broad clinical spectrum possible in Cushing's syndrome. His clinical presentation was most remarkable for weight loss, hypokalemic alkalosis, hyperglycemia, and marked edema. Such a presentation is more common in the ectopic adrenocorticotropic hormone (ACTH) syndrome that is caused by highly malignant tumors (eg, small-cell lung carcinoma) than in the more indolent neuroendocrine tumors (eg, carcinoid) in which ectopic ACTH syndrome often presents with the typical cushingoid features of central obesity, moon facies, cervical fat pad, purple striae, and hirsutism. His edema and hypokalemic alkalosis are very suggestive of ectopic ACTH syndrome.
Hypokalemic alkalosis is seen in 74% to 95% of patients with ectopic ACTH syndrome but in less than 10% of those with Cushing's disease.1,2 This is because of the higher cortisol levels seen in ectopic ACTH syndrome that overwhelm the 11-beta-hydroxysteroid dehydrogenase enzyme, resulting in hypertension, edema, and hypokalemia as a result of the mineralocorticoid effects of cortisol.3 Atypically, this patient did not have hyperpigmentation, which often occurs in malignant ectopic ACTH syndrome as a result of the markedly elevated ACTH levels typically seen in these patients.
This patient's markedly elevated 24-hour urinary free cortisol is diagnostic of Cushing's syndrome, and the elevated ACTH levels classifies his syndrome as ACTH-dependent. In cases with less robust urinary cortisol elevations, this test may need to be repeated on several occasions for confirmation of the diagnosis of Cushing's syndrome. After ACTH-dependent Cushing's syndrome is established, the clinical presentation and either the high-dose dexamethasone suppression test (HDDST) or the corticotropin- releasing hormone stimulation test can be used to guide further testing and imaging. Findings suggestive of Cushing's disease (pituitary source of ACTH) should prompt magnetic resonance imaging (MRI) scanning of the pituitary. Microadenomas (<10 mm) account for 90% of Cushing's disease; therefore the finding of a pituitary lesion larger than 6 mm in this scenario may be diagnostic of Cushing's disease.4 However, it should be noted that 10% of patients have incidental pituitary lesions on MRI, most of which are smaller than 5 mm.5 Therefore, in cases not clearly consistent with Cushing's disease, further testing is warranted to evaluate for ectopic ACTH syndrome.
A recent review of ectopic ACTH syndrome cases suggests the preferred test to differentiate Cushing's disease from ectopic ACTH syndrome is inferior petrosal sinus sampling (IPSS).2 In this retrospective review of 90 patients with ectopic ACTH syndrome, one third had normal basal ACTH levels, and 26% had an abnormal pituitary MRI, both of which may lead to the erroneous diagnosis of Cushing's disease. Pulmonary carcinoid, the most common cause of ectopic ACTH syndrome, was the most frequent diagnosis in patients who responded to HDDST and was seen in 14% to 31% of all the cases. IPSS was found to have a sensitivity and specificity of 94% for ruling out Cushing's disease.2
Localization of the ACTH-secreting tumor is often difficult and may require multiple modalities, including computed tomography, MRI, and octreotide scanning to lessen the likelihood of false-positive results by a single imaging technique.2 Optimal treatment for ectopic ACTH syndrome is dependent on the ability to localize the source of ACTH. Surgical resection of the source may be curative in many cases. In other cases, treatment by bilateral adrenalectomy or steroidogenesis inhibitors may need to be considered as options or to control the hypercortisolemia during the localization process. Patients with ectopic ACTH syndrome caused by occult neuroendocrine tumors have a more favorable prognosis than cases caused by small-cell lung cancer, medullary carcinoma of the thyroid, or gastrinoma.2
It is regrettable that the patient presented in this case was lost to follow-up. He was started on ketoconazole, an inhibitor of steroid production; this should have lowered his cortisol levels and stabilized his condition, allowing for therapeutic intervention to definitively treat his underlying olfactory neuroblastoma and ectopic ACTH syndrome.
1. Howlett TA, Drury PL, Perry L, et al. Diagnosis and management of ACTH-dependent Cushing's syndrome: comparison of the features in ectopic and pituitary ACTH production. 1986;24:699-713.
J Clin Endocrinol Metab
2. Ilias I, Torpy DJ, Pacak K, et al. Cushing's syndrome due to ectopic corticotropin secretion: twenty years'experience at the National Institutes of Health. . 2005;90:4955-4962.
J Clin Endocrinol Metab
3. Stewart PM, Walker BR, Holder G, et al. 11 beta-Hydroxysteroid dehydrogenase activity in Cushing's syndrome: explaining the mineralocorticoid excess state of the ectopic adrenocorticotropin syndrome. . 1995;80:3617-3620.
Williams Textbook of Endocrinology.
4. Stewart PM. The adrenal cortex. In: Larsen PR, Kronenberg HM, Melmed S, et al, eds. 10th ed. Philadelphia, Pa: WB Saunders; 2003:519-520.
J Clin Endocrinol
5. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing's syndrome: a consensus statement. . 2003;88:5593-5602.