Final Diagnosis -- Refractory hypokalemia due to Ectopic ACTH production


Refractory hypokalemia due to Ectopic ACTH

Based on the findings of hypokalemia, metabolic alkalosis, normal serum aldosterone, makedly elevated ACTH and cortisol levels and a history of widespread metastatic prostate carcinoma, the patient was diagnosed as refractory hypokalemia due to Ectopic ACTH production. The generation of hypokalemia, metabolic alkalosis and hypertension were likely the result of sustained activation of mineralocorticoid receptors by high levels of circulating cortisol.

His anemia and thrombocytopenia were thought to be secondary to marrow involvement by metastatic prostate carcinoma.


The various causes of hypercorticolism (Cushing's syndrome) are:

The serum electrolyte abnormalities are more common in ectopic ACTH syndrome than other forms of Cushing's syndrome.

Patients with ectopic ACTH syndrome have excessively high cortisol and elevated ACTH levels, hypokalemia, metabolic alkalosis and glucose intolerance. Only one of three patients with classic Cushing's syndrome has hypokalemia and metabolic alkalosis.

The approach to the diagnosis of various causes of hypercorticolism is shown below:

Etiology of Ectopic ACTH

Cushing's syndrome is caused by ectopic ACTH or corticotropin-releasing hormone (CRH) production in 10-20% of cases. The spectrum of non-pituitary tumors associated with ACTH production includes neuroendocrine tumors of respiratory and gastrointestinal tract, small cell lung cancer (SCLC), medullary thyroid carcinoma, and pheochromocytoma. Rarely prostatic tumors are associated with ectopic ACTH and/or CRH production.

Patient's with ectopic Cushing's syndrome secondary to carcinoma often lack the clinical manifestations associated with classic Cushing's syndrome. Presenting symptoms of ectopic ACTH can include rapid progressive weakness and weight loss.

Evidence suggests that ACTH levels correlate with the degree of metastasis or rapid tumor growth. Study by Coates et al in 18 tumors causing ectopic Cushing's syndrome found greatest ACTH levels in rapidly growing tumors with widespread metastasis.

Immunohistochemical staining of tumors for ACTH is insufficient evidence to rule out biosynthesis or activity of these hormones. It has been suggested that cells of highly malignant tumors causing Cushing's syndrome have a high secretion rate and do not store sufficient hormone for immunostaining.

Treatment of Ectopic ACTH

Surgical removal of the primary tumor is the treatment of choice for ectopic CS. However in as many as one third of patients surgery or radiation are not therapeutic options.

Medical interventions include potassium replacement and spironolactone and steroid biosynthesis inhibitors (ketoconazole, metyrapone, etomidate and mitotane).

Prognosis of patient's with ectopic ACTH is correlated with the histology of tumor and severity of hypercorticolism.


  1. Rickman T, Garmany R, Doherty T, Benson D, Okusa MD Hypokalemia, metabolic alkalosis, and hypertension:Cushing's syndrome in a patient with metastatic prostate adenocarcinoma. Am J Kidney Dis (2001) 37:838-846 Medline.
  2. Alwani RA, Neggers SJ, van der Klift M, Baggen MG, van Leenders GJ, van Aken MO, van der Lely AJ, de Herder WW, Feelders RA. Cushing's syndrome due to ectopic ACTH production by (neuroendocrine) prostate carcinoma Pituitary.2008 Mar 6.
  3. Coates PJ, Doniach I, Howlett TA, Rees LH, Besser GM. Immunocytochemical study of 18 tumours causing ectopic Cushing's syndrome. J Clin Pathol (1986) 39:955-960 Medline. doi:10.1136/jcp.39.9.955
  4. Isidori a M. Kaltsas GA, Pozza C, Frajese V, Newell-Price J, Reznek, RH, Jenkins PJ, Monson JP, Grossman a B, BesserGM. The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up. J Clin Endocrinol Metab (2006) 91:371-377 Medline. doi:10.1210/jc.2005-1542
  5. Salgado LR, Fragoso MC, Knoepfelmacher M, Machado MC, Domenice S, Pereira MA, De Mendonca BB Ectopic ACTH syndrome: our experience with 25 cases. Eur J Endocrinol (2006)155:725-733 Medline. doi:10.1530/eje.1.02278.

Contributed by Shveta Hooda MD and Mohamed A.Virji MD, PhD

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