Severe Refractory Hypokalemia Secondary to Paraneoplastic Cushing Syndrome in Small Cell Lung Cancer

Introduction: Hypokalemia is a frequent electrolyte disorder in hospitalized patients. Severe, recurrent, and refractory hypokalemia warrants evaluation for uncommne causes. Paraneoplastic Cushing’s syndrome due to ectopic ACTH production is a rare complication of small cell lung cancer (SCLC) that may manifest primarily as severe hypokalemia. Case Description: A 62-year-old man with SCLC on durvalumab maintenance and whole-brain radiation therapy presented with recurrent, profound hypokalemia (K=1.6 mEq/L), prompting repeated hospitalizations. On the third hospitilization nephrology was consulted. Despite aggressive repletion, hypokalemia persisted, with renal potassium wasting confirmed by elevated urinary K+ excretion with 24-hour urinary K+ of 144 mmol/24 hours. Evaluation also revealed elevated ACTH (395 pg/mL) and serum cortisol level as high as (139 μg/dL), with 24-hour urine free Cortisol level of 20,486 mcg/24 hours, Low Renin, Aldostone levels (0.87 ng/ml/hr, 5 ng/dl) consistent with ectopic ACTH production. Management included initally extremely high doses of potassium replacment averaging 150 meq/24 hour. Subsequent to diagnosis, high-dose spironolactone and octreotide were added, leading to normalization of serum potassium. Discussion: This case highlights a rare endocrine complication of SCLC where hypokalemia was the predominant feature of ectopic ACTH syndrome. The diagnosis of the ectopic ACTH syndrome due to small cell lung cancer is suggested by hypokalemia, markedly increased 24-hour urinary free cortisol excretion, and elevated serum Cortisol and ACTH. The mechanism of hypokalemia is due to mineralocorticoid receptor hyperstimulation by cortisol. Renal mineralocorticoid receptors bind aldosterone and cortisol with similar affinity, however activation of the receptor by biologically active cortisol is normally limited due to i conversion of cortisol to inactive cortisone by the enzyme 11-beta-hydroxysteroid dehydrogenase type 2. In setting of extremely high cortisol levels due to nonstop ectopic ACTH, the metabolic capacity of the enzyme is exceeded, and excess cortisol stimulates the mineralocorticoid receptor. Ectopic ACTH syndrome should be considered in patients with SCLC and unexplained hypokalemia. A comprehensive workup is needed with timely nephrologic involvement to minimize repeated hospitlization.