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Hypokalemia associated with a solitary pulmonary nodule

Abstract Background: Differential diagnosis of hypokalemia and adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome often presents challenging in endocrinology and requires careful clinical, biochemical, radiological, and pathological investigations. Hypokalemia is a common abnormality and systematic approach is required to avoid delays in diagnosis of important underlying causes. Case Summary: A 49-year-old woman presented with moderate hypokalemia. Further evaluation showed hypercortisolism due to ectopic ACTH secretion. Chest computed tomography (CT) revealed a peripheral solitary pulmonary nodule. Excision biopsy of the nodule showed carcinoid tumor. After excision biopsy, all of the patient's symptoms improved and electrolytes and ACTH levels also became normal. Conclusion: Carciniod tumors should be considered as a differential diagnosis in patients presenting with hypokalemia and ectopic ACTH syndrome. Carcinoid tumor often present as solitary pulmonary nodule and excision biopsy can be curative.


Introduction
Hypokalemia is a common and often benign electrolyte abnormality. But hypokalemia associated with metabolic alkalosis and hypertension is highly suggestive for overproduction of adrenocorticotropic hormone (ACTH).
Cushing's syndrome due to cancer was first described in 1928 in a patient with small cell carcinoma of the lung. [1] In the 1960s ACTH was shown to be produced by nonpituitary tumors. [2] Various tumors can secret ectopic ACTH that small cell lung carcinoma, carcinoid tumors (especially of the lungs, thymus, and gastrointestinal tract), islet cell tumors, pheochromocytoma, and medullary thyroid carcinomas are the most frequent causes. [3] We describe a case with carcinoid tumor in lung periphery producing ACTH with unusual biochemical and imaging finding.

Case presentation
A 49-year-old woman with past medical history of diabetes mellitus and hypertension was admitted in the General Internal Medicine ward with chief complaint of abdominal pain, constipation, and malaise for 5 days. She also had history of unexplained weight gain since 2 months ago and denied any history of taking exogenous steroid or herbal medications. Family history was unremarkable.
Physical examination showed a body mass index (BMI) of 32 kg/m 2 , blood pressure equal to 140/90 mm Hg (on antihypertensive medications), abdominal obesity, decreased bowel sounds, and proximal muscle weakness of upper and lower extremities.
Hypothalamopituitary axis magnetic resonance imaging (MRI) with and without contrast was normal. To find the possible source of ectopic ACTH secretion, the spiral chest and abdominal and pelvic computed tomography (CT) scan requested. The finding was only a 17 Â 15 mm solitary peripheral pulmonary nodule in medial aspect of base of right lower lobe adjacent to the diaphragm (Fig. 1).
The functional imaging like positron emission tomography (PET) CT was not available. The pulmonary nodule was too small to biopsy. So, the patient underwent wedge resection with video-assisted thoracoscopic surgery as a diagnostic and possible therapeutic procedure. The nodule was excised with free margin. Histologic examination of the biopsy specimens showed carcinoid tumor.
One day after tumor resection the basal morning cortisol and plasma ACTH levels were significantly decreased to 8 mgr/dL (normal range: 5.5-28.7 mgr/dL) and 34.41 pg/mL (normal range: 8.3-57.8 pg/mL), respectively. Prednisolone was administered and tapered slowly in 3 months. Signs and symptoms of hypercortisolism (such as hypokalemia, proximal muscle weakness, skin darkening, and weight gain) recovered gradually. Now after 6 months of operation she is well with no complaint, normal K levels, controlled blood sugar, normal suppression of serum cortisol level with low-dose dexamethasone suppression test, and normal chest CT.

Discussion
The causes of endogenous ACTH-dependent Cushing's syndrome are Cushing's disease (pituitary adenoma) in about 80% to 85% of cases and the remaining 15% to 20% are due to ectopic secretion by nonpituitary tumors. [3,4] Hypokalemia is much more prevalent in Cushing's syndrome due to ectopic ACTH secretion than other causes of Cushing's syndrome. However, hypertension is similar between the 2 subgroups. [5] Typically, patients with ectopic ACTH tumors have high ACTH levels and cortisol levels fail to suppression with high doses of dexamethasone. However, 20% to 40% of patients with ectopic ACTH demonstrates cortisol suppression on high-dose dexamethasone. [6] So after normal result of pituitary MRI, we evaluate the patient for ectopic source of ACTH. Axial imaging with thin-cut multislice CT of chest and abdomen or MRI of the thorax has the highest detection rate for ectopic ACTH syndrome. [3] The most common causes of ectopic ACTH are small-cell carcinoma of the lung and bronchial carcinoid tumors. [3] Bronochpulmonary carcinoid tumors are subclassified by the World Health Organization into typical and atypical carcinoids, according to histopathologic criteria: Typical carcinoids with slow growth that include 90% of lung carcinoids and atypical types grow a little faster with more likely spread to other organs and commonly located in periphery. [7] Small peripheral bronchial carcinoids can be missed easily on chest CT scans due to poor inspiratory effort, abdominal fat, and basal atelectasis. [8] So using a modern multidetector highresolution CT with 2.5 mm slices from lung apex to iliac crests is recommended. [9] With advances in medical and surgical treatments, survival rates for patients with ectopic ACTH have increased. Prognosis depends on the primary tumor histology. Patients with bronchial carcinoids have the best prognosis and considered as a low to moderate grade malignancy. [9] In conclusion, the differential diagnosis of ACTH-dependent Cushing's syndrome often presents challenging in endocrinology and requires careful clinical, biochemical, radiological, and pathological investigations. Carciniod tumors as a treatable cause of hypokalemia and ectopic ACTH syndrome presented as a small peripheral solitary pulmonary nodule should not be missed in clinical practice.