Hypokalemia, metabolic alkalosis, and hypertension in a lung cancer patient

A 69-year-old man was admitted to hospital for the evaluation of refractory hypokalemia and metabolic alkalosis. The patient had a 1-year history of a stage pT4N0M1 non-small cell squamous lung carcinoma (NSCLC) that was managed by Pemetrexed (Alimta 500 mg/m2 every 21 days) for the last 6 months. The patient had a 45-pack/y history of smoking without history of alcohol abuse, hypertension, or diabetes mellitus. He was married, had 2 children without health problems and used to work as a truck driver. He had no family history of cancer or metabolic problems. He was in his usual state of health until 1 month before admission. His medication list contained only paracetamol every 6 h. Two weeks before admission, he was examined in the emergency department when his family noticed increasing muscle weakness. On admission in nephrology, blood pressure was 170/90 mm Hg, and heart rate was 76 beats per min. There was no peripheral edema, and his mucous membranes were dry. Skin color had recently become generally darker as confirmed by the patient. Cardiovascular and chest examination were unremarkable. Abdominal examination showed no central obesity, nor striae. Neurological examination showed normal reflexes and no localized sensory deficits. Bilateral proximal muscle weakness was noted: 4/5 and 3/5 in upper and lower limbs respectively. Routine peripheral blood and biochemical examination revealed hyperleukocytosis, hypokalemia, metabolic alkalosis, and hyperglycemia. Clinical and laboratory values are listed in Table 1. The patient was managed with oral and intravenous potassium supplementation without improvement. The primary diagnosis was severe dehydration associated with contraction metabolic alkalosis, hypokalemia, hypertension, and type 2 diabetes mellitus (fasting blood sugar 11 mmol/l with glycosuria at 18.6 mmol/l). Supportive treatments included hydration, potassium supplementation, antihypertensive, and oral antidiabetic medications. His alkalosis and hypokalemia partially improved. Endocrine laboratory studies were performed; results are listed in Table 2. Doppler ultrasound study of the renal arteries and adrenal computed tomography (CT) scan were performed. In front of a renal hypokalemia associated with hypertension, excess mineralocorticoids should be evoked including primary and secondary hyperaldosteronism or pseudohyperaldosteronism (algorithm 1). As aldosterone and renin level were normal, primary and secondary hyperaldosteronism could be ruled out. In what concerns the third heterogenous group of pseudohyperaldosteronism, Liddle's syndrome and congenital adrenal hyperplasia can be ruled out because of the late occurrence of signs and absence of suggestive family history. There were no liquorice intake reported by the patient, furthermore these patients usually have markedly lowered renin aldosterone levels. The diagnosis of Cushing syndrome (CS) became then plausible. Markedly elevated serum cortisol (62.7 g/100 ml), adrenocorticotropic hormone (ACTH) level (380 pg/ml), and urine-free cortisol excretion rates (15,576 g/24 h) were found. An overnight dexamethasone suppression test (8 mg) reduced plasma cortisol levels to 61.2% of baseline values. CS was made. The generation and maintenance of hypokalemia, metabolic alkalosis, and hypertension in this patient were likely the result of sustained activation of circulating cortisol. Abdominal and pelvic CT scans showed normal adrenal glands and confirm previously known hepatic metastases. Brain magnetic resonance imaging (MRI) showed normal pituitary gland and no cerebral metastases. These results supported the diagnosis of ectopic ACTH secretion. The patient was first managed with spironolactone and potassium supplementation reaching subnormal serum potassium (3.2 mmol/l) and bicarbonates (31 mmol/l) values, but he had no remission. He was then treated with metyrapone to counteract ectopic ACTH production. At 1 week after switching spironolactone for amiloride 10 mg and metyrapone 1000 mg/d in accordance to endocrine tests, he made a dramatic recovery: serum potassium levels increased to 4.1 mmol/l with serum carbon dioxide levels decreasing to 27 mmol/l. Hypertension control (average 120–130 mm Hg systolic blood pressure) was obtained by amlodipine 10 mg/d in addition to amiloride. Glycemic control was partial (treated fasting blood sugar 7.2 mmol/l) using repaglinide 1 mg TID (Novonorm). We described a case of CS. Because he had no pituitary adenoma and primary adrenal disorders, non-small-cell lung cancer (NSCLC) was suspected as the source of the excess ACTH. Tumors that paraneoplastically synthesize ACTH are far more likely to be malignant than pituitary tumors, with the consequence of rapid development of hypercortisolism. Exposure to high levels of glucocorticoids, mineralocorticoids, and adrenal androgens may therefore develop within a short time, and classical stigmata of CS may still be absent when this disease reaches its power to limit life. Hence, there are subtle clinical differences in patients with primary Cushing's disease and CS in excess ACTH secretion. Purple striae and buffalo hump are infrequent and the entire spectrum of features associated with ACTH excess are rarely seen in patients with underlying cancer.2 Hypokalemia and accompanying metabolic alkalosis are more common in ectopic ACTH syndrome than other forms of CS. Hypertensive crises and profound loss of potassium may lead to cardiac and vascular complications, including ventricular arrhythmias.3 In addition, polyglobulia with thrombocytosis and leukocytosis are typical signs for ectopic ACTH production. Finally marked suppression of the immune system may cause severe infections, which easily can lead to septicemia and opportunistic infections. When ACTH-dependent CS is diagnosed, it is necessary to confirm or rule out ectopic ACTH production based on several diagnostic tests such as 24-h urine-free cortisol levels or the dexamethasone suppression. On another hand, paraneoplastic syndrome should be strongly suspected over primary CS in the setting of lung cancer. In our patient, a primary pituitary source was excluded based on laboratory and imaging studies. In this patient, plasma ACTH levels were markedly elevated (Table 2). Overnight administration of dexamethasone (8 mg) reduced the plasma cortisol level to 61.2% of baseline. (reduced by 38.8%). With overnight dexamethasone testing, a decrease in cortisol level to less than 50% of baseline is indicative of pituitary-dependent disease. A negative response is considered lack of suppression to less than 50% of baseline and can occur with adrenal or ectopic tumor production.4 Overnight dexamethasone testing has an approximate sensitivity of 57–92% and a specificity of 57–100% in diagnosing pituitary disease.5 It was found that precursors of ACTH were markedly elevated in patients with ectopic ACTH syndrome, in contrast to patients with Cushing's disease, and that the concentration of ACTH precursors correlated with plasma cortisol levels in patients with ectopic ACTH syndrome.6 Otherwise, aggressive pituitary tumors producing high molecular weight adrenocorticotropin-related peptides have been described, presenting both with and without the clinical features of CS.7, 8 The cortisol level in our patient was partially suppressed (38.8% decrease) with an overnight dose of dexamethasone (8 mg), but only to 61.2% of baseline that was not enough to substantiate a positive response. This degree of suppression is consistent with an ectopic source of ACTH secretion. In addition, normal brain MRI findings essentially excluded pituitary or hypothalamic pathological states. Although NSCLC was infrequently associated with ectopic ACTH secretion, it is likely to be the cause of paraneoplastic Cushing syndrome in our patient. To date, immunohistological staining of suspected ectopic ACTH-secreting tumors has rarely shown hormone immunoreactivity. Evidence suggests that ACTH levels correlate with the degree of metastasis or rapid growth.9 Immunocytochemistry was performed on 18 tumors causing ectopic CS. In that study, patients were divided into two groups; those with clinical signs of an underlying tumor (group 1) and those with occult tumors not detected by radiological examination (group 2). Of note, there was one pancreatic endocrine tumor in each group and no prostate carcinomas in either group. Rapidly growing tumors with widespread metastases found in group 1 were associated with the greatest ACTH levels (662–2340 ng/l). Conversely, occult tumors in group 2 were associated with the lowest ACTH levels (82–399 ng/l).9 On the basis of this observation, it is unlikely that our patient, who showed extremely high levels of ACTH (>1300 pg/100 ml) had an occult tumor. The rapid onset of our patient's illness and excessively elevated ACTH levels were not indicative of a slow-growing tumor that might not be detected by CT scan or MRI. Thus, by exclusion, we believe that the high-grade, widely metastatic, prostatic tumor could have been responsible for the ectopic production of ACTH, although we cannot prove this point with absolute certainty. CT and MRI are the best imaging techniques for tumor localization they can identify lesions with diameters less than 0.5 cm, and their sensitivity approaches 100%.10, 11 However, because these tumors can remain occult, octreotide scintigraphy may be indicated to identify them. Glucocorticoids affect a variety of renal functions. Metabolic alkalosis and potassium depletion are the two most common acid base and electrolyte abnormalities associated with glucocorticoid excess. These are predominantly mediated by the direct effects of glucocorticoids in the kidney. The receptors for glucocorticoids are expressed in the proximal tubule and collecting ducts. Mineralocorticoid receptors are absent in the proximal tubule and are exclusively expressed in distal nephron segments. In the proximal tubule, glucocorticoids have been shown to have a direct effect on the luminal Na+/H+ exchanger. Approximately 80% of the filtered load of HCO3- is reabsorbed in the proximal tubule by a process of active acid secretion by the luminal membrane. The major mechanism for the transport of HCO3- across the basolateral membrane is by the electrogenic Na+:3HCO3- co-transporter (NBC). Recent molecular cloning experiments have identified the existence of three NBC isoforms (NBC-1, NBC-2, and NBC-3).13 Specifically, NBC-1 may be upregulated in metabolic acidosis and potassium depletion and in response to glucocorticoid excess and may be downregulated in response to HCO3- loading or alkalosis.14 Glucocorticoids but not mineralocorticoids enhance both mRNA expression and functional activity of renal proximal tubule NBC-1. Enhanced NBC activity could result in increased HCO3- reabsorption in proximal tubule in pathophysiological states associated with increased glucocorticoid production. Glucocorticoid excess is associated with potassium depletion or hypokalemia. This effect is predominantly thought to be by the 'spillover' effect of glucocorticoids onto the mineralocorticoid receptors, with resulting enhanced potassium secretion in the cortical collecting duct. Potassium deprivation increases HCO3- reabsorption in proximal tubule by enhancing NBC-1 expression and activity. The results further indicate that by inducing NBC-1 expression in medullary thick ascending limb (mTAL) and inner medullary collecting duct (IMCD), potassium deprivation enhances HCO3- reabsorption in these nephron segments. It becomes apparent that upregulation of NBC-1 is an early event and precedes the onset of hypokalemia,15 indicating that the signal responsible for enhanced NBC-1 expression is likely activated by intracellular potassium depletion rather than hypokalemia.16 Paraneoplastic CS is frequently seen in patients with SCLC. However, the incidence of paraneoplastic CS is 5% or less of all SCLC patients.12 In contrast, paraneoplastic CS is very rare in NSCLC including adenocarcinoma, and to our knowledge there are only a few reports of NSCLC associated with CS.20, 21, 22 The present patient had severe ACTH-dependent CS. Because he had no pituitary adenoma and primary adrenal disorders, adenocarcinoma of the lung was suspected as the source of the excess ACTH. An immunohistochemical study of ACTH with primary or metastatic tumor specimens was not performed. However, ACTH produced from a neoplasm has been shown to have a different structure than wild-type ACTH and the usual immunohistochemical staining with a polyclonal anti-ACTH antibody may not prove ACTH in tumor cells.23 Paraneoplastic Cushing syndrome caused by ectopic ACTH production can cause a poor clinical outcome due to various complications. SCLC patients with ectopic ACTH production have a much higher rate of complications during therapy than patients without ectopic ACTH production.12, 24 Treatment of the underlying malignancy is the primary management of the ectopic ACTH secretion. Medical therapy for ectopic ACTH production can be accomplished with the use of steroid synthesis inhibitors, such as ketoconazole,26 mitotane, metyrapone,27 octreotide,28 and aminoglutethemide,29 although successful treatment of the underlying malignancy is critically needed. Other medical interventions include potassium replacement and spironolactone. Ketoconazole (400–1200 mg/day), which acts by blocking corticosteroid production by inhibiting 17-hydroxylase and 11-hydroxylase, is the therapy of choice because of its low incidence of side effects. The dose–response relationship between ketoconazole and cortisol has not been well described in the literature. Ketoconazole has been reported to be persistently effective at 200–1200 mg/d, without escape from suppressive effect for prolonged use.30 Octeotride suppression of ACTH release has shown efficacy alone and in combination with ketoconazole.4 An alternative agent is metyrapone; however, clinical efficacy of this agent is less than that of ketoconazole, it lacks the antiandrogenic effect of ketoconazole, and it may cause hypokalemia as a side effect.27 Spironolactone, an aldosterone-receptor antagonist, is used to decrease urinary potassium wasting secondary to activation of mineralocorticoid receptors.31 In this patient, potassium replacement and spironolactone remained insufficient and amiloroide–metyrapone combination normalized serum potassium level. On another hand, ketoconazole decreased both cortisol and ACTH levels in 38% of the patients with ectopic ACTH secretion.32 In summary, we described a rare case of paraneoplastic CS seemingly associated with NSCLC. Early detection and appropriate treatment for this syndrome remains necessary even if it does not generally improve the poor clinical outcome.