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

2008; Elsevier BV; Volume: 76; Issue: 1 Linguagem: Inglês

10.1038/ki.2008.427

1523-1755

Hassane Izzedine, Benjamin Besse, Anne Lazareth, Edward Bourry, Jean Charles Soria,

Ion Transport and Channel Regulation

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.Table 1Clinical and laboratory valuesParametersValuesBefore admissionAdmissionReferencesWeek 8Week 4Week 2Blood pressure (mm Hg)130/70163/82170/95160/93Serum parameters Sodium139141142149132–145 (mmol/l) Potassium4.102.92.62.93.6–5.0 (mmol/l) Chloride1051009710295–105 (mmol/l) Bicarbonate2935363622–29 (mmol/l) Glucose59.7NA10.83.9–5.8 (mmol/l) Calcium2.322.172.192.252.10–2.65 (mmol/l) Phosphorus1.03NA0.880.660.80–1.40 (mmol/l) Uric acidNANANA136200–420 (μmol/l) Magnesium0.82NA0.850.800.74–0.85 (mmol/l) Urea4.83.23.54.102.5–7 (mmol/l) Creatinine0.850.920.890.6862–106 (mg/dl) OsmolalityNANANA314280–300 (mOsm/kg) White blood cell count630014,900990082604000–7000 per μl Arterial blood pHNANA7.527.507.38–7.42 Arterial PCO2NANA41.940.138–42 (mm Hg)Urine parameters SodiumNANA10982100–200 (mmol/l) PotassiumNANA404850–130 (mmol/l) OsmolalityNANANA460100–1400 (mOsm/kg)NA, not applicable. Open table in a new tab Table 2Endocrine laboratory valuesParametersValuesReferencesSerum Calcitonin 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.De Herder W. Krenning E. Malchoff C. et al.Somatostatin receptor scintigraphy: its value in tumor localization in patients with Cushing's syndrome caused by ectopic corticotropin or corticotropin-releasing hormone secretion.Am J Med. 1994; 96: 305-311Abstract Full Text PDF PubMed Scopus (99) Google Scholar,11.Kopf D. Bockisch A. Steinert H. et al.Octreotide scintigraphy and catecholamine response to an octreotide challenge in malignant phaeochromocytoma.Clin Endocrinol. 1997; 46: 39-44Crossref PubMed Scopus (56) Google Scholar However, because these tumors can remain occult, octreotide scintigraphy may be indicated to identify them. The pathophysiology of ectopic adrenocorticotropin syndrome in patients with cancer includes ectopic ACTH production, increased production of the ACTH precursor propiomelanocortin, and increased conversion of propiomelanocortin to ACTH. Up to 50% of small-cell lung cancer (SCLC) can be associated with ectopic ACTH production, but only 2% to 10% have clinically significant disease. Unlike syndrome of inappropriate antidiuretic hormone (SIADH), patients with ectopic ACTH secretion (EAS) from SCLC have poorer prognosis.12.Shepherd F.A. Laskey J. Evans W.K. et al.Cushing’ s syndrome associated with ectopic corticotropin production and small-cell lung cancer.J Clin Oncol. 1992; 10: 21-27Crossref PubMed Scopus (111) Google Scholar 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.Mahnensmith R.L. Aronson P.S. The plasma membrane sodium-hydrogen exchanger and its role physiological and pathophysiological processes.Circ Res. 1985; 56: 773-778Crossref PubMed Scopus (444) Google Scholar 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.Soleimani M. Burnham C.E. Physiologic and molecular aspects of the Na+:HCO3- cotransporter in health and disease processes.Kidney Int. 2000; 57: 371-384Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar 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.Amlal H. Habo K. Soleimani M. Potassium deprivation upregulates expression of renal basolateral Na(+)-HCO(3)(−) cotransporter (NBC-1).Am J Physiol Renal Physiol. 2000; 279: F532-F543PubMed Google Scholar indicating that the signal responsible for enhanced NBC-1 expression is likely activated by intracellular potassium depletion rather than hypokalemia.16.Ali R. Amlal H. Burnham C.E. et al.Glucocorticoids enhance the expression of the basolateral Na+:HCO3- cotransporter in renal proximal tubules.Kidney Int. 2000; 57: 1063-1071Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar Ectopic ACTH production is defined as the secretion of ACTH from a tumor outside the pituitary gland. The association between CS and tumors of ‘non-endocrine’ organs dates back to 1928.17.Brown W.H. A case of pluriglandular syndrome. Diabetes of beared women.Lancet. 1928; ii: 1022-1023Abstract Scopus (167) Google Scholar ‘Ectopic’ hormone production is said to account for between 12 and 25% of cases of CS, and small-cell carcinomas are the most commonly recognized tumor.18.Neville A.M. Ectopic production of hormones by tumours. Pathological aspects of the para-endocrine syndrome.Proc R Soc Med. 1972; 65: 55-59PubMed Google Scholar Other causes included nonpituitary neoplasms, mostly of neuroendocrine origin19.Odell W.D. Ectopic ACTH secretion. A misnomer.Endocrinol Metab Clin North Am. 1991; 20: 371-379PubMed Google Scholar (such as pancreatic islet cell tumors, bronchial, thymic, and gastrointestinal neuroendocrine cancers, bronchial adenomas, and medullary carcinomas of the thyroid or pheochromocytomas5.Newell-Price J. Trainer P. Besser M. et al.The diagnosis and differential diagnosis of Cushing's syndrome and pseudo-Cushing's states.Endocr Rev. 1998; 19: 647-672Crossref PubMed Scopus (641) Google Scholar or carcinomas (such as hypernephromas, colon cancers, and paragangliomas). Paraneoplastic CS is frequently seen in patients with SCLC. However, the incidence of paraneoplastic CS is 5% or less of all SCLC patients.12.Shepherd F.A. Laskey J. Evans W.K. et al.Cushing’ s syndrome associated with ectopic corticotropin production and small-cell lung cancer.J Clin Oncol. 1992; 10: 21-27Crossref PubMed Scopus (111) Google Scholar 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.Boon E.S. Leers M.P. Tjwa M.K. Ectopic Cushing's syndrome in a patient with squamous cell carcinoma of the lung due to CRF-like production.Monaldi Arch Chest Dis. 1994; 49: 19-21PubMed Google Scholar, 21.Myers E.A. Hardman J.M. Worsham G.F. et al.Adenocarcinoma of the lung causing ectopic adrenocorticotropic hormone syndrome.Arch Intern Med. 1982; 142: 1387-1389Crossref PubMed Scopus (11) Google Scholar, 22.Schott R. Chaouat A. Tavernier M. et al.Paraneoplastic hypercorticism associated with a bronchial adenocarcinoma.Rev Mai Respir. 1999; 16: 395-397PubMed Google Scholar 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.Singer W. Kovacs K. Ryan N. et al.Ectopic ACTH syndrome: clinicopathological correlations.J Clin Pathol. 1978; 31: 591-598Crossref PubMed Scopus (21) Google Scholar 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.Shepherd F.A. Laskey J. Evans W.K. et al.Cushing’ s syndrome associated with ectopic corticotropin production and small-cell lung cancer.J Clin Oncol. 1992; 10: 21-27Crossref PubMed Scopus (111) Google Scholar,24.Abeloff M.D. Trump D.L. Baylin S.B. Ectopic adrenocorticotrophic (ACTH) syndrome and small cell carcinoma of the lung: assessment of clinical implications in patients on combination chemotherapy.Cancer. 1981; 48: 1082-1087Crossref PubMed Scopus (24) Google Scholar In general, surgery is the therapy of choice in CS caused by ectopic ACTH secretion. However, in 30 percent of patients with CS,4.Rickman T. Garmany R. Doherty T. et al.Hypokalemia, metabolic alkalosis, and hypertension: Cushing's syndrome in a patient with metastatic prostate adenocarcinoma.Am J Kidney Dis. 2001; 37: 838-846Abstract Full Text PDF PubMed Scopus (39) Google Scholar surgery is not a therapeutic option and bilateral adrenalectomy is rarely used in refractory cases.25.Collichio F.A. Woolf P.D. Brower M. Management of patients with small cell carcinoma and the syndrome of ectopic corticotropin secretion.Cancer. 1994; 73: 1361-1367Crossref PubMed Scopus (39) Google Scholar 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.Winquist E.W. Laskey J. Crump M. et al.Ketoconazole in the management of paraneoplastic Cushing's syndrome secondary to ectopic adrenocorticotropin production.J Clin Oncol. 1995; 13: 157-164PubMed Google Scholar mitotane, metyrapone,27.Verhelst J.A. Trainer P.J. Howlett T.A. et al.Short and long-term responses to metyrapone in the medical managementof 91 patients with Cushing's syndrome.Clin Endocrinol (Oxf). 1991; 35: 169-178Crossref PubMed Scopus (223) Google Scholar octreotide,28.Hearn P.R. Reynolds C.L. Johansen K. et al.Lung carcinoid with Cushing's syndrome: control of serum ACTH and cortisol levels using SMS 201–995 (sandostatin).Clin Endocrinol (Oxf). 1988; 28: 181-185Crossref PubMed Scopus (55) Google Scholar and aminoglutethemide,29.Thoren M. Adamson U. Sjoberg H.E. Aminoglutethimide and metyrapone in the management of Cushing's syndrome.Acta Endocrinol (Copenh). 1985; 109: 451-457PubMed Google Scholar 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.Wajchenberg B. Mendonca B. Libermna B. et al.Ectopic adrenocorticotropic hormone syndrome.Endocrinol Rev. 1994; 15: 752-787PubMed Google Scholar Octeotride suppression of ACTH release has shown efficacy alone and in combination with ketoconazole.4.Rickman T. Garmany R. Doherty T. et al.Hypokalemia, metabolic alkalosis, and hypertension: Cushing's syndrome in a patient with metastatic prostate adenocarcinoma.Am J Kidney Dis. 2001; 37: 838-846Abstract Full Text PDF PubMed Scopus (39) Google Scholar 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.Verhelst J.A. Trainer P.J. Howlett T.A. et al.Short and long-term responses to metyrapone in the medical managementof 91 patients with Cushing's syndrome.Clin Endocrinol (Oxf). 1991; 35: 169-178Crossref PubMed Scopus (223) Google Scholar Spironolactone, an aldosterone-receptor antagonist, is used to decrease urinary potassium wasting secondary to activation of mineralocorticoid receptors.31.Okusa M.D. Ellison D.H. Physiology and pathophysiology of diuretic action.in: Seldin D.W. Giebisch G. The Kidney: Physiology and Pathophysiology. 3rd edn. Lippincott, Williams & Wilkins, Philadelphia, PA2000: 2877-2922Google Scholar 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.Miller J. Crapo L. The medical treatment of Cushing's syndrome.Endocrinol Rev. 1993; 14: 443-458Crossref PubMed Scopus (168) Google Scholar 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.