Chapter 096. Paraneoplastic Syndromes: Endocrinologic/Hematologic (Part 4)

Etiology Vasopressin is an antidiuretic hormone normally produced by the posterior pituitary gland. Ectopic vasopressin production by tumors is a common cause of the syndrome of inappropriate antidiuretic hormone (SIADH), occurring in at least half of patients with SCLC.Compensatory mechanisms, such as decreased thirst, suppression of aldosterone, and production of atrial natriuretic peptide (ANP), may mitigate the development of hyponatremia in patients who produce excessive vasopressin. Tumors with neuroendocrine features, such as SCLC and carcinoids, are the most common sources of ectopic vasopressin production, but it also occurs in other forms of lung cancer and with central nervous system...
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Chapter 096. Paraneoplastic Syndromes: Endocrinologic/Hematologic (Part 4) Chapter 096. Paraneoplastic Syndromes: Endocrinologic/Hematologic (Part 4) Etiology Vasopressin is an antidiuretic hormone normally produced by the posteriorpituitary gland. Ectopic vasopressin production by tumors is a common cause ofthe syndrome of inappropriate antidiuretic hormone (SIADH), occurring in at leasthalf of patients with SCLC. Compensatory mechanisms, such as decreased thirst, suppression ofaldosterone, and production of atrial natriuretic peptide (ANP), may mitigate thedevelopment of hyponatremia in patients who produce excessive vasopressin.Tumors with neuroendocrine features, such as SCLC and carcinoids, are the mostcommon sources of ectopic vasopressin production, but it also occurs in otherforms of lung cancer and with central nervous system (CNS) lesions, head andneck cancer, and genitourinary, gastrointestinal, and ovarian cancers. Themechanism of activation of the vasopressin gene in these tumors is unknown butoften involves concomitant expression of the adjacent oxytocin gene, suggestingderepression of this locus. Clinical Manifestations Most patients with ectopic vasopressin secretion are asymptomatic and areidentified because of the presence of hyponatremia on routine chemistry testing.Symptoms may include weakness, lethargy, nausea, confusion, depressed mentalstatus, and seizures. The severity of symptoms reflects the rapidity of onset as well as the extentof hyponatremia. Hyponatremia usually develops slowly but may be exacerbatedby the administration of IV fluids or the institution of new medications. Thirst istypically suppressed. Diagnosis The diagnostic features of ectopic vasopressin production are the same asthose of other causes of SIADH (Chaps. 46 and 334). Hyponatremia and reducedserum osmolality occur in the setting of an inappropriately normal or increasedurine osmolality. Urine sodium excretion is normal or increased unless volumedepletion is present. Other causes of hyponatremia should be excluded, includingrenal, adrenal, or thyroid insufficiency. Physiologic sources of vasopressinstimulation (CNS lesions, pulmonary disease, nausea), adaptive circulatorymechanisms (hypotension, heart failure, hepatic cirrhosis), and medications,including many chemotherapeutic agents, should also be considered as possiblecauses of hyponatremia. Vasopressin assay is not usually necessary to make thediagnosis. Ectopic Vasopressin: Tumor-Associated SIADH: Treatment Most patients with ectopic vasopressin production develop hyponatremiaover several weeks or months. The disorder should be corrected gradually unlessmental status is altered or there is risk of seizures. Treatment of the underlyingmalignancy may reduce ectopic vasopressin production but this response is slow,if it occurs at all. Fluid restriction to less than urine output, plus insensible losses,is often sufficient to partially correct hyponatremia. However, strict monitoring ofthe amount and types of liquids consumed or administered intravenously isrequired for fluid restriction to be effective. Salt tablets or saline are not helpfulunless volume depletion is also present. Demeclocycline (150–300 mg orally threeto four times daily) can be used to inhibit vasopressin action on the renal distaltubule but its onset of action is relatively slow (1–2 weeks). Conivaptan, anonpeptide V2-receptor antagonist, can be administered either PO (20–120 mgbid) or IV (10–40 mg), and is particularly effective when used in combination withfluid restriction in euvolemic hyponatremia. Severe hyponatremia (Na < 115meq/L) or mental status changes may require treatment with hypertonic (3%) ornormal saline infusion together with furosemide, to enhance free water clearance.The rate of sodium correction should be slow (0.5–1 meq/L per h) to prevent rapidfluid shifts and the possible development of central pontine myelinolysis. Cushings Syndrome Caused by Ectopic ACTH Production (See also Chap. 336) Etiology Ectopic ACTH production accounts for 10–20% of Cushings syndrome.The syndrome is particularly common in neuroendocrine tumors. SCLC (>50%) isby far the most common cause of ectopic ACTH, followed by thymic carcinoid(15%), islet cell tumors (10%), bronchial carcinoid (10%), other carcinoids (5%),and pheochromocytomas (2%). Ectopic ACTH production is caused by increasedexpression of the proopiomelanocortin (POMC) gene, which encodes ACTH,along with melanocyte-stimulating hormone (MSH), β lipotropin, and severalother peptides. In many tumors, there is abundant but aberrant expression of thePOMC gene from an internal promoter, proximal to the thi ...