Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)
- Richard H Sterns, MD
Richard H Sterns, MD
- Editor-in-Chief — Nephrology
- Section Editor — Fluid and Electrolytes
- Professor of Medicine
- University of Rochester School of Medicine and Dentistry
The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a disorder of impaired water excretion caused by the inability to suppress the secretion of antidiuretic hormone (ADH) . If water intake exceeds the reduced urine output, the ensuing water retention leads to the development of hyponatremia.
The SIADH should be suspected in any patient with hyponatremia, hypoosmolality, and a urine osmolality above 100 mosmol/kg. In SIADH, the urine sodium concentration is usually above 40 meq/L, the serum potassium concentration is normal, there is no acid-base disturbance, and the serum uric acid concentration is frequently low . (See "Diagnostic evaluation of adults with hyponatremia".)
The pathophysiology and etiology of SIADH will be reviewed here. The treatment of this disorder is discussed separately. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".)
Pathogenesis of hyponatremia — The plasma sodium concentration (PNa) is a function of the ratio of the body's content of exchangeable sodium and potassium (NaE and KE) and total body water (TBW) as described by Edelman's classic equation:
PNa ≈ NaE + KE/Total body water
- Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.703.
- Steele A, Gowrishankar M, Abrahamson S, et al. Postoperative hyponatremia despite near-isotonic saline infusion: a phenomenon of desalination. Ann Intern Med 1997; 126:20.
- Robertson GL. Regulation of arginine vasopressin in the syndrome of inappropriate antidiuresis. Am J Med 2006; 119:S36.
- Robertson GL, Shelton RL, Athar S. The osmoregulation of vasopressin. Kidney Int 1976; 10:25.
- Verbalis JG, Drutarosky MD. Adaptation to chronic hypoosmolality in rats. Kidney Int 1988; 34:351.
- Gross PA, Anderson RJ. Effects of DDAVP and AVP on sodium and water balance in conscious rat. Am J Physiol 1982; 243:R512.
- LEAF A, BARTTER FC, SANTOS RF, WRONG O. Evidence in man that urinary electrolyte loss induced by pitressin is a function of water retention. J Clin Invest 1953; 32:868.
- JAENIKE JR, WATERHOUSE C. The renal response to sustained administration of vasopressin and water in man. J Clin Endocrinol Metab 1961; 21:231.
- Ecelbarger CA, Nielsen S, Olson BR, et al. Role of renal aquaporins in escape from vasopressin-induced antidiuresis in rat. J Clin Invest 1997; 99:1852.
- Murase T, Ecelbarger CA, Baker EA, et al. Kidney aquaporin-2 expression during escape from antidiuresis is not related to plasma or tissue osmolality. J Am Soc Nephrol 1999; 10:2067.
- Saito T, Higashiyama M, Nagasaka S, et al. Role of aquaporin-2 gene expression in hyponatremic rats with chronic vasopressin-induced antidiuresis. Kidney Int 2001; 60:1266.
- Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med 2007; 356:2064.
- Johnson BE, Chute JP, Rushin J, et al. A prospective study of patients with lung cancer and hyponatremia of malignancy. Am J Respir Crit Care Med 1997; 156:1669.
- Ferlito A, Rinaldo A, Devaney KO. Syndrome of inappropriate antidiuretic hormone secretion associated with head neck cancers: review of the literature. Ann Otol Rhinol Laryngol 1997; 106:878.
- Talmi YP, Wolf GT, Hoffman HT, Krause CJ. Elevated arginine vasopressin levels in squamous cell cancer of the head and neck. Laryngoscope 1996; 106:317.
- Sørensen JB, Andersen MK, Hansen HH. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in malignant disease. J Intern Med 1995; 238:97.
- Kim JK, Summer SN, Wood WM, Schrier RW. Osmotic and non-osmotic regulation of arginine vasopressin (AVP) release, mRNA, and promoter activity in small cell lung carcinoma (SCLC) cells. Mol Cell Endocrinol 1996; 123:179.
- Weissman PN, Shenkman L, Gregerman RI. Chlorpropamide hyponatremia: drug-induced inappropriate antidiuretic-hormone activity. N Engl J Med 1971; 284:65.
- Hensen J, Haenelt M, Gross P. Water retention after oral chlorpropamide is associated with an increase in renal papillary arginine vasopressin receptors. Eur J Endocrinol 1995; 132:459.
- Gold PW, Robertson GL, Ballenger JC, et al. Carbamazepine diminishes the sensitivity of the plasma arginine vasopressin response to osmotic stimulation. J Clin Endocrinol Metab 1983; 57:952.
- Kamiyama T, Iseki K, Kawazoe N, et al. Carbamazepine-induced hyponatremia in a patient with partial central diabetes insipidus. Nephron 1993; 64:142.
- Van Amelsvoort T, Bakshi R, Devaux CB, Schwabe S. Hyponatremia associated with carbamazepine and oxcarbazepine therapy: a review. Epilepsia 1994; 35:181.
- Nielsen OA, Johannessen AC, Bardrum B. Oxcarbazepine-induced hyponatremia, a cross-sectional study. Epilepsy Res 1988; 2:269.
- Sachdeo RC, Wasserstein A, Mesenbrink PJ, D'Souza J. Effects of oxcarbazepine on sodium concentration and water handling. Ann Neurol 2002; 51:613.
- Bressler RB, Huston DP. Water intoxication following moderate-dose intravenous cyclophosphamide. Arch Intern Med 1985; 145:548.
- Salido M, Macarron P, Hernández-García C, et al. Water intoxication induced by low-dose cyclophosphamide in two patients with systemic lupus erythematosus. Lupus 2003; 12:636.
- Nausea and vasopressin. Lancet 1991; 337:1133.
- ten Holt WL, van Iperen CE, Schrijver G, Bartelink AK. Severe hyponatremia during therapy with fluoxetine. Arch Intern Med 1996; 156:681.
- Liu BA, Mittmann N, Knowles SR, Shear NH. Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone associated with the use of selective serotonin reuptake inhibitors: a review of spontaneous reports. CMAJ 1996; 155:519.
- Covyeou JA, Jackson CW. Hyponatremia associated with escitalopram. N Engl J Med 2007; 356:94.
- Ozturk S, Ozsenel EB, Kazancioglu R, Turkmen A. A case of fluoxetine-induced syndrome of inappropriate antidiuretic hormone secretion. Nat Clin Pract Nephrol 2008; 4:278.
- Fabian TJ, Amico JA, Kroboth PD, et al. Paroxetine-induced hyponatremia in older adults: a 12-week prospective study. Arch Intern Med 2004; 164:327.
- Holden R, Jackson MA. Near-fatal hyponatraemic coma due to vasopressin over-secretion after "ecstasy" (3,4-MDMA). Lancet 1996; 347:1052.
- Wilkins B. Cerebral oedema after MDMA ("ecstasy") and unrestricted water intake. Hyponatraemia must be treated with low water input. BMJ 1996; 313:689.
- Adler D, Voide C, Thorens JB, Desmeules J. SIADH consecutive to ciprofloxacin intake. Eur J Intern Med 2004; 15:463.
- Liapis K, Apostolidis J, Charitaki E, et al. Syndrome of inappropriate secretion of antidiuretic hormone associated with imatinib. Ann Pharmacother 2008; 42:1882.
- Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis 2008; 52:144.
- Fieldman NR, Forsling ML, Le Quesne LP. The effect of vasopressin on solute and water excretion during and after surgical operations. Ann Surg 1985; 201:383.
- Anderson RJ. Hospital-associated hyponatremia. Kidney Int 1986; 29:1237.
- Gowrishankar M, Lin SH, Mallie JP, et al. Acute hyponatremia in the perioperative period: insights into its pathophysiology and recommendations for management. Clin Nephrol 1998; 50:352.
- Aronson D, Dragu RE, Nakhoul F, et al. Hyponatremia as a complication of cardiac catheterization: a prospective study. Am J Kidney Dis 2002; 40:940.
- Sane T, Rantakari K, Poranen A, et al. Hyponatremia after transsphenoidal surgery for pituitary tumors. J Clin Endocrinol Metab 1994; 79:1395.
- Olson BR, Rubino D, Gumowski J, Oldfield EH. Isolated hyponatremia after transsphenoidal pituitary surgery. J Clin Endocrinol Metab 1995; 80:85.
- Dunn AL, Powers JR, Ribeiro MJ, et al. Adverse events during use of intranasal desmopressin acetate for haemophilia A and von Willebrand disease: a case report and review of 40 patients. Haemophilia 2000; 6:11.
- Shepherd LL, Hutchinson RJ, Worden EK, et al. Hyponatremia and seizures after intravenous administration of desmopressin acetate for surgical hemostasis. J Pediatr 1989; 114:470.
- Humphries JE, Siragy H. Significant hyponatremia following DDAVP administration in a healthy adult. Am J Hematol 1993; 44:12.
- Feeney JG. Water intoxication and oxytocin. Br Med J (Clin Res Ed) 1982; 285:243.
- Li C, Wang W, Summer SN, et al. Molecular mechanisms of antidiuretic effect of oxytocin. J Am Soc Nephrol 2008; 19:225.
- Vitting KE, Gardenswartz MH, Zabetakis PM, et al. Frequency of hyponatremia and nonosmolar vasopressin release in the acquired immunodeficiency syndrome. JAMA 1990; 263:973.
- Gitelman SE, Feldman BJ, Rosenthal SM. Nephrogenic syndrome of inappropriate antidiuresis: a novel disorder in water balance in pediatric patients. Am J Med 2006; 119:S54.
- Feldman BJ, Rosenthal SM, Vargas GA, et al. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med 2005; 352:1884.
- Carpentier E, Greenbaum LA, Rochdi D, et al. Identification and characterization of an activating F229V substitution in the V2 vasopressin receptor in an infant with NSIAD. J Am Soc Nephrol 2012; 23:1635.
- Decaux G, Vandergheynst F, Bouko Y, et al. Nephrogenic syndrome of inappropriate antidiuresis in adults: high phenotypic variability in men and women from a large pedigree. J Am Soc Nephrol 2007; 18:606.
- Tian W, Fu Y, Garcia-Elias A, et al. A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia. Proc Natl Acad Sci U S A 2009; 106:14034.
- Goldstein CS, Braunstein S, Goldfarb S. Idiopathic syndrome of inappropriate antidiuretic hormone secretion possibly related to advanced age. Ann Intern Med 1983; 99:185.
- Sterns RH. The syndrome of inappropriate antidiuretic hormone secretion of unknown origin. Am J Kidney Dis 1999; 33:161.
- Miller M, Hecker MS, Friedlander DA, Carter JM. Apparent idiopathic hyponatremia in an ambulatory geriatric population. J Am Geriatr Soc 1996; 44:404.
- Anpalahan M. Chronic idiopathic hyponatremia in older people due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) possibly related to aging. J Am Geriatr Soc 2001; 49:788.
- Inappropriate antidiuretic hormone secretion of unknown origin. Kidney Int 1980; 17:554.
- Gentric A, Baccino E, Mottier D, et al. Temporal arteritis revealed by a syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 1988; 85:559.
- Pathogenesis of hyponatremia
- Patterns of ADH secretion
- Determinants of urine output
- - Solute excretion
- - Escape from the effect of ADH
- CNS disturbances
- Pulmonary disease
- Hormone deficiency
- Hormone administration
- HIV infection
- Hereditary SIADH
- CEREBRAL SALT WASTING
- INFORMATION FOR PATIENTS