Sections

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

Sections Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
Overview
Presentation
DDx
Workup
Treatment
Medication
Questions & Answers
References

Presentation

History

Depending on the magnitude and rate of development, hyponatremia may or may not cause symptoms.Consequently, the syndrome of inappropriate antidiuretic hormone secretion.(SIADH). is usually detected by laboratory testing.

In general, slowly progressive hyponatremia is associated with fewer symptoms than is a rapid drop of serum Na⁺ to the same value. Patients with moderate, chronic hyponatremia may have decreased reaction times, cognitive slowing, and ataxia resulting in frequent falls.^{[19, 22]}

Signs and symptoms of acute hyponatremia do not precisely correlate with the severity or the acuity of the hyponatremia. Some patients with profound hyponatremia may be relatively asymptomatic. Anorexia, nausea, and malaise are early symptoms and may be seen when the serum Na⁺ level is less than 125 mEq/L. A further decrease in the serum Na⁺ level can lead to headache, muscle cramps, irritability, drowsiness, confusion, weakness, seizures, and coma. These occur as osmotic fluid shifts result in cerebral edema and increased intracranial pressure.

Important considerations related to the history are symptoms that reflect the cause of SIADH. Patients may have symptoms that suggest increased secretion of ADH, such as chronic pain, symptoms from CNS or pulmonary tumors (eg, hemoptysis, chronic headaches), or head injury, and drug use. It is important to determine if the patient has had excessive fluid intake because of inappropriate thirst or psychogenic polydipsia or because hypotonic fluids were administered in a healthcare setting. The history may also give important information about the chronicity of the condition, which may, in turn, influence the rate of correction of hyponatremia.

Physical Examination

After the identification of hyponatremia, the approach to the patient depends on the clinically assessed volume status. In SIADH, the patient is typically euvolemic and normotensive. Peripheral and pulmonary edema, dry mucous membranes, reduced skin turgor, and orthostatic hypotension are usually absent. Edema in a hyponatremic patient warrants consideration of another hyponatremic state, such as congestive heart failure (CHF), cirrhosis, or chronic kidney disease.

Prominent physical examination findings may be seen only in severe or rapid-onset hyponatremia and can include the following:

Confusion
Disorientation
Delirium
Generalized muscle weakness
Myoclonus
Tremor
Asterixis
Hyporeflexia
Ataxia
Dysarthria
Cheyne-Stokes respiration
Pathologic reflexes
Generalized seizures
Coma

Differential Diagnoses

Cuesta M, Thompson CJ. The syndrome of inappropriate antidiuresis (SIAD). Best Pract Res Clin Endocrinol Metab. 2016 Mar. 30 (2):175-87. [QxMD MEDLINE Link].
Yasir M, Mechanic OJ. Syndrome of Inappropriate Antidiuretic Hormone Secretion. 2021 Jan. [QxMD MEDLINE Link]. [Full Text].
Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med. 1967 May. 42(5):790-806. [QxMD MEDLINE Link].
Sterns RH. Disorders of plasma sodium--causes, consequences, and correction. N Engl J Med. 2015 Jan 1. 372 (1):55-65. [QxMD MEDLINE Link].
Christ-Crain M, Fenske W. Copeptin in the diagnosis of vasopressin-dependent disorders of fluid homeostasis. Nat Rev Endocrinol. 2016 Mar. 12 (3):168-76. [QxMD MEDLINE Link].
Verbalis JG. Disorders of water balance. Skorecki K, Chertow GM, Marsden PA, Yu ASL, Taal MW. Brenner & Rector's The Kidney. 10th ed. Philadelphia, PA: Elsevier; 2016. Vol 1: 460-510.
Elhassan EA, Schrier RW. Hyponatremia: diagnosis, complications, and management including V2 receptor antagonists. Curr Opin Nephrol Hypertens. 2011 Mar. 20(2):161-8. [QxMD MEDLINE Link].
Sheikh MM, Ahmad E, Jeelani HM, Riaz A, Muneeb A. COVID-19 Pneumonia: An Emerging Cause of Syndrome of Inappropriate Antidiuretic Hormone. Cureus. 2020 Jun 26. 12 (6):e8841. [QxMD MEDLINE Link]. [Full Text].
Vitting KE, Gardenswartz MH, Zabetakis PM, et al. Frequency of hyponatremia and nonosmolar vasopressin release in the acquired immunodeficiency syndrome. JAMA. 1990 Feb 16. 263(7):973-8. [QxMD MEDLINE Link].
Shepshelovich D, Schechter A, Calvarysky B, Diker-Cohen T, Rozen-Zvi B, Gafter-Gvili A. Medication-induced SIADH: distribution and characterization according to medication class. Br J Clin Pharmacol. 2017 Aug. 83 (8):1801-1807. [QxMD MEDLINE Link]. [Full Text].
Marcelino GP, Collantes CMC, Oommen JK, Wang S, Baldassari H, Muralidharan R, et al. Amiodarone-Induced Syndrome of Inappropriate Antidiuretic Hormone: A Case Report and Review of the Literature. P T. 2019 Jul. 44 (7):416-423. [QxMD MEDLINE Link]. [Full Text].
Hoorn EJ, Lindemans J, Zietse R. Development of severe hyponatraemia in hospitalized patients: treatment-related risk factors and inadequate management. Nephrol Dial Transplant. 2006 Jan. 21(1):70-6. [QxMD MEDLINE Link].
Schrier RW. Body water homeostasis: clinical disorders of urinary dilution and concentration. J Am Soc Nephrol. 2006 Jul. 17(7):1820-32. [QxMD MEDLINE Link].
Stelfox HT, Ahmed SB, Khandwala F, Zygun D, Shahpori R, Laupland K. The epidemiology of intensive care unit-acquired hyponatraemia and hypernatraemia in medical-surgical intensive care units. Crit Care. 2008. 12(6):R162. [QxMD MEDLINE Link]. [Full Text].
Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med. 2006 Jul. 119(7 Suppl 1):S30-5. [QxMD MEDLINE Link].
Ayus JC, Varon J, Arieff AI. Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners. Ann Intern Med. 2000 May 2. 132(9):711-4. [QxMD MEDLINE Link].
Kumar S, Fowler M, Gonzalez-Toledo E, Jaffe SL. Central pontine myelinolysis, an update. Neurol Res. 2006 Apr. 28(3):360-6. [QxMD MEDLINE Link].
Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007 May 17. 356(20):2064-72. [QxMD MEDLINE Link].
Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006 Jan. 119(1):71.e1-8. [QxMD MEDLINE Link].
Usala RL, Fernandez SJ, Mete M, Cowen L, Shara NM, Barsony J, et al. Hyponatremia Is Associated With Increased Osteoporosis and Bone Fractures in a Large US Health System Population. J Clin Endocrinol Metab. 2015 Aug. 100 (8):3021-31. [QxMD MEDLINE Link].
Clayton JA, Le Jeune IR, Hall IP. Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome. QJM. 2006 Aug. 99(8):505-11. [QxMD MEDLINE Link].
Decaux G. Is asymptomatic hyponatremia really asymptomatic?. Am J Med. 2006 Jul. 119(7 Suppl 1):S79-82. [QxMD MEDLINE Link].
Hew-Butler T, Noakes TD, Siegel AJ. Practical management of exercise-associated hyponatremic encephalopathy: the sodium paradox of non-osmotic vasopressin secretion. Clin J Sport Med. 2008 Jul. 18(4):350-4. [QxMD MEDLINE Link].
Sterns RH, Silver SM. Cerebral salt wasting versus SIADH: what difference?. J Am Soc Nephrol. 2008 Feb. 19(2):194-6. [QxMD MEDLINE Link].
Yee AH, Burns JD, Wijdicks EF. Cerebral salt wasting: pathophysiology, diagnosis, and treatment. Neurosurg Clin N Am. 2010 Apr. 21(2):339-52. [QxMD MEDLINE Link].
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 Aug 18. 106(33):14034-9. [QxMD MEDLINE Link]. [Full Text].
Feldman BJ, Rosenthal SM, Vargas GA, et al. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med. 2005 May 5. 352(18):1884-90. [QxMD MEDLINE Link].
Powlson AS, Challis BG, Halsall DJ, Schoenmakers E, Gurnell M. Nephrogenic syndrome of inappropriate antidiuresis secondary to an activating mutation in the arginine vasopressin receptor AVPR2. Clin Endocrinol (Oxf). 2016 Aug. 85 (2):306-12. [QxMD MEDLINE Link].
Maesaka JK, Miyawaki N, Palaia T, Fishbane S, Durham JH. Renal salt wasting without cerebral disease: diagnostic value of urate determinations in hyponatremia. Kidney Int. 2007 Apr. 71 (8):822-6. [QxMD MEDLINE Link].
Fenske W, Sandner B, Christ-Crain M. A copeptin-based classification of the osmoregulatory defects in the syndrome of inappropriate antidiuresis. Best Pract Res Clin Endocrinol Metab. 2016 Mar. 30 (2):219-33. [QxMD MEDLINE Link].
[Guideline] Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant. 2014 Apr. 29 Suppl 2:i1-i39. [QxMD MEDLINE Link].
Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013 Oct. 126 (10 Suppl 1):S1-42. [QxMD MEDLINE Link].
Sterns RH, Hix JK, Silver S. Treating profound hyponatremia: a strategy for controlled correction. Am J Kidney Dis. 2010 Oct. 56 (4):774-9. [QxMD MEDLINE Link].
Voets PJGM, Vogtländer NPJ. A quantitative approach to intravenous fluid therapy in the syndrome of inappropriate antidiuretic hormone secretion. Clin Exp Nephrol. 2019 Aug. 23 (8):1039-1044. [QxMD MEDLINE Link]. [Full Text].
Zeltser D, Rosansky S, van Rensburg H, Verbalis JG, Smith N. Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol. 2007. 27(5):447-57. [QxMD MEDLINE Link].
Nemerovski C, Hutchinson DJ. Treatment of hypervolemic or euvolemic hyponatremia associated with heart failure, cirrhosis, or the syndrome of inappropriate antidiuretic hormone with tolvaptan: a clinical review. Clin Ther. 2010 Jun. 32(6):1015-32. [QxMD MEDLINE Link].
Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006 Nov 16. 355(20):2099-112. [QxMD MEDLINE Link].
Berl T, Quittnat-Pelletier F, Verbalis JG, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol. 2010 Apr. 21(4):705-12. [QxMD MEDLINE Link]. [Full Text].
Morris JH, Bohm NM, Nemecek BD, Crawford R, Kelley D, Bhasin B, et al. Rapidity of Correction of Hyponatremia Due to Syndrome of Inappropriate Secretion of Antidiuretic Hormone Following Tolvaptan. Am J Kidney Dis. 2018 Jun. 71 (6):772-782. [QxMD MEDLINE Link].
Hoorn EJ, Zietse R. Diagnosis and Treatment of Hyponatremia: Compilation of the Guidelines. J Am Soc Nephrol. 2017 May. 28 (5):1340-1349. [QxMD MEDLINE Link]. [Full Text].

Media Gallery

of 0

Author

Christie P Thomas, MBBS, FRCP, FASN, FAHA Professor, Department of Internal Medicine, Division of Nephrology, Departments of Pediatrics and Obstetrics and Gynecology, Medical Director, Kidney and Kidney/Pancreas Transplant Program, University of Iowa Hospitals and Clinics

Christie P Thomas, MBBS, FRCP, FASN, FAHA is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Nephrology, Royal College of Physicians

Disclosure: Nothing to disclose.

Specialty Editor Board

Eleanor Lederer, MD, FASN Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital

Eleanor Lederer, MD, FASN is a member of the following medical societies: American Association for the Advancement of Science, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Society of Nephrology<br/>Received income in an amount equal to or greater than $250 from: Healthcare Quality Strategies, Inc.

Chief Editor

Vecihi Batuman, MD, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Interim Chair, Deming Department of Medicine, Tulane University School of Medicine

Vecihi Batuman, MD, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Mony Fraer, MD, MHCDS, FACP, FASN Associate Professor, Division of Nephrology, Department of Medicine, University of Iowa Hospitals and Clinics; Staff Physician, Iowa City Veterans Affairs Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

Howard A Bessen, MD Professor of Medicine, Department of Emergency Medicine, UCLA School of Medicine; Program Director, Harbor-UCLA Medical Center

Howard A Bessen, MD is a member of the following medical societies: American College of Emergency Physicians

Disclosure: Nothing to disclose.

Keenan Bora, MD Fellow, Medical Toxicology, Detroit Medical Center; Attending Physician, Medical Center Emergency Services, Detroit

Keenan Bora, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and American Medical Association

Disclosure: Nothing to disclose.

Meher Chaudhry, MD Chief Resident, Department of Emergency Medicine, Detroit Receiving Hospital, University Health Center

Disclosure: Nothing to disclose.

Sonali Deshmukh, MBBS Consulting Staff, Omaha Nephrology, Nebraska

Sonali Deshmukh, MBBS is a member of the following medical societies: American Society of Nephrology

Disclosure: Nothing to disclose.

R obert J Ferry Jr, MD Chief, Division of Pediatric Endocrinology and Metabolism, Le Bonheur Children's Hospital; Professor, Department of Pediatrics, University of Tennessee Health Science Center at Memphis; St. Jude Children's Research Hospital, Memphis, TN; Brigade Surgeon, 36th Sustainment Brigade, U.S. Army; Adjunct Professor, Pediatric Surgery Department, King Saud University, Riyadh, Saudi Arabia

Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Disclosure: Nutropin Speakers Bureau Honoraria Speaking and teaching; Genotropin Speakers Bureau Honoraria Speaking and teaching; Eli Lilly & Co. Grant/research funds Investigator; MacroGenics, Inc. Grant/research funds Investigator; Ipsen, S.A. (formerly Tercica, Inc.) Grant/research funds Investigator; NovoNordisk SA Grant/research funds Investigator; Diamyd Investigator

Stephen Kemp, MD, PhD Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas College of Medicine and Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Eleanor Lederer, MD Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital

Eleanor Lederer, MD is a member of the following medical societies: American Association for the Advancement of Science, American Federation for Medical Research, American Society for Biochemistry and Molecular Biology, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation, and Phi Beta Kappa

Disclosure: Dept of Veterans Affairs Grant/research funds Research

Lynne Lipton Levitsky, MD Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor of Pediatrics, Harvard Medical School

Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Pfizer Grant/research funds P.I.; Tercica Grant/research funds Other; Eli Lily Grant/research funds PI; NovoNordisk Grant/research funds PI

Chike Magnus Nzerue, MD Associate Dean for Clinical Affairs, Vice-Chairman of Internal Medicine, Meharry Medical College

Chike Magnus Nzerue, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Society of Nephrology, and National Kidney Foundation

Disclosure: Nothing to disclose.

Jose F Pascual-y-Baralt, MD Chief, Division of Pediatric Nephrology, San Antonio Military Pediatric Center; Clinical Professor, Department of Pediatrics, University of Texas Health Science Campus

Jose F Pascual-y-Baralt, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, American Society of Pediatric Nephrology, Association of Military Surgeons of the US, and International Society of Nephrology

Disclosure: Nothing to disclose.

Alexandr Rafailov, MD Staff Physician, Department of Emergency Medicine, State University of New York Downstate/Kings County Hospital

Disclosure: Nothing to disclose.

Arlan L Rosenbloom, MD Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology

Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Florida Pediatric Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Erik D Schraga, MD Consulting Staff, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates; Consulting Staff, Permanente Medical Group, Kaiser Permanente, Santa Clara Medical Center

Disclosure: Nothing to disclose.

Richard H Sinert, DO Associate Professor of Emergency Medicine, Clinical Assistant Professor of Medicine, Research Director, State University of New York College of Medicine; Consulting Staff, Department of Emergency Medicine, Kings County Hospital Center

Richard H Sinert, DO is a member of the following medical societies: American College of Physicians and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, Medscape

Disclosure: Nothing to disclose.