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Syndrome of Inappropriate Antidiuretic Hormone Secretion: Differential Diagnoses & Workup

Author: Robert J Ferry Jr, MD,, Chief, Division of Pediatric Endocrinology and Metabolism, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis, and St. Jude Children's Research Hospital; Brigade Surgeon, 36th Sustainment Brigade, 13th Expeditionary Sustainment Command, U.S. Army
Coauthor(s): 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
Contributor Information and Disclosures

Updated: Oct 22, 2009

Differential Diagnoses

Adrenal Insufficiency
Hyponatremia
Hypothyroidism

Other Problems to Be Considered

Cerebral salt-wasting syndrome
Chronic liver disease
Drugs that impair renal water excretion (see Media file 2)
Pituitary insufficiency
Primary polydipsia
Pure right-sided congestive heart failure
Renal disease with salt-losing nephritis
Reset osmostat
Surreptitious diuretic use
Water intoxication

Workup

Laboratory Studies

  • In the absence of a single laboratory test to confirm the diagnosis, syndrome of inappropriate antidiuretic hormone (SIADH) secretion is best defined by the classic criteria defined by Bartter and Schwartz in 1967, which remain valid today. A summary is as follows follows:2
    • Hyponatremia with corresponding hypoosmolality
    • Continued renal excretion of sodium
    • Urine less than maximally dilute
    • Absence of clinical evidence of volume depletion
      • Normal skin turgor
      • Blood pressure within the reference range
    • Absence of other causes of hyponatremia
      • Adrenal insufficiency - Mineralocorticoid deficiency, glucocorticoid deficiency
      • Hypothyroidism
      • Cardiac failure
      • Pituitary insufficiency
      • Renal disease with salt wastage
      • Hepatic disease
      • Drugs that impair renal water excretion
    • Correction of hyponatremia by fluid restriction
  • Hyponatremia (ie, serum sodium <135 mmol/L) is a cardinal finding of syndrome of inappropriate antidiuretic hormone secretion with concomitant hypo-osmolality (ie, serum osmolality <280 mOsm/kg). The combination of hyponatremia, low serum osmolality, and low urine volume is the hallmark of syndrome of inappropriate antidiuretic hormone secretion. Hyponatremia may not be present early in the process and may develop only when fluid retention occurs. Hypotonic hyponatremia does not develop unless the patient is drinking or otherwise receiving and retaining water or other hypotonic solution. Hyponatremia may be the first clue in the diagnosis of syndrome of inappropriate antidiuretic hormone secretion.
  • Symptoms are more likely to be observed when the serum sodium concentration is less than 120 mmol/L and serum osmolality is below 240 mOsm/kg of water and when this has happened rapidly. However, no predictable correlation between the degree of hyponatremia and the severity of symptoms is recognized.
  • Consider the diagnosis of syndrome of inappropriate antidiuretic hormone secretion only after making sure that hyponatremia is not the result of physiologic (ie, appropriate) antidiuretic hormone (ADH) secretion, such as observed in the presence of a decreased intravascular volume or pharmacologic agents that may impair water excretion.
  • Serum bicarbonate remains within the reference range despite hypotonic expansion of body fluids in syndrome of inappropriate antidiuretic hormone secretion. This is postulated to be due to the movement of hydrogen ions into the cells and to increased hydrogen ion excretion by the renal tubules, both of which avert a dilutional fall in the serum bicarbonate concentration.
  • Serum potassium concentration also remains unchanged. Movement of potassium from the intracellular space to the extracellular space prevents dilutional hypokalemia. As hydrogen ions move intracellularly, they are exchanged for potassium in order to maintain electroneutrality.
  • The anion gap is reduced in syndrome of inappropriate antidiuretic hormone secretion secondary to equal dilution of all the electrolytes, particularly serum sodium and chloride, as well as secondary to an unaffected bicarbonate (HCO3-). Another factor that further decreases the anion gap is that the volume expansion decreases the tubular reabsorption of unmeasured anions, such as sulfate, phosphate, and urate.
  • Urinary loss of sodium continues despite significant hyponatremia. In these patients, as in healthy patients, urinary sodium excretion is a reflection of sodium intake and, therefore, usually is greater than 20 mmol/L. However, in the setting of sodium restriction or of volume depletion due to extrarenal losses in patients with syndrome of inappropriate antidiuretic hormone secretion, renal conservation proceeds normally and urinary sodium concentration may be very low.
  • Patients with hyponatremia have a urine that is maximally dilute (ie, 50-80 mOsm/kg); however, in patients with syndrome of inappropriate antidiuretic hormone secretion, the urine osmolality is usually less than maximally dilute, with values ranging from 250-1400 mOsm/kg depending on the course of the disease. Urine osmolality usually exceeds that of plasma; however, urine must only be submaxillary dilute (ie, >100 mOsm/kg) to establish a diagnosis of syndrome of inappropriate antidiuretic hormone secretion. The most common error in recognizing syndrome of inappropriate antidiuretic hormone secretion is the failure to realize that urine osmolality must only be inappropriately elevated and not necessarily greater than the corresponding serum osmolality.
  • BUN levels are unusually low, usually below 10 mg/dL. A low BUN levels in syndrome of inappropriate antidiuretic hormone secretion occurs secondary to volume expansion because urea is distributed in total body water.
  • Hypouricemia is frequently observed in patients with syndrome of inappropriate antidiuretic hormone secretion during the period of hyponatremia. An increase in uric acid excretion occurs as a result of volume expansion and a decrease in distal tubular reabsorption. A decrease in serum uric acid concentration has been suggested as a screening procedure in patients with hyponatremia secondary to syndrome of inappropriate antidiuretic hormone secretion. Hypouricemia appears to occur in any volume expanded state and, therefore, lacks both sensitivity and specificity for making the diagnosis of syndrome of inappropriate antidiuretic hormone secretion.
  • Glomerular filtration rate (GFR) is increased as a result of extracellular water expansion induced by water retention.

Imaging Studies

  • MRI or CT scanning of the brain might be indicated if cerebral edema, a relatively rare complication of syndrome of inappropriate antidiuretic hormone secretion, is clinically suspected. These are not routine procedures.

Other Tests

  • Acute water loading test: The use of this procedure to test renal diluting capacity in patients with syndrome of inappropriate antidiuretic hormone secretion is unnecessary, and the test may be unsafe.
  • Thyroid function tests: Results are normal.
  • Adrenal function tests
    • Results are normal.
    • Aldosterone excretion or secretion rates are characteristically within the reference range.
    • Plasma cortisol or urinary 17-hydroxycorticoid levels are within the reference range.
  • ADH levels
    • The use of radioimmunoassay for ADH may provide supportive evidence for the diagnosis of syndrome of inappropriate antidiuretic hormone secretion. However, the values are not usually available quickly enough to assist in clinical decision-making.
    • The plasma ADH is typically elevated, but its determination is not crucial for the diagnosis of syndrome of inappropriate antidiuretic hormone secretion.

More on Syndrome of Inappropriate Antidiuretic Hormone Secretion

Overview: Syndrome of Inappropriate Antidiuretic Hormone Secretion
Differential Diagnoses & Workup: Syndrome of Inappropriate Antidiuretic Hormone Secretion
Treatment & Medication: Syndrome of Inappropriate Antidiuretic Hormone Secretion
Follow-up: Syndrome of Inappropriate Antidiuretic Hormone Secretion
Multimedia: Syndrome of Inappropriate Antidiuretic Hormone Secretion
References
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Further Reading

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Keywords

syndrome of inappropriate antidiuretic hormone secretion, SIADH, euvolemic hyponatremia, arginine vasopressin, vasopressin secretion, osmoregulatory defect, hypervolemia, hypotonic normovolemic hyponatremia, cerebral edema, hyponatremic encephalopathy, brain injury, treatment, diagnosis

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Contributor Information and Disclosures

Author

Robert J Ferry Jr, MD,, Chief, Division of Pediatric Endocrinology and Metabolism, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis, and St. Jude Children's Research Hospital; Brigade Surgeon, 36th Sustainment Brigade, 13th Expeditionary Sustainment Command, U.S. Army
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 Independent contractor; MacroGenics, Inc. Grant/research funds Independent contractor; Ipsen, S.A. (formerly Tercica, Inc.) Grant/research funds Independent contractor

Coauthor(s)

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.

Medical Editor

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.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Lynne Lipton Levitsky, MD, Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor, Department of Pediatrics, Harvard University 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 PI, also occasional consultant

CME Editor

Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences
Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas 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: Genentech, Inc. Honoraria Speaking and teaching; Pfizer, Inc. Honoraria Consulting

 
 
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