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Syndrome of Inappropriate Antidiuretic Hormone Secretion Workup

  • Author: Christie P Thomas, MBBS, FRCP, FASN, FAHA; Chief Editor: Vecihi Batuman, MD, FACP, FASN  more...
 
Updated: Oct 28, 2015
 

Approach Considerations

In the absence of a single laboratory test to confirm the diagnosis, SIADH is best defined by the classic criteria introduced by Bartter and Schwartz in 1967, which remain valid today. The criteria can be summarized as follows[1] :

  • Hyponatremia with corresponding hypoosmolality
  • Continued renal excretion of Na +
  • 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 Na+ <135 mmol/L) with concomitant hypo-osmolality (serum osmolality <280 mOsm/kg) and high urine osmolality is the hallmark of SIADH. However, these findings only indicate that ADH is present and acting on the distal nephron; it does not indicate if the ADH secretion is “inappropriate.” A good clinical examination is required to confirm that the hyponatremia is not the result of decreased effective intravascular volume from volume depletion or from states of volume excess such as congestive heart failure and cirrhosis for which the secretion of ADH is “appropriate.”

In SIADH, serum osmolality is generally lower than urine osmolality. In the setting of serum hypo-osmolality, ADH secretion is usually suppressed to allow the excess water to be excreted, thus moving the plasma osmolality toward normal. If ADH secretion is shut down completely, urine should have an osmolality of less than 100 mOsm. Therefore, urine osmolality of more than 100 mOsm in the context of plasma hypo-osmolality is sufficient to confirm ADH excess. Inappropriate water retention causes the dilutional hyponatremia.

Urine Na+ concentration in persons with SIADH is usually more than 40 mEq/L because, in SIADH, Na+ handling is not abnormal and the urine Na+ concentration reflects Na+ intake, which is generally more than 40 mEq/d (usually 50-100 mEq/d). However, the urine Na+ concentration in persons with SIADH can be modulated by dietary Na+ intake. Thus, on a low-Na+ diet, patients with SIADH may have a urine Na+ level of less than 40 mEq/L.

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Laboratory Tests

Order the following tests to help in the diagnosis of SIADH:

  • Serum Na +, potassium, chloride, and bicarbonate
  • Plasma osmolality
  • Serum creatinine
  • Blood urea nitrogen
  • Blood glucose
  • Urine osmolality
  • Serum uric acid
  • Serum cortisol
  • Thyroid-stimulating hormone

Serum osmolality

In persons with SIADH, the hyponatremia is associated with measured serum hypo-osmolality.

Serum Na

Hyponatremia (ie, serum Na+ < 135 mmol/L) is a defining feature of SIADH.

Serum bicarbonate

Serum bicarbonate remains within the reference range despite hypotonic expansion of body fluids in SIADH. 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

Serum potassium concentration generally 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.

If both hypokalemia and metabolic alkalosis are present, consider diuretic therapy or vomiting as the cause of hyponatremia. If hyperkalemia and metabolic acidosis coexist with hyponatremia, consider adrenal insufficiency and volume depletion leading to AKI.

Anion gap

The anion gap is reduced in SIADH secondary to equal dilution of serum Na+ and chloride, with unaffected bicarbonate (HCO3-). The anion gap is further decreased because the volume expansion probably reduces the tubular reabsorption of unmeasured anions, such as sulfate, phosphate, and urate.

Urinary Na excretion

In SIADH, urinary loss of Na+ continues despite significant hyponatremia. In these patients, as in healthy patients, urinary Na+ excretion is a reflection of Na+ intake and, therefore, usually is greater than 20 mmol/L. However, in the setting of Na+ restriction in patients with SIADH or in patients with volume depletion due to extrarenal losses, the urinary Na+ concentration may be very low.

Urinary osmolality

Patients with hyponatremia should turn off ADH and have a urine that is maximally dilute (ie, 50-100 mOsm/kg); however, in patients with SIADH, the urinary osmolality is usually submaximally dilute (ie, >100 mOsm/kg). One of the more common errors in recognizing SIADH is the failure to realize that the urine’s osmolality must be only inappropriately elevated and not necessarily greater than the corresponding serum osmolality.

BUN levels

Blood urea nitrogen (BUN) levels are unusually low, usually below 10 mg/dL. A low BUN level in SIADH occurs secondary to volume expansion because urea is distributed in total body water.

Uric acid

Measurement of the serum uric acid concentration has been suggested as a screening procedure in patients with hyponatremia secondary to SIADH. Hypouricemia (uric acid <4 mg/dL) is frequently observed in patients with SIADH during the period of hyponatremia. However, hypouricemia lacks sensitivity and specificity for making the diagnosis of SIADH.

Calculation of the fractional excretion of uric acid (FEUA) may prove useful.[23] The FEUA is defined as the percentage of urate filtered by glomeruli that is excreted in urine. The formula is as follows:

(Urinary uric acid [mg/mL] × serum creatinine [mg/mL] ÷ (serum uric acid [mg/mL] × urinary creatinine [mg/mL])  × 100% = FEUA

An increase in FEUA (usually >9%) occurs as a result of volume expansion and a decrease in distal tubular reabsorption. In contrast, the serum uric acid is usually increased in hypovolemia. Hypouricemia and an elevated FEUA may be seen in either salt-wasting syndromes or SIADH. However, hypouricemia and elevation of the FEUA typically resolve after correction of hyponatremia in patients with SIADH, but persist in  those with salt-wasting syndromes.

Glomerular filtration rate

The glomerular filtration rate (GFR) is increased as a result of extracellular water expansion induced by water retention.

ADH

The use of radioimmunoassay for ADH may provide supportive evidence for the diagnosis of SIADH. However, the values are not usually available quickly enough to assist in clinical decision making. Moreover, although the plasma ADH is typically elevated, this determination is not as important for the diagnosis of SIADH.

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Volume Assessment

Hypovolemia

The patient should be assessed clinically to help rule out the presence of hypovolemia. Clues from the physical examination include hypotension with or without orthostasis, dry mucosae, cold peripheries, reduced skin turgor, and low central venous pressures (if central venous pressure or pulmonary capillary wedge pressure measurements are available).

In persons with hypovolemic hyponatremia, the urinary Na+ concentration is usually less than 20 mEq/L and the fractional excretion of Na+ is low. Thus, if the urinary Na+ concentration is less than 25 mEq/L, volume depletion from extrarenal volume loss should be excluded.

Volume depletion causes an appropriate (nonosmotic) secretion of ADH and leads to hyponatremia if hypotonic fluid is used to replace isotonic fluid losses. Typically, a volume-depleted person responds to thirst induced by volume depletion by drinking free water. Replacing isotonic losses (lost from the extracellular compartment) with water or hypotonic fluids makes a patient hyponatremic.

Hypovolemia can also be associated with a urine Na+ concentration more than 25 mEq/L if the source of volume loss is the kidney. Thus, diuretic use, mineralocorticoid deficiency, and salt-losing nephropathies can lead to hyponatremia with a high urine Na+ concentration.

Hypervolemia

The presence of peripheral edema with elevated jugular venous pressure, pulmonary rales, or ascites indicates increased volume, such as in heart failure or cirrhosis (with other signs of liver failure).

Euvolemia

In euvolemic states, before attributing the hyponatremia to SIADH, renal disease and endocrine disorders such thyroid, pituitary, and adrenal insufficiency should be excluded.

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Imaging Studies

Chest radiographs

Chest radiographs may reveal an underlying pulmonary cause of SIADH.

CT or MRI scans

Computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the head may be appropriate in selected cases. The study may show evidence of cerebral edema (eg, narrowing of the ventricles), a complication of SIADH, or may identify a CNS disorder responsible for SIADH (eg, brain tumor). CT scanning or MRI can also help rule out other potential causes of a change in neurologic status.

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Contributor Information and Disclosures
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.

Coauthor(s)

Mony Fraer, MD, 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.

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, International Society of Nephrology, American Society for Biochemistry and Molecular Biology, American Federation for Medical Research, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, Kentucky Medical Association, National Kidney Foundation, Phi Beta Kappa

Disclosure: Received grant/research funds from Dept of Veterans Affairs for research; Received salary from American Society of Nephrology for asn council position; Received salary from University of Louisville for employment; Received salary from University of Louisville Physicians for employment; Received contract payment from American Physician Institute for Advanced Professional Studies, LLC for independent contractor; Received contract payment from Healthcare Quality Strategies, Inc for independent cont.

Chief Editor

Vecihi Batuman, MD, FACP, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Vecihi Batuman, MD, FACP, 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

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.

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.

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