Syndrome of Inappropriate Antidiuretic Hormone Secretion Workup
- Author: Christie P Thomas, MBBS, FRCP, FASN, FAHA; Chief Editor: Vecihi Batuman, MD, FACP, FASN more...
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 :
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.
Order the following tests to help in the diagnosis of SIADH:
Serum Na +, potassium, chloride, and bicarbonate
Blood urea nitrogen
Serum uric acid
In persons with SIADH, the hyponatremia is associated with measured serum hypo-osmolality.
Hyponatremia (ie, serum Na+ < 135 mmol/L) is a defining feature of SIADH.
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 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.
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.
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.
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.
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. 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.
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.
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.
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).
In euvolemic states, before attributing the hyponatremia to SIADH, renal disease and endocrine disorders such thyroid, pituitary, and adrenal insufficiency should be excluded.
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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