As I prepare for my nephrology fellowship, I find that in preparing my didactics as a chief resident, I selfishly (and perhaps subconsciously) include kidney-related teaching wherever I can. During one such moment, I came across a something I feel is worth reviewing for early learners: the many causes of hypotonic euvolemic hyponatremia.
We have all been taught that hyponatremia is almost always the result of excess ADH. It is then up to us to determine whether this excess hormone production is part of the body’s appropriate physiologic response to volume depletion and hyperosmolarity. In SIADH, urinary dilution is impaired despite the absence of hypovolemia. Rather than volume depletion, the stimuli for ADH range anywhere from malignancy-related ectopic hormone production, to CNS injury, to chronic hypoxia. The resulting expansion of extracellular volume decreases aldosterone and renin activity and increases urinary sodium excretion. This excess fluid retention in the setting of sodium loss results in a euvolemic, rather than hypervolemic hyponatremia.
Similarly, hyponatremia due to hypothyroidism is thought to be a consequence of the kidney’s inability to excrete a free water load due to an increased secretion of ADH and decreased water delivery to the distal nephron. Others implicate the depressed cardiac output and reduction in renal perfusion seen in patients with thyroid hormone deficiency, though this effect has mainly been demonstrated in myxedema coma. Because sodium excretion is intact despite excess fluid retention, these patients will also be clinically euvolemic.
Because of the negative feedback that glucocorticoids exert on ADH, secondary adrenal insufficiency also results in an ADH-related hyponatremia. Unlike those with primary adrenal insufficiency, patients with secondary adrenal insufficiency are less at risk for stress-induced adrenal shock. This is because mineralocorticoid secretion from RAAS activation is still intact. In fact, patients with secondary adrenal insufficiency may only present with vaguesymptoms such as malaise and depression.
As a result of the subtle ways that these patients present, secondary adrenal insufficiency is an often-overlooked cause of euvolemic hyponatremia. One study revealed that hyponatremic patients with adrenal insufficiency due to hypopituitarism were admitted to hospitals up to fourtimes before their true diagnoses were discovered. Due to many of these patients presenting with symptoms of a “failure to thrive,” they inappropriately receive hydration. This has important clinical implications, as normal saline can paradoxically worsen the hyponatremia seen in SIADH, hypothyroidism, and secondary adrenal insufficiency.
To understand why this occurs, remember that sodium and water regulation are handled independently by the kidney. In any clinical scenario of inappropriately-elevated ADH, the mechanism for sodium excretion is intact. This means that the kidneys will excrete whatever salt load is given to them and inappropriately retain water. When administering normal saline to a euvolemic patient with hyponatremia and a very high urine osmolality, all of the sodium will be excreted, but a portion of the water will be retained. This can worsen a patient’s hyponatremia.
This concept is better illustrated in the below example:
Suppose our patient has a hypotonic, euvolemic hyponatremia with an inappropriately-elevated urine osmolality of 600 mosms/kg. Remember that 1 liter of normal saline contains 154 mosms of Na and 154 mosms of Cl. If the patient is given 1 liter of normal saline, he is receiving 308 mosms of solute in total. Because the sodium regulation of his kidneys is intact, all 308 mosms of solute will be excreted in a small portion of free water. The remaining free water will be retained, thus exacerbating his hyponatremia. It should be noted that this effect is seen as long as the patient’s urine osmolality (a surrogate for his degree of ADH elevation) is greater than the osmolality of the administered fluid; that is to say, as long as the concentration of sodium in his urine is greater than the concentration of sodium in normal saline.
How then, can we distinguish “inappropriate ADH” due to medications and malignancy from “inappropriate ADH” due to secondary adrenal insufficiency? Unfortunately, lab tests appear to be of limited value. In addition to an elevated urine osmolality and urine sodium, both sets of patients often have low uric acid levels, thought to be due to decreased tubular uric acid resorption and increased clearance. Some point out the elevated ACTH and propiomelanocortin (POMC)-derived peptide levels seen in primary adrenal insufficiency as possible distinguishing factors, but these test results often fluctuate are not used frequently in clinical practice.
The need to be meticulous in evaluating euvolemic hyponatremia was once again illustrated during a fluid and electrolyte workshop I attended at the National Kidney Foundation’s Spring Clinical Meeting this year. The patient being discussed presented with a hypotonic euvolemic hyponatremia that many assumed to be due to SIADH, though he had no risk factors for it. Ultimately, he was found to have secondary adrenal insufficiency from a growing pituitary tumor.
As a medical student and early resident, I always felt that SIADH was a label given to hyponatremic patients with an otherwise unrevealing work-up, aka “hyponatremia NOS.” However, budding nephrologists such as myself must remember one of the original diagnostic criteria of SIADH as first described by Schwartz and colleagues in 1957: in the evaluation of euvolemic hyponatremia, SIADH is a diagnosis of exclusion. While most of us know to rule out hypothyroidism, the subtle signs and symptoms of secondary adrenal insufficiency often make it easy to overlook. Clinical situations such as these remind us of the importance of being systematic in our approaches to chief complaints and laboratory abnormalities regardless of our level of training.
Devika Nair, Nephrology Fellow, Vanderbilt