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
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