Discussion:
The initial diagnostic approach to hyponatremia includes a serum
osmolality evaluation. A serum osmolarity of 280-295 mOsm/kg defines
isotonic hyponatremia. Isotonic hyponatremia can be seen with bladder
irrigation and pseudohyponatremia where normal plasma sodium
concentration is erroneously reported as low due to the presence of
hyperlipidemia or hyperproteinemia. Differential diagnosis for
hypertonic hyponatremia, defined as serum osmolarity >295
mOsm/kg, includes hyperglycemia, mannitol, or contrast agents. Hypotonic
hyponatremia is defined as a serum osmolarity of <280
mOsm/kg.9 However, determination of etiology and
appropriate management for hypotonic hyponatremia first requires a
thorough assessment of volume status.9 In contrast to
isotonic and hypertonic hyponatremia, the development of hypotonic
hyponatremia may be secondary to a multitude of pathologies impacting
fluid balance. As such, hypotonic hyponatremia may be dilutional due to
volume overload or the result of drugs and/or conditions that cause
volume contraction.
As seen in this case, hypotonic hyponatremia may occur in euvolemic
states as well. SIADH remains the leading cause of euvolemic
hyponatremia although other etiologies may also be responsible (Figure
1).9 As in this patient, adrenal insufficiency and
hypothyroidism must be excluded prior to reaching the diagnosis of
SIADH.9 Given the severe decline in sodium, laboratory
findings, and medication review, the development of hyponatremia in our
patient was likely SIADH exacerbated by the use of thiazide diuretics.
Since 1957, thiazide diuretics have been widely prescribed for the
management of hypertension.10 Though adverse effects
such as hypokalemia are generally appreciated, thiazide-associated
hyponatremia (TAH) is a frequently occurring electrolyte abnormality
that has been well described yet not widely
known.10-12 Diagnosis of TAH can be difficult as the
laboratory data of individuals with TAH are compatible with those of
SIADH. In both etiologies, a state of euvolemia is accompanied by
hyponatremia and serum hypoosmolality, inappropriate hyperosmolality of
the urine for the associated plasma tonicity, and an inappropriate
urinary sodium excretion (usually >40
mmol/L).13 Measurement of serum uric acid levels can
be helpful to determine the presence of TAH with coexistent SIADH.
Individuals with serum uric acid levels < 4gm/dL usually
exhibit SIADH with concurrent TAH, as the case here.14
Although a number of risk factors for TAH have been proposed, female
gender, low body weight and advanced age are the most frequently
reported.10-12,14 Our patient was a 73-year-old female
who weighed 54.5 kg and was taking chlorthalidone. The relative risk
for TAH is 3-4-fold higher in those 70 years or older. This is likely
the result of age-related reductions in the glomerular filtration rate
and subsequent impairment of free water
excretion.12,14 Though not fully elucidated, low body
weight is suggested to impair the renal diluting
capacity.14 Within the class of thiazide diuretics,
chlorthalidone is observed to have a higher incidence of
TAH.14 The onset of TAH is typically within 14-19 days
of starting therapy however it has been reported to occur as early as
1-2 days or be delayed with an onset of months to
years.11,12
Several proposed mechanisms describe the pathophysiology of TAH. These
include reduced sodium reabsorption in the distal tubules, impaired free
water excretion or both. Impaired free water excretion in TAH is
potentially secondary to impaired regulation of ADH. Studies have shown
that water reabsorption in the collecting duct of the renal tubule is
inducible by thiazide administration. Specifically, thiazides upregulate
ADH mediated water permeable transporters, or aquaporins, which increase
water permeability of apical cells in the renal collecting duct. This
increase in water permeability is inhibited by the ADH antagonist
prostaglandin-E2.11,12,14