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