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Mr. D is a 42-year-old man who is brought to the emergency department by the police department. He is disoriented and confused. Initial labs reveal a serum sodium concentration of 118 mEq/L.

Image not available.What is the differential diagnosis of hyponatremia? How would you frame the differential?

Constructing a Differential Diagnosis


Hyponatremia develops when the body is unable to excrete free water. Hyponatremia is defined as serum sodium concentration < 134 mEq/L and is significant when the concentration is < 130 mEq/L. The first step in evaluating the hyponatremic patient is to review the history and laboratory results for a few diagnostic fingerprints that may be present (ie, a history of thiazide ingestion suggests diuretic-induced hyponatremia, hyperkalemia suggests primary adrenal insufficiency, a urine osmolality ≈100 mOsm/L suggests psychogenic polydipsia, and marked hyperglycemia suggests hyperglycemia-induced hyponatremia.) For most patients, these tests will not be diagnostic and the key pivotal point in the differential diagnosis is to determine the patient's volume status and identify who is clinically hypervolemic, euvolemic, or hypovolemic. This step narrows the differential diagnosis and is necessary to properly interpret test results. Correct classification of the patient's volume status requires a review of the history, physical exam findings, and laboratory results (Figure 21–1). After the patient's volume status has been determined, the different etiologies can be considered (Figure 21–2).

Figure 21-1
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Determination of volume status in true (hypo-osmolar) hyponatremia.

Figure 21-2
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Differential diagnosis of true (hypo-osmolar) hyponatremia by volume status.


Differential Diagnosis of Hyponatremia


  1. Hypervolemia

    1. Heart failure (HF)

    1. Cirrhosis

    1. Nephrotic syndrome

    1. Renal failure (glomerular filtration rate [GFR] < 5 mL/min)

  2. Euvolemia

    1. Syndrome of inappropriate antidiuretic hormone (SIADH)

      1. Cancers (eg, pancreas, lung)

      1. CNS disease (eg, cerebrovascular accident, trauma, infection, hemorrhage, mass)

      1. Pulmonary diseases (eg, infections, respiratory failure)

      1. Drugs

        1. Thiazides

        1. Antidiuretic hormone (ADH) analogues (vasopressin, desmopressin acetate [DDAVP], oxytocin)

        1. Chlorpropamide (6–7% of treated patients)

        1. Carbamazepine

        1. Antidepressants (tricyclics and selective serotonin reuptake inhibitors) and antipsychotics

        1. Nonsteroidal antiinflammatory drugs (NSAIDs)

        1. Ecstasy (MDMA)

        1. Others (cyclophosphamide, vincristine, nicotine, opioids, clofibrate)

    1. Hypothyroidism

    1. Psychogenic polydipsia

    1. Secondary adrenal insufficiency

    1. Exercise-associated hyponatremia

  3. Hypovolemia

    1. Salt and water loss with free water replacement

      1. Severe diarrhea with free water ingestion

      1. Large burns with free water replacement

      1. Third-spacing with free water replacement

    1. Primary adrenal insufficiency

    1. Renal disease

      1. Diuretics

      1. Salt-wasting nephropathy


Before proceeding, it is useful to briefly review the pathophysiology of hyponatremia. Hyponatremia develops when patients do not excrete their daily ingested excess (or free) water. Free water excretion requires 3 distinct mechanisms (Figure 21–3):


  1. Glomerular filtration

  2. Separation of water from solute so that free water can be excreted. This occurs in the thick ascending loop of Henle. This section of the tubule is impermeable to water. Therefore, sodium pumped out of the lumen leaves free water within the tubule.

  3. Excretion of free water. Finally, water must travel through the tubules without being reabsorbed into the kidney. This requires absent or low levels of ADH. (ADH increases the permeability of the tubules [via aquaporin channels] allowing water within the tubules to leak back into the interstitium.)


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