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.
|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).
Determination of volume status in true (hypo-osmolar) hyponatremia.
Differential diagnosis of true (hypo-osmolar) hyponatremia by volume status.
Differential Diagnosis of Hyponatremia
Heart failure (HF)
Renal failure (glomerular filtration rate [GFR] < 5 mL/min)
Syndrome of inappropriate antidiuretic hormone (SIADH)
Cancers (eg, pancreas, lung)
CNS disease (eg, cerebrovascular accident, trauma, infection, hemorrhage, mass)
Pulmonary diseases (eg, infections, respiratory failure)
Antidiuretic hormone (ADH) analogues (vasopressin, desmopressin acetate [DDAVP], oxytocin)
Chlorpropamide (6–7% of treated patients)
Antidepressants (tricyclics and selective serotonin reuptake inhibitors) and antipsychotics
Nonsteroidal antiinflammatory drugs (NSAIDs)
Others (cyclophosphamide, vincristine, nicotine, opioids, clofibrate)
Secondary adrenal insufficiency
Salt and water loss with free water replacement
Severe diarrhea with free water ingestion
Large burns with free water replacement
Third-spacing with free water replacement
Primary adrenal insufficiency
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):
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.
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.)
Pathophysiology of free water excretion. Free water diuresis requires (1) GFR, (2) functioning TAHL, and (3) absence of ADH. (ADH, antidiuretic hormone; GFR, glomerular filtration rate; TAHL, thick ascending loop of Henle.)
In short, free water excretion requires glomerular filtration, a functioning thick ascending loop of Henle, and low levels of ADH. Interference with these 3 mechanisms contributes to hyponatremia.
The adverse effects and manifestations of hyponatremia depend on its severity and rapidity of development. Acute hyponatremia leaves the brain hypertonic relative to the serum. This osmotic gradient drives water into the brain, resulting in cerebral edema and CNS symptoms. Typically, patients with serum sodium levels >130 mEq/L are asymptomatic; those with levels from 125 mEq/L to 130 mEq/L may have nausea, vomiting, or abdominal symptoms. Headache, agitation, and confusion may develop in patients with levels < 125 mEq/L. Levels below 120 mEq/L have been associated with seizures and coma. Severe acute hyponatremia may cause brain damage, brainstem herniation, respiratory arrest, and death. Rhabdomyolysis may occur. On the other hand, chronic hyponatremia allows neurons to decrease their intracellular osmolality and thereby causes less cerebral edema. Although minor symptoms are common, seizures and herniation are much less frequent in chronic hyponatremia.
|Because the classification scheme of hyponatremia relies on the correct determination of the patient's volume status, it is important to ask, “How reliable is the physical exam for classifying the patient's volume status?”|
In patients with hypervolemic hyponatremia, the hypervolemia is easily detected because the hyponatremia only develops in advanced disease (ie, HF, cirrhosis, or nephrotic syndrome).
There is often a known history of HF, cirrhosis, or nephrosis.
Physical findings of volume overload (eg, edema, jugular venous distention [JVD], S3, and ascites) are usually present.
In contrast, separating euvolemic patients from hypovolemic patients is more difficult.
Hypovolemic patients may have a history of volume loss (ie, diarrhea, intense prolonged sweating) or physical findings of hypotension, tachycardia, or orthostatic hypotension.
However, many hypovolemic patients with hyponatremia appear euvolemic, and the history and physical findings are neither sensitive nor specific for hypovolemia with LRs around 1.0 (Table 21–1).
Given the limitations of the history and physical exam, certain laboratory tests are critical to distinguish euvolemic patients from hypovolemic patients. The 3 most accurate biochemical parameters are the spot urine sodium, the fractional excretion of sodium (FENa), and the fractional excretion of urea (FEurea). All parameters were studied in patients who were either euvolemic or hypovolemia. Hypervolemic patients (with ascites or edema) were excluded because hyponatremia in these patients is usually due to ineffective circulating volume, and thus such patients usually avidly reabsorb sodium. Obtaining urine sodium measurements in them may mislead clinicians into thinking these patients are hypovolemic. The accuracy of these tests in euvolemic and hypovolemic patients is summarized in Table 21–1. These results are for patients not taking diuretics, since diuretics promote sodium loss and interfere with the ability to interpret the urine sodium concentration and FeNa+.
Spot urine sodium
Most hypovolemic patients avidly reabsorb sodium resulting in decreased urine sodium concentration.
Average urinary sodium in hypovolemic patients: 18.4 mEq/L, compared with 72 mEq/L in ...
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