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PATIENT
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?
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CONSTRUCTING A DIFFERENTIAL DIAGNOSIS
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As noted in Chapter 1, the first task when evaluating patients is to identify their problem(s). Mr. D’s problems clearly include delirium and marked hyponatremia. While other causes of delirium should be considered, (see Chapter 11 Delirium & Dementia) the hyponatremia clearly requires evaluation because it is severe and thus likely to be causing the delirium.
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Hyponatremia is defined as serum sodium concentration < 135 mEq/L and is significant when the concentration is < 130 mEq/L. The differential diagnosis for hyponatremia is long but the diagnostic approach can be easily framed in a few simple steps. These pivotal steps include (1) a quick search for rapid diagnostic clues; (2) a clinical assessment of the patients volume status to limit the differential; (3) in clinically euvolemic patients, a review of the patients urine sodium and response to a saline challenge to unmask subtle hypovolemia (4) in euvolemic patient further tests to distinguish the syndrome of inappropriate antidiuretic hormone (SIADH) from other less common causes of euvolemic hyponatremia; and finally (5) an exploration for the risk factors, associated symptoms, and signs for the diagnoses within each subgroup. Each of these steps is discussed below.
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The first step recognizes that a few key clinical and laboratory features occasionally point to very specific diagnoses. Examples of these include thiazide use (suggesting diuretic-induced hyponatremia), recent participation in marathon events (suggesting exercise-associated hyponatremia [EAH]), hyperkalemia (suggesting kidney disease or primary adrenal insufficiency), very low urine osmolality (suggesting psychogenic polydipsia, Ecstasy use, or beer potomania) or markedly elevated blood glucose, or a normal serum osmolality (suggesting hyperglycemia-induced hyponatremia and pseudohyponatremia, respectively). Thus, the first pivotal step in approaching hyponatremia systematically reviews these few variables to search for clues (Figure 24-1).
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For many patients, the previously mentioned clues are absent and the second pivotal step evaluates the patient’s clinical volume status in order to determine whether they are clinically hypervolemic, clinically euvolemic, or clinically hypovolemic. This allows the differential diagnosis to be narrowed to that appropriate subset of diagnoses (Figure 24-2). Correct classification of the patient’s volume status requires a review of the history, physical exam findings, and laboratory results. The clinical recognition of hypervolemic patients is very accurate because hyponatremia typically develops in patients with advanced heart failure (HF), cirrhosis, nephrotic syndrome, and chronic kidney disease when the disease is easily recognized. Similarly marked hypovolemia is often readily apparent when hypotension or orthostasis is present. However, hypovolemia may also be subtle. Hypovolemic patients may appear clinically euvolemic. Therefore, the differential diagnosis of patients that appear clinically euvolemic includes both euvolemic and hypovolemic etiologies.
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The third pivotal step analyzes the clinically euvolemic group to unmask subtle hypovolemia by analyzing (1) the urine Na+ or FeNa+ and (2) the response to a small saline challenge (Figure 24-3).
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Spot urine sodium and FeNa+
Since hypovolemia promotes avid sodium reabsorption, hypovolemia is usually associated with a low urinary sodium concentration (< 20–30 mEq/L) and low FeNa+(< 0.5%). On the other hand, euvolemic patients do not have a stimulus to reabsorb urine sodium and usually have a higher urinary sodium (> 20–30 mEq/L) and FeNa+.
Average urinary sodium in hypovolemic patients: 18.4 mEq/L, compared with 72 mEq/L in euvolemic patients
Urine Na+ < 30 mEq/L: 63–80% sensitive for hypovolemia, 72–100% specific, LR+ 2.2-∞, LR– 0.2–0.5
FeNa+ may be more sensitive.
FENa+ = (UNa+ × PCr)/(PNa+ × UCr)
Compares fraction of sodium excreted to fraction of sodium filtered. In hypovolemic states, the fraction excreted should be low (< 0.5%).
One study reported FeNa+ < 0.5% 100% sensitive for hypovolemia, 72% specific, LR+ 3.5, LR- 0
False-negative results (elevated urine sodium or FeNa+ in hypovolemic patients) may be seen in hypovolemia secondary to:
Diuretics
Primary adrenal insufficiency in which the hypoaldosteronism directly leads to urinary sodium wasting.
Vomiting with accompanying metabolic alkalosis. The metabolic alkalosis causes an obligatory urinary HCO3− loss, which is accompanied by sodium. Urine chloride may be low and diagnostic in such cases.
False-positive results (low urine sodium in euvolemic patients) may be seen in certain euvolemic patients.
Psychogenic polydipsia. These patients are euvolemic but usually have low urine sodium concentration due to dilution of the excreted sodium in vast quantities of water.
Some patients with SIADH ingest little sodium causing decreased urinary sodium output.
Finally the urine Na+ and the FeNa+ should not be measured in clinically hypervolemic patients. Hypervolemia in such patients is usually associated with ineffective circulating volume, which promotes avid sodium reabsorption. Obtaining urine sodium measurements in such patients may mislead clinicians into classifying these patients as hypovolemic.
The response to a small saline challenge can also be diagnostically useful. In hypovolemic hyponatremia patients, antidiuretic hormone (ADH) is triggered by the hypovolemia and suppressed by volume resuscitation. Therefore, saline challenges can suppress ADH, promote a water diuresis, and cause a rise in the serum sodium. On the other hand, in euvolemic patients ADH is not volume dependent and persists despite the saline challenge. The persistent ADH results in retention of the water contained in the saline whereas the sodium is excreted resulting in a paradoxical fall in the serum sodium with a normal saline challenge.
Together the urinary sodium and saline challenge can usually accurately categorize euvolemic and hypovolemic patients (see Figure 24-3). Because normal saline can decrease the serum sodium in patients with SIADH, normal saline should not be used in patients with an initial serum sodium < 120 mEq/L. Consultation is advised.
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In euvolemic patients a fourth step is required to distinguish SIADH from less common causes of euvolemic hyponatremia (Figure 24-4). Attending “raves” may suggest Ecstasy use. Maximally dilute urine suggests beer potomania, psychogenic polydipsia, or Ecstasy use and a high thyroid-stimulating hormone (TSH) or low cortisol can suggest hypothyroidism or adrenal insufficiency, respectively. Euvolemic patients without any of the aforementioned diagnoses likely have SIADH.
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The final step reviews the diagnoses within the appropriate subset, searching for risk factors and associated symptoms or signs that suggest one of those diseases.
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The differential diagnosis of hyponatremia classified by volume status is listed below.
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Differential Diagnosis of Hyponatremia
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Hypervolemia
HF
Cirrhosis
Nephrotic syndrome
Renal failure (glomerular filtration rate [GFR] < 5 mL/min)
Euvolemia
Thiazide diuretics
SIADH
Cancers (eg, pancreas, lung)
CNS disease (eg, cerebrovascular accident, trauma, infection, hemorrhage, mass)
Pulmonary diseases (eg, infections, respiratory failure)
Drugs
Hypothyroidism, severe
Psychogenic polydipsia
Secondary adrenal insufficiency
EAH
Beer potomania
Hypovolemia
Thiazide diuretics
Salt and water loss with free water replacement (ie, vomiting or diarrhea)
Primary adrenal insufficiency
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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: glomerular filtration, a functioning thick ascending loop of Henle (to separate water from solute), and low levels of ADH, which prevent water reabsorption from the tubules into the interstitium. Interference with these 3 mechanisms contributes to hyponatremia (Figure 24-5).
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Symptoms of Hyponatremia
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The adverse effects and manifestations of hyponatremia depend on its severity and rapidity of development. Acute hyponatremia leaves the serum hypotonic relative to the brain. This osmotic gradient drives water into the brain, resulting in cerebral edema and CNS symptoms. Severe acute hyponatremia may cause brain damage, brainstem herniation, respiratory arrest, and death. Rhabdomyolysis may occur. On the other hand, in chronic hyponatremia (most cases) CNS adaptations occur. Neurons decrease their intracellular osmolality, decreasing the osmotic flux of water into the brain in turn causing less cerebral edema. Although minor symptoms are common in chronic hyponatremia, seizures and herniation are much less frequent. Typically, patients with serum sodium levels > 130 mEq/L are asymptomatic; those with levels from 120 mEq/L to 130 mEq/L may have nausea, vomiting, abdominal symptoms, mild cognitive and gait disturbances. 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.
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Due to his confusion, Mr. D cannot give a medical history. His chart is requested. Physical exam reveals a disheveled man appearing older than 42. He smells of alcohol. His vital signs are BP, 90/50 mm Hg; pulse, 90 bpm; temperature, 36.0°C; RR, 18 breaths per minute. He has no orthostatic changes. Neck veins are flat. His lungs are clear to auscultation. Cardiac exam reveals a regular rate and rhythm. There is no jugular venous distention (JVD), S3 gallop, or murmur. His abdomen is distended, and his flanks are bulging. Extremity exam reveals 3+ pitting edema extending all the way up his thighs.
Laboratory studies reveal a glucose of 100 mg/dL, K+ 3.8 mEq/L, a BUN of 28 mg/dL, creatinine 1.0 mg/dL, and a serum osmolality of 252 mOsm/L. Urine osmolality is 480 mOsm/L.
At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?