Causes Of Hyponatremia

I. Pseudohyponatrcmia

A. Normal plasma osmolarity

1. Hyperlipidcmia

2. Hyperproteinemia

3. Posttransurethral resection of prostate/bladder tumor

B. Increased plasma osmolarity

1. Hyperglycemia

2. Mannitol

II. Hyposmolar Hyponatremia

Primary Na* loss (secondary water gain)

1. Integumentary loss: sweating, burns

2. Gastrointestinal loss: vomiting, tube drainage, fistula, obstruction, diarrhea

3. Renal loss: diuretics, osmotic diuresis, hypoaldosleronism. salt-wasting nephropathy, postobstructive diuresis, nonoliguric acute tubular necrosis

A. Primary water gain (secondary Na+ loss)

1. Primary polydipsia

2. Decreased solute intake (e.g.. beer potomania)

3. AVP release as a result of pain, nausea, drugs

4. Syndrome of inappropriate AVP secretion

5. Glucocorticoid deficiency

6. Hypothyroidism

7. Chronic renal insufficiency

B. Primary Na+ gain (exceeded by secondary water gain)

1. Heart failure

2. Hepatic cirrhosis

3. Nephrotic syndrome

Reproduced, with permission, from Braunwald E. Fauci AS. Kasper KL. et al. eds. Harrison's principles of internal medicine. 16th ed. New York: McGraw-Hill. 2(M)5:255.

resection of the prostate is a common cause of hyponatremia because of the large volume of mannitol-containing bladder irrigation fluid used intraopera-tively. For either of these states, correction of the glucose level (or excretion of the mannitol) corrects the hyponatremia.

Pseudohyponatremia refers to an artifact of measurement in states where the serum sodium level and. thus, the tonicity are. in fact, normal. In the past this occurred when high serum proteins levels (as in a paraproteinemia such as multiple myeloma) or very high lipid levels interfered with measurement of the serum sodium level. With current laboratory technology, the sodium level is directly measured, so pseudohyponatremia is not common. One can suspect pseudohyponatremia if the measured and calculated serum osmolarities are different.

Hypotonic hyponatremia always occurs because there is water gain, that is, restriction or impairment of free water excretion. If one considers that the normal kidney capacity to excrete free water is approximately 18-20 L/d, it becomes apparent that it is very difficult to overwhelm this capacity solely through excessive water intake. Therefore, when hyponatremia develops, the kidney is usually holding on to free water, either pathologically, as in SIADH, or physiologically, as an attempt to maintain effective circulating volume when patients are significantly volume depleted. Hyponatremia can also occur in cases of sodium loss, for example, as a consequence of diuretic use, or because of aldosterone deficiency. However, in those cases, there is then a secondary gain of free water.

To determine the cause of the hypotonic hyponatremia, the physician must clinically assess the volume status of the patient by history and physical examination. A history of vomiting, diarrhea, or other losses, such as profuse sweating, suggests hypovolemia, as do flat neck veins, dry oral mucous membranes, and diminished urine output. In cases of significant hypovolemia, there is a physiologic increase in ADH in an attempt to retain free water to maintain circulating volume, even at the expense of hypotonicity. In these cases, the excess ADH is not "inappropriate" as in SIADH, but extremely appropriate. At this point, one can check the urinary sodium levels. In hypovolemia, the kidney should be avidly retaining sodium, so the urine sodium level should be <20 mmol/L. If the urine sodium level is >20 mmol/L, the kidneys do not have the ability to retain sodium normally. Either kidney function is impaired by the use of diuretics, or the kidney is lacking necessary hormonal stimulation, as in adrenal insufficiency, or there is a primary renal problem, such as tubular damage from acute tubular necrosis. When patients are hypovolemic, treatment of the hyponatremia requires correction of the volume status, usually replacement with isotonic (0.9%) or "normal" saline.

Hypervolemia is usually apparent as edema or elevated jugular venous pressure. It commonly occurs as a result of congestive heart failure, cirrhosis of the liver, or the nephrotic syndrome. In these edematous disorders, there is usually a total body excess of both sodium and water, yet arterial baroreceptors perceive hypoperfusion or a decrease in intravascular volume, which leads to an increase in the level of ADH and, therefore, retention of free water by the kidneys. Renal failure itself can lead to hypotonic hyponatremia because of an inability to excrete dilute urine. In any of these cases, the usual initial treatment of hyponatremia is administration of diuretics to reduce both salt and water excess. Thus, hypovolemic or hypervolemic hyponatremia is often apparent clinically and often does not present a diagnostic challenge. Euvolemic hyponatremia, however, is a frequent problem that is not so easily diagnosed. Once the clinician has diagnosed the patient with euvolemic hypotonic hyponatremia, the next step is to measure the urine osmolarity. This measurement is taken to determine whether the kidney is actually capable of excreting the free water normally (osmolality should be maximally dilute, <100 mOsm/kg in the face of hyposmolality or free water excess) or whether the free water excretion is impaired (urine not maximally concentrated, >150-200 mOsm/kg). If the urine is maximally dilute, it is handling free water normally but its capacity for excretion has been overwhelmed, as in central polydipsia. More commonly, free water excretion is impaired and the urine is not maximally dilute as it should be. Two important diagnoses must be considered at this point: hypothyroidism and adrenal insufficiency. Thyroid hormone and Cortisol both are permissive for free water excretion, so their deficiency causes water retention. Isolated Cortisol deficiency can mimic SIADH. In contrast, patients with Addison disease also lack aldosterone, so they have impaired ability to retain sodium. Patients with adrenal insufficiency are usually hypovolemic and often present in shock.

Euvolemic hyponatremia is most commonly caused by SIADH. Nonphysiologic nonosmotically mediated (therefore "inappropriate") secretion can occur in the setting of pulmonary disease, CNS disease, pain, in the postoperative period, or as part of a paraneoplastic syndrome. Because of retention of free water, patients actually have mild (although clinically inap-parent) volume expansion. Additionally, if they have a normal dietary sodium intake, the kidneys do not retain sodium avidly. Therefore, modest natriuresis occurs so that the urine sodium level is elevated to >20 mmol/L. SIADH is a diagnosis of exclusion: the patient must be hyposmolar but euvolemic, with urine that is not maximally dilute (osmolality >150-200 mosm/L), urine sodium >20 mmol/L, and normal adrenal and thyroid function. Some laboratory clues to SIADH are low BUN and low uric acid levels. Unless the patient has severe neurologic symptoms, the treatment of SIADH is water restriction.

Patients with severe neurologic symptoms, such as seizures or coma, require rapid partial correction of the sodium level. The treatment of choice is hypertonic (e.g., 3%) saline. When there is concern that the saline infusion might cause volume overload, the infusion can be administered with a loop diuretic such as furosemide. The diuretic will cause the excretion of hypotonic urine that is essentially "half-normal saline," so a greater portion of sodium than water will be retained, helping to correct the serum sodium level.

When hyponatremia occurs for any reason, especially when it occurs slowly, the brain adapts to prevent cerebral edema. Solutes leave the intracellular compartment of the brain over hours to days, so patients may have few neurologic symptoms despite very low serum sodium levels. If the serum sodium level is corrected rapidly, the brain does not have time to readjust, and it may shrink rapidly as it loses fluid to the extracellular space. It is believed that this rapid shrinkage may trigger demyelination of the cerebellar and pontine neurons. This osmotic cerebral demyelination. or central pontine myeiinolysis. may cause quadriplegia, pseudobulbar palsies, a "locked-in" syndrome, coma, or death. Demyelination can occur even when fluid restriction is the treatment used to correct the serum sodium level. Therefore, several expert authors have published formulas and guidelines for the slow and judicious correction of hyponatremia, but the general rule is not to correct the serum sodium concentration faster than 0.5-1 mEq/h.

Comprehension Questions

[5.1] A young man develops seizures following an emergent splenectomy after a car accident. His serum sodium level is initially 116 mEq/L and is corrected to 120 mEq/L over the next 3 hours with hypertonic saline. Which of the following factors most likely led to his hyponatremia?

A. Elevation of serum vasopressin

B. Administration of hypertonic solutions

C. Volume depletion

D. Seizure-induced hyponatremia

[5.2] A 56-year-old man presents to the doctor for the first time complaining of fatigue and weight loss. He has never had any health problems, but he has smoked a pack of cigarettes per day for about 35 years. He is a day laborer and is currently homeless and living in a shelter. His physical examination is notable for a low-normal blood pressure, skin hyperpigmentation, and digital clubbing. He appears euvolemic. You tell him you are not sure of the problem as yet, but you will draw some blood tests and schedule him for follow-up in 1 week. The laboratory calls that night and informs you that the patient's sodium level is 126 mEq/L, potassium level is 6.7 mEq/L. creatine level is normal, and bicarbonate and chloride levels are low. What is the likely cause of his hyponatremia given his presentation?


B. Hypothyroidism

C. Gastrointestinal losses

D. Adrenal insufficiency

E. Renal insufficiency

[5.3] An 83-year-old woman comes to your office complaining of a headache and mild confusion. Her only medical history is remarkable only for hypertension, which is well controlled with hydrochlorothiazide. Her examination and laboratory tests show no signs of infection, but her serum sodium level is 119 mEq/L, and plasma osmolarity is 245 mOsm/kg. She appears to be clinically hypovolemic. What is the best initial therapy?

A. Fluid restriction

B. Infusion of 0.9% saline

C. Infusion of 3% saline

D. Infusion of 3% saline with furosemide

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