Hyponatremia, Syndrome of Inappropriate Secretion of Antidiuretic Hormone Case File

Hyponatremia, Syndrome of Inappropriate Secretion of Antidiuretic Hormone Case File

Eugene C. Toy, MD, Gabriel M. Aisenberg, MD

Case 47

A 65-year-old woman is brought to the emergency department (ED) by her family for increasing confusion and lethargy over the past week. She was recently diagnosed with limited-stage small-cell lung cancer but has not begun cancer treatment. She has been afebrile and has not had any illnesses. She is not taking any medications. Her blood pressure is 136/82 mm Hg, heart rate is 84 beats per minute (bpm), and respiratory rate is 14 breaths per minute and unlabored. On examination, she is an elderly woman who is difficult to arouse and reacts only to painful stimuli. She is able to move her extremities without apparent motor deficits, and her deep tendon reflexes are decreased symmetrically. The remainder of her examination is normal, with normal jugular venous pressure and no extremity edema. You order some laboratory tests, which reveal a serum sodium level of 108 mmol/L, potassium 3.8 mmol/L, bicarbonate 24 mEq/L, blood urea nitrogen (BUN) 5 mg/dL, and creatinine 0.5 mg/dL. Serum osmolality is 220 mOsm/kg, and urine osmolality is 400 mOsm/kg. Urine sodium concentration is 50 mEq/L. A computed tomography (CT) scan of the brain shows no masses or hydrocephalus.

▶ What is the most likely diagnosis?

▶ What is your next step in therapy?

▶ What is the most serious complication of this therapy?

ANSWERS TO CASE 47:

Hyponatremia, Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Summary: A 65-year-old woman with small-cell lung cancer presents with

• Increasing confusion and lethargy over the past week, but no focal deficit
• Normal temperature and blood pressure
• No edema or jugular venous distention
• Symmetrically decreased deep tendon reflexes
• Significant hyponatremia and low serum osmolality, with unexpectedly high urine osmolality
• No masses or hydrocephalus on brain CT scan

Most likely diagnosis: Coma/lethargy secondary to severe hyponatremia, which is most likely caused by a paraneoplastic syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

Next therapeutic step: Treat the hyponatremia with hypertonic saline.

Most serious complication of this therapy: Osmotic demyelination syndrome, formerly referred to as central pontine myelinolysis.

ANALYSIS

Objectives

1. List the causes of hyponatremia. (EPA 1, 2)
2. Understand the use of laboratory testing in the diagnosis of hyponatremia. (EPA 3)
3. Describe the treatment of hyponatremia and some of the potential complications of therapy. (EPA 4, 10)

Considerations

This 65-year-old woman with small-cell lung cancer presents in a stuporous state with hypotonic hyponatremia. She appears euvolemic, as she does not have findings suggestive of either volume overload (jugular venous distention or peripheral edema) or volume depletion (diminished skin turgor). Of note, the term volemia refers to intravascular volume. In this chapter, we use volemia to represent total body sodium (in this case, both variables are not coincident all the time). She has no focal neurologic deficits or apparent masses on CT scan of the brain suggesting cerebral metastases. The most likely cause of her altered mental status is hyponatremia. The patient does not take medications. Thus, in the situation of hypotonic hyponatremia in a euvolemic state and with inappropriately concentrated urine, the most likely etiology is inappropriate antidiuretic hormone (ADH) produced by the lung cancer. Therapy is guided by the severity of the hyponatremia and the symptoms. Because this individual is stuporous and the sodium level is severely decreased, hypertonic saline is required with fairly rapid partial correction. This therapy is not benign and requires monitoring in the intensive care unit. Also, the goal is not correction of the sodium level to normal (135 mmol/L) but rather an increase in serum sodium concentration by 4 to 6 mmol/L in 24 hours.

APPROACH TO:

Hyponatremia

DEFINITIONS

ANTIDIURETIC HORMONE: The posterior pituitary hormone that controls excretion of free water and thus, indirectly, sodium concentration and serum tonicity. Also referred to as arginine vasopressin.

OSMOLALITY: Concentration of osmotically active particles, which draw water into a compartment; the normal range for serum osmolality is 280 to 300 mOsm/kg.

SYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE: Nonphysiologic elevation of ADH levels as a consequence of ectopic production, as in malignancy, or stimulation of excess pituitary production by various pulmonary or central nervous system (CNS) diseases.

CLINICAL APPROACH

Pathophysiology

Hyponatremia is defined as a serum sodium level < 135 mmol/L and is, by far, the most common electrolyte disturbance among hospitalized patients. Patients are often asymptomatic, especially if the hyponatremia develops slowly. Depending on how rapidly the hyponatremia develops, most patients do not have symptoms until the serum sodium level is in the low 120 mmol/L range. Note: since sodium is a monovalent cation, 1 mmol/L = 1 mEq/L.

Serum sodium concentrations are important because they almost always reflect tonicity, the effect of extracellular fluid on cells that will cause the cells (eg, brain cells) to swell (hypotonicity) or to shrink (hypertonicity). For purposes of this discussion, we use serum osmolality as an indicator of tonicity.

Hypotonic hyponatremia always occurs because there is water gain, that is, impairment of free water excretion. If one considers that the normal kidney capacity to excrete free water is approximately 18 to 20 L/d, it becomes apparent that it is very difficult to overwhelm this capacity solely through excessive water intake, as in psychogenic polydipsia. 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 health care provider must clinically assess the volume status of the patient by history and physical examination. A useful algorithm for assessment of patients with hyponatremia is seen in Figure 47–1. Please note that the figure uses the term volemia. Though less commonly used, the “volume status” we refer to is actually “total body sodium.” A more comfortable way to name the issue at stake is “interstitial volume status.”

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 less than 20 mmol/L. If the patient is hypovolemic, yet the urine sodium level is more than 20 mmol/L, then the kidneys do not have the ability to retain sodium normally. In this case, kidney function is impaired by the use of diuretics, 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%) saline.

Hypervolemia is usually apparent as edema or elevated jugular venous pressure. It commonly occurs as a result of heart failure, cirrhosis of the liver, or 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 excess salt and water.

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 osmolality. This measurement is taken to determine whether the kidney is actually capable of excreting the free water normally (urine osmolality should be maximally dilute, < 100 mOsm/kg) or whether the free water excretion is impaired (urine not maximally diluted, > 100 mOsm/kg). If the urine is maximally diluted, 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 diluted 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. Cortisol deficiency in secondary (pituitary) adrenal insufficiency can mimic SIADH. In contrast, patients with primary adrenal insufficiency (Addison disease) may also lack aldosterone, so they have impaired ability to retain sodium and often appear hypovolemic and may even present in shock.

Figure 47–1. Assessment of hyponatremia. (Reproduced with permission, from Longo DL, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 18th ed. 2012. Copyright © McGraw Hill LLC. All rights reserved.)

Euvolemic hyponatremia is most commonly caused by SIADH. However, as mentioned, Addison disease and hypothyroidism should also be considered as potential causes of euvolemic hyponatremia (it should be noted that forms of Addison disease that impair both cortisol and aldosterone production will present with hypovolemia, while those that affect only cortisol production will present with euvolemia).

Clinical Presentation

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 insignificant) 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 > 40 mmol/L.

SIADH is a diagnosis of exclusion: The patient must be hypoosmolar but euvolemic, with urine that is not maximally dilute (osmolality > 100 mOsm/L), urine sodium more than 40 mmol/L, and normal adrenal and thyroid function. Some laboratory clues to SIADH are low blood urea nitrogen (BUN) and low uric acid levels.

The clinical manifestations are related to osmotic water shifts leading to cerebral edema; thus, the symptoms are mainly neurologic. Early symptoms include headache, nausea, and vomiting; later symptoms may progress to lethargy, confusion, seizures, or coma.

Treatment

Unless the patient has severe neurologic symptoms, the usual initial treatment of SIADH is free 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 (eg, 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.

For patients with chronic hypervolemic hyponatremia, as in heart failure or cirrhosis, vasopressin antagonists (tolvaptan and conivaptan are approved for use in the United States) are now available and are very effective in increasing free water excretion and raising serum sodium concentrations. Therapy with these agents is initiated in the hospital with close monitoring of sodium concentration.

Complications

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 demyelination syndrome 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. For any patient with hyponatremia, the general rule is that chronic hyponatremia should be corrected slowly, and acutely developing hyponatremia can be corrected more quickly. In chronic hyponatremia, the serum sodium concentration should be corrected no faster than 4 to 6 mEq/L in the first 24 hours.

CASE CORRELATION

• See also Case 18 (Hemoptysis/Lung Cancer), Case 37 (Alzheimer Disease/Dementia), Case 49 (Adrenal Insufficiency), and Case 50 (Hypercalcemia/Multiple Myeloma).

COMPREHENSION QUESTIONS

47.1 A 24-year-old man developed seizures 12 hours after an emergent splenectomy, which he required after a motor vehicle collision. After a search for etiology, he was found to have a serum sodium level of 116 mEq/L. He was treated with intravenous hypertonic saline; after 3 hours, the serum sodium level was 120 mEq/L. Which of the following factors most likely led to his hyponatremia?

A. Postoperatively inappropriate elevation of serum vasopressin

B. Administration of hypertonic solutions

C. Acute kidney injury

D. Seizure-induced hyponatremia

47.2 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 one 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-to-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 a week. The laboratory calls you that night and informs you that the patient’s sodium level is 126 mEq/L, potassium level is 6.7 mEq/L, creatinine level is normal, and bicarbonate and chloride levels are low. Which of the following is the likely cause of his hyponatremia given his presentation?

A. SIADH

B. Hypothyroidism

C. Gastrointestinal losses

D. Adrenal insufficiency

E. Renal insufficiency

47.3 An 83-year-old woman comes to your clinic complaining of a headache and mild confusion. Her 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 osmolality is 245 mOsm/kg. She confides that she has been drinking and eating less since her husband passed away 4 months ago. She appears to be clinically hypovolemic. Which of the following 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

47.4 A 58-year-old man has undergone a lengthy colon cancer surgery. On the first postoperative day, he is noted to have hyponatremia with a sodium level of 128 mEq/L. You suspect that the hyponatremia is due to the intravenous infusion of hypotonic solution. Which of the following laboratory findings best supports your diagnosis?

A. Urine sodium > 20 mmol/L

B. Urine osmolality > 200 mOsm/L

C. Serum osmolality < 280 mOsm/kg

D. Serum potassium > 5 mmol/L

ANSWERS

47.1 A. In the postoperative state or in situations where the patient is in pain, the serum vasopressin level may rise, leading to inappropriate retention of free water, which leads to dilution of the serum. Concomitant administration of hypotonic fluids (not hypertonic, as in answer B) may exacerbate the situation. Acute kidney injury (answer C) may lead to mild hyponatremia due to inability to excrete free water; usually, the sodium level will be > 125 mmol/L. Seizures (answer D) are likely a result of this patient’s hyponatremia, rather than causing the low sodium; in fact, seizures are more likely to lead to hypernatremia.

47.2 D. Hyponatremia in the setting of hyperkalemia and acidosis (low bicarbonate level) is suspicious for adrenal insufficiency. This patient’s examination is also suggestive of the diagnosis, given his complaints of fatigue, weight loss, low blood pressure, and hyperpigmentation. The diagnosis is made by an early morning cortisol test or by measuring the response to adrenocorticotropic hormone (ACTH) stimulation, showing low cortisol levels. In this case, the cause of the adrenal gland destruction is probably due to either tuberculosis or metastatic lung cancer. As a reminder, some forms of Addison disease can cause reduced production of cortisol and aldosterone, which can present as a hyponatremic hypovolemia, while forms that affect cortisol production only will present with hyponatremic euvolemia. SIADH (answer A) and hypothyroidism (answer B) do not lead to hyperpigmentation, low blood pressure, hyperkalemia, or acidosis. Gastrointestinal fluid losses (answer C) also would not lead to hyperpigmentation; furthermore, the electrolyte derangements would be hypokalemia and alkalosis with diarrhea. Renal insufficiency (answer E) would not be associated with hyperpigmentation or digital clubbing.

47.3 B. Because the patient is hypovolemic, probably as a result of the use of diuretics, volume replacement with isotonic saline is the best initial therapy. Hyponatremia caused by thiazide diuretics can occur by several mechanisms, including volume depletion. It is most common in elderly women. Volume replacement takes precedence over sodium correction (answers C and D). A fluid restriction (answer A) would be inappropriate at this time.

47.4 C. In a patient with hyponatremia due to the infusion of excessive hypotonic solution, the serum osmolarity should be low. When responding normally, the kidneys should attempt to retain sodium and excrete water; hence, the urine sodium concentration should be low, and the urine osmolality should be low (not high, as in answer B). When the infusion of hypotonic solution is used, the serum potassium level will also be low. This is in contrast to a situation of mineralocorticoid deficiency, in which the serum sodium level will be decreased (answer A) and potassium level may be elevated (answer D). Similarly, hyperaldosteronism can lead to hypertension and hypokalemia (Conn syndrome). In summary, while a low serum osmolality is common to many possible diagnoses, the alternative answers are clearly wrong, because in essence, the kidneys will be excreting free water.

CLINICAL PEARLS

▶ Hyponatremia almost always occurs by impairment of free water excretion.

▶ SIADH is a diagnosis of exclusion. Criteria include a euvolemic patient, urine that is not maximally dilute (osmolality > 150-200 mmol/L), urine sodium > 20 mmol/L, and normal adrenal and thyroid function.

▶ Hypovolemic patients with hyponatremia should be treated with volume replacement, typically with isotonic (0.9%) saline.

▶ Euvolemic patients with asymptomatic hyponatremia can be treated with fluid restriction. Patients with severe symptoms, such as coma or seizures, can be treated with hypertonic (3%) saline.

▶ The rate of sodium correction generally should not exceed 4-6 mmol/L per day; otherwise, central pontine myelinolysis (osmotic demyelination) can occur.

REFERENCES

Adrogue H, Madias N. Hyponatremia. N Engl J Med. 2000;342:1581-1589. 

Lin M, Liu SJ, Lim IT. Disorders of water imbalance. Emerg Med Clin North Am. 2005;23:749-770. 

Mount DB. Fluid and electrolyte disturbances. In: Kasper DL, Fauci AS, Hauser SL, et al, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw Hill Education; 2015:295-312. 

Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Semin Nephrol. 2009;29(3):175-318. 

Yasir M, Mechanic OJ. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) In: StatPearls. Treasure Island, FL: StatPearls; 2019. https://www.ncbi.nlm.nih.gov/books/NBK507777/. Updated April 2, 2019. Accessed April 24, 2020.

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