Samuel H. Sigal, MD

Cirrhosis is one of the main causes of hypervolemic hyponatremia, a dilutional form of hyponatremia that occurs when there is an increase in total body water but a relatively smaller increase in total serum sodium. Portal hypertension is the main precipitating factor in fluid retention that leads to the development of cirrhotic hyponatremia. In cirrhosis, portal hypertension is determined by 2 main factors: increased intrahepatic resistance and increased spanchnic blood flow. The increased intrahepatic resistance is due to both structural (fibrosis, conversion of low resistance fenestrated sinusoids into capillaries) and dynamic (vasoconstriction due to endothelial cell dysfunction) changes.1

The hepatic circulation normally is able to accommodate an increase in portal blood flow associated with postprandial hyperemia. The elevated intrahepatic resistance in cirrhosis results in an inability to accommodate the normal increase in portal blood flow that occurs in the postprandial hyperemia state.3 As a result, portal pressure increases during postprandial hyperemia, leading to reflex vasoconstriction, which creates a shear stress and increases splanchnic nitric oxide (NO) production.4 NO, one of the most important vasodilators in the splanchnic circulation, increases splanchnic blood flow and portal pressures. When this happens repeatedly, it leads to a progressive dilation of preexisting portosystemic vascular channels and the development of varices.5 At the same time, levels of vascular endothelial growth factor rise; this is a very important mediator for angiogenesis because it increases NO, further increasing splanchnic vasodilation.6

Progressive splanchnic vasodilation and increased blood flow into the splanchnic circulation leads to central hypovolemia, arterial underfilling, and decreased blood flow in renal afferent arterioles. Vasoconstrictor norepinephrine and antinatriuretic mechanisms are subsequently activated in an attempt to normalize renal perfusion pressures. Baroreceptor‐mediated nonosmotic release of arginine vasopressin (AVP) is triggered and renin angiotensin‐aldosterone system activity is increased, which increases sodium reabsorption and activates the stellate cells, causing fibrosis, vasoconstriction, and increased portal pressures.6, 7

AVP acts at vasopression‐1A (V_1A) receptors to increase arterial vasoconstriction, and at V₂ receptors in renal tubule cells for solute‐free water retention.1 The increased sodium and water reabsorption leads to fluid retention, increased central blood volume, venous return to the heart, and an increase in cardiac output to maintain arterial perfusion and create the hyperdynamic circulation that is characteristic of cirrhosis with advanced portal hypertension. Dilutional hyponatremia develops when free water retention is more pronounced than that of sodium retention.

CLINICAL FACTORS ASSOCIATED WITH CIRRHOTIC HYPONATREMIA

Diuretics lead to hyponatremia through several mechanisms.8 First, they induce a contraction of the central blood volume, leading to the nonosmotic release of AVP. In advanced cirrhosis, there is activation of the renin‐angiotensin system in addition to the nonosmotic release of AVP, leading to sodium and free water reabsorption. Diuretics block the sodium reabsorption. However, the water‐retaining effects persist, further contributing to dilutional hyponatremia.8 This cycle is made worse by low sodium intake and frequent thirst experienced by these patients.8 Other medications (eg, non‐steroidal anti‐inflammatory drugs, proton pump inhibitors, and selective serotonin reuptake inhibitors) commonly prescribed for cirrhotic patients may also contribute to the development or worsening of dilutional hyponatremia.8

Increased intrathoracic pressure in patients with tense ascites can also contribute to dilutional hyponatremia by increasing baroreceptor‐mediated release of AVP.9 Large volume paracentesis without the oncotic influence of albumin, an intervention commonly required in patients with cirrhosis and recurrent ascites, may also lead to significant increases in plasma renin activity and plasma aldosterone, which further worsen these pathophysiologic mechanisms, resulting in reduced serum sodium concentration.10 Following removal of excess peritoneal fluid, blood flow to the kidneys is initially improved, but ascitic fluid reaccumulates and the patient becomes intravascularly depleted.10

Infection is an important clinical mediator for the development of both portal hypertension as well as hyponatremia. Bacterial translocation leads to endotoxemia and increased tumor necrosis factor (TNF)‐alpha, resulting in increased splanchnic NO and splanchnic arterial vasodilatation. This process reduces cardiac output, which leads to increased AVP secretion.11, 12 Endotoxin‐mediated splanchnic vasodilatation, especially with spontaneous bacterial peritonitis (SBP), can adversely affect central blood volume status, especially in the presence of severe ascites.1 Clinicians providing care for patients with cirrhosis should be aware of these factors and closely monitor at‐risk patients for the onset or worsening of hyponatremia.1

PROGNOSTIC SIGNIFICANCE OF HYPONATREMIA IN CIRRHOSIS

Hyponatremia has several important clinical implications for patients with cirrhosis.13 Hyponatremia is associated with refractory ascites, greater fluid accumulation, the need for paracentesis, and, importantly, impaired renal function. In patients with ascites and cirrhosis, approximately 50% have some degree of hyponatremia.2 Moreover, the severity of hyponatremia associated with advanced cirrhosis correlates with the degree of cirrhosis complications, especially hyponatremia associated with hepatorenal syndrome, encephalopathy, and SBP (Table 1).2

Similarly, hyponatremia is strongly associated with increasing Child‐Pugh and Model for End‐Stage Liver Disease (MELD) scores.14 In an analysis of data among candidates for liver transplantation from the Organ Procurement and Transplantation Network, the combination of MELD score and serum sodium concentration was a better predictor of death than the MELD score alone.14 In addition, the effect of hyponatremia on clinical outcomes was greater in patients with a low MELD score than those with a relatively high MELD score.. These results suggest that combining serum sodium concentrations with MELD scores to assign transplantation priority might reduce mortality among patients on the waiting list.14

Hyponatremia is also a marker for the development of overt hepatic encephalopathy in patients with cirrhosis.13 One of the proposed mechanisms for encephalopathy is low‐grade cerebral edema. This leads to the conversion of glutamate to glutamine by ammonia, which accumulates within astrocytes, causing astrocyte swelling and dysfunction. Because hyponatremia complicates the management of fluid overload, it increases the risk of developing or exacerbating hepatic encephalopathy.13

Hyponatremia is intimately involved with the development of renal failure in the patient with cirrhosis. It is an earlier and more sensitive marker of renal impairment and/or circulatory dysfunction than serum creatinine.15 It is often the precursor to the development of hepatorenal syndrome.16, 17

Hyponatremia is more common in hospitalized versus ambulatory patients with cirrhosis.1 In a study of 126 patients with cirrhosis admitted to an intensive care unit, patients with serum [Na⁺] 135 mEq/L had a greater frequency of ascites, illness severity scores, hepatic encephalopathy, sepsis, renal failure, and in‐hospital mortality than normonatremic patients (73.1% vs 55.9%).18 Persistent ascites and low serum sodium identified cirrhotic patients with a high mortality risk, despite low MELD scores, in a study of 507 veterans in the United States with cirrhosis.19 In a retrospective review of 127 patients, hyponatremia was predictive of the development of acute renal failure during hospitalization; among patients with hyponatremia who developed renal failure in the hospital, 72% died.20

Clinical assessment of a patient with cirrhosis who has hyponatremia can be difficult.1 These patients have too much salt and water in the wrong spaces (ie, in the peritoneal cavity and peripheral tissue). As a result, it is possible to have fluid overload with intravascular depletion. A further complication is that dilutional hyponatremia is associated with hepatorenal syndrome. Because these patients have elevated blood urea nitrogen (BUN) and creatinine, and decreased urine output and urine sodium concentration, they appear to be indistinguishable from a patient with prerenal azotemia prior to volume expansion.1 Many of these factors and concerns are illustrated in the following case we handled several years ago.

A 70‐YEAR‐OLD WOMAN WITH CIRRHOSIS

K.R. is a 70‐year‐old white woman recently discharged from the hospital following treatment of recurrent cellulitis. Her past medical history is positive for cirrhosis secondary to active alcohol use, chronic autoimmune hepatitis, and iron overload. Her hospital course was notable for tense ascites, asterixis, and a serum [Na⁺] of 126 mEq/L at admission. K.R. was managed with large volume paracentesis with 25% salt‐poor albumin, elevation of her lower extremities, discontinuation of diuretics, and 1 L fluid restriction. Her serum [Na⁺] increased to 128 mEq/L. Although her cellulitis and edema both improved, both persisted. In addition, her mental status also improved, but asterixis persisted. At this point in the hospitalization, effective management of the cellulitis was hindered by the persistent edema, and its treatment with diuretics was limited by the hyponatremia and hepatic encephalopathy.

Today, we have better treatment options for managing this patient. To effectively correct the hyponatremia and facilitate treatment of the other complications of cirrhosis, we can now initiate therapy with one of the vaptans currently available.

TREATMENT OF MILD ASYMPTOMATIC HYPERVOLEMIC HYPONATREMIA

The initial approach to treatment of patients with mild asymptomatic, hypervolemic hyponatremia consists of fluid restriction and a sodium‐restricted diet.1 Fluid restriction, however, has limited efficacy and is often not well tolerated by patients. For patients with severe or progressive hyponatremia, diuretics should be minimized or discontinued to avoid intravascular volume depletion. If patients have severe dilutional hyponatremia and tense ascites, therapeutic paracentesis with plasma expanders is safe.1

The pharmacologic approach to treating hyponatremia has advanced with the discovery of vaptans, drugs that inhibit V₂ receptors in cells of the collecting ducts.21 In contrast to conventional diuretics, vaptans do not increase natriuresis. Administration of a vaptan agent for 1 to 2 weeks has been shown to significantly improve low serum sodium levels in patients with hyponatremia, and promote aquaresis without significantly altering renal or circulatory function or activity of the renin‐angiotensin‐aldosterone system. The most frequent side effect of vaptan therapy is thirst.21

Two vaptan agents are currently approved for use in the United States: conivaptan and tolvaptan. Conivaptan is administered intravenously, and is a nonselective vasopressin inhibitor, blocking both V_1A and V₂ receptors. The course of therapy for conivaptan is 4 days. Tolvaptan, on the other hand, selectively blocks V₂ receptors, and is a once‐daily oral vaptan that can be given long‐term.21

The efficacy of tolvaptan was evaluated in the Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2 (SALT‐1 and SALT‐2).22 In these multicenter, prospective, randomized, placebo‐controlled trials, patients with dilutional hyponatremia (serum [Na⁺] <135 mEq/L) associated with cirrhosis (22.4% in SALT‐1, 30.5% in SALT‐2), heart failure, or syndrome of inappropriate antidiuretic hormone (ADH) hypersecretion, and who were hospitalized and clinically stable, received tolvaptan 15 mg daily or placebo. Repeat serum sodium levels were obtained at 8 hours, 2, 3, and 4 days, and then weekly at days 11, 18, 25, and 30. The study drug was discontinued on day 30, with follow‐up serum sodium levels taken 7 days later. (In patients with persistent hyponatremia, the tolvaptan dose was adjusted to 30 mg and then 60 mg with the goal of achieving a serum [Na⁺] <135 mEq/L.) Increases in serum sodium concentration were seen as early as 8 hours after the first administration of tolvaptan and persisted throughout the study period. After tolvaptan was discontinued, serum sodium levels decreased to baseline within 1 week.22 Tolvaptan was well tolerated, with the most common side effects being increased thirst, dry mouth, and increased urination.22

Longer‐term administration of tolvaptan was shown to maintain a higher serum sodium concentration with an acceptable safety profile in SALTWATER, the open‐label extension of the SALT‐1 and SALT‐2 trials.23 The study included 111 patients with hyponatremia who received oral tolvaptan for a mean follow‐up of 701 days. The most common adverse effects potentially related to tolvaptan were thirst, dry mouth, polydipsia, and polyuria.22, 23 Overall, there were 9 possible and 1 probable serious adverse events, which represents an acceptable safety profile over 77,369 patient‐days of exposure. Over time, 64 patients discontinued tolvaptan, 30 due to adverse reactions or death.22 The results of SALTWATER indicated that most patients received benefit from treatment with tolvaptan, with a decreased need for fluid restriction.23

PATIENT CHARACTERISTICS FOR TOLVAPTAN

In the SALT trials, tolvaptan was administered to clinically stable patients. Based on recommendations by the US Food and Drug Administration (FDA), tolvaptan should be initiated or reinitiated in a hospital setting.1 Patients with severe neurologic symptoms due to hyponatremia should be treated with normal saline instead of tolvaptan; combination therapy with tolvaptan and normal saline should be avoided due to the potential for a too‐rapid correction of hyponatremia and the potential for central pontine myelinolysis. Saline should be discontinued and persistent hyponatremia confirmed before beginning tolvaptan therapy.1

Several additional factors should be considered before patients begin tolvaptan. First, tolvaptan increases thirst, as well as the frequency and volume of urination. Therefore, patients must be able to respond appropriately to thirst with increased water intake. Patients should not be fluid‐restricted during the first day of tolvaptan therapy; instead, they should be instructed to respond to their thirst with increased water ingestion. Because of these factors, caution should be exercised in administering tolvaptan to a confused, restrained patient. In addition, patients should have adequate toileting aids, such as a bedside urinal or commode.1

As with most new drugs, acquisition costs for tolvaptan should be considered in light of the clinical benefits of treatment outcomes. In a retrospective review, median hospital costs for patients with moderate‐to‐severe ($16,606) and mild‐to‐moderate hyponatremia ($14,266) were higher than matched patients without hyponatremia ($13,066).24 In the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial, in which patients with severe congestive heart failure (including those with and without hyponatremia) were randomized to tolvaptan or placebo, the adjusted mean length of hospital stay for those with hyponatremia at baseline who received tolvaptan was 1.72 days shorter than those who received placebo.25 Although tolvaptan is somewhat expensive, the cost compares favorably with the daily cost of hospitalization.

SUMMARY

Portal hypertension plays a pivotal role in the development of hyponatremia in patients with cirrhosis. Reflex vasodilation in the splanchnic circulation compromises the effective central blood volume, triggering compensatory vasoconstrictor and antinatriuretic mechanisms. The net effect is greater free water accumulation than sodium retention, creating dilutional hyponatremia.

The severity of hyponatremia correlates with the severity of cirrhosis complications, such as hepatorenal syndrome, encephalopathy, SBP, and renal failure. The presence of hyponatremia is a marker for poor outcomes and shortened survival, regardless of MELD scores.

In a hospitalized, acutely ill patient with cirrhosis, such as the person in this case, therapy may involve discontinuation of diuretics, evaluation and treatment of infection, volume expansion with salt‐poor albumin, and tolvaptan for treatment of hyponatremia. Regarding tolvaptan, early morning administration is recommended. At initiation of therapy, fluid restriction should be discontinued, and off‐floor testing should be avoided. Concomitant medications should be reviewed to avoid potentially harmful interactions.

Cirrhosis is one of the main causes of hypervolemic hyponatremia, a dilutional form of hyponatremia that occurs when there is an increase in total body water but a relatively smaller increase in total serum sodium. Portal hypertension is the main precipitating factor in fluid retention that leads to the development of cirrhotic hyponatremia. In cirrhosis, portal hypertension is determined by 2 main factors: increased intrahepatic resistance and increased spanchnic blood flow. The increased intrahepatic resistance is due to both structural (fibrosis, conversion of low resistance fenestrated sinusoids into capillaries) and dynamic (vasoconstriction due to endothelial cell dysfunction) changes.1

The hepatic circulation normally is able to accommodate an increase in portal blood flow associated with postprandial hyperemia. The elevated intrahepatic resistance in cirrhosis results in an inability to accommodate the normal increase in portal blood flow that occurs in the postprandial hyperemia state.3 As a result, portal pressure increases during postprandial hyperemia, leading to reflex vasoconstriction, which creates a shear stress and increases splanchnic nitric oxide (NO) production.4 NO, one of the most important vasodilators in the splanchnic circulation, increases splanchnic blood flow and portal pressures. When this happens repeatedly, it leads to a progressive dilation of preexisting portosystemic vascular channels and the development of varices.5 At the same time, levels of vascular endothelial growth factor rise; this is a very important mediator for angiogenesis because it increases NO, further increasing splanchnic vasodilation.6

Progressive splanchnic vasodilation and increased blood flow into the splanchnic circulation leads to central hypovolemia, arterial underfilling, and decreased blood flow in renal afferent arterioles. Vasoconstrictor norepinephrine and antinatriuretic mechanisms are subsequently activated in an attempt to normalize renal perfusion pressures. Baroreceptor‐mediated nonosmotic release of arginine vasopressin (AVP) is triggered and renin angiotensin‐aldosterone system activity is increased, which increases sodium reabsorption and activates the stellate cells, causing fibrosis, vasoconstriction, and increased portal pressures.6, 7

AVP acts at vasopression‐1A (V_1A) receptors to increase arterial vasoconstriction, and at V₂ receptors in renal tubule cells for solute‐free water retention.1 The increased sodium and water reabsorption leads to fluid retention, increased central blood volume, venous return to the heart, and an increase in cardiac output to maintain arterial perfusion and create the hyperdynamic circulation that is characteristic of cirrhosis with advanced portal hypertension. Dilutional hyponatremia develops when free water retention is more pronounced than that of sodium retention.

CLINICAL FACTORS ASSOCIATED WITH CIRRHOTIC HYPONATREMIA

Diuretics lead to hyponatremia through several mechanisms.8 First, they induce a contraction of the central blood volume, leading to the nonosmotic release of AVP. In advanced cirrhosis, there is activation of the renin‐angiotensin system in addition to the nonosmotic release of AVP, leading to sodium and free water reabsorption. Diuretics block the sodium reabsorption. However, the water‐retaining effects persist, further contributing to dilutional hyponatremia.8 This cycle is made worse by low sodium intake and frequent thirst experienced by these patients.8 Other medications (eg, non‐steroidal anti‐inflammatory drugs, proton pump inhibitors, and selective serotonin reuptake inhibitors) commonly prescribed for cirrhotic patients may also contribute to the development or worsening of dilutional hyponatremia.8

Increased intrathoracic pressure in patients with tense ascites can also contribute to dilutional hyponatremia by increasing baroreceptor‐mediated release of AVP.9 Large volume paracentesis without the oncotic influence of albumin, an intervention commonly required in patients with cirrhosis and recurrent ascites, may also lead to significant increases in plasma renin activity and plasma aldosterone, which further worsen these pathophysiologic mechanisms, resulting in reduced serum sodium concentration.10 Following removal of excess peritoneal fluid, blood flow to the kidneys is initially improved, but ascitic fluid reaccumulates and the patient becomes intravascularly depleted.10

Infection is an important clinical mediator for the development of both portal hypertension as well as hyponatremia. Bacterial translocation leads to endotoxemia and increased tumor necrosis factor (TNF)‐alpha, resulting in increased splanchnic NO and splanchnic arterial vasodilatation. This process reduces cardiac output, which leads to increased AVP secretion.11, 12 Endotoxin‐mediated splanchnic vasodilatation, especially with spontaneous bacterial peritonitis (SBP), can adversely affect central blood volume status, especially in the presence of severe ascites.1 Clinicians providing care for patients with cirrhosis should be aware of these factors and closely monitor at‐risk patients for the onset or worsening of hyponatremia.1

PROGNOSTIC SIGNIFICANCE OF HYPONATREMIA IN CIRRHOSIS

Hyponatremia has several important clinical implications for patients with cirrhosis.13 Hyponatremia is associated with refractory ascites, greater fluid accumulation, the need for paracentesis, and, importantly, impaired renal function. In patients with ascites and cirrhosis, approximately 50% have some degree of hyponatremia.2 Moreover, the severity of hyponatremia associated with advanced cirrhosis correlates with the degree of cirrhosis complications, especially hyponatremia associated with hepatorenal syndrome, encephalopathy, and SBP (Table 1).2

Similarly, hyponatremia is strongly associated with increasing Child‐Pugh and Model for End‐Stage Liver Disease (MELD) scores.14 In an analysis of data among candidates for liver transplantation from the Organ Procurement and Transplantation Network, the combination of MELD score and serum sodium concentration was a better predictor of death than the MELD score alone.14 In addition, the effect of hyponatremia on clinical outcomes was greater in patients with a low MELD score than those with a relatively high MELD score.. These results suggest that combining serum sodium concentrations with MELD scores to assign transplantation priority might reduce mortality among patients on the waiting list.14

Hyponatremia is also a marker for the development of overt hepatic encephalopathy in patients with cirrhosis.13 One of the proposed mechanisms for encephalopathy is low‐grade cerebral edema. This leads to the conversion of glutamate to glutamine by ammonia, which accumulates within astrocytes, causing astrocyte swelling and dysfunction. Because hyponatremia complicates the management of fluid overload, it increases the risk of developing or exacerbating hepatic encephalopathy.13

Hyponatremia is intimately involved with the development of renal failure in the patient with cirrhosis. It is an earlier and more sensitive marker of renal impairment and/or circulatory dysfunction than serum creatinine.15 It is often the precursor to the development of hepatorenal syndrome.16, 17

Hyponatremia is more common in hospitalized versus ambulatory patients with cirrhosis.1 In a study of 126 patients with cirrhosis admitted to an intensive care unit, patients with serum [Na⁺] 135 mEq/L had a greater frequency of ascites, illness severity scores, hepatic encephalopathy, sepsis, renal failure, and in‐hospital mortality than normonatremic patients (73.1% vs 55.9%).18 Persistent ascites and low serum sodium identified cirrhotic patients with a high mortality risk, despite low MELD scores, in a study of 507 veterans in the United States with cirrhosis.19 In a retrospective review of 127 patients, hyponatremia was predictive of the development of acute renal failure during hospitalization; among patients with hyponatremia who developed renal failure in the hospital, 72% died.20

Clinical assessment of a patient with cirrhosis who has hyponatremia can be difficult.1 These patients have too much salt and water in the wrong spaces (ie, in the peritoneal cavity and peripheral tissue). As a result, it is possible to have fluid overload with intravascular depletion. A further complication is that dilutional hyponatremia is associated with hepatorenal syndrome. Because these patients have elevated blood urea nitrogen (BUN) and creatinine, and decreased urine output and urine sodium concentration, they appear to be indistinguishable from a patient with prerenal azotemia prior to volume expansion.1 Many of these factors and concerns are illustrated in the following case we handled several years ago.

A 70‐YEAR‐OLD WOMAN WITH CIRRHOSIS

K.R. is a 70‐year‐old white woman recently discharged from the hospital following treatment of recurrent cellulitis. Her past medical history is positive for cirrhosis secondary to active alcohol use, chronic autoimmune hepatitis, and iron overload. Her hospital course was notable for tense ascites, asterixis, and a serum [Na⁺] of 126 mEq/L at admission. K.R. was managed with large volume paracentesis with 25% salt‐poor albumin, elevation of her lower extremities, discontinuation of diuretics, and 1 L fluid restriction. Her serum [Na⁺] increased to 128 mEq/L. Although her cellulitis and edema both improved, both persisted. In addition, her mental status also improved, but asterixis persisted. At this point in the hospitalization, effective management of the cellulitis was hindered by the persistent edema, and its treatment with diuretics was limited by the hyponatremia and hepatic encephalopathy.

Today, we have better treatment options for managing this patient. To effectively correct the hyponatremia and facilitate treatment of the other complications of cirrhosis, we can now initiate therapy with one of the vaptans currently available.

TREATMENT OF MILD ASYMPTOMATIC HYPERVOLEMIC HYPONATREMIA

The initial approach to treatment of patients with mild asymptomatic, hypervolemic hyponatremia consists of fluid restriction and a sodium‐restricted diet.1 Fluid restriction, however, has limited efficacy and is often not well tolerated by patients. For patients with severe or progressive hyponatremia, diuretics should be minimized or discontinued to avoid intravascular volume depletion. If patients have severe dilutional hyponatremia and tense ascites, therapeutic paracentesis with plasma expanders is safe.1

The pharmacologic approach to treating hyponatremia has advanced with the discovery of vaptans, drugs that inhibit V₂ receptors in cells of the collecting ducts.21 In contrast to conventional diuretics, vaptans do not increase natriuresis. Administration of a vaptan agent for 1 to 2 weeks has been shown to significantly improve low serum sodium levels in patients with hyponatremia, and promote aquaresis without significantly altering renal or circulatory function or activity of the renin‐angiotensin‐aldosterone system. The most frequent side effect of vaptan therapy is thirst.21

Two vaptan agents are currently approved for use in the United States: conivaptan and tolvaptan. Conivaptan is administered intravenously, and is a nonselective vasopressin inhibitor, blocking both V_1A and V₂ receptors. The course of therapy for conivaptan is 4 days. Tolvaptan, on the other hand, selectively blocks V₂ receptors, and is a once‐daily oral vaptan that can be given long‐term.21

The efficacy of tolvaptan was evaluated in the Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2 (SALT‐1 and SALT‐2).22 In these multicenter, prospective, randomized, placebo‐controlled trials, patients with dilutional hyponatremia (serum [Na⁺] <135 mEq/L) associated with cirrhosis (22.4% in SALT‐1, 30.5% in SALT‐2), heart failure, or syndrome of inappropriate antidiuretic hormone (ADH) hypersecretion, and who were hospitalized and clinically stable, received tolvaptan 15 mg daily or placebo. Repeat serum sodium levels were obtained at 8 hours, 2, 3, and 4 days, and then weekly at days 11, 18, 25, and 30. The study drug was discontinued on day 30, with follow‐up serum sodium levels taken 7 days later. (In patients with persistent hyponatremia, the tolvaptan dose was adjusted to 30 mg and then 60 mg with the goal of achieving a serum [Na⁺] <135 mEq/L.) Increases in serum sodium concentration were seen as early as 8 hours after the first administration of tolvaptan and persisted throughout the study period. After tolvaptan was discontinued, serum sodium levels decreased to baseline within 1 week.22 Tolvaptan was well tolerated, with the most common side effects being increased thirst, dry mouth, and increased urination.22

Longer‐term administration of tolvaptan was shown to maintain a higher serum sodium concentration with an acceptable safety profile in SALTWATER, the open‐label extension of the SALT‐1 and SALT‐2 trials.23 The study included 111 patients with hyponatremia who received oral tolvaptan for a mean follow‐up of 701 days. The most common adverse effects potentially related to tolvaptan were thirst, dry mouth, polydipsia, and polyuria.22, 23 Overall, there were 9 possible and 1 probable serious adverse events, which represents an acceptable safety profile over 77,369 patient‐days of exposure. Over time, 64 patients discontinued tolvaptan, 30 due to adverse reactions or death.22 The results of SALTWATER indicated that most patients received benefit from treatment with tolvaptan, with a decreased need for fluid restriction.23

PATIENT CHARACTERISTICS FOR TOLVAPTAN

In the SALT trials, tolvaptan was administered to clinically stable patients. Based on recommendations by the US Food and Drug Administration (FDA), tolvaptan should be initiated or reinitiated in a hospital setting.1 Patients with severe neurologic symptoms due to hyponatremia should be treated with normal saline instead of tolvaptan; combination therapy with tolvaptan and normal saline should be avoided due to the potential for a too‐rapid correction of hyponatremia and the potential for central pontine myelinolysis. Saline should be discontinued and persistent hyponatremia confirmed before beginning tolvaptan therapy.1

Several additional factors should be considered before patients begin tolvaptan. First, tolvaptan increases thirst, as well as the frequency and volume of urination. Therefore, patients must be able to respond appropriately to thirst with increased water intake. Patients should not be fluid‐restricted during the first day of tolvaptan therapy; instead, they should be instructed to respond to their thirst with increased water ingestion. Because of these factors, caution should be exercised in administering tolvaptan to a confused, restrained patient. In addition, patients should have adequate toileting aids, such as a bedside urinal or commode.1

As with most new drugs, acquisition costs for tolvaptan should be considered in light of the clinical benefits of treatment outcomes. In a retrospective review, median hospital costs for patients with moderate‐to‐severe ($16,606) and mild‐to‐moderate hyponatremia ($14,266) were higher than matched patients without hyponatremia ($13,066).24 In the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial, in which patients with severe congestive heart failure (including those with and without hyponatremia) were randomized to tolvaptan or placebo, the adjusted mean length of hospital stay for those with hyponatremia at baseline who received tolvaptan was 1.72 days shorter than those who received placebo.25 Although tolvaptan is somewhat expensive, the cost compares favorably with the daily cost of hospitalization.

SUMMARY

Portal hypertension plays a pivotal role in the development of hyponatremia in patients with cirrhosis. Reflex vasodilation in the splanchnic circulation compromises the effective central blood volume, triggering compensatory vasoconstrictor and antinatriuretic mechanisms. The net effect is greater free water accumulation than sodium retention, creating dilutional hyponatremia.

The severity of hyponatremia correlates with the severity of cirrhosis complications, such as hepatorenal syndrome, encephalopathy, SBP, and renal failure. The presence of hyponatremia is a marker for poor outcomes and shortened survival, regardless of MELD scores.

In a hospitalized, acutely ill patient with cirrhosis, such as the person in this case, therapy may involve discontinuation of diuretics, evaluation and treatment of infection, volume expansion with salt‐poor albumin, and tolvaptan for treatment of hyponatremia. Regarding tolvaptan, early morning administration is recommended. At initiation of therapy, fluid restriction should be discontinued, and off‐floor testing should be avoided. Concomitant medications should be reviewed to avoid potentially harmful interactions.

Cirrhosis is one of the main causes of hypervolemic hyponatremia, a dilutional form of hyponatremia that occurs when there is an increase in total body water but a relatively smaller increase in total serum sodium. Portal hypertension is the main precipitating factor in fluid retention that leads to the development of cirrhotic hyponatremia. In cirrhosis, portal hypertension is determined by 2 main factors: increased intrahepatic resistance and increased spanchnic blood flow. The increased intrahepatic resistance is due to both structural (fibrosis, conversion of low resistance fenestrated sinusoids into capillaries) and dynamic (vasoconstriction due to endothelial cell dysfunction) changes.1

The hepatic circulation normally is able to accommodate an increase in portal blood flow associated with postprandial hyperemia. The elevated intrahepatic resistance in cirrhosis results in an inability to accommodate the normal increase in portal blood flow that occurs in the postprandial hyperemia state.3 As a result, portal pressure increases during postprandial hyperemia, leading to reflex vasoconstriction, which creates a shear stress and increases splanchnic nitric oxide (NO) production.4 NO, one of the most important vasodilators in the splanchnic circulation, increases splanchnic blood flow and portal pressures. When this happens repeatedly, it leads to a progressive dilation of preexisting portosystemic vascular channels and the development of varices.5 At the same time, levels of vascular endothelial growth factor rise; this is a very important mediator for angiogenesis because it increases NO, further increasing splanchnic vasodilation.6

Progressive splanchnic vasodilation and increased blood flow into the splanchnic circulation leads to central hypovolemia, arterial underfilling, and decreased blood flow in renal afferent arterioles. Vasoconstrictor norepinephrine and antinatriuretic mechanisms are subsequently activated in an attempt to normalize renal perfusion pressures. Baroreceptor‐mediated nonosmotic release of arginine vasopressin (AVP) is triggered and renin angiotensin‐aldosterone system activity is increased, which increases sodium reabsorption and activates the stellate cells, causing fibrosis, vasoconstriction, and increased portal pressures.6, 7

AVP acts at vasopression‐1A (V_1A) receptors to increase arterial vasoconstriction, and at V₂ receptors in renal tubule cells for solute‐free water retention.1 The increased sodium and water reabsorption leads to fluid retention, increased central blood volume, venous return to the heart, and an increase in cardiac output to maintain arterial perfusion and create the hyperdynamic circulation that is characteristic of cirrhosis with advanced portal hypertension. Dilutional hyponatremia develops when free water retention is more pronounced than that of sodium retention.

CLINICAL FACTORS ASSOCIATED WITH CIRRHOTIC HYPONATREMIA

Diuretics lead to hyponatremia through several mechanisms.8 First, they induce a contraction of the central blood volume, leading to the nonosmotic release of AVP. In advanced cirrhosis, there is activation of the renin‐angiotensin system in addition to the nonosmotic release of AVP, leading to sodium and free water reabsorption. Diuretics block the sodium reabsorption. However, the water‐retaining effects persist, further contributing to dilutional hyponatremia.8 This cycle is made worse by low sodium intake and frequent thirst experienced by these patients.8 Other medications (eg, non‐steroidal anti‐inflammatory drugs, proton pump inhibitors, and selective serotonin reuptake inhibitors) commonly prescribed for cirrhotic patients may also contribute to the development or worsening of dilutional hyponatremia.8

Increased intrathoracic pressure in patients with tense ascites can also contribute to dilutional hyponatremia by increasing baroreceptor‐mediated release of AVP.9 Large volume paracentesis without the oncotic influence of albumin, an intervention commonly required in patients with cirrhosis and recurrent ascites, may also lead to significant increases in plasma renin activity and plasma aldosterone, which further worsen these pathophysiologic mechanisms, resulting in reduced serum sodium concentration.10 Following removal of excess peritoneal fluid, blood flow to the kidneys is initially improved, but ascitic fluid reaccumulates and the patient becomes intravascularly depleted.10

Infection is an important clinical mediator for the development of both portal hypertension as well as hyponatremia. Bacterial translocation leads to endotoxemia and increased tumor necrosis factor (TNF)‐alpha, resulting in increased splanchnic NO and splanchnic arterial vasodilatation. This process reduces cardiac output, which leads to increased AVP secretion.11, 12 Endotoxin‐mediated splanchnic vasodilatation, especially with spontaneous bacterial peritonitis (SBP), can adversely affect central blood volume status, especially in the presence of severe ascites.1 Clinicians providing care for patients with cirrhosis should be aware of these factors and closely monitor at‐risk patients for the onset or worsening of hyponatremia.1

PROGNOSTIC SIGNIFICANCE OF HYPONATREMIA IN CIRRHOSIS

Hyponatremia has several important clinical implications for patients with cirrhosis.13 Hyponatremia is associated with refractory ascites, greater fluid accumulation, the need for paracentesis, and, importantly, impaired renal function. In patients with ascites and cirrhosis, approximately 50% have some degree of hyponatremia.2 Moreover, the severity of hyponatremia associated with advanced cirrhosis correlates with the degree of cirrhosis complications, especially hyponatremia associated with hepatorenal syndrome, encephalopathy, and SBP (Table 1).2

Similarly, hyponatremia is strongly associated with increasing Child‐Pugh and Model for End‐Stage Liver Disease (MELD) scores.14 In an analysis of data among candidates for liver transplantation from the Organ Procurement and Transplantation Network, the combination of MELD score and serum sodium concentration was a better predictor of death than the MELD score alone.14 In addition, the effect of hyponatremia on clinical outcomes was greater in patients with a low MELD score than those with a relatively high MELD score.. These results suggest that combining serum sodium concentrations with MELD scores to assign transplantation priority might reduce mortality among patients on the waiting list.14

Hyponatremia is also a marker for the development of overt hepatic encephalopathy in patients with cirrhosis.13 One of the proposed mechanisms for encephalopathy is low‐grade cerebral edema. This leads to the conversion of glutamate to glutamine by ammonia, which accumulates within astrocytes, causing astrocyte swelling and dysfunction. Because hyponatremia complicates the management of fluid overload, it increases the risk of developing or exacerbating hepatic encephalopathy.13

Hyponatremia is intimately involved with the development of renal failure in the patient with cirrhosis. It is an earlier and more sensitive marker of renal impairment and/or circulatory dysfunction than serum creatinine.15 It is often the precursor to the development of hepatorenal syndrome.16, 17

Hyponatremia is more common in hospitalized versus ambulatory patients with cirrhosis.1 In a study of 126 patients with cirrhosis admitted to an intensive care unit, patients with serum [Na⁺] 135 mEq/L had a greater frequency of ascites, illness severity scores, hepatic encephalopathy, sepsis, renal failure, and in‐hospital mortality than normonatremic patients (73.1% vs 55.9%).18 Persistent ascites and low serum sodium identified cirrhotic patients with a high mortality risk, despite low MELD scores, in a study of 507 veterans in the United States with cirrhosis.19 In a retrospective review of 127 patients, hyponatremia was predictive of the development of acute renal failure during hospitalization; among patients with hyponatremia who developed renal failure in the hospital, 72% died.20

Clinical assessment of a patient with cirrhosis who has hyponatremia can be difficult.1 These patients have too much salt and water in the wrong spaces (ie, in the peritoneal cavity and peripheral tissue). As a result, it is possible to have fluid overload with intravascular depletion. A further complication is that dilutional hyponatremia is associated with hepatorenal syndrome. Because these patients have elevated blood urea nitrogen (BUN) and creatinine, and decreased urine output and urine sodium concentration, they appear to be indistinguishable from a patient with prerenal azotemia prior to volume expansion.1 Many of these factors and concerns are illustrated in the following case we handled several years ago.

A 70‐YEAR‐OLD WOMAN WITH CIRRHOSIS

K.R. is a 70‐year‐old white woman recently discharged from the hospital following treatment of recurrent cellulitis. Her past medical history is positive for cirrhosis secondary to active alcohol use, chronic autoimmune hepatitis, and iron overload. Her hospital course was notable for tense ascites, asterixis, and a serum [Na⁺] of 126 mEq/L at admission. K.R. was managed with large volume paracentesis with 25% salt‐poor albumin, elevation of her lower extremities, discontinuation of diuretics, and 1 L fluid restriction. Her serum [Na⁺] increased to 128 mEq/L. Although her cellulitis and edema both improved, both persisted. In addition, her mental status also improved, but asterixis persisted. At this point in the hospitalization, effective management of the cellulitis was hindered by the persistent edema, and its treatment with diuretics was limited by the hyponatremia and hepatic encephalopathy.

Today, we have better treatment options for managing this patient. To effectively correct the hyponatremia and facilitate treatment of the other complications of cirrhosis, we can now initiate therapy with one of the vaptans currently available.

TREATMENT OF MILD ASYMPTOMATIC HYPERVOLEMIC HYPONATREMIA

The initial approach to treatment of patients with mild asymptomatic, hypervolemic hyponatremia consists of fluid restriction and a sodium‐restricted diet.1 Fluid restriction, however, has limited efficacy and is often not well tolerated by patients. For patients with severe or progressive hyponatremia, diuretics should be minimized or discontinued to avoid intravascular volume depletion. If patients have severe dilutional hyponatremia and tense ascites, therapeutic paracentesis with plasma expanders is safe.1

The pharmacologic approach to treating hyponatremia has advanced with the discovery of vaptans, drugs that inhibit V₂ receptors in cells of the collecting ducts.21 In contrast to conventional diuretics, vaptans do not increase natriuresis. Administration of a vaptan agent for 1 to 2 weeks has been shown to significantly improve low serum sodium levels in patients with hyponatremia, and promote aquaresis without significantly altering renal or circulatory function or activity of the renin‐angiotensin‐aldosterone system. The most frequent side effect of vaptan therapy is thirst.21

Two vaptan agents are currently approved for use in the United States: conivaptan and tolvaptan. Conivaptan is administered intravenously, and is a nonselective vasopressin inhibitor, blocking both V_1A and V₂ receptors. The course of therapy for conivaptan is 4 days. Tolvaptan, on the other hand, selectively blocks V₂ receptors, and is a once‐daily oral vaptan that can be given long‐term.21

The efficacy of tolvaptan was evaluated in the Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2 (SALT‐1 and SALT‐2).22 In these multicenter, prospective, randomized, placebo‐controlled trials, patients with dilutional hyponatremia (serum [Na⁺] <135 mEq/L) associated with cirrhosis (22.4% in SALT‐1, 30.5% in SALT‐2), heart failure, or syndrome of inappropriate antidiuretic hormone (ADH) hypersecretion, and who were hospitalized and clinically stable, received tolvaptan 15 mg daily or placebo. Repeat serum sodium levels were obtained at 8 hours, 2, 3, and 4 days, and then weekly at days 11, 18, 25, and 30. The study drug was discontinued on day 30, with follow‐up serum sodium levels taken 7 days later. (In patients with persistent hyponatremia, the tolvaptan dose was adjusted to 30 mg and then 60 mg with the goal of achieving a serum [Na⁺] <135 mEq/L.) Increases in serum sodium concentration were seen as early as 8 hours after the first administration of tolvaptan and persisted throughout the study period. After tolvaptan was discontinued, serum sodium levels decreased to baseline within 1 week.22 Tolvaptan was well tolerated, with the most common side effects being increased thirst, dry mouth, and increased urination.22

Longer‐term administration of tolvaptan was shown to maintain a higher serum sodium concentration with an acceptable safety profile in SALTWATER, the open‐label extension of the SALT‐1 and SALT‐2 trials.23 The study included 111 patients with hyponatremia who received oral tolvaptan for a mean follow‐up of 701 days. The most common adverse effects potentially related to tolvaptan were thirst, dry mouth, polydipsia, and polyuria.22, 23 Overall, there were 9 possible and 1 probable serious adverse events, which represents an acceptable safety profile over 77,369 patient‐days of exposure. Over time, 64 patients discontinued tolvaptan, 30 due to adverse reactions or death.22 The results of SALTWATER indicated that most patients received benefit from treatment with tolvaptan, with a decreased need for fluid restriction.23

PATIENT CHARACTERISTICS FOR TOLVAPTAN

In the SALT trials, tolvaptan was administered to clinically stable patients. Based on recommendations by the US Food and Drug Administration (FDA), tolvaptan should be initiated or reinitiated in a hospital setting.1 Patients with severe neurologic symptoms due to hyponatremia should be treated with normal saline instead of tolvaptan; combination therapy with tolvaptan and normal saline should be avoided due to the potential for a too‐rapid correction of hyponatremia and the potential for central pontine myelinolysis. Saline should be discontinued and persistent hyponatremia confirmed before beginning tolvaptan therapy.1

Several additional factors should be considered before patients begin tolvaptan. First, tolvaptan increases thirst, as well as the frequency and volume of urination. Therefore, patients must be able to respond appropriately to thirst with increased water intake. Patients should not be fluid‐restricted during the first day of tolvaptan therapy; instead, they should be instructed to respond to their thirst with increased water ingestion. Because of these factors, caution should be exercised in administering tolvaptan to a confused, restrained patient. In addition, patients should have adequate toileting aids, such as a bedside urinal or commode.1

As with most new drugs, acquisition costs for tolvaptan should be considered in light of the clinical benefits of treatment outcomes. In a retrospective review, median hospital costs for patients with moderate‐to‐severe ($16,606) and mild‐to‐moderate hyponatremia ($14,266) were higher than matched patients without hyponatremia ($13,066).24 In the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial, in which patients with severe congestive heart failure (including those with and without hyponatremia) were randomized to tolvaptan or placebo, the adjusted mean length of hospital stay for those with hyponatremia at baseline who received tolvaptan was 1.72 days shorter than those who received placebo.25 Although tolvaptan is somewhat expensive, the cost compares favorably with the daily cost of hospitalization.

SUMMARY

Portal hypertension plays a pivotal role in the development of hyponatremia in patients with cirrhosis. Reflex vasodilation in the splanchnic circulation compromises the effective central blood volume, triggering compensatory vasoconstrictor and antinatriuretic mechanisms. The net effect is greater free water accumulation than sodium retention, creating dilutional hyponatremia.

The severity of hyponatremia correlates with the severity of cirrhosis complications, such as hepatorenal syndrome, encephalopathy, SBP, and renal failure. The presence of hyponatremia is a marker for poor outcomes and shortened survival, regardless of MELD scores.

In a hospitalized, acutely ill patient with cirrhosis, such as the person in this case, therapy may involve discontinuation of diuretics, evaluation and treatment of infection, volume expansion with salt‐poor albumin, and tolvaptan for treatment of hyponatremia. Regarding tolvaptan, early morning administration is recommended. At initiation of therapy, fluid restriction should be discontinued, and off‐floor testing should be avoided. Concomitant medications should be reviewed to avoid potentially harmful interactions.

The serum sodium (Na) level is the major determinant of serum osmolality. In normal physiologic states is tightly regulated between 135 mEq/L to 145 mEq/L despite variable intake of water and solute through the interaction of osmoreceptors in the hypothalamus where arginine vasopressin (AVP) is synthesized and then released by the posterior pituitary and the binding of AVP with V2 AVP receptors on the basolateral surface of the principal cells within the collecting duct of the kidney. Binding of AVP to the V2 receptors promotes the translocation and fusion of cytoplasmic vesicles which carry the water channel protein aquaporin 2 (AQP2) to the apical membrane of the cell and, in this manner, increases water permeability and absorption.1, 2, 3

Patients with hyponatremia, defined by a serum Na level <135 mEq/L, can be broadly classified by their volume status into those who are euvolemic, hypervolemic, and hypovolemic (Table 1). In patients with euvolemic hyponatremia such as those with Syndrome of Inappropriate Antidiuretic Hormone (SIADH), total body Na is nearly normal, but total body water is increased. In patients with hypervolemic hyponatremia, both total body Na and water are increased, but water to a much greater degree. These patients typically have increased extracellular fluid such as edema and/or ascites. The most common conditions associated with this condition are cirrhosis, congestive heart failure (CHF), and renal failure. In contrast, hypovolemic hyponatremia is associated with a reduction in both total body Na and water, but Na to a greater degree. This condition is encountered in patients with excessive fluid losses such as those with over‐diuresis, excessive gastrointestinal losses, burns, and pancreatitis.4

Hyponatremia is the most common electrolyte abnormality seen in general hospital patients.5 In a database of over 120,000 patients, a serum sodium level of <136mEq/L was observed in 28.2%.6 Hyponatremia is associated with selected medical conditions (especially cirrhosis and CHF), the extremes of age, and those receiving selected medications, including several that are commonly administered to cirrhotic patients (diuretics, selective serotonin reuptake inhibitors, opiates, proton‐pump inhibitors).7, 8 Hyponatremia is associated with increased total costs per hospital admission.5, 9 In an analysis of the effect of hyponatremia on length of stay in a retrospective cohort study of hospitalized patients derived from a large administrative database of 198,281 discharges from 39 US hospitals, mean length of stay was significantly greater among patients with hyponatremia than those with normal Na levels (8.6 8.0 vs. 7.2 8.2 days). After adjusting for confounders that may be associated with more severe disease and hyponatremia (age, gender, race, geographic region, teaching status of the hospital, admission source, principal payer, comorbidity index score and primary diagnosis), the presence of hyponatremia contributed an increase in length of stay of 1.0 day. Patients with hyponatremia are more frequently admitted to the intensive care unit (ICU) and require mechanical ventilation. In patients with CHF, the presence of hyponatremia at discharge is associated with increased risk for early mortality and rehospitalization.10

Although frequently asymptomatic, hyponatremia may be associated with a range of findings, from subtle and non‐specific complaints, including headache, fatigue, confusion, malaise, to severe and life‐threatening manifestations with lethargy, seizures, brainstem herniation, respiratory arrest and death.11 The most important complications are neurologic consequences related to cerebral edema. However, there is increased morbidity even in hyponatremic patients considered to be asymptomatic. Patients with low serum sodium have attention deficients, and falls are common. In a study of 122 patients who were considered to have chronic asymptomatic hyponatremia, the incidence of falls was significantly higher at 21.3% compared to only 5.3% in a control population.12

In hyponatremia, water enters into the cells to attain osmotic balance, resulting in cellular swelling.4 To avoid cerebral edema, the brain is capable of adapting to hyponatremia by regulating its volume to avoid swelling, especially when hyponatremia is chronic. In acute hyponatremia, astrocytes and neurons adapt through osmoregulatory mechanisms by extruding intracellular electrolytes such as potassium.13 Chronically, adaption occurs through the loss of low‐molecular weight organic compounds termed organic osmolytes including myoinsoitol, glutamine, choline and taurine. As a result, both the severity and the rate of its development are critical factors in determining the neurologic manifestation of hyponatremia in a given patient.14

Dilutional Hyponatremia and Cirrhosis

Patients with hyponatremia who are either euvolemic or hypervolemic are considered to have dilutional hyponatremia (DH). Management of these patients is distinct from those who are hypovolemic in whom appropriate therapy consists of the administration of normal saline. The remainder of this article addresses the pathogenesis, management and treatment of cirrhotic patients with DH.

Pathogenesis

The development of hyponatremia in cirrhosis is intimately related to the pathophysiology of portal hypertension and the non‐osmotic release of AVP3, 15 (Figure 1). In the early phases of cirrhosis, portal hypertension is the result of an increase in intrahepatic resistance. With the development of porto‐systemic collaterals, a hyperdynamic splanchnic circulation develops as a result of splanchnic arterial vasodilatation and increased vascular capacity. Nitric oxide, an endothelial derived relaxing factor, is the critical mediator of this process, and upregulation of its expression is pivotal in the pathogenesis of portal hypertension.

Figure 1

Multiple factors are related to the development of DH in cirrhosis. A reduction of effective central blood volume due to the development of porto‐venous collaterals and arterial splanchnic vasodilation, leading to baroreceptor‐mediated nonosmotic release of AVP, is considered the initiating and most important factor. Patients with cirrhosis and DH have higher plasma and urine vasopressin levels, higher plasma renin activity, and decreased plasma levels of atrial natriuretic factor than those with normal serum sodium concentrations, findings consistent with the presence of a decreased effective plasma volume.16 Arterial underfilling is sensed by baroreceptors located in the left ventricle, aortic arch, carotid sinus and renal afferent arterioles. Decreased activation leads to neurohumoral compensatory responses which include non‐osmotic release of vasopressin from the neurohypophysis and increased levels. Impaired catabolism of AVP that has been correlated with the severity of liver dysfunction may further contribute to increased levels.17 Initially, the increased AVP maintains arterial circulatory integrity by inducing splanchnic, peripheral and renal arterial vasoconstriction through its action on the V1a receptors and expansion of blood volume through renal water retention by its action on the V2 receptors located on the collecting ducts.

The initial adaptive response which leads to increased central blood volume can chronically result in detrimental effects, including the development of fluid overload with ascites, edema, and hyponatremia.16, 18 Additional factors that contribute to hyponatremia include decreased glomerular filtration rate (GFR) and/or increased proximal reabsorption of sodium (that reduce the distal delivery of filtrate and the potential for water reabsorption) and decreased cardiac function that further impairs effective central blood volume.19 In addition, urinary levels of AQP2 are increased in cirrhotic patients, especially those with decompensated disease with higher Child‐Pugh scores and ascites, and provide another potential mechanism to increase water reabsorption.20

Prevalence and Prognostic Significance

Hyponatremia in cirrhosis is a common finding. In a survey of 997 cirrhotic patients with ascites from 28 centers in Europe, North and South America, the prevalence of serum sodium concentration 135, 130, 125, 120 meq/L were 49.4%, 21.6%, 5.7%, and 1.2%, respectively.21 In a retrospective analysis of 188 inpatients, the prevalence of DH of 135, 130, and 125 were 20.8%, 14.9%, and 12.2%, respectively.22 The development of hyponatremia is a manifestation of increasing portal hypertension. In a natural history study of 263 patients hospitalized for first episode of significant ascites, 74 patients developed DH (Na level < 130 mEq/L), including 11 patients in whom it appeared during the first episode and 63 cases during follow‐up (mean period of 40 3 months) with a 5‐year incidence of 37.1%.23

The presence of hyponatremia carries significant adverse prognostic significance. It is strongly associated with severity of liver function impairment as assessed by Child‐Pugh and model for end‐stage liver disease (MELD) scores.22 Even mild hyponatremia is associated with severe complications such as massive ascites, severe hepatic encephalopathy, spontaneous bacterial peritonitis (SBP), and hepatic hydrothorax, and the severity of hyponatremia is directly related to the severity of these complications.21, 22 (Figure 2). In a natural history study of patients presenting with large volume ascites, 1‐year survival after its development was reduced to only 25.6%.230

Figure 2

Figure 3

Hyponatremia is an especially poor prognostic sign for a hospitalized cirrhotic patient. In a retrospective analysis of 156 cirrhotic patients, hyponatremiapresent in 57 (29.8%) of admissionswas associated with increased hospital mortality (26.3% vs. 8.9% among those with normal Na levels), and the mortality rate was even higher (48%) among the 25 patients who developed severe hyponatremia during the hospital stay.24 In hospitalized patients, hyponatremia is predictive of the development of acute renal failure which is associated with substantially increased mortality (73% vs. 13%).25 Similarly, a low serum sodium level in critically ill cirrhotic patients admitted to the ICU is associated with complications, in‐hospital mortality, and poor short‐term prognosis.26

Whether hyponatremia should impact liver transplant prioritization remains an area of controversy. The United Network for Organ Sharing (UNOS) contracted by the Organ Procurement and Transplant Network (OPTN) to optimize the efficient use of deceased organs through fair and timely allocation, currently uses the MELD score, a formula that calculates the risk of death within three months from the bilirubin, creatinine, and International Normalized Ratio (INR) levels. Hyponatremia is an earlier and more sensitive marker than serum creatinine to detect renal impairment and/or circulatory dysfunction in patients with advanced cirrhosis and adds to MELD in predicting waitlist mortality.2729 In patients with a MELD score of <21, only low serum sodium and persistent ascites are independent predictors of mortality.28 To account for the importance of hyponatremia on survival, both modification of the MELD score in which the Na level is incorporated (MELD‐Na model) and the MELD to serum sodium ratio (MESO) have been developed. Adding hyponatremia to the MELD score is a better predictor of death than MELD alone, particularly in patients with low MELD scores.27, 2931 The OPTN/UNOS Liver and Intestinal Organ Transplantation Committee has discussed updating the liver allocation system to include the Na level. However, it was concluded that implementation of MELD‐Na would change the allocation status of only 4% of candidates. Further, based on the concerns about the ability to manipulate serum sodium levels and the utility of employing resources to change the system for a relatively small number of patients, it was decided to defer incorporating the Na level pending further analysis (Report of the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee To the Board of Directors, Los Angeles, California, September 17‐18, 2007). At this time, the use of Na is a regional decision.32 However, the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee has recently solicited feedback from the transplant community about including Na in allocation for review at a forum in April 2010.

Management of the Hospitalized Cirrhotic Patient With Hyponatremia: Recommendations

Hyponatremia in hospitalized cirrhotic patients is a marker for severe disease and high risk of hospital mortality.24 As a result, prompt evaluation and treatment is imperative. The availability of tolvaptan potentially revolutionizes the manner in which these patients are treated. In the SALT trials, only clinically stable patients were enrolled. In this last section, a guideline for the evaluation and treatment of acutely ill, hospitalized cirrhotic patients with DH is presented.

Unanswered Questions

The vaptans provide an important opportunity to clarify the role that hyponatremia plays in the pathogenesis of cirrhosis. In the past, DH in a cirrhotic patient represented a sign of advanced disease. With the availability of safe and effective therapy, we can now determine whether it also plays an important role in the pathophysiology of end‐stage liver disease and whether its treatment will have a beneficial effect on patient outcomes.

Specific clinical questions that will inevitably be addressed over the next few years to determine whether DH is only a marker for advanced disease or whether it plays a direct but modifiable role in the pathophysiology of cirrhosis will include:

• 1

  Role of vaptans in the management of ascites: In a 14‐day randomized, trial of a satavaptan, another selective vasopressin V(2) receptor antagonist, vs. placebo with spironolactone, combination therapy was associated with improved control of ascites and improvements in serum sodium levels in hyponatremic patients with ascites.59 If future similar studies demonstrate more prolonged benefits, this would constitute an important advance in the treatment of ascites in cirrhosis.

• 2

  Effect on renal function: Prolonged use of tolvaptan leads to a compensatory increase in endogenous levels of AVP and, potentially, increased stimulation of V1a receptors, which might be helpful in the setting of portal hypertension. In patients with hepatorenal syndrome, vasopressin stimulation of splanchnic V1a receptors leads to improved renal function, presumably by decreasing splanchnic blood flow and improving central blood volume.60 As a result, tolvaptan may indirectly improve kidney function in patients with advanced cirrhosis and refractory ascites. Whether long‐term tolvaptan therapy will help to prevent hepatorenal syndrome through this mechanism remains to be determined but is an exciting possibility.61

• 3

  Effect on hepatic encephalopathy: Hepatic encephalopathy is associated with poor quality of life in patients with cirrhosis. Although hepatic encephalopathy was not directly assessed in the SALT trials, the mean mental component summary of the Short Form General Health Survey, a quality of life measure, improved in cirrhotic patients receiving tolvaptan to a greater degree that those receiving placebo.62 A possible explanation for this finding is a beneficial effect of tolvaptan on hepatic encephalopathy. Confirmation of this hypothesis, however, will require prospective studies in which hepatic encephalopathy is directly assessed.

• 4

  Effect on medical economics: Based on retrospective reviews, hyponatremia has an adverse impact on length of stay and outcomes following liver transplantation. It will be important to demonstrate in prospective studies that correction of hyponatremia with tolvaptan reduces length of stay, complications, and costs.

The serum sodium (Na) level is the major determinant of serum osmolality. In normal physiologic states is tightly regulated between 135 mEq/L to 145 mEq/L despite variable intake of water and solute through the interaction of osmoreceptors in the hypothalamus where arginine vasopressin (AVP) is synthesized and then released by the posterior pituitary and the binding of AVP with V2 AVP receptors on the basolateral surface of the principal cells within the collecting duct of the kidney. Binding of AVP to the V2 receptors promotes the translocation and fusion of cytoplasmic vesicles which carry the water channel protein aquaporin 2 (AQP2) to the apical membrane of the cell and, in this manner, increases water permeability and absorption.1, 2, 3

Patients with hyponatremia, defined by a serum Na level <135 mEq/L, can be broadly classified by their volume status into those who are euvolemic, hypervolemic, and hypovolemic (Table 1). In patients with euvolemic hyponatremia such as those with Syndrome of Inappropriate Antidiuretic Hormone (SIADH), total body Na is nearly normal, but total body water is increased. In patients with hypervolemic hyponatremia, both total body Na and water are increased, but water to a much greater degree. These patients typically have increased extracellular fluid such as edema and/or ascites. The most common conditions associated with this condition are cirrhosis, congestive heart failure (CHF), and renal failure. In contrast, hypovolemic hyponatremia is associated with a reduction in both total body Na and water, but Na to a greater degree. This condition is encountered in patients with excessive fluid losses such as those with over‐diuresis, excessive gastrointestinal losses, burns, and pancreatitis.4

Hyponatremia is the most common electrolyte abnormality seen in general hospital patients.5 In a database of over 120,000 patients, a serum sodium level of <136mEq/L was observed in 28.2%.6 Hyponatremia is associated with selected medical conditions (especially cirrhosis and CHF), the extremes of age, and those receiving selected medications, including several that are commonly administered to cirrhotic patients (diuretics, selective serotonin reuptake inhibitors, opiates, proton‐pump inhibitors).7, 8 Hyponatremia is associated with increased total costs per hospital admission.5, 9 In an analysis of the effect of hyponatremia on length of stay in a retrospective cohort study of hospitalized patients derived from a large administrative database of 198,281 discharges from 39 US hospitals, mean length of stay was significantly greater among patients with hyponatremia than those with normal Na levels (8.6 8.0 vs. 7.2 8.2 days). After adjusting for confounders that may be associated with more severe disease and hyponatremia (age, gender, race, geographic region, teaching status of the hospital, admission source, principal payer, comorbidity index score and primary diagnosis), the presence of hyponatremia contributed an increase in length of stay of 1.0 day. Patients with hyponatremia are more frequently admitted to the intensive care unit (ICU) and require mechanical ventilation. In patients with CHF, the presence of hyponatremia at discharge is associated with increased risk for early mortality and rehospitalization.10

Although frequently asymptomatic, hyponatremia may be associated with a range of findings, from subtle and non‐specific complaints, including headache, fatigue, confusion, malaise, to severe and life‐threatening manifestations with lethargy, seizures, brainstem herniation, respiratory arrest and death.11 The most important complications are neurologic consequences related to cerebral edema. However, there is increased morbidity even in hyponatremic patients considered to be asymptomatic. Patients with low serum sodium have attention deficients, and falls are common. In a study of 122 patients who were considered to have chronic asymptomatic hyponatremia, the incidence of falls was significantly higher at 21.3% compared to only 5.3% in a control population.12

In hyponatremia, water enters into the cells to attain osmotic balance, resulting in cellular swelling.4 To avoid cerebral edema, the brain is capable of adapting to hyponatremia by regulating its volume to avoid swelling, especially when hyponatremia is chronic. In acute hyponatremia, astrocytes and neurons adapt through osmoregulatory mechanisms by extruding intracellular electrolytes such as potassium.13 Chronically, adaption occurs through the loss of low‐molecular weight organic compounds termed organic osmolytes including myoinsoitol, glutamine, choline and taurine. As a result, both the severity and the rate of its development are critical factors in determining the neurologic manifestation of hyponatremia in a given patient.14

Dilutional Hyponatremia and Cirrhosis

Patients with hyponatremia who are either euvolemic or hypervolemic are considered to have dilutional hyponatremia (DH). Management of these patients is distinct from those who are hypovolemic in whom appropriate therapy consists of the administration of normal saline. The remainder of this article addresses the pathogenesis, management and treatment of cirrhotic patients with DH.

Pathogenesis

The development of hyponatremia in cirrhosis is intimately related to the pathophysiology of portal hypertension and the non‐osmotic release of AVP3, 15 (Figure 1). In the early phases of cirrhosis, portal hypertension is the result of an increase in intrahepatic resistance. With the development of porto‐systemic collaterals, a hyperdynamic splanchnic circulation develops as a result of splanchnic arterial vasodilatation and increased vascular capacity. Nitric oxide, an endothelial derived relaxing factor, is the critical mediator of this process, and upregulation of its expression is pivotal in the pathogenesis of portal hypertension.

Figure 1

Multiple factors are related to the development of DH in cirrhosis. A reduction of effective central blood volume due to the development of porto‐venous collaterals and arterial splanchnic vasodilation, leading to baroreceptor‐mediated nonosmotic release of AVP, is considered the initiating and most important factor. Patients with cirrhosis and DH have higher plasma and urine vasopressin levels, higher plasma renin activity, and decreased plasma levels of atrial natriuretic factor than those with normal serum sodium concentrations, findings consistent with the presence of a decreased effective plasma volume.16 Arterial underfilling is sensed by baroreceptors located in the left ventricle, aortic arch, carotid sinus and renal afferent arterioles. Decreased activation leads to neurohumoral compensatory responses which include non‐osmotic release of vasopressin from the neurohypophysis and increased levels. Impaired catabolism of AVP that has been correlated with the severity of liver dysfunction may further contribute to increased levels.17 Initially, the increased AVP maintains arterial circulatory integrity by inducing splanchnic, peripheral and renal arterial vasoconstriction through its action on the V1a receptors and expansion of blood volume through renal water retention by its action on the V2 receptors located on the collecting ducts.

The initial adaptive response which leads to increased central blood volume can chronically result in detrimental effects, including the development of fluid overload with ascites, edema, and hyponatremia.16, 18 Additional factors that contribute to hyponatremia include decreased glomerular filtration rate (GFR) and/or increased proximal reabsorption of sodium (that reduce the distal delivery of filtrate and the potential for water reabsorption) and decreased cardiac function that further impairs effective central blood volume.19 In addition, urinary levels of AQP2 are increased in cirrhotic patients, especially those with decompensated disease with higher Child‐Pugh scores and ascites, and provide another potential mechanism to increase water reabsorption.20

Prevalence and Prognostic Significance

Hyponatremia in cirrhosis is a common finding. In a survey of 997 cirrhotic patients with ascites from 28 centers in Europe, North and South America, the prevalence of serum sodium concentration 135, 130, 125, 120 meq/L were 49.4%, 21.6%, 5.7%, and 1.2%, respectively.21 In a retrospective analysis of 188 inpatients, the prevalence of DH of 135, 130, and 125 were 20.8%, 14.9%, and 12.2%, respectively.22 The development of hyponatremia is a manifestation of increasing portal hypertension. In a natural history study of 263 patients hospitalized for first episode of significant ascites, 74 patients developed DH (Na level < 130 mEq/L), including 11 patients in whom it appeared during the first episode and 63 cases during follow‐up (mean period of 40 3 months) with a 5‐year incidence of 37.1%.23

The presence of hyponatremia carries significant adverse prognostic significance. It is strongly associated with severity of liver function impairment as assessed by Child‐Pugh and model for end‐stage liver disease (MELD) scores.22 Even mild hyponatremia is associated with severe complications such as massive ascites, severe hepatic encephalopathy, spontaneous bacterial peritonitis (SBP), and hepatic hydrothorax, and the severity of hyponatremia is directly related to the severity of these complications.21, 22 (Figure 2). In a natural history study of patients presenting with large volume ascites, 1‐year survival after its development was reduced to only 25.6%.230

Figure 2

Figure 3

Hyponatremia is an especially poor prognostic sign for a hospitalized cirrhotic patient. In a retrospective analysis of 156 cirrhotic patients, hyponatremiapresent in 57 (29.8%) of admissionswas associated with increased hospital mortality (26.3% vs. 8.9% among those with normal Na levels), and the mortality rate was even higher (48%) among the 25 patients who developed severe hyponatremia during the hospital stay.24 In hospitalized patients, hyponatremia is predictive of the development of acute renal failure which is associated with substantially increased mortality (73% vs. 13%).25 Similarly, a low serum sodium level in critically ill cirrhotic patients admitted to the ICU is associated with complications, in‐hospital mortality, and poor short‐term prognosis.26

Whether hyponatremia should impact liver transplant prioritization remains an area of controversy. The United Network for Organ Sharing (UNOS) contracted by the Organ Procurement and Transplant Network (OPTN) to optimize the efficient use of deceased organs through fair and timely allocation, currently uses the MELD score, a formula that calculates the risk of death within three months from the bilirubin, creatinine, and International Normalized Ratio (INR) levels. Hyponatremia is an earlier and more sensitive marker than serum creatinine to detect renal impairment and/or circulatory dysfunction in patients with advanced cirrhosis and adds to MELD in predicting waitlist mortality.2729 In patients with a MELD score of <21, only low serum sodium and persistent ascites are independent predictors of mortality.28 To account for the importance of hyponatremia on survival, both modification of the MELD score in which the Na level is incorporated (MELD‐Na model) and the MELD to serum sodium ratio (MESO) have been developed. Adding hyponatremia to the MELD score is a better predictor of death than MELD alone, particularly in patients with low MELD scores.27, 2931 The OPTN/UNOS Liver and Intestinal Organ Transplantation Committee has discussed updating the liver allocation system to include the Na level. However, it was concluded that implementation of MELD‐Na would change the allocation status of only 4% of candidates. Further, based on the concerns about the ability to manipulate serum sodium levels and the utility of employing resources to change the system for a relatively small number of patients, it was decided to defer incorporating the Na level pending further analysis (Report of the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee To the Board of Directors, Los Angeles, California, September 17‐18, 2007). At this time, the use of Na is a regional decision.32 However, the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee has recently solicited feedback from the transplant community about including Na in allocation for review at a forum in April 2010.

Management of the Hospitalized Cirrhotic Patient With Hyponatremia: Recommendations

Hyponatremia in hospitalized cirrhotic patients is a marker for severe disease and high risk of hospital mortality.24 As a result, prompt evaluation and treatment is imperative. The availability of tolvaptan potentially revolutionizes the manner in which these patients are treated. In the SALT trials, only clinically stable patients were enrolled. In this last section, a guideline for the evaluation and treatment of acutely ill, hospitalized cirrhotic patients with DH is presented.

Unanswered Questions

The vaptans provide an important opportunity to clarify the role that hyponatremia plays in the pathogenesis of cirrhosis. In the past, DH in a cirrhotic patient represented a sign of advanced disease. With the availability of safe and effective therapy, we can now determine whether it also plays an important role in the pathophysiology of end‐stage liver disease and whether its treatment will have a beneficial effect on patient outcomes.

Specific clinical questions that will inevitably be addressed over the next few years to determine whether DH is only a marker for advanced disease or whether it plays a direct but modifiable role in the pathophysiology of cirrhosis will include:

• 1

  Role of vaptans in the management of ascites: In a 14‐day randomized, trial of a satavaptan, another selective vasopressin V(2) receptor antagonist, vs. placebo with spironolactone, combination therapy was associated with improved control of ascites and improvements in serum sodium levels in hyponatremic patients with ascites.59 If future similar studies demonstrate more prolonged benefits, this would constitute an important advance in the treatment of ascites in cirrhosis.

• 2

  Effect on renal function: Prolonged use of tolvaptan leads to a compensatory increase in endogenous levels of AVP and, potentially, increased stimulation of V1a receptors, which might be helpful in the setting of portal hypertension. In patients with hepatorenal syndrome, vasopressin stimulation of splanchnic V1a receptors leads to improved renal function, presumably by decreasing splanchnic blood flow and improving central blood volume.60 As a result, tolvaptan may indirectly improve kidney function in patients with advanced cirrhosis and refractory ascites. Whether long‐term tolvaptan therapy will help to prevent hepatorenal syndrome through this mechanism remains to be determined but is an exciting possibility.61

• 3

  Effect on hepatic encephalopathy: Hepatic encephalopathy is associated with poor quality of life in patients with cirrhosis. Although hepatic encephalopathy was not directly assessed in the SALT trials, the mean mental component summary of the Short Form General Health Survey, a quality of life measure, improved in cirrhotic patients receiving tolvaptan to a greater degree that those receiving placebo.62 A possible explanation for this finding is a beneficial effect of tolvaptan on hepatic encephalopathy. Confirmation of this hypothesis, however, will require prospective studies in which hepatic encephalopathy is directly assessed.

• 4

  Effect on medical economics: Based on retrospective reviews, hyponatremia has an adverse impact on length of stay and outcomes following liver transplantation. It will be important to demonstrate in prospective studies that correction of hyponatremia with tolvaptan reduces length of stay, complications, and costs.

The serum sodium (Na) level is the major determinant of serum osmolality. In normal physiologic states is tightly regulated between 135 mEq/L to 145 mEq/L despite variable intake of water and solute through the interaction of osmoreceptors in the hypothalamus where arginine vasopressin (AVP) is synthesized and then released by the posterior pituitary and the binding of AVP with V2 AVP receptors on the basolateral surface of the principal cells within the collecting duct of the kidney. Binding of AVP to the V2 receptors promotes the translocation and fusion of cytoplasmic vesicles which carry the water channel protein aquaporin 2 (AQP2) to the apical membrane of the cell and, in this manner, increases water permeability and absorption.1, 2, 3

Patients with hyponatremia, defined by a serum Na level <135 mEq/L, can be broadly classified by their volume status into those who are euvolemic, hypervolemic, and hypovolemic (Table 1). In patients with euvolemic hyponatremia such as those with Syndrome of Inappropriate Antidiuretic Hormone (SIADH), total body Na is nearly normal, but total body water is increased. In patients with hypervolemic hyponatremia, both total body Na and water are increased, but water to a much greater degree. These patients typically have increased extracellular fluid such as edema and/or ascites. The most common conditions associated with this condition are cirrhosis, congestive heart failure (CHF), and renal failure. In contrast, hypovolemic hyponatremia is associated with a reduction in both total body Na and water, but Na to a greater degree. This condition is encountered in patients with excessive fluid losses such as those with over‐diuresis, excessive gastrointestinal losses, burns, and pancreatitis.4

Hyponatremia is the most common electrolyte abnormality seen in general hospital patients.5 In a database of over 120,000 patients, a serum sodium level of <136mEq/L was observed in 28.2%.6 Hyponatremia is associated with selected medical conditions (especially cirrhosis and CHF), the extremes of age, and those receiving selected medications, including several that are commonly administered to cirrhotic patients (diuretics, selective serotonin reuptake inhibitors, opiates, proton‐pump inhibitors).7, 8 Hyponatremia is associated with increased total costs per hospital admission.5, 9 In an analysis of the effect of hyponatremia on length of stay in a retrospective cohort study of hospitalized patients derived from a large administrative database of 198,281 discharges from 39 US hospitals, mean length of stay was significantly greater among patients with hyponatremia than those with normal Na levels (8.6 8.0 vs. 7.2 8.2 days). After adjusting for confounders that may be associated with more severe disease and hyponatremia (age, gender, race, geographic region, teaching status of the hospital, admission source, principal payer, comorbidity index score and primary diagnosis), the presence of hyponatremia contributed an increase in length of stay of 1.0 day. Patients with hyponatremia are more frequently admitted to the intensive care unit (ICU) and require mechanical ventilation. In patients with CHF, the presence of hyponatremia at discharge is associated with increased risk for early mortality and rehospitalization.10

Although frequently asymptomatic, hyponatremia may be associated with a range of findings, from subtle and non‐specific complaints, including headache, fatigue, confusion, malaise, to severe and life‐threatening manifestations with lethargy, seizures, brainstem herniation, respiratory arrest and death.11 The most important complications are neurologic consequences related to cerebral edema. However, there is increased morbidity even in hyponatremic patients considered to be asymptomatic. Patients with low serum sodium have attention deficients, and falls are common. In a study of 122 patients who were considered to have chronic asymptomatic hyponatremia, the incidence of falls was significantly higher at 21.3% compared to only 5.3% in a control population.12

In hyponatremia, water enters into the cells to attain osmotic balance, resulting in cellular swelling.4 To avoid cerebral edema, the brain is capable of adapting to hyponatremia by regulating its volume to avoid swelling, especially when hyponatremia is chronic. In acute hyponatremia, astrocytes and neurons adapt through osmoregulatory mechanisms by extruding intracellular electrolytes such as potassium.13 Chronically, adaption occurs through the loss of low‐molecular weight organic compounds termed organic osmolytes including myoinsoitol, glutamine, choline and taurine. As a result, both the severity and the rate of its development are critical factors in determining the neurologic manifestation of hyponatremia in a given patient.14

Dilutional Hyponatremia and Cirrhosis

Patients with hyponatremia who are either euvolemic or hypervolemic are considered to have dilutional hyponatremia (DH). Management of these patients is distinct from those who are hypovolemic in whom appropriate therapy consists of the administration of normal saline. The remainder of this article addresses the pathogenesis, management and treatment of cirrhotic patients with DH.

Pathogenesis

The development of hyponatremia in cirrhosis is intimately related to the pathophysiology of portal hypertension and the non‐osmotic release of AVP3, 15 (Figure 1). In the early phases of cirrhosis, portal hypertension is the result of an increase in intrahepatic resistance. With the development of porto‐systemic collaterals, a hyperdynamic splanchnic circulation develops as a result of splanchnic arterial vasodilatation and increased vascular capacity. Nitric oxide, an endothelial derived relaxing factor, is the critical mediator of this process, and upregulation of its expression is pivotal in the pathogenesis of portal hypertension.

Figure 1

Multiple factors are related to the development of DH in cirrhosis. A reduction of effective central blood volume due to the development of porto‐venous collaterals and arterial splanchnic vasodilation, leading to baroreceptor‐mediated nonosmotic release of AVP, is considered the initiating and most important factor. Patients with cirrhosis and DH have higher plasma and urine vasopressin levels, higher plasma renin activity, and decreased plasma levels of atrial natriuretic factor than those with normal serum sodium concentrations, findings consistent with the presence of a decreased effective plasma volume.16 Arterial underfilling is sensed by baroreceptors located in the left ventricle, aortic arch, carotid sinus and renal afferent arterioles. Decreased activation leads to neurohumoral compensatory responses which include non‐osmotic release of vasopressin from the neurohypophysis and increased levels. Impaired catabolism of AVP that has been correlated with the severity of liver dysfunction may further contribute to increased levels.17 Initially, the increased AVP maintains arterial circulatory integrity by inducing splanchnic, peripheral and renal arterial vasoconstriction through its action on the V1a receptors and expansion of blood volume through renal water retention by its action on the V2 receptors located on the collecting ducts.

The initial adaptive response which leads to increased central blood volume can chronically result in detrimental effects, including the development of fluid overload with ascites, edema, and hyponatremia.16, 18 Additional factors that contribute to hyponatremia include decreased glomerular filtration rate (GFR) and/or increased proximal reabsorption of sodium (that reduce the distal delivery of filtrate and the potential for water reabsorption) and decreased cardiac function that further impairs effective central blood volume.19 In addition, urinary levels of AQP2 are increased in cirrhotic patients, especially those with decompensated disease with higher Child‐Pugh scores and ascites, and provide another potential mechanism to increase water reabsorption.20

Prevalence and Prognostic Significance

Hyponatremia in cirrhosis is a common finding. In a survey of 997 cirrhotic patients with ascites from 28 centers in Europe, North and South America, the prevalence of serum sodium concentration 135, 130, 125, 120 meq/L were 49.4%, 21.6%, 5.7%, and 1.2%, respectively.21 In a retrospective analysis of 188 inpatients, the prevalence of DH of 135, 130, and 125 were 20.8%, 14.9%, and 12.2%, respectively.22 The development of hyponatremia is a manifestation of increasing portal hypertension. In a natural history study of 263 patients hospitalized for first episode of significant ascites, 74 patients developed DH (Na level < 130 mEq/L), including 11 patients in whom it appeared during the first episode and 63 cases during follow‐up (mean period of 40 3 months) with a 5‐year incidence of 37.1%.23

The presence of hyponatremia carries significant adverse prognostic significance. It is strongly associated with severity of liver function impairment as assessed by Child‐Pugh and model for end‐stage liver disease (MELD) scores.22 Even mild hyponatremia is associated with severe complications such as massive ascites, severe hepatic encephalopathy, spontaneous bacterial peritonitis (SBP), and hepatic hydrothorax, and the severity of hyponatremia is directly related to the severity of these complications.21, 22 (Figure 2). In a natural history study of patients presenting with large volume ascites, 1‐year survival after its development was reduced to only 25.6%.230

Figure 2

Figure 3

Hyponatremia is an especially poor prognostic sign for a hospitalized cirrhotic patient. In a retrospective analysis of 156 cirrhotic patients, hyponatremiapresent in 57 (29.8%) of admissionswas associated with increased hospital mortality (26.3% vs. 8.9% among those with normal Na levels), and the mortality rate was even higher (48%) among the 25 patients who developed severe hyponatremia during the hospital stay.24 In hospitalized patients, hyponatremia is predictive of the development of acute renal failure which is associated with substantially increased mortality (73% vs. 13%).25 Similarly, a low serum sodium level in critically ill cirrhotic patients admitted to the ICU is associated with complications, in‐hospital mortality, and poor short‐term prognosis.26

Whether hyponatremia should impact liver transplant prioritization remains an area of controversy. The United Network for Organ Sharing (UNOS) contracted by the Organ Procurement and Transplant Network (OPTN) to optimize the efficient use of deceased organs through fair and timely allocation, currently uses the MELD score, a formula that calculates the risk of death within three months from the bilirubin, creatinine, and International Normalized Ratio (INR) levels. Hyponatremia is an earlier and more sensitive marker than serum creatinine to detect renal impairment and/or circulatory dysfunction in patients with advanced cirrhosis and adds to MELD in predicting waitlist mortality.2729 In patients with a MELD score of <21, only low serum sodium and persistent ascites are independent predictors of mortality.28 To account for the importance of hyponatremia on survival, both modification of the MELD score in which the Na level is incorporated (MELD‐Na model) and the MELD to serum sodium ratio (MESO) have been developed. Adding hyponatremia to the MELD score is a better predictor of death than MELD alone, particularly in patients with low MELD scores.27, 2931 The OPTN/UNOS Liver and Intestinal Organ Transplantation Committee has discussed updating the liver allocation system to include the Na level. However, it was concluded that implementation of MELD‐Na would change the allocation status of only 4% of candidates. Further, based on the concerns about the ability to manipulate serum sodium levels and the utility of employing resources to change the system for a relatively small number of patients, it was decided to defer incorporating the Na level pending further analysis (Report of the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee To the Board of Directors, Los Angeles, California, September 17‐18, 2007). At this time, the use of Na is a regional decision.32 However, the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee has recently solicited feedback from the transplant community about including Na in allocation for review at a forum in April 2010.

Management of the Hospitalized Cirrhotic Patient With Hyponatremia: Recommendations

Hyponatremia in hospitalized cirrhotic patients is a marker for severe disease and high risk of hospital mortality.24 As a result, prompt evaluation and treatment is imperative. The availability of tolvaptan potentially revolutionizes the manner in which these patients are treated. In the SALT trials, only clinically stable patients were enrolled. In this last section, a guideline for the evaluation and treatment of acutely ill, hospitalized cirrhotic patients with DH is presented.

Unanswered Questions

The vaptans provide an important opportunity to clarify the role that hyponatremia plays in the pathogenesis of cirrhosis. In the past, DH in a cirrhotic patient represented a sign of advanced disease. With the availability of safe and effective therapy, we can now determine whether it also plays an important role in the pathophysiology of end‐stage liver disease and whether its treatment will have a beneficial effect on patient outcomes.

Specific clinical questions that will inevitably be addressed over the next few years to determine whether DH is only a marker for advanced disease or whether it plays a direct but modifiable role in the pathophysiology of cirrhosis will include:

• 1

  Role of vaptans in the management of ascites: In a 14‐day randomized, trial of a satavaptan, another selective vasopressin V(2) receptor antagonist, vs. placebo with spironolactone, combination therapy was associated with improved control of ascites and improvements in serum sodium levels in hyponatremic patients with ascites.59 If future similar studies demonstrate more prolonged benefits, this would constitute an important advance in the treatment of ascites in cirrhosis.

• 2

  Effect on renal function: Prolonged use of tolvaptan leads to a compensatory increase in endogenous levels of AVP and, potentially, increased stimulation of V1a receptors, which might be helpful in the setting of portal hypertension. In patients with hepatorenal syndrome, vasopressin stimulation of splanchnic V1a receptors leads to improved renal function, presumably by decreasing splanchnic blood flow and improving central blood volume.60 As a result, tolvaptan may indirectly improve kidney function in patients with advanced cirrhosis and refractory ascites. Whether long‐term tolvaptan therapy will help to prevent hepatorenal syndrome through this mechanism remains to be determined but is an exciting possibility.61

• 3

  Effect on hepatic encephalopathy: Hepatic encephalopathy is associated with poor quality of life in patients with cirrhosis. Although hepatic encephalopathy was not directly assessed in the SALT trials, the mean mental component summary of the Short Form General Health Survey, a quality of life measure, improved in cirrhotic patients receiving tolvaptan to a greater degree that those receiving placebo.62 A possible explanation for this finding is a beneficial effect of tolvaptan on hepatic encephalopathy. Confirmation of this hypothesis, however, will require prospective studies in which hepatic encephalopathy is directly assessed.

• 4

  Effect on medical economics: Based on retrospective reviews, hyponatremia has an adverse impact on length of stay and outcomes following liver transplantation. It will be important to demonstrate in prospective studies that correction of hyponatremia with tolvaptan reduces length of stay, complications, and costs.