INTRODUCTION — Hyponatremia is a common problem in patients with advanced cirrhosis. The pathogenesis of hyponatremia in these patients is directly related to the hemodynamic changes and secondary neurohumoral adaptations that occur, resulting in an impaired ability to excrete ingested water. The severity of the hyponatremia is related to the severity of the cirrhosis [1-5]. (See "Pathogenesis of ascites in patients with cirrhosis", section on 'Water retention'.)
The pathogenesis, epidemiology, and special management considerations of hyponatremia in patients with cirrhosis are presented in this topic. The causes, evaluation, and treatment of hyponatremia in general are discussed elsewhere:
PATHOGENESIS — A variety of factors can contribute to the development of hyponatremia in patients with cirrhosis. The most important factor is systemic vasodilation, which lowers mean arterial pressure and leads to activation of endogenous vasoconstrictors including antidiuretic hormone (ADH); ADH promotes the water retention that is responsible for the fall in serum sodium. The use of antihypertensive drugs in these patients further reduces mean arterial pressure and can exacerbate hyponatremia.
Systemic vasodilation — Systemic vasodilation plays a central role in the pathogenesis of hyponatremia in patients with cirrhosis and ascites. These patients usually have a marked reduction in systemic vascular resistance (SVR) and in mean arterial pressure and an increase in cardiac output [5-8]. The vascular territory in which the reduced SVR is most obvious is the splanchnic circulation .
The presence of vasodilation in other vascular territories is less obvious and the subject of controversy [10,11]. As an example, the factors that cause splanchnic vasodilatation may have a biphasic effect on the renal circulation. Early in the course of the disease—stable cirrhosis without ascites—the dilating substances also may influence the renal vasculature, and the glomerular filtration rate may be greater than normal (150 versus 105 mL/min in one study) at this stage . With more severe disease, the splanchnic vasodilatation becomes more marked, resulting in a fall in mean arterial pressure and decreased kidney perfusion, leading in some patients to the hepatorenal syndrome .
The precise mechanisms of vasodilation in cirrhosis have become better understood, with increased generation of nitric oxide and prostaglandins appearing to play an important role (algorithm 1). Nitric oxide production may be stimulated by absorbed endotoxin from the gastrointestinal tract, which is less efficiently cleared due to portal-systemic shunting and decreased reticuloendothelial cell function in cirrhosis [13,14]. (See "Pathogenesis of ascites in patients with cirrhosis".)
Iatrogenic factors — As noted above, patients with worsening cirrhosis and ascites develop progressive declines in SVR and mean arterial pressure. (See 'Systemic vasodilation' above.)
Many patients, especially those with obesity and cirrhosis due to nonalcohol steatohepatitis, are hypertensive before this occurs. Although "cirrhosis cures hypertension," antihypertensive therapy is continued in many patients and, in conjunction with systemic vasodilation due to cirrhosis, contributes to low mean arterial pressures. Too often, clinicians who start antihypertensive agents fail to follow these patients over time and may not realize that these medications produce worsening hypotension, hyponatremia, and azotemia as liver disease progresses and patients develop ascites.
Beta blockers, for example, are commonly used in such patients to prevent variceal hemorrhage (see "Primary prevention of bleeding from esophageal varices in patients with cirrhosis", section on 'Preventive strategies'). However, these agents may be hazardous in patients with ascites and hypotension .
Activation of endogenous vasoconstrictors — The reduction in pressure (or stretch) at the carotid and renal baroreceptors induced by cirrhotic vasodilation and antihypertensive drug therapy leads to activation of the sodium- and water-retaining neurohumoral mechanisms in an attempt to restore perfusion pressure to normal (algorithm 1). These include the renin-angiotensin system, the sympathetic nervous system, and ADH. The secretion of these three "hypovolemic" hormones is proportional to the severity of the hemodynamic insufficiency (figure 1) [16-18].
The net effect is avid renal sodium and water retention because the patient is effectively volume depleted even though extracellular sodium stores, the plasma volume, and the cardiac output are increased. Sodium retention leads to the development of ascites unless the patient is adequately treated with dietary sodium restriction and diuretics. (See "Ascites in adults with cirrhosis: Initial therapy".)
Water retention — Water excretion is usually normal in patients with cirrhosis before the development of ascites and then becomes increasingly impaired as the liver disease progresses. This abnormality is largely related to the increased release of ADH [16-18] since suppression of ADH release is required to excrete a water load. (See "Causes of hypotonic hyponatremia in adults".)
The pathogenetic importance of ADH in water retention has been demonstrated in rats with cirrhosis in which the administration of a vasopressin (ADH) receptor antagonist restores near-normal water excretory ability . Although of lesser importance, the renal vasoconstriction and reduction in renal blood flow induced by neurohumoral activation also may contribute to diminished water excretion .
The inability to excrete water normally leads to the development of hyponatremia . Thus, patients who have cirrhosis with ascites typically demonstrate urinary sodium retention, increased total body sodium, increased total body water, and hypotonic hyponatremia.
Because the increase in ADH secretion (and therefore the degree of water retention) is roughly proportional to the severity of the cirrhosis (figure 1), the degree of hyponatremia parallels the severity of the hepatic disease and is, along with the degree of sodium retention, of prognostic value. A serum sodium concentration below 130 mEq/L carries a relatively poor prognosis, whereas values below 125 mEq/L may indicate impending hepatorenal syndrome .
Two factors other than high ADH levels may contribute to the tendency toward hyponatremia in selected patients with cirrhosis:
●Diuretic therapy can exacerbate the reduction in tissue perfusion, further impairing the ability to excrete free water . This is most likely to occur with rapid fluid removal in patients with ascites but no peripheral edema. (See "Ascites in adults with cirrhosis: Initial therapy".)
●Large-volume beer drinkers ingest a large volume of fluid, thereby increasing the tendency to hyponatremia [24,25].
EPIDEMIOLOGY — Hyponatremia is common in patients with cirrhosis. In an international prospective study involving 997 patients in 28 liver units, the prevalence of a serum sodium concentration less than 135, 130, 125, and 120 mEq/L in patients with cirrhosis and ascites was 50, 22, 6, and 1 percent, respectively . The prevalence was high in both inpatients and outpatients.
Serum sodium concentrations do not usually fall spontaneously below 120 mEq/L in patients with cirrhosis until they are close to death or there has been an overly aggressive diuresis, as with the addition of a thiazide diuretic to maximum doses of a loop diuretic (usually furosemide) and spironolactone.
CLINICAL MANIFESTATIONS — Symptoms of hyponatremia can be difficult to separate from symptoms that are often present in patients with end-stage liver disease and may include fatigue, confusion, dizziness, nausea, gait instability, and muscle cramps . The clinical manifestations of hyponatremia are presented in detail elsewhere. (See "Manifestations of hyponatremia and hypernatremia in adults", section on 'Hyponatremia'.)
As in hyponatremic patients without cirrhosis, raising the serum sodium in hyponatremic patients with cirrhosis may improve symptoms, although data are limited. As an example, in one unblinded and uncontrolled study of 24 cirrhotic patients with a serum sodium <130 mEq/L, raising the serum sodium with fluid restriction, withholding diuretics, and, in some patients, prescribing tolvaptan was associated with modest improvement in some but not all cognitive tests .
MANAGEMENT — Hyponatremia in patients with cirrhosis typically develops slowly (paralleling the rate of progression of the liver disease) and usually produces no obvious clinical manifestations unless the serum sodium concentration falls below 120 mEq/L, which, in one large, multicenter series, occurred in only 1 percent of cirrhotic patients . (See "Manifestations of hyponatremia and hypernatremia in adults".)
Correction of the hyponatremia has no effect on the hemodynamic abnormalities associated with the severe underlying liver disease, and there are no data that increasing the serum sodium concentration in patients with cirrhosis improves morbidity or mortality.
Regardless of the method chosen to increase the serum sodium concentration, daily correction by more than 4 to 6 mEq/L should be avoided to minimize the risk of central demyelinating lesions with neurologic dysfunction, which is called the osmotic demyelination syndrome (ODS; also called central pontine and extrapontine myelinolysis). (See "Osmotic demyelination syndrome (ODS) and overly rapid correction of hyponatremia", section on 'Overly rapid rate of correction'.)
Treatment approach in all patients — In patients with cirrhosis and hyponatremia, we attempt to raise the serum sodium by:
●Withdrawing beta blockers, alpha blockers, diuretics (particularly thiazide diuretics), and other antihypertensive medications (see 'Discontinue beta blockers and other antihypertensive drugs' below)
●Correcting hypokalemia, if present (see 'Correct hypokalemia if present' below)
●Treating patients who have persistent hypotension with midodrine to achieve a mean arterial pressure of higher than 82 mmHg (see 'Midodrine in patients with persistent hypotension' below)
Discontinue beta blockers and other antihypertensive drugs — In our experience, antihypertensive medications (including beta blockers and alpha blockers) should be discontinued in patients with cirrhosis when the mean arterial pressure falls to 82 mmHg or below; values below this threshold have been associated with hyponatremia and substantially increased mortality in patients with cirrhosis and ascites [15,29]. Some practice guidelines suggest discontinuing beta blockers when blood pressure is below 90/60 mmHg (which corresponds to a mean arterial pressure of 70 mmHg) [30,31]; others suggest their discontinuation when the mean arterial pressure falls below 65 mmHg . However, we discontinue these and other antihypertensive drugs before the blood pressure falls to these levels.
As noted above, blood pressure decreases in patients with progressive cirrhosis due in large part to systemic vasodilation. Many such patients are also taking beta blockers and other antihypertensive medications. (See 'Iatrogenic factors' above.)
Correct hypokalemia if present — Hypokalemia in patients with cirrhosis can result from increased urinary losses due to diuretic therapy or increased gastrointestinal losses in patients with diarrhea or vomiting. Since potassium is as osmotically active as sodium, the administration of potassium will tend to raise the serum sodium concentration. The mechanism by which this occurs is discussed separately. (See "Overview of the treatment of hyponatremia in adults", section on 'Potassium replacement in hypokalemic patients'.)
In addition, hypokalemia, which may be accompanied by metabolic alkalosis, can promote the development of hepatic encephalopathy by at least two mechanisms: Hypokalemia increases renal ammonia synthesis, which delivers additional ammonia into the systemic circulation, and alkalemia increases the fraction of unionized ammonia in the plasma. Unionized ammonia more readily penetrates cells, including brain cells, which can worsen hepatic encephalopathy. (See "Hepatic encephalopathy in adults: Treatment", section on 'Correct hypokalemia'.)
Midodrine in patients with persistent hypotension — Patients with cirrhosis and hyponatremia are typically hypotensive. In patients with persistent hypotension despite discontinuation of antihypertensive medications, we prescribe midodrine (titration up to a maximum dose of 15 mg orally three times daily) to maintain a mean arterial pressure >82 mmHg.
In one observational study, 10 patients with cirrhosis and hyponatremia (mean serum sodium, 124 mEq/L) who failed to respond to albumin infusion were initiated on midodrine 10 mg orally three times daily (titrated to a maximal dose of 15 mg orally three times daily); octreotide, 100 mcg subcutaneously three times daily (titrated to a maximum of 200 mcg subcutaneously three times daily) was also given. After three days, the mean serum sodium had increased to 130 mEq/L and the daily electrolyte-free water clearance increased from 0.33 L pretreatment to 0.82 L posttreatment. Long-term midodrine is practical and has also been shown to improve survival in patients with cirrhosis and refractory ascites (figure 2) [33-35].
A placebo-controlled trial of 196 patients with cirrhosis and ascites awaiting liver transplantation found that the combination of long-term midodrine (15 to 30 mg/day) and albumin (40 g every 15 days) for one year slightly reduced the incidence of hyponatremia (11 versus 13 percent) although this was not statistically significant . However, when hyponatremia did occur, it was less severe among those receiving midodrine and albumin (mean trough serum sodium of 134 versus 129 mEq/L). Survival rates did not differ, although the baseline mean arterial pressure in this study (81 mmHg) and the baseline serum sodium (134 mEq/L) indicate that midodrine was unnecessary in a large proportion of participants.
Additional therapeutic options in selected patients — The treatments noted above (discontinuation of antihypertensive therapy, correction of hypokalemia, midodrine) can gradually raise the serum sodium. However, some patients should have their serum sodium raised more urgently:
●Patients with severe symptomatic hyponatremia (ie, serum sodium <120 mEq/L) (see 'Patients with severe symptomatic hyponatremia (<120 mEq/L)' below)
●Patients who have a serum sodium <125 mEq/L and in whom liver transplantation is expected within the subsequent several days (see 'Patients undergoing imminent liver transplantation (within several days)' below)
Patients with severe symptomatic hyponatremia (<120 mEq/L) — In hospitalized patients who have severe hyponatremia due to cirrhosis and symptoms that might be attributable to hyponatremia, we attempt to raise the serum sodium with infusion of albumin or hypertonic saline. Correction of hyponatremia by more than 4 to 6 mEq/L per day should be avoided. (See 'Albumin infusion' below and 'Hypertonic saline combined with diuretics or paracentesis' below.)
Hemodialysis is an alternative treatment in such patients with advanced kidney function impairment who are candidates for liver transplantation. (See 'Hemodialysis (only in liver transplant candidates with severe kidney function impairment)' below.)
Albumin infusion — Albumin infusion may improve hyponatremia in patients with cirrhosis while other measures to raise the serum sodium are instituted [37,38]. (See 'Treatment approach in all patients' above.)
When we use albumin in such patients, we prescribe 1 g/kg body weight (maximum 100 g), infused daily. We discontinue infusions once symptoms improve or if the effect on hyponatremia is negligible.
In a retrospective cohort study of 1126 hospitalized hyponatremic patients (serum sodium <130 mEq/L), those given albumin during admission experienced a greater maximum serum sodium concentration and a higher rate of hyponatremia resolution compared with patients who did not receive albumin (69 versus 61 percent), despite having a higher Model for End-stage Liver Disease (MELD) score, worse serum creatinine, lower initial serum sodium, and lower initial mean arterial pressure .
A randomized trial published only in abstract form reported that albumin infusions improved serum sodium (as well as kidney function and mortality) , but the trial was not published as a peer-reviewed manuscript.
Hypertonic saline combined with diuretics or paracentesis — Hypertonic saline may be used as initial therapy in patients with symptomatic, severe hyponatremia while other measures to raise the serum sodium are instituted. (See 'Treatment approach in all patients' above.)
We also use hypertonic saline to raise the serum sodium in hyponatremic patients who are about to undergo liver transplantation in an effort to prevent overly rapid correction of hyponatremia.
If patients with cirrhosis are treated with hypertonic saline, loop diuretics (but not thiazide diuretics) can also be given (if azotemia does not worsen) in an attempt to prevent progressive hypervolemia. Paracentesis is an alternative to the use of diuretics. Our approach to the use of hypertonic saline to raise the serum sodium is presented separately. (See "Overview of the treatment of hyponatremia in adults", section on 'Chronic hyponatremia: Initial therapy (first six hours)'.)
Hemodialysis (only in liver transplant candidates with severe kidney function impairment) — Hemodialysis is an appropriate option to raise the serum sodium in patients with severe kidney function impairment (eg, estimated glomerular filtration rate <15 mL/min/1.73 m2) who are candidates for liver transplantation. We do not typically dialyze cirrhotic patients who are not candidates for liver transplantation; dialysis is often difficult to perform due to hemodynamic instability, and prognosis without a liver allograft in these patients is dismal. (See "Hepatorenal syndrome", section on 'Kidney replacement therapy'.)
We use a low dialysate sodium concentration when performing hemodialysis in patients with hyponatremia in order to avoid overly rapid correction. This issue is discussed elsewhere in detail. (See "Acute hemodialysis prescription", section on 'Chronic hyponatremia'.)
Patients undergoing imminent liver transplantation (within several days) — We attempt to raise the serum sodium concentration to above 125 mEq/L in patients with cirrhosis who have a serum sodium <125 mEq/L if liver transplantation is expected within the subsequent several days [5,27,37,40]. The rationale for this goal is presented below. (See 'Goal serum sodium if liver transplantation is imminent' below.)
Our approach in these patients includes withdrawing antihypertensive medications (including beta blockers, alpha blockers, and diuretics), correction of hypokalemia (if present), and midodrine therapy (in patients with a persistent mean arterial pressure ≤82 mmHg). (See 'Treatment approach in all patients' above.)
If these measures do not successfully raise the serum sodium to above 125 mEq/L, we attempt to raise the serum sodium with hypertonic saline or albumin infusion (or hemodialysis in patients with severe kidney function impairment).
We do not use tolvaptan or other vasopressin receptor antagonists to raise the serum sodium in such patients, although practice varies and some authorities prescribe tolvaptan instead of hypertonic saline.
Goal serum sodium if liver transplantation is imminent — If liver transplantation is imminent (expected within several days), and the serum sodium is <125 mEq/L, we attempt to raise the serum sodium to above 125 mEq/L [37,40].
Partial correction before transplantation is preferable to rapid correction in the operating room. Thus, we recommend partial, slow correction of hyponatremia prior to transplantation in patients with serum sodium concentrations of 125 mEq/L or less to avoid large increases in serum sodium during surgery [41-43].
Overly rapid correction of hyponatremia can occur after liver transplantation and is associated with neurologic complications . In different studies, the rate of ODS after liver transplantation ranged from 5 to 29 percent in patients with hyponatremia [40,45-47]. The median time to onset of ODS in reported cases is five to seven days; late development beyond 12 days is rare . The following observations illustrate the range of findings:
●In a review of 2175 liver transplant recipients, 10 (0.5 percent) developed ODS after transplantation . The mean baseline serum sodium concentration was 129 mEq/L in the patients who developed ODS, significantly lower than the mean value of 136 mEq/L in those who did not. The likelihood of developing ODS increased with lower baseline serum sodium concentrations: 0.1, 0.8, and 4.6 percent at serum sodium concentrations of 135 mEq/L or higher, 125 to 134 mEq/L, and less than 125 mEq/L, respectively. Data were not available on the use of hypertonic saline or on the rate of correction of the serum sodium.
●Another large retrospective study evaluated 379 liver transplant recipients . Among 12 patients with a serum sodium less than or equal to 127 mEq/L, ODS developed in three (25 percent). The rise in serum sodium during transplantation in these patients was 21 mEq/L compared with only 7 mEq/L in those who did not develop ODS. A third study found a similar rate of ODS following liver transplantation (29 percent [4 of 14 patients]) . The serum sodium concentration prior to surgery in these four patients was markedly reduced in two. The perioperative rise in serum sodium was 21 to 32 mEq/L with the maximum increase on the day of surgery.
Thus, ODS after liver transplantation primarily occurs in patients who have a baseline serum sodium concentration below 125 to 130 mEq/L and a rapid elevation in the serum sodium in the peritransplant period. Large volumes of isotonic fluid administered intraoperatively are sufficient to induce rapid correction of hyponatremia .
The number of documented cases of ODS may underestimate the actual incidence of brain injury caused by rapid correction of hyponatremia. Two studies that did not identify any patients with ODS found a significant association between correction rates and postoperative neurologic complications:
●In a retrospective study of 512 liver transplant patients, perioperative increases in serum sodium ≥12 mEq/L in 24 hours or ≥16 mEq/L in 24 hours were independently associated with, respectively, threefold and sevenfold higher rates of postoperative neurologic complications .
●A second retrospective study of 69 liver transplant patients with preoperative serum sodium <130 mEq/L found that a perioperative increase in serum sodium >10 mEq/L predicted postoperative neurologic deficits, swallowing dysfunction, discharge to a rehabilitation or long-term care facility, and six-month mortality .
However, these approaches will not protect all patients, since pontine and extrapontine myelinolysis can occur in patients who are not hyponatremic prior to liver transplantation and do not have a rapid elevation in serum sodium after transplantation .
Therapies we typically avoid
Fluid restriction — Although fluid restriction is frequently employed in hospitalized patients with cirrhosis and ascites because of concerns related to hyponatremia, such an approach is not supported by the available data.
Proper patient selection for fluid restriction is important since, in our experience, fluid restriction tends to alienate the patient, cohabitants, nurses, and dietitians without proven benefit. One of the important limitations to adherence with fluid restriction is that the systemic vasodilation that stimulates antidiuretic hormone (ADH) release (figure 1) also enhances thirst. (See 'Activation of endogenous vasoconstrictors' above.)
There is much confusion about the degree of fluid restriction. Some clinicians order 1000 mL or 1500 mL free water restriction per day. Some nurses and dietitians include all fluids, and others include only fluids on the tray.
However, for fluid restriction to raise the serum sodium, the total fluid intake should be less than the urine volume, which is usually quite low; as a result, fluid restriction is often difficult to achieve in patients with cirrhosis who have hyponatremia. Because of thirst, most patients with end-stage liver disease will not tolerate fluid restriction below 1 to 1.5 L per day . Sucking on ice chips or lollipops may be helpful in patients with severe thirst.
Modest fluid restriction may be helpful in preventing or improving severe hyponatremia in nonhospitalized patients who habitually drink large amounts of fluid for reasons other than thirst (eg, beer drinkers) . If the serum sodium concentration does not increase within the first 48 to 72 hours, the degree of fluid restriction has been insufficient.
Vasopressin receptor antagonists — Although we do not use vasopressin receptor antagonists in patients with hyponatremia due to cirrhosis, some authorities suggest tolvaptan rather than hypertonic saline in symptomatic patients whose serum sodium fails to improve despite other interventions .
Vasopressin receptor antagonists can raise the serum sodium in patients with hyponatremia due to cirrhosis. There are multiple receptors for vasopressin (ADH): the V1a, V1b, and V2 receptors. The V2 receptors primarily mediate the antidiuretic response, while V1a and V1b receptors principally cause vasoconstriction and mediate adrenocorticotropin release, respectively [48,49]. The vasopressin receptor antagonists produce a selective water diuresis without affecting sodium and potassium excretion [48,49]. The ensuing loss of free water will tend to correct the hyponatremia in patients with cirrhosis [43,50,51]. (See "Overview of the treatment of hyponatremia in adults", section on 'Vasopressin receptor antagonists'.)
Some oral formulations—tolvaptan, satavaptan, and lixivaptan—are selective for the V2 receptor, while an intravenous agent, conivaptan, blocks both the V2 and V1a receptors. Only tolvaptan and conivaptan are currently available in the United States, and conivaptan is usually avoided in patients with cirrhosis because it can lower blood pressure (which is already low in cirrhotic patients with hyponatremia) and might increase the risk of both variceal bleeding and kidney function decline [48,52].
Tolvaptan has been shown to be effective in improving the serum sodium concentration in hyponatremic patients with cirrhosis  and can be used in patients who are awaiting liver transplantation. However, fewer than one-half of cirrhotic patients with a serum sodium <125 mEq/L will respond with a ≥5 mEq/L increase [54,55].
Concerns about the safety of tolvaptan in patients with liver disease were raised by a multicenter trial (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes [TEMPO] 3:4) that examined its effect on the progression of kidney disease in polycystic kidney disease [56,57]. A greater than 2.5-fold increase in liver enzymes was more common among patients who received tolvaptan compared with placebo. Based upon these and other data, the US Food and Drug Administration (FDA) determined that tolvaptan should not be used in patients with liver disease (including cirrhosis), because it may potentially lead to liver failure or death .
A reasonable exception to this US FDA recommendation can be made for hyponatremic patients with end-stage liver disease who are awaiting liver transplantation . Correction of hyponatremia is desirable in such patients to avoid a rapid perioperative increase in the serum sodium concentration, and the clinical impact of a drug-related exacerbation of liver injury in this setting should not impact outcome if transplant is imminent. (See 'Patients undergoing imminent liver transplantation (within several days)' above.)
Other — Demeclocycline, a tetracycline derivative that increases free water excretion by partially antagonizing the action of ADH, has been evaluated for the treatment of hyponatremia in patients with cirrhosis . However, demeclocycline is expensive and should not be used in patients with cirrhosis because of the common development of nephrotoxicity; this problem is due in part to high circulating drug levels that result from diminished hepatic drug metabolism .
Sodium chloride tablets should not be used, as they can worsen hypervolemia; urea should not be used, since it may exacerbate hepatic encephalopathy.
PROGNOSIS — In keeping with the correlation between hyponatremia and systemic hemodynamics in cirrhosis, the presence of hyponatremia is associated in a graded fashion with severe ascites (high prevalence of refractory ascites, large fluid accumulation rate, frequent use of large-volume paracentesis); impaired kidney function; and higher rates of hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome [26,61].
Hyponatremia is also a powerful predictor of death in patients with cirrhosis and ascites who are on the wait list for a liver transplant. In three studies, for example, serum sodium concentrations of less than 135, 126, or 130 mEq/L were independent risk factors for death in such patients [62-64].
The current system for prioritizing patients for liver transplantation uses the serum bilirubin, serum creatinine, and international normalized ratio (INR) for the prothrombin time to calculate the Model for End-stage Liver Disease (MELD) score. Adding hyponatremia to the MELD score is a better predictor of death than the MELD score alone, particularly in patients with low MELD scores [62-65].
The magnitude of the effect of serum sodium on prognosis in patients with end-stage liver disease was evaluated in a report of the 6769 candidates for primary liver transplantation who were registered in the Organ Procurement and Transplantation Network in the United States in 2005 and 2006 . The hazard rate for death was 1.05 per 1 mEq/L decrease in serum sodium at values between 140 and 125 mEq/L. In addition to being a risk factor for death, low serum sodium concentrations (particularly below 130 mEq/L) are associated with an increased risk of the osmotic demyelination syndrome (ODS) with severe neurologic dysfunction shortly after liver transplantation. (See 'Goal serum sodium if liver transplantation is imminent' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyponatremia" and "Society guideline links: Fluid and electrolyte disorders in adults".)
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Hyponatremia (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Pathogenesis – A variety of factors can contribute to the development of hyponatremia in patients with cirrhosis. The most important factor is systemic vasodilation, which lowers mean arterial pressure and leads to activation of endogenous vasoconstrictors including antidiuretic hormone (ADH). The use of antihypertensive drugs (including beta blockers and alpha blockers) in these patients further reduces mean arterial pressure and can exacerbate hyponatremia. (See 'Pathogenesis' above.)
●Epidemiology – Hyponatremia is common in patients with cirrhosis, and the severity of the hyponatremia is related to the severity of the cirrhosis. Hyponatremia is also a powerful predictor of death in patients with cirrhosis, and serum sodium concentrations do not usually fall spontaneously below 120 mEq/L until patients are close to death or if there has been an overly aggressive diuresis in those ascites. (See 'Epidemiology' above.)
●Clinical manifestations – Symptoms of hyponatremia can be difficult to separate from symptoms that are often present in patients with end-stage liver disease and may include fatigue, confusion, dizziness, nausea, gait instability, and muscle cramps. As in hyponatremic patients without cirrhosis, raising the serum sodium in hyponatremic patients with cirrhosis may improve symptoms. (See 'Clinical manifestations' above.)
●Management in all patients – In all patients with cirrhosis and hyponatremia, we attempt to raise the serum sodium by (see 'Treatment approach in all patients' above):
•Withdrawing beta blockers, alpha blockers, diuretics (particularly thiazide diuretics), and other antihypertensive medications. (See 'Discontinue beta blockers and other antihypertensive drugs' above.)
•Correcting hypokalemia, if present. (See 'Correct hypokalemia if present' above.)
•Treating patients who have persistent hypotension. Specifically, we suggest therapy to raise the mean arterial pressure to above 82 mmHg, rather than permitting the patient to have persistent hypotension (Grade 2C). Midodrine is the agent typically used to increase blood pressure in cirrhotic patients. (See 'Midodrine in patients with persistent hypotension' above.)
●Additional treatment in selected settings – In addition, some patients should have their serum sodium raised more urgently (see 'Additional therapeutic options in selected patients' above):
•Patients with severe symptomatic hyponatremia (ie, serum sodium <120 mEq/L) (see 'Patients with severe symptomatic hyponatremia (<120 mEq/L)' above):
-In hospitalized patients who have severe hyponatremia due to cirrhosis and symptoms that might be attributable to hyponatremia, we attempt to raise the serum sodium with infusion of albumin or hypertonic saline. (See 'Albumin infusion' above and 'Hypertonic saline combined with diuretics or paracentesis' above.)
-Hemodialysis is an alternative treatment in such patients with advanced kidney function impairment who are candidates for liver transplantation. (See 'Hemodialysis (only in liver transplant candidates with severe kidney function impairment)' above.)
•Patients who have a serum sodium <125 mEq/L and in whom liver transplantation is expected within the subsequent several days. In such patients we suggest raising the serum sodium concentration to above 125 mEq/L, before liver transplantation, using the strategies outlined above (Grade 2C). (See 'Patients undergoing imminent liver transplantation (within several days)' above.):
●Rate of correction – Daily correction by more than 4 to 6 mEq/L should be avoided to minimize the risk of central demyelinating lesions with neurologic dysfunction, which is called the osmotic demyelination syndrome (ODS; also called central pontine and extrapontine myelinolysis). (See "Osmotic demyelination syndrome (ODS) and overly rapid correction of hyponatremia", section on 'Overly rapid rate of correction'.)
●Therapies of limited use – Although fluid restriction is frequently employed in hospitalized patients with cirrhosis and ascites, such an approach is difficult to implement and not supported by the available data. We do not use vasopressin receptor antagonists in patients with hyponatremia due to cirrhosis, although some authorities suggest tolvaptan rather than hypertonic saline in patients awaiting liver transplantation whose serum sodium fails to improve despite other interventions. (See 'Therapies we typically avoid' above.)
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