Hyponatremia in Patients with End-Stage Liver Disease is Associated with Longer Hospital Stays and Increased Mortality

Research into prognostic models that focus on serum sodium levels in an effort to identify patients awaiting liver transplant who may be at higher risk of poor outcomes have been inconclusive.

Researchers who conducted a literature review of studies focusing on hyponatremia in cirrhosis recently reported that although prognostic models incorporating serum sodium levels may be better able “to predict urgency and need for transplant” in patients with end-stage liver disease (ESLD), the benefits and “post-transplant effects of redefining a liver allocation score have yet to be established.” They published their findings in the February issue of Experimental and Clinical Transplantation.

The authors reviewed 95 studies published in scientific journals that “provided information about pathophysiologic mechanisms behind hyponatremia in cirrhosis, associated clinical implications, various therapeutic options, and competing prognostic models.”

Hyponatremia prevalence varies according to several factors, including clinical setting and disease severity, but nearly half of patients with cirrhosis may also be hyponatremic (serum sodium concentrations of ≤ 135 mmol/L), with 21-28% having serum sodium levels of < 130 mmol/L.

In pre-transplant patients with ESLD, hyponatremia “appears to be associated with manifestations of decompensated liver disease,” such as ascites, hepatic encephalopathy, and spontaneous bacterial peritonitis,” with these complications appearing with greater frequency in patients with more severe hyponatremia. However, the authors note that because hyponatremia may be “either a marker for severity of liver disease or an injurious clinical entity in itself,” it raises the question of whether “treatment of hyponatremia would alter the complications of cirrhosis and the overall long-term survival.”

Because hyponatremia is also associated with the development of hepatorenal syndrome, the authors recommend that “serum creatinine should be closely monitored in the setting of hyponatremia and cirrhosis as an objective marker for development of hepatorenal syndrome.”

Interestingly, although several studies have shown serum sodium level to be “a pre-transplant and post-transplant predictor of morbidity and short-term mortality,” and a variant of the Model for End-stage Liver Disease (MELD) score that incorporates serum sodium level is also a better predictor of mortality than the standard MELD score, the authors wrote that a system that incorporates a factor such as serum sodium “with such wide variability depending on the use of diuretics and fluid status may prevent pre-transplant deaths, but also may increase post-transplant mortality, as patients with pre-transplant hyponatremia have been shown to have more complications” post-transplant, including delirium, renal failure, and infectious complications within the first months after transplant.

Treating hyponatremia in this patient population presents several challenges, as “some therapies administered in patients with normal serum sodium levels differ in those with hyponatremia in cirrhosis.” For example, the use of one standard treatment, hypertonic saline, increases the incidence of edema and ascites in patients with cirrhosis. Other treatment modalities such as fluid restriction and the use of albumin to shift fluid back into intravascular space have been shown to have only limited or transient effects.

Vaptans (V2 receptor antagonists) have been shown to “effectively increase the amount of solute-free water excreted from the body with a decrease in urine osmolality and subsequent improvement of hypervolemic hyponatremia.” Tolvaptan and conivaptan have been approved by the FDA for treatment of hypervolemic hyponatremia, with only tolvaptan approved for treating hyponatremia in patients with cirrhosis. Although tolvaptan has been shown to “significantly promote increases in serum sodium levels” in hyponatremic patients after 30 days of treatment, including in cirrhotic patients, there is no data examining the long-term effects of tolvaptan on morbidity and mortality.

In their conclusions based on their findings the authors wrote “the presence of hypervolemic hyponatremia in the setting of end-stage liver disease forecasts worsened outcomes in both before-liver and after-liver transplant settings with increased associations with hepatic encephalopathy, hepatorenal syndrome, mortality, and longer hospital stays. Various prognostic models incorporating serum sodium levels are currently being trialed; yet, there is no clear evidence to suggest that incorporation and even correction of serum sodium affects overall mortality, but instead shifts the number of deaths from pre-transplant to post-transplant.” They also wrote that “A growing body of evidence supports the efficacy and safety of tolvaptan, the only FDA-approved agent specifically for hyponatremia in cirrhosis. Current evidence shows that a statistically significant achievement of a normonatremic state is possible with tolvaptans compared to placebo and that maintenance requires continued use of tolvaptan. However, longer-term studies are lacking and more data examining tolvaptan’s effects on other hyponatremia-related clinical implications are needed.”