Approach to Hyponatremia in Cirrhosis

Potential conflict of interest: Nothing to report. Consult Case A 60‐year‐old woman with nonalcoholic steatohepatitis (NASH) cirrhosis complicated ascites who is taking diuretics presents to clinic for follow‐up with lower extremity edema. Laboratory results reveal a serum sodium (sNa) concentration of 120 mmol/L and creatinine concentration of 1.5 mg/dL. What is the approach to hyponatremia in patients with cirrhosis? Introduction Hyponatremia is the most common electrolyte abnormality in patients with advanced cirrhosis and portends a poor prognosis. Hyponatremia in patients with cirrhosis, defined as sNa concentration ≤130 mmol/L, has a prevalence rate of 22%.1 In patients with cirrhosis, the prevalence rate of severe hyponatremia, sNa ≤125 mmol/L, is 6%, and the prevalence rate of sNa ≤120 mmol/L is 1.2%.2 Pathophysiology Hyponatremia has three clinical types: hypervolemic, euvolemic, and hypovolemic. In patients with cirrhosis, the majority of cases (90%) have hypervolemic (dilutional) hyponatremia because of an increase in extracellular fluid volume. Patients with cirrhosis experience reduction in effective arterial blood volume because of splanchnic arterial vasodilation secondary to increased production of nitric oxide, endotoxins, and other vasodilators.5 This leads to activation of the renin‐angiotensin‐aldosterone axis and impairment of free water excretion secondary to excessive antidiuretic hormone.6 In 10% of cases, hyponatremia is hypovolemic,3 typically from overdiuresis. Clinical Significance Hyponatremia is a marker of the severity of cirrhosis and is more prevalent in patients with cirrhosis with Child‐Pugh class C.4 Patients with hyponatremia are less sensitive to diuretics and have higher rates of hospitalization with spontaneous bacterial peritonitis, hepatic encephalopathy, and hepatorenal syndrome.8 There is a correlation between hyponatremia and the increased risk for mortality. sNa has been found to be an independent predictor of mortality with a hazard ratio of 1.05 per mmol reduction in sNa concentration between 125 and 140 mmol/L.10 This finding led to the incorporation of sNa in the calculation of the score of Model for End‐Stage Liver Disease (MELD) (MELD‐Na). MELD‐Na is a better predictor of survival among candidates for liver transplantation. It is estimated that with the use of MELD‐Na, 7% of deaths have been prevented as patients await liver transplantation in comparison with using the MELD score alone.11 Severe hyponatremia (sNa ≤125 mmol/L) has been found to be an even better predictor of mortality than the MELD‐Na in patients with cirrhosis with refractory ascites.12 In another study, a group of patients with cirrhosis with renal failure who experienced development of hyponatremia had a higher 3‐month mortality (45% versus 19%) compared with the group without hyponatremia.13 Clinical Manifestations The majority of patients with sNa greater than 125 mEq/L are asymptomatic. Symptoms include headache, anorexia, and nausea and vomiting. Because the development of hyponatremia is gradual in onset, the body and especially the central nervous system is able to initially adapt to the slow hyponatremic changes in extracellular fluid by reduction in the intracellular osmolality.14 A rapid decline of sNa to less than 120 mEq/L has serious complications, such as seizures, coma, and death.14 Importantly, there is synergy between hyponatremia and increased concentration of ammonia levels. In astrocytes, this increase in ammonia levels triggers glutamine synthase, leading to an increase in glutamine levels that favors water entry into astrocytes, resulting in brain edema and hepatic encephalopathy.1 Management Hypovolemic Hyponatremia Hypovolemic hyponatremia can be prevented by the use of balanced crystalloids and avoiding overdiuresis, especially when using loop diuretics.1 Hypervolemic Hyponatremia Treatment of hypervolemic hyponatremia in patients with cirrhosis is a challenge. Patients with an sNa less than 130 mEq/L should be considered for treatment.3 Correction of Identifiable Cause Initial management of patients with cirrhosis with hyponatremia should be the assessment of volume status and identification of the underlying causes of hyponatremia. Withholding Diuretics and Correction of Hypokalemia In a hyponatremic state, diuretics should be held. In addition, because potassium is as osmotically active as sodium, the administration of potassium tends to increase sNa concentration.14 Fluid Restriction In individuals who are determined to be hypervolemic, fluid restriction may improve sNa concentration, but patient compliance is poor. Fluid restriction (<1.5 L/day) has not shown significant effectiveness in improving sNa or free water clearance.10 Albumin Infusion Although intravenous albumin infusion may be useful, larger long‐term studies are needed. A small randomized pilot study has shown improved sNa concentrations by 9 mmol/L in 24 patients who were admitted with an initial sNa concentration of less than 130 mmol/L.20 A recent study of 777 hospitalized patients with cirrhosis with hyponatremia (Na <130 mEq/L) who received 225 g (interquartile range 100–400) of intravenous albumin had a higher rate of resolution of hyponatremia and a better 30‐day survival rate.21 Vaptans The vaptan agents block vasopressin receptors in the renal collecting ducts responsible for water reabsorption. Studies in patients with hypervolemic dilutional hyponatremia concluded that tolvaptan normalized sNa concentration to more than 135 mEq/L in 41% of patients in 4 days and in 33% by day 30. However, due to the development of significant elevation of liver enzymes in patients with autosomal dominant polycystic kidney disease, the US Food and Drug Administration placed a black box warning regarding the use of tolvaptan in patients with liver disease.22 In addition, satavaptan was associated with increased mortality and was withdrawn from development.1 A meta‐analysis regarding the efficacy and safety of vaptans in patients with cirrhosis with hyponatremia showed that vaptans improved sNa concentrations and improved ascites fluid mobilization, but no survival benefit (relative risk, 1.06; 95% confidence interval: 0.90‐1.26).24 In addition, blood urea nitrogen greater than 28.2 mg/dL, or 29 mg/dL and creatinine concentration of more than 0.98 are important independent predictors of reduced response to tolvaptan.25 Hypertonic Saline and Liver Transplantation Correction with hypertonic saline may be considered in patients who are refractory to free water restriction, symptomatic patients with seizures, profound hyponatremia (<110 mEq), or sNa less than 120 mEq/L within hours of liver transplant.15 Because hypertonic saline leads to ascites and edema, it is not recommended for long‐term treatment of hypervolemic hyponatremia. Overly rapid correction greater than 8 mEq/L per 24 hours should be avoided because of the risk for osmotic demyelination syndrome.20 Liver transplantation is the only definitive treatment for advanced liver disease complicated with hyponatremia.20 Summary The patient in the case presented with hypervolemic hyponatremia associated with ascites and edema. The sNa concentration of 120 mmol/L is bordering severe hyponatremia and is associated with renal insufficiency. The management of this patient includes free water restriction, holding diuretics, and consideration of albumin infusion (Fig. 1). Tolvaptan is not recommended in patients with liver disease. Furthermore, hyponatremia and renal dysfunction are associated with poor prognosis. If the hyponatremia is persistent, liver transplant evaluation should be considered.