LIVER (B BACON, SECTION EDITOR)

Management of Hyponatremia in Clinical Hepatology Practice

Paul Y. Kwo

# Springer Science+Business Media New York 2014

Abstract The burden of liver disease continues to increase inthe United States, with the epidemics of hepatitis C, alcoholicliver disease, and the coming wave of nonalcoholic fatty liverdisease patients all contributing to a high burden of individ-uals with end-stage liver disease. The complications of cirrho-sis have been related to portal hypertension or synthetic dys-function with variceal bleeding, ascites, hepatic encephalopa-thy, jaundice, hepatorenal syndrome, and the pulmonary com-plications of cirrhosis being described classically. Over thepast decade, a body of evidence has now been assembleddemonstrating that hyponatremia is also an important compli-cation in patients with decompensated cirrhosis, with recentdata demonstrating that hyponatremia is an important prog-nostic indicator in those with cirrhosis [1]. Seminal researchhas demonstrated the pathophysiologic role of thehyperdynamic circulation and vasodilation in those with de-compensated cirrhosis that leads to many of the complica-tions, including hyponatremia [2]. Moreover, a new class ofdrugs, the vaptans, have provided important insights into thepathophysiology and potential therapy of those withhyponatremia and possibly in those with hyponatremia andcirrhotic ascites [3]. However, there are safety concerns withsome drugs in this class. In this article, the pathophysiology ofhyponatremia, clinical relevance to patients with decompen-sated cirrhosis, and management options will be addressed.

Keywords Hyponatremia . Cirrhosis . Liver disease .

Vaptans . Tolvaptan . Satavaptan

Introduction

The definition of hyponatremia has been established as a levelof 130 mEq/L in patients with cirrhosis and/or ascites/edemaand it is believed that approximately 30 % of individuals withcirrhosis have a serum sodium level less than 130 mEq/ml[2]. The vast majority of patients with cirrhosis develophyponatremia due to expanded volume status, which is anincrease in the extracellular volume as well as plasma, andtypically these patients clinically will present with ascites andedema. This hypervolemic hyponatremia is a dilutionalhyponatremia and is due to an excess of water retention dueto the distal tubule being unable to excrete free water [4]. Asecond less common type of hyponatremia occurs in thosewith cirrhosis, and this is typically a hypovolemichyponatremia that occurs due to aggressive use of diuretictherapy to treat edema and/or ascites, or from excess GI lossesthat can be seen, for instance, in those receiving lactulose forencephalopathy. Unlike hypervolemic hyponatremia, theseindividuals have a low plasma volume, low extracellular fluid,and typically have little or no ascites and edema, and presentwith signs of azotemia. The vast majority of individuals withcirrhosis have hypervolemic hyponatremia.

Pathophysiology

The primary pathophysiologic mechanism that leads tohypervolemic hyponatremia is the overall arterial vasodilatedstate in cirrhosis [5]. Classically, this has been described in thepathophysiology of ascites with greater degrees of vasodila-tion leading to greater degrees of ascites, and ultimatelyhepatorenal syndrome in cases of extreme vasodilation. Thisarterial vasodilation is driven by excess nitric oxide synthesisby the vascular endothelial cells that leads to reduced arteriolarresistance due to the intense systemic vasodilation. This

This article is part of the Topical Collection on Liver

P. Y. Kwo (*)Gastroenterology/Hepatology Division, Indiana University School ofMedicine, 975 W. Walnut, IB 327, Indianapolis, IN 46202-5121,USAe-mail: pkwo@iu.edu

Curr Gastroenterol Rep (2014) 16:382DOI 10.1007/s11894-014-0382-4

vasodilation leads to a reduction in effective arterial bloodvolume in the setting of sinusoidal hypertension (hepaticvenous pressure gradient greater than 12 mmHg). This reduc-tion in effective arterial blood flow leads to activation of theneurohumoral system, specifically the renin angiotensin aldo-sterone system. In addition, the non-osmotic synthesis ofarginine vasopressin (AVP) occurs in the hypothalamus andis released in the posterior pituitary gland. It is these mecha-nisms that contribute to the dilutional hyponatremia. Theactivation of the renin angiotensin aldosterone system leadsto sodium retention with arteriolar vasodilation and renalvasoconstriction. The excess AVP that is released from pitu-itary gland binds to vasopressin 2 (V2 receptors) in thecollecting duct cells of the kidneys. The V2 receptors regulatethe rate of solute free water excretion by activating a cyclicAMP-dependent protein kinase, which generates water chan-nel proteins or aquaporins (AQP2), which fuse to the luminalmembrane and increase the permeability of the collectingtubule to water allowing free water absorption. Reduction ofAVP levels or blocking the V2 receptor leads to a reduction inthe number of aquaporin channels by a process of endocyto-sis, and the collecting tubule permeability will return to itsnormal state.

In patients with hyponatremia due to loss of extracellularfluid from diuresis or the gastrointestinal tract, these individ-uals typically present with prerenal azotemia and clinical signsof dehydration. The key component for clinicians to recognizeis that these individuals are typically on diuretics (typically aloop diuretic in combination with a distal convoluted tubulealdosterone antagonist) and therefore therapy can beredirected towards discontinuing or reducing these diureticsto allow volume status to normalize. In addition, those withhepatic encephalopathy can also develop dehydration simplyby excess gastrointestinal losses, particularly with aggressivetherapy with a nonabsorbable sugar such as lactulose. Thus,the difference between the 2 types of hyponatremia is relatedto overall volume status.

Clinical Significance of Hyponatremia

While there is a vast literature on the clinical consequences ofother complications of cirrhosis, such as variceal bleeding,ascites, encephalopathy, and hepatopulmonary syndrome,there exists limited, but emerging, information on the clinicalconsequences of hyponatremia and cirrhosis [6]. Multiplestudies have demonstrated that hyponatremia is associatedwith the development of hepatic encephalopathy as well asreduced quality of life [7]. Because the mechanism ofhyponatremia arises in concert with higher levels of vasodila-tion, other complications of cirrhosis also occur withhyponatremia, including spontaneous bacterial peritonitisand hepatorenal syndrome, while in those who undergo

orthotopic liver transplant, hyponatremia has been found tobe associated with higher rates of mortality than those withelevated MELD scores without hyponatremia [8]. Patientswith hyponatremia can also develop complications post-orthotopic transplant. Reports of central pontine myelinolysis(CPM) have been reported in patients with hyponatremia, andthese patients must be carefully managed during the peri-transplant period to prevent rapid changes in sodium levels.One review of a large database demonstrated that, while rare(0.5 %), the presence of significant hyponatremia correlatedwith the development of post-transplant CPM [9]. It is pre-sumed that it is the changes of astrocytes swelling and cellulardeath that leads to these adverse outcomes. Bothhyponatremia and hepatic encephalopathy can affect mentalstatus. Indeed, while complicated, there is some preliminaryevidence that patients with cirrhosis may indeed have low-grade cerebral edema [7]. This year, a report demonstrated thatcirrhotic patients with hyponatremia with and without hepaticencephalopathy have poor health related quality of life(HRQOL). Indeed, it was suggested that those withhyponatremia without hepatic encephalopathy may have su-perior cognition compared to those with hepatic encephalop-athy and hyponatremia, but poor HRQOL persists, and a smallsubset of individuals with hyponatremia improved with with-drawal of diuretics. This recent article suggests that furtherefforts to correct hyponatremia in patients with cirrhosis mayimprove overall quality of life in this population.

A recent study noted that the presence of hyponatremia wasa risk factor for the development of hepatic encephalopathy ina cohort of cirrhotic patients followed prospectively [10].Indeed, hyponatremia (serum sodium

were seen in those with MELD-Na scores of 23, thoughhyponatremia (and ChildPugh score) were better predictorsof mortality. This single-center study again suggests that thepresence of severe hyponatremia in the presence of refractoryascites is a substantial concern, and should alert clinicians tothe significant risk of mortality and poor prognosis.

Management of Hyponatremia in Cirrhosis

The management of hypovolemic hyponatremia is related tovolume repletion. These patients clinically will have evidenceof low volume status with findings of prerenal azotemia.Correction with normal saline typically addresses the volumedeficit, though the correction should be at a rate of no morethan 46 mEq/L per day to avoid complications such asdemyelination.

The management of hypervolemic hyponatremia is moreproblematic than hypovolemic hyponatremia. Most cirrhoticpatients do not develop symptoms until the serum sodium is

The application of satavaptan was withdrawn from the EMEAdue to safety concerns and unclear efficacy. This meta-analysis again suggests that the use of vaptans for treatmentof chronic dilutional hyponatremia in the setting of cirrhosisdeserves additional study, though safety concerns will need tobe addressed and longer-term outcomes will need to bestudied.

A recent FDA drug safety communication recommendedthat tolvaptan should not be used for longer than 30 days andshould not be used in patients with underlying liver diseasedue to a risk of liver injury leading to liver transplant or death.This arose from surveillance in a 3-year placebo-controlledstudy of 1,400 patients who are enrolled in an autosomal-dominant polycystic kidney disease therapeutic study withtolvaptan. Three patients treated with tolvaptan at a dose of120 mg developed significant increases in serum ALT levelsas well as significant increases in total serum bilirubin. Mostof these abnormalities were observed in the first 18 months oftherapy, and all patients improved after withdrawal of therapy.Even though these doses (120 mg) were higher than a dose60 mg approved for the treatment of hyponatremia, the FDAhas now recommended that those with liver disease such ascirrhosis who develop hyponatremia should not use tolvaptan.Finally, conivapatan is a vaptan that binds to V2 as well asV1a receptors, but safety data in cirrhotics for this vaptan arelimited and there are potential safety concerns regarding lowblood pressure in this population.

Conclusion

Clinicians who treat patients with cirrhosis should be alert tothe development of hyponatremia, which remains an addition-al important marker of advanced liver disease, and may heraldadditional complications. Management remains problematic(Fig. 1). For now, dietary fluid restriction remains the standardof care, though it can be difficult to adhere to in the clinicalsetting. The decision to initiate this should be dependent onthe patients clinical status, and neurologic status should beassessed carefully. Some have advocated for intervention witha serum sodium of

cirrhosis and skin and soft tissue infection. A retrospective study. JHepatol. 2012;56:10406.

12. Crdenas A, Gins P, Marotta P, Czerwiec F, Oyuang J, Guevara M,et al. Tolvaptan, an oral vasopressin antagonist, in the treatment ofhyponatremia in cirrhosis. J Hepatol. 2012;56:5718.

13. Okita K, Kawazoe S, Hasebe C, Kajimura K, Kaneko A, OkadaM,Sakaida I, et al. Dose-finding trial of tolvaptan in livercirrhosis patients with hepatic edema: A randomized,double-blind, placebo-controlled trial. Hepatology Research2013:n/a-n/a.

Curr Gastroenterol Rep (2014) 16:382 Page 5 of 5, 382

Management of Hyponatremia in Clinical Hepatology PracticeAbstractIntroductionPathophysiologyClinical Significance of HyponatremiaManagement of Hyponatremia in CirrhosisConclusionReferencesPapers of particular interest, published recently, have been highlighted as: Of importance Of major importance