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Curr Gastroenterol Rep (2014) 16:382

DOI 10.1007/s11894-014-0382-4

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 in


the United States, with the epidemics of hepatitis C, alcoholic
liver disease, and the coming wave of nonalcoholic fatty liver
disease patients all contributing to a high burden of individuals with end-stage liver disease. The complications of cirrhosis have been related to portal hypertension or synthetic dysfunction with variceal bleeding, ascites, hepatic encephalopathy, jaundice, hepatorenal syndrome, and the pulmonary complications of cirrhosis being described classically. Over the
past decade, a body of evidence has now been assembled
demonstrating that hyponatremia is also an important complication in patients with decompensated cirrhosis, with recent
data demonstrating that hyponatremia is an important prognostic indicator in those with cirrhosis [1]. Seminal research
has demonstrated the pathophysiologic role of the
hyperdynamic circulation and vasodilation in those with decompensated cirrhosis that leads to many of the complications, including hyponatremia [2]. Moreover, a new class of
drugs, the vaptans, have provided important insights into the
pathophysiology and potential therapy of those with
hyponatremia and possibly in those with hyponatremia and
cirrhotic ascites [3]. However, there are safety concerns with
some drugs in this class. In this article, the pathophysiology of
hyponatremia, clinical relevance to patients with decompensated cirrhosis, and management options will be addressed.

Introduction
The definition of hyponatremia has been established as a level
of 130 mEq/L in patients with cirrhosis and/or ascites/edema
and it is believed that approximately 30 % of individuals with
cirrhosis have a serum sodium level less than 130 mEq/ml
[2]. The vast majority of patients with cirrhosis develop
hyponatremia due to expanded volume status, which is an
increase in the extracellular volume as well as plasma, and
typically these patients clinically will present with ascites and
edema. This hypervolemic hyponatremia is a dilutional
hyponatremia and is due to an excess of water retention due
to the distal tubule being unable to excrete free water [4]. A
second less common type of hyponatremia occurs in those
with cirrhosis, and this is typically a hypovolemic
hyponatremia that occurs due to aggressive use of diuretic
therapy to treat edema and/or ascites, or from excess GI losses
that can be seen, for instance, in those receiving lactulose for
encephalopathy. Unlike hypervolemic hyponatremia, these
individuals have a low plasma volume, low extracellular fluid,
and typically have little or no ascites and edema, and present
with signs of azotemia. The vast majority of individuals with
cirrhosis have hypervolemic hyponatremia.

Pathophysiology
Keywords Hyponatremia . Cirrhosis . Liver disease .
Vaptans . Tolvaptan . Satavaptan
This article is part of the Topical Collection on Liver
P. Y. Kwo (*)
Gastroenterology/Hepatology Division, Indiana University School of
Medicine, 975 W. Walnut, IB 327, Indianapolis, IN 46202-5121,
USA
e-mail: pkwo@iu.edu

The primary pathophysiologic mechanism that leads to


hypervolemic hyponatremia is the overall arterial vasodilated
state in cirrhosis [5]. Classically, this has been described in the
pathophysiology of ascites with greater degrees of vasodilation leading to greater degrees of ascites, and ultimately
hepatorenal syndrome in cases of extreme vasodilation. This
arterial vasodilation is driven by excess nitric oxide synthesis
by the vascular endothelial cells that leads to reduced arteriolar
resistance due to the intense systemic vasodilation. This

382, Page 2 of 5

vasodilation leads to a reduction in effective arterial blood


volume in the setting of sinusoidal hypertension (hepatic
venous pressure gradient greater than 12 mmHg). This reduction in effective arterial blood flow leads to activation of the
neurohumoral system, specifically the renin angiotensin aldosterone system. In addition, the non-osmotic synthesis of
arginine vasopressin (AVP) occurs in the hypothalamus and
is released in the posterior pituitary gland. It is these mechanisms that contribute to the dilutional hyponatremia. The
activation of the renin angiotensin aldosterone system leads
to sodium retention with arteriolar vasodilation and renal
vasoconstriction. The excess AVP that is released from pituitary gland binds to vasopressin 2 (V2 receptors) in the
collecting duct cells of the kidneys. The V2 receptors regulate
the rate of solute free water excretion by activating a cyclic
AMP-dependent protein kinase, which generates water channel proteins or aquaporins (AQP2), which fuse to the luminal
membrane and increase the permeability of the collecting
tubule to water allowing free water absorption. Reduction of
AVP levels or blocking the V2 receptor leads to a reduction in
the number of aquaporin channels by a process of endocytosis, and the collecting tubule permeability will return to its
normal state.
In patients with hyponatremia due to loss of extracellular
fluid from diuresis or the gastrointestinal tract, these individuals typically present with prerenal azotemia and clinical signs
of dehydration. The key component for clinicians to recognize
is that these individuals are typically on diuretics (typically a
loop diuretic in combination with a distal convoluted tubule
aldosterone antagonist) and therefore therapy can be
redirected towards discontinuing or reducing these diuretics
to allow volume status to normalize. In addition, those with
hepatic encephalopathy can also develop dehydration simply
by excess gastrointestinal losses, particularly with aggressive
therapy with a nonabsorbable sugar such as lactulose. Thus,
the difference between the 2 types of hyponatremia is related
to overall volume status.

Clinical Significance of Hyponatremia


While there is a vast literature on the clinical consequences of
other complications of cirrhosis, such as variceal bleeding,
ascites, encephalopathy, and hepatopulmonary syndrome,
there exists limited, but emerging, information on the clinical
consequences of hyponatremia and cirrhosis [6]. Multiple
studies have demonstrated that hyponatremia is associated
with the development of hepatic encephalopathy as well as
reduced quality of life [7]. Because the mechanism of
hyponatremia arises in concert with higher levels of vasodilation, other complications of cirrhosis also occur with
hyponatremia, including spontaneous bacterial peritonitis
and hepatorenal syndrome, while in those who undergo

Curr Gastroenterol Rep (2014) 16:382

orthotopic liver transplant, hyponatremia has been found to


be associated with higher rates of mortality than those with
elevated MELD scores without hyponatremia [8]. Patients
with hyponatremia can also develop complications postorthotopic transplant. Reports of central pontine myelinolysis
(CPM) have been reported in patients with hyponatremia, and
these patients must be carefully managed during the peritransplant 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 correlated
with the development of post-transplant CPM [9]. It is presumed that it is the changes of astrocytes swelling and cellular
death that leads to these adverse outcomes. Both
hyponatremia and hepatic encephalopathy can affect mental
status. Indeed, while complicated, there is some preliminary
evidence that patients with cirrhosis may indeed have lowgrade cerebral edema [7]. This year, a report demonstrated that
cirrhotic patients with hyponatremia with and without hepatic
encephalopathy have poor health related quality of life
(HRQOL). Indeed, it was suggested that those with
hyponatremia without hepatic encephalopathy may have superior cognition compared to those with hepatic encephalopathy and hyponatremia, but poor HRQOL persists, and a small
subset of individuals with hyponatremia improved with withdrawal of diuretics. This recent article suggests that further
efforts to correct hyponatremia in patients with cirrhosis may
improve overall quality of life in this population.
A recent study noted that the presence of hyponatremia was
a risk factor for the development of hepatic encephalopathy in
a cohort of cirrhotic patients followed prospectively [10].
Indeed, hyponatremia (serum sodium <130 mEq/l), history
of overt HE, serum bilirubin, and serum creatinine all independently predicted overt encephalopathy. Moreover, using
1H-magnetic resonance spectroscopy, it was shown that patients with low brain concentration of organic osmolytes,
particularly myo-inositol (MI) had a higher probability of
development of overt HE compared with that of patients with
high brain MI levels.
Prognostically hyponatremia has been associated with poor
clinical outcomes. A review published this past year reported
92 cirrhotic patients with skin and soft tissue infection who
were hospitalized compared to a control group with cirrhosis
matched for severity of liver disease, but without skin or soft
tissue infection [11]. Higher rates of renal failure, and
hyponatremia occurred in the infection group. Factors associated with mortality included site of infection and MELDsodium score. Another recent study evaluated the MELD
sodium score as a predictor of mortality in patients with
cirrhosis and refractory ascites [1]. In this single-center
study, predictive factors included the presence of severe
hyponatremia (sodium <125 mEq/mL), higher ChildPugh
score, beta-blocker therapy, and requirement for greater frequency of paracenteses. In addition, higher rates of mortality

Curr Gastroenterol Rep (2014) 16:382

Page 3 of 5, 382

were seen in those with MELD-Na scores of 23, though


hyponatremia (and ChildPugh score) were better predictors
of mortality. This single-center study again suggests that the
presence of severe hyponatremia in the presence of refractory
ascites is a substantial concern, and should alert clinicians to
the significant risk of mortality and poor prognosis.

Management of Hyponatremia in Cirrhosis


The management of hypovolemic hyponatremia is related to
volume repletion. These patients clinically will have evidence
of low volume status with findings of prerenal azotemia.
Correction with normal saline typically addresses the volume
deficit, though the correction should be at a rate of no more
than 46 mEq/L per day to avoid complications such as
demyelination.
The management of hypervolemic hyponatremia is more
problematic than hypovolemic hyponatremia. Most cirrhotic
patients do not develop symptoms until the serum sodium is
<120 mEq/l and, even then, symptoms, typically neurologic,
are not common. Restriction of free water is the mainstay of
therapy, but remains difficult to implement as patients have
marked difficulty in restricting total free water to less than 1.5 l
daily. Moreover, correction of hyponatremia has not been
shown to improve survival. A guiding principle is that the
amount of fluid restriction should be less than the total urine
volume, though we do not advocate aggressive measures
unless the serum sodium is less than 120 mEq/l.
An additional emerging approach relates to increasing the
renal excretion of free water with V2-receptor antagonists.
This class of medicines (vaptans) blocks the V2 AVP receptor
of the renal collecting tubule, thereby restoring free water

Fig. 1 Management of
hyponatremia

excretion. Emerging data suggest that these agents may play


a key role in the management of dilutional hyponatremia,
though safety concerns may limit the use of some of the
vaptans including tolvaptan, and satavaptan. (http://www.
f d a . g o v / S a f e t y / M e d Wa t c h / S a f e t y I n f o r m a t i o n /
SafetyAlertsforHumanMedicalProducts/ucm350185.htm).
A recently reported study evaluated the effectiveness of
ascending doses of tolvaptan from 15 to 60 mg for 30 days in
cirrhotic patients with hyponatremia [12]. On treatment, improvement in serum sodium levels was significantly higher in
the tolvaptan group by day 4 and day 30, regardless of the
degree of hyponatremia. In addition, improvement in quality
of life indices was noted. The improvement was short-lived
and, with the discontinuation of tolvaptan, hyponatremia recurred. This year an additional dose finding study was published to determine the optimal dose of tolvaptan in patients
with cirrhosis and hepatic edema. In this ascending dose study
from Japan, patients with cirrhosis without an adequate diuretic response were enrolled to receive ascending doses of
tolvaptan beginning at 7.5 mg ascending to 15 or 30 mg as
treatment for hepatic edema [13]. A dose of 7.5 mg led to the
optimal response for the treatment of edema related to cirrhosis who did not respond to diuretics without substantial changes in serum sodium, though patients were not hyponatremic at
initiation. Besides tolvaptan, other vaptans that have been
studied include satavaptan and lixivaptan. A recent metaanalysis examined 12 trials with 2,266 patients who received
vaptans including tolvaptan, satavaptan, and lixivaptan for
hyponatremia [3]. In this meta-analysis, vaptans were not
found to affect mortality, though they did increase serum
sodium levels in addition to producing weight reduction and
reducing the time to first paracentesis. However, there were
increased adverse events including an excessive urine volume.

Management of hyponatremia

Hypervolemic hyponatremia

Hypovolemic hyponatremia

Awaiting OLT

Assess for etiology of volume depletion

Na < 125 meq/l

Not awaiting OLT

Na < 120 mEq/l

Rehydration to correct Na slowly


Fluid restriction 1.5 L daily
Consider correction to
assessfor clinical symptoms
improve post OLT outcomes
No clinical symptoms
Observe

Consider clinical trial


with vaptan if available

clinical symptoms
Fluid restrict to
less than urine
output

382, Page 4 of 5

The application of satavaptan was withdrawn from the EMEA


due to safety concerns and unclear efficacy. This metaanalysis again suggests that the use of vaptans for treatment
of chronic dilutional hyponatremia in the setting of cirrhosis
deserves additional study, though safety concerns will need to
be addressed and longer-term outcomes will need to be
studied.
A recent FDA drug safety communication recommended
that tolvaptan should not be used for longer than 30 days and
should not be used in patients with underlying liver disease
due to a risk of liver injury leading to liver transplant or death.
This arose from surveillance in a 3-year placebo-controlled
study of 1,400 patients who are enrolled in an autosomaldominant polycystic kidney disease therapeutic study with
tolvaptan. Three patients treated with tolvaptan at a dose of
120 mg developed significant increases in serum ALT levels
as well as significant increases in total serum bilirubin. Most
of these abnormalities were observed in the first 18 months of
therapy, and all patients improved after withdrawal of therapy.
Even though these doses (120 mg) were higher than a dose
60 mg approved for the treatment of hyponatremia, the FDA
has now recommended that those with liver disease such as
cirrhosis who develop hyponatremia should not use tolvaptan.
Finally, conivapatan is a vaptan that binds to V2 as well as
V1a receptors, but safety data in cirrhotics for this vaptan are
limited and there are potential safety concerns regarding low
blood pressure in this population.

Conclusion
Clinicians who treat patients with cirrhosis should be alert to
the development of hyponatremia, which remains an additional important marker of advanced liver disease, and may herald
additional complications. Management remains problematic
(Fig. 1). For now, dietary fluid restriction remains the standard
of care, though it can be difficult to adhere to in the clinical
setting. The decision to initiate this should be dependent on
the patients clinical status, and neurologic status should be
assessed carefully. Some have advocated for intervention with
a serum sodium of <120 mEq/l though data to demonstrate
that correcting at this level improves survival is lacking. One
population in which careful management and potential correction of hyponatremia should be considered is in the pretransplant setting where careful management is required to
prevent post-transplant CPM. While V2-receptor antagonists
(vaptans) have been demonstrated to provide short-term correction of sodium levels, safety concerns are limiting their use
and 2 vaptans (tolvaptan and satavaptan) are not approved for
use in those with cirrhosis or are not available in Europe due to
safety concerns. Another vaptan, conivaptan, is approved in
the US, but there are safety concerns regarding hypotension
and bleeding which limits its use. Moreover, thus far, vaptans

Curr Gastroenterol Rep (2014) 16:382

have not yet been shown to improve mortality. Although the


safety signals with tolvaptan occurred at higher doses than
used in liver patients, for now, additional studies will be
required to provide safety data with this vaptan in this population, and tolvapatan should not be used in patients with
cirrhosis. Thus, while this class appears promising for the
treatment of hyponatremia, additional safety and efficacy
studies, as well as therapeutic strategies, will be required that
address directly the vasodilated state of cirrhosis.
Compliance with Ethics Guidelines
Conflict of Interest Paul Y. Kwo declares no conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by the
author.

References
Papers of particular interest, published recently, have been
highlighted as:
Of importance
Of major importance
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