1. health and fitness
2. disease

The Management of Ascites and
Hyponatremia in Cirrhosis
Pere Gine`s, M.D.,1 and Andre´s Ca´rdenas, M.D., M.M.Sc.2
ABSTRACT
Ascites is the most common complication of cirrhosis and is associated with an
increased risk for the development of infections, dilutional hyponatremia, renal failure, and
mortality. Cirrhotic patients who develop ascites and associated complications have a low
probability of long-term survival without liver transplantation, and therefore should be
referred for evaluation of liver transplantation. While the initial management of uncomplicated ascites with low-sodium diet and diuretic treatment is straightforward in the
majority of patients, there is a group of patients who fail to respond to diuretics and develop
refractory ascites. The development of specific associated complications such as dilutional
hyponatremia may further challenge the management of patients with ascites. New
pharmacological agents such as the V2 receptor antagonists, drugs that directly antagonize
the effects of elevated plasma antidiuretic hormone levels, induce solute-free water diuresis
and seem to be promising in the management of patients with cirrhosis, ascites, and
dilutional hyponatremia. This article focuses on the pathophysiology, clinical consequences,
current management, and new treatment modalities for ascites and dilutional hyponatremia
in cirrhosis.
KEYWORDS: Ascites, hyponatremia, vaptans
C
irrhosis is the twelfth-leading cause of mortality in the United States, accounting for over 26,000
deaths.1 Ascites is the most common complication of
cirrhosis resulting in poor quality of life, high risk of
development of complications of cirrhosis, increased
morbidity and mortality associated with surgical interventions, high risk of renal failure, and poor long-term
outcome.2–4 Cirrhotic patients who develop ascites have
a probability of survival of 85% at 1 year and 56% at
5 years without liver transplantation.3 Hyponatremia is a
frequent complication of patients with cirrhosis and
ascites that is also associated with increased morbidity
and mortality, the importance of which is increasingly
being recognized.5 This article reviews current concepts
of the pathophysiology and management of ascites and
dilutional hyponatremia (DH) in patients with cirrhosis.
Moreover, we review the significance of hyponatremia in
the setting of cirrhosis and the possible efficacy of the
arginine vasopressin (AVP) V2 receptor antagonists that
are currently under investigation.6
1
M.D., Liver Unit, Hospital Clı´nic, Villarroel 170, 08036 Barcelona,
Spain (e-mail: [email protected]).
Complications of Cirrhosis; Guest Editor, Pere Gine`s, M.D.
Semin Liver Dis 2008;28:43–58. Copyright # 2008 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,
USA. Tel: +1(212) 584-4662.
DOI 10.1055/s-2008-1040320. ISSN 0272-8087.
Liver Unit, Hospital Clı´nic and University of Barcelona, Institut
d’Investigacions Biome`diques August Pi-Sunyer (IDIBAPS), Ciber
de Enfermedades Hepaticas y Digestivas (CIBERHED), Barcelona,
Spain; 2GI Unit, Hospital Clı´nic and University of Barcelona, Institut
d’Investigacions Biome`diques August Pi-Sunyer (IDIBAPS), Ciber de
Enfermedades Hepaticas y Digestivas (CIBERHED), Barcelona,
Spain.
Address for correspondence and reprint requests: Pere Gine`s,
PATHOPHYSIOLOGY OF ASCITES
The major factor contributing to ascites formation is a
splanchnic vasodilation resulting in a decreased effective
arterial blood volume.7 Increased hepatic resistance to
portal flow due to cirrhosis causes gradual development
of portal hypertension and collateral vein formation with
43
44
SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1
2008
Figure 1 Pathogenesis of ascites formation in cirrhosis and current therapeutic options for ascites and dilutional hyponatremia. Portal hypertension is the main factor responsible for the development of splanchnic vasodilation and a decrease in
effective arterial blood volume. The transjugular intrahepatic portosystemic shunt (TIPS), by reducing portal pressure, is an
effective treatment for reducing ascites, particularly in patients with refractory ascites. The compensatory homeostatic
response occurs secondary to a reduced effective arterial blood volume and leads to the activation of antinatriuretic factors
(mainly the renin angiotensin-aldosterone system) with subsequent sodium retention. The use of diuretics (spironolactone) that
promote natriuresis is the preferred therapy for patients with sodium retention and fluid accumulation. Patients with largevolume ascites should be treated with therapeutic paracentesis and albumin administration (8 g per liter tapped) followed by
diuretics as required. In the later stages of the disease solute-free water retention may occur due to high levels of arginine
vasopressin; this contributes to hyponatremia and ascites accumulation. The new V2 receptor antagonists that block the action
of arginine vasopressin in the distal tubule of the kidney are the most promising therapy for dilutional hyponatremia.
shunting of blood to the systemic circulation. As portal
hypertension develops, splanchnic arterial vasodilation
occurs due to the enhanced local production of nitric
oxide and other vasodilators (including calcitonin generelated peptide, substance P, carbon monoxide, and
endogenous cannabinoids) as a consequence of endothelial stretching and possibly bacterial translocation.8,9
Recent studies have provided evidence indicating
that bacterial translocation to mesenteric lymph nodes
with increased production of bacterial products and
subsequent stimulation of cytokine synthesis play a
major role in the pathogenesis of arterial vasodilation
and associated circulatory abnormalities that occur in
cirrhosis.10–12 In early stages of cirrhosis, splanchnic
arterial vasodilation is moderate and has no major effect
on effective arterial blood volume, which is maintained
within normal limits due to an increase in plasma volume
and cardiac output.7 In advanced stages, splanchnic
arterial vasodilation is so intense that effective arterial
blood volume becomes markedly reduced and arterial
pressure falls. A reduction in cardiac output, possibly
related to the presence of cirrhotic cardiomyopathy,
occurs in the late stages of cirrhosis and may also
contribute to the impairment in effective arterial blood
volume.13–15 As a consequence of the impairment in
effective arterial blood volume, there is homeostatic
activation of vasoconstrictor and antinatriuretic factors
to maintain arterial pressure, resulting in renal sodium
and fluid retention. The combination of portal
hypertension and splanchnic arterial vasodilation alters
intestinal capillary pressure and permeability, which
facilitates the accumulation of the retained fluid in the
abdominal cavity. With disease progression, there is
a marked impairment in renal solute-free water excretion
and renal vasoconstriction, leading to DH and hepatorenal syndrome (HRS), respectively. The pathophysiological rationale for the treatment of patients with
cirrhosis and hyponatremia is described in Fig. 1.
EVALUATION OF PATIENTS WITH ASCITES
The evaluation of patients with ascites should include
standard hematology, electrolyte, renal (serum creatinine
and blood urea nitrogen), coagulation (prothombin time
MANAGEMENT OF ASCITES AND HYPONATREMIA/GINE`S, CA´RDENAS
or international normalized ratio), and liver tests
(aminotransferases, bilirubin, albumin, total protein,
alkaline phosphatase).16,17 An abdominal ultrasonography to rule out hepatocellular carcinoma and evaluate the
patency of the portal venous system should be performed. In addition, an upper gastrointestinal endoscopy
to assess the presence and characteristics of esophageal
and gastric varices is recommended. In patients with
renal failure (serum creatinine greater than 1.5 mg/dL),
urine sediment and 24-hour urine protein should be
assessed and the kidneys examined by ultrasonography.
Evaluation of circulatory function should include measurement of arterial pressure and heart rate.
A diagnostic paracentesis (30 mL of fluid) is
required in all patients presenting with their first episode
of ascites and in all patients with any evidence of clinical
deterioration such as fever, abdominal pain, gastrointestinal bleeding, hepatic encephalopathy, hypotension, or
renal failure. The ascitic fluid in cirrhotics is mostly
transparent and yellow/amber in color. Tests in the
ascitic fluid should include cell count, albumin, total
protein, and cultures in blood culture bottles (10 mL of
fluid injected at the bedside).17–20 The cell count is the
most helpful test in determining bacterial infection. In
most cases the ascitic fluid white blood cell count is less
than 100/mm3 with a predominance of mononuclear
cells (> 75%) and a low number of neutrophils. An
increased number of white blood cells with predominance of neutrophils indicates peritoneal infection. The
diagnosis of spontaneous bacterial peritonitis (SBP) is
made when the fluid sample has > 250/mm3 neutrophils
and there are no signs of peritonitis due to perforation or
inflammation of intrabdominal organs.19–21 The difference between serum albumin concentration and ascites
albumin concentration (serum-ascites albumin gradient)
in patients with cirrhosis and ascites is usually greater
than 11 g/L; values lower than 11 g/L suggest a cause of
ascites other than cirrhosis.20 A low total protein concentration in ascitic fluid (< 15 g/L) is associated with an
increased risk of SBP and in selected patients may
indicate a need for antibiotic prophylaxis with oral
quinolones to reduce the risk of SBP and HRS
(see below). Finally, cultures in blood culture bottles
increase the probability of isolating an organism to
50% of cases if the fluid is inoculated into the bottles
at the bedside.20,22
and elimination of ascites in only 10% of patients. Fluid
restriction is not necessary unless patients have DH, a
condition defined as serum sodium less than 130 mEq/L
together with ascites and/or edema5,23 (see below). In
DH, fluid restriction of 1000 to 1500 mL/day is
recommended.6,23 Patients with serum sodium concentration between 130 and 135 mEq/L should be cautious
about fluid intake to prevent fluid retention and development of DH. An evaluation by a nutritionist is of utmost
importance for appropriate education regarding suitable
caloric and salt intake. Improvement of the nutritional
status is essential because patients with advanced liver
disease have decreased intake and absorption of nutrients,
increased energy expenditure, and altered fuel metabolism with an accelerated starvation metabolism.24,25
Nutritional therapy in cirrhotic patients can improve
nutritional status, reduce infection rates, and decrease
perioperative morbidity.24,25 It is also recommended that
nutritional therapy be instituted for long periods of
time or until patients reach liver transplantation. The
goal is for nutritional supplementation to correct the
underlying protein energy malnutrition. In advanced
cases of malnutrition, supplemental enteral nutrition in
cirrhotic patients with ascites may improve liver function
and hepatic encephalopathy.24–27
MANAGEMENT OF PATIENTS WITH
ASCITES
MODERATE-VOLUME ASCITES
General Measures
A low-sodium diet of 2000 mg per day (90 mmol per
day) may facilitate the elimination of ascites and delay
the reaccumulation of fluid.16,17 However, a reduction in
sodium intake alone achieves a negative sodium balance
Specific Measures
The current classification of ascites defined by the
International Ascites Club divides patients into three
groups.19 Patients with grade 1 ascites are those in whom
ascites is detected only by ultrasonography; these patients do not require any specific treatment, but they
should be cautioned about avoiding foods with large
amounts of salt. Patients with grade 2 ascites are those in
whom ascites cause moderate distension of the abdomen
associated with mild/moderate discomfort. Patients with
grade 3 ascites have large amounts of ascitic fluid causing
marked abdominal distension and associated with significant discomfort. Patients with refractory ascites
are those who do not respond to high doses of diuretics
or develop side effects that preclude their use. The
discussion of the management of ascites may therefore
be divided into three parts: moderate-volume ascites
(grade 2 ascites), large-volume ascites (grade 3), and
refractory ascites. A summary of recommendations for
the management of ascites is included in Table 1.
Patients with moderate ascites usually accumulate fluid
slowly, such that they typically do not develop large
ascites unless their sodium intake is very high or they do
not seek medical attention for long periods of time.
Renal solute-free water excretion and glomerular filtration rate are normal in most cases; therefore, serum
sodium and creatinine concentration are usually within
45
46
SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1
2008
Table 1 Management Practice Points in Patients with
Ascites and Cirrhosis
Treatment strategy for patients with cirrhosis and moderate
volume (grade 2) ascites
Start with a low-sodium diet (90 mmol/day) and spironolactone
(50–100 mg/day) to reach goal of weight loss: 300–500 g/day.
If needed, doses to be increased every 7 days up to
with diuretic therapy, may require a reduction in diuretic
dosage. Isolated reports indicate that quinidine (quinidine sulfate, 400 mg/day)31 and intravenous albumin
administration (25 g/week)32 reduce the frequency and
intensity of muscle cramps in cirrhotic patients with
ascites treated with diuretics.
400 mg/day of spironolactone. Furosemide can be added
LARGE-VOLUME ASCITES
at a starting dose of 20–40 mg/day and subsequently increased
Patients with large-volume ascites can be treated as
outpatients unless they have associated complications.
The majority of these patients have intense sodium
retention (urine sodium frequently lower than 10 mEq/
L), so that ascites accumulate rapidly even under sodium
restriction. Some of these patients have a mild impairment in solute-free water excretion and may develop
DH if they have increased fluid intake. Serum creatinine
levels are normal or only moderately increased, indicating
normal or moderately reduced glomerular filtration rate.
Patients can be treated with diuretics alone or
with large-volume paracentesis followed by diuretics.
Diuretics alone are given at increasing doses (maximum
of 400 mg/day of spironolactone and 160 mg/day of
furosemide) following the same schedule as indicated
above. Nonetheless, complete removal of ascites with
one session of large-volume paracentesis with intravenous albumin (8 g per liter tapped) is a faster and more
effective measure in controlling tense ascites and is
associated with a lower number of complications than
conventional diuretic therapy.33,34 Therefore, current
guidelines support paracentesis followed by diuretics as
the method of choice to treat large-volume ascites.19,35
Although there is no difference between the two strategies in regard to long-term mortality, large-volume
paracentesis is faster, more effective, and associated
with fewer adverse events compared with diuretics.
Large-volume paracentesis without plasma expanders is associated with a derangement in circulatory
function, characterized by reduction of effective arterial
blood volume with subsequent activation of vasoconstrictor and antinatriuretic factors.36–38 Circulatory dysfunction after large-volume paracentesis is associated
with high ascites recurrence rate, development of HRS
and/or DH in 20% of cases, and shortened survival.36–38
This disorder can be effectively prevented with the
administration of plasma expanders.33–38 When less
than 5 L of ascites are removed, artificial plasma expanders, saline, and albumin are equally effective.38–40
However, if more than 5 L are removed, albumin is
recommended.36–38 Since ascites will invariably recur,
patients need to be started or continued on diuretics to
prevent a positive sodium balance.41 Although the use
of albumin after paracentesis is controversial due to the
lack of data proving a survival benefit and high cost in
some countries, the protective effect of albumin on the
circulatory system compared with other expanders favors
its use in this setting.
to 160 mg/day if needed.
Treatment strategy for patients with cirrhosis and
large-volume (grade 3) ascites
Total paracentesis plus intravenous albumin (8 g per liter of
ascites removed) followed by a low-sodium diet
(90 mmol/day) and diuretics if patient tolerated them
beforehand.
Treatment strategy for refractory ascites
Total paracentesis plus intravenous albumin can be performed
as needed. Consider use of TIPS in patients with very
frequent recurrent ascites without severely impaired hepatic
function, aged < 70 years, and no hepatic encephalopathy.
TIPS, transjugular intrahepatic portosystemic shunts.
normal limits. These patients typically can be managed
as outpatients and do not require hospitalization unless
other complications of cirrhosis are present. A negative
sodium balance with loss of ascites is quickly and easily
obtained in most cases with low doses of diuretics.17,19,20,28,29 Diuretics of choice are either spironolactone (starting dose: 50 to 100 mg/day) or amiloride
(5 to 10 mg/day). Low doses of furosemide (20 to 40 mg/
day) may be useful during the first few days to increase
natriuresis, especially when marked peripheral edema is
present; however, it should be used with caution because
it can cause overdiuresis leading to hypokalemia and
prerenal renal failure. The goal of treatment is to
produce an average weight loss of 300 to 500 g/day
in patients without peripheral edema and 800 to 1000 g/
day in those with peripheral edema until ascites have
decreased markedly, following which diuretic dosage can
be reduced.17,19 In the uncommon cases of no response
to low doses of diuretics, spironolactone may be
increased up to a dose of 400 mg/day and furosemide
up to 160 mg/day in progressively increasing doses.29
In patients who do not respond, compliance with a lowsodium diet and diuretics should always be assessed. In
these cases measurement of urine sodium, which provides an accurate assessment of the response to diuretics,
may help in deciding whether there is a need to increase
dose. Spironolactone may cause tender gynecomastia in
some patients and in most instances the dose needs to be
reduced or the medication needs to be stopped. Tamoxifen (20 mg by mouth twice a day) may be useful in
reducing pain in some cases; however, information is
very limited.30 Muscle cramps, which also may appear
MANAGEMENT OF ASCITES AND HYPONATREMIA/GINE`S, CA´RDENAS
Complications related to paracentesis, such as
bleeding, infection, or intestinal perforation, are exceedingly rare if paracentesis is performed under sterile
conditions and with an appropriate technique and
needle.20,33,35–38,42–45 The recommended location for
performing paracentesis is the left lower quadrant,
2 finger breadths cephalad and 2 finger breadths medial
to the anterior superior iliac spine. In this area, the skin is
thin and there is a larger pool of fluid than at the
midline.46 The risk of bleeding in cirrhotic patients
when performing a paracentesis is extremely low; the
frequency of severe hemorrhage after a tap is 0.20%
and a lethal outcome occurs in less than 0.01% of cases.43
In some cases, severe hemorrhage due to a paracentesis
may occur due to trauma of the inferior hypogastric
artery. In such cases, the patient requires urgent
arteriography with embolization to arrest bleeding
(P. Gine`s, unpublished observations). Therefore, when
performing paracentesis, the area of the inferior hypogastric arteries (midway between the pubis and anterior
superior iliac spines) should be avoided. Most clinical
trials in patients with cirrhosis and ascites have excluded
patients with an elevated prothrombin time greater than
21 seconds or international normalized ratio greater than
1.6 or platelet count below 50,000 per mL. Therefore,
the risk of bleeding complications in patients with more
severe coagulopathy is unknown and deserves investigation. Nonetheless, consensus meetings, guidelines, and
expert opinion consider that the abnormal coagulation
profile of the cirrhotic patient (mild prolonged prothrombin time and low platelets with a value > 50,000 per mL)
is not an absolute contraindication for paracentesis and
the routine administration of platelets or fresh frozen
plasma as prophylaxis for bleeding is not recommended.20,35,44 In patients with severe thrombocytopenia
with a platelet count < 50,000 per mL, transfusion of
platelets should be considered prior to the procedure.35
Patients with suspected disseminated intravascular
coagulopathy should not undergo a paracentesis.20
REFRACTORY ASCITES
Refractory ascites occur in nearly 10% of patients with
cirrhosis and ascites.19,47 In patients with nonrefractory
ascites, sodium excretion may be increased with the use
of diuretics, but in patients with refractory ascites,
sodium excretion cannot be increased with diuretics,
either because patients do not respond to high doses of
diuretics (spironolactone 400 mg/day plus furosemide
160 mg/day) or they develop side effects with lower
doses that preclude their use19,47 (Table 2). These
patients in general have features of advanced liver disease, a high recurrence rate of ascites after large-volume
paracentesis, an increased risk of Type-1 HRS, and
a poor prognosis.48 Patients can be treated with
either repeated large-volume paracentesis with plasmaexpansion or transjugular intrahepatic portosystemic
Table 2 Definition and Diagnostic Criteria for Refractory
Ascites in Cirrhosis
Diuretic-resistant ascites
Ascites that cannot be mobilized or the early recurrence of which
cannot be prevented because of a lack of response to sodium
restriction and diuretic treatment.
Diuretic-intractable ascites
Ascites that cannot be mobilized or the early recurrence of which
cannot be prevented because of the development of
diuretic-induced complications that preclude the use of an
effective diuretic dosage.
Requisites
(1) Treatment duration: Patients must be on intensive diuretic
therapy (spironolactone 400 mg/day and furosemide
160 mg/day) for at least 1 week and on a salt-restricted diet
of less than 90 mmol/day.
(2) Lack of response: Mean weight loss of < 0.8 kg over 4 days
and urinary sodium output less than the sodium intake.
(3) Early ascites recurrence: Reappearance of grade 2 or 3
ascites within 4 weeks of initial mobilization.
(4) Diuretic-induced complications: Diuretic-induced hepatic
encephalopathy is the development of encephalopathy in the
absence of any other precipitating factor. Diuretic-induced
renal impairment is an increase of serum creatinine by > 100%
to a value > 2 mg/dL in patients with ascites responding to
treatment. Diuretic-induced hyponatremia is defined as a
decrease of serum sodium by > 10 mEq/L to a serum sodium
of < 125 mEq/L. Diuretic induced hypo- or hyperkalemia is
defined as a change in serum potassium to < 3 mEq/L or
> 6 mEq/L despite appropriate measures.
Modified with permission from Moore KP, Wong F, Gine`s P, et al.
The management of ascites in cirrhosis: report on the consensus
conference of the International Ascites Club. Hepatology
2003;38:258–266.
shunts (TIPS). Repeated large-volume paracentesis
plus albumin is the most accepted initial therapy for
refractory ascites. Patients generally require paracentesis
every 2 to 4 weeks, which can be done in the outpatient
setting. This approach is therefore easy to perform and
relatively inexpensive49.The main drawback is early recurrence of ascites, because paracentesis does not modify
the mechanisms responsible for ascites formation. In
contrast to paracentesis, TIPS, a nonsurgical method
of portal decompression that consists of the insertion of
an intrahepatic stent between one hepatic vein and the
portal vein using a transjugular approach, is effective
in preventing ascites recurrence in refractory ascites
because reduction in portal pressure is accompanied by
a resolution of ascites in most patients. Uncovered TIPS
are very effective in relieving ascites, but are frequently
complicated by stenosis of the prosthesis (18 to 78%).50
Polytetrafluoroethylene-covered prostheses seem to improve TIPS patency and decrease the number of clinical
relapses and reinterventions without increasing the
risk of encephalopathy.51 A randomized trial comparing
large-volume paracentesis plus albumin versus covered
47
48
SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1
2008
TIPS is being conducted in patients with refractory
ascites (www.clinicaltrials.gov). Randomized clinical
trials comparing uncovered TIPS versus repeated
paracentesis demonstrate that TIPS controls ascites
effectively and is associated with a lower rate of ascites
recurrence.49,52–55 In addition, patients with ascites who
undergo TIPS improve their nutritional status as measured by resting energy expenditure, total body nitrogen,
body fat, and food intake.56 Hepatic encephalopathy
occurs in 30 to 50% of patients.49,50,52,53 Two studies
showed a survival benefit with TIPS,53,55 but two other
studies demonstrated no difference in survival.49,54
Three meta-analyses of these randomized controlled
studies conclude that TIPS is better at controlling ascites
but does not improve survival compared with paracentesis.57–59 Another recent meta-analysis that reviewed
individual patient data of three trials53–55 indicates that
TIPS significantly improves transplant-free survival of
cirrhotic patients with refractory ascites.60 Although
meta-analysis using individual data is in theory a more
reliable tool compared with standard meta-analysis, it
cannot overcome deficiencies of individual studies, such
as inclusion of patients who did not have refractory
ascites in two of the studies,53,55 use of large-volume
paracentesis without albumin in one study,53 and use of
TIPS as rescue therapy in a large proportion of patients
treated with large-volume paracentesis in another
study.55 Until more information becomes available, the
higher frequency of hepatic encephalopathy as well as
the higher cost of TIPS compared with large-volume
paracentesis plus albumin, in the context of a lack of
survival benefit, leaves TIPS as a second-line therapy in
the management of refractory ascites. The first line of
treatment for refractory ascites is repeated large-volume
paracentesis associated with albumin.49,54,57–59 TIPS
placement may an option for patients with very
rapid recurrence of ascites and preserved liver function
(bilirubin < 3 mg/dL, serum sodium level > 130 mEq/
L, Child-Pugh score < 12, model for end-stage
liver disease (MELD) score < 18), aged < 70, without
hepatic encephalopathy, central hepatocellular carcinoma, or cardiopulmonary disease.58–61
EVALUATION FOR LIVER TRANSPLANTATION
Patients with cirrhosis developing their first episode
of ascites have a relatively good mid-term prognosis
(probability of survival of 85% at 1 year and 76% at
3 years).3 This prognosis is similar to the outcome of
liver transplant recipients (probability of survival of 87%
at 1 year and 78% at 3 years) (www.unos.org). Several
factors associated with poor prognosis have been described in patients with cirrhosis and ascites. These
factors, which are usually not present at the time
of development of first ascites and occur later in the
course of the disease, include low serum sodium concentration, low arterial pressure, high serum creatinine,
intense sodium retention (urine sodium less than
10 mEq/day), and high Child-Pugh scores.62,63 Thus,
patients with cirrhosis and the first episode of ascites
without associated poor prognostic factors may not
benefit from liver transplantation, particularly if they
have a MELD score < 15 (A. Ca´rdenas, P. Gine`s,
unpublished data). Nevertheless, whenever some of
these factors are present patients should be promptly
referred for evaluation of liver transplantation.
The allocation of organs for patients awaiting liver
transplantation is currently based on MELD score in
many countries.64 Although MELD score predicts survival in patients with cirrhosis and ascites, some studies
have suggested that it may not be accurate enough for all
patients with ascites, particularly for those with persistent
or refractory ascites, who may have a poor prognosis
despite low MELD scores. In fact, in one study, half of a
cohort of patients awaiting liver transplantation with a
MELD score < 21 died within 180 days, suggesting that
these patients did not get transplanted soon enough.65
Therefore, there is a need for scores with higher accuracy
in the prediction of survival in patients with cirrhosis and
ascites. In this regard, several recent studies have shown
that serum sodium concentration is a very sensitive
prognostic factor, independent of that of the MELD
score, in patients with cirrhosis and ascites awaiting liver
transplantation.66–71 Moreover, some studies, but not all,
have shown that serum sodium improves the prognostic
accuracy of the MELD score in the prediction of survival
in these patients. Therefore, the suggestion has been
made that a new score, MELD-sodium, could be more
useful than MELD score alone.68 Nevertheless, the
inclusion of serum sodium in a new score for survival
prediction in cirrhosis has in our opinion two major
limitations. The first and more important one is that
serum sodium is a very modifiable parameter. While
the parameters currently included in the MELD score
(bilirubin, creatinine, and international normalized ratio)
are relatively steady despite common therapeutic measures, serum sodium concentration can fluctuate markedly.
In fact, the administration of diuretics or moderate
amounts of hypotonic fluids may induce significant
reductions in serum sodium concentration which may
not reflect changes in the prognostic status of the
patients. Second, studies are being conducted to investigate the effects of V2 receptor antagonists, drugs that
increase serum sodium concentration by improving
solute-free water excretion, in the management of DH
in cirrhosis.6 Should these drugs have beneficial effects in
the management of patients with cirrhosis, their clinical
use may be hampered by the inclusion of serum sodium in
a prognostic score. In this regard, it is important to
remark that hyponatremia before liver transplantation is
associated with an increased risk of neurological as well as
other complications which result in a poor outcome after
transplantation.72,73 Therefore, the use of drugs that can
MANAGEMENT OF ASCITES AND HYPONATREMIA/GINE`S, CA´RDENAS
increase serum sodium before transplantation could
result in reduction of complications and improved posttransplantation outcome. Taken together, all these data
suggest that a greater understanding of hyponatremia and
its clinical consequences as well as management in
patients with cirrhosis should be obtained before serum
sodium is included as a new parameter in an improved
MELD score to be used for organ allocation in liver
transplantation.
Future Therapies
New treatments for ascites are being evaluated based on
two approaches. The first stems from what is known
regarding the underlying pathophysiological abnormalities that cause sodium and water retention. In this
approach the use of new agents (V2 vasopressin receptor
antagonists) that act on the kidney and promote solutefree water diuresis can be combined with diuretics to
improve mobilization of ascites and edema. Animal and
human studies suggest that these drugs, apart from
causing solute-free water excretion, enhance sodium
excretion.74,75 The second approach relates to the use
of vasoconstrictor drugs that are able to improve the
underlying hemodynamic derangements that lead to
ascites formation in cirrhosis, thereby reducing the
activity of antinatriuretic factors. These drugs may
theoretically improve the action of diuretics to maximize
ascites mobilization.
The use of specific antagonists of the vasopressin
receptor (V2 receptor antagonists) on the distal tubule of
the kidney by means of counteracting AVP and increasing the excretion of solute-free water is being investigated in the management of ascites in cirrhosis. These
drugs are not yet approved for patients with cirrhosis and
ascites; however, an intravenous V1-V2 receptor antagonist (conivaptan) is approved by the U.S. Food and
Drug Administration for the treatment of euvolemic
hyponatremia in hospitalized patients (www.fda.gov).
Two large, multicenter, randomized controlled studies
evaluated the effects of satavaptan (an oral V2 receptor
antagonist) in patients with cirrhosis and ascites.76,77 In
one study, 184 cirrhotic patients with ascites were
randomized to receive three fixed doses of satavaptan
(5 mg, 12.5 mg, and 25 mg daily) or placebo for
14 days.76 Patients were given spironolactone (100 mg/
day) and furosemide (20 to 25 mg/day) during the study
period. In the study, 24-hour urine volume of those
receiving satavaptan significantly increased in a dosedependent fashion compared with placebo. In addition
there was a significant reduction in body weight in the
satavaptan group, without any significant side effects
compared with placebo. In the other study, 151 cirrhotic
patients with recurrent ascites requiring large-volume
paracentesis were randomized to receive either three
fixed doses of satavaptan (5 mg, 12.5 mg, and 25 mg
daily) or placebo for 12 weeks.77 All patients were given
spironolactone (100 mg/day) during the study period.
The frequency of recurrent ascites was decreased in all
groups receiving satavaptan compared with placebo. The
clinical utility of these agents in cirrhosis has been
assessed only in short-term studies; therefore further
controlled studies during longer periods of time are
needed to evaluate the safety, efficacy, and applicability
of these agents in patients with cirrhosis and ascites.
Other potential therapies for patients with ascites
stem from data on the use of vasoconstrictors with
plasma expansion in patients with cirrhosis and
HRS.78,79 These agents improve renal function, urinary
sodium excretion, and serum sodium levels, and decrease
the levels of vasoctive/antinatriuretic systems in patients
with advanced cirrhosis and HRS. Therefore the use of
an oral vasoconstrictor is an attractive approach in the
treatment of patients with ascites without HRS who do
not respond to diuretics. In one study of 39 patients with
cirrhosis, oral midodrine (an a-1 adrenergic agonist)
10 mg, three times a day, was given to 11 patients
without ascites and 12 with ascites and compared with
placebo in 8 patients without ascites and 8 with ascites
for 7 days.80 In the midodrine group there was a
moderate increase in urine sodium excretion in patients
with ascites (urinary sodium from 30 15 to 49 16 mEq/L) as well as glomerular filtration rate (from
80 23 mL/min to 92 27 mL/min) and urine volume
(from 0.98 0.26 L to 1.15 0.34 L) and significant
decreases in plasma renin activity and aldosterone.
Nonetheless, in this study neither body weight or abdominal girth as measures of an effect on ascites were
recorded. Finally, clonidine, a centrally acting a2-agonist
and sympatholitic agent, was evaluated as an adjunct
treatment in patients with cirrhosis and ascites. In a
randomized study, oral clonidine (0.075 mg twice a day)
led to a more rapid mobilization of ascites with
fewer complications than placebo in patients with cirrhosis, ascites, and a plasma norepinephrine level of
> 300 pg/mL.81 The use of these drugs in cirrhosis
and ascites is limited to a small number of reports;
therefore, more controlled studies are needed to evaluate
their efficacy and safety in treating patients with ascites.
HYPONATREMIA IN CIRRHOSIS
In a subset of patients with cirrhosis, hyponatremia may
occur due to excessive losses of sodium and extracellular
fluid, either from the kidney (as a result of high doses
of diuretics) or from the gastrointestinal tract (due to
diarrhea or excessive vomiting). In this type of hyponatremia (also termed hypovolemic hyponatremia), there is
significant volume depletion and serum sodium levels
improve after correcting the precipitating cause; that is,
stopping diuretics and replacing sodium losses. Nevertheless, in the majority of patients with advanced
49
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SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1
2008
cirrhosis, hyponatremia develops in the setting of ascites
where there is an expanded extracellular fluid volume
along with increased renal sodium retention. This
type of hyponatremia is known as hypervolemic hyponatremia or DH. In this condition, renal retention of
solute-free water is disproportionate to that of sodium
retained and serum sodium levels decrease despite the
existence of increased total body sodium.
DH in cirrhosis is defined as a reduction in serum
sodium concentration below 130 mEq/L in the setting
of ascites and/or edema.5,23 The cut-off level of
130 mEq/L was defined arbitrarily in a consensus meeting; however, there are many patients with cirrhosis and
ascites with serum sodium levels between 130 and
135 mEq/L that also have an impaired ability to eliminate solute-free water. In patients with refractory ascites
or HRS, this proportion may increase up to 50%.49
Prospective data on 997 patients in a multicenter trial
showed that the prevalence of hyponatremia in cirrhosis
as defined by a serum sodium level 135 mEq/L was
49%; with levels 130 mEq/L, 125 mEq/L, and
120 mEq/L the prevalence was 21.6%, 5.7%, and
1.2%, respectively.5 When compared with patients without hyponatremia, those with hyponatremia had more
severe liver disease, worse control of their ascites, a
higher rate of hepatic encephalopathy, SBP, and HRS.5
Pathogenesis
Sodium concentration in blood is maintained by a
complex interaction between baroreceptors, osmoreceptors, and central neurohormonal systems, which include
the thirst drive and the antidiuretic hormone or AVP. A
decrease in serum sodium concentration may lead to a
range of symptoms from mild cognitive and motor
dysfunction to seizures and/or coma. Abnormalities in
AVP arise from either an increased or decreased production or a deranged action. Diseases such as cirrhosis
may cause hyponatremia by nature of an increased
production of AVP. In cirrhosis, splanchnic vasodilation
leads to arterial underfilling which unloads high-pressure baroreceptors that stimulate a nonosmotic hypersecretion of AVP, leading to solute-free water retention
and DH (Fig. 1).7,82 The biological effects of AVP are
mediated through three types of G protein-coupled
receptors known as V1a, V1b, and V2 receptors. V1a
and V1b are associated to the phosphoinositol-signaling
pathway with intracellular calcium as second messenger.
V1a is responsible for vascular smooth muscle cell
contraction, platelet aggregation, and hepatic glycogenolysis, and V1b is expressed in the anterior pituitary
where it mediates adrenocorticotropin release.83,84 The
V2 receptors are located on the basolateral (capillary)
membrane of the principal cells of the collecting
ducts and are responsible for the AVP-induced water
reabsorption.
The effect of AVP on V2-mediated water reabsorption is due to selective water channels called aquaporins (AQP). The most important one is AQP2. This
water channel has been characterized in human and rat
kidneys and is expressed almost exclusively in the principal cells of the collecting ducts.85,86 The binding of AVP
to the V2 receptor stimulates adenyl cyclase via the
stimulatory G protein and promotes the formation of
cyclic AMP (cAMP). This cAMP binds to a regulatory
subunit of protein kinase A, which in turn phosphorylates
AQP2, which is then translocated from vesicular bodies
present in the cytosol to the luminal (apical) plasma
membrane of the collecting duct cells, and acts as a water
channel thereby increasing water permeability.83 The
water entering the cell by the luminal plasma membrane
leaves the cell through the basolateral membrane and
enters the capillaries that are in close contact with tubular
cells. Recent data indicate that in patients with cirrhosis
and ascites the excretion of AQP2 is reduced possibly as a
protective mechanism that would prevent ongoing and
continuous solute-free water absorption from the collecting duct.87 Data from large clinical studies using specific
V2 receptor antagonists of AVP indicate that hypersecretion of AVP plays a major role in the development
of DH because the administration of these drugs is
associated with an increase in serum sodium concentration in the large proportion of patients with DH.88–92
Cerebral Adaptation to Hyponatremia
In health, brain osmolality and extracellular fluid osmolality are in balance with similar amounts of electrolytes
and water. When serum sodium falls, water moves into
brain cells in response to osmotic gradients to attain
osmotic equilibrium, thereby producing brain edema.
This cell swelling leads to extrusion of intracellular
solutes (mainly potassium) and organic osmolytes within
24 to 48 hours to decrease brain cell osmolality and to
therefore try to match that of plasma93,94 (Fig. 2).
Organic osmolytes (glutamine, glutamate, taurine, and
myo-inositol) are intracellular compounds involved in
the long-term adaptation of osmotic changes. Once the
solute removal is successfully achieved, osmolytes are
extruded afterward and osmotic equilibrium will be
maintained between brain and plasma, and no symptoms
arise from hyponatremia. In acute hyponatremia, adaptation to this new environment is difficult to achieve and
therefore patients may develop symptoms. In chronic
hyponatremia there is a slow coordinated loss of solutes
and osmolytes that allows effective management of
brain volume and explains why in chronic hyponatremia
patients often do not have symptoms.95–97
CEREBRAL CHANGES IN CIRRHOSIS
Although it has been proposed that patients with cirrhosis and hepatic encephalopathy have some degree of
MANAGEMENT OF ASCITES AND HYPONATREMIA/GINE`S, CA´RDENAS
Figure 2 Brain volume adaptation to hyponatremia. (A) Under normal conditions brain osmolality and the extracellular fluid
osmolality are in balance (the intracellular solutes are potassium and osmolytes and the extracellular solute is sodium). (B) With
hyposmolality, water moves into the brain due to changes in osmotic gradients causing edema depicted by the dotted line
(middle A). In response to this swelling, the brain loses both intra- and extracellular solutes (B). Water losses accompany losses
of brain solute and the expanded volume returns to normal (C). If hyposmolality is sustained, brain volume will eventually
normalize and the brain will become adapted to the hyponatremic extracellular fluid. (Adapted from Verbalis JG. The syndrome
of inappropriate secretion of antidiuretic hormone secretion and other hyposmolar disorders. In: Schrier R, ed. Diseases of the
Kidney and Urinary Tract. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:2214.)
cerebral edema, they do not develop signs of significant
brain edema or increased intracranial pressure. Studies
with 1H-MRS spectroscopy in patients with hepatic
encephalopathy reveal a reduction of myo-inositol along
with an increased glutamine/glutamate signal that likely
contributes to the development of a low-grade brain
edema.98 It has therefore been suggested that in cirrhosis, hepatic encephalopathy may be a manifestation of a
low-grade cerebral edema, which may deteriorate with
other precipitant factors and thereby alter astrocyte
function.99,100 Magnetic resonance imaging (MRI) findings in patients with minimal hepatic encephalopathy
show changes consistent with a low-grade cerebral
edema and these changes become more evident with
advanced stages of hepatic encephalopathy or with the
insertion of TIPS.98–101 Interestingly, patients with
portal hypertension and minimal hepatic encephalopathy but without cirrhosis also have MRI findings
consistent with increased brain water content.102 Other
factors including drugs, hyponatremia, and inflammatory cytokines can induce astrocyte swelling that in turn
leads to a complex series of steps that are implicated in
the pathogenesis of hepatic encephalopathy.100 In cirrhosis there is evidence of an increase in brain glutamine
and reduction in other organic osmolytes, particularly
myo-inositol.103,104 The high levels of glutamine lead to
a compensatory loss of myo-inositol and other organic
osmolytes but do not appear to completely prevent some
degree of brain swelling.98,105,106
The relationship between hyponatremia and hyperammonemia in animals and humans has shed light
into the complex interactions between these two states
which commonly occur in cirrhosis. In a study of
patients with cirrhosis and hyponatremia, levels of
organic osmolytes, as measured by MR spectroscopy,
correlated directly with serum sodium and osmolality;
brain glutamine levels were higher in patients with
cirrhosis when compared with those of healthy subjects
and correlated with ammonia levels but not with serum
sodium. The high levels of glutamine, which in noncirrhotic patients with hyponatremia were low, may be
the consequence of a prolonged exposure of the brain to
51
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SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1
2008
high ammonia levels.106 These findings suggest that
organic osmolytes play an important role in cerebral
fluid homeostasis in cirrhosis. Hyponatremia in cirrhosis is accompanied by significant changes in osmolytes
that possibly prevent significant neurological damage
and occur as high levels of glutamine trigger a compensatory response against cell swelling. Several studies
indicate that a low serum sodium concentration increases the risk of hepatic encephalopathy: (1) A study
in an animal model of acute liver failure and hepatic
encephalopathy induced by ammonia infusion indicated that the presence of hyponatremia increases
brain edema compared with animals with normal
serum sodium levels107; (2) Patients with low brain
myo-inositol levels have a marked impairment in neuropsychological tests after oral administration of an
amino acid solution (mimicking a protein content
that can trigger hepatic encephalopathy), compared
with patients with normal brain myo-inositol content108; (3) In patients with acute liver failure, hyponatremia, and high ammonia levels, the administration
of hypertonic saline reduces intracerebral pressure109;
(4) Hyponatremia by means of producing metabolic
changes in brain cells (either the direct effects of low
sodium on the brain or the adaptation of the brain to
hyponatremia) may act as predisposing factor of hepatic
encephalopathy110; (5) Hyponatremia is an independent predictive factor for the development of hepatic
encephalopathy in patients with refractory ascites111;
(6) Prospective data from a large multicenter trial
in patients with hyponatremia indicate there is an
inverse relationship between serum sodium levels and
the frequency of hepatic encephalopathy, SBP, and
HRS. Patients with a serum sodium concentration
130 mEq/L have a higher rate of these complications
compared with subjects with normal serum sodium
concentration5 (Fig. 3).
Clinical Features
There is limited information on the clinical consequences of DH in the setting of cirrhosis. Most of the clinical
symptoms associated with hyponatremia in patients
without liver disease are related to the central nervous
system. The typical manifestations of acute hyponatremic encephalopathy in patients without liver disease,
which range from confusion and disorientation to more
severe symptoms associated with brain herniation, such
as coma and seizures, rarely occur in cirrhosis. Hyponatremia in cirrhosis usually develops slowly over several
days or weeks, giving the brain time to adapt to a
hypotonic state, although occasionally some patients
may present with an acute onset of hyponatremia. As
discussed before, recent data suggest that hyponatremia
is a risk factor for the development of hepatic encephalopathy.111 Moreover, a recent analysis of health-related
Figure 3 Clinical data from a large multicenter trial in
patients with hyponatremia. Patients with hyponatremia
(serum sodium 130 mEq/L) had a higher frequency of
spontaneous bacterial peritonitis (SBP), hepatic encephalopathy, and hepatorenal syndrome (HRS) compared with
patients without hyponatremia. (Adapted from Angeli
P et al. Hyponatremia in cirrhosis: results of a patient
population survey. Hepatology 2006;44:1535–1542.)
quality of life data by using the SF-36 questionnaire
collected on 523 patients with cirrhosis with and without
hyponatremia enrolled in multicenter double-blind
studies of treatment with the V2-receptor antagonist
satavaptan showed that the serum sodium concentration
was an independent predictor of six out of the eight
domains analyzed.112 Its predictive value was independent of liver function, strongly suggesting that serum
sodium concentration is a major determinant of quality
of life in patients with cirrhosis.
Hyponatremia before liver transplantation has
important clinical implications. Since liver transplantation is associated with a rapid correction of low serum
sodium levels in hyponatemic patients, this sudden
normonatremic state may put patients at risk for deleterious effects on the brain. In fact, there are reports of
severe neurological complications, particularly osmotic
demyelination syndrome, in patients with cirrhosis with
hyponatremia submitted to liver transplantation.113,114
Also, as mentioned above, patients that undergo liver
transplantation with low serum sodium levels are prone
to more neurological complications, renal failure,
and bacterial infections during the first 30 days after
transplant and increased 3-month mortality with respect
to patients without hyponatremia.73
Prevention
There is limited information regarding specific measures
that prevent DH. Patients with ascites who undergo
large-volume paracentesis without plasma expansion
may develop DH due to a postparacentesis circulatory
dysfunction.37 This complication may be effectively
prevented with the administration of albumin (see
MANAGEMENT OF ASCITES AND HYPONATREMIA/GINE`S, CA´RDENAS
above). Patients with ascites who receive large amounts
of intravenous hypotonic fluids (i.e., 5% dextrose) may
develop worsening DH as the renal capacity to excrete a
water load is limited in most patients with advanced
cirrhosis. Therefore, care should be taken when administering hypotonic fluids to patients with cirrhosis and
ascites to prevent the development of DH.
hyponatremia, although probably impractical due to
the need for daily intravenous administration, could be
further investigated in a subset of patients that would
benefit from a short-term therapy (i.e., patients with very
advanced liver disease awaiting liver transplantation).
PHARMACOLOGICAL THERAPY
Pharmacological approaches to the management of DH
in cirrhosis have focused on inhibiting the actions of
AVP. Although some drugs used for DH in cirrhosis,
such as demeclocycline, urea, and kappa-opioids, have
been reported to be effective, their use has been abandoned due to important side effects.116–119 The aim of
therapy in DH is to increase solute-free water excretion,
which has been done by antagonizing the action of AVP
by means of blocking the V2 receptor for AVP with
specific antagonists. These drugs have been evaluated in
the treatment of DH in hypervolemic states such as
congestive heart failure, the syndrome of inappropriate
antidiuretic hormone secretion (SIADH), and cirrhosis.
Several nonpeptide V2 receptor antagonists including
mozavaptan (OPC-31260), lixivaptan (VPA-985), satavaptan (SR-121463), tolvaptan (OPC-41061), and
RWJ-351647 have been tested in patients with cirrhosis
and ascites.88–92,120–122 Published clinical studies using
the V2 receptor antagonist satavaptan in patients with
cirrhosis and hyponatremia are included in Table 3.
Management
The most commonly accepted method for the management of DH in cirrhosis and other water-retaining states
is fluid restriction of 1 to 1.5 L/day 23. However, fluid
restriction in patients with cirrhosis and DH has very
limited efficacy in improving serum sodium levels.88,89
The routine administration of hypertonic saline solution
is not recommended because additional expansion of the
extracellular fluid worsens edema and ascites and its
effect in increasing serum sodium is modest. Plasma
expansion with albumin seems to be beneficial in transiently correcting DH in patients with cirrhosis and
ascites. In a preliminary report, 24 patients with refractory ascites and DH (serum sodium 130 mEq/L) were
randomized to fluid restriction (1.5 L/day) versus intravenous albumin (40 gm/day) for 7 days. In patients who
received albumin, serum sodium levels improved in 8/12
patients. In addition, there was a reduced incidence of
infections, hepatic encephalopathy, and in-hospital mortality in the albumin group.115 Although these results are
encouraging, the study period was only 1 week and the
effects therefore short-lived. The use of albumin for
V2 RECEPTOR ANTAGONISTS IN CIRRHOSIS AND DH
Two multicenter, randomized, placebo-controlled trials
evaluated the use of lixivaptan in cirrhotic patients with
Table 3 Published Clinical Studies Using V2 Receptor Antagonists in Patients with Cirrhosis and Ascites and
Hyponatremia
Author (ref)
Compound
Dose
Phase
Patients
Comments
Wong et al (2003)88
Lixivaptan*
50–500 mg/day p.o.
II
44y with
Increased urine output, CH2O,
for 7 days
hyponatremia
S osm, serum Na. Dehydration
with doses of 500 mg. Drop-out
rate was 27%
Gerbes et al (2003)89
Lixivaptan*
100–200 mg/day p.o.
II
for 7 days
60 with
hyponatremia
Increased serum Na, decreased
U osm and body weight. Thirst
appeared in patients at the
200-mg dose.
Gine`s et al (2006)91
Satavaptan þ
5 mg, 12.5 mg, and
II
25 mg daily for
110 with
hyponatremia
Concomitant spironolactone
100 mg/day. Serum Na increased
to 135 mEq/L or > 5 mEq/L in
2 weeks
54–64% of cases, depending
on dose.
Gine`s et al (2007)92
Satavaptan þ
5 mg, 12.5 mg,
and 25 mg
daily for 1 year
II
73 with
hyponatremia
Concomitant spironolactone
100 mg/day. Median serum Na
increased from 131 mEq/L up to
136 mEq/L by week 40.
*Randomized, double-blind, placebo-controlled trial.
y
Included 5 patients with cardiac disease and 5 with SIADH.
p.o., by mouth; U osm, urinary osmolality; S osm, serum osmolality; CH2O, solute-free water clearance; Serum Na, serum sodium; U vol, urine
volume.
53
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SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1
2008
DH.88,89 In these two studies this agent caused a doserelated increase in serum sodium levels and free water
clearance. Unfortunately, the drug caused significant
dehydration in some patients at the effective doses in
one study,88 and in the other study, which evaluated two
doses of the drug versus placebo, a small number of
patients in each group was included (20 per arm) and the
effects of lixivaptan were only evaluated until serum
sodium normalized without information on long-term
response.89
Recent data from a large multicenter randomized
controlled study evaluating the use of tolvaptan in
patients with euvolemic or hypervolemic hyponatremia
(SIADH, congestive heart failure, and cirrhosis) indicate
that this agent is effective in raising serum sodium
concentration when used for 30 days.90 In this study, a
subgroup of 63 patients with cirrhosis and DH were
assigned tolvaptan and 57 placebo starting at 15 mg
in ascending doses according to response.122 There
were no significant side effects compared with placebo.
Tolvaptan rapidly improved serum sodium and fluid
balance and caused significant weight loss in patients
with cirrhosis and hyponatremia compared with placebo,
and markedly increased solute-free water clearance
without adversely affecting renal function. In patients
with cirrhosis and DH, normalization of sodium levels
(> 135 mEq/L) occurred in 30% and 22% of subjects at
days 4 and 30, respectively.122 This agent therefore
seems to be safe, effective, and likely to be promising
in the treatment of DH.
Finally, data from a multicenter study indicates
that the short- and long-term use of satavaptan in
patients with cirrhosis and DH improves serum sodium
levels.91,92 The short-term use (14 days) of satavaptan
at doses of 5 mg, 12.5 mg, 25 mg once daily in patients
with cirrhosis and hyponatremia receiving 100 mg of
spironolactone was effective in correcting serum sodium
levels. After 5 days, patients with a dose of 5 mg,
12.5 mg, and 25 mg increased serum sodium level to
135 mEq/L or > 5 mEq/L in 61%, 54%, and 64%
of cases, respectively. Seventy-three patients where
followed for a year. Forty-seven were randomized to
satavaptan and 26 to placebo.92 Satavaptan was used at
5 mg/day and titrated up as needed to 50 mg/day. The
majority of patients in the satavaptan group were maintained on 5 mg or 12.5 mg daily. Median serum sodium
concentration at baseline in patients treated with satavaptan was 131 mEq/L and increased up to136 mEq/L
by week 40. By contrast, in the placebo group serum
sodium values did not change. In a subset of patients,
serum sodium levels fell back to their baseline after
discontinuation of satavaptan. There were no significant
differences between the two groups with respect to
the incidence of serious adverse events. These results
demonstrate that the improvement of hyponatremia
by satavaptan in patients with cirrhosis is maintained
with long-term treatment and that discontinuation of
treatment leads to recurrence of hyponatremia.92
The results of these studies demonstrate that V2
receptor antagonists are beneficial in correcting DH in
advanced cirrhosis. The clinical utility of these agents in
cirrhosis has been assessed in short-term studies and one
long-term study; however, more controlled studies are
needed to evaluate the safety, efficacy, and applicability
of these agents in patients with cirrhosis and ascites.
ACKNOWLEDGMENTS
Grant support: Some of the studies reported in this
manuscript and performed in the authors’ Unit have
been supported by grants from the Fondo de Investigacio´n Sanitaria (FIS 05/0246), Ministerio de Educacio´n y
Ciencia (SAF 2005/01917), and Fundacio´ Marato´ TV3
(U-2000-TV2710).
ABBREVIATIONS
AQP
aquaporins
AVP
arginine vasopressin
cAMP
cyclic AMP
DH
dilutional hyponatremia
HRS
hepatorenal syndrome
MELD model for end-stage liver disease
MRI
magnetic resonance imaging
SBP
spontaneous bacterial peritonitis
SIADH syndrome of inappropriate antidiuretic
hormone secretion
TIPS
transjugular intrahepatic portosystemic shunt
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