See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/26250635

Ascites: Pathogenesis and therapeutic principles

Article  in  Scandinavian Journal of Gastroenterology · June 2009

DOI: 10.1080/00365520902912555 · Source: PubMed

CITATIONS READS
35 2,881

3 authors, including:

Jens H Henriksen Flemming Bendtsen

University of Copenhagen University of Copenhagen
406 PUBLICATIONS   11,452 CITATIONS    434 PUBLICATIONS   9,170 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Chronic intestinal ischemia View project

All content following this page was uploaded by Jens H Henriksen on 24 November 2014.

The user has requested enhancement of the downloaded file.

 Scandinavian Journal of Gastroenterology, 2009; 44: 902
911

REVIEW ARTICLE

Ascites: Pathogenesis and therapeutic principles

SØREN MØLLER1, JENS H. HENRIKSEN1 & FLEMMING BENDTSEN2

1
Department of Clinical Physiology 239, and 2Department of Medical Gastroenterology 439, Hvidovre Hospital, Faculty of
Health Sciences, University of Copenhagen, Hvidovre, Denmark
Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11

Abstract
Ascites is a classic complication of advanced cirrhosis and it often marks the first sign of hepatic decompensation. Ascites
occurs in more than 50% of patients with cirrhosis, worsens the course of the disease, and reduces survival substantially.
Portal hypertension, splanchnic vasodilatation, liver insufficiency, and cardiovascular dysfunction are major pathophysio-
logical hallmarks. Modern treatment of ascites is based on this recognition and includes modest salt restriction and stepwise
diuretic therapy with spironolactone and loop-diuretics. Tense and refractory ascites should be treated with large volume
paracentesis followed by plasma volume expansion or transjugular intrahepatic portosystemic shunt. Ascites complicated by
spontaneous bacterial peritonitis requires adequate treatment with antibiotics. New potential treatment strategies include
the use of vasopressin V2-receptor antagonists and vasoconstrictors. Since formation of ascites is associated with a poor
prognosis, and treatment of fluid retention does not substantially improve survival, such patients should always be
For personal use only.

considered for liver transplantation.

Key Words: Ascites, hepatobiliary-clinical, portal-hypertension

Introduction grades of ascites is not just a cosmetic problem since it

The genesis and perpetuation of ascites is a common
complication, occurring in more than 50% of patients
within 10 years of the diagnosis of cirrhosis [1]. Ascites
is defined as more than 25 ml fluid in the peritoneal
cavity and can be seen in various diseases, but is most
frequently caused by cirrhosis with portal hyperten-
sion and by peritoneal carcinomatosis. Less common
aetiologies of ascites are hepatocellular carcinoma,
Budd-Chiari syndrome, congestive heart failure,
pancreatitis, and tuberculosis. The normal hepatos-
planchnic lymph formation is about 1 ml/min. In
patients with cirrhosis, this rate can increase up to 10
ml/min [2,3]. When the production of lymphatic fluid
exceeds the lymphatic transport capacity, ascites
develops. According to the amount of ascites, this
can be divided into grades 0
3 [4]. Grade 3 represents
the gross and tense ascites with vast discomfort to the
patient (Table I). However, the presence of even lower
is associated with poor survival with a 50% mortality
rate within 3 years [5,6]. In these patients, survival
depends mainly on the degree of portal hypertension,
liver insufficiency, and circulatory dysfunction. In
about 25% of patients, bacterial translocation leads to
the development of spontaneous bacterial peritonitis
(SBP), which further worsens the prognosis [7]. A
substantial number of patients with ascites caused by
advanced cirrhosis also develop hepatic nephropathy,
which carries a very poor prognosis despite new
treatment modalities [1,8
10]. Contemporary treat-
ments range from diuretics, the use of new therapeutic
principles such as aquaretics and vasoconstrictors,
large volume paracentesis, transjugular intrahepatic
portosystemic shunts (TIPS), liver-supporting de-
vices, antibiotics, and, at the end stage, liver trans-
plantation. In this paper we summarize the most
recent advances in our understanding of the forma-
tion of ascites and modern aspects of treatment.

Correspondence: Søren Møller, MD, DMSc, Associate Professor, Department of Clinical Physiology 239, Hvidovre Hospital, DK-2650 Hvidovre, Denmark.
Tel: 45 3632 3568. Fax: 45 3632 3750. E-mail: soeren.moeller@hvh.regionh.dk

(Received 28 January 2009; accepted 18 March 2009)

ISSN 0036-5521 print/ISSN 1502-7708 online # 2009 Informa UK Ltd.
DOI: 10.1080/00365520902912555
 Treatment of ascites 903
Table I. Grades of ascites according to the International Club of
Portal hypertension
Ascites [4].
In cirrhosis, portal and sinusoidal hypertension is a
Grade of ascites Explanation prerequisite for the development of ascites. The
hydrostatic pressure within the hepatic sinusoids
Grade 0 No detectable ascites
Grade 1 Mild ascites that is only detectable by
favours transudation of fluid into hepatic lymphatics
ultrasound examination and the peritoneal cavity [2,13]. The topographic
Grade 2 Moderate ascites with moderate distension of site of the lesion is therefore important. Patients with
the abdomen post-hepatic portal hypertension with hepatic vein
Grade 3 Large or tense ascites with marked distension thrombosis, as in Budd-Chiari syndrome, often
of the abdomen
develop ascites which is difficult to treat [14]. On
the other hand, development of ascites is considered
a late-phase manifestation in patients with portal
Pathogenesis and perpetuation of the ascites
hypertension due to portal vein thrombosis, and
syndrome
ascites in these patients is usually easy to control
Major factors involved in the complex pathogenesis [15]. The hepatic vascular resistance and portal
Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11

of ascites are portal and sinusoidal hypertension, venous inflow together with the development of
arterial vasodilatation, and neurohumoral activation, portosystemic collaterals determine the height of
all leading to sodium and water retention [10,11]. the portal pressure. Factors that determine hepatic
According to the peripheral arterial vasodilatation vascular resistance include both structural and
theory, development of systemic and splanchnic dynamic components [16]. Among the structural
vasodilatation results in a decrease in the effective components are fibrosis and regeneration nodules.
arterial blood volume and a hyperdynamic circula- Dynamic structures include hepatic stellate cells,
tion [12]. This theory has lately been modified into myofibroblasts, and other cells with contractile
what has been termed ‘‘the forward theory of ascites properties. A preferential sinusoidal constriction in
For personal use only.

formation’’ (Figure 1) which combines arterial the liver seems to be attributed to a defective nitric
oxide (NO) production but also to endogenous
underfilling with a forward increase in splanchnic
vasoconstrictors like endothelin-1 (ET-1), angioten-
capillary pressure and filtration with increased
sin II, catecholamines, and leukotrienes may all
lymph formation [3].
increase the hepatic sinusoidal resistance [16
18].
The haemodynamic imbalance with a predominant
sinusoidal constriction contributes significantly to
the development of portal hypertension and thereby
Cirrhosis and liver
dysfunction is an important target for treatment.
Moreover, the formation of ascites depends on the
Portal
hypertension balance between the increased local transvascular
TIPS
filtration and augmented lymph drainage [2]. Thus,
Increased splanchnic β-adrenergic Increased production
the amount of ascitic fluid produced is governed by
capillary pressure blockers of vasodilators
increased transsinusoidal filtration of protein and
fluid and by accelerated transperitoneal hydrostatic
Increased lymph
Splanchnicarteriolar and oncotic dynamics. However, in contrast to
formation vasodilatation earlier assumptions, the decreased plasma oncotic
pressure may be of minor importance for the
Paracentesis
generation of ascites and low plasma concentrations
Ascites plasma
Volume V1 receptor Central hypovolaemia of albumin have little influence on the rate of ascites
expansion agonists Arterial hypotension formation (Figure 2) [2,19,20]. In this context, the
α-1agonist Deloadingof arterial
baroreceptors
increased hydrostatic pressure in the sinusoids and
Plasma volume intestinal capillaries is critical, and ascites rarely
expansion
β-adrenergic
develops in patients with a hepatic venous pressure
Activation of
blockers SNS gradient below 12 mmHg [21].
Activation of Aldosterone
Loop- Sodium and water RAAS antagonists
diuretics retention
Activation of
vasopressin
V2 receptor
antagonists
Pathophysiology of arterial vasodilatation and
neurohumoral activation
Figure 1. Pathophysiology of the development of ascites in
cirrhosis and potential targets for treatment. SNS  sympathetic The pathophysiological coupling between early portal
nervous system; RAAS  renin-angiotensin-aldosterone system; hypertension and the development of the systemic
AVP  arginine vasopressin. and splanchnic vasodilatation and the hyperdynamic
 904 S. Møller et al.
WHVP = 20 mmHg FHVP = 2 mmHg

HVPG = WHVP –FHVP = 18 mmHg

Hepatocytes
Space of Disse
with stellate cells
Sinusoid lined by
endothelial cells

Total splanchnic Peritoneal

lymph flow: spill-over:
Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11

10-25 l/24h 0.5 l/24h

Figure 2. Hydrostatic pressures and transperitoneal fluid dynamics in cirrhosis: An increased hepatic venous pressure gradient (HVPG)
generates increased transsinusoidal fluid filtration with an overall increased hepatosplanchnic lymph flow of 10
25 l/24 h. As long as the
transsinusoidal filtration keeps pace with lymphatic drainage, no surplus protein-rich fluid will spill over into the peritoneal cavity. When
filtration exceeds the lymphatic drainage, protein-rich fluid will accumulate in the peritoneal cavity as ascites. However, this spillover
fraction (0.5 l/24 h) is relatively small compared to the overall transsinusoidal filtration and lymphatic drainage. WHVPwedged hepatic
venous pressure; FHVPfree hepatic venous pressure.
For personal use only.

syndrome is still obscure. It may be brought about
either by overproduction of circulating vasodilators
induced by shear stress in the splanchnic circulation or
by direct neurohumoral signals from the liver to the
brain [18,22]. Several findings indicate that the
splanchnic vasodilatation precedes renal sodium and
water retention [23]. In experimental as well as in
human portal hypertension, splanchnic vasodilata-
tion leads to reduced systemic vascular resistance,
decreased effective blood volume, and a reduction in
arterial blood pressure with activation of potent
vasoconstricting systems such as the sympathetic
nervous system (SNS), the renin-angiotensin-aldos-
terone system (RAAS), and non-osmotic release of
vasopressin [3,11,18]. The haemodynamic conse-
quences of the development of a hyperdynamic
circulation with an increased heart rate and cardiac
output have previously been described as a mediator
of the effective blood volume, and underfilling of the
arterial circulation occurs in these patients as a result
of diminished systemic vascular resistance [12].
However, at a much later stage of the disease, under-
filling of the arterial circulation may also occur
secondary to a reduction of the increased cardiac
output, as described in patients with renal failure and
SBP [24].
NO is among the vasodilators that have been
implicated in the systemic vasodilatation, and is
primarily synthesized in the systemic vascular
endothelium by NO synthase [25,26]. In portal
hypertension, there seems to be a diminished release
of NO from sinusoidal endothelial cells in the
cirrhotic liver, whereas in the systemic circulation
there is evidence of an up-regulation of the NO
synthesis [27]. Calcitonin gene-related peptide
(CGRP) and adrenomedulin are potent vasodilatat-
ing neuropeptides, which have been found increased
especially in patients with ascites and the hepator-
enal syndrome (HRS) [18,23]. The increase in
circulating vasoactive substances is mainly due to
increased production and, to a lesser extent, to a
decrease in hepatic clearance [28]. It is likely that
these peptides play a role as neurotransmitters, both
in the initiation of the haemodynamic changes and in
the perpetuation of the hyperdynamic circulation
and the formation of ascites. Systemic vasodilatation
has also been related to resistance to pressor
substances, such as noradrenaline, angiotensin II,
and vasopressin. An impaired response to these
vasoconstrictors is most likely related to changes in
receptor affinity, down-regulation of receptors, and
to post-receptor defects related to increased NO
expression [18,29,30]. Recently, alterations in arter-
ial and total vascular compliance have also been
considered [31,32].

Although the pathophysiology and the role of
arterial vasodilatation are complex, there is definite
experimental and clinical evidence to show that it
precedes the counter-regulatory neurohumoral acti-
vation and the renal sodium and water retention in
cirrhosis.
Renal dysfunction
In the early phases of cirrhotic portal hypertension,
the renal sodium excretion capacity is impaired, with
reduced natriuretic response to acute administration
of sodium chloride or to changes in posture [33,34].
These early events are seen before the development
of ascites, but in most of the patients they represent
the initiation of a more pronounced renal dysfunc-
Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11
tion. This includes progressively increased sodium
and water reabsorption and decreases in renal
perfusion and the glomerular filtration rate (GFR)
often in parallel with reduced liver function [35]. In
healthy individuals on a normal intake of sodium
chloride, the free water clearance approximates
10 ml/min [36]. In particular decompensated cir-
rhotic patients, the free water clearance is often less
than 1 ml/min, equivalent to an intake of 1.5 l/day
For personal use only.
before accumulation of fluid begins. The conse-
quences are the development of dilutional hypona-
traemia (serum sodium concentration of less than
130 mmol/l) [37]. At later stages, there is a
progressive fall in GFR and renal blood flow
(RBF) [8]. According to the sequence of the devel-
opment of the functional renal abnormalities, gen-
esis of ascites has been divided into successive
pathophysiological phases (Table II). The early
phase 1 is also called the pre-ascitic phase, because
ascites is not present, but the renal metabolism of
sodium is impaired, despite normal RBF, GFR, and
free water clearance [38,39]. From a haemodynamic
point of view, these patients often exhibit an
increased plasma volume, supporting the presence
of a period with increased sodium and water reten-
tion and adaptation between the vascular capaci-
tance and the circulating medium [38]. The second
phase denotes a negative sodium balance despite
Table II. Pathophysiological phases in the development of ascites and the hepatorenal syndrome.
Term Phase Sodium and water retention
Pre-ascitic cirrhosis Phase 1 No/Yes
Mild
moderate ascites Phase 2 Yes
Moderate
tense ascites Phase 3 Yes
HRS type 2 Phase 4 Yes
HRS type 1 Phase 5 Yes
Abbreviations: RAASrenin-angiotensin-aldosterone system; SNSsympathetic nervous system; RBFrenal blood flow; GFR
glomerular filtration rate; HRShepatorenal syndrome.
Modified from Arroyo et al. [3].
Treatment of ascites 905
decreased urinary sodium excretion, and the absence
of ascites in this phase can be achieved by reducing
the dietary intake of sodium. At this stage there is
only activation of the RAAS and SNS in some
patients, and the GFR and RBF may be normal
[40]. In phase 3, sodium excretion is often below
10 mmol/day and there is immense activation of the
RAAS and SNS, but the RBF and GFR are still
normal or low normal [41,42]. The arterial blood
pressure is often low or low normal, despite activa-
tion of RAAS and SNS, and therefore these patients
are highly susceptible to the hypotensive effects of
angiotensin-converting enzyme (ACE) inhibitors,
angiotensin II receptor inhibitors, and V1-vasopres-
sin antagonist [8]. Phases 4 and 5 ascites denote the
development of the HRS type 2 and type 1,
respectively. Type-2 HRS is characterized by mod-
erate renal failure with a slow progressive course and
it is typically associated with refractory ascites. Type-
1 HRS is characterized by a rapid decrease in renal
function which is often precipitated by SBP [43].
The new diagnostic criteria for HRS according to
The International Club of Ascites are presented in
Table III [43].
Principles of ascites therapy
Diagnostic investigations
The presence of ascites should be confirmed by
abdominal ultrasonography. In the case of identifica-
tion of ascitic fluid, diagnostic paracentesis should,
as a minimum, include measurement of albumin or
protein concentrations, a neutrophil count, and
aerobic and anaerobic cultures of the ascitic fluid.
Presence of SBP, defined as a neutrophil count

250 cells/ml, is seen in about 15% of patients
with ascites [20,44]. Determination of the serum-
ascites albumin gradient may be helpful in distin-
guishing between ascites caused by cirrhosis, cardiac
failure, and primary renal diseases from ascites
caused by pancreatic and malignant diseases. Thus,
a serum-ascites albumin gradient
11 g/l favours a
hepatic, cardiac, or renal aetiology [20]. Ascitic fluid
Activated RAAS and SNS Impaired RBF and GFR
No No
No/Yes No
Yes No/Yes
Yes Yes
Yes Yes

 906 S. Møller et al.
Table III. New diagnostic criteria of the hepatorenal syndrome
(HRS) according to The International Club of Ascites [43].
Cirrhosis with ascites.
Serum creatinine
133 mmol/l (1.5 mg/dl)
No improvement of serum creatinine (decrease to a level of
5133 mmol/l) after at least 2 days with diuretic withdrawal and
volume expansion with albumin. The recommended dose of
albumin is 1 g/kg body weight per day up to a maximum of
100 g/day
Absence of shock
No current or recent treatment with nephrotoxic drugs
Absence of parenchymal kidney disease as indicated by
proteinuria
500 mg/day, microhaematuria (
50 red
blood cells per high-power field) and/or abnormal renal
ultrasonography
Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11
amylase should be measured on clinical suspicion of
pancreatic disease. Analyses of cytology should be
carried if malignancy is suspected [45].
Treatment of non-complicated ascites
Para-medical treatment. Previous studies have shown
that the supine position ameliorates the RBF and
GFR and improves sodium and water excretion [46].
For personal use only.
A less activated RAAS and SNS and a more
favourable diuretic response in the supine patient
have led to the assumption that bedrest would
benefit the treatment of ascites. However, severe
side effects of prolonged bedrest, for example an
increased risk of thromboembolic complications,
decalcification of the bones, and muscular atrophy,
imply that bedrest in general cannot be recom-
mended for the treatment of ascites [20].
Reduced salt intake will counteract the sodium
imbalance in patients with fluid retention and may
create a negative sodium balance in some of the
patients; therefore a low salt diet should be part of
the basic treatment of ascites. However, a rigorous
low salt diet is usually unacceptable to the patient
and thus a no-salt-added diet of 80
120 mmol NaCl
per day is recommended. In patients with dilutional
hyponatraemia in particular, water restriction (1.0

1.5 l/day) has been used, but the effectiveness of this
treatment to increase the serum sodium concentra-
tion more than 5 mmol/l is limited and ranges from
0% to 26% [47]. Moreover, water restriction has a
limited effect on improving serum sodium, because
the daily fluid intake cannot be reduced to less than
one litre per day, which is insufficient to ensure a
negative fluid balance [48]. Water restriction should
be reserved only for patients who are clinically
hypervolaemic with severe hyponatraemia and de-
creased free water clearance. Thus, for practical
purposes, water can only be restricted in very few
(if any) patients.
Medical treatment. A strategy for the treatment of
ascites is presented in Table IV. Diuretics have been
used for the treatment of fluid retention for more than
60 years. The diuretic treatment of ascites should be
initiated with an aldosterone antagonist that acts
mainly on the distal tubules in order to increase
natriuresis, since, if furosemide is administered alone,
its natriuretic effects on the loop of Henle will be
counteracted by sodium reabsorbed in the distal
tubules, because of activation of aldosterone. The
initial prescription in mild to moderate ascites should
be 100 mg/day, a dose that can be gradually increased
up to 400 mg/day [3,4]. But, to avoid hyperkalaemia,
it is often necessary to give a loop diuretic supplement
before the full aldosterone antagonist dose. The full
effect of diuretic treatment is normally seen after 3
5
days. Body-weight should be checked daily and serum
sodium, potassium, and creatinine concentrations
monitored. A daily weight loss of no more than 500

800 g is recommended to prevent intravascular vo-
lume depletion [1]. In the case of massive peripheral
oedema, higher weight losses can be accepted. When
this is insufficient, a loop diuretic should be added,
usually furosemide, as it may induce marked diuresis
and natriuresis. The initial recommended dose is 40
mg/day and can be increased to 160 mg/day with a
stepwise increase every 2
3 days [4]. Additional
diuresis can sometimes be achieved with the supple-
mentation of other diuretics such as amiloride or a
thiazide, but side effects are common. The main
purpose of the treatment is to keep the patient free
of ascites. When the ascites has been resolved,
Table IV. Suggestions for a progressive strategy in the treatment
of sodium and fluid retention and renal complications in cirrhosis.
Clinical Treatment
condition
Pre-ascitic No treatment
cirrhosis Modest salt restriction (80
120 mmol/day)
Mild ascites Salt restriction
Stepwise spironolactone (100
400 mg/day)
Moderate
tense Salt restriction
ascites Spironolactone
Stepwise furosemide (40
160 mg/day)
Refractory Large volume paracentesis and plasma volume
ascites substitution and diuretics
TIPS
Hyponatraemia Serum sodiumB125 mmol/l: diuretics
discontinued
Serum sodiumB120 mmol/l: plasma volume
expansion
Hyper/euvolaemia: modest water restriction
Experimental vasopressin V2 receptor
antagonists
Abbreviation: TIPStransjugular intrahepatic portosystemic
shunt.

Table V. Definition of and diagnostic criteria for refractory ascites
in cirrhosis according to a consensus report from the International
Club of Ascites [4].
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 dose
Conditions
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 a salt-restricted diet of less than
Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11
90 mmol/day or 5.2 g salt per day
2. Lack of response: Mean weight loss B0.8 kg over 4 days and
urinary sodium output less than the sodium intake
3. Early ascites recurrence: Reappearance of grades 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 factors. Diuretic-induced
renal impairment is an increase of serum creatinine by

100% to a value
2 mg/dl (177 mmol/l) in patients
with ascites responding to treatment. Diuretic-induced
For personal use only.
hyponatraemia is defined as a decrease in serum sodium by

10 mol/l to B125 mmol/l. Diuretic-induced hypo- or
hyperkalaemia is defined as a change in serum potassium to
B3 mol/l or
6 mmol/l, despite appropriate measures
Adopted from Moore et al. The management of ascites in
cirrhosis: Report on the consensus conference of the International
Club of Ascites [4].
the diuretic dose should be reduced to the minimum
and, if possible, discontinued. Non-steroidal anti-
inflammatory drugs (NSAIDs) enhance sodium re-
tention and formation of ascites, and are associated
with the development of renal failure, hyponatraemia
and resistance to diuretics and, for these reasons,
should be avoided [20]. Drugs that can induce arterial
hypotension and interfere with renal function, such as
ACE inhibitors, angiotensin II antagonists, and a1-
adrenergic blockers, should be used cautiously and
only when weight loss, blood pressure, serum creati-
nine, and clinical status are monitored.
Treatment of refractory ascites
Ten percent of patients with ascites become refractory
to medical treatment and paracentesis, and so other
treatment modalities are necessary [20]. Refractory
ascites is defined as diuretic-resistant ascites which
cannot be mobilized by intensive diuretic therapy and
a low salt diet (weight loss less than 200 g/day over 4
days) (Table V). Diuretic-intractable ascites is char-
acterized by the presence of diuretic-induced compl
Treatment of ascites 907
ications, such as encephalopathy and hyponatraemia
[4]. The response to diuretics and the salt diet should
be validated only in stable patients without bleeding or
infection, since such conditions affect the ability to
excrete salt and water.
Ascites recurs in as much as 90% of patients
particularly in those with post-sinusoidal alcoholic
cirrhosis after therapeutic paracentesis, and supple-
mentation with a minimum dose of diuretics is
therefore essential [49]. Therapeutic paracentesis
should be done in a single session and should always
be combined with plasma volume expansion. The
intra-abdominal, right atrial, and pulmonary capil-
lary wedge pressures decrease after large volume
paracentesis [31]. Cardiac output increases after 2
3
h and the mean arterial blood pressure decreases by
an average of 8
10 mmHg [50,51]. Large volume
paracentesis without adequate volume substitution
may result in the development of post-paracentesis-
induced circulatory dysfunction (PICD) in up to
75% of patients [52]. This condition is characterized
by pronounced activation of the RAAS and SNS,
which reflects central hypovolaemia. PICD is mainly
caused by paracentesis-induced splanchnic arteriolar
vasodilatation and brings about a further reduction
in systemic vascular resistance and an increase in
portal pressure [53]. Several randomized, controlled
trials of albumin versus synthetic plasma expanders,
such as dextran, collagen-based colloids, and starch,
have shown equal effectiveness as synthetic plasma
expanders and albumin in the prevention of post-
paracentesis-induced complications after small vo-
lume paracentesis [54
57]. After paracentesis of
large volume ascites (
5 l), albumin (8 g/l) seems
to be more effective than polygeline in preventing the
paracentesis-induced increase in RAAS and liver-
related complications [58,59]. Intravenous albumin
may therefore prevent the development of complica-
tions caused by circulatory dysfunction, such as
HRS and rapid recurrence of ascites, and may also
improve survival [52,53]. For these reasons alter-
native plasma expanders should be avoided for the
prevention of PICD after large volume paracentesis.
In the case of tense ascites, which may cause the
patient abdominal discomfort and haemodynamic or
respiratory dysfunction, therapeutic paracentesis
should be preferred because of fewer complications
and a shorter hospital stay compared to intensive
diuretic treatment [3]. Recent studies have shown
that administration of vasoconstrictors such as
terlipressin, midodrine, or noradrenaline may also
be effective, either alone or in combination with
albumin [60
62]. In a recent study, the vasocon-
strictor midodrine was as effective as albumin in
preventing PICD, and at a lower cost [63]. This has,
however, been questioned in a newer pilot study of
 908 S. Møller et al.
24 patients [64]. PICD is an example of a complica-
tion attributable to further vasodilatation and reduc-
tion in effective blood volume, which can be
prevented by specific volume support and vasocon-
striction. The use of specific vasoconstrictors such as
midodrine or terlipressin may potentially play a role
in the future strategy of treatment.
In the case of recurrent ascites, insertion of a TIPS
should be considered. In experienced centres the
technical success rate is usually high, at about 95%
[65]. Control of ascites is achieved in 80
90%, with
complete resolution in 75%. TIPS is now considered
more effective than large volume paracentesis for the
control of ascites [66
68]. A major problem with
insertion of TIPS is the relatively high frequency of
hepatic encephalopathy, and, although patients often
Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11
report a better quality of life, no significant effect on
survival has been demonstrated after TIPS insertion
[69]. However, improved survival after TIPS for
refractory ascites has been demonstrated in a meta-
analysis based on individual patient data from three
large randomized trials [68]. The use of polytetra-
fluoroethylene-covered stents improves shunt pa-
tency and may contribute to enhance the overall
efficacy of this procedure [70]. Risk factors and
For personal use only.
relative contraindications for TIPS insertion include
serum bilirubin
85 mmol/l, INR
2, episodic or
chronic encephalopathy greater than grade 2, and
bacterial infections and renal, cardiac, and respira-
tory failure [71]. Although TIPS is more effective in
removing ascites compared with large volume para-
centesis, it is at the cost of a higher frequency of
hepatic encephalopathy and it may not significantly
affect transplant-free survival. Large volume para-
centesis with plasma expander infusion should there-
fore continue to be the first-line treatment for
refractory ascites. TIPS should be regarded as a
second-choice treatment in patients with preserved
liver function and recurrence of ascites [48].
Hyponatraemia
Hyponatraemia in cirrhosis is defined as a reduction
in serum sodium below 130 mmol/l [48]. Hypona-
traemia often develops in cirrhosis, preferentially
because of immense release of vasopressin. In the
presence of plasma volume expansion, this is hyper-
volaemic or dilutional hyponatraemia [48]. Vaso-
pressin acts on V2 receptors (G protein coupled with
cyclic AMP as second messenger) in the collecting
ducts and is responsible for the vasopressin-induced
reabsorption of water [48]. This effect is mediated
through aquaporins (AQPs), which are selective
water channels, AQP2 being the most important
[72]. Activation of AQPs increases water perme-
ability and in patients with ascites there is evidence
of reduced excretion of AQP2 [72,73]. Clinical use
of V2-receptor antagonists, known as the vaptans,
may prove to be effective in the treatment of
dilutional hyponatraemia. Up to the present time,
data on the long-term effects are needed but
randomized trials are currently in progress [47,74].
Diuretics should be discontinued if serum sodium is
lower than 120 mmol/l.
Spontaneous bacterial peritonitis (SBP)
As mentioned above, SBP is defined as
250
neutrophil cells/ml. Culture from ascitic fluid often
discloses bacterial species, such as Escherichia coli and
Streptococcus [44]. Antibiotic treatment of SBP sig-
nificantly improves survival and third-generation
cephalosporins should be considered, such as
cefotaxime 2 g twice a day for up to two weeks.
Alternatively, amoxicillin/clavolanic acid can be con-
sidered. Fluoroquinolones are also effective. Other
recommended antibiotics are ceftizoxime, cefonicid,
ceftriaxone, and ceftazidime. In patients with ascites
and a history of SBP, prophylactic treatment with, for
example, ciprofloxacin 250 mg/day orally is recom-
mended, especially in the case of low ascites protein
[4,20,48,75]. Prophylactic treatment of patients with
SBP with antibiotics alone or in combination with
albumin has significantly reduced the risk of devel-
opment of type-1 HRS [76,77]. Aminoglycosides
should not be used, because of their nephrotoxic side
effects.
Summary and conclusions
Ascites and its complications, including HRS, are
still conditions associated with a poor prognosis
despite treatment. However, our knowledge of the
pathophysiology underlying these severe complica-
tions has improved considerably and novel medical
treatments combined with different pharmacological
approaches may improve prognosis. The future
approach will probably be to attack various aspects
in the pathophysiological process. A multitarget
strategy should seek efficiently to counteract the
splanchnic vasodilatation, central hypovolaemia, and
arterial hypotension by administration of potent
vasoconstrictors, such as midodrine or terlipressin,
combined with plasma expanders such as albumin.
Development of long-acting systemic vasoconstric-
tors should be encouraged. Aquaporins may have a
future, especially in the treatment of dilutional
hyponatraemia. TIPS or beta-blockers should be
applied to reduce portal pressure, whereas nitrates,
COX-inhibitors and nephrotoxic antibiotics should
be used with caution. Cardiac function should be

supported, especially in the presence of simulta-
neous infections.
References
[1] Gines P, Cardenas A, Arroyo V, Rodes J. Management of
cirrhosis and ascites. N Engl J Med 2004;350:1646
54.
[2] Henriksen JH, Møller S. Alterations of hepatic and splanch-
nic microvascular exchange in cirrhosis: local factors in the
formation of ascites. In: Gines P, Arroyo V, Rodes J ,
Schrier RW, editors. Ascites and renal dysfunction in liver
disease. Malden: Blackwell; 2005. pp 174
85.
[3] Arroyo V, Colmenero J. Ascites and hepatorenal syndrome in
cirrhosis: pathophysiological basis of therapy and current
management. J Hepatol 2003;38(Suppl 1):S69
89.
/ /
[4] Moore KP, Wong F, Gines P, Bernardi M, Ochs A, Salerno
F, et al. The management of ascites in cirrhosis: report on
Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11
the consensus conference of the International Ascites Club.
Hepatology 2003;38:258
66./ /
[5] Fernandez-Esparrach G, Sanchez-Fueyo A, Gines P, Uriz J,
Quinto L, Ventura PJ, et al. A prognostic model for
predicting survival in cirrhosis with ascites. J Hepatol 2001;
34:46
52.
[6] Guevara M, Cardenas A, Ginés P. Prognosis of patients with
cirrhosis and ascites. In: Ginés P, Arroyo V, Rodes J,
Schrier RW, editors. Ascites and renal dysfunction in liver
disease. Malden: Blackwell; 2005. pp 260
70.
[7] Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in
For personal use only.
cirrhosis. Hepatology 2005;41:422
33. / /
[8] Arroyo V, Terra C, Gines P. Advances in the pathogenesis
and treatment of type-1 and type-2 hepatorenal syndrome. J
Hepatol 2007;46:935
46.
/ /
[9] Dagher L, Moore K. The hepatorenal syndrome. Gut 2001;
49:729
37.
/
[10] Gentilini P, Vizzutti F, Gentilini A, Zipoli M, Foschi M,
Romanelli RG. Update on ascites and hepatorenal syn-
drome. Dig Liver Dis 2002;34:592
605. / /
[11] Bernardi M, Caraceni P. Pathogenesis of ascites and
hepatorenal syndrome: altered haemodynamics and neuro-
humoral systems. In: Gerbes AL, Beuers U, Jungst D,
Pape G, Sackmann M, Sauerbruch T, editors. Hepatology
2000. Falk symposium 117. Dordrecht: Kluwer Academic
Publishers; 2001. pp 185
203.
[12] Schrier RW. Decreased effective blood volume in edematous
disorders: what does this mean? J Am Soc Nephrol 2007;18:
2028
31.
[13] Kravetz D, Bildozola M, Argonz J, Romero G, Korula J,
Munoz A, et al. Patients with ascites have higher variceal
pressure and wall tension than patients without ascites. Am J
Gastroenterol 2000;95:1770
5. / /
[14] Plessier A, Valla DC. Budd-Chiari syndrome. Semin Liver
Dis 2008;28:259
69.
/ /
[15] Garcia-Pagan JC, Hernandez-Guerra M, Bosch J. Extra-
hepatic portal vein thrombosis. Semin Liver Dis 2008;28:
282
92.
[16] Bosch J, Abraldes JG, Groszmann R. Current management
of portal hypertension. J Hepatol 2003;38:S54
68.
[17] Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of
chronic liver diseases: from the patient to the molecule.
Hepatology 2006;43:S121
31. / /
[18] Møller S, Henriksen JH. The systemic circulation in
cirrhosis. In: Gines P, Arroyo V, Rodes J, Schrier RW,
editors. Ascites and renal dysfunction in liver disease.
Malden: Blackwell; 2005. pp 139
55.
Treatment of ascites 909
[19] Henriksen JH, Siemssen O, Krintel JJ, Malchow-Moller A,
Bendtsen F, Ring-Larsen H. Dynamics of albumin in plasma
and ascitic fluid in patients with cirrhosis. J Hepatol 2001;34: / /
53
60.
[20] Moore KP, Aithal GP. Guidelines on the management of
ascites in cirrhosis. Gut 2006;55 Suppl 6:vi1
vi12. / /
[21] Casado M, Bosch J, Garcia-Pagan JC, Bru C, Banares R,
Bandi JC, et al. Clinical events after transjugular intrahepatic
portosystemic shunt: correlation with hemodynamic find-
/ /
ings. Gastroenterology 1998;114:1296
303.
/ /
[22] Liu H, Schuelert N, McDougall JJ, Lee SS. Central neural
activation of hyperdynamic circulation in portal hypertensive
rats depends on vagal afferent nerves. Gut 2008;57:966
73.
/ /
[23] Wiest R. Splanchnic and systemic vasodilation: the experi-
mental models. J Clin Gastroenterol 2007;41:S272
87.
/ /
[24] Ruiz-Del-Arbol L, Monescillo A, Arocena C, Valer P, Gines
P, Moreira V, et al. Circulatory function and hepatorenal
syndrome in cirrhosis. Hepatology 2005;42:439
47.
/ /
[25] Ferguson JW, Dover A, Chia S, Cruden N, Hayes PC,
Newby D. Inducible nitric oxide synthase activity contri-
butes to the regulation of peripheral vascular tone in patients
with cirrhosis and ascites. Gut 2005;55:542
6.
/ /
[26] Iwakiri Y, Groszmann RJ. Vascular endothelial dysfunction
/
in cirrhosis. J Hepatol 2007;46:927
34.
/ /
[27] Wiest R, Groszmann RJ. The paradox of nitric oxide in
cirrhosis and portal hypertension: too much, not enough.
Hepatology 2002;35:478
91.
/ /
[28] Henriksen JH, Møller S. Hemodynamics, distribution of
blood volume, and kinetics of vasoactive substances in
cirrhosis. In: Epstein M, editor. The kidney in liver disease.
Philadelphia: Hanley and Belfus; 1996. pp 241
58.
[29] Farzaneh-Far R, Moore K. Nitric oxide and the liver. Liver
2001;21:161
74.
/ /
/
[30] Helmy A, Newby DE, Jalan R, Johnston NR, Hayes PC,
Webb DJ. Nitric oxide mediates the reduced vasoconstrictor
response to angiotensin II in patients with preascitic cirrho-
sis. J Hepatol 2003;38:44
050.
/ /
[31] Møller S, Henriksen JH. Cardiovascular complications of
cirrhosis. Gut 2008;57:268
78./ /
[32] Henriksen JH, Møller S, Schifter S, Abrahamsen J, Becker
U. High arterial compliance in cirrhosis is related to elevated
circulating calcitonin gene-related peptide (CGRP) and low
adrenaline, but not to activated vasoconstrictor systems. Gut
2001;49:112
8.
/ /
[33] La Villa G, Salmeron JM, Arroyo V, Bosch J, Gines P,
/ /
Garcia-Pagan JC, et al. Mineralocorticoid escape in patients
with compensated cirrhosis and portal hypertension. Gastro-
enterology 1992;102:2114
9.
/ /
[34] Bernardi M, Li BS, Arienti V, de Collibus C, Scialpi C,
Boriani L, et al. Systemic and regional hemodynamics in pre-
ascitic cirrhosis: effects of posture. J Hepatol 2003;39:502
8. / /
[35] Wensing G, Lotterer E, Link I, Hahn EG, Fleig WE. Urinary
sodium balance in patients with cirrhosis: relationship to
quantitative parameters of liver function. Hepatology 1997; /
/ /
26:1149
55.
/
[36] Møller S, Henriksen JH. Pathogenesis and pathophysiology
of hepatorenal syndrome: is there scope for prevention?
/ /
Aliment Pharmacol Ther 2004;20(Suppl 3):31
41. / /
[37] Angeli P, Wong F, Watson H, Gines P. Hyponatremia in
cirrhosis: results of a patient population survey. Hepatology
2006;44:1535
42.
/ /
[38] Bernardi M, Matco CD, Trevisani F, Collibus CD, Fornalé
L, Baraldini M, et al. The hemodynamic status of preascitic
cirrhosis: an evaluation under steady-state conditions and
after postural change. Hepatology 1992;16:341
6. / /
 910 S. Møller et al.
[39] Sansoe G, Ferrari A, Baraldi E, Castellana CN, De Santis
MC, Manenti F. Renal distal tubular handling of sodium in
central fluid volume homoeostasis in preascitic cirrhosis. Gut
1999;45:750
5.
/ /
[40] Claria J, Rodes J. Renal sodium handling in preascitic
cirrhosis. Gut 2001;48:740
1. / /
[41] Pozzi M, Grassi G, Redaelli E, Dell’Oro R, Ratti L, Redaelli
A, et al. Patterns of regional sympathetic nerve traffic in
preascitic and ascitic cirrhosis. Hepatology 2001;34:1113
8.
[42] Bernardi M, Domenicali M. The renin-angiotensin-aldos-
terone system in cirrhosis. In: Ginés P, Arroyo V, Rodes J,
Schrier RW, editors. Ascites and renal dysfunction in liver
disease. Malden: Blackwell Publishing; 2005. Pp 43
54.
[43] Salerno F, Gerbes A, Gines P, Wong F, Arroyo V. Diagnosis,
prevention and treatment of the hepatorenal syndrome in
cirrhosis. A consensus workshop of the International Ascites
Club. Gut 2007;56:1310
8. / /
[44] Tandon P, Garcia-Tsao G. Bacterial infections, sepsis, and
multiorgan failure in cirrhosis. Semin Liver Dis 2008;28:
Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11
26
42.
[45] Salerno F, Restelli B, Incerti P, Annoni G, Capozza L,
Badalamenti S, et al. Utility of ascitic fluid analysis in
patients with malignancy-related ascites. Scand J Gastro-
enterol 1990;25:251
6./ /
[46] Ring-Larsen H, Henriksen JH, Wilken C, Clausen J, Pals H,
Christensen NJ. Diuretic treatment in decompensated cir-
rhosis and congestive heart failure: effect of posture. Br Med
J 1986;292:1351
3.
/ /
[47] Gerbes AL, Gulberg V, Gines P, Decaux G, Gross P,
Gandjini H, et al. Therapy of hyponatremia in cirrhosis
For personal use only.
with a vasopressin receptor antagonist: A randomized
double-blind multicenter trial. Gastroenterology 2003;124:
933
9.
[48] Gines P, Cardenas A. The management of ascites and
hyponatremia in cirrhosis. Semin Liver Dis 2008;28:43
58.
[49] Fernandez-Esparrach G, Guevara M, Sort P, Pardo A,
Jimenez W, Gines P, et al. Diuretic requirements after
therapeutic paracentesis in non-azotemic patients with
cirrhosis. A randomized double-blind trial of spironolactone
versus placebo. J Hepatol 1997;26:614
20. / /
[50] Cabrera J, Falcon L, Gorriz E, Pardo MD, Granados R,
Quinones A, et al. Abdominal decompression plays a major
role in early postparacentesis haemodynamic changes in
cirrhotic patients with tense ascites. Gut 2001;48:384
9.
[51] Pozzi M, Ratti L, Redaelli E, Guidi C, Mancia G.
Cardiovascular abnormalities in special conditions of ad-
vanced cirrhosis. The circulatory adaptative changes to
specific therapeutic procedures for the management of
refractory ascites. Gastroenterol Hepatol 2006;29:263
72.
[52] Gines P, Guevara M, De Las HD, Arroyo V. Review article:
albumin for circulatory support in patients with cirrhosis.
Aliment Pharmacol Ther ;16 Suppl 2002;5:24
31.
[53] Sola-Vera J, Minana J, Ricart E, Planella M, Gonzalez B,
Torras X, et al. Randomized trial comparing albumin and
saline in the prevention of paracentesis-induced circulatory
dysfunction in cirrhotic patients with ascites. Hepatology
2003;37:1147
53.
/ /
[54] Salerno F, Badalamenti S, Lorenzano E, Moser P, Incerti P.
Randomized comparative study of hemaccel vs. albumin
infusion after total paracentesis in cirrhotic patients with
refractory ascites. Hepatology 1991;13:707
13. / /
[55] Fassio E, Terg R, Landeira G, Abecasis R, Salemne M,
Podesta A, et al. Paracentesis with Dextran 70 vs. paracent-
esis with albumin in cirrhosis with tense ascites. Results of a
randomized study. J Hepatol 1992;14:310
6. / /
[56] Altman C, Bernard B, Roulot D, Vitte RL, Ink O.
Randomized comparative multicenter study of hydroxyethyl
starch versus albumin as a plasma expander in cirrhotic
patients with tense ascites treated with paracentesis. Eur J
Gastroenterol Hepatol 1998;10:5
10. / /
[57] Planas R, Gines P, Arroyo V, Llach J, Panes J, Vargas V
et al. Dextran-70 versus albumin as plasma expanders in
cirrhotic patients with tense ascites treated with total
paracentesis. Gastroenterology 1990;99:1736
44. / /
[58] Gines A, Fernandez-Esparrach G, Monescillo A, Vila C,
/ /
Domenech E, Abecasis R, et al. Randomized trial comparing
albumin, dextran 70, and polygeline in cirrhotic patients
with ascites treated by paracentesis. Gastroenterology 1996; /
111:1002
10.
/
[59] Moreau R, Valla DC, Durand-Zaleski I, Bronowicki JP,
Durand F, Chaput JC, et al. Comparison of outcome in
patients with cirrhosis and ascites following treatment with
albumin or a synthetic colloid: a randomised controlled pilot
trail. Liver Int 2006;26:46
54.
/ /
[60] Moreau R, Asselah T, Condat B, de Kerguenec C, Pessione
F, Bernard B, et al. Comparison of the effect of terlipressin
/ /
and albumin on arterial blood volume in patients with
cirrhosis and tense ascites treated by paracentesis: a rando-
mised pilot study. Gut 2002;50:90
4. / /
[61] Singh V, Kumar B, Nain CK, Singh B, Sharma N, Bhalla A,
et al. Noradrenaline and albumin in paracentesis-induced
circulatory dysfunction in cirrhosis: a randomized pilot
study. J Intern Med 2006;260:62
8. / /
[62] Krag A, Møller S, Henriksen JH, Holstein-Rathlou NH,
Larsen FS, Bendtsen F. Terlipressin improves renal function
in patients with cirrhosis and ascites without hepatorenal
syndrome. Hepatology 2007;46:1863
71.
/ /
[63] Singh V, Dheerendra PC, Singh B, Nain CK, Chawla D,
Sharma N, et al. Midodrine versus albumin in the prevention
/ /
of paracentesis-induced circulatory dysfunction in cirrhotics:
a randomized pilot study. Am J Gastroenterol 2008;103:
/ /
/ /
1399
405.
[64] Appenrodt B, Wolf A, Grunhage F, Trebicka J, Schepke M,
Rabe C, et al. Prevention of paracentesis-induced circulatory
dysfunction: midodrine vs albumin. A randomized pilot
study. Liver Int 2008;28:1019
25.
/ /
[65] D’amico G, Luca A, Morabito A, Miraglia R, D’Amico M.
Uncovered transjugular intrahepatic portosystemic shunt for
refractory ascites: a meta-analysis. Gastroenterology 2005; /
/ /
129:1282
93.
/
[66] Rössle M, Ochs A, Gulberg V, Siegerstetter V, Holl J,
Deibert P, et al. A comparison of paracentesis and transju-
gular intrahepatic portosystemic shunting in patients with
ascites. N Engl J Med 2000;342:1701
7. / /
/ /
[67] Gines P, Uriz J, Calahorra B, Garcia-Tsao G, Kamath PS,
del Arbol LR, et al. Transjugular intrahepatic portosystemic
shunting versus paracentesis plus albumin for refractory
/ /
ascites in cirrhosis. Gastroenterology 2002;123:1839
47. / /
[68] Salerno F, Camma C, Enea M, Rossle M, Wong F.
Transjugular intrahepatic portosystemic shunt for refractory
ascites: a meta-analysis of individual patient data. Gastro-
enterology 2007;133:825
34.
/ /
[69] Saab S, Nieto JM, Lewis SK, Runyon BA. TIPS versus
paracentesis for cirrhotic patients with refractory ascites.
Cochrane Database Syst Rev 2006;CD004889.
[70] Bureau C, Garcia-Pagan JC, Otal P, Pomier-Layrargues G,
Chabbert V, Cortez C, et al. Improved clinical outcome
using polytetrafluoroethylene-coated stents for TIPS: results
of a randomized study. Gastroenterology 2004;126:469
75. / /
[71] Arroyo V, Fernandez J, Gines P. Pathogenesis and treatment
of hepatorenal syndrome. Semin Liver Dis 2008;28:81
95. / /
[72] Esteva-Font C, Baccaro ME, Fernandez-Llama P, Sans L,
Guevara M, Ars E, et al. Aquaporin-1 and aquaporin-2
 Treatment of ascites 911
urinary excretion in cirrhosis: relationship with ascites and [76] Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-
hepatorenal syndrome. Hepatology 2006;44:1555
63.
/ /

Del-Arbol L, et al. Effect of intravenous albumin on renal

[73] Krag A, Bendtsen F, Pedersen EB, Holstein-Rathlou NH, impairment and mortality in patients with cirrhosis and
Møller S. Effects of terlipressin on the aquaretic system: spontaneous bacterial peritonitis. N Engl J Med 1999;341:/ /

evidence of antidiuretic effects. Am J Physiol Renal Physiol 403
9.

2008;295:F1295
300.
/ /

[77] Fernandez J, Navasa M, Planas R, Montoliu S, Monfort D,

[74] Gines P. Vaptans: A promising therapy in the management of Soriano G, et al. Primary prophylaxis of spontaneous
advanced cirrhosis. J Hepatol 2007;46:1150
2.
/ /

bacterial peritonitis delays hepatorenal syndrome and im-

[75] Gerbes AL, Gulberg V. Progress in treatment of massive proves survival in cirrhosis. Gastroenterology 2007;133:
/ /

ascites and hepatorenal syndrome. World J Gastroenterol 818
24.

2006;12:516
9.
/ /
Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11
For personal use only.

View publication stats