Management problems in liver disease

Ascites

hypertension induce progressive splanchnic vasodilatation

leading to an effective decreased plasma volume, which results
in overactivity of endogenous vasoconstrictor systems and
renal sodium and water retention (hyperdynamic circulation).
In the early stages of cirrhosis, splanchnic arterial vasodila
tation is moderate and the effective arterial blood volume is
maintained within normal limits through increases in plasma
volume and cardiac output. In the later stages of cirrhosis,
splanchnic arterial vasodilatation is more important, the effec
tive arterial blood volume decreases markedly, and arterial
pressure decreases. Arterial pressure is maintained by activa
tion of vasoconstrictor and antinatriuretic factors, determin
ing sodium and fluid retention and ascites formation. As the
disease progresses, there is impairment in sodium and water
excretion followed by renal vasoconstriction that determines
dilutional hyponatremia at first and hepatorenal syndrome
later (Figure 1).24

Mara E Baccaro
Mnica Guevara
Juan Rods

Abstract
Ascites is the abnormal accumulation of fluid in the peritoneal cavity.
The most frequent cause of ascites is portal hypertension related to
cirrhosis. Ascites in patients with cirrhosis is the consequence of the
homeostatic activation of vasoconstrictor systems and sodium retention. These mechanisms are triggered by a decrease in effective arterial
blood volume due to a severe arterial vasodilatation located mainly in
the splanchnic circulation. The ascitic fluid of patients with cirrhosis is
generally low in proteins and albumin. Since the presence of ascites
is associated with poor prognosis and low survival, the patients with
ascites should be evaluated for liver transplantation. The treatment consists basically of a negative sodium balance that is obtained by decreasing the sodium intake and increasing its excretion by the administration
of diuretic agents. The patients in whom these drugs are not effective
or cannot be administered (because they develop adverse effects, a
condition well known as refractory ascites), should be treated with largevolume paracentesis plus albumin.

Classification
Uncomplicated ascites is ascites that is not infected and
that is not associated with the development of the hepatorenal
syndrome (HRS).
Grade 1 ascites is mild ascites only detectable by ultrasound
examination.
Grade 2 ascites, or moderate ascites, is manifest by moderate
symmetrical distension of the abdomen.
Grade 3 ascites is large or gross ascites with marked abdom
inal distension.
Refractory ascites in 1996, the International Ascites Club
defined refractory ascites as ascites that cannot be mobilized
or the early recurrence of which cannot be satisfactorily pre
vented by medical therapy.4 It occurs in approximately 510%
of cases of ascites.5 Refractory ascites can be divided into

Keywords ascites; cirrhosis; diuretic; paracentesis

Ascites is defined as the accumulation of fluid in the peritoneal

cavity exceeding the normal maximum volume of 25 ml. Cir
rhotic ascites accounts for over 75% of patients who present with
ascites, the remaining 25% being due to malignancy (10%), car
diac failure (3%), pancreatitis (1%), tuberculosis (2%) or other
rarer causes.1 Ascites occurs in more than 50% of patients within
10 years of the diagnosis of cirrhosis.

Proposed pathogenesis of ascites formation in

cirrhosis according to the arterial vasodilatation
hypothesis
Cirrhosis
Portal hypertension

Pathogenesis

Splanchnic arterial vasodilatation

The peripheral vasodilatation theory is currently the most

accepted hypothesis to explain ascites formation in cirrhotic
patients.2 This hypothesis suggests that cirrhosis and portal

Effective blood volume

Mara E Baccaro MD is Fellow of the Liver Unit at the Hospital ClinicBarcelona, Barcelona, Spain. Competing interests: none declared.

Stimulation of:
Reninangiotensin system
Sympathetic nervous systems
Arginine vasopressin

Mnica Guevara MD is Associate Investigator of IDIBAPS at the Liver

Unit at the Hospital Clinic-Barcelona, Barcelona, Spain. Competing
interests: none declared.

Sodium and water retention

Ascites

Juan Rods FRCP is Professor of Medicine and General Manager at

Hospital Clinic-Barcelona, Barcelona, Spain. Competing interests:
none declared.

MEDICINE 35:2

Figure 1

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Management problems in liver disease

two subgroups: diuretic-resistant ascites and diuretic-intractable

ascites.4

Differential diagnosis of ascites by the serumascites

albumin gradient*

General evaluation of patients with cirrhosis and ascites

High gradient (1.1 g/dL)

Cirrhosis
Congestive heart failure
Fulminant hepatic failure
Alcoholic hepatitis
Liver metastases
Portal vein thrombosis
BuddChiari syndrome
Veno-occlusive disease
Myxedema

The evaluation of patients with cirrhosis and ascites should

include, not only the evaluation of liver function, but also the
evaluation of renal and circulatory function (Table 1).6
Diagnosis
Diagnosis of ascites is simple when a large amount of fluid is
accumulated in the peritoneal cavity. On physical examination,
the abdomen is distended, the flanks bulge and a fluid wave may
be demonstrable. If the volume of ascitic fluid is small, an abdom
inal ultrasound scan is useful; it can detect as little as 100 ml
of abdominal fluid and may suggest the cause. The diagnosis
is confirmed by fluid aspiration by paracentesis. The procedure
should be performed by inserting a needle into the left lower
abdominal quadrant under strict sterile conditions.
Characteristics of cirrhotic ascites biochemical and cyto
logical analysis of ascitic fluid provides important information.
Traditionally, ascites in patients with cirrhosis was considered
to have the characteristics of a transudate, with a total protein
concentration of less than 2.5 g/dL and relatively few cells. It is
helpful to subtract the concentration of the ascites fluid albumin
from serum albumin; a serumascites albumin gradient of more
than 1.1 g/dL predicts portal hypertension with great accuracy
(Table 2).7,8 The ascitic fluid in cirrhosis usually contains fewer
than 300500 white blood cells/mm3. More than 70% of these

*Serum ascitesalbumin gradient = serum albumin concentration minus

ascites albumin concentration.

Table 2

cells are mononuclear leucocytes. When the ascitic fluid contains

more than 250 neutrophils/mm3, a diagnosis of spontaneous
bacterial peritonitis is made.9
Differential diagnosis
The most frequent causes of ascites due to non-hepatic dis
eases are cardiac failure and neoplasm.1 In the first case,
the protein content of the ascites is usually elevated and the
abdominal ultrasound shows expansion of suprahepatic veins.
The existence of jugular ingurgitation suggests cardiac asci
tes.10 The neoplasic invasion of the peritoneum causes the
exudation of liquid that is usually rich in proteins (generally
superior to 25 g/litre).11 The diagnosis is made through the
cytology of the ascitic fluid, which is positive in 6090% of the
cases. If the cytological examinations are repeatedly negative,
the last option is to perform laparoscopy and biopsy of the
peritoneum.
Other less frequent causes of ascites are peritoneal tuberculo
sis and pancreatic ascites. Ascitic fluid in peritoneal tuberculosis
contains abundant lymphocytes, has a high concentration of the
adenosindeaminase enzyme and is generally rich in proteins.12
The culture of ascitic fluid is frequently negative. The diagnostic
confirmation must be made by means of laparoscopy and biopsy
of the peritoneum looking for granulomas. In pancreatic asci
tes, the ascitic fluid is very rich in amylase and lipase, making
the diagnosis relatively easy.13 Abdominal computerized tomo
graphy is useful to define the cause of ascites.

Evaluation of patients with cirrhosis and ascites6

Evaluation of liver disease
Liver function and coagulation tests
Standard haematological tests
Abdominal ultrasonography or computed tomography
Endoscopy of the upper gastrointestinal tract
Liver biopsy in selected patients
Evaluation of renal and circulatory function
Measurement of serum creatinine and electrolytes
Measurement of urinary sodium (preferably from a 24-hour
urine collection)*
Measurement of urinary protein (from a 24-hr urine
collection)
Arterial blood pressure
Evaluation of ascitic fluid
Cell count
Bacterial culture
Measurement of total protein
Other tests (measurement of albumin, glucose, lactate
dehydrogenase, amylase, and triglycerides; an acid-fast
smear; and cytological examination)

Managment of ascites
General measures
All patients with ascites should be evaluated as if they were pos
sible candidates for liver transplantation because the presence of
large ascites is associated with poor long-term survival.7,14
Reduction of sodium intake is beneficial in patients with asci
tes, particularly those with severe sodium retention who do not
respond, or respond poorly, to diuretics.15 A low-sodium diet
(6090 mEq/day) may facilitate the elimination of ascites and

*If possible, patients should be evaluated when they are not receiving
diuretic drugs, since some variables related to these drugs may alter renal
function.

Table 1

MEDICINE 35:2

Low gradient (<1.1 g/dL)

Peritoneal carcinomatosis
Peritoneal tuberculosis
Pancreatitis
Biliary pancreatitis
Chlamydia/gonococcal infection
Nephrotic syndrome
Connective tissue diseases

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Management problems in liver disease

delay the reaccumulation of fluid.15,16 More strict restriction of

sodium intake is not recommended because it is poorly toler
ated.16 Fluid intake should be restricted only in patients with
dilutional hyponatremia (serum sodium concentration lower
than 130 mEq/L in the presence of ascites, oedema, or both) to
avoid a further decrease in serum sodium concentration.17

paracentesis plus albumin. TIPS should probably be reserved for

patients without severe liver failure or encephalopathy who have
loculated fluid that cannot be treated with paracentesis and for
those who are unwilling to undergo repeated paracentesis.

Specific measures
Grade II ascites (moderate volume)
Patients with moderate ascites can be treated as outpatients and
do not require hospitalization unless they have other compli
cations of cirrhosis. In most cases, a negative sodium balance
and loss of ascitic fluid are quickly achieved with low doses of
diuretics.16,18,19 The diuretic of choice is either spironolactone
(50200 mg/day) or amiloride (510 mg/day). Low doses of
furosemide (2040 mg/day) may be added during the first few
days to increase natriuresis, especially in patients with peripheral
oedema. Furosemide should be used with caution because of the
risk of excessive diuresis, which may lead to prerenal failure. The
recommended weight loss is 300500 g/day in patients without
peripheral oedema and 8001000 g/day in those with peripheral
oedema.20

The development of ascites in patients with cirrhosis indicates a

poor prognosis. The probability of death in cirrhotic patients hos
pitalized with ascites is 40% at 2 years.5 The prognosis is worse
for those with refractory ascites and those who develop spontane
ous bacterial peritonitis or hepatorenal syndrome.9,35

Prognosis of patients with cirrhosis and ascites

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Grade III ascites (large volume)

The treatment of choice for large-volume ascites is large-volume
paracentesis followed by intravenous albumin (8 g/litre of ascitic
fluid removed) whenever the total volume of ascites is elim
inated. The administration of albumin prevents paracentesisinduced circulatory dysfunction (PICD). PICD is characterized by
a reduction in effective arterial blood volume and is associated
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survival.2124 In patients where less than 5 litres of ascites has
been removed, the incidence of PICD is very low. In these cases
synthetic plasma expanders are effective in preventing this com
plication.21,22 The complications associated with the paracentesis
procedure are extremely low and these include: abdominal wall
haematomas, infection or bleeding in the puncture site, leakage
of ascitic fluid, haemoperitoneum, and intestinal perforation.
The practice guideline of the American Association for the
Study of Liver Diseases states that routine correction of pro
longed prothrombin time or thrombocytopenia (common altera
tions in patients with cirrhosis) is not required when experienced
personnel carry out paracentesis.25 However, most clinical tri
als evaluating paracentesis complications have included patients
with an international normalized ratio around 1.7, or a platelet
count around 50,000/mm.3,21,24,2630
Refractory ascites
There are two therapeutic strategies for large-volume refractory
ascites: large-volume paracentesis with intravenous albumin
and transjugular intrahepatic portosystemic shunts (TIPS). The
peritoneovenous shunt was abandoned because of significant
rates of complications.30 Although several studies have demon
strated that TIPS is more effective in the control of the ascites
compared to paracentesis, it increases the risk of developing
hepatic encephalopathy, has a greater cost, and it does not
improve survival compared to paracentesis.3134 For this rea
son, the treatment of choice in patients with refractory ascites is

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Management problems in liver disease

16 Runyon B A. Management of adult patients with ascites caused by

cirrhosis. Hepatology 1998; 27: 26472.
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28 Salerno F, Badalamenti S, Incerti P et al. Repeated paracentesis and

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Acknowledgements
Supported in part by grants from Fondo de Investigacin
Sanitaria (FIS 05/0273 and 05/0246), Instituto de Salud Carlos III
(Co3/2) and Instituto Reina Sofia de Investigacin Nefrolgica.

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2006 Elsevier Ltd. All rights reserved.