Subido por Cintia Alvarez

capitulo de ascitis

C H A P T ER 10
Guadalupe Garcia-Tsao
Yale University School of Medicine, New Haven, and VA-CT Healthcare System, West Haven, CT, USA
Learning points
• Ascites is the most common decompensating event in
• Its pathophysiology is mostly explained by splanchnic
and peripheral vasodilatation that lead to a decrease in
effective blood volume.
• The natural history of ascites results from a progressively
more deranged circulatory status; with ascites that initially responds to diuretics, then becoming refractory to
diuretics, at which time the patient may develop hyponatraemia and, finally, hepatorenal syndrome.
• Most patients respond to diuretics. Patients who no
longer respond should be treated with repeated largevolume paracenteses. Transjugular intrahepatic portosystemic shunt (TIPS) should be considered in those
requiring frequent paracenteses. Fluid restriction is recommended in patients with hyponatraemia. Vasoconstrictors may reverse hepatorenal syndrome and are
useful as a bridge to liver transplantation.
• Ascites per se is not lethal unless it becomes infected
(spontaneous bacterial peritonitis). Infection often precipitates the hepatorenal syndrome leading to death.
Antibiotic prophylaxis is indicated for secondary prevention of spontaneous bacterial peritonitis and in highrisk patients.
Ascites is free fluid within the peritoneal cavity. It forms
because of conditions directly involving the peritoneum
(infection, malignancy), or diseases remote from the
peritoneum (liver disease, heart failure, hypoproteinaemia). Cirrhosis is the commonest cause of ascites in the
Western world (∼75%), followed by peritoneal malignancy (12%), cardiac failure (5%) and peritoneal tuberculosis (2%) [1] (Fig. 10.1). In patients with cirrhosis, the
development of ascites marks the transition from compensated to decompensated cirrhosis [2,3]; and is the
most frequent first decompensating event, occurring in
48% [4].
The mechanisms of ascites formation in cirrhosis are
complex but portal (sinusoidal) hypertension and renal
retention of sodium are universal. The natural history
of cirrhotic ascites progresses from diuretic-responsive
(uncomplicated) ascites to the development of dilutional hyponatraemia, refractory ascites, and finally,
hepatorenal syndrome (HRS) (Fig. 10.2). While 1-year
survival in patients who develop ascites is 85%, it
decreases to 25% once it has progressed to hyponatraemia, refractory ascites or HRS [4].
Treatment of ascites has not resulted in a significant
improvement in survival. However, treating ascites is
important, not only because it improves quality of life
but because spontaneous bacterial peritonitis (SBP), a
lethal complication of cirrhosis, does not occur in the
absence of ascites. New treatments are being evaluated
that modify its pathophysiology, such as the transjugular intrahepatic portosystemic shunt (TIPS) for refractory ascites and vasoconstrictors for HRS. Liver
transplantation is the ultimate therapy and should be
considered when the patient first presents with ascites.
Mechanisms of ascites formation
In cirrhosis, the source of ascites is mainly the hepatic
sinusoids. Therefore sinusoidal hypertension is the
initial mechanism that determines leakage of ascites into
the peritoneal space [5,6]. Sinusoidal hypertension
results from hepatic venous outflow block secondary to
regenerative nodules and fibrosis. The other essential
factor in the pathogenesis of cirrhotic ascites is sodium
and water retention which allows for the replenishment
of the intravascular volume and maintenance of ascites
formation [7]. Inappropriate sodium retention is either
secondary to vascular changes (underfill and peripheral
Sherlock’s Diseases of the Liver and Biliary System, Twelfth Edition. Edited by
James S. Dooley, Anna S.F. Lok, Andrew K. Burroughs, E. Jenny Heathcote.
© 2011 by Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.
Peripheral vasodilatation
Diminished effective
arterial blood volume
Heart failure
Rise in renin, aldosterone, vasopressin
Sympathetic system stimulated
Sodium and water retention
Renal vasoconstriction
Plasma volume expansion
plus portal hypertension
Fig. 10.1. Causes of ascites.
Fig. 10.3. The peripheral arterial vasodilatation hypothesis
for ascites formation in cirrhosis [7].
No ascites
for their presence [8]; the development of ascites also
requires a minimal portal pressure gradient of 12 mmHg
[5,6]. A threshold portal pressure gradient of 10 mmHg
or more has been defined as ‘clinically significant portal
hypertension’ because it best predicts the development
of complications of cirrhosis, such as ascites [9,10].
Uncomplicated ascites
Ascites + hyponatraemia
Sodium retention
In patients with cirrhosis and ascites, the normal regulation of sodium balance is lost. Sodium is retained avidly;
urinary sodium excretion is often below 5 mmol/day.
Inappropriate sodium retention occurs even in the
absence of ascites [11].
Refractory ascites
Hepatorenal syndrome
Vasodilatation theory (Fig. 10.3)
Fig. 10.2. Natural history of cirrhotic ascites.
Table 10.1. Sequence of events for the hypotheses of ascites
Primary event
Secondary event
Underfill/ peripheral arterial
vasodilatation theory
arterial vasodilatation hypotheses) or as a primary event
(overfill theory) (Table 10.1).
Sinusoidal hypertension
Similar to gastro-oesophageal varices, in which a
minimal portal pressure gradient of 12 mmHg is needed
Arterial vasodilatation, a haemodynamic abnormality
typical of the patient with cirrhosis, is the most likely
mechanism that explains sodium retention [7]. An
increased production of the vasodilator nitric oxide
(NO) is considered the main cause of vasodilatation [12].
In experimental models of cirrhosis, inhibition of NO
synthase increases systemic blood pressure and renal
sodium excretion, resulting in a reduced volume of
ascites [13,14]. Other vasodilators implicated in the
vasodilatation of cirrhosis include adrenomedullin,
carbon monoxide, endocannabinoids, prostacyclin,
tumour necrosis factor alpha and urotensin [15].
Arterial vasodilatation results in a reduction in
‘effective’ arterial blood volume and a decrease in systemic arterial pressure, leading to the activation of the
renin–angiotensin–aldosterone system (RAAS) and
the sympathetic nervous system (through carotid sinus
baroreceptors). Renin is produced by the kidney
Chapter 10
(juxtaglomerular apparatus) in response to low blood
volume and β-adrenergic stimulation. Under the influence of renin, angiotensinogen (produced by the liver)
is converted to angiotensin I (a decapeptide), which in
turn is converted to angiotensin II (an octapeptide) by
angiotensin-converting enzyme (ACE). Angiotensin II is
the main stimulant to the synthesis and secretion of
aldosterone, a mineralocorticoid, from the glomerular
cells of the adrenal cortex. Aldosterone acts on cells in
the collecting duct(ule) and, through a cytoplasmic
interaction, increases both luminal uptake and basolateral passage of sodium (Fig. 10.3). Natriuresis after
spironolactone, an aldosterone antagonist, supports
hyperaldosteronism as a major contributor to sodium
retention in cirrhosis [16].
In addition to sodium (and water) retention, angiotensin II is a potent vasoconstrictor (both venules and
arterioles), a potent stimulant for the non-osmotic
release of antidiuretic hormone (ADH) from the posterior pituitary and a potent activator of the adrenergic
system (Fig. 10.4).
Bacterial translocation to mesenteric lymph nodes
with increased endotoxin production and consequent
stimulation of cytokine synthesis plays a major role in
enhancing vasodilatation in animals with cirrhosis and
ascites [17,18]. Further vasodilatation, with further activation of the RAAS, leads to hyponatraemia (through
secretion of ADH) [19], and to the HRS (through maximal
renal vasoconstriction) [7]. The time course of circulatory, neurohumoral and renal function abnormalities is
depicted in Fig. 10.5 [20].
ascites, suggests that in some cases sodium retention
occurs unrelated to vasodilatation. An alternative proposal is that, early on in the process, there is a primary
renal change—responding to hepatic insufficiency or
sinusoidal hypertension—that leads to sodium retention (overfill theory). Several signals have been suggested: reduced hepatic synthesis of a natriuretic agent,
reduced hepatic clearance of a sodium-retaining
hormone, or a ‘hepatorenal reflex’ of unknown aetiology. This theory is based on findings of sodium
Degree of splanchnic
arterial vasodilatation
Hyperdynamic circulation
Sodium retention
Activation SNS and RAAS
ADH and hyponatremia
Type-2 HRS
Type-1 HRS
Overfill theory (Fig. 10.6)
The presence of normal or low levels of plasma renin
activity in about a third of patients with cirrhosis and
cortical perfusion
Fig. 10.5. Time course of circulatory, neurohormonal and
renal function abnormalities in cirrhosis (in sequence of
peripheral arterial vasodilation theory). ADH, antidiuretic
hormone; HRS, hepatorenal syndrome; RAAS, renin–
angiotensin–aldosterone system; SNS, sympathetic nervous
system. (From [20] with permission.)
Hepatic signal
(baroreceptor, other)
Renal Na+ and H2O retention
Plasma volume
Cardiac output
Systemic vascular resistance
Portal hypertension
Fig. 10.4. Mechanisms of increased sodium and water
reabsorption in cirrhosis. * Increased ADH-stimulated water
reabsorption in collecting ducts.
Overflow into peritoneal cavity
Fig. 10.6. Overfill hypothesis.
Ascites 213
handling abnormalities, in the absence of systemic
vasodilatation or arterial under-filling, when patients
with preascitic cirrhosis are challenged with a sodium
load [21]. This hypothesis proposes that primary sodium
and water retention lead to expansion of the plasma
volume, an increase in cardiac output and a fall in systemic vascular resistance (vasodilatation).
Whether vasodilatation is a primary or secondary
event, therapy that counteracts the mechanisms that
lead to vasodilatation (e.g. NO inhibition) or vasodilation itself (e.g. vasoconstrictors), improves renal haemodynamics and increases sodium excretion [13,22].
Other renal factors
Atrial natriuretic peptides (ANP)
The plasma concentration of ANP is markedly increased
in patients with cirrhosis and ascites, regardless of
plasma levels of renin, aldosterone and noradrenaline
(norepinephrine). This is a potent natriuretic peptide
released from the cardiac atria, probably in response to
intravascular volume expansion. In compensated cirrhosis, ANF may maintain sodium homeostasis despite
the presence of mild antinatriuretic factors. In later
stages, renal resistance to ANF develops, rendering it
ineffective [23]. Therefore, sodium retention in cirrhosis
cannot be explained on the basis of a deficient synthesis
of natriuretic peptides.
Several prostaglandins are synthesized in the kidney
and have both vascular and tubular actions. Although
they are not primary regulators, they modulate the
effects of other factors and hormones locally. Prostaglandin (PG) I2 and E2 are vasodilators, and also
increase sodium excretion through vasodilatation and a
direct effect on the loop of Henle. They inhibit cyclic
adenosine monophosphate (cAMP) synthesis, thereby
interfering with the action of vasopressin (ADH). PGI2
is synthesized in the tubules and increases sodium and
water excretion. Therefore, prostaglandins have a significant role in sodium and water homeostasis. In conditions where there is a reduced circulating volume, which
includes cirrhosis, there is increased prostaglandin synthesis. This counterbalances renal vasoconstriction by
antagonizing the local effects of renin, angiotensin II,
endothelin 1, vasopressin and catecholamines.
The importance of this role is demonstrated clinically
by the renal dysfunction precipitated by the administration non-steroidal anti-inflammatory agents to decompensated [24] and compensated [25] patients with
cirrhosis. Without the vasodilatory influence of prostaglandins, renal blood flow and glomerular filtration rate
fall because of unopposed vasoconstriction due to renin
and other factors. Such an imbalance may be a trigger
for HRS.
Circulation of ascites
Once formed, ascitic fluid can exchange with blood
through a large capillary bed under the visceral peritoneum. This plays a vital, dynamic role, sometimes
actively facilitating transfer of fluid into ascites and
sometimes retarding it. Ascitic fluid is continuously circulating, with about half entering and leaving the peritoneal cavity every hour, there being a rapid transit in
both directions. The constituents of the fluid are in
dynamic equilibrium with those of the plasma. Rate of
ascitic fluid reabsorption is limited to 700–900 mL daily.
Summary (Fig. 10.5)
Ascites in cirrhosis results from sinusoidal hypertension
and sodium retention. The most accepted theory for
sodium retention is the peripheral arterial vasodilatation
hypothesis, which proposes that renal sodium (and water
retention) is due to reduced effective blood volume secondary to peripheral arterial vasodilatation (Figs 10.3,
10.4, 10.5). The renal changes are mediated by stimulation of the RAAS, an increase in sympathetic function,
and other systemic and local peptide and hormone disturbances. The overfill view suggests that renal retention
of sodium is primary with secondary vascular changes
and accumulation of ascites and oedema. Depending on
the degree of circulatory changes (Table 10.2), these
same mechanisms will lead to hyponatraemia and, at
the extreme end of severity of renal and vascular
changes, HRS develops (Fig. 10.5).
Clinical features
The most frequent symptoms are increased abdominal
girth (the patient notices tightness of the belt or garments around the waist) and recent weight gain [26]. As
Table 10.2. Circulatory changes in patients with cirrhosis
Plasma/ total blood volume
Non-central blood volume
Cardiac output
Portal pressure and flow
Central blood volume
Arterial blood pressure
Splanchnic vascular resistance
Systemic vascular resistance
Renal blood flow
Chapter 10
fluid continues to accumulate, it leads to elevation of the
diaphragm that may cause shortness of breath. Fluid accumulation may also be associated with a feeling of satiety
and generalized abdominal pain. The rapid onset of symptoms in a matter of weeks in ascites helps to distinguish
it from obesity, which develops over a period of months
to years.
The presence of ascites in patients with cirrhosis denotes
a decompensated, more advanced stage of cirrhosis,
therefore stigmata of cirrhosis are usually present
(spider angiomata, palmar erythema, muscle wasting).
There may also be jaundice and signs of portal hypertension, such as splenomegaly and abdominal wall collaterals. Inferior vena caval collaterals result from a
secondary, functional block of the inferior vena cava due
to pressure of the peritoneal fluid. They commonly run
from the groin to the costal margin or flanks and disappear when the ascites is controlled and intra-abdominal
pressure is reduced.
Physical examination is relatively insensitive for
detecting ascitic fluid, particularly when the amount is
small and/or the patient is obese. Patients must have at
least 1500 mL of fluid to be detected reliably on physical
examination. The clinical diagnosis of ascites will be
questionable or incorrect in roughly a third of the cases
[27]. When present in small amounts, ascites can be
identified by bulging flanks. Flank dullness is very sensitive in detecting ascites [28]. When flank dullness is
detected, it is useful to see whether it shifts with rotation
of the patient (shifting dullness). This sign is the most
sensitive finding (compared to abdominal distension,
bulging flanks and fluid wave) [29]. The fluid wave sign
has the poorest sensitivity in the diagnosis of peritoneal
fluid, even though its specificity is high [26,28,29]. With
tense ascites it is difficult to palpate abdominal viscera,
but with moderate amounts of fluid the liver or spleen
may be ballotted. The presence of a ballotable liver is a
good indicator of the presence of ascites [26].
Associated conditions
Umbilical hernias. Increased intra-abdominal pressure
favours the development of diastasis recti or hernias in
the umbilical, femoral or inguinal regions or through old
abdominal incisions. Hernias develop in about 20 % of
patients with cirrhosis and ascites (whereas only 3% have
hernias without ascites), and may increase to up to 70%
in patients with long-standing, recurrent, tense ascites
[30]. The main risks of these hernias are rupture [31] and
incarceration, the latter complication observed mostly in
patients in whom ascites has reduced after paracentesis,
peritoneovenous shunt or after transjugular intrahepatic
portosystemic shunt [32]. Once ascites is optimally
Fig. 10.7. A right-sided pleural effusion may accompany
ascites and is related to defects in the diaphragm.
treated, elective hernia repair with permanent mesh is
the best treatment for symptomatic hernias, with far less
complications than following emergent repair [33].
Hepatic hydrothorax. Pleural effusion develops in about
5–10% of patients with cirrhosis [34] and although it
usually develops in patients with ascites, hepatic hydrothorax may develop in patients without detectable
ascites [35]. Pleural effusion is right-sided in 85%, leftsided in 13% and bilateral in 2% of the cases [36]. It is
due to defects in the diaphragm allowing ascites to pass
into the pleural cavity (Fig. 10.7). Examination of pleural
and ascitic fluid may not be reliable to differentiate an
effusion due to local pleural disease from that due to
hepatic hydrothorax [37].The diagnosis of hepatic
hydrothorax can be established by radionuclide scanning of the chest after the intraperitoneal injection of
Tc-99m-labelled sulphur colloid or macroaggregated
serum albumin [35]. Presence of radiotracer in the
pleural space is demonstrated generally within 2 hours
following its intraperitoneal injection [38]. Although
large amounts of ascites can accumulate in the peritoneal cavity before resulting in significant patient discomfort, the accumulation of smaller amounts of fluid
(1–2 litres) in the pleural space results in severe shortness of breath and hypoxaemia. As pleural fluid is in
equilibrium with peritoneal fluid, control depends on
medical treatment of ascites. Aspiration is followed by
rapid filling up of the pleural space by ascitic fluid. TIPS
have been successful [39]; pleurodesis following complete drainage is less successful.
Peripheral oedema. This usually follows ascites and is
related to hypoproteinaemia. A functional inferior vena
caval block due to pressure of the abdominal fluid is an
additional factor. The presence of oedema without
ascites should therefore lead to investigations of causes
of fluid retention other than ascites.
Ascites 215
Ascitic fluid
Diagnostic paracentesis (of about 30 mL) should always
be performed in a patient with new-onset ascites,
however obvious its cause. In patients with known cirrhotic ascites, diagnostic paracentesis should be performed at every hospital admission and whenever SBP
is suspected. Diagnostic paracentesis is a safe procedure
with a very low incidence of serious complications,
mostly transfusion-requiring haematomas that occur at
a rate of 0.2 to 0.9% [40,41].
Fluid appearance is clear, green, straw-coloured or bilestained. The volume is variable and up to 70 litres have
been recorded. A blood-stained fluid indicates malignant disease or a recent paracentesis or an invasive
investigation, such as liver biopsy or transhepatic
Ascites total protein and serum-ascites albumin gradient
(SAAG) are two inexpensive tests that, taken together,
are most useful in determining the source of ascites
(Table 10.3). A high (>2.5 g/dL) ascites total protein
occurs with peritoneal involvement (malignancy, tuberculosis) due to leakage of high protein mesenteric lymph
from obliterated lymphatics and/or from an inflamed
peritoneal surface. A high ascites total protein also
occurs in cases of postsinusoidal or posthepatic sinusoidal hypertension when sinusoids are normal and
protein-rich lymph leaks into the peritoneal cavity [42].
In cirrhosis, an abnormally low protein content of liver
lymph has been demonstrated as a result of deposition
of fibrous tissue in the sinusoids (‘capillarization of the
sinusoid’), which renders the sinusoid less leaky to macromolecules [43]. On the other hand, the SAAG, which
involves subtracting ascites fluid albumin concentration
from serum albumin, has been shown to correlate with
hepatic sinusoidal pressure [44]. A SAAG more than
1.1 g/dL indicates that there is sinusoidal hypertension
and that the source of ascites is the hepatic sinusoid as
in the case of cirrhosis, heart failure or Budd–Chiari
syndrome [45] (Table 10.3).
Ascites polymorphonuclear cells increase with peritoneal
infection or with other intra-abdominal inflammatory
conditions such as diverticulitis, cholecystitis. The diagnosis of SBP is established with a polymorphonuclear
cell count of more than 250/mm3 [46]. In sterile ascites,
ascitic fluid white blood cell count is usually less than
100/mm3 with a predominance of mononuclear cells
and a low number of polymorphonuclear cells.
Ascites bacteriological culture is negative in approximately 40% of patients with clinical manifestations suggestive of SBP and increased ascites polymorphonuclear
cells [46]. Nevertheless, aerobic and anaerobic cultures
should be performed. The percentage of positive cultures increases when ascitic fluid is inoculated directly
into blood culture bottles at the bedside, which is the
recommended method of culture [46].
Electrolyte concentrations are those of other extracellular fluids.
The rate of accumulation of fluid is variable and depends
on the dietary intake of sodium and the ability of the
kidneys to excrete it.
Ascitic fluid protein and white cell count, but not
polymorph concentration, increase during diuresis.
Radiological features
Plain X-ray of the abdomen shows a diffuse groundglass appearance. Distended loops of bowel simulate
intestinal obstruction. Ultrasound and CT scan show a
space around the liver and these can be used to demonstrate quite small amounts of fluid (Fig. 10.8).
Differential diagnosis
Heart failure/ constrictive pericarditis. Diagnostic points
include jugular vein distension and, in constrictive
pericarditis, the paradoxical pulse and the radiological
demonstration of a calcified pericardium [47]. In both
cases SAAG will be more than 1.1 mg/dL and ascites
protein will be more than 2.5 g/dL [48]. Right and left
Table 10.3. Differential diagnosis among the three most common causes of ascites
Hepatic vein pressures*
Serum-ascites albumin
gradient (cutoff 1.1 g/dL)
Ascites protein
(cutoff 2.5 g/dL)
Cardiac ascites
Peritoneal malignancy/
peritoneal TB
* Only to be performed in equivocal cases. WHVP, wedged hepatic venous pressure; FHVP, free hepatic venous pressure;
HVPG, hepatic venous pressure gradient.
Chapter 10
Table 10.4. Spontaneous bacterial peritonitis
Suspect grade B and C cirrhosis with ascites
Clinical features may be absent and peripheral WBC normal
Ascitic protein usually <1 g/dL
Usually monomicrobial and Gram-negative
Start antibiotics if ascites >250 mm polymorphs
Concomitant albumin use if renal dysfunction or jaundice
20% die
69% recur in 1 year
non-surgical chylous ascites is cirrhosis [51,52].
Management is of the underlying cause and a low-fat
medium chain triglyceride diet for 3 weeks, or if this
fails total parenteral nutrition for 4–6 weeks.
Fig. 10.8. CT scan showing an irregular cirrhotic small liver,
splenomegaly and ascites (arrow).
heart catheterization and transjugular liver biopsy with
measurements of hepatic venous pressure gradient may
be necessary to make the differential between cardiac
and cirrhotic ascites [27] (Table 10.3).
Malignant ascites. There may be symptoms and localizing signs due to the primary tumour. After paracentesis,
the liver may be enlarged and nodular. Fluid cytological
exam should be performed, although normal endothelial cells in the peritoneum can resemble malignant cells.
Massive hepatic metastasis can lead to the development
of ascites but since the mechanism of ascites formation
is sinusoidal hypertension, these cases of ‘malignant
ascites’ will have the characteristics of cirrhotic ascites
Tuberculous ascites. This should be suspected particularly in the severely malnourished alcoholic who may
be febrile. Rarely, lumps of matted omentum can be
palpated after paracentesis. Ascitic fluid has many lymphocytes. When suspected, ascites should be stained for
tubercle bacilli, and suitable cultures set up.
Mixed aetiology ascites. In patients with mixed ascites
(e.g. cirrhosis with superimposed peritoneal malignancy
or tuberculosis), the SAAG is high and the ascites protein
is low, that is the findings of ascites due to cirrhosis
predominate [48,50].
Chylous ascites. This results from accumulation of fat,
predominantly chylomicrons, in the ascitic fluid. Its
appearance is milky and diagnosis is confirmed on a
triglyceride ascites content more than 200 mg/dL. The
most common cause of chylous ascites is postsurgical
disruption of lymphatics. The most common cause of
Hepatic venous obstruction (Budd–Chiari syndrome). This
must be considered, especially if the protein content of
the ascitic fluid is high and the SAAG is high.
Pancreatic ascites. Ascites is rarely gross. It develops as
a complication of acute pancreatitis with pseudocyst
rupture, or from pancreatic duct disruption. The amylase
content of the ascitic fluid is very high.
Ovarian tumour. This is suggested by resonance in the
flanks. The maximum bulge is anteroposterior and the
maximum girth is below the umbilicus.
Spontaneous bacterial peritonitis
(Table 10.4) [46]
The most common infection in cirrhosis is spontaneous
bacterial peritonitis (SBP). It is called spontaneous
because it occurs in the absence of a contiguous source
of infection (e.g. intestinal perforation, intra-abdominal
abscess) and in the absence of an intra-abdominal
inflammatory focus (e.g. abscess, acute pancreatitis,
cholecystitis). SBP occurs in 9% of hospitalized patients
with cirrhosis and accounts for 25% of all infections [53].
It is particularly frequent in severely decompensated
cirrhosis. Spontaneous bacterial empyema is an entity
akin to SBP in which hepatic hydrothorax becomes
infected. Its diagnosis and management are the same as
for SBP [54].
SBP is blood-borne and in 90% monomicrobial.
Bacteria of gut origin are the most commonly isolated
causative organisms. Therefore, migration of enteric
bacteria across the intestinal mucosa to extraintestinal
sites and the systemic circulation (bacterial translocation) has been implicated in its pathogenesis [55]. In
cirrhosis, an overactive sympathetic nervous system
slows gut motility and facilitates bacterial stasis and
overgrowth, thereby facilitating bacterial translocation.
Ascites 217
GI haemorrhage
RE function
Enteric bacterial
Invasive procedures,
Ascitic fluid
opsonic activity
tion generated by tumour necrosis factor and interleukin 6 [60].
Fig. 10.9. The pathogenesis of spontaneous bacterial
peritonitis (SBP) in patients with cirrhosis. GI,
gastrointestinal; RE, reticuloendothelial.
With SBP, 10–20% of patients will die during that hospital admission. The 1-year probability of SBP recurrence is 69% and median survival of a patient who
develops SBP is 9 months [61]. Mortality depends on the
development of renal dysfunction [62] and the site of
acquisition of the infection, with nosocomial infection
being an important predictor of death [63–65].
SBP resolution and immediate survival are 100% in
community-acquired SBP that is uncomplicated (i.e. no
renal dysfunction, no encephalopathy) whether patients
receive oral or intravenous antibiotics [66].
Persistence of bacteria in extraintestinal sites is
favoured by impaired host defences. In cirrhosis, host
defences are abnormal because of portosystemic shunting and impaired reticuloendothelial function. Neutrophils are abnormal in the alcoholic. Decreased
synthesis of proteins, such as complement and fibronectin, result in diminished adhesiveness and decreased
bacterial phagocytosis [56]. Ascitic fluid favours bacterial growth and deficient ascitic opsonins lead to defective coating of bacteria which are indigestible by
polymorphs. The opsonic activity of the ascitic fluid is
proportional to protein concentration and SBP is more
likely if ascitic fluid protein is less than 1 g/dL [57] (Fig.
10.9). Infection with more than one organism or with
fungi is likely to be associated with colonic perforation
or dilatation, or any intra-abdominal source of infection
(i.e. secondary peritonitis).
SBP should be suspected when a patient with cirrhosis deteriorates, particularly with encephalopathy and/
or jaundice. Patients with variceal bleeding or with previous SBP are at particular risk. Pyrexia, local abdominal
pain and tenderness, and systemic leukocytosis may be
noted. These features, however, may be absent and the
diagnosis is made following a high index of suspicion
with examination of the ascitic fluid.
The diagnosis of SBP is established with an ascites
polymorophonuclear count more than 250/ mm3 [46].
The infecting organisms are commonly Escherichia coli
or group D streptococci [58]. Anaerobic bacteria are
rarely found. Blood cultures are positive in 50%.
Bacterascites (positive culture, polymorphonuclear
cells <250/mm3) may resolve without treatment but can
progress to SBP [59].
Patients with SBP are particularly at risk of renal
complications, probably related to systemic vascular
changes secondary to inflammatory response to infec-
Antibiotics should be started empirically in all patients
with ascites showing more than 250 polymorphonuclear
cells/mm3, except in those in whom a local inflammatory reaction is identified (e.g. diverticulitis, cholecystitis, etc.).
Five to seven days of a third-generation cephalosporin
such as cefotaxime administered intravenously is
usually effective [67,68]. For cefotaxime the optimal
cost-effective dosage is 2 g every 12 h. Amoxycillinclavulanic acid is as effective as cefotaxime [69].
The antibiotic choice should be reviewed once results
of ascitic culture and sensitivity of the bacterial isolates
are known. Because of renal toxicity, aminoglycosides
should be avoided.
In a randomized study the administration of intravenous albumin to patients with SBP treated with cefotaxime significantly reduced the incidence of renal
impairment (10 vs. 33%) and hospital mortality (10 vs.
29%) [62]. Patients that benefit most from the use of
albumin are those with renal dysfunction at baseline
(creatinine >1.0 mg/dL and/or blood urea nitrogen
>30 mg/dL) and serum bilirubin more than 4 mg/dL
Success rates for cefotaxime and amoxicillin-clavulanic
may be as low as 44% in nosocomial SBP because of the
presence of multidrug-resistant organisms [72,73].
Extended spectrum antibiotics (e.g. carbapenems, piperacillin/ tazobactam) should be used as initial empirical therapy in patients with hospital-acquired SBP,
particularly in those who had been on beta-lactams
during admission, had been recently hospitalized or on
quinolone prophylaxis [72].
Secondary bacterial peritonitis should be suspected
when a suspected SBP fails to respond to antibiotic
Because of reduced survival, SBP is an indication to
consider hepatic transplantation, particularly if recurrent.
Chapter 10
Long-term prophylaxis will lead to the emergence of
resistant bacteria [53]. Therefore, only patients at the
highest risk of developing SBP should receive antibiotic
The risk of SBP is particularly high in patients with
cirrhosis with upper gastrointestinal haemorrhage. Oral
administration of norfloxacin (400 mg/12 h for a
minimum of 7 days) is currently recommended for this
group [46]. However, intravenous ceftriaxone should be
considered in high quinolone resistance settings or in
patients with two or more of the following: malnutrition, ascites, encephalopathy or serum bilirubin more
than 3 mg/dL [74]. SBP and other infections should
be ruled out by bacterial cultures before starting
In patients with a previous episode of SBP, the risk of
recurrence during the subsequent year is 40–70%. Oral
administration of norfloxacin (400 mg/day) is recommended in such patients, who should then be evaluated
for liver transplantation [46,75].
There is currently insufficient evidence to recommend
prophylaxis for patients with a low ascitic fluid protein
(<1 g/dL). However, norfloxacin prophylaxis appears
justified in patients with advanced liver failure (Child–
Pugh score >9 points with serum bilirubin level >3 mg/
dL) or impaired renal function (serum creatinine level
>1.2 mg/dL, blood urea nitrogen level >25 mg/dL, or
serum sodium level <130 mEq/L). In these patients, the
1-year probability of first SBP is 60% and is significantly
reduced with norfloxacin [76] .
In patients with a high ascitic fluid protein (>1 g/dL)
without a past history of SBP, prophylaxis is not necessary as the 1-year probability of SBP is nil [77].
Treatment of cirrhotic ascites [78,79]
Therapy of ascites, whether by diuretics or paracentesis,
reduces clinical symptoms and improves quality of life.
However, although the initial clinical response may be
excellent, if fluid loss is excessive it may lead to hyponatraemia, hyperkalaemia, renal failure or encephalopathy.
Treatment must therefore be appropriate to the clinical
state and the response properly monitored. The approach
must be tailored to the patient. The spectrum of therapeutic intervention ranges from sodium restriction
alone (rarely used), to diuretic use, therapeutic paracentesis (Table 10.5), and, for the most severe groups, TIPS
and eventually liver transplantation.
Indications for treatment include the following:
• Symptomatic ascites with abdominal distension sufficient to be obvious and produce physical or emotional
distress requires treatment with sodium restriction and
diuretics. The presence of subclinical ascites (that seen
only on ultrasound without clinical symptoms) may not
require active treatment, although to prevent deterioration advice on a reduction in sodium intake is wise.
Inappropriate introduction of excessive treatment for
ascites may lead to symptomatic hypotension, muscle
cramps, dehydration, and renal dysfunction.
• Large ascites, causing abdominal discomfort or pain
and/or dyspnoea most often demands paracentesis.
• Tense ascites with pain may lead to eversion and ulceration of an umbilical hernia, which is near to rupture.
This complication has a very high mortality, due to
shock, renal failure and sepsis, and urgent paracentesis
is indicated.
Monitoring during treatment is mandatory. The
patient should be weighed daily as it provides a satisfactory guide to progress. Urinary electrolyte (sodium,
potassium) determinations are helpful in determining
dosage, monitoring the response and assessing compliance. Serum electrolytes and creatinine should be measured two to three times per week while the patient is in
hospital. Where liver disease is due to alcohol, the
patient should be encouraged to abstain. The mild case
is managed as an out-patient by diet and diuretics, but
if admitted to hospital, paracentesis is usually a first
procedure. In a survey of European hepatologists, 50%
used paracentesis initially, followed by diuretics [80].
Fifty per cent regarded complete control of ascites as
Table 10.5. General management of ascites
Diagnostic paracentesis with first presentation or with any symptom/ sign suggestive of SBP
70–90 mmol sodium diet; weigh daily; check serum creatinine and electrolytes
Spironolactone 100 mg daily
If tense ascites consider paracentesis (see Table 10.7)
After 4 days consider adding frusemide (furosemide) 40 mg daily; check serum creatinine and electrolytes
Maximum daily weight loss 0.5 kg/day (1.0 kg/day in those with peripheral oedema)
Stop diuretics if precoma (‘flap’), hypokalaemia, azotaemia or alkalosis
Continue to monitor weight; increase diuretics as necessary
Avoid non-steroidal anti-inflammatory drugs
SBP, spontaneous bacterial peritonitis.
Ascites 219
desirable, whereas the other half was satisfied with
symptomatic relief without removing all the ascites.
Thus consensus on standardized treatment regimes is
difficult to reach because of the clinical spectrum of
ascites, the clinical success of the different regimens and
the lack of evidence-based studies comparing individual approaches.
Bed rest used to be a feature of initial therapy. Evidence
for benefit is sparse but as part of an overall strategy in
combination with diuretics it has been found to be
beneficial [81]. This may be related to increased renal
perfusion and portal venous blood flow during
Sodium restriction/ diet
The patient with cirrhosis who is accumulating ascites
on an unrestricted sodium intake excretes less than
10 mmol (approximately 0.2 g) sodium daily in the urine.
Extrarenal loss is about 0.5 g. Sodium taken in excess of
0.75 g will result in ascites, with every gram retaining
200 mL of fluid. Historically, such patients were recommended a diet containing 22–40 mmol/day of sodium
(approximately 0.5–1.0 g/day). However, such diet is
unpalatable and also compromises protein and calorie
intake, which in patients with cirrhosis is critical for
proper nutrition. Current recommendations are to use a
‘no added salt’ diet (approximately 70–90 mmol or
approximately 1.5–2.0 g/day) combined with diuretics
to increase urinary sodium excretion (Table 10.6). In this
diet, salt should not be used at the table or when cooking.
Also, various foods containing sodium should be
restricted or avoided (Table 10.6). Many low-sodium
foods are now available.
A few patients with ascites may respond to this
regimen alone, but usually the first line of treatment for
ascites includes diuretics. Patients prefer the combination of diuretics and a modest restriction of sodium to
severe sodium restriction alone. Very occasionally if
there is a good response, diuretics may be withdrawn
and the patient maintained on dietary sodium restriction alone.
Good responders are liable to be those:
• with ascites and oedema presenting for the first time
in an otherwise stable patient;
• with a normal creatinine clearance (glomerular filtration rate);
• with an underlying reversible component of liver
disease such as alcoholic hepatitis;
• in whom the ascites has developed acutely in response
to a treatable complication such as infection or bleeding,
or after a non-hepatic operation;
• with ascites following excessive sodium intake, such
as in sodium-containing antacids or purgatives, or
mineral waters with a high sodium content.
The major reason for sodium retention in cirrhosis is
hyperaldosteronism due to increased activity of the
renin–angiotensin system. There is avid reabsorption of
sodium from the distal tubule and collecting duct (Fig.
Diuretics can be divided into two main groups (Fig.
10.10) according to their site of action. The first group
inhibits Na+–K+–Cl− (NKCC2) cotransporter in the
ascending limb of the loop of Henle and includes frusemide (furosemide) and bumetamide. It is not appropriate to use these alone since the sodium remaining in the
tubule as a result of diuretic action is reabsorbed in the
distal tubule and collecting duct because of hyperaldosteronism. A randomized controlled trial has shown
frusemide alone to be less effective than spironolactone
[16]. Thiazides inhibit sodium in the distal convoluted
tubule, have a longer half-life, may cause hypotension,
and should not be used in the treatment of ascites.
The second group, spironolactone (an aldosterone
antagonist), amiloride and triamterene, (inhibitors of
the sodium channel) block sodium reabsorption in the
distal tubule and collecting duct. They are the drugs of
first choice in the treatment of ascites due to cirrhosis.
They are weakly natriuretic but conserve potassium.
Potassium supplements are not usually necessary—
indeed this type of diuretic sometimes needs to be temporarily stopped because of hyperkalaemia [82].
There are two therapeutic approaches that can be
used initially: spironolactone alone, or a combination of
spironolactone with frusemide. Both have their advocates and may be chosen depending on the degree of
ascites [82,83].
Spironolactone alone. The starting dose is 50–100 mg/day
according to the degree of ascites. If there has been
insufficient clinical response after 3–4 days (weight loss
less than 300 g/day), then the dose is increased by
100 mg/day every 4 days to a maximum of 400 mg/day,
unless hyperkalaemia develops. Lack of clinical response
indicates the need to check the urinary sodium, because
a high value will identify the occasional patient who is
exceeding the prescribed low sodium diet.
The disadvantage of starting with spironolactone
alone is the delay before its clinical effect and associated
hyperkalaemia [82].
If there is insufficient clinical response or no response
on spironolactone alone (when taking 200 mg/day) or
associated hyperkalaemia, a loop diuretic such as frusemide is added at a dose of 20–40 mg/day.
Combination therapy. Treatment is started with the combination of spironolactone (100 mg) and frusemide
(40 mg) daily. The disadvantage of starting with
Chapter 10
Table 10.6. Advice for ‘no added salt diet’ (70–90 mmol/day or 1.5–2.0 g/day)
Anything containing baking powder or baking soda (contains sodium bicarbonate): pastry, biscuits, crackers, cakes, self-raising flour
and ordinary bread (see restriction below)
All commercially prepared foods (unless designated low salt—check packet)
Dry breakfast cereals except Shredded Wheat, Puffed Wheat or Sugar Puffs
Tinned/ bottled savouries: pickles, olives, chutney, salad cream, bottled sauces
Tinned meats/ fish: ham, bacon, corned beef, tongue, oyster, shellfish
Meat and fish pastes; meat and yeast extracts
Tinned/ bottled vegetables, soups, tomato juice
Sausages, kippers
Cheese, ice-cream
Candy, pastilles, milk chocolate
Salted nuts, potato crisps, savoury snacks
Drinks: especially Lucozade, soda water, mineral waters according to sodium content (essential to check sodium content of mineral
waters, varies from 5 to 1000 mg/L)
Milk (300 mL = half pint/day)
Bread (two slices/day)
Free use
Fresh and home-cooked fruit and vegetables of all kinds
Meat/poultry/fish (100 g/day) and one egg; egg may be used to substitute 50 g meat (2 oz)
Unsalted butter or margarine, cooking oils, double cream
Boiled rice, pasta (without salt), semolina
Seasonings help make restricted salt meal more palatable: include lemon juice, onion, garlic, pepper, sage, parsley, thyme,
marjoram, bay leaves
Fresh fruit juice, coffee, tea
Mineral water (check sodium content)
Marmalade, jam
Dark chocolate, boiled sweets, peppermints, chewing gum
Salt substitutes (not potassium chloride)
Salt-free bread, crispbread, crackers or matzos
combination therapy may be the need for closer laboratory monitoring [83].
Monitoring of daily weight is necessary. The rate of
ascitic fluid reabsorption is limited to 700–900 mL/day.
If a diuresis of 2–3 litres is induced, much of the fluid
must come from non-ascitic, extracellular fluids including oedema fluid and the intravenous compartment.
This is safe so long as oedema persists. Indeed diuresis
may be rapid (greater than 2 kg daily) until oedema
disappears [84]. To avoid the risk of renal dysfunction
there should be a maximum daily weight loss of 0.5 kg/
day, with a maximum of 1.0 kg/day in those with
Intravascular volume expansion with intravenous
albumin increases natriuresis in response to diuretics,
but is expensive and not cost-effective [85].
Long-term spironolactone causes painful gynaecomastia in males and should then be replaced by 10–
15 mg/day of amiloride. However, this is less effective
than spironolactone.
Before diuretic therapy is deemed to have failed
(diuretic-refractory ascites) non-compliance with sodium
Ascites 221
night is often helpful to prevent cramps [87], otherwise
quinine water can be recommended; weekly intravenous albumin is also effective [87].
Follow-up advice
Fig. 10.10. Site of action of diuretics. 1 = loop diuretics:
frusemide (furosemide), bumetamide. 2 = distal tubule/
collecting duct: spironolactone, amiloride, triamterene.
restriction should be ruled out by measuring 24-h
urinary sodium excretion. If this is greater than the ‘prescribed dietary’ sodium intake the patient is not complying with the restriction. Another cause of a lack of
response to diuretics are concomitant use of nonsteroidal anti-inflammatory agents, and angiotensin
converting enzyme blockers or angiotensin receptor
blockers [86].
Failure to respond to diuretics often occurs in those
with very poor hepatocellular function who have a poor
prognosis without liver transplantation. In such refractory patients, diuretics have eventually to be withdrawn
because of intractable uraemia, hypotension or
Rising urea and creatinine reflect contraction of the extracellular fluid volume and reduced renal circulation (prerenal azotaemia). Hepatorenal syndrome may be
precipitated. It is necessary to interrupt or reduce diuretic therapy and use plasma expansion with albumin
in more severe cases.
Encephalopathy may follow any profound diuresis and
is usually associated with prerenal azotaemia, hypokalaemia and hypochloraemic acidosis.
Hyperkalaemia reflects the effect of spironolactone,
which should be reduced or interrupted according to
the level of serum potassium. If the level of potassium
is not dangerous, frusemide can be added to therapy at
this point.
Painful gynaecomastia may be caused by spironolactone, which should be reduced or discontinued and substituted by amiloride.
Muscle cramps may be a problem. They indicate the
need to review the dose of diuretic, but can occur
without their use. Quinine sulphate 300 mg given at
The out-patient should adhere to the low-sodium diet,
and abstain from alcohol where this is the cause of liver
disease. Bathroom scales should be used to allow a
record of daily weight at the same time of day, nude or
with similar clothing. This daily record should be kept
and brought to the physician at each visit.
The dose of diuretics depends upon the degree of
ascites and the severity of the liver disease. A usual
regime is 100–200 mg spironolactone (or 10–20 mg amiloride) daily with frusemide 40–80 mg daily for the
patient with more marked ascites initially, or with a
poor response to spironolactone alone. Serum electrolytes, creatinine, urea and liver function tests are monitored every 4 weeks for the stable out-patient. In the
patient who has been treated initially as an in-patient,
an earlier check at 1 week after discharge allows an
adjustment to the management plan before electrolyte
or clinical imbalance has occurred. As liver function
improves and the oedema and ascites resolve, it may be
possible to stop the frusemide first and then the spironolactone. Symptoms such as postural dizziness and thirst
indicate over-enthusiastic treatment. The ‘no added salt’
(70–90 mmol/day or 1.5–2.0 g/day) is maintained in the
majority of patients.
Therapeutic abdominal paracentesis (Table 10.7)
This procedure was abandoned in the 1960s because of
the fear of causing acute renal failure. Moreover, the loss
of approximately 50 g of protein in a 5-litre paracentesis
led to patients becoming severely malnourished. New
interest came with the observation that a 5-litre paracentesis was safe in fluid- and salt-restricted patients with
ascites and peripheral oedema [88]. This work was
extended to daily 4–5-litre paracenteses with 40 g saltpoor albumin infused intravenously over the same
period [81]. Finally, a single total paracentesis, about
10 litres in 1 h combined with intravenous albumin
(6–8 g/L ascites removed) was shown to be equally
effective and safe (Table 10.7) [89,90].
In a controlled trial, serial large-volume paracenteses
(LVP) reduced hospital stay compared with standard
diuretic treatment [81]. However, readmissions to hospital, survival and causes of death did not differ significantly between the LVP and diuretic groups. Total
paracentesis results in hypovolaemia as reflected by a
rise in plasma renin levels [88], and can lead to hypotension and renal failure (postparacentesis circulatory syndrome) [88].
Chapter 10
Table 10.7. Therapeutic paracentesis
Large or tense ascites
No volume limit
Table 10.8. Hyponatraemia
Serum sodium <130 mEq/L
Present in 22% of patients with ascites
May contribute to encephalopathy and poor quality of life
Water restriction (1–1.5 L/day)
‘Vaptans’ correct sodium but are still under investigation
Poor prognostic marker
i.v. salt-poor albumin: 6–8 g/L removed
No need to perform cell count unless symptoms/ signs
suggestive of SBP
Shortens hospital stay
SBP, spontaneous bacterial peritonitis.
Albumin replacement is more effective in preventing
postparacentesis hypovolaemia and hyponatraemia
than less costly plasma expanders such as dextran 70,
dextran 40 and polygeline [91].
Major complications, mostly bleeding, have been
associated with therapeutic but not diagnostic procedures and tend to be more prevalent in patients with
low platelet count (<50 000) and Child–Pugh class C
[92]. Major bleeding occurs rarely but may be lethal [93]
and is mostly related to puncture of collaterals rather
than as a result of coagulopathy. In a series of over 1000
LVPs there was no significant bleeding, even in patients
with marked thrombocytopenia or prothrombin time
prolongation [94]. Therefore clotting abnormalities
should not be considered a contraindication to LVP.
Leakage of ascitic fluid is rare and occurs when extraction of ascites is incomplete. Therefore, this complication can be solved by completing the LVP, preferably in
a site remote from the leaking puncture site. Similarly,
another rare complication of paracentesis is the development of sudden scrotal oedema that results from
subcutaneous tracking of peritoneal fluid into the
scrotum and which should be treated by elevation of
the scrotum [95].
Paracentesis is a safe, cost-effective treatment for cirrhotic ascites. However, approximately 90% of patients
with ascites respond to sodium restriction and diuretics,
and paracentesis is generally a second-line treatment
except for patients with tense and refractory ascites (see
below). Despite this, many clinicians opt for early paracentesis rather than waiting for diuretics to be effective
[81]. Intravenous salt-poor albumin should be used concomitant to LVP, particularly when more than 5 litres are
removed. The paracentesis must be followed by an
optimal salt-restricted diet and diuretic regimen.
Hyponatraemia [96] (Table 10.8)
Hyponatraemia develops in approximately 20–30% of
cirrhotic patients with ascites and is defined as a serum
sodium concentration less than 130 mEq/L [97,98].
Hyponatraemia in cirrhosis is dilutional. Although
hyponatraemia is usually asymptomatic, some patients
may complain of anorexia, nausea and vomiting, lethargy and occasionally seizures. Hyponatraemia has
been associated with a further reduction in brain organic
osmolytes, particularly myoinositol, suggesting that it
may play a role in the pathogenesis of hepatic encephalopathy [99].
Serum sodium concentrations of less than 130 mmol/L
are treated by fluid restriction, to avoid further reduction in concentrations. Advances in the understanding
of the pathogenesis are leading to pharmacological
approaches to treatment.
Eighty per cent of the water in the glomerular filtrate is
reabsorbed in the proximal tubule and descending limb
of Henle. The ascending limb of Henle and distal tubule
are impermeable to water. Control of the volume of
water passed in urine is dependent on the amount of
water reabsorbed in the collecting tubule and collecting
duct. This is under the control of vasopressin, which
interacts with V2 receptors on the cells of the renal collecting ducts (Fig. 10.4). Vasopressin receptor activation
stimulates the translocation of the water channel
aquaporin 2 from a cytoplasmic vesicular compartment
to the apical membrane. This mechanism may be affected
by prostaglandins which inhibit vasopressin-stimulated
water reabsorption.
Vasopressin is produced in the hypothalamus.
Production is controlled in two ways: by osmoreceptors
in the anterior hypothalamus under the influence of
plasma osmolarity, and by parasympathetic stimulation
as a result of activation of baroreceptors in the atria,
ventricles, aortic arch and carotid sinus. Water retention
in patients with cirrhosis and ascites is due to excess
vasopressin as a result of baroreceptor stimulation. This
Ascites 223
is thought to be related to the reduced effective circulating volume as a result of splanchnic and systemic
vasodilatation—the same circulatory abnormality which
leads to activation of the renin–angiotensin–aldosterone
axis and the sympathetic nervous system and sodium
retention. However, alterations in sodium and water
handling are not synchronous, sodium abnormalities
occurring first (Fig. 10.5).
Vasopressin concentrations are not grossly elevated in
cirrhosis. However, the normal inhibition of vasopressin
by a water load is blunted or absent. Although there is
reduced hepatic metabolism of vasopressin in patients
with cirrhosis, related to the severity of disease, this is
not thought to be the primary reason for water
Hyponatraemia reflects reduced free water clearance. In
the patient with severe hepatocellular dysfunction it
may also indicate the passage of sodium into the cells.
If the serum sodium falls below 130 mmol/L, fluid
intake should be restricted to 1–1.5 litres per day [19].
Intravenous albumin is beneficial but its effect is transient [100].
Several approaches are being studied to increase free
water clearance. Drugs such as kappa-opioid receptor agonists, which inhibit vasopressin release, and demeclocycline, which interferes with generation and action of
cAMP in collecting ducts, have been reported to be
effective but their use has been abandoned due to
important side effects [101,102].
V2 receptor antagonists (‘vaptans’) have been the
most investigated aquaretic agents. The short-term
(7–14 days) use of lixivaptan [103,104] or satavaptan
[105] was effective in increasing serum sodium.
However, their use was associated with severe sideeffects, dehydration and Q–T prolongation, respectively,
and has led to their withdrawal. In a large multicenter
randomized trial, tolvaptan used for 30 days in patients
with euvolaemic or hypervolaemic hyponatraemia (of
whom 63 had cirrhosis), was associated with a rapid
improvement in serum sodium and significant weight
loss compared to placebo, without significant side
effects [106]. Longer-term trials targeting patients with
cirrhosis are awaited.
nized that hyponatraemia is a predictor of reduced survival in cirrhotic patients with ascites [107,108] and is a
risk factor for encephalopathy and the HRS syndrome
[96,98]. Liver transplantation should be considered providing serum sodium can be increased to 125 mmol/L
or more.
Refractory ascites [109,110] (Table 10.9)
This is defined as ascites that cannot be mobilized or
prevented from recurring by medical therapy. It is
divided into diuretic-resistant (ascites is not mobilized
despite maximal diuretic dosage) and diuretic-intractable
ascites (development of diuretic-induced complications
that preclude the use of an effective diuretic dosage)
[109]. Dietary history, use of NSAID or angiotension
converting enzyme or angiotensin II receptor blockers
[86], and patient compliance with the treatment regimen
must be reviewed before confirming the diagnosis.
The therapeutic options for patients with refractory
ascites include repeated LVPs, TIPS, peritoneovenous
(Le Veen) shunting and liver transplantation.
Therapeutic paracentesis
This has been discussed above as initial treatment for
the patient with tense severe ascites. For refractory
ascites repeated LVP plus albumin is the most accepted
initial therapy. It is easy to perform and relatively inexpensive compared to other therapies such as the peritoneovenous shunt. In this group of patients recurrence of
ascites is the rule because paracentesis is symptomatic
therapy that does not act on the mechanisms responsible
for ascites formation. Patients generally require paracentesis every 2 to 4 weeks. Reintroduction of diuretic
treatment after paracentesis lengthens time to recurrence [111] in patients with a urinary sodium greater
Table 10.9. Refractory ascites
First line:
Second line:
Although advances are being made in pharmacological
approaches to correct water retention and the associated
hyponatraemia, these are not yet clinically applicable.
The mainstay of treatment is fluid restriction. Intravenous
albumin infusion may be effective in the short term
[100]. Whichever approach is used, it should be recog-
Third line:
Serial therapeutic paracenteses
Relapse is the rule
When paracenteses >1–2/month
MELD <15
?Survival benefit
Peritoneovenous shunt
Non-LVP, non-TIPS candidates
TIPS, transjugular intrahepatic portosystemic shunt;
MELD, Model for End Stage Liver Disease; LVP, largevolume paracenteses.
Chapter 10
and have reasonable hepatic reserve with normal or
minimal renal dysfunction.
Peritoneovenous (Le Veen) shunt
Fig. 10.11. The transjugular intrahepatic portosystemic
shunt (TIPS) decompresses hepatic sinusoids.
than 30 mEq/L. In others, diuretics should be discontinued, particularly if associated with complications [110].
Transjugular intrahepatic portosystemic shunt (TIPS)
Side-to-side portacaval shunts, unlike end-to-side
shunts, decompress the hepatic sinusoids (Fig. 10.11)
and had been shown to be effective in the treatment of
ascites. However, they have been abandoned because of
the associated morbidity and mortality of major surgery
and the advent of TIPS, which is a less invasive procedure that achieves the same decompression of the sinusoid [112].
Early experience with TIPS showed a reduction in
diuretic requirements, and a fall in plasma renin and
aldosterone activities. However, TIPS may precipitate
hepatic encephalopathy and/or liver failure.
Not surprisingly, since TIPS acts on the pathophysiological mechanisms responsible for ascites TIPS is more
effective than LVP in preventing recurrence of ascites in
randomized comparative trials [113,114], but had a higher
risk for severe encephalopathy, without differences in
mortality. A meta-analysis of individual patient data in
randomized studies showed that mortality was significantly lower in patients treated with TIPS and identified
a Model for End Stage Liver Disease (MELD) score above
15 as having a high risk of death [115]. In trials performed
to date, uncovered TIPS stents were used. Uncovered
stents frequently obstruct (18 to 78%) [116] and have been
largely substituted by polytetrafluoroethylene-covered
stents which are associated with a significantly lower
obstruction rate. [117]. Until results of ongoing trials
using covered stents are available, TIPS should be considered second-line treatment for refractory ascites, and
reserved for patients who require frequent paracentesis
This consists of a plastic tube with multiple holes that
is placed in the peritoneal cavity and is connected to a
unidirectional pressure-sensitive valve lying extraperitoneally, from which a silicone rubber tube passes subcutaneously to the neck and thence to the internal
jugular vein and superior vena cava (SVC). When the
diaphragm descends during inspiration, the intraperitoneal fluid pressure rises while that in the intrathoracic
SVC falls. This allows ascitic fluid to pass from the peritoneal cavity into the general circulation. It is generally
inserted under general anaesthesia. Flow of ascites
along the shunt depends upon this pressure gradient
between peritoneal cavity and SVC.
The peritoneovenous shunt may control ascites over
many months. It produces sustained expansion of the
circulating blood volume and a fall in plasma levels of
renin–angiotensin, noradrenaline and antidiuretic
hormone. Renal function and nutrition improve.
In uncontrolled studies, peritoneovenous shunts
resulted in frequent blockage, severe complications (disseminated intravascular coagulation, pulmonary
oedema, variceal haemorrhage) and high perioperative
mortality. However, randomized trials comparing peritoneovenous shunt with LVP and albumin replacement
resulted in similar efficacy, with similar complication
rates and survival [89,118]. Since paracentesis with
albumin replacement is simpler and can be done on an
out-patient basis, it is the preferred procedure.
Additionally, peritoneovenous shunt may hinder future
placement of TIPS and may complicate liver transplant
surgery due to peritoneal adhesions. Therefore, it is
mostly indicated in patients who require LVP frequently
and who are not candidates for TIPS [119].
Hepatorenal syndrome [120]
Hepatorenal syndrome (HRS) is the development of
renal failure in patients with severe liver disease in the
absence of any identifiable renal pathology. It is a functional rather than structural disturbance in renal function. The histology of the kidney is virtually normal.
Such kidneys have been successfully transplanted, following which they functioned normally. After liver
transplantation, kidney function also usually returns to
The mechanism is not fully understood, but the renal
disturbance is thought to represent the severest form of
vascular and neurohumoral changes associated with
severe liver disease, which in a less severe form results
in ascites (Figs 10.5, 10.12) [7].
Ascites 225
• Worsening liver function
• Precipitants*
Peripheral vasodilatation
Further vasodilatation
Diminished effective
arterial blood volume
Further decrease in effective
arterial blood volume
Rise in renin, aldosterone, vasopressin
Sympathetic stimulated
Further rise in
vasoactive systems
Sodium and water retention
Renal vasoconstriction
Intense renal
Plasma volume expansion
plus portal hypertension
Decreased renal perfusion
Hepatorenal syndrome
cardiac output
Fig. 10.12. Mechanism for hepatorenal syndrome. *Precipitants include bacterial infections (particularly spontaneous
bacterial peritonitis), hypovolaemia (gastrointestinal haemorrhage, over-diuresis, diarrhoea), vasodilators.
Table 10.10. Criteria for diagnosis of hepatorenal syndrome [122]
1 Cirrhosis with ascites
2 Serum creatinine >1.5 mg/dL (>133 μmol/L)
3 No improvement in serum creatinine (decrease to 1.5 mg/dL or less) after at least 2 days of diuretic withdrawal and expansion of
plasma volume with albumin (1 g/kg of body weight/day up to a maximum of 100 g/day)
4 Absence of shock
5 No current or recent treatment with nephrotoxic drugs or vasodilators
6 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
HRS is a rare but severe complication in patients with
cirrhosis and ascites. From first presentation with ascites,
the 5-year probability of developing HRS is 11% [97],
with increasing probability in patients who develop
hyponatraemia or refractory ascites. Without liver transplantation and prior to the recent studies of treatment
using vasocontrictors, recovery of renal function was
unusual (<5% of patients) and prognosis was poor with
a median survival of 2 weeks [121].
Diagnostic criteria (Table 10.10)
These are based largely on abnormal creatinine, the
absence of other causes of renal failure and the absence
of sustained improvement in renal function after diuretic withdrawal and plasma volume expansion [122].
The occurrence of shock before deterioration of renal
function precludes a diagnosis of HRS and is more
indicative of acute tubular necrosis (ATN) [120].
Additional criteria describe the characteristics of
urine volume and content, but since these may be
present with other types of renal failure, for example
ATN, they are not considered essential for the diagnosis
of HRS [120].
HRS syndrome may be classified into two types:
Type 1. Patients have a rapidly progressive (less than
2 weeks) reduction of renal function with doubling of
the initial serum creatinine to greater than 2.5 mg/dL
(220 μmol/L) [122]. However, as recently proposed
[120], a diagnosis of HRS (type 1) should be considered
whenever there are criteria for acute kidney injury,
namely an abrupt increase in serum creatinine ≥0.3 mg/
dL (≥26.4 μmol/L) or an increase ≥150% (1.5-fold) from
baseline [123]. This ensures that treatment is not unnecessarily delayed as baseline creatinine is a predictor of
HRS reversal with vasoconstrictors [124].
Type 2. Patients satisfy the criteria for the diagnosis of
HRS but the renal failure does not progress rapidly
[122]. These patients usually have relatively preserved
Chapter 10
hepatic function with refractory ascites. Survival is
reduced compared with patients with cirrhosis and
ascites and normal renal function.
The peripheral arterial vasodilatation theory for the formation of ascites proposes initial splanchnic and systemic arterial dilatation with consequent stimulation of
the sympathetic nervous system (raised noradrenaline)
and the renin–angiotensin system. This is the result of
activation of volume receptors responding to vascular
under-filling. Initially, despite changes in vasoconstrictors and vasodilators, renal function is preserved. HRS
occurs with extreme vasodilatation, decrease in cardiac
output [125] and an imbalance between systemic and
intrarenal vasodilator and vasoconstrictor mechanisms,
with increases in vasoconstrictors such as thromboxane
A2 and endothelin [126] and decreases in vasodilators
such as prostaglandin E2 and nitric oxide [127].
Table 10.11. Iatrogenic causes of acute kidney injury in
NSAID (prostaglandin inhibition)
Volume expansion
Volume expansion
Stop drug
Diagnose urine
NSAID, non-steroidal anti-inflammatory drug.
usually in the alcoholic. Hepatitis B and C are associated
with immune-related glomerulonephritis. These lesions
are diagnosed by finding proteinuria with microscopic
haematuria and casts. The main differential diagnosis
and the most difficult to make is ATN. A history of
shock, increased urine sodium and granular casts indicate ATN, however all these findings can also be present
in HRS.
Clinical features
Many features are associated with an increased risk for
HRS including marked sodium (<5 mmol/L) and water
retention (hyponatraemia), low mean arterial blood
pressure (<80 mmHg) and marked elevation of the
RAAS [121], all indicative of a worsening haemodynamic status. A lower cardiac output (<6 L/min) (in the
setting of severe arterial vasodilatation) has also been
identified as an independent predictor of HRS [125].
Patients with HRS characteristically have advanced
liver disease (median Child–Pugh score 11.2), difficult
to control ascites, a low mean arterial pressure and
hyponatraemia [120]. Hyperkalaemia is unusual. Death
is due to liver failure; survival depends on the reversibility of the liver disease.
The risk of HRS syndrome is reduced by careful use and
monitoring of diuretic therapy, and the early recognition
of any complication such as electrolyte imbalance,
haemorrhage or infection. Nephrotoxic drugs should be
avoided. The risk of renal deterioration after large
volume paracentesis is reduced by the administration of
salt-poor albumin. The risk of further worsening renal
failure in patients with SBP is prevented by intravenous
albumin and concomitant antibiotics [62]. The risk of
SBP and HRS in high-risk patients without a prior
episode of SBP is reduced by prophylactic antibiotics
Differential diagnosis
Prerenal azotaemia (or volume-responsive acute kidney
injury). In a patient with cirrhosis this must be differentiated from HRS as the management and prognosis are
different (Table 10.11). Causes include over-diuresis and
severe diarrhoea, for example due to lactulose. Bacterial
infection, particularly SBP, may present with reversible
impairment of renal function. Non-steroidal antiinflammatory drugs reduce renal prostaglandin production, thereby reducing the glomerular filtration rate and
free water clearance.
Intrinsic renal failure. Nephrotoxic drugs should be identified, including aminoglycosides and X-ray contrast
media. Glomerular mesangial IgA deposits, accompanied by complement deposition, complicate cirrhosis,
General measures
Since renal dysfunction may be related to hypovolaemia
and since assessment of volume status may be uncertain, diuretics are stopped and intravascular volume is
assessed by measuring central venous pressure (CVP).
A normal or increased CVP indicates that the cause of
renal failure is not volume-related, but this must be
interpreted in relation to diaphragmatic pressure secondary to ascites. Intravascular volume should be
expanded with intravenous albumin at a dose of 1 g/kg
body weight up to a maximum of 100 g [122]. This dose
can be repeated in 12 hours if the serum creatinine has
not normalized, provided that the CVP is less than
10 mmHg. A reduction in serum creatinine indicates that
acute kidney injury is due to prerenal azotaemia.
Ascites 227
Intravenous albumin is preferred over saline solution as
a volume expander.
Potentially nephrotoxic drugs, diuretics and vasodilators are stopped. A search for sepsis is made. Ascites is
tapped for white cell count, Gram stain and culture.
Blood, urine and cannula tips are cultured. A broadspectrum antibiotic is started if infection is suspected.
Renal replacement therapy (mainly continuous arteriovenous and venovenous haemofiltration) should be
started if there is severe volume overload, acidosis or
hyperkalaemia. However, it does not lead to renal recovery, unless liver transplantation occurs. Complications
occur, including arterial hypotension, coagulopathy,
sepsis and gastrointestinal haemorrhage, and many
patients die during this treatment.
Suitability for liver transplantation needs to be rapidly
evaluated as this is the only curative therapy for HRS.
New therapeutic pharmacological approaches may act
as a bridge to liver transplantation by lengthening survival time.
Liver transplantation
Liver transplantation is the only definitive therapy for
HRS, and the only therapy that results in improved
survival. However, it is important to try to reverse HRS
prior to transplantation because lower pretransplantation serum creatinine is associated with improved posttransplantation outcomes [128,129]. Patients with HRS
have longer stays in intensive care units (21 vs. 4.5 days)
and haemodialysis is required more often post-transplant (35 vs. 5%). Since calcineurin inhibitors may con-
tribute to renal deterioration, it has been suggested that
azathioprine and steroids or interleukin 2 receptor
blockers, be given until a diuresis has started—usually
by 48–72 hours [130]. In patients with type 2 HRS, liver
transplantation results in return of acceptable renal
function in 90%, and the overall survival rates are
similar to those without HRS [130].
Pharmacological treatment [120]
Vasodilators. These have been used in an attempt to
reverse renal vasoconstriction. Dopamine at renal
support doses has a renal vasodilatory effect, however
it has no effect in HRS [131]. Prostaglandin administration is not associated with significant improvement in
renal function.
Vasoconstrictors (Table 10.12). The rationale for use of
these agents is to reverse the intense splanchnic and
systemic vasodilatation. Administration of vasoconstrictors (ornipressin, terlipressin, octreotide with midodrine, noradrenaline) for periods greater than 3 days is
associated with significant increases in mean arterial
pressure, decreased serum creatinine and plasma renin
activity as well as an increase in serum sodium
The best evidence supports the use of terlipressin, a
synthetic analogue of vasopressin. It has intrinsic vasoconstrictor effects and in vivo slow conversion to vasopressin, with a longer biological half-life. It has fewer
side effects than ornipressin. Terlipressin is more effective than control therapy in randomized controlled trials
Table 10.12. Vasoconstrictors in HRS: doses used and adverse events
Dose range
Observed adverse events
0.5–2.0 mg i.v. every 4–6 h
Cardiac: arrhythmia, angina, myocardial infarction
GI: abdominal cramps, diarrhoea, nausea, vomiting,
intestinal ischaemia
Peripheral: livedo reticularis, finger ischaemia,
cutaneous necrosis at the infusion site, scrotal
Others: arterial hypertension, dyspnoea,
bronchospasm, respiratory acidosis
0.01–0.8 U/min (continuous intravenous infusion)
None reported although expectedly same as for
0.5–3.0 mg/h (continuous i.v. infusion)
Chest pain with or without ventricular hypokinesia
Octreotide + midodrine
100–200 μg subcutaneously three times a day
7.5–12.5 mg orally three times a day
25 μg → 25 μg/h (continuous intravenous infusion)
2.5 mg/day orally
i.v., intravenous; GI, gastrointestinal.
Chapter 10
[135–138], the largest being a double-blind, placebocontrolled trial [138]. Meta-analysis of these studies
shows that vasoconstrictors are associated with significantly higher HRS-1 reversal rates compared to controls
(46% vs. 11%) and a decreased risk of death, although
mortality is still very high in patients treated with
vasoconstrictors (58 vs. 74% in controls)[139]. Survival
is significantly better in terlipressin ‘responders’.
Terlipressin should be started at a dose 0.5–1 mg i.v.
every 4–6 hours. If there is no early response (>25%
decrease in creatinine levels) after 2 days of therapy, the
dose can be doubled every 2 days up to a maximum of
12 mg/day (i.e. 2 mg i.v. every 4 hours). Treatment can
be stopped if serum creatinine does not decrease by at
least 50% after 7 days at the highest dose, or if there is
no reduction in creatinine after the first 3–4 days. In
patients with early response, treatment should be
extended until reversal of HRS (decrease in creatinine
below 1.5 mg/dL or 130 μmol/L) or for a maximum of
14 days [122]. The dose of vasoconstrictors can be
adjusted by monitoring mean arterial blood pressure
(an indirect indicator of vasodilatation).
Alternative pharmacological approaches have used
intravenous noradrenaline infusion [134] with one small
randomized trial showing it to be equivalent to terlipressin [140], vasopressin infusion [141] or long-term
midrodine (an α-adrenergic agonist) combined with
octreotide (an inhibitor of the release of glucagon) and
intravenous albumin [142]. Randomized trials for the
latter are lacking.
Transjugular intrahepatic portosystemic shunt (TIPS)
Uncontrolled studies have shown that TIPS may
improve renal perfusion and reduce the activity of the
RAAS. In a prospective study of 31 non-transplantable
patients, approximately 75% had improvement in renal
function after TIPS [143]. The 1-year survival was significantly better in type 2 than type 1 patients (70 vs.
20%). This study excluded patients with a Child score
above 12, serum bilirubin above 15 mg/dL (250 μmol/L)
and severe spontaneous encephalopathy. Sequential
treatment with vasoconstrictors and albumin followed
by TIPS also resulted long-term success in some patients
[144]. TIPS can be considered if HRS recurs after discontinuation of successful vasoconstrictor therapy, with
creatinine returning to near normal values, particularly
if transplantation is not likely in the near future and the
patient has refractory ascites [120].
Extracorporeal albumin dialysis
A small randomized trial of the molecular absorbent
recirculating system, has shown benefit for patients
with type 1 HRS syndrome [145]. This modified dialysis
method uses an albumin-containing dialysate. Studies
are ongoing to establish whether it has a role in such
patients as a bridge to transplantation.
New approaches offer hope that HRS syndrome, which
previously had a dismal outlook, may be improved or
reversed. Once the diagnosis of HRS is suspected, specific treatment with vasoconstrictors and intravenous
albumin should be initiated. The best evidence supports
the use of terlipressin, which should be started at a dose
of 0.5 mg i.v. every 6 hours.
The prognosis is poor when ascites develops in a patient
with cirrhosis. While median survival in patients with
compensated cirrhosis is around 9 years [146], once
decompensation occurs, median survival decreases to
1.6–1.8 years [146,147]; with ascites, mortality is about
20% per year [148,149]. An analysis of over 200 patients
with cirrhosis admitted to hospital for the treatment of
ascites showed four variables with independent prognostic value. These were renal water excretion (diuresis
after water load), mean arterial pressure, Child–Pugh
class and serum creatinine [150]. Except for the Child–
Pugh score, which is indicative of a poor liver function,
all other parameters indicate a worsened haemodynamic status (that is, a more vasodilated state) and are
consistent with other studies that have shown that
hyponatraemia and renal dysfunction are predictors of
a poor survival in cirrhosis [97,151,152].
Because of the poor prognosis, liver transplantation
should be considered in all patients with ascites. Early
assessment is needed and a decision taken before the
clinical decline associated with refractory ascites or
hepatorenal syndrome.
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