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THE LANCET

Seminar

Hepatic encephalopathy and ascites

Rajiv Jalan, Peter C Hayes

Hepatic encephalopathy West Haven Criteria for grading mental state in hepatitic
Hepatic encephalopathy (HE) is a neuropsychiatric encephalopathy30
syndrome that occurs only with significant liver Grade 0 No abnormality detected
dysfunction and has a potential for full reversibility. Two Grade 1 Trivial lack of awareness, euphoria, anxiety
distinct forms can be identified in patients with cirrhosis. Shortened attention span
The overt form, which is easy to diagnose, and the Impaired performance in addition or subtraction
subclinical form. The prevalence of subclinical HE in Grade 2 Lethargy, apathy, disorientation for time and
cirrhosis ranges from 30% to 84%; this wide variation is place
due to differences in definition, diagnostic methods, and Obvious personality change
patients studied. Subclinical HE is identified by Inappropriate behaviour
abnormalities in electrophysiological and psychometric Grade 3 Somnolence to semi-stupor, but responsive to
tests. The most clinically useful tests for diagnosis are stimuli
number-connection tests, and digit-symbol and digit- Confusion
copying tests. The role of electroencephalography for Gross disorientation
diagnosis is limited. Because the degree of consciousness Grade 4 Coma
Mental state not testable
is not disturbed, the clinical impact of subclinical HE is
difficult to judge. An association has, however, been
reported with a reduced ability to drive and with poorer Changes in energy metabolism
quality of life.1 Overt HE is associated with asterixis, Patients with HE have decreased cerebral blood flow and
hyper-reflexia, and with slow dominant rhythm on decreased consumption of glucose and oxygen.5 Positron
electroencephalography. Lateralising neurological signs emission tomography scanning has shown correlations
should not be attributed to HE without further between alterations in cerebral blood flow and the
investigations, such as computed tomography scan of the severity of neuropsychological function.6 In animal
brain. Various methods have been described for models, abnormalities in cerebral energy metabolism
estimating the severity of HE, but the most useful one is occur after the onset of coma.7 Extrapolation of this
the West-Haven criteria (panel).2 However, this method model to human beings is difficult, but changes in
has limitations because it is subjective, and has little cerebral blood flow and glucose metabolism may be an
relation to prognosis. A more objective system of epiphenomenon, secondary to a global depression in the
classification is being developed. This seminar will focus function of the central nervous system, rather than the
on recent developments in the pathogenesis of HE and cause of HE. Longitudinal studies are required for further
the principles of management. clarification.

Pathogenesis of HE The role of gut-derived factors


The pathogenesis of HE remains unclear and many Any putative toxin that may be of pathogenetic
mechanisms have been popular at different times. The importance in HE should have the following
most important factors are summarised in figure 1. characteristics: be nitrogenous; originate in the gut; be
produced by the action of gut bacteria or be present in
Alterations in blood-brain barrier the diet; be found in the portal circulation; be
The blood-brain barrier ensures protection of the metabolised in the liver; and be able to cross the blood-
biochemical environment of the brain. Patients with HE brain barrier.8
have a functional derangement in the blood-brain barrier Historically, ammonia has been judged the most
that results in increased transport of neutral aminoacids important factor in the genesis of HE. Concentrations of
and decreased transport of basic aminoacids.3 The ammonia are raised in the systemic circulation and in the
mechanism of this functional disturbance is not clear, cerebrospinal fluid. Ammonia inhibits cellular chloride
although increased concentrations of ammonia and channels, which contributes to depression of the central
methanthiols have been implicated. Studies with nervous system (figure 1). Ammonia was thought to
magnetic-resonance spectroscopy have shown a reduction combine with α-ketoglutarate, thereby depleting the
in choline in the brains in HE. This disturbance in the intermediates of the citric-acid cycle in the central
blood-brain barrier probably provides the mechanism by nervous system. This is unlikely, however, because
which other factors in HE may operate.4 ammonia is metabolised in the brain by combining with
glutamate to form glutamine, but it may affect energy
Lancet 1997; 350: 1309–15 metabolism by disturbing the malate-aspartate shuttle.
Centre for Liver and Digestive Disorders (P C Hayes PhD) and Ammonia facilitates the uptake into the brain of
Department of Medicine (R Jalan MRCP), Royal Infirmary of tryptophan, which is a substrate for the generation of
Edinburgh, Edinburgh EH3 9YW, UK various neuroactive metabolites, including serotonin.
Correspondence to: Dr Rajiv Jalan Ammonia decreases glutamatergic neurotransmission,
(e-mail: rjalan@srv2.med.ed.ac.uk) causing neurodepression. Factors supporting the

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Energy metabolism
Brain

Capillary
Functional disturbance tight junction
of blood-brain barrier
Alteration in neurotransmission
Neuroexcitation Neuroinhibition
Glutamate GABA
Dopamine Endogenous Glutamine synthase
Aspartate benzodiazepines
Glutamate Glutamine
Catecholamines Diazepam binding
inhibitor Inhibition Derangement
Serotonin of chloride of blood-
Taurine channels brain barrier
Opiates NH3
ammonia
Cerebral Alteration
Gut-derived neurotoxins tryptophan in energy
Ammonia metabolism
Mercaptans Portacaval
shunts ␣-ketoglutarate
Phenols Serotonin Tryptamine
Manganese Changes
Short-chain fatty acids Intestine in GABAergic glutamine
Quinolinic acid
BCAA:AAA ratio neurotransmission

Figure 1: Schematic representation of pathogenesis of hepatic encephalopathy


Inset: proposed mechanisms of neurotoxicity of ammonia.

importance of ammonia include the production of a that is seen as hyperintensity of the globus pallidus.3,13 HE
syndrome resembling HE by hyperammonaemia, caused and manganese toxic effects produce similar changes in
by factors unassociated with cirrhosis or portosystemic magnetic-resonance images of the basal ganglia. Increased
shunting (such as urea-cycle enzyme deficiencies); manganese concentrations have been found in the basal
reduction of circulating ammonia concentrations by ganglia of patients with HE, and this finding correlates
treatment with lactulose and antibiotics, which improves strongly with abnormalities on magnetic-resonance
HE; and precipitation of encephalopathy in patients with images and blood manganese concentrations. Manganese
cirrhosis by administration of ammoniagenic substances. concentrations may be raised in patients with cirrhosis
Observations against ammonia as the sole factor in the because of impaired excretion in bile, but the significance
development of HE are: the poor correlation between of these findings is uncertain.14
serum and cerebrospinal-fluid concentrations of ammonia
and the severity of HE; the occurrence of HE despite Changes in cerebral neurotransmission
normal concentrations of ammonia; and the seemingly The normal state of wakefulness is determined by a fine
contradictory effect of ammonia on the function of the balance between the state of excitatory and inhibitory
central nervous system, with low ammonia concentrations neurotransmission.
producing excitation rather than neurodepression.8,9 Glutamate is the most important cerebral excitatory
Studies have focused on the role of ammonia in the neurotransmitter in the brain and its concentration at the
modulation of other neurotransmitter systems such as synaptic level is dependent on the glutamate-glutamine
γ-aminobutyric acid (GABA), benzodiazepines, and cycle, in which glutamate is released by the presynaptic
serotonin.10 neurons; there, the glutamate reacts with the postsynaptic
Although derangements in mercaptans, phenols, and neurons and is inactivated to glutamine in the astrocyte.
fatty acids have been described in HE, there is no In patients with HE, cerebral glutamate is decreased,15,16
consistent evidence that they are of major importance in reuptake mechanisms for glutamate are impaired, and
HE and they possibly work in conjunction with ammonia. down-regulation of glutamate-binding sites on the
Magnetic-resonance spectroscopy studies of the brain in postsynaptic neurons occurs,16 resulting in decreased
patients with HE show a reduction in brain myoinositol neuroexcitation.
and an increase in brain glutamine.11 A good correlation GABA is an important neuroinhibitory
has been found between decreased myoinositol and neurotransmitter, and although it does not cross the
increased glutamine and the severity of HE. blood-brain barrier, GABAergic tone is increased in HE.8
Derangements in plasma aminoacid concentrations in Endogenous benzodiazepine concentrations are raised in
patients with HE include typically a pattern of increased the plasma and cerebrospinal fluid of patients with HE;17
aromatic aminoacids and decreased or normal branched- they may be present in the diet or may be metabolic
chain aminoacids.8,12 products of the microbial flora of the gut.18 Positron
Patients with cirrhosis have a characteristic abnormality emission tomography suggests a diffuse increase in the
on T1-weighted magnetic-resonance imaging of the brain benzodiazepine receptor binding in the brain after

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Aim of treatment Treatment vs lactulose Treatment vs placebo hypokalaemia, hypoxia, use of sedatives, or constipation.
Ammonia hypothesis Second are patients with spontaneous encephalopathy.
Decrease ammoniagenic substrate Management of HE therefore involves the detection
Vegetable protein diet .. ± and treatment of precipitating events, the HE itself, and
Lactulose enema .. +
the underlying liver disease. In patients with spontaneous
Inhibit production of ammonia
Neomycin = NA
HE, measures should be introduced to prevent episodes
Vancomycin =/+ NA of encephalopathy. Treatment efficacy is difficult to
Metronidazole = NA judge, since about half of the patients with HE recover
Lactobacillus = ..
spontaneously. Therefore, large numbers of patients are
Decrease absorption and production of ammonia required to assess the beneficial effect of a new treatment.
Lactulose .. ?
Lactitol = NA Furthermore, many trials compare newer drugs against
Increase removal of ammonia
established treatments, which themselves have not been
Ornithine .. + rigorously tested. A summary of different treatments are
Sodium benzoate = .. described in the table.
GABA hypothesis
Flumazenil .. ± Reduction of ammonia toxicity
False-neurotransmitter hypothesis Management of the precipitating event, restriction of
Branched-chain aminoacids = ±
L-DOPA, bromocriptine mesilate .. –
dietary protein, avoidance of constipation, and
manipulation of the bowel flora are the mainstays of
Other hypotheses
Zinc .. ± therapy.2,23–25 Restriction of dietary protein is effective but
+Significantly better than control regimen; =as good as control regimen; – no effect;
should be used only in the short term to avoid harmful
±unclear data; NA data not available. nutritional consequences. Protein intake in individual
Treatment of overt HE modified from Ferenci and colleagues23 patients requires careful titration. In three studies, a
vegetable diet was shown to be better tolerated than diets
containing animal protein.23 In a further study, this
administration of carbon-11-labelled flumazenil.19
finding was not confirmed, but increasing the fibre
Diazepam-binding inhibitors modulate the activity of
content of the diet seemed to have a favourable effect. In
GABAergic and glutamatergic tone by inducing the glial
practice, lactulose and lactitol are of greatest value in the
cells to produce neurosteroids, which have been
short and long term, and they probably act by ensuring
implicated in the pathogenesis of HE.20 The significance
bowel movement and by affecting bacterial metabolism,
of increased GABAergic tone is unclear, but it may
including production and absorption of ammonia.
contribute to the neurodepression seen in HE.11,13
Brain concentrations of catecholamines are decreased Antibiotics are rarely used. Neomycin is effective for
in animal models of hepatic encephalopathy but such a modifying the bacterial flora but it has serious ototoxicity
decrease has not been proved in human beings. Studies and renal toxicity and should not be used long-term or in
show that dopamine-2 receptors are downregulated in patients with renal dysfunction. Alternative antibiotics,
patients with severe HE and may be the cause of the such as tetracycline, metronidazole, and vancomycin also
derangements in psychomotor function.21 Serotonin have significant long-term toxic effects.23 Newer agents,
concentrations are increased in animal models of HE, such as sodium benzoate26 and ornithine,27 are aimed at
but the concentration of cerebral serotonin receptors is metabolic removal of ammonia. Although both these
debated. The increased cerebral concentrations of agents have been studied in controlled clinical trials and
aromatic aminoacids inhibit tyrosine hydroxylase, thereby been shown to have significant beneficial effects in
generating false neurotransmitters, such as octopamine, patients, further studies are needed before their role in
tyramine, and phenyl ethanolamine, which are believed to clinical practice can be defined.
compete with both catecholamine and dopaminergic
neurotransmission. Although their concentrations are Cerebral neurotransmission
increased in HE, direct injection of octopamine into the Five controlled trials of flumazenil (benzodiazepine
brains of animals did not produce any substantial antagonist) have been done in patients with cirrhosis and
abnormality.22 Decreased aspartate (a neuroexcitator) has varying severity of encephalopathy.23 Flumazenil was
been found in comatose rats, concentrations of taurine (a shown to be superior to placebo in three of the studies. In
neuroinhibitor) are increased in animal models, and the two studies, which included patients with mild HE or
density of opiate receptor (a neuroinhibitor) is increased subclinical HE, no significant improvement was found
in dogs with portacaval shunts.8,15 with flumazenil. Overall, the use of flumazenil in patients
HE seems to be a disorder of multiple neurotransmitter with HE cannot be routinely recommended apart from in
systems, and ammonia has a central role in its patients who have received benzodiazepines, and as part
pathogenesis. of clinical studies.

Principles of management of HE Other approaches


The question of treatment for subclinical HE is unclear Supplementation with branched-chain aminoacids was
and, therefore, we limit our discussion to management of aimed at testing the false-neurotransmitter hypothesis. Of
overt HE. Patients with HE fall into two groups. First are nine controlled trials, only three have shown a beneficial
those patients who have episodes of encephalopathy and effect of administration of branched-chain aminoacids.
are well between attacks. Encephalopathy is generally This effect seems to be greatest in patients with HE who
preceded by a precipitating event, such as dietary- are severely intolerant of protein, and no beneficial effects
protein loading, gastrointestinal bleeding, exacerbation of were seen in patients who were protein tolerant.23,28
the underlying liver disease, sepsis, dehydration, Orthotopic liver transplantation is the only treatment that

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Refractory ascites is defined as ascites that cannot


Cirrhosis be mobilised, or early recurrence (after therapeutic
paracentesis) that cannot be prevented by medical
Impaired liver function
therapy. This term includes diuretic-resistant ascites,
Portal hypertension
in which there is a lack of response to dietary
sodium restriction and intensive diuretic treatment, and
Portal systemic shunt diuretic-intractable ascites, in which diuretic-induced
complications develop that preclude the use of an
effective diuretic regimen.29 The hepatorenal syndrome
Vasodilators can be classified into two types. Type 1 is characterised
Nitric oxide, glucagon, prostacyclin, activation of K+ channels,
Cytokines, endotoxaemia, adenosine
by rapidly progressive reduction of renal function,
defined by a doubling of the initial serum creatinine to a
concentration greater than 250 µmol/L or a 50%
Peripheral and splanchnic vasodilatation
reduction of the initial 24 h creatinine clearance to less
than 20 mL/min in less than 2 weeks. In type 2, renal
effective blood volume failure has a less rapidly progressive course.29 The kidneys
are histologically normal in hepatorenal syndrome.
Volume receptors

Pathogenesis of ascites
The pathogenesis of renal dysfunction in cirrhosis is
Neural factors Humoural factors Intrarenal factors controversial and not completely understood (figure 2).
sympathetic renin endothelin
nervous activity aldosterone urinary kallikrein Patients with cirrhosis have characteristic circulatory
Role of hepatorenal angiotensin II Changes in abnormalities, which manifest as increased cardiac
reflex antidiuretic prostaglandins output, arterial hypotension, decreased peripheral
hormone thromboxane E2 vascular resistance, and splanchnic vasodilatation. The
refractoriness to leukotrienes
atrial natriuretic platelet activating pathogenesis of these circulatory abnormalities is not
factor factor clear but possible causes include portosystemic shunting,
adenosine or impaired clearance of vasodilators such as nitric oxide,
endotoxins, prostacyclin, glucagon, and adenosine. These
vasodilators lead to peripheral and splanchnic
Tubular sodium retention
vasodilation, which is perceived as a reduction in
and reduced renal blood flow
“effective” plasma volume. Neurohumoral factors are
activated in an attempt to maintain arterial pressure.
Figure 2: Schematic representation of factors involved in These changes in the neurohumoral systems and
initiation and maintainence of sodium retention in patients activation of intrarenal factors lead to the renal
with cirrhosis dysfunction of cirrhosis.30 In addition, the severity of
hepatic dysfunction seems to be directly related to the
reverses the mental disorder permanently by correcting onset of renal manifestations, which supports the
the poor liver function and the portacaval shunting. Other argument for an interaction between the liver and the
treatments currently under investigation include drugs kidneys that has been postulated to be neural or
aimed at serotonin, opiate, melatonin, and zinc biochemical in nature.31,32 Abnormal Starling’s forces in
metabolism. the abdomen result in the localisation of fluid in this area.
Patients with cirrhosis and portal hypertension manifest
Summary renal dysfunction with sodium retention, water retention,
HE is a complex metabolic disorder that may result from and hepatorenal syndrome. These manifestations may
regional rather than global effects in the brain. No single either present de novo or appear step wise.
mediator has been found to account for the syndrome,
and HE may result from the effect of several interacting Retention of sodium
mediators. Further research should be directed at There is substantial evidence for increased activity
developing newer radioligands for positron emission of the renin-angiotensin-aldosterone system.33,34 High
tomography and increasing the sensitivity of the concentrations of aldosterone, plasma renin activity, and
magnetic-resonance spectroscopy, which will provide a angiotensin II have been found in patients with cirrhosis;
better understanding of the biochemical and metabolic the raised concentrations are probably due to increased
changes directly. Effective therapy will emerge only once production rather than decreased metabolism of these
the pathogenesis of this syndrome is fully understood. substances by the liver. Plasma renin activity is inversely
related to sodium excretion and to renal blood flow.
Ascites Concentrations of angiotensin II are also notably higher
The kidney is central to the development of ascites. in patients with cirrhosis who also have ascites than in
Ascites in patients with cirrhosis is a major cause of those without.35 Atrial natriuretic factor is a powerful
morbidity and is a serious prognostic development. vasodilator and its role in sodium retention is
Cirrhosis has a spectrum of renal abnormalities. In its controversial. Concentrations of the hormone are raised
mildest form, patients retain sodium and develop in patients with cirrhosis, but its effects are not
diuretic-responsive ascites, which may progress to pronounced because of raised renal refractoriness. This
diuretic-refractory ascites. The most severe abnormality is refractoriness may enhance the action of vasopressors.36
hepatorenal syndrome. Several studies have shown that plasma norepinephrine

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not clearly establish a role for


Tense Peritoneovenous shunt Orthotopic renal prostaglandins, the
Controlled liver
ascites relative deficiency of renal
TIPSS transplant prostaglandins may contribute
Total Refractory to the pathogenesis of water
Therapeutic retention.47 Findings on the
paracentesis ascites
paracentesis
programme Consider role of the sympathetic system
Poor control TIPSS in causing water retention are
Sodium restricted Terlipressin not entirely clear. Studies have
diet and diuretics Poor Total
control paracentesis shown that there is an inverse
Exclude and treat relation between the plasma
Controlled Hepatorenal
Moderate failure precipitating factors concentrations of norepine-
ascites General supportive phrine and free water
measures clearance, but mechanisms
Reassess compliance
that decrease sympathetic
Deterioration in liver function?
Exclude spontaneous bacterial peritonitis stimulation show no relation
Increase diuretics between changes in free
water clearance and plasma
Figure 3: An approach to management of ascites in patients with cirrhosis norepinephrine.48
TIPSS=transjugular intrahepatic portosystemic stent-shunt.

concentrations are raised in patients with cirrhosis who Hepatorenal syndrome


have ascites because of increased production rather than The hepatorenal syndrome is characterised by severe
reduced clearance.37 Renal blood flow is inversely related renal hypoperfusion due to an increase in renal vascular
to norepinephrine concentrations. These findings suggest resistance. The syndrome develops in the presence of
that the activity of the sympathetic nervous system is decompensated liver disease, poorly controlled ascites,
increased and plays a significant part in sodium retention and after substantial alterations in splanchnic and
in cirrhosis.38 Urinary kallikrein excretion in patients with systemic haemodynamics. In some patients, hepatorenal
cirrhosis and ascites deteriorates in parallel with syndrome may be precipitated by gastrointestinal
glomerular filtration rate. Infusion of aprotinin (kallikrein bleeding, sepsis, use of non-steroidal or nephrotoxic
inhibitor) gives a pronounced improvement in renal blood agents, hypovolaemia, progressive liver failure, or
flow, glomerular filtration rate, and sodium excretion.39 excessive use of diuretics.48 The pathogenesis of
The role of prostaglandins in the renal dysfunction of hepatorenal syndrome is multifactorial. The sympathetic
cirrhosis is not clear. Urinary excretion of prostaglandin nervous system becomes highly activated, which
metabolites is increased when ascites is present but produces renal vasoconstriction and reduction in renal
decreased in some patients with hepatorenal syndrome.40 plasma flow.49 Poor liver function and altered
Cyclo-oxygenase inhibitors, such as non-steroidal anti- splanchnic haemodynamics further contribute to renal
inflammatory drugs, increase renal vascular resistance and vasoconstriction through the hepatorenal axis. The renin-
decrease glomerular filtration rate in patients without angiotensin-aldosterone system is stimulated in cirrhosis
ascites. These agents can produce oliguric renal failure in and produces afferent arteriolar vasoconstriction.32,50
patients with ascites.41 Endothelin is the most potent Further renal vasoconstriction is produced by increased
naturally occurring vasoconstrictor substance. Raised endothelin-1 concentrations, which correlate with the
concentrations of endothelin-1 have been found in severity of renal dysfunction. Renal prostaglandins
patients with ascites. The concentration does not change generally compensate for the vasoconstriction induced by
with volume expansion or tilting, and no correlation with the various vasopressors.51 In hepatorenal syndrome, this
endotoxaemia has been found. The exact physiological compensatory mechanism fails to maintain renal
role of this raised concentration is not clear.42,43 perfusion. Patients with hepatorenal syndrome have
decreased mean arterial pressure, which is a risk factor for
Retention of water the syndrome’s development.52 In normal circumstances,
Hyponatraemia is the biochemical expression of a the renal blood flow is autoregulated, but in patients
reduction in water excretion. In patients with cirrhosis, with hepatorenal syndrome who have an activated
hyponatraemia may occur because of diuretic treatment neurohumoral system, the autoregulatory curve (renal
or spontaneously. The former is diagnosed by low central blood flow and renal perfusion pressure) is shifted to the
filling pressures. Patients with cirrhosis have an inverse right.53 This shift means that a small reduction in the
relation between the concentrations of antidiuretic arterial pressure produces pronounced reduction in renal
hormone and glomerular filtration rate. The use of a κ blood flow.
opioid-receptor agonist, RU51599, which inhibits
antidiuretic-hormone secretion, increases free water Principles of management of ascites
clearance.44 Similarly, demeclocycline, an antidiuretic- Ascites is a common complication of cirrhosis and occurs
hormone antagonist, improves free water clearance.45 within 10 years of diagnosis in about 50% of patients. Of
Patients with ascites and cirrhosis have low glomerular the patients who have ascites, 18% develop hepatorenal
filtration rate, which may decrease the delivery of filtrate syndrome at 1 year, and 39% at 5 years.52 Patients may
to the diluting segments, thereby lessening water present with moderate ascites, tense ascites, refractory
clearance.46 Increase of the distal delivery of filtrate ascites, hyponatraemia, or with hepatorenal syndrome.
by plasma-volume expansion improves free water Restriction of dietary sodium to 80 mmol/day and use
generation. Renal prostaglandins increase free water of diuretics are the most important treatments for ascites.
generation by many mechanisms. Although the data do When ascites is diagnosed, patients should be admitted to

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hospital to establish the underlying diagnosis, to exclude The presence of hyponatraemia in a patient with
spontaneous bacterial peritonitis, and to educate the ascites denotes a dilutional state and impaired water
patient about diet, which is the mainstay of treatment. In excretion. Therefore, the most important treatment is
patients with moderate ascites, a combination of water restriction. However, to rule out the effect of
spironolactone and furosemide plus dietary sodium overdiuresis and concomitant use of nephrotoxic drugs,
restriction is the most effective regimen for controlling central venous filling pressure should be measured and a
ascites, and decreasing the number of admissions to meticulous history taken. Although demeclocyline has
hospital and hypokalaemia. Patients should be monitored been suggested by some investigators, this treatment
by bodyweight, and the dose of the diuretics adjusted to should be avoided in patients with cirrhosis because of the
produce a weight loss of 1 kg/day in patients with ascites risk of precipitating renal failure.45 Some patients may
and peripheral oedema, and 500 g in patients with ascites benefit from plasma-volume expansion, which acts by
alone. Total paracentesis with infusion of a solution of increasing the delivery of fluid to the diluting segments of
human albumin (8 g/L of ascites drained) is the kidney.59
recommended for patients who present with tense ascites. The death rate among patients with hepatorenal
After discharge from hospital, patients should remain on syndrome and endstage cirrhosis is almost 100%.52
such dietary sodium restriction and diuretic therapy. Management of hepatorenal syndrome is largely
The options for the management of refractory supportive, and care must be taken to avoid potential
ascites are total paracentesis, peritoneovenous shunt, precipitating factors such as hypovolaemia, drugs, and
transjugular intrahepatic portosystemic stent-shunt sepsis. Although TIPSS may improve renal function,60 it
(TIPSS), and orthotopic liver transplantation. The most has not been shown to reduce mortality and can at
important advance in the management of refractory present be used as no more than a bridging treatment
ascites has been the reintroduction of large-volume before orthotopic liver transplantation, which is the only
paracentesis. This treatment is safe and effective as long treatment that decreases mortality in patients with
as adequate plasma-volume expansion with a solution of refractory ascites and hepatorenal syndrome.61,62
human albumin is provided.54 A cheaper alternative is to
use synthetic gelatins, which are effective but may be Summary
followed by slight circulatory disturbances.55 Insertion of The first abnormality leading to sodium and water
TIPSS decreases portal pressure, and some authorities retention in cirrhosis is the renal tubular defect that
suggest that this is useful in the treatment of refractory is related to deteriorating liver function and
ascites.56 A randomised trial comparing TIPSS with hyperaldosteronism. With progression of liver disease and
paracentesis showed lower survival among patients portal hypertension, renal blood flow declines because of
treated with TIPSS.57 At present, TIPSS should be used the hepatorenal reflex, and is then maintained by the
for refractory ascites only as a part of randomised trials. vasoactive hormonal systems. With increasing peripheral
Peritoneovenous shunts are based on the principle of a vasodilatation, intrarenal factors for maintenance of renal
pressure difference between the intra-abdominal pressure perfusion cause intense cortical vasoconstriction.
and the superior vena cava in the thorax. A randomised The systemic vasoactive factors are predominantly
study showed that paracentesis was as effective as compensatory; any attempts to counteract their action
peritoneovenous shunt in relieving refractory ascites, but risk circulatory collapse. Future studies should be
the shunts were associated with better long-term control directed at intrarenal factors. The ideal drug for the
of ascites; shunt occlusion was common (50%) and there treatment of portal hypertension would reduce portal
were no significant differences in survival between the pressure, increase renal blood flow, and produce
groups (50% at 1 year).58 Patients with refractory ascites insignificant changes in arterial pressure.
who are otherwise good candidates for transplantation
should undergo liver transplantation, since this treatment Acknowledgments
improves survival. We thank N D C Finlayson and I A D Bouchier for helpful advice.

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