Hindawi Publishing Corporation
Journal of Nutrition and Metabolism
Volume 2010, Article ID 489823, 12 pages
Role of Nutrition in the Management of Hepatic Encephalopathy
in End-Stage Liver Failure
emeur,1, 2 Paul Desjardins,1and Roger F. Butterworth1
1Neuroscience Research Unit, CHUM, Saint-Luc Hospital, University of Montreal, 1058 St-Denis Street, Montreal, QC, Canada
2Department of Nutrition, University of Montreal, Montreal, QC, Canada
Correspondence should be addressed to Roger F. Butterworth, email@example.com
Received 9 July 2010; Accepted 11 November 2010
Academic Editor: Linda J. Wykes
Copyright © 2010 Chantal B´
emeur et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Malnutrition is common in patients with end-stage liver failure and hepatic encephalopathy, and is considered a signiﬁcant
prognostic factor aﬀecting quality of life, outcome, and survival. The liver plays a crucial role in the regulation of nutrition
by traﬃcking the metabolism of nutrients, their distribution and appropriate use by the body. Nutritional consequences with
the potential to cause nervous system dysfunction occur in liver failure, and many factors contribute to malnutrition in hepatic
failure. Among them are inadequate dietary intake, malabsorption, increased protein losses, hypermetabolism, insulin resistance,
gastrointestinal bleeding, ascites, inﬂammation/infection, and hyponatremia. Patients at risk of malnutrition are relatively diﬃcult
to identify since liver disease may interfere with biomarkers of malnutrition. The supplementation of the diet with amino acids,
antioxidants, vitamins as well as probiotics in addition to meeting energy and protein requirements may improve nutritional
status, liver function, and hepatic encephalopathy in patients with end-stage liver failure.
Malnutrition is a common complication of end-stage liver
failure (cirrhosis) and is an important prognostic indicator
of clinical outcome (survival rate, length of hospital stay,
posttransplantation morbidity, and quality of life) in patients
with cirrhosis. Several studies have evaluated nutritional
status in patients with liver cirrhosis of diﬀerent etiologies
and varying degrees of liver insuﬃciency [1,2] leading to a
consensus of opinion that malnutrition is recognizable in all
forms of cirrhosis  and that the prevalence of malnutrition
in cirrhosis has been estimated to range from 65%–100%
[4,5]. The causes of malnutrition in liver disease are complex
The present paper reviews the role of nutrition in relation
to the management of hepatic encephalopathy (HE), a major
neuropsychiatric complication of end-stage liver failure.
Nutritional consequences of liver failure with the potential
to cause central nervous system dysfunction are reviewed.
In particular, the roles of dietary protein (animal versus
vegetable), branched-chain amino acids, dietary ﬁbre, probi-
otics, vitamins and antioxidants, minerals (zinc, magnesium)
as well as L-carnitine in relation to HE are discussed. An
update of the impact of nutritional supplementation on the
management of HE is included.
2. Malnutrition in Liver Disease
The functional integrity of the liver is essential for nutrient
supply (carbohydrates, fat, and proteins), and the liver plays a
fundamental role in intermediary metabolism. For example,
the liver regulates the synthesis, storage, and breakdown
of glycogen, and hepatocytes express enzymes that enable
them to synthesize glucose from various precursors such
as amino acids, pyruvate, and lactate (gluconeogenesis). In
addition, the liver is a major site of fatty acid breakdown
and triglyceride synthesis. The breakdown of fatty acids
provides an alternative source of energy when glucose is
limited during, for example, fasting or starvation. The liver
also plays a crucial role in the synthesis and degradation
of protein. Protein synthesis by the liver is inﬂuenced by
the nutritional state, as well as by hormones and alco-
Tab le 1: Metabolic alterations leading to malnutrition in end-stage liver failure.
Protein Carbohydrate Fat
(i) Increased catabolism
(ii) Increased utilization of BCAAs
(iii) Decreased ureagenesis
(i) Decreased hepatic and skeletal muscle
(ii) Increased gluconeogenesis
(iii) Glucose intolerance and insulin
(i) Increased lipolysis
(ii) Enhanced turnover and oxidation of fatty acids
(iii) Increased Ketogenesis
by traﬃcking the metabolism of nutrients, and many factors
disrupt this metabolic balance in end-stage liver failure.
Consequently, when the liver fails, numerous nutritional
problems occur (Table 1). Several factors contribute to
malnutrition in liver failure including inadequate dietary
intake of nutrients, reduction in their synthesis or absorption
(diminished protein synthesis, malabsorption), increased
protein loss, disturbances in substrate utilization, a hyperme-
tabolic state as well as increased energy-protein expenditure
and requirements. Because of decreased glycogen stores and
gluconeogenesis , energy metabolism may shift from
carbohydrate to fat oxidation  while insulin resistance may
also develop. Consequently, liver cirrhosis frequently results
in a catabolic state resulting in a lack of essential nutrients.
It has been estimated that at least 25% of patients with
liver cirrhosis experience HE during the natural history of
the disease. HE is more frequent in patients with more
severe liver insuﬃciency and in those with spontaneous
or surgically created portal-systemic shunts. Whether or
not malnourished patients are more prone to develop HE
has not been clearly established, but could be anticipated
based on several factors. Firstly, malnutrition tends to be
more common in patients with advanced liver disease,
and HE is more likely in this group. Secondly, nutri-
tional deﬁcits such as decreased lean body mass (muscle
is important in ammonia uptake) and hypoalbuminemia
(which increases free tryptophan levels) could promote HE
3. Factors Contributing to
Malnutrition in Cirrhosis
A range of factors are known to contribute to malnutrition
in cirrhosis. These factors include (Figure 1) the following.
3.1. Inadequate Dietary Intake. Cirrhotic patients may unin-
tentionally consume a low energy diet, an observation that
is attributed to several factors including loss of appetite ,
anorexia, nausea, vomiting, early satiety, taste abnormalities,
poor palatability of diets, reﬂux disease [10,11], and
impaired expansion capacity of the stomach .
3.2. Inadequate Synthesis or Absorption of Nutrients. The
cirrhotic liver may inadequately synthesize proteins and has
diminished storage capacity and an impaired enterohepatic
cycle. In addition, portal hypertensive enteropathy may lead
to impaired absorption of essential nutrients. Moreover,
pancreatic insuﬃciency, cholestasis, and drug-related diar-
rhea may all contribute to malabsorption in liver disease.
3.3. Increased Protein Losses. Loss of proteins and minerals
may result from complications of cirrhosis or from iatrogenic
interventions such as the use of diuretics for the treatment
lactulose for the management of HE. Other potentially
important causes of increased protein losses are blood loss
from oesophageal and gastric varices and from the intestinal
lumen due to ulcers or portal enteropathy.
3.4. Hypermetabolic State/Increased Energy-Protein Expen-
diture and Requirements. The hyperdynamic circulation in
cirrhosis leads to systemic vasodilation and an expanded
intravascular blood volume. As a direct eﬀect, a higher
cardiac blood volume and therefore a greater use of macro-
and micronutrients is a common cause of high energy
expenditure and demand. Furthermore, the inability of the
damaged liver to adequately clear activated proinﬂammatory
mediators such as cytokines may promote the development
of an inﬂammatory response with an increase in both
energy expenditure and protein catabolism . It has been
suggested that elevated pro- and anti-inﬂammatory cytokine
levels have the potential to result in hypermetabolism in
3.5. Insulin Resistance. Insulin resistance and diabetes mel-
litus are common in patients with liver cirrhosis [15,16].
Hyperinsulinemia and hyperglucagonemia are frequently
present in cirrhotic patients where glucagon is dispropor-
tionately increased resulting in an elevated glucagon/insulin
ratio. There is also impairment of glucose homeostasis due
to hepatic insulin resistance characterized by altered gluco-
neogenesis, low glycogen stores, and impaired glycogenolysis
3.6. Gastrointestinal Bleeding. Bleeding esophageal varices as
a consequence of portal hypertension are frequent and severe
complications of liver cirrhosis. Gastrointestinal bleeding
is also a precipitating factor in HE and may accelerate
progression of malnutrition in cirrhotic patients.
3.7. Ascites. Impaired expansion capacity of the stomach
due to the presence of clinically evident ascites may lead
to an inadequate intake of nutrients , and cirrhotic
patients with ascites often report early satiety and subsequent
decreased oral intake which may result in signiﬁcant weight
Figure 1: Factors contributing to malnutrition in end-stage liver failure.
3.8. Inﬂammation/Infection. Malnourished patients with cir-
rhosis are prone to the development of inﬂammation and
sepsis and their survival may be further shortened by these
complications. There is a signiﬁcant negative correlation
between plasma levels of proinﬂammatory cytokines such
as tumor necrosis factor-alpha (TNF-α) and nutrient intake
. In order to reduce intestinal bacterial translocation and
to improve gut immune function, it has been proposed that
pre- and probiotics be added to the diet .
3.9. Hyponatremia. Hyponatremia is a common complica-
tion of patients with advanced liver disease  and is
an important predictor of short-term mortality. Hypona-
tremia is also an important pathogenic factor in patients
with HE. Cirrhotic patients have abnormal sodium and
water handling that may lead to refractory ascites. These
patients retain sodium, and dilutional hyponatremia may
develop, characterized by reduced serum sodium. In such
situations, saline infusion should be avoided and it has
been suggested that sodium intake should not exceed 2g
4. Assessment of Nutritional Status in
End-Stage Liver Failure
The nutritional assessment of the cirrhotic patient begins
with the dietary history that should focus on nutritional
intake and assessment of recent weight loss. However, altered
mental status may preclude obtaining a meaningful history,
and interviewing family members may be helpful.
Liver disease may interfere with biomarkers of mal-
nutrition such as albumin, making it diﬃcult to identify
subjects at risk of malnutrition and to evaluate the need
for nutritional intervention. Furthermore, anthropometric
and bioelectrical impedance analysis may be biased by
the presence of edema or ascites associated with liver
failure. Body mass index (BMI), an index of nutritional
status, may also be overvalued in patients with edema and
ascites. Careful interpretation of nutritional data using these
techniques in the presence of these complications is therefore
Generally accepted methods for assessing the clinical
status and severity of disease in cirrhotic patients are the
Child-Pugh-Turcotte classiﬁcation  and the model for
end-stage liver disease (MELD) [23,24]. Unfortunately, these
systems do not include an assessment of nutritional status in
spite of the fact that malnutrition plays an important role
in morbidity and mortality in end-stage liver failure. The
omission of nutritional assessment results no doubt from
the heterogeneous nature of the nutritional deﬁcits in this
Subjective Global Assessment (SGA) and anthropometric
parameters are the methods that are frequently used to
evaluate nutritional status in end-stage liver failure .
SGA collects clinical information through history-taking,
physical examination, and recent weight change and is
considered to be reliable since it is minimally aﬀected
by ﬂuid retention or the presence of ascites. The use of
anthropometric parameters which are not aﬀected by the
presence of ascites or peripheral edema has also been
recommended [22,25]. Such parameters include mid-arm
muscle circumference (MAMC), mid-arm circumference
(MAC), and triceps skin fold thickness (TST). Diagnosis
of malnutrition is established by values of MAMC and/or
TST below the 5th percentile in patients aged 18–74 years,
or the 10th percentile in patients aged over 74 years
BMI changes may aﬀord a reliable indicator of mal-
nutrition using diﬀerent BMI cutoﬀvalues depending on
the presence and severity of ascites ; patients with
a BMI below 22 with no ascites, below 23 with mild
ascites, or below 25 with tense ascites are considered to be
malnourished. Hand-grip examination by dynamometer has
also been proposed as a simple method to detect patients
at risk for the development of malnutrition . In an
interesting new development, Morgan et al.  validated
a method where BMI and MAMC are combined with
details of dietary intake in a semistructured algorithmic
construct to provide a method for nutritional assessment
in patients with end-stage liver failure . Despite these
advances, a standardized simple and accurate method
for evaluating malnutrition in cirrhosis remains to be
5. Consequences of Cirrhosis with
a Potential to Impact upon Nutritional
Status and Brain Function
Cirrhosis results in multiple metabolic abnormalities and
alterations in the synthesis, turnover, and elimination of a
range of metal and micronutrients with the potential to alter
nutritional status and consequently cerebral function. Such
alterations include the following.
5.1. Hyperammonemia. Under normal physiological condi-
tions, ammonia is metabolized by the liver, brain, muscle,
and kidney (Figure 2). In well-nourished cirrhotic patients,
the aﬀected liver has an impaired capacity for removal
of ammonia in the form of urea, which may result in
increased muscle glutamine synthetase in order to provide an
alternative mechanism for ammonia removal as glutamine.
Glutamine synthesis also increases to some extent in the
brain of these patients. HE may develop as a consequence
of increased circulating and cerebral ammonia in well-
nourished cirrhotic patients. On the other hand, in malnour-
ished cirrhotic patients, the loss of muscle mass, commonly
seen as a consequence of malnutrition, can adversely aﬀect
this alternative route of ammonia removal. The brain being
the main organ metabolizing ammonia in these conditions,
severe HE is commonly diagnosed in malnourished cirrhotic
Hyperammonemia may lead to increased uptake of tryp-
tophan by the brain which may lead to increased synthesis
and release of serotonin and anorexia. This symptom may
render the patient prone to chronic catabolism and malnu-
trition, and in turn to increased ammonia load, resulting
in a vicious cycle [29,30]. In addition, hyperammonemia
may be more prominent after gastrointestinal bleeding
due to the absence of isoleucine . Since haemoglobin
molecule lacks the essential amino acid isoleucine, gastroin-
testinal bleed may stimulate the induction of net catabolism
5.2. Zinc. Zinc is an essential trace element that plays an
important role in the regulation of protein and nitrogen
metabolism as well as in antioxidant defense. Reduced
zinc content is common in cirrhotic patients, but zinc
deﬁciency cannot be eﬀectively diagnosed based upon serum
concentrations since zinc is bound to albumin, which
is also decreased in these patients [33,34]. Among the
mechanisms contributing to zinc deﬁciency, poor dietary
intake , reduced intestinal absorption , reduced
hepatointestinal extraction , portal-systemic shunting,
and altered protein and amino acid metabolism have all been
implicated . Zinc deﬁciency may impair the activity of
enzymes of the urea cycle as well as glutamine synthetase
[39,40], and decreased activity of these enzymes has the
potential to lead to further increases in circulating and brain
ammonia with the potential to cause worsening of HE.
Not surprisingly, therefore, an inverse relationship between
serum zinc and ammonia concentrations has been described
[41,42]. Zinc deﬁciency has been implicated in multiple
complications of cirrhosis, including poor appetite, immune
Figure 2: Inter-organ traﬃcking of ammonia in normal physio-
logical conditions, in well-nourished patients with end-stage liver
failure compared to malnourished end-stage liver failure patients.
dysfunction, altered taste and smell, anorexia as well as
altered protein metabolism [43,44]. Surprisingly, in spite of
evidence of hypozincemia in cirrhosis, zinc supplementation
in the treatment of HE based on a small number of
controlled trials has so far provided inconsistent results, a
ﬁnding that may be attributable to variations in the nature
and doses of zinc salts used and to duration of therapy
5.3. Selenium. Decreased levels of selenium have been
reported in cirrhotic patients [46,47]. However, the relation-
ship of diminished selenium to the pathogenesis of cirrhosis
and its complications, including HE, has not been clearly
5.4. Manganese. In cirrhotic patients, the elimination of
manganese is decreased secondary to impaired hepatobiliary
function and portal-systemic shunting, which result in
increased blood manganese levels and increased manganese
deposition in basal ganglia structures of the brain, in
particular in globus pallidus [48–52]. Manganese has also
been correlated to increased brain glutamine levels and
changes in dopamine metabolism [49,54] and may be related
to other alterations in cirrhotic patients with HE, such as
the characteristic astrocytic morphologic changes . Toxic
eﬀects of manganese on central nervous system could be
mediated by eﬀects on the glycolytic enzyme glyceraldehyde-
3-phosphate dehydrogenase (GAPDH) . It was also
suggested that manganese-induced increases of “peripheral-
type” benzodiazepine receptors (PTBRs) could contribute to
the pathogenesis of HE .
5.5. L-Carnitine. The liver is a major site for the production
of ketone bodies from the oxidation of fatty acids. Fatty
acids cannot penetrate the inner mitochondrial matrix and
cross the mitochondrial membrane to undergo oxidation
unless they are transported by a carrier process involving L-
carnitine (3-hydroxy-4-trimethylammoniobutanoate). Car-
nitine is a cofactor for mitochondrial oxidation of fatty acids
and prevents the body from using fats for energy production
particularly during starvation. Carnitine deﬁciency may
result in lethargy, somnolence, confusion, and encephalopa-
thy. Studies of carnitine status in cirrhotic patients have
yielded conﬂicting results; the source of this lack of con-
sensus likely results from both the etiology of cirrhosis and
the severity of liver disease. For example, Rudman et al. 
reported reduced plasma and tissue carnitine concentrations
in patients with alcoholic cirrhosis complicated by cachexia,
whereas later studies by Fuller and Hoppel [59,60]reported
an increase of plasma carnitine in alcoholics with or without
cirrhosis. De Sousa et al. reportednosuchchanges
in a similar patient population. In a subsequent study by
Amodio et al. , plasma carnitine levels were measured
in cirrhotic patients and the relationship to nutritional
status and severity of liver damage was assessed. Plasma
carnitine levels did not diﬀer between Child-Pugh class A, B,
and C patients. Signiﬁcantly higher levels of acetylcarnitine,
short chain acylcarnitine, total esteriﬁed carnitine, and total
carnitine were observed in cirrhotic patients independent
of etiology of cirrhosis. The issue of carnitine in relation
to liver disease was re-evaluated in 1997 by Kr¨
and Reichen  who studied carnitine metabolism in
29 patients with chronic liver disease of varying degrees
of severity and various etiologies. Patients with alcoholic
cirrhosis manifested increased total plasma carnitine levels
with a close correlation to serum bilirubin. Urinary carnitine
excretion was not diﬀerent between cirrhotic patients and
controls with the exception of patients with primary biliary
cirrhosis. It was concluded that patients with cirrhosis are
not normally carnitine deﬁcient and that patients with
alcohol-induced cirrhosis manifest hypercarnitinemia which
results primarily from increased carnitine synthesis due to
increased skeletal muscle protein turnover .
5.6. Vitamin B1(Thiamine). Wernicke’s Encephalopathy
caused by vitamin B1deﬁciency and characterized by a
triad of neurological symptoms (ophthalmoplegia, ataxia,
global confusional state) is common in cirrhotic patients.
In a retrospective neuropathological study of sections from
patients with end-stage liver failure who died in hep-
atic coma, 64% were found to manifest thalamic lesions
typical of Wernicke’s Encephalopathy . None of the
cases of Wernicke’s Encephalopathy had been suspected
based upon clinical symptoms during life, a ﬁnding
which draws into question the classical textbook deﬁnition
based upon symptomatology associated with the disorder
Causes of vitamin B1deﬁciency in cirrhosis include
reduced dietary intake, impaired absorption, and loss of hep-
atic stores of the vitamin. Alcoholic cirrhotic patients man-
ifest increased incidence of vitamin B1deﬁciency compared
to nonalcoholic cirrhotics . Moreover, ethanol is known
to impair both intestinal absorption of vitamin B1and
to impair the transformation of the vitamin into its active
(diphosphorylated) form . It has been suggested that
common pathophysiologic mechanisms exist in Wernicke’s
and hepatic encephalopathies, related to deﬁcits of vitamin
B1-dependent enzymes . Vitamin B1supplementation is
highly recommended in patients with end-stage liver failure
of either alcoholic or nonalcoholic etiologies.
6. Nutrition, HE, and Liver Transplantation
HE in end-stage liver failure may contribute to malnutrition
in the pretransplant period as a consequence of diminished
food uptake . Alterations in markers of nutritional
status such as serum albumin are signiﬁcant risk factors
for both surgical  and postsurgical  complications
of liver transplantation. Moreover, it has been suggested
that nonabsorbable disaccharides (such as lactulose) admin-
istered for the management of HE may result in intesti-
nal malabsorption in patients with end-stage liver failure
with the potential to result in poor transplant outcome
The negative impact of malnutrition on liver trans-
plantation had been reported in early retrospective studies
. Both preoperative hypermetabolism and body cell mass
depletion proved to be of prognostic value for transplanta-
tion outcome . Malnutrition is known to lead to glycogen
depletion, and this has been suggested to increase the plasma
lactate:pyruvate ratio during the anhepatic phase and to
induce an exacerbated proinﬂammatory cytokine response,
thereby favouring the development of postoperative systemic
inﬂammatory response syndrome and multiorgan failure in
these patients . To date, there are still insuﬃcient data
in the pretransplant period upon which to base speciﬁc
recommendations. In the posttransplant period, nutritional
therapy improves nitrogen balance, decreases viral infection,
and shows a trend to shortened intensive care unit stays with
lowering of hospitalisation costs [77,78].
7. Nutritional Recommendations for HE in
End-Stage Liver Failure (Table 2)
7.1. General Considerations. Considering the high prevalence
of malnutrition in cirrhotic patients together with the lack of
simple and accurate methods of assessment of malnutrition
in this patient population, it is reasonable to assume that
malnutrition occurs in all patients. Nutritional requirements
may vary according to the speciﬁc clinical situation. Multiple
(5-6) small feedings with a carbohydrate-rich evening snack
have been recommended with complex rather than simple
carbohydrates used for calories. Lipids could provide 20%–
40% of caloric needs. Long-term nutritional supplements
may be necessary to provide recommended caloric and
protein requirements. Additional studies are needed in order
to formulate speciﬁc recommendations for nutrients such as
zinc, selenium, and carnitine.
7.2. Energy Requirements. The primary goal for a patient
suﬀering from end-stage liver failure should be to avoid by
all means possible intentional or unintentional weight loss
and sustain a diet rich in nutrients. It has been suggested that
patients with liver cirrhosis should receive 35–40 kcal/kg per
7.3. Low Protein Diet to Be Avoided. Restriction of dietary
protein was long considered a mainstay in the management
of liver disease and HE [79,80]. In particular, protein
restriction (0–40 g protein/day) was shown to decrease
encephalopathy grade in patients following surgical creation
of a portal-systemic shunt, the only available therapy at
one time for bleeding varices. Protein restriction (0–40 g
protein/day) was later extended to include all patients with
cirrhosis who developed encephalopathy. However, more
recently, studies have shown that protein restriction in these
patients has no impact on encephalopathy grade and that it
may even worsen their nutritional status . The increased
awareness of the progressive deterioration of nutritional sta-
tus in liver cirrhosis combined with a better understanding
of metabolic alterations in the disorder has questioned the
practice of prolonged protein restriction in the management
of HE . In fact, protein requirements are increased
in cirrhotic patients, and high protein diets are generally
well tolerated in the majority of patients. Moreover, the
inclusion of adequate protein in the diets of malnourished
patients with end-stage liver failure is often associated with a
sustained improvement in their mental status. Furthermore,
protein helps preserve lean body mass; this is crucial in
patients with liver failure in whom skeletal muscle makes a
signiﬁcant contribution to ammonia removal. The consensus
of opinion nowadays is that protein restriction be avoided
in all but a small number of patients with severe protein
intolerance and that protein be maintained between 1.2 and
1.5 g of proteins per kg of body weight per day. In severely
protein intolerant patients, particularly in patients in grades
Tab le 2: Nutritional recommendations for the management of HE
in end-stage liver failure.
Energy 35–40 kcal/kg/day
Protein 1.2–1.5 g/kg of body weight/day∗
BCAA In severely protein-intolerant patients
Antioxidant and vitamins Multivitamin supplements
Probiotics, prebiotics Increasing use for ammonia-lowering
and anti-inﬂammatory actions
∗In severely protein intolerant patients, protein may be reduced for short
periods of time, particularly in grade III-IV hepatic encephalopathy.
III-IV HE, protein may be reduced for short periods of time
7.4. Vegetable versus Animal Proteins. It has been suggested
that vegetable proteins are better tolerated than animal pro-
teins in patients with end-stage liver failure, a ﬁnding that has
been attributed to either their higher content of branched-
chain amino acids and/or because of their inﬂuence on
intestinal transit [86,87]. One study reported that a diet
rich in vegetable protein (71g/d) signiﬁcantly improved the
mental status of patients suﬀering from HE while increasing
their nitrogen balance . Vegetable proteins may also
increase intraluminal pH and decrease gastric transit time.
High dietary ﬁbre diet has been recommended in order to
abolish constipation which is an established precipitating
factor for HE in patients with cirrhosis [89,90]. A daily
intake of 30–40 g vegetable protein has been found to be
eﬀective in the majority of patients .
7.5. Branched-Chain Amino Acids (BCAAs). These amino
acids (leucine, isoleucine, and valine) cannot be synthesized
de novo but must be obtained from dietary sources and
have a unique role in amino acid metabolism, regulating the
intra- and interorgan exchange of nitrogen and amino acids
by diﬀerent tissues . Chronic liver disease and portal-
systemic shunting are characterized by a decrease in the
plasma concentrations of BCAAs , whereas hyperam-
monemia increases their utilization. Since hyperammonemia
results in increased utilization of BCAAs, which are largely
metabolized by the muscle, it would be anticipated that
providing BCAAs could facilitate ammonia detoxiﬁcation
by supporting muscle glutamine synthesis. Administration
of BCAAs has been shown to stimulate hepatic protein
synthesis; indeed, leucine stimulates the synthesis of hep-
atocyte growth factor by stellate cells . Also, BCAAs
reduce postinjury catabolism and improve nutritional status.
Inadequate dietary protein intake or low levels of BCAAs
may have a deleterious eﬀect on HE , nutritional status
, and clinical outcome [25,81] in patients with end-stage
liver failure. Clinical trials of BCAAs in the treatment of HE
have yielded inconsistent ﬁndings. Several controlled clinical
studies reported no eﬃcacy of BCAAs on encephalopathy
grade in patients with cirrhosis [95,96]. However, other trials
demonstrated that BCAAs were beneﬁcial in similar patients
A double-blind, randomized clinical trial demonstrated
that, in advanced cirrhosis, long-term nutritional supple-
mentation with oral BCAA was useful to prevent progressive
hepatic failure . Furthermore, administration of solu-
tions enriched with BCAAs has been shown to improve
cerebral perfusion in cirrhotic patients . Muto et al.
 conﬁrmed the beneﬁcial eﬀects of BCAAs using a more
palatable granular formula. In a multicenter randomized
study, it was also reported that long-term oral supplementa-
tion with a BCAA mixture improved the serum albumin level
as well as cellular energy metabolism in cirrhotic patients
The timing of BCAA supplementation in patients with
end-stage liver failure may be crucial. This issue was
addressed by a crossover study of 12 cirrhotic patients
. Daytime administration improved nitrogen balance
and Fischer’s ratio (ratio of BCAA/AAAs); however, both
were further improved with nocturnal administration. At 3
months, a signiﬁcant increase in serum albumin level was
observed in patients administered nocturnal BCAAs, but not
daytime BCAAs. It is possible that daytime BCAAs may be
used primarily as calories, whereas nocturnal BCAAs may
be preferentially used for protein synthesis. Furthermore,
the long-term use of BCAAs in liver cirrhosis leads to an
increase of serum protein of approximately 10% if given
before bedtime . Problems that limit the widespread
use of BCAAs in the treatment of HE include their expense
and unpalatability , both of which may result in poor
8.1. Rationale for Use of Antioxidants. Cirrhotic patients
manifest evidence of increased expression of biomarkers of
oxidative stress such as increased lipid peroxidation [106,
107], as well as impaired antioxidant defences. Decreased
levels of antioxidant micronutrients, including zinc [33,
107], selenium [46,47], and vitamin E [107,108]have
been described in patients with end-stage liver failure. The
potential beneﬁts of vitamin E have been investigated, but
results are conﬂicting. One randomized, placebo-controlled
trial of vitamin E supplementation revealed a signiﬁcant
amelioration in terms of liver inﬂammation and ﬁbrosis in
patients with nonalcoholic steatohepatitis , while other
studies with biochemical end points did not demonstrate
any signiﬁcant beneﬁcial eﬀect of vitamin E supplements
. In an earlier placebo-controlled randomized trial, 1-
year vitamin E supplementation to patients with end-stage
liver failure led to increased serum alpha-tocopherol levels,
but did not result in any improvement in survival or quality
of life . The beneﬁts of vitamin E therapy in relation to
HE have not been assessed.
8.2. N-Acetylcysteine. A widely used complementary medical
therapy for acute liver failure is the glutathione prodrug,
N-acetylcysteine (NAC) [112,113]. Glutathione is a major
component of the pathways by which cells are protected
from oxidative stress. NAC is an antioxidant with a thiol-
containing compound and is used to restore cytosolic
glutathione and detoxify reactive oxygen species and free
radicals. NAC has proven beneﬁcial in patients with type I
hepatorenal syndrome  but was ineﬃcient in patients
with hepatitis C . While NAC is widely used to
treat acetaminophen hepatotoxicity, its beneﬁt in end-stage
liver failure with speciﬁc reference to HE remains to be
established. In this regard, NAC is known to cross the blood-
brain barrier and to improve central antioxidant status in the
brain in mice with acute liver failure due to azoxymethane-
induced hepatotoxicity .
9. Water-Soluble and Fat-Soluble Vitamins
Deﬁciencies in water-soluble vitamins (particularly the vita-
min B complex) are common in end-stage liver failure .
A wide range of neuropsychiatric symptomatology associ-
ated with liver disease may be the consequence of water-
soluble vitamin deﬁciencies. For example, peripheral neu-
ropathy may result from pyridoxine, thiamine, or vitamin
B12 deﬁciency. Confusion, ataxia and ocular disturbances
are cardinal features of a lack of thiamine, and thiamine
deﬁciency has been reported in patients with hepatitis C-
related cirrhosis . Deﬁciencies in vitamin B12, thiamine,
and folic acid may develop faster in cirrhotic patients due to
diminished hepatic storage.
Fat-soluble vitamins (A, D, and K) deﬁciencies are
likely to arise from malabsorption associated with end-
stage liver failure. Vitamin A supplementation may be
considered since vitamin A deﬁciency results in nyctalopia
and dry cornea, and is associated with increased risk of
hepatocellular carcinoma in patients with end-stage liver
disease [117,118]. Prescription of vitamin D, especially
in patients with cholestasis (in combination with calcium
since osteoporosis may be a complication of end-stage liver
failure), is advised [118,119]. Also, supplementation of
vitamin K in conditions with high risk of bleeding such as
the presence of impaired prothrombin time and oesophageal
varices, should be considered . In view of these
ﬁndings, administration of multivitamin preparations is
10. Probiotics, Prebiotics, and Synbiotics
Probiotics are live microbiological dietary supplements with
beneﬁcial eﬀects on the host beyond their nutritional
properties. Prebiotics stimulate the growth and activity of
beneﬁcial bacteria within the intestinal ﬂora. Synbiotics
are a combination of pro- and prebiotics. Their mecha-
nisms of action include the deprivation of substrates for
potentially pathogenic bacteria, together with the provi-
sion of fermentation end products for potentially ben-
eﬁcial bacteria. Probiotic or prebiotic treatments aim at
increasing the intestinal content of lactic acid-type bacteria
at the expense of other species with more pathogenic
The concept of treating HE with probiotics was already
suggested several decades ago [120–122]. The therapeutic
beneﬁt of acidifying the gut lumen with synbiotics in
cirrhotic patients with minimal HE was demonstrated
by Liu et al.  who showed that synbiotic/probiotic
supplementation ameliorates hepatic function as reﬂected
by reduced bilirubin and albumin levels and prothrombin
times . Modulation of gut ﬂora was also associated
with a signiﬁcant reduction in blood ammonia levels and a
reversal of minimal HE in 50% of patients ; improved
hepatic function and serum transaminase levels in patients
with alcohol- and hepatitis C-related cirrhosis have also
been reported . Another group reported improvement
in biochemical and neuropsychological tests in cirrhotic
patients receiving probiotics [125,126]. Furthermore, liver
transplant recipients who received a synbiotic regimen
developed signiﬁcantly fewer bacterial infections . In
a subsequent clinical trial, the incidence of postoperative
bacterial infection as well as the duration of antibiotic
therapy was signiﬁcantly reduced in liver transplant patients
receiving prebiotics . More recently, Bajaj et al. 
demonstrated a signiﬁcant rate of minimal HE reversal
in cirrhotic patients after probiotic yogurt supplements.
Probiotics may provide additional beneﬁts over dietary
supplementation in reducing episodes of infection. Given
the eﬃcacy of probiotics and their lack of side eﬀects,
they are increasingly being used in the management of
Malnutrition is common in patients with end-stage liver
failure and HE and adversely aﬀects prognosis. Inade-
quate dietary intake, altered synthesis and absorption of
nutrients, increased protein losses, hypermetabolism, and
inﬂammation are among the factors contributing to mal-
nutrition in this patient population. Although there are
now several available methods to assess malnutrition, a
standardized simple and accurate method for evaluating
malnutrition in end-stage liver failure remains a challenge.
Consequences of end-stage liver failure with a potential
to impact upon nutritional status and brain function are
numerous and include hyperammonemia, reduced zinc and
selenium, manganese accumulation as well as deﬁciencies of
carnitine and water-soluble vitamins, particularly thiamine.
The primary goal for a patient with end-stage liver failure
is to avoid by all means possible weight loss and sustain a
diet rich in nutrients. A caloric intake of 35–40 kcal/kg/day
is recommended. Low protein diets should be avoided and
protein intake maintained at 1.2–1.5 g/kg/day. Particular
attention should also be drawn to vegetable protein as well
as to BCAAs which have proven beneﬁcial in the treatment
of HE. Antioxidants as well as probiotics are increasingly
being employed in order to optimize the nutritional status
in cirrhotic patients. Administration of multivitamin prepa-
rations, particularly thiamine, is recommended for patients
with end-stage liver failure. Nutritional support to meet
energy and substrate needs and to optimize the removal of
circulating ammonia, reduce proinﬂammatory mechanisms,
and improve antioxidant defenses has the potential to
limit the progression of liver dysfunction, treat HE, and
improve quality of life in patients with end-stage liver
List of Abbreviations
AAA: Aromatic amino acids
BCAA: Branched-chain amino acid
BMI: Body mass index
GAPDH: Glyceraldehyde-3-phosphate dehydrogenase
HE: Hepatic encephalopathy
MAC: Mid-arm circumference
MAMC: Mid-arm muscle circumference
MELD: Model for end-stage liver disease
PTBR: Peripheral-type benzodiazepine receptor
SGA: Subjective global assessment
TNF-α: Tumor necrosis factor-alpha
TST: Triceps skin fold thickness.
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