GASTROENTEROLOGY 2008;134:1729 1740

Nutrition in End-Stage Liver Disease: Principles and Practice

Alastair OBrien

Roger Williams

Institute of Hepatology, Royal Free and University College Medical School, University College London, London, England

alnutrition is commonly seen in both alcoholic

and nonalcoholic liver disease13 and has been
shown to adversely affect outcome (see Figure 1).4,5 By
definition, it occurs when diet does not provide adequate
calories and protein to maintain nutritional status or the
body is unable to fully absorb or utilize food eaten
secondary to liver disease. Despite the obvious relevance,
clinical research in this field is surprisingly limited and
malnutrition is frequently underdiagnosed in clinical
practice.6
The prevalence of malnutrition in cirrhosis is as high
as 65%90%.13 Evidence concerning the impact of etiology (of cirrhosis) on malnutrition is conflicting. Some
studies have shown no difference in prevalence and severity of malnutrition in patients with viral- and alcoholrelated cirrhosis who were abstinent.2,7,8 Others have
shown that alcoholic cirrhosis was associated with a
poorer nutritional state compared with virus-associated
cirrhosis.9 Active alcoholism is a major cause of malnutrition per se and could contribute to the earlier development observed.10 Protein depletion and reduced muscle function are common in cirrhosis, particularly in men
and patients with alcoholic liver disease.11 The reason for
the male preponderance is unknown and is not related to
hypermetabolism or reduced energy and protein intake.11
The reduced levels of testosterone observed in male patients with cirrhosis12 may contribute to decreased protein anabolism, but this requires further investigation.
The largest studies on prevalence and severity have been
the Veterans Affairs Cooperative Studies in 1984 and
1993, which focused on alcoholic hepatitis.13,14 These
and other studies showed that the severity of malnutrition correlated with that of the liver disease and the
development of serious complications such as hepatic
encephalopathy, ascites, hepatorenal syndrome, posttransplantation outcome, and mortality.1518 Also, shortterm survival is reduced in parallel with severity of malnutrition.19 The majority of patients in these pivotal
studies had advanced liver disease; however, more sophisticated methods of analysis (neutron activation analysis

or intracellular/extracellular body water) have shown that

significant losses of body cell mass may occur in Child A
cirrhosis.20
In this review, we examine the mechanisms underlying
malnutrition in chronic liver disease, the assessment
methods available, and the role of nutritional therapy
(advice, supplementation, enteral or parenteral) in the
various stages of chronic liver disease. Acute liver failure
and transplantation and the emerging data on probiotics
are considered separately.

Mechanisms of Malnutrition in
Cirrhosis
A variety of mechanisms are considered to contribute to malnutrition in cirrhosis: poor dietary intake,
malabsorption, increased intestinal protein losses, low
protein synthesis, disturbances in substrate utilization,
and hypermetabolism. Many of these are not fully understood.
In advanced liver disease, patients often have poor
dietary intake. Recommended diets may be unpalatable
because of the sodium restriction needed for control of
ascites and peripheral edema. A distortion or decrease in
taste sensation (dysgeusia) associated with zinc or magnesium deficiency is well described and may contribute.21
Nausea and early satiety are well recognized, secondary to
gastroparesis, tense ascites, small bowel dysmotility, and
bacterial overgrowth.22,23 When admitted to the hospital,
malnutrition is paradoxically further worsened as patients are often starved, for instance, for endoscopy. In
addition, as glucose storage is reduced in alcohol-induced
cirrhosis,24 gluconeogenesis is active and can cause muscle mass breakdown to provide amino acids for glucose
Abbreviations used in this paper: BCAA, branched-chain amino acid;
DEXA, dual-energy x-ray absorptiometry; PUFA, polyunsaturated fatty
acid; SAMe, S-adenosylmethionine.
2008 by the AGA Institute
0016-5085/08/$34.00
doi:10.1053/j.gastro.2008.02.001

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OBRIEN AND WILLIAMS

Figure 1. Malnutrition is predictive of survival in patients with liver

cirrhosis. Survival rates in patients with midarm muscle circumferences
below the 5th (group 1), 10th (group 2), and 75th (group 3) percentiles
and above the 75th percentile (group 4). P .001 at 6, 12, and 24
months between patients with severe and moderate malnutrition
(groups 1 and 2, respectively) and those with normal and overnourished
nutrition (groups 3 and 4, respectively). Patients with transplants were
screened at the time of transplantation. Reprinted with permission from
Alberino et al.5

formation.25 Patients need frequent meals to protect

muscle mass, which are not always provided. However,
even when inpatients receive specific attention to nutrition, as in the Veterans Affairs Cooperative Studies, only
67% were found to consume the recommended 2500-kcal
diet.13,14 In severe cholestasis, intraluminal bile salts are
reduced with consequent malabsorption of fat and fatsoluble vitamins. This can be further worsened by neomycin, which may blunt intestinal villi, and the use of
cholestyramine for pruritus, which may induce bile salt
deficiency.26
The metabolic disturbances consequent to liver disease, such as increased energy expenditure,27,28 insulin
resistance,29 and low respiratory quotient (indicating reduced glucose and increased lipid oxygenation),30 may
contribute to malnutrition even in the early stages. Hypermetabolic patients tend to weigh less, are more frequently malnourished, and have a higher mortality than
normometabolic patients.31 The estimated prevalence of
hypermetabolism varies considerably, with the largest
study of 473 cirrhotic patients reporting 34%.32 A smaller
study of 50 cirrhotic patients found only 2 hypermetabolic patients,33 whereas a more recent study of 268
patients found 15%.11 The cause of hypermetabolism is
unclear, with one group finding no association with sex,
etiology, severity of disease, protein depletion, and presence of ascites or tumor.11 Indirect evidence suggests that
25% of hypermetabolism in cirrhosis may be explained by
increased sympathetic nervous system activity, possibly
as part of the commonly observed hyperdynamic circulation.34 Sepsis is common in liver disease and is likely to
increase energy expenditure further. The use of -block-

GASTROENTEROLOGY Vol. 134, No. 6

ade for variceal bleeding prophylaxis, which will reduce

metabolic rate, is likely to be a confounding variable.
Measurement of energy expenditure by indirect calorimetry is not straightforward or frequently available, and
estimates such as the HarrisBenedict equation are commonly applied.35 It should be noted that significant differences have been shown between resting energy expenditure values measured by indirect calorimetry and such
estimations.36
Polyunsaturated fatty acid (PUFA) deficiency is common in cirrhosis, especially alcoholic cirrhosis, because
PUFA synthesis from essential fatty acid precursors occurs in the liver.37 PUFA deficiency has been found in
plasma lipids, erythrocytes, platelets, and adipocytes.37
Parenchymal cells are most likely deficient, although no
data exist. The consequences of PUFA deficiency are unclear, and supplementation is controversial.38 PUFA contributes to the fluidity of cell membranes and the release
of an array of secondary messengers (including eicosanoids), and PUFA deficiency is an independent predictive factor of mortality in alcoholic cirrhosis.37 However,
attempts to reverse deficiency have been disappointing;
for example, parenteral nutrition containing Intralipid (a
soybean oil, linoleic acid based lipid emulsion; Fresenius
Kabi, Uppsala, Sweden) failed to improve long-chain
PUFA deficiency in 9 malnourished alcoholic patients.39
Intriguingly, in alcohol-fed rats, a PUFA-enriched diet led
to more severe liver injury than a diet enriched in saturated fatty acids.40 Also, PUFA deficiency has been shown
to reverse alcohol-related mitochondrial dysfunction in
rodents via an increase in phospholipid arachidonic over
linoleic ratio, which raises cytochrome oxidase activity.41
Thus, PUFA deficiency may be an adaptive phenomenon
to counteract the decline in adenosine triphosphate synthesis flux.

Micronutrient Deficiencies in Cirrhosis

Deficiencies in water-soluble vitamins (vitamin B
complex and C) are common in alcoholic cirrhosis in
particular but also occur in nonalcoholic liver disease.42
The risks of Wernickes encephalopathy and Korsakoffs
dementia are well described in alcoholic patients deficient
in thiamine.43 Thiamine deficiency has also been shown
in hepatitis Crelated cirrhosis,44 and administration of
thiamine to all cirrhotic patients has been recommended.
Fat-soluble vitamin deficiencies occur more commonly in
the cholestatic liver syndromes. Vitamin A (retinol) deficiency has been described in cirrhosis and is considered a
risk factor for development of cancer, including hepatocellular carcinoma.45 Vitamin E, an antioxidant, is reduced in cholestasis and alcoholic liver disease. Low levels
of trace elements such as selenium and zinc have been
described.46 Zinc deficiency in patients with chronic alcoholism is attributed to decreased intake and absorption and diuretic-induced increased urinary excretion.47
Supplementation with zinc has been shown to improve

May 2008

glucose disposal in cirrhotic patients,48 and deficiency

may contribute to the impaired glucose tolerance and
diabetes commonly observed. Zinc deficiency is considered to precipitate hepatic encephalopathy49; however,
trials of supplementation have shown conflicting results.50,51 Zinc is also used in alcoholic patients for treatment of night blindness not responsive to vitamin A.47
Magnesium deficiency occurs in alcoholic liver disease,
and muscle magnesium is an independent predictor of
muscle strength.52 This is probably related to the reduced
content of sodium-potassium pumps in skeletal muscle
that accompanies magnesium deficiency. However, supplementation did not restore muscle magnesium or improve muscle function in patients with alcoholic liver
disease.53 Interestingly, patients treated with spironolactone had higher contents of sodium-potassium pumps;
the underlying mechanism is unclear and the subject of
ongoing investigation.
Studies have shown that serum levels of 25-hydroxyvitamin D are low in patients with liver disease54 and fall
with disease progression.55 The likely causes include reduced exposure to UV light, dietary insufficiency, and
malabsorption. A high prevalence of osteoporosis is reported in both cholestatic and noncholestatic cirrhosis.56
Treatment with corticosteroids as part of immunosuppressive regimens for autoimmune hepatitis and following liver transplantation is a risk factor. Few randomized
controlled trials have assessed the role of intervention in
prevention of osteoporosis in chronic liver disease.57
However, it is reasonable to recommend correction of
vitamin D insufficiency with vitamin D3 and calcium in
conditions where osteoporosis is likely. In addition, hormone replacement therapy increases bone mineral density in primary biliary cirrhosis and should always be
considered for postmenopausal women.58 All patients
with chronic liver disease should undergo a dual-energy
x-ray absorptiometry (DEXA) scan to assess bone mineral
density.57 Treatment with bisphosphonates is recommended in those with osteoporosis, as for noncirrhotic
patients. Oral alendronate (not risedronate) may cause
esophageal ulceration and should be avoided in view of
the risk of precipitating variceal hemorrhage; cyclical
etidronate appears safe.

Diagnosis and Assessment

It is not difficult to diagnose malnutrition in a
cachectic patient with advanced liver disease, but in earlier stages of the disease diagnosis is more challenging.20
In addition, the cachexia of liver disease may develop
insidiously and be masked by edema. Early diagnosis is
important to allow appropriate intervention, because
malnutrition is predictive of complications of liver disease and mortality.6 There is no gold standard for clinical
assessment. Body weight can be misleading in patients
with ascites and peripheral edema, although one study
has validated body mass index in cirrhotic patients with

NUTRITION IN END-STAGE LIVER DISEASE

1731

cut-off values of 22 kg/m2 in nonascitic patients, 23

kg/m2 for patients with mild ascites, and 25 kg/m2 for
patients with tense ascites.59 The creatinine height index
can be unreliable owing to frequent disturbances in renal
function in patients with liver disease.60
Protein catabolism is a hallmark of critical illness. One
can assess protein requirement by measuring the nitrogen balance, intake excretion, in which intake represents
nutritional nitrogen and excretion, the sum of measured
urinary nitrogen plus an estimate of cutaneous and gastrointestinal losses.61 Achievement of a positive nitrogen
balance is widely considered to be the primary goal of
nutritional support, and several studies of nutrition in
liver disease have reported clinical improvements associated with increases in nitrogen balance.62,63 Indeed, improved nitrogen balance calculations of improvement
over time in response to nutrition is the single nutritional variable most consistently associated with improved outcome during critical illness.63 However, nitrogen balance is rarely measured outside clinical trials and
is not routine practice at the authors hospital.
The 2 common bedside assessments, plasma protein
concentration and anthropometry, both have significant
drawbacks. Plasma protein concentration correlates better with the severity of liver disease than with malnutrition.64 Anthropometric techniques such as midarm muscle circumference assess body composition. Fat-free mass
(lean body weight; water, protein, and mineral) and fat
mass are measured, and these techniques are referred to
as 2-compartment systems. Anthropometric techniques
may be affected by edema65 and have been shown in one
study to classify up to 20%30% of healthy controls as
undernourished.66 However, several other studies have
shown that anthropometric measurements and handgrip
strength correlate well with more sophisticated assessments such as DEXA in cirrhotic patients.67,68 Indeed,
midarm muscle circumference was shown to be an independent predictor of mortality in advanced cirrhosis.69 In
an Italian multicenter study of more than 1000 patients,
survival was related to midarm muscle circumference for
Child A and B but not C.70 Midarm muscle circumference
has also been shown to be independently associated with
survival and improve prognostic accuracy when combined with the Child score.5 The measurement of phase
angle by bioimpedance analysis as an indicator of body
cell mass has been shown to be of prognostic significance
in cirrhosis71; however, most, but not all, investigators
deem it unreliable in patients with ascites.72-74 Subjective
global assessment uses clinical information obtained during history taking and examination to determine nutritional status without objective measurements and can
determine outcome in patients with cirrhosis.75 However,
when compared with nutritional prognostic index and
handgrip strength, handgrip strength was the only
method that predicted a poorer clinical outcome.69 The
European Society for Clinical Nutrition and Metabolism

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GASTROENTEROLOGY Vol. 134, No. 6

Figure 2. Scheme for determining nutritional status in patients with cirrhosis. Patients are categorized in relation to their body mass index (BMI),
midarm muscle circumference (MAMC), and dietary intake into one of 3 categories: adequately nourished, moderately malnourished (or suspected
to be), and severely malnourished. A subjective override based on factors such as profound weight loss or recent significant improvements in appetite
and dietary intake can be used to modify the classification by one category only. Reprinted with permission from Morgan et al.78

guidelines state that bedside methods such as subjective

global assessment, anthropometry, or handgrip strength
are adequate for identification of undernutrition and
that composite scores do not add value. For quantitative
analysis, the determination of phase angle or body cell
mass using bioimpedance analysis is recommended
rather than anthropometry, despite limitations with ascites.76 The authors current practice is to use subjective
global assessment or handgrip strength.
Although anthropometrical methods are useful for
initial assessment, they are of much less value for monitoring treatment effects because of their high coefficient
of variation and interobserver variability. Thus, more
sophisticated methods are often used in research studies,
such as DEXA and in vivo neutron activation analysis.
The limitations of 2-compartment assessment methods that distinguish fat mass from fat-free mass have
been recently highlighted.77 This study compared a
4-component model (data obtained from densitometry,
deuterium dilution, and DEXA) with reference and bedside 2-component techniques, such as anthropometry,
DEXA, and bioimpedance analysis. Significant differences were found between 2-compartment and 4-compartment techniques, and the authors concluded that
assumptions relating to the density and hydration fraction of fat-free mass were violated in cirrhosis and thus
standard 2-component techniques are inaccurate. They
advocate multicomponent models for research or when
precise data are required. In a separate study, they described a new method for assessing nutritional status in
cirrhosis using midarm muscle circumference, dietary
intake, and a subjective override. This method was found
to be reproducible, valid against a 4-component model,
and a significant predictor of survival78 (see Figure 2).

Treatment
Patients with cirrhosis should have a full assessment of nutritional status at presentation (see previous

text and Table 1). An intake of 35 40 kcal kg1 day1

(dry body weight) and 1.21.5 g kg1 day1 of protein
is desirable.79 Conventional diet therapy combined with
supplementation is the mainstay of long-term nutritional support in the majority. The first report showing
the benefit of a nutritious diet in alcoholic cirrhosis was
published as long ago as 1948,80 and several studies since
have shown that a modified eating pattern with 4 7
small meals, including at least one late evening carbohydrate-rich snack, improves nitrogen economy and partially reverses the abnormal substrate oxidation of cirrhotic patients.81,82
Restriction of sodium, the main extracellular compartment electrolyte, is crucial to minimize the diuretic dose

Table 1. Standard Approach

1. Assess nutritional status
Body mass index subjective global assessment or handgrip
strength
2. Teach
Frequent meals (47/day with 1 late evening snack)
Low-sodium diet (2 g or 88 mmol/day) if ascites or edema
3. If moderate-severe malnourishment
Encourage oral intake
Add oral nutritional supplement
Prospective calorie count every 23 days
Provide multivitamins and correct specific deficiencies (eg,
vitamin D, zinc)
Fluid restriction only when hyponatremia present (sodium level
120 mmol/L)
Consider patients for indirect calorimetric studies
Consider DEXA scan for bone mineral density and treatment if
osteoporotic
4. If intake 3540 kcal kg1 day1 and protein 1.21.5
g kg1 day1
Start enteral nutrition to provide above requirements
5. If hepatic encephalopathy or protein intolerant
Maximize encephalopathy treatment (lactulose, rifaximin, and
so on)
Consider BCAAs

May 2008

necessary to control ascites, peripheral edema, and hepatic hydrothorax. A 2-g (88 mmol/L) sodium-restricted
diet is recommended rather than the previous 0.5 g,
which is very unpalatable.
In severely malnourished patients with cirrhosis, feeding approximately 40 kcal kg1 day1 orally over 1
month increases body fat mass, irrespective of the degree
of liver damage.83 When counseling is insufficient to
maintain an intake of 35 40 kcal kg1 day1 and 1.2
1.5 g kg1 day1 protein, as documented by calorie
count, chemically defined nutritional oral supplements
should be added.79 A controlled trial with a daily supplement of 1000 kcal and 34 g protein for 1 year in alcoholic
cirrhosis showed a reduction in hospitalization due to
fewer infective episodes and a trend to improved survival.84 Additionally, 3 months of treatment with a daily
supplement containing 500 kcal, 32 g protein, 11 g fat,
and 70 g carbohydrate improved nutritional and biological parameters in malnourished cirrhotic patients.85
If nutritional supplementation is insufficient to maintain desired intake, then artificial nutrition should be
commenced, either via a nasogastric feeding tube (enterally) or intravenously (parenterally). A nasoenteric (nasoduodenal or nasojejunal) feeding tube is considered a
better option; however, insertion requires an endoscopic
procedure, and thus nasogastric tubes are used more
commonly. Although mostly used for inpatients because
of practical considerations, both forms of artificial nutrition may be tolerated at home, with appropriate support.
A whole protein formula providing 35 40
kcal kg1 day1 energy and 1.21.5 g kg1 day1 protein is recommended for enteral feeding.77 Standard preparations contain approximately 100 kcal energy, 4 g protein,
and 3.5 mmol of sodium and potassium per 100 mL. Concentrated high energy (1.5 kcal/mL) and protein formulas
are available in many countries and may be preferable in
patients with hyponatremia and ascites to regulate fluid
balance. This may also improve treatment adherence because less volume needs to be consumed. For patients who
develop steatorrhea, it is important to limit long-chain fatty
acids and increase short-chain and medium-chain fatty acids in the formula. Pancreatic enzymes should be supplemented, especially in patients with alcohol-related cirrhosis
in whom pancreatic insufficiency is common. As these enzymes are inactivated by gastric acid, proton pump inhibitors are necessary. Four randomized trials concerning total
enteral nutrition in cirrhosis have been reported.86 89 Three
showed an increased dietary intake over conventional oral
diet,87 89 and 2 showed improvements in liver function.88,89
One showed lower hospital mortality compared with conventional diet.87 The fourth was performed in well-nourished patients admitted with variceal bleeding and failed to
show benefit in nutritional status or disease-related morbidity and mortality.89 However, most of these patients were
able to eat 2000 kcal/day from day 4. In hospitalized patients with an inadequate dietary intake, enteral nutrition

NUTRITION IN END-STAGE LIVER DISEASE

1733

should be commenced as soon as possible, ideally within

24 48 hours of admission.90 This is illustrated by a prospective study in 396 patients showing that a decrease in
dietary intake was an independent predictor of hospital
mortality and corresponded with a deterioration of liver
function.91
Two important considerations during nasogastric
feeding are hepatic encephalopathy and variceal bleeding. Hepatic encephalopathy must be treated aggressively with lactulose or rifaximin and attention given
to possible precipitating causes (eg, electrolyte status,
hypoxemia, sedative use, and presence of sepsis or
variceal bleed). Traditionally, a restricted protein diet
has been considered a mainstay of treatment92; however, cirrhotic patients exhibit increased protein requirements to achieve balanced nitrogen metabolism,93 and normal protein diets have been given safely
to patients with hepatic encephalopathy.94 Thus, restriction is rarely required but, if necessary, usually for
no more than 48 hours. It should be noted that the
recommended protein supplementation is based on
dry body weight and may need alteration in edematous patients. Importantly, the risk of aspiration pneumonia in patients with advanced hepatic encephalopathy during tube feeding must be weighed against the
potential complications of parenteral nutrition (see
below). The European Society for Parenteral and Enteral Nutrition guidelines support insertion of finebore nasogastric tubes in patients with esophageal
varices.77 This has been addressed in only one study, in
which 22 patients with esophageal varices after bleeding and endoscopic treatment were randomized to
either nasogastric feeding or no oral diet for 3 days.89
Recurrent bleeding occurred in 3 patients from the
nasogastric tube group but none of the controls. In
light of these findings, it has been suggested that the
guidelines should state that tube feeding is dangerous
in patients with esophageal varices that have bled
before and that in patients without former bleeding,
there is a tendency for an adverse effect.95 The European Society for Clinical Nutrition and Metabolism
authors responded that endoscopic therapies in this
study were unbalanced between the 2 groups, which
might have influenced outcome, with a higher proportion of injection sclerotherapy in the feeding group as
opposed to a greater number of band ligations in
controls.96 They also referred to a small series of tubefed cirrhotic patients in which fine-bore tubes did not
provoke variceal hemorrhage97 and a trial of low/normal protein diets via fine-bore tube in hepatic encephalopathy in which gastrointestinal bleeding occurred
in only one of 30 patients.83 They concluded if patients are unable to maintain adequate oral intake,
tube feeding is recommended (even when esophageal
varices are present).96 They acknowledged that there is
concern in the immediate days following a bleed. In-

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OBRIEN AND WILLIAMS

deed, our current practice is to wait at least 24 hours

following endoscopic therapy for a bleed and then
insert a nasogastric tube and commence feeding.
Total parenteral nutrition (containing Intralipid,
amino acids, dextrose, electrolytes, vitamins, and minerals) in severe alcoholic hepatitis has shown benefit in liver
function but not (short-term) survival.98,99 One study in
patients with transjugular intrahepatic portosystemic
shunts concluded that small intestinal metabolism contributes to postfeeding (enteral) hyperammonemia,
which may worsen hepatic encephalopathy, and that, in
such cases, parenteral nutrition may be superior to enteral nutrition.100 Further supportive evidence comes
from a meta-analysis of studies performed in the 1980s
using parenteral nutrition in hepatic coma. This showed
probable improved survival, but the studies were very
heterogeneous and so firm conclusions are difficult to
draw.101 However, the risks of mechanical complications
(eg, pneumothorax) and catheter-related sepsis are high
in malnourished cirrhotic patients; it is essential that
parenteral nutrition is administered via a dedicated line
to reduce the incidence of sepsis. Also, the osmotic
strength of parenteral mixtures requires the infusion of
large amounts of fluid that may be excessive for patients
with ascites. Thus, enteral feeding is the preferred mode
of artificial nutrition in liver disease, and the parenteral
route is reserved for intensive care patients with multiorgan failure and subsequent paralytic ileus that prevents
successful enteral feeding. It should be mentioned that a
randomized trial comparing the two in liver disease has
never been performed.
Severe alcoholic hepatitis, defined by a Maddrey
score 32, has a significant mortality rate. Although
corticosteroids remain the mainstay of treatment,102
there have been several studies of nutritional support.
A multicenter, randomized, controlled trial that compared 4 weeks of treatment with total enteral nutrition
or corticosteroids showed no difference in mortality
during treatment between the 2 groups.103 Deaths were
found to occur earlier in the enteral nutrition group.
However, 10 of the survivors treated with corticosteroids died in the first year of follow-up compared with
2 of 24 who received enteral nutrition. The majority of
these deaths were due to sepsis. The investigators hypothesized that the increase in infection seen with
prolonged immunosuppression could be reduced by
improving gut barrier function and thus reducing bacterial translocation. They went on to examine the combination of enteral nutrition with corticosteroid treatment in a pilot study in 13 patients and found no
deaths related to infection.104
Finally, insertion of a percutaneous feeding gastrostomy may be indicated in patients with an esophageal/
upper gastrointestinal stricture, but ascites, impairment
of the coagulation system, and portosystemic collateral

GASTROENTEROLOGY Vol. 134, No. 6

circulation due to portal hypertension are significant risk

factors.105

Value of Branched-Chain Amino Acids

Over the years, the use of the branched-chain
amino acids (BCAAs) leucine, isoleucine, and valine has
been the subject of continued interest. These are essential
amino acids, meaning that they cannot be synthesized de
novo, must be obtained from the diet, and are largely
metabolized by muscle rather than liver. In cirrhosis,
there is a likely reduced total body pool of BCAAs due to
reduced lean muscle mass and defective use secondary to
hyperinsulinemia.106 Conversely, amino acids metabolized by the liver are elevated in cirrhosis (eg, the circulating aromatic amino acids phenylalanine, tryptophan,
and tyrosine).106 BCAAs compete with the serotonin precursor tryptophan for the same amino acid transporter in
the blood-brain barrier, and the imbalance between the
two in cirrhosis probably influences brain ammonia levels directly or indirectly.107 This is considered to be an
important mechanism underlying the development of
hepatic encephalopathy, and so supplementation with
BCAAs may reduce brain uptake of tryptophan and improve encephalopathy.108 Additionally, both enteral and
parenteral BCAA supplementation improved cerebral
perfusion in cirrhotic patients, which again may improve
encephalopathy; the underlying mechanism is unclear.109,110
Oral BCAAs have been shown to benefit patients with
hepatic encephalopathy111,112; moreover, a large multicenter study showed that oral BCAAs given for 1 year
improved the Child score, reduced hospital admissions,
and prolonged event-free survival.113 A further large trial
showed improved event-free survival and quality of life in
Japanese patients treated with BCAAs for 2 years compared with controls.114 However, a Cochrane analysis
based on 11 trials of oral supplementation and 556
patients found no convincing evidence of benefit.115 Although no toxicity was reported, many patients stop
supplementation because of the taste and amount of
water required. Importantly, no benefit of BCAA supplementation was observed in protein-tolerant patients.
Parenteral administration of BCAAs to patients with
acute liver failurerelated encephalopathy within intensive
care units has been advocated because these patients have
increased total amino acids but reduced BCAAs.116,117 However, there have been no controlled studies.
The timing of BCAA supplementation was addressed
by one crossover study of 12 cirrhotic patients.118 Daytime administration improved nitrogen balance and
Fischers ratio; however, both were further significantly
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
are used primarily as calories, whereas nocturnal

May 2008

BCAAs may be preferentially used for protein synthesis.

The use of BCAAs remains controversial, and they are
not widely available in many centers due to their expense
and unpalatability.106 The authors currently follow the
European Society for Parenteral and Enteral Nutrition
guidelines,77 which recommend that enteral feed enriched with BCAAs be reserved for patients who develop
encephalopathy with enteral feeding despite appropriate
treatment. This represents a very small proportion of
patients.

Additional Nutritional Supplements

Nutritional supplements containing S-adenosylmethionine (SAMe), a coenzyme involved in methyl
group transfers, are postulated to improve gut or systemic defenses to infection and injury.119 Experimental
models have shown that SAMe protects against tumor
necrosis factor hepatotoxicity.120 Patients with alcoholinduced liver disease have reduced SAMe levels that may
predispose to mitochondrial glutathione depletion and
dysfunction, and oral administration resulted in significantly decreased liver transplantation and liver mortality
in patients with alcoholic liver disease compared with
placebo.121 Supplementation also reduced pruritus and
elevated serum bilirubin levels in gestational cholestasis.122 However, a Cochrane analysis concluded that there
was no evidence supporting or refuting the use of SAMe
and high-quality randomized trials were needed before
they could be recommended.123 Another frequently taken
supplement is polyenylphosphatidylcholine (lecithin), a
mixture of glycolipids, triglycerides, and phospholipids
and an essential component of the plasma membrane.
Lecithin has been shown to prevent cirrhosis in alcoholfed baboons,124 but in humans it did not improve clinical
outcome in heavy drinkers.125

Acute Liver Failure

Because there is usually no preceding illness in
acute liver failure, the patient is not generally malnourished at presentation. The aim of treatment is to maintain a nutritional balance in the face of the markedly
increased catabolic state that occurs both as a result of
severe hepatic impairment and frequently coexistent sepsis. Hypoglycemia is commonly seen in the initial stages
due to impaired gluconeogenesis, depletion of hepatic
glycogen, and hyperinsulinism, and hence administration
of intravenous glucose at 1.52 g kg1 day1 has been
widely adopted. At a later stage, often secondary to sepsis,
hyperglycemia related to insulin resistance may be observed. In general intensive care patients, 2 large randomized trials have shown that intensive insulin therapy to
maintain normoglycemia produced an absolute reduction in risk of hospital death of 3% 4% and an improvement in morbidity.126 Strict blood glucose control (110

NUTRITION IN END-STAGE LIVER DISEASE

1735

mg/dL) is required to obtain the most clinical benefit,

but this inherently increases the risk of hypoglycemia.
These studies did include patients with hepatic disorders;
however, no study has formally addressed strict glycemic
control in acute liver failure. Because hypoglycemia is
more frequent in these patients, great care must be taken
with insulin regimens.
A recent European survey was answered by 33 hepatology units attending 2170 cases of acute liver failure per
year. All units used specific nutrition regimens, but these
varied considerably and mostly resembled those used in
critically ill patients with near-normal liver function.127
Eight units preferentially used enteral feeding and 25
parenteral. Two thirds used standard parenteral regimens
containing amino acids, although plasma amino acid
levels are already greatly elevated due to liver failure and
increased protein catabolic rate.128

Liver Transplantation
Several studies have examined the impact of preoperative malnutrition on outcome posttransplantation.
A series of 100 patients 6 months posttransplantation
found that muscle wasting was one of 6 variables associated with reduced survival.129 Other studies have shown
that preoperative malnutrition impacts negatively on
posttransplantation outcome.15,27,31 These include a prospective study of 150 patients who underwent transplantation for cirrhosis and who could be divided into highrisk and low-risk groups, with survival rates of 54% and
88%, respectively, based on preoperative nutrition and
resting energy expenditure.31 Other studies have shown
higher rates of complications and mortality in cirrhotic
patients with malnutrition compared with those with
adequate nutrition who undergo transplantation.129,130
More recently, however, this has been questioned. A prospective series of 53 patients from the Mayo Clinic who
underwent transplantation failed to show an association
between any preoperative nutritional parameters and survival or global resource utilization.131 In this series, the
postoperative mortality was quite low after 1 year (7.5%),
as was the frequency of preoperative malnutrition (9.4%),
and patients were offered preoperative nutritional support. Thus, this study could be interpreted as showing
either that adverse outcome after transplantation is associated with factors other than preoperative nutritional
state, or that preoperative nutritional support can overcome the adverse effect of malnutrition on outcome. An
older study used a prognostic nutritional index based on
serum albumin and transferrin levels, triceps skinfold
thickness, and delayed hypersensitivity responses to assess malnutrition and outcome posttransplantation. All
patients were found to be malnourished pretransplantation, but there was no correlation between this index and
mortality or morbidity posttransplantation.132 A further
prospective series of 61 candidates for transplantation
showed poor correlation between nutritional parameters

1736

OBRIEN AND WILLIAMS

and the Child score and Model of End-Stage Liver Disease score.133 Interestingly, a retrospective study in 121
patients examined risk factors for acute rejection and
found that the only significant predictor on multivariate
analysis of a reduction in acute cellular rejection was
decreased midarm muscle circumference, that is, malnourished patients had a lower incidence of acute rejection.134
To date, no controlled trial has shown that preoperative intervention improves clinically relevant outcomes. A
study of 82 patients randomized to enteral supplementation (750 kcal, 20 g protein, and 34 g fat) and conventional diet or conventional diet alone showed an improvement in handgrip strength and midarm muscle
circumference but not outcome.135 The difference in
overall survival at 6 months posttransplantation almost
reached significance, and a larger sample size might have
shown benefit. Two studies have examined nutritional
support following transplantation. Early postoperative
enteral nutrition, within 12 hours, reduced the rate of
viral infections and showed a trend toward a lower rate of
bacterial infections.136 Postoperative parenteral nutrition
compared with intravenous administration of fluid and
electrolytes reduced the length of intensive care stay.137
Obesity has a negative impact on outcome after nonliver surgery.138 However, the published reports on obesity in liver transplantation are inconclusive.139 141 Most
recently, a case-control study from John Hopkins University Hospital examined 121 patients undergoing transplantation. Although postoperative complications, hospital stay, and cost were higher in severely obese patients
(body mass index 32.3 kg/m2 for women, 31.1 kg/m2
for men) compared with nonobese patients, there was no
difference in overall survival rates.142
Immunonutrition, supplementation with nutrients
that have been shown to beneficially influence immunologic or inflammatory parameters in clinical or laboratory
studies (eg, glutamine), has shown positive results in
other gastrointestinal surgery.143 A pilot study of 15
patients given an immunomodulatory diet containing
arginine, n-3 fatty acids, and nucleotides (Impact; Novartis Consumer Health, Nyon, Switzerland) before and after transplantation showed an increase in total body
protein and a trend to reduction in infections compared
with historical controls receiving standard nutrition.144

Use of Probiotics and Synbiotics

Although not directly related to nutrition and
liver disease, the use of probiotics and synbiotics alongside nutritional supplements merits consideration in the
treatment of the frequent septic episodes that accompany
liver decompensation. Probiotics are living microorganisms, prebiotics are indigestible carbohydrates that stimulate the growth and activity of beneficial bacteria within
the intestinal flora, and synbiotics are a combination of
the two.145 There is increasing evidence that bacterial

GASTROENTEROLOGY Vol. 134, No. 6

translocation of intestinal flora combined with failure of

antibacterial defense mechanisms plays a key role in the
development of sepsis.146 Probiotic or prebiotic treatment aims to augment the intestinal content of lactic
acidtype bacteria at the expense of other species with
more pathogenic potential and thus reduce the incidence
of sepsis.
A randomized study compared postoperative infections in 95 liver transplant recipients treated with an
early supply of standard enteral feed supplemented with
either a synbiotic regimen including Lactobacillus plantarum and fermentable fiber, a heat-inactivated Lactobacillus
plantarum and fiber, or selective intestinal decontamination.147 The patients who received the synbiotic regimen
developed significantly fewer bacterial infections (13%)
than those undergoing intestinal decontamination (48%).
The mean duration of antibiotic therapy, hospital stay,
and intensive care unit stay was also shorter in the synbiotic group but did not reach significance. The same
group compared the postoperative use of a mixture of 4
prebiotics versus the same mixture plus a probiotic preparation containing lactic acid bacteria (synbiotic) in 66
patients.148 The incidence of postoperative bacterial infections was significantly reduced (48% given prebiotics
compared with 3% given synbiotics), and the duration of
antibiotic therapy was significantly shorter in the latter.
There is also evidence that synbiotic/probiotic supplementation improves hepatic function. Synbiotic treatment improved the Child score in 55 cirrhotic patients
with minimal hepatic encephalopathy, with significant
improvements in bilirubin level, albumin level, and prothrombin time.149 Also, supplementation with the probiotic VSL#3 (lactobacillus and bifidobacterium bacteria: VSL
Pharmaceuticals, Inc, Fort Lauderdale, FL) improved hepatic function and serum alanine transferase level in
patients with alcohol-related and hepatitis Crelated cirrhosis.150

Conclusions
In summary, malnutrition is common in endstage liver disease and adversely affects prognosis. Nutritional support improves outcome in patients unable to
maintain an intake of 35 40 kcal kg1 day1 and 1.2
1.5 g kg1 day1 protein. Simple methods of assessment such as subjective global assessment, midarm muscle circumference, and calorie counting are useful, and
standard enteral products may be used in the majority of
patients.
However, considerable difficulties remain concerning
the treatment modalities. Enteral nutrition is usually
considered first line, but the parenteral route may be
required if the patient is intolerant due to nausea and
vomiting or develops increasing encephalopathy. However, there is a significant risk of catheter-related sepsis.
The value of BCAAs remains uncertain despite a considerable number of studies, and a more palatable form

May 2008

would help clarify their value. There is very little information concerning nutrition in acute liver failure and
conflicting data regarding the effect of preoperative malnutrition and intervention on outcome in liver transplantation, although early postoperative nutrition seems to
be of benefit. Synbiotics may provide additional benefits
over dietary supplementation in reducing infective episodes, which impact malnutrition. Future research
should be aimed at answering these questions. In particular, disease-specific nutritional therapy should be considered for acute liver failure, sepsis, transplantation, and
encephalopathy. Further large-scale intervention studies
are required before treatment guidelines can be based on
a formal meta-analysis. The implementation of these
crucial studies will be extremely difficult, and researchers
will need to collaborate on a national or international
scale.
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Received November 28, 2007. Accepted February 1, 2008.

Address requests for reprints to: Alastair OBrien, BSc, MBBS, PhD,
Institute of Hepatology, Royal Free and University College Medical
School, University College London, 69 - 75 Chenies Mews, London
WC1E 6HX, England. e-mail: a.obrien@ucl.ac.uk; fax: (44) 207 380
0405.