CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10:117125

Prevalence and Mechanisms of Malnutrition in Patients With Advanced

Liver Disease, and Nutrition Management Strategies
KALLY CHEUNG,* SAMUEL S. LEE, and MAITREYI RAMAN
*Alberta Health Services, Calgary, Alberta, Canada; Liver Unit, and Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary,
Alberta, Canada

This article has an accompanying continuing medical education activity on page e18. Learning ObjectiveAt the end
of this activity, the learner will appreciate that morbidity and mortality is related to nutritional status in patients with
advanced liver disease; recognize the multifactorial nature of malnutrition in patients with cirrhosis; and appreciate the
importance of the liver in the many derangements of nutritional status in patients with cirrhosis.

Malnutrition is prevalent among cirrhotic patients and is

an important prognostic factor. Etiologic factors include
hypermetabolism, malabsorption, altered nutrient metabolism, and anorexia. It is a challenge to manage nutrition in
cirrhotic patients because of alterations to metabolic and
storage functions of the liver; use of traditional assessment
tools, such as anthropometric and biometric measures, is
difficult because of complications such as ascites and inflammation. In addition to meeting macro- and micronutrient requirements, the composition and timing of supplements
have been proposed to affect efficacy of nutrition support.
Studies have indicated that branched chain aromatic acid can
be given as therapeutic nutrients, and that probiotics and
nocturnal feeding improve patient outcomes.
Keywords: Liver Disease; Nutrient Therapies; Diet; Cirrhosis;
Malnutrition.

utrition status is recognized as a predictor of morbidity

and mortality in patients with advanced liver disease.13
The liver is an important regulator of metabolism, storage,
synthesis, and absorption of nutrients. Accordingly, the severity
of malnutrition increases with decreases in liver function.4 The
mechanisms involved in the pathogeneses of malnutrition are
not fully understood, though it is important to continue to
explore this relationship; improvements in nutritional status
can improve outcomes of patients with advanced liver disease.
We review the prevalence and mechanisms of malnutrition and
provide recommendations for nutrition management.

Prevalence of Malnutrition
Patients with chronic diseases frequently become malnourished; they have an inability to meet macronutrient and
micronutrient requirements through oral intake.5 Inadequate
intake and/or associated malabsorption alters body composition and diminishes biological functions.5 Parameters used to
assess malnutrition in patients with liver disease include anthropometric and serum measurements and qualitative data on
weight history and food intake.6,7
Malnutrition is common in patients with advanced liver
disease; the prevalence is reported to be 50%90% among cirrhotic patients.711 In a study of 300 patients, more than 75% of

those with advanced liver disease presented with some degree of

malnutrition, and almost 40% presented with moderate or severe malnutrition, based on anthropometric and serum measurements.7 In the same study, 95% of patients of ChildPugh
class C presented with malnutrition, compared with 84% and
46% of classes B and A, respectively.7
The prevalence of malnutrition among patients with even
early-stage cirrhosis is concerning, given that nutrition status is
associated with mortality and complications.12,13 In a large
nationwide analysis of hospitalized patients with cirrhosis and
portal hypertension, patients with protein calorie malnutrition
had greater incidences of complications such as ascites (65%,
compared with 48% without malnutrition) and hepatorenal
syndrome (5% vs 3%).12 Malnourished patients also had longer
hospital stays and had a 2-fold increase in in-hospital mortality,
compared with well-nourished patients.12 The incidence of malnutrition in this study was 6% among patients with cirrhosis,
compared with 2% of general medical patients captured using
International Classification of Diseases, 9th Version (ICD-9)
coding, which might have led to underreporting of malnutrition; rates of malnutrition were significantly lower compared
with those reported in other studies.12 The impact of malnutrition on mortality and complications might have been larger
in magnitude if a more sensitive measure of malnutrition was
used.
A study of patients of ChildPugh class A demonstrated that
malnutrition, even in early stages of cirrhosis, had large effects
on patient outcomes. Among a cohort of patients that were
primarily ChildPugh class A, those that were malnourished
had a 1-year mortality rate of about 20%, whereas none of the
patients that received sufficient amounts of nutrients died
within the 1-year period.13 Complications such as infections,
hepatic encephalopathy, ascites, and hepatorenal syndrome also
Abbreviations used in this paper: AAA, aromatic amino acid; ASPEN,
American Society of Parenteral and Enteral Nutrition; BCAA, branched
chain aromatic acid; ESPEN, European Society of Clinical Nutrition and
Metabolism; HE, hepatic encephalopathy; MHE, minimal hepatic encephalopathy; PBC, primary biliary cirrhosis; REE, resting energy expenditure; SGA, subjective global assessment; TPN, total parenteral
nutrition.
2012 by the AGA Institute
1542-3565/$36.00
doi:10.1016/j.cgh.2011.08.016

118

CHEUNG ET AL

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 2

Figure 1. Possible factors

contributing to lipid maldigestion or malabsorption in patients with cirrhosis or chronic
pancreatitis.

increased with malnutrition; in the same study, 65% of malnourished patients developed complications compared with
11% of well-nourished patients.13
After liver transplantation, malnutrition has been associated
with higher rates of infectious complications, longer stays in
the intensive care unit, and higher mortality.6,8 Additionally,
patients with more severe malnutrition have longer postoperative hospital stays.6

Etiology of Malnutrition
The etiology of malnutrition is multifactorial and primarily related to reduced liver function; poor oral intake and
complications of cirrhosis such as ascites and hepatic encephalopathy also contribute.

Hypermetabolism
Resting energy expenditure (REE) is the amount of
energy an individual uses to perform vital organ functions, free
of activity and digestion.14 A commonly used predictive equation for REE is the Harris Benedict Equation, which factors
weight, height, and sex in the calculation. Whereas most cirrhotic patients have a REE that is similar to predicted values,
15%30% of patients are hypermetabolic.15,16 Hypermetabolism is
defined as REE 120% compared with the predicted value.15,16 The
causes of hypermetabolism are unclear; a recent study of 268
patients did not associate hypermetabolism with sex, etiology,

severity of disease, protein depletion, presence of ascites, or

tumors.16 This finding is inconsistent with results from older
studies that reported that energy expenditure increased among
patients with ascites or hepatocellular carcinoma.17,18
The increase in REE among patients with cirrhosis might result
from infections or immune compromise. Plasma concentrations
of catecholamines are increased in cirrhotic patients, indicating
activation of the sympathetic nervous system.19 Sympathetic overactivity could induce systemic responses such as tachycardia and
increases in cardiac output and blood glucose levels,20 which could
all increase energy expenditure.15 Proposed causes for the increased
levels of catecholamine include gastrointestinal bacterial translocation, an inflammatory phenotype of chronic liver failure, or
central neural dysregulation of the circulation.21,22

Malabsorption
There are multiple mechanisms that can lead to malabsorption of nutrientsparticularly of fatin cirrhotic patients (Figure 1). One complication that affects nutrient absorption in patients with cirrhosis is portosystemic shunting. As
cirrhosis progresses, portosystemic shunting causes nutrients to
bypass the liver, without metabolic processing.2,23 In addition,
many patients with cirrhosis that is secondary to alcohol abuse
have chronic pancreatitis, which contributes to malabsorption.
An analysis of autopsy results found that 18% of cirrhotic
patients also had chronic pancreatitis.24

February 2012

Another factor that leads to fat malabsorption in patients

with cirrhosis is intraluminal bile acid deficiency, which results
from the decreased capacity for bile production and portosystemic shunting; intraluminal bile acid deficiency impairs formation of micelles and absorption of long chain fatty acids
through the usual lymphatic route.25 Portal absorption of long
chain fatty acids might also occur in patients with cirrhosis;
Cabre et al showed that the incorporation of radiolabeled fatty
acid in chylomicron and very-low-density lipoprotein (VLDL)associated plasma tricylglycerols was lower and less sustained in
cirrhotic patients compared with healthy controls.26 This finding is consistent with reports of impaired lipoprotein export
in cirrhotic patients, probably from decreased synthesis of triaclyglycerols.27,28 The findings of Cabre et al indicate an alternate route for fat absorption in cirrhotic patients, which bypasses standard lymphatic transport. A portal route for fat
absorption has pathophysiologic implications; it could result in
excess hepatic storage of fat, which can reduce liver function
and the systemic availability of fat for organic functions.

Altered Macronutrient Metabolism

Glucose metabolism has been well studied in patients
with liver disease. Those with cirrhosis have increased levels of
gluconeogenesis and protein catabolism and decreased levels of
glycogenlysis, compared with healthy individuals.29,30 The altered rates of metabolism reflect a significant depletion in
protein and fat reserves, reported in about 50% of cirrhotic
patients.6,16
Patients with chronic liver disease have increased rates of
gluconeogenesisa number of factors contribute to this. First,
cirrhosis reduces the ability of hepatocytes to store, synthesize,
and break down glycogen. These defects promote gluconeogenesis from fats and protein as alternate fuel sources. Following a
short overnight fast, the rate of fat and protein catabolism in
patients with cirrhosis is similar to that of healthy subjects who
underwent 2 to 3 days of starvation.31
Second, cirrhosis and insulin resistance are related; patients
with cirrhosis have high serum levels of insulin after fasting and
postprandial levels of glucose.32 Fasting plasma levels of insulin,
among 31 patients with cirrhosis, were 3-fold higher than those
of healthy individuals.32 Insulin resistance decreases peripheral
glucose utilization and contributes to decreased hepatic glucose
production and hepatic glycogen reserves.33 Increased serum
levels of glucagon, which result from impaired degradation by
the liver, increases the rate of gluconeogenesis.
Third, infection can increase rates of protein catabolism. The
production of cytokines and other infection mediators activate
proteolysis and increase oxidation of branched chain aromatic
acids (BCAAs). This can promote the breakdown of muscle cells
for substrates, if dietary protein intake is insufficient. In patients with cirrhosis, the utilization of oxidative fuels is associated with an increased rate of lipid oxidationparticularly in
the fasting state.34

Anorexia
As in other chronic illnesses, anorexia makes a significant contribution to malnutrition. Anorexia can be caused by
physical symptoms of discomfort such as nausea, bloating,
fatigue, and vomiting. Patients with ascites often experience
early satiety resulting from the mechanical effects of ascitic
fluid, which compress the stomach.35

MALNUTRITION IN ADVANCED LIVER DISEASE

119

Additionally, loss of appetite can be related to the up-regulation of inflammation and appetite mediators.16,36 Levels of
tumor necrosis factor (TNF)- and leptin correlate with satiety
and energy expenditure; patients with cirrhosis have increased
serum levels of this cytokine.37 Tumor necrosis factor- might
affect appetite and metabolism by acting on the central nervous
system, altering the release and function of neurotransmitters.38
Leptin is an appetite-regulating hormone that is secreted by
adipose tissue.39 Cirrhotic patients had a 2-fold increase in
fasting levels of leptin compared with healthy individuals; this
might contribute to anorexia in these patients.32
Ghrelin, which stimulates appetite, is produced primarily by
the stomach. Although some cirrhotic patients have been observed to have abnormal fasting levels of this hormone, the
relationship between ghrelin and anorexia is unclear; some
studies have reported increases and others reported decreases.32,40 Changes in ghrelin levels might be related to the
systemic response to liver disease and state of anorexia or a
consequence of the livers role in hormone regulation.32,40
Aside from hormonal influences and physical discomfort,
disinterest in food can result from dietary restrictions and taste
alterations. Dietary limitations, such as sodium restriction for
ascites management, preoperative fasting, and limitation of
protein intake for severe hepatic encephalopathy can reduce
food variety; many patients do not accept the allowable foods.
Although taste alterations have been commonly attributed to
micronutrient deficiencies, researchers have questioned whether
they are a consequence of cirrhosis itself.41,42
It is also important to consider alcohol-related anorexia.
According to the American Liver Foundation, 10%20% of
chronic users of alcohol develop cirrhosis. Poor and irregular
feeding is common among patients with alcoholic cirrhosis.
Before hospital admission, 53% of alcoholic patients reported
anorexia, 40% reported irregular feeding, and 36% ate only 1
meal per day.43 In a study of middle-income patients with
alcoholic cirrhosis, although their energy intake was similar to
that of nonalcoholics, their overall intake of nutrients was
lower, because they acquired most of their energy from alcohol
rather than nutrient-rich foods.44 The socioeconomic status of
patients can also affect oral intake; patients who have alcoholic
cirrhosis and low socioeconomic status are prone to poor and
irregular feeding. As a result, they develop nutrient deficiencies,
such as low serum levels of folate, B12, and B6, and macronutrient deficiencies.45

Micronutrient Status
Patients with advanced liver disease have an increased
risk of micronutrient deficiencies that arise from anorexia,
diuretic use, fat malabsorption, and hepatitis C. Because patients with ascites have restricted intake of animal protein and
are treated with diuretics, they commonly acquire zinc deficiency.46 Similarly, magnesium deficiency can result from decreased oral intake of nutrients and use of diuretics.
Although rates of deficiencies in fat-soluble vitamins vary
among studies, vitamin A and vitamin D deficiencies are most
commonly reported.47 More than 90% of patients with cirrhosis
have some level of vitamin D deficiency and 29% have severe
vitamin D deficiency (17.5 nmol/L).48 Low serum levels of
fat-soluble vitamins can impair absorption of other nutrients,
such as vitamin D and calcium. In patients with primary biliary
cirrhosis (PBC), reduced concentrations of intraluminal bile

120

CHEUNG ET AL

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 2

increase the risk of malabsorption and deficiencies in fat and

fat-soluble vitamins (A, D, E, and K).23,47 49 In a study of 180
patients with PBC, 33%, 13%, 2%, and 8% had deficiencies in
vitamins A, D, E, or K, respectively.47 Although these differences
were not statistically significant (likely due to the small sample
size), the authors associated the stage of PBC with the degree of
vitamin deficiency.47
Hepatitis C virus (HCV) infection has been associated with
decreased levels of vitamin B6 and folate; therapy with pegylated interferon and ribavirin further decreased the levels of
vitamin B6 and reduced plasma levels of vitamins B1 and B2.
Many B-complex vitamins are cofactors for enzymatic reactions,
so standard antiviral therapy for hepatitis C might impair
physiological functions and cause complications.50 In this
study, dietary intake of B-complex vitamins did not differ between patients with hepatitis C and healthy individuals, indicating that hepatitis C virus might compete with human cells
for vitamins; therapy might therefore affect nutrient utilization.

Nutrition Assessment
Because nutrition is correlated with outcome of patients with liver disease, it is important to accurately assess
nutritional status and provide timely nutritional support. This
task is challenging, due to the complications of altered rates of
protein metabolism and presence of ascites and edema. The
European Society of Clinical Nutrition and Metabolism
(ESPEN) 2006 guideline recommends the use of the subjective
global assessment (SGA), anthropometry analysis, or the hand-

Table 1. Nutrition Recommendations

Energy requirement, based on dry weight
or determined ideal body weight,
for patients with ascites
ASPEN
Without encephalopathy
With acute encephalopathy
Stable and malnourished
ESPEN
All stable cirrhosis patients
Macronutrients
Carbohydrate
Protein
All patients, except acute
encephalopathy
Acute encephalopathy
Fat
Micronutrients
Fat-soluble vitamins (vitamins A, D, E,
and K); all patients with
compensated liver disease
Zinc
Selenium
Folic acid and thiamine; patients with
history of alcohol abuse
Sodium; patients with ascites and
edema

2540 kcal per d

2535 kcal/kg per d

35 kcal/kg per d
3040 kcal/kg per d
3540 kcal/kg per d
45%65% of daily caloric
intake per DRI
1.01.5 g/kg per d
0.60.8 g/kg per d
25%30% of daily caloric
intake per DRI
Up to RDA levelsa

Up to RDA levelsa
Up to RDA levelsa
Up to RDA levelsa
Restricted to 2 g per d

DRI, daily recommended intake; RDA, recommended dietary allowance.

aFor patients without signs of deficiency.

grip strength test to identify patients with cirrhosis who are at

risk of malnutrition.51
SGA is a bedside assessment tool used to collect information
on dietary intake, weight change, and gastrointestinal symptoms; it includes an examination for subcutaneous fat loss,
muscle wasting, edema, and ascites.14 The SGA is commonly
used to assess patients with liver disease because it is simple and
cost-effective.14
Although traditional anthropometric measures such as
weight, midarm circumference, and triceps skin-fold thickness
are considered to be adequate for determination of nutritional
status of cirrhotic patients, efforts to document these parameters in patients with advanced liver disease should be made on
a regular basis. Determination of body mass with weight scales,
or body composition with bioelectric impedance analysis, is not
always accurate, due to the prevalence of ascites or edema in
this population.51 Albumin levels are poor nutritional markers
because they are typically reduced in patients with advanced
liver disease and fluctuate during periods of inflammation.14
The handgrip strength test measures the strength of hand
and forearm muscles. Subjects are classified as malnourished if
their grip strength is less than 2 standard deviations from the
mean of the age and sex groups.13 This is a simple and quick
tool to assess nutritional status, though its use as a sole assessment technique is not widespread. The handgrip test has been
compared with the SGA in patients with cirrhosis and found to
be a superior predictor of clinical complications such as uncontrolled ascites, hepatic encephalopathy, spontaneous bacterial
peritonitis, and hepatorenal syndrome.13 Complications developed in 65% of patients who were classified as malnourished
using the handgrip strength test, compared with 35.7% of
patients classified as malnourished using the SGA.13
Dual-energy x-ray absorptiometry, in vivo neutron activation
analysis, and isotope dilution are other methods used to measure nutritional status.51 Though they provide relevant and
accurate information, their widespread application has been
limited by cost and technical complexity.52 So, the SGA, anthropometric measures, and the handgrip test are most commonly
used in routine nutritional assessments.
Although the SGA is adequate as a stand-alone nutrition assessment tool, some studies have shown it can underestimate the
frequency and severity of malnutrition of patients in the initial
stages of the disease.14,52,53 Figueiredo et al52 suggested that nutritional intervention should be automatically initiated in patients
with cirrhosis of ChildPugh class B or C, due to the prevalence of
malnutrition in these groups, with more extensive nutritional
assessment for patients of class A, to provide timely support.
Therefore, a combination of subjective and objective data indicate the
need for a comprehensive analysis of patients nutritional status.52,54
Diabetes is associated with poor prognoses for cirrhotic
patients; because of the prevalence of impaired glucose tolerance among these patients, physicians should consider screening them for glucose intolerance.55 Often, diabetes presents in
patients with subclinical cirrhosis who have normal fasting
glucose levels; the 75 g oral glucose tolerance test might be a
better diagnostic tool.55 Studies do not support routine assessment of serum levels of insulin or glucagon, or use of homeostasis model assessment scores, to identify patients with impaired glucose tolerance or hepatogenous diabetes.

February 2012

Nutrition Recommendations
Current nutritional recommendations aim to provide
patients with cirrhosis with sufficient energy intake for daily
activities, the increased energy requirements associated with
liver disease, to prevent further protein catabolism for energy,
and to meet nutritional requirements, based on recommended
daily intake. The recommendations proposed in the literature
reflect the higher nutritional needs of patients with advanced
liver disease, who have impaired nutrient absorption, and altered micro- and macronutrient metabolism (Table 1). These
are the basic recommendations for patients changes might be
necessary based on trends in body composition, deficiencies
detected in serologic analyses, and further deterioration of liver
function.
Energy requirements determined for patients are based on
the severity of cirrhosis and the presence of ascites, hypermetabolism, or malnutrition.56 It is important to continuously
monitor weight trends and maintain nutritional status. The
energy recommendation, based on the American Society of
Parenteral and Enteral Nutrition (ASPEN) and ESPEN guidelines, ranges from 25 to 40 kcal/kg per day.51,56 The ASPEN
guideline recommends 25 to 35 kcal/kg per day for patients
without encephalopathy and 35 kcal/kg per day in those with
acute encephalopathy. The 2006 ESPEN guidelines recommend
a much higher energy intake, at 35 to 40 kcal/kg per day for all
patients with stable cirrhosis.51 The ESPEN recommendation
appears to focus on prevention and treatment, due to the
prevalence of malnutrition among cirrhotic patients; the ASPEN guideline also recommends 30 to 40 kcal/kg per day for
stable and malnourished patients.51,56
Energy recommendations are created based on patients dry
weight or, in the presence of ascites, their determined ideal body
weight. The ESPEN guideline recommends use of oral supplement or overnight enteral feeds if patients cannot maintain
adequate intake from food.51
Carbohydrate restriction is not recommended for patients
with cirrhosis despite the high prevalence of insulin resistance
and diabetes in this population.51 With impaired glycogen synthesis and limited glycogen stores in the liver, regular intake of
carbohydrates can help prevent hypoglycemia. Patients are advised to have frequent meals and snacks to reduce the risk of
hypoglycemia, which might subsequently improve oral intake
among patients with poor appetites.56,57 Some studies investigated the use of low glycemic and high-fiber carbohydrate
sources to manage hyperinsulinemia and hyperglycemia; these
were either small or case studies, so their findings cannot be
generalized to all cirrhotic patients.58 60 It has been recommended that carbohydrates account for 45% 65% of caloric
intake, based on the dietary reference intake.61
Historically, protein restriction was recommended in patients with liver disease. The practice originated from the 1970s
and 1980s, when uncontrolled observational studies reported
improvements in hepatic encephalopathy following protein restriction.62 Studies have shown that high-protein diets are not
only well-tolerated in patients with cirrhosis and/or moderate
hepatic encephalopathy, but can also improve their prognosis
and mental status.63 Conversely, protein restriction can lead to
increased protein catabolism, which worsens hepatic encephalopathy, because of the release of ammonia, a by-product of
catabolism. A randomized study showed that patients with
protein intake of 0.5 g/kg per day had an increase in muscle

MALNUTRITION IN ADVANCED LIVER DISEASE

121

breakdown compared with patients with 1.2 g/kg per day protein intake.63
The current protein recommendation for patients with cirrhosis is 1.0 to 1.5 g/kg per day.51,56 This amount is higher than
the 0.8 g/kg per day recommended for healthy individuals,
because of increases in gluconeogenesis, muscle catabolism, and
decreased absorption as in cirrhotic patients. Patients with
acute encephalopathy are placed on temporary protein restriction (0.6 0.8 g/kg per day) until the cause of encephalopathy is
diagnosed and eliminated; then normal protein intake can be
resumed.56
Although several mechanisms appear to contribute to fat
malabsorption, there are no guidelines to support the use of
medium chain triglycerides for patients with cirrhosis. However, if patients appear to have overt fat malabsorption, based
on an abnormal, 72-hour fecal fat test result following a challenge with 100 g fat, it is reasonable to consider this approach.
For patients with advanced liver disease, diet supplementation with fat-soluble vitamins (A, D, E, and K), zinc, and
selenium are recommended; deficiencies in these nutrients are
frequently observed in patients with compensated liver disease.49,56 The recommended intake levels of fat-soluble vitamins
are substantially higher for patients with chronic cholestasis;
when these patients are suspected of having deficiencies
in fat-soluble vitamins, serum levels of vitamin A and 25hydroxyvitamin D [25(OH)D] should be checked, at baseline
and then annually.47,64 For patients with a history of alcohol
abuse, administration of folic acid and thiamin is also advised.56
Because of the increased risks of micronutrient deficiencies
among most patients with advanced liver disease, they should
take a multivitamin routinely.
Patients with edema and ascites are usually placed on
sodium-restricted diets (2 g per day).65 Hospitalized patients with refractory or diuretic-resistant ascites might benefit temporarily from more stringent restrictions in sodium.
It is generally not recommended to discharge patients on
severe sodium restriction dietstheir poor palatability usually leads to poor compliance.66

Probiotics
Patients with cirrhosis have disruptions in the composition of the gastrointestinal microflora, due to medical therapies and abnormal intestinal motility;67 25% have small bowel
bacterial overgrowth, which can promote intestinal wall permeability that results in bacteria translocation, secondary infections, and fat malabsorption with associated consequences.67
Changes in microflora observed in patients with gastrointestinal bacterial overgrowth have been associated with minimal
hepatic encephalopathy (MHE).67 69 MHE is the mildest form
of hepatic encephalopathy, in which patients do not necessarily
have recognizable symptoms but can exhibit mild cognitive and
psychomotor deficits that impact health-related quality of life.
MHE can be treated with lactulose and antibiotics, but use of
these agents is limited by the development of resistant strains of
bacteria and low levels of patient adherence, because of side
effects such as abdominal pain, flatulence, bloating, and diarrhea.68,70
Probiotics are being investigated for their ability to restore
intestinal integrity. They could improve or reverse MHE by
lowering intestinal levels of ammonia and decreasing pH, which
would inhibit growth of pathogenic bacteria and decrease in-

122

CHEUNG ET AL

testinal permeability.68,71,72 Results from several randomized

control trials have demonstrated that they lead to significant
improvements, based on psychometric tests results.68,69,73 However, the application of probiotics to treatment of MHE is a
relatively new area of study; more research is required to determine the most effective probiotic strain and therapeutic dose.68
Probiotics appear to be a safe, natural, and well-tolerated form
of therapy for long-term use in patients with mild hepatic
encephalopathy (HE).68

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 2

variceal bleeding. Instead, the rate of decompensation, which

included potentially subjective criteria such as development of
refractory ascites or encephalopathy, was the parameter that
differed between groups.65,79 This study had a high rate of
patient compliance (85%) because the authors used a bettertasting, granulated form of BCAAs.
Although we can propose a biological mechanism for the
efficacy of BCAAs in patients with advanced liver disease, their
poor palatability in commercial formulas and high cost remain
a barrier to patient acceptance.57,75,78

Branched-Chain Amino Acids

BCAA are amino acids that are essential for protein
synthesis, protein turnover, and regulation of energy metabolism.2 The use of BCAA in the treatment of HE has been well
studied. Ammonia and aromatic amino acids (AAAs) are normally metabolized and/or detoxified by the liver. However, in
patients with advanced liver disease, AAAs accumulate as a
result of impaired hepatocyte function and portal shunting.
Patients with cirrhosis have a low ratio of BCAA:AAA; BCAA
levels decrease because they are taken up by skeletal muscle
cells, as a substrate for energy or ammonia degradation.2 AAA
levels increase due to the impaired capacity of hepatocytes in
deamination.74 BCAA and AAA compete for the same bloodbrain barrier transporter, so decreased serum concentrations of
BCAA increase brain uptake of tryptophan, an AAA.2 Greater
uptake of tryptophan has been proposed to cause an imbalance
of neurotransmitter synthesis in the brain, leading to the confusion and altered consciousness that are characteristic of HE.75
BCAA supplementation might help restore the balance between
BCAA and AAA transport in the brain.
Increased serum concentration of ammonia might also affect
neurotransmission and interfere with the normal flow of nutrients, fluids, substrates, and hormones, and with neurotransmitter function, to lead to HE.75 BCAA supplementation can
reduce hyperammonemia, because ammonia is detoxified as
part of the skeletal muscle metabolism of BCAA for energy.76
The ESPEN 2006 consensus that supports the use of oral
BCAA supplement to improve clinical outcomes was based
largely on results from 2 randomized trials.52 Marchesini et al
conducted a 1-year, double-blind study of 174 patients with
advanced cirrhosis who were randomly assigned to a group that
was given BCAA (14 g per day; 59 patients) or control groups
that were given equicaloric amounts of lactoalbumin or maltodextrin.77 The primary end point was a combination of death
and liver decompensation, defined by worsening hepatic encephalopathy, refractory ascites, or a ChildPugh score 12.
Even though the rates of death or decompensation, when considered individually, did not differ significantly between groups,
the combined rate of death and decompensation was significantly lower in the group given BCAAs, compared with those
given lactoalbumin (but not maltodextrin). However, the BCAA
formulation had a poor taste, which contributed to a higher
dropout rate in that group; it is likely that the study was
therefore not actually blinded.77
Muto et al performed a multicenter, randomized, controlled
trial of 646 patients; they reported an increase in serum levels of
albumin and reduced rate of liver failure (ie, decreased further
decompensating events) among subjects with decompensated
cirrhosis who were given 12 g of BCAA per day, compared with
controls, and followed for 2 years.78 Again, BCAAs did not
improve survival or other important end points such as rates of

Nocturnal Supplements
Nocturnal oral supplements have been investigated as a
method to reduce gluconeogenesis and protein catabolism. A
12-month randomized control trial followed 108 patients who
received either daytime or bedtime oral nutritional supplementation with 700 calories.80 The study reported a significant
increase in total body protein stores over 3-, 6-, and 12-month
periods in the group given bedtime supplementation, which the
authors attributed to the decreased length of the overnight fast
and associated progression of nocturnal gluconeogenesis.80 The
difference between the 2 groups was equivalent to a gain of 2 kg
of lean muscle tissue, sustained over 12 months.80 Comparatively, there were no significant changes in total body protein
stores over the 12-month period in the group that received
daytime supplements. Improvements in protein stores might be
dependent on the type of nutrients provided, as opposed to the
timing of supplementation.57 For example, a BCAA-rich snack
significantly improved serum levels of albumin, nitrogen balance, and respiratory quotients, compared with the control
group, which was given carbohydrate for 3 months.57 These 2
studies indicate that bedtime supplementation can shorten the
length of overnight fasts and improve protein stores.

What About Parenteral Nutrition?

Total parenteral nutrition (TPN) should be restricted to
patients that have contraindications to oral or enteral nutrition
and to situations whereby adequate oral or enteral caloric intake is not being met despite best efforts. Patients who receive
parenteral nutrition are at risk for infectionsparticularly
catheter-related infections. Patients with advanced liver disease
are also at risk for infections, because of alterations in intestinal
permeability and endotoxemia; the presence of foreign bodies
such as indwelling catheters, combined with the high dextrose
milieu, could significantly increase the risk of infectious complications in this immunocompromised population. Additionally, when TPN is used for an extended period of time, liver
function can worsen.
However, TPN might meet metabolic needs of hospitalized,
malnourished patients when enteral requirements cannot be
met. For the critically ill and patients who have received liver
transplantation, the combined effects of preoperative malnutrition, surgical stress, and postoperative protein catabolism,
could lead to a need for early nutritional therapy.
TPN was reported to be reasonably well tolerated in patients
after liver transplantation, compared with those given enteral
nutrition.81 Recent ESPEN guidelines (grade C) recommend
that TPN should be considered after surgery for patients who
cannot tolerate oral and/or enteral nutrition; following liver
transplantation, nutrition support is indicated, with TPN as a

February 2012

clear second choice to enteral nutrition.82 Recommended nutrient intake includes provision of carbohydrate to cover 50%
60% of nonprotein energy, with lipid provision to cover 40%
50% of nonprotein energy requirements. Amino acid provision
should amount to 1.2 g/kg per day in patients with compensated cirrhosis and to a dose of 1.5 g/kg per day in those with
decompensated disease.

Conclusions
Many different factors contribute to malnutrition in
patients with chronic liver disease. Impaired hepatocyte functions disrupt the nutrient balance and metabolism, which (in
addition to ascites, protein catabolism, and nutrient deficiencies) can lead to hepatic encephalopathy. Studies have shown
that early detection and treatment of malnutrition is imperative
to improve patient outcomes. In addition to current recommendations for macro- and micronutrient supplementation, the
therapeutic uses of nutrients such as BCAA and probiotics
continue to be investigated.
References
1. Merli M, Riggio O, Dally L. Does malnutrition affect survival in
cirrhosis? PINC (Policentrica Italiana Nutrizione Cirrosi). Hepatology 1996;23:10411046.
2. Tsiaousi ET, Hatzitolios AI, Trygonis SK, et al. Malnutrition in end
stage liver disease: recommendation and nutritional support. J
Gastroenterol Hepatol 2008;23:527533.
3. Hirsch S, de la Maza MP, Gatts V, et al. Nutritional support in
alcoholic cirrhotic patients improves host defenses. J Am Coll
Nutr 1999;18:434 441.
4. Tai ML, Goh KL, Mohd-Taib SH, et al. Anthropometric, biochemical and clinical assessment of malnutrition in Malaysian patients
with advanced cirrhosis. Nutr J 2010;9:27.
5. Jensen GL, Mirtallo J, Compher C, et al. Adult starvation and
disease-related malnutrition: a proposal for etiology-based diagnosis in the clinical practice setting from the International Consensus Guideline Committee. JPEN J Parenter Enteral Nutr 2010;
34:156 159.
6. Stephenson GR, Moretti EW, EL-Moalem H, et al. Malnutrition in
liver transplant patients: preoperative subjective global assessment is predictive of outcome after liver transplantation. Transplantation 2001;72:666 670.
7. Carvalho L, Parise ER. Evaluation of nutritional status of nonhospitalized patients with liver cirrhosis. Arq Gastroenterol 2006;43:
269 274.
8. Merli M, Giusto M, Gentili F, et al. Nutritional status: its influence
on the outcome of patients undergoing liver transplantation. Liver
Int 2010;30:208 214.
9. Kalaitzakis E, Simrn M, Olsson R, et al. Gastrointestinal symptoms in patients with liver cirrhosis: associations with nutritional
status and health-related quality of life. Scand J Gastroenterol
2006;41:1464 1472.
10. Qin H, Li H, Xing M, et al. Nutritional support treatment for severe
chronic hepatitis and posthepatitic cirrhosis. J Huazhong Univ Sci
Technolog Med Sci 2006;26:217220.
11. Anonymous. Nutritional Status in Cirrhosis. Italian multicentre
cooperative project on nutrition in liver cirrhosis. J Hepatol 1994;
21:317325.
12. Sam J, Nguyen GC. Protein-calorie malnutrition as a prognostic
indicator of mortality among patients hospitalized with cirrhosis
and portal hypertension. Liver Int 2009;29:1396 1402.
13. Alvares-da-Silva MR, Reverbel da Silveira T. Comparison between
handgrip strength, subjective global assessment, and prognostic
nutritional index in assessing malnutrition and predicting clinical
outcome in cirrhotic outpatients. Nutrition 2005;21:113117.

MALNUTRITION IN ADVANCED LIVER DISEASE

123

14. Mahan LK Escott-stump S. Krausess food nutrition and diet

therapy. 10th ed. Philipdelphia, PA: WB Saunders Company,
2000.
15. Mller MJ, Bttcher J, Selberg O, et al. Hypermetabolism in
clinically stable patients with liver cirrhosis. Am J Clin Nutr 1999;
69:1194 1201.
16. Peng S, Plank LD, McCall JL, et al. Body composition, muscle
function, and energy expenditure in patients with liver cirrhosis: a
comprehensive study. Am J Clin Nutr 2007;85:12571266.
17. Dolz C, Ravrich JM, Ibanez J, et al. Ascites increases the resting
energy expenditure in liver cirrhosis. Gastroenterology 1991;
100:738.
18. Chen WJ, Chung YC. Energy expenditure in patients with hepatocellular carcinoma. Cancer 1994;73:590 595.
19. Braillon A, Gaudin C, Poo JL, et al. Plasma catecholamine concentrations are a reliable index of sympathetic vascular tone in
patients with cirrhosis. Hepatology 1992;15:58 62.
20. Braillon A, Cales P, Valla D, et al. Influence of the degree of liver
failure on systemic and splanchnic haemodynamics and on response to propranolol in patients with cirrhosis. Gut 1986;27:
1204 1209.
21. Lee SSBaik SK. Clinical consequences of cirrhosis: cardiovascular.
In: Boyer TD, Wright TL, Manns MP, eds. Zakim and Boyers hepatology. 5th ed. Philadephia: Saunders Elsevier 2006:457 475.
22. Ruiz-del-Arbol L, Urman J, Fernndez J, et al. Systemic, renal, and
hepatic hemodynamic derangement in cirrhotic patients with
spontaneous bacterial peritonitis. Hepatology 2003;38:1210
1218.
23. Dudrick SJ, Kavic SM. Hepatobiliary nutrition: history and future.
J Hepato Biliary Pancreat Surg 2002;9:459 468.
24. Pace A, de Weerth A, Berna M, et al. Pancreas and liver injury are
associated in individuals with increased alcohol consumption.
Clin Gastroenterol Hepatol 2009;7:12411246.
25. Badley BWD, Murphy FM, Bouchier IAD, et al. Diminishede micellular phase lipid in patients with chronic non-alcoholic liver disease and steatorrhea. Gastroenterology 1970;58:781789.
26. Cabre E, Hernandez-Perez JM, Fluvia L, et al. Absorption and
transport of dietary long-chain fatty acids in cirrhosis: a stableisotope-tracing study. Am J Clin Nutr 2005;81:692701.
27. Pignon JP, Baraona E, Poynard T, et al. Serum lipoproteins and
alcoholic diseases of the liver [in French]. Gastroenterol Clin Biol
1987;11:460 472.
28. Santos M, Friedberg SJ, Kudzma DJ, et al. Conversion of free
fatty acids to triglycerides. Determination in obstructive vs hepatocellular jaundice and cirrhosis. Arch Intern Med 1974;134:
457 460.
29. Bugianesi E, Kalhan S, Burkett E, et al. Quantification of gluconeogenesis in cirrhosis: response to glucagon. Gastroenterologist 1998;115:1530 1540.
30. Changani KK, Jalan R, Cox IJ, et al. Evidence for altered hepatic
gluconeogenesis in patients with cirrhosis using in vivo 31-phosphorus magnetic resonance spectroscopy. Gut 2001;49:557
564.
31. Owen OE, Reichle FA, Mozzoli MA, et al. Hepatic, gut, and renal
substrate flux rates in patients with hepatic cirrhosis. J Clin
Invest 1981;68:240 252.
32. Kalaitzakis E, Bosaeus I, Ohman L, et al. Altered postprandial
glucose, insulin, leptin, and ghrelin in liver cirrhosis: correlations
with energy intake and resting energy expenditure. Am J Clin Nutr
2007;85:808 815.
33. Merli M, Leonetti F, Riggio O, et al. Glucose intolerance and
insulin resistance in cirrhosis are normalized after liver transplantation. Hepatology 1999;30:649 654.
34. Mller MJ, Lautz HU, Plogmann B, et al. Energy expenditure and
substrate oxidation in patients with cirrhosis: the impact of
cause, clinical staging and nutritional state. Hepatology 1992;
15:782794.

124

CHEUNG ET AL

35. Aqel BA, Scolapio JS, Dickson RC, et al. Contribution of ascites to
impaired gastric function and nutritional intake in patients with
cirrhosis and ascites. Clin Gastroenterol Hepatol 2005;3:1095
1100.
36. Mccullough AJ, Bugianesi E, Marchesini G, et al. Gender dependent alterations in serum leptin in alcoholic cirrhosis. Gastroenterology 1998;119:947953.
37. Le Moine O, Marchant A, De Groote D, et al. Role of defective
monocyte interleukin-10 release in tumor necrosis factor-alpha
overproduction in alcoholics cirrhosis. Hepatology 1995;22:
1436 1439.
38. Grossberg AJ, Scarlett JM, Marks DL. Hypothalamic mechanisms
in cachexia. Physiol Behav 2010;100:478 489.
39. Ockenga J, Bischoff SC, Tillmann HL, et al. Elevated bound leptin
correlates with energy expenditure in cirrhotics. Gastroenterology
2001;119:1656 1662.
40. Marchesini G, Bianchi G, Lucidi P, et al. Plasma ghrelin concentrations, food intake, and anorexia in liver failure. J Clin Endocrinol Metab 2004;89:2136 2141.
41. Sturniolo GC, DInc R, Parisi G, et al. Taste alterations in liver
cirrhosis: are they related to zinc deficiency? J Trace Elem Electrolytes Health Dis 1992;6:1519.
42. Madden AM, Bradbury W, Morgan MY. Taste perception in cirrhosis: its relationship to circulating micronutrients and food preferences. Hepatology 1997;26:40 48.
43. de la Vega MJ, Santolaria F, Gonzlez-Reimers E, et al. High
prevalence of hyperhomocysteinemia in chronic alcoholism: the
importance of the thermolabile form of the enzyme methylenetetrahydrofolate reductase (MTHFR). Alcohol 2001;25:59 67.
44. Bergheim I, Parlesak A, Dierks C, et al. Nutritional deficiencies in
German middle-class male alcohol consumers: relation to dietary
intake and severity of liver disease. Eur J Clin Nutr 2003;57:431
438.
45. Levine JA, Morgan MY. Weighed dietary intakes in patients with
chronic liver disease. Nutrition 1996;12:430 435.
46. Yoshida Y, Higashi T, Nouso K, et al. Effects of zinc deficiency/
zinc supplementation on ammonia metabolism in patients with
decompensated liver cirrhosis. Acta Med Okayama 2001;55:
349 355.
47. Phillips JR, Angulo P, Petterson T, et al. Fat-soluble vitamin levels
in patients with primary biliary cirrhosis. Am J Gastroenterol
2001;96:27452750.
48. Arteh J, Narra S, Nair S. Prevalence of vitamin D deficiency in
chronic liver disease. Dig Dis Sci 2010;55:2624 2628.
49. Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. Hepatology 2009;50:291308.
50. Lin CC, Yin MC. Vitamins B depletion, lower iron status and
decreased antioxidative defense in patients with chronic hepatitis C treated by pegylated interferon alfa and ribavirin. Clin Nutr
2009;28:34 38.
51. Plauth M, Cabr E, Riggio O, et al. ESPEN guidelines on enteral
nutrition: liver disease. Clin Nutr 2006;25:285294.
52. Figueiredo FA, Perez RM, Freitas MM, et al. Comparison of three
methods of nutritional assessment in liver cirrhosis: subjective
global assessment, traditional nutritional parameters, and body
composition analysis. J Gastroenterol 2006;41:476 482.
53. Taniguchi E, Kawaguchi T, Itou M, et al. Subjective global assessment is not sufficient to screen patients with defective hepatic
metabolism. Nutrition 2011;27:282286.
54. Morgan MY, Madden AM, Soulsby CT, et al. Derivation and validation of a new global method for assessing nutritional status in
patients with cirrhosis. Hepatology 2006;44:823 835.
55. Nishida T, Tsuji S, Tsujii M, et al. Oral glucose tolerance test
predicts prognosis of patients with liver cirrhosis. Am J Gastroenterol 2006;101:70 75.
56. Delich PC, Siepler JK, Parker P. Liver disease. In: Gottschlich
MM, ed. The A.S.P.E.N. nutrition support core curriculum: a case

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 2

57.
58.

59.

60.

61.

62.
63.

64.

65.
66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.
77.

based approachthe adult patient. Silver Spring, MD: American

Society for Parenteral and Enternal Nutrition, 2007:540 557.
Nakaya Y, Okita K, Suzuki K, et al. BCAA-enriched snack improves
nutritional state of cirrhosis. Nutrition 2007;23:113120.
Matsumoto D, Yamanaka-Okumura H, Arai H, et al. Nutritional treatment of a patient with hepatic cirrhosis with the novel low glycemic
index liquid food (Inslow). J Med Invest 2007;54:375380.
Barkoukis H, Fiedler KM, Lerner E. A combined high fiber, low
glycemic index diet normalizes glucose tolerance and reduces
hyperglycemia and hyperinsulinemia in adults with hepatic cirrhosis. J Am Diet Assoc 2002;102:15031507.
Jenkins DJ, Shapira N, Greenberg G, et al. Low glycemic index foods
and reduced glucose, amino acid, and endocrine responses in
cirrhosis. Am J Gastroenterol 1989;84:732739.
Institute of Medicine. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino
acids. Washington, DC: National Academies Press, 2005.
Schulz GJ, Campos AC, Coelho JC. The role of nutrition in hepatic
encephalopathy. Curr Opin Clin Nutr Metab Care 2008;11:275280.
Crdoba J, Lpez-Helln J, Planas M, et al. Normal protein diet for
episodic hepatic encephalopathy: results of a randomized study.
J Hepatol 2004;41:38 43.
Sokol RJ. Fat-soluble vitamins and their importance in patients
with cholestatic liver diseases. Gastroenterol Clin North Am
1994;23:673705.
Moore KP, Aithal GP. Guidelines on the management of ascites in
cirrhosis. Gut 2006;55:112.
Salerno F, Guevara M, Bernardi M, et al. Refractory ascites:
pathogenesis, definition and therapy of a severe complication in
patients with cirrhosis. Liver Int 2010;30:937947.
Gupta A, Dhiman RK, Kumari S, et al. Role of small intestinal
bacterial overgrowth and delayed gastrointestinal transit time in
cirrhotic patients with minimal hepatic encephalopathy. J Hepatol
2010;53:849 855.
Malaguarnera M, Gargante MP, Malaguarnera G, et al. Bifidobacterium combined with fructo-oligosaccharide versus lactulosei n
the treatment of patients with hepatic encephalopathy. Eur J
Gastroenterol Hepatol 2010;22:199 206.
Malaguarnera M, Greco F, Barone G, et al. Bifidobacterium
longum with fructo-oligosaccharide (FOS) treatment in minimal
hepatic encephalopathy: a randomized, double-blind, placebocontrolled study. Dig Dis Sci 2007;52:3259 3265.
Sharma P, Sharma BC, Sarin SK. Predictors of nonresponse to
lactulose for minimal hepatic encephalopathy in patients with
cirrhosis. Liver Int 2009;29:13651371.
Pereg D, Kotliroff A, Gadoth N, et al. Probiotics for patients with
compensated liver cirrhosis: a double-blind placebo-controlled
study. Nutrition 2011;27:177181.
Bajaj JS, Saeian K, Christensen KM, et al. Probiotic yogurt for the
treatment of minimal hepatic encephalopathy. Am J Gastroenterol 2008;103:17071715.
Liu Q, Duan ZP, Ha DK, et al. Symbiotic modulation of gut flora:
effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004;39:14411449.
Lam V, Poon R. Role of branched chain amino acids in management of cirrhosis and hepatocellular carcinoma. Hepatol Res
2008;38(Suppl 1):107115.
James JH, Ziparo V, Jeppsson B, et al. Hyperammonaemia,
plasma aminoacid imbalance, and blood-brain aminoacid transport: a unified theory of portal-systemic encephalopathy. Lancet
1979;2:772775.
Chadalavada R, Sappati Biyyani RS, Maxwell J, et al. Nutrition in
Hepatic encephalopathy. Nutr Clin Pract 2010;25:257264.
Marchesini G, Bianchi G, Merli M, et al. Nutritional supplementation with branched-chain amino acid in advanced cirrhosis: a
double blind, randomized trial. Gastroenterology 2003;124:
17921801.

February 2012

78. Muto Y, Sato S, Watanabe A, et al. Effects of oral branched chain

amino acid granules on event-free survival in patients with liver
cirrhosis. Clin Gastroenterol Hepatol 2005;3:705713.
79. Charlton M. Branched-chain amino acids: metabolism, physiological function, and application. J Nutr 2006;136:295S298S.
80. Plank LD, Gane EJ, Peng S, et al. Noctural nutritional supplementation improves total body protein status of patients with liver
cirrhosis: a randomized 12-month trial. Hepatology 2008;48:
557566.
81. Wicks C, Somasundaram S, Bjarnason I, et al. Comparison of
enteral feeding and total parenteral nutrition after liver transplantation. Lancet 1994;344:837 840.

MALNUTRITION IN ADVANCED LIVER DISEASE

125

82. Plauth M, Cabr E, Campillo B, et al. ESPEN Guidelines on

Parenteral Nutrition: hepatology. Clin Nutr 2009;28:436 444.

Reprint requests
Address requests for reprints to: Maitreyi Raman, MD, MSc, 6D26
TRW Building, 3280 Hospital Drive, Calgary, Alberta T2N 4N1, Canada.
e-mail: mkothand@ucalgary.ca; fax: (403) 592-5090.
Conicts of interest
The authors disclose no conicts.