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Nutrition and Liver Diseases

J. Carlos Teran, MD

Address
Department of Gastroenterology, Cleveland Clinic Florida,
3000 West Cypress Creek Road, Fort Lauderdale, FL 33309, USA.
Current Gastroenterology Reports 1999, 1:335340
Current Science Inc. ISSN 1522-8037
Copyright 1999 by Current Science Inc.

Malnutrition and micronutrient deficiencies are common


in patients with liver diseases. The pathogenesis of protein
energy malnutrition in cirrhosis involves many factors,
including poor oral intake, malabsorption, and metabolic
abnormalities similar to stress. Encephalopathy may
complicate cirrhosis but is usually not caused by diet.
Protein restriction is only necessary in rare patients with
refractory encephalopathy. The use of branched-chain
amino-acid solutions is not supported by the literature.
Chronic liver diseases without cirrhosis are not usually
associated with proteinenergy malnutrition, but vitamin
and mineral deficiencies are common, especially with significant cholestasis. Fatty liver may result from excessive triglyceride uptake and production by the liver or by a secretory
defect. Therapy for fatty liver depends on its cause. Chronic
total parenteral nutrition may induce fatty liver and inflammation especially in patients with short-bowel syndrome.
Deficiency of choline in parenteral nutrition has been
proposed as the mechanism for liver disease. Acute liver
diseases such as fulminant hepatic failure or alcoholic hepatitis are considered hypercatabolic diseases and thus require
prompt nutritional intervention with a high-calorie enteral or
parenteral formula. In fulminant hepatic failure, low-protein,
fluid-restricted formulas are recommended.

Introduction
Nutritional deficiencies and proteinenergy malnutrition
(PEM) are often present in chronic liver diseases but are
also seen in acute liver diseases, especially in cases of
hepatic failure. Most information in this field comes from
studies of end-stage cirrhotic patients whose diseases
followed various etiologies. Some information is also
available regarding nutritional therapy for acute alcoholic
hepatitis or fulminant hepatic failure. Less is known about
nutrition in noncirrhotic chronic liver diseases such as
chronic hepatitis, chronic cholestasis, or hepatic steatosis.
In this review, current knowledge of the pathogenesis of
and therapy for nutritional problems in liver diseases is
discussed, with emphasis on end-stage liver disease and
hepatic encephalopathy.

Chronic Liver Diseases with Cirrhosis


Prevalence of proteinenergy
malnutrition in cirrhosis
Cirrhosis represents the end stage of most chronic liver
diseases. The association of PEM with cirrhosis of any
etiology is well-known. A high prevalence of PEM exists in
end-stage liver disease. Prevalence ranges from 34% to
82% in patients with alcoholic cirrhosis, based on anthropometric parameters [1]. In patients with nonalcoholic
cirrhosis, the prevalence of PEM ranges from 27% to 87%
[1]. The largest published nutritional survey showed a
30% prevalence of PEM in male patients and a 40% prevalence in female patients with cirrhosis [2]. Regardless of
the cause of cirrhosis, poor nutritional status is associated
with a bad prognosis for survival. This prognosis is shown
in patients awaiting liver transplantation, decompensated
patients with ascites, and cirrhotic patients undergoing
abdominal surgery [3]. Whether PEM is an independent
predictor of survival or simply a reflection of the severity of
liver insufficiency is still open for debate [4,5].
Problems with data interpretation arise from the lack
of agreement on the diagnostic criteria for PEM in cirrhosis. The traditional nutritional assessment techniques used
for most patients and healthy control subjects do not
translate well to cirrhotic patients. The diagnosis of depletion of the visceral protein compartment in cirrhotic
patients is particularly troublesome because most
nutritional markers are proteins produced in the liver.
Levels of albumin, prealbumin, and retinol-binding
protein, as well as immunologic parameters such as total
lymphocyte count and delayed hypersensitivity reactions,
are all abnormal in patients with cirrhosis. In one study,
81% of cirrhotic patients had decreased levels of visceral
proteins, 59% had abnormal results on immunologic tests,
and 35% had abnormal results on anthropometric tests
[6]. Estimation of fat and muscle protein compartments by
anthropometry of the upper extremities has been used by
most investigators to determine the prevalence of PEM.
New assessment techniques such as bioelectrical
impedance have proven unreliable in cirrhotics with
ascites or edema [7]. Perhaps the most accurate technique
of nutritional assessment in patients with cirrhosis is the
measurement of body cell mass either by whole-body
potassium count or by stable isotope dilution. Unfortunately, these techniques are not readily available to the
clinician and remain investigational. Nevertheless, body
cell mass has been shown to decrease even in early stages
of cirrhosis [8].

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Pathogenesis of proteinenergy
malnutrition in cirrhosis
The pathogenesis of malnutrition in cirrhosis is thought to
be multifactorial (Table 1). A majority of cirrhotic patients
suffer from gastrointestinal symptoms such as anorexia,
taste dysfunction, nausea, and vomiting, which affect their
nutrient intake [9]. Taste abnormalities have been associated with zinc and magnesium deficiencies [10]. Also, 40%
of cirrhotic patients have steatorrhea caused by cholestasis
or chronic pancreatitis. A survey on the food intake of hospitalized patients with cirrhosis showed a decrease in calor i e s a n d p r o t e i n i n g e s t i o n ave r a g i n g 50 % o f t h e
recommended dietary allowance [11]; however, a recent
controlled study showed that hospitalized cirrhotics have
similar intake to that of other hospitalized patients with
different conditions [12].
Perhaps the most interesting and important aspect of
the pathogenesis of PEM in cirrhosis is the presence of
serious metabolic abnormalities that mimic a state of
catabolism similar to sepsis or trauma [3]. Measurements
of the basal energy expenditure in cirrhotics have not
shown a statistically significant difference from measurements in healthy control subjects when energy expenditure
is expressed in calories per kilogram of body weight [13].
Prediction of resting energy expenditure based on HarrisBenedict equations is either too low or too high in 50% of
cirrhotics. When resting energy expenditure is expressed in
calories per kilogram of lean body mass, a significant
increase is seen in patients with cirrhosis compared to
healthy control subjects [14]. The presence of ascites
increases the resting energy expenditure. This means that
cirrhotic patients are spending more energy per unit of
metabolically active tissue, but their overall energy expenditure tends to be equal to that of healthy control subjects
because the cirrhotic patients body cell mass is decreased.
These patients tend to have respiratory quotients (RQ) that
are significantly lower than those of healthy control subjects after an overnight fast. The amount of fuel cirrhotic
patients utilize after an overnight fast is similar to that used
by healthy control subjects after 72 hours of starvation
[15]. In other words, the metabolism of cirrhotics mimics
that of starving control subjects even at early phases of
fasting. However, as opposed to a chronically starving
patient in whom the energy expenditure decreases over
time, cirrhotics continue to have increased energy expenditure that leads to progressive loss of muscle and fat mass,
which results in PEM.
Studies on carbohydrate metabolism in cirrhosis have
shown that these patients have a high prevalence of
glucose intolerance [17]. The pathogenesis of this abnormality is not well-defined, but it seems to be caused by a
postreceptor intracellular abnormality in both liver and
muscle. This is probably associated with the increase in
circulating catabolic hormones such as glucagon, cortisol,
and catecholamines. Associated with this insulin resistance
is a decreased storage of glycogen in the liver and muscle,

Table 1. Causes of Malnutrition in Cirrhosis


Decrease in oral intake
Anorexia, nausea, vomiting, early satiety, taste
abnormalities, iatrogenic due to restrictive diets.
Maldigestion and malabsorption
Fat malabsorption caused by cholestasis or chronic
pancreatitis; associated with calcium and liposoluble
vitamin malabsorption.
Metabolic abnormalities
Glucose intolerance; increased protein and lipid
catabolism similar to sepsis or other catabolic states.

which leads to decreased availability of glucose during the


fasting period. The result of these carbohydrate metabolism abnormalities is a decrease in the availability of
glucose in the fasting period, which leads to the early utilization of lipids and protein as fuel sources, manifested as a
low RQ. Abnormalities in lipid metabolism have also been
described in cirrhosis. Fatty acid levels are increased, as is
ketone body production. Studies with labeled isotopes
have shown that the fasting turnover of fatty acids and glycerol is increased in cirrhosis. However, impairment of fatty
acid storage is evident in the form of triglycerides probably
due to lipoprotein lipase inhibition and a decrease in availability of glycerol phosphate in the adipocyte. This imbalance between fat synthesis and fat catabolism results in the
long-term depletion of fatty reserves in the adipose tissue.
One of the most remarkable metabolic abnormalities in
patients with end-stage liver disease is the change in amino
acid metabolism. The catabolism of muscle protein seems to
be increased in the fasting state as shown by leucine turnover
studies [16]. When the rate of leucine turnover is expressed
per kilogram of body cell mass, there is an increase that is significantly different from that occurring in control subjects
[14]. These studies seem to indicate that during a fasting state
there is an increase in muscle protein catabolism in cirrhosis.
However, total body leucine oxidation is decreased, which
implies that leucine is not used as a source of energy. In cirrhosis, the plasma levels of branched-chain amino acids are
low because of an increase in uptake by the skeletal muscle to
generate glutamine and alanine. The latter amino acids are
released into the blood stream and go to the liver to become
the substrates of hepatic gluconeogenesis [3]. This serum
amino acid imbalance is also seen in sepsis and trauma and
is probably mediated by an increase in insulin concentrations. In the past, this imbalance in serum amino acids was
thought to be caused by the neurologic impairment frequently seen in cirrhotic patients, known as hepatic encephalopathy. This false neurotransmitter hypothesis has not
been proven experimentally. In cirrhosis, excessive glutamine
is synthesized by the skeletal muscle and constitutes a
backup mechanism for ammonia elimination through the
kidneys. This phenomenon underscores the importance of
preserving the skeletal muscle mass as a means of preventing
chronic hepatic encephalopathy. In addition, urinary nitro-

Nutrition and Liver Diseases Teran

gen losses are increased in cirrhotic patients with normal


renal function. This occurrence is consistent with the concept
that cirrhosis is a hypercatabolic disease.
Cirrhotic patients have a decreased carbohydrate utilization and storage capacity along with increased fat and
protein catabolism, which lead to a chronic catabolic state
that results in depletion of protein and lipid reserves. These
metabolic abnormalities, paired with decreased food
intake and nutrient absorption, constitute the basis of the
pathogenesis of PEM in end-stage liver disease. One important unresolved question is: What is the cause of this continuous catabolic state of cirrhotic patients? Sufficient
information is available to postulate that this hypercatabolic state is mediated by cytokines. More specifically,
cirrhotic patients show higher blood levels of tumor necrosis factor, interleukin-1, and interleukin-6, which have
catabolic effects in muscle, adipose tissue, and liver [18].
Perhaps the reason for an increase in the levels of these
catabolic cytokines is the elevation of plasma endotoxin
concentration in cirrhosis [19]. One hypothesis suggests
that cirrhotic patients have an increase in intestinal permeability, which allows the leakage of endotoxin from the
intestine to the lymphatics and the blood stream [20].
Endotoxin triggers the release of cytokines and nitric oxide,
which may be the mediator of the metabolic and hemodynamic disturbances of cirrhosis [21].

Nutritional therapies in cirrhosis


Several studies report benefits from nutritional therapy in
end-stage liver disease. Short-term benefits include
improved nitrogen balance, decreased length of hospital
stay, and improvement in liver function. [22]. Some studies
have also reported long-term benefits such as decreased incidence and severity of encephalopathy, improved
nitrogen balance, and, arguably, improvement in overall survival rates [23]. Oral supplementation with liquid diets is
often unsuccessful in cirrhotic patients due to anorexia and
other gastrointestinal symptoms. Short-term tube feedings
have resulted in improvements in length of hospital stay and
severity of liver disease [24]. Long-term enteral nutrition is
difficult to test in cirrhotic patients mainly because of the
need to rely on nasogastric or nasoenteric tubes given the
poor outcomes of percutaneous endoscopic gastrostomy in
patients with portal hypertension. Methods for nutritional
therapy are summarized in Table 2.
One of the most important issues in clinical practice is
the amount and quality of protein required by patients
with end-stage liver disease. The widespread practice of
protein restriction for all cirrhotic patients is not justified
and often leads to iatrogenic malnutrition. A diet containing 1.0 g of mixed protein/kg/d is well-tolerated by most
patients. Only patients with intractable chronic encephalopathy need protein restricted to 0.6 to 0.8 g/kg/d. During
acute episodes of encephalopathy, temporary protein
restriction may be needed, but normal protein intake
should be resumed soon after the cause of encephalopathy

337

Table 2. Nutritional Therapy in Cirrhosis


Cirrhosis without encephalopathy
No protein restriction (1.01.5 g/kg/d).
High-carbohydrate, high-calorie diet (12601400 J/kg/d).
Frequent small meals and bedtime snack.
Sodium and water restriction only if ascites or edema
is present.
Multivitamins, calcium, zinc, and magnesium supplements
as needed.
Cirrhosis with acute encephalopathy
Temporary protein restriction (0.60.8 g/kg/d) until cause
of encephalopathy is diagnosed and eliminated.
Resume normal protein intake as soon as possible.
Provide high-calorie formula via enteral feeding or
parenteral nutrition.
Cirrhosis with chronic encephalopathy
Protein restriction (0.60.8 g/kg/d).
Encourage vegetarian diet or low animal protein intake.
Multiple small carbohydrate-rich meals.
Sodium and water restriction usually required; vitamin and
mineral supplements as needed.

has been identified and treated. Branched-chain aminoacid formulas are thought to be beneficial for cirrhotic
patients with encephalopathy; randomized clinical trials
have not shown a significant advantage for branched-chain
amino-acid formulas over standard protein solutions
[25,26]. While branched-chain amino-acid formulas have
proven more effective than placebo and shown similar
results to lactulose or neomycin in the treatment of hepatic
encephalopathy, they are not better than standard protein
formulas, and they are more costly [23]. For these reasons, branched-chain amino-acid formulas are rarely recommended. In our practice we use them only occasionally
in cirrhotic patients with refractory encephalopathy or profound hepatic coma. In noncritically ill patients with
hepatic encephalopathy, other means of dietary manipulation can be attempted, such as supplementation of fiber or
vegetarian diets [23]. These regimens have proven beneficial mainly because soluble fiber ferments in the colon by
the same mechanism as lactulose.
The preservation of the skeletal muscle mass seems to
be beneficial in preventing recurrent encephalopathy. This
may be true because of the role of skeletal muscle in
ammonia elimination. Given the metabolic abnormalities
described in cirrhosis, which result in increased catabolism
during fasting, frequent small meals and a bedtime snack
are recommended to patients. Frequent meals have also
been shown to promote a positive nitrogen balance in
cirrhotic patients [27]. If ascites and hyponatremia are
present, water restriction is indicated. In cholestatic types
of cirrhosis such as primary sclerosing cholangitis and
primary biliary cirrhosis, supplementation of lipid soluble
vitamins (A, D, E, and K) and calcium may be necessary if
steatorrhea is present. Zinc deficiency is common in
cirrhotic patients from a decrease in hepatic storage
capacity. Vitamin A deficiency may arise due to decreased

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release from the liver. Zinc supplements should be considered for patients whose plasma levels are low or in those
with dysgeusia or night blindness. There is no evidence,
however, that zinc improves encephalopathy [23].

Chronic Liver Disease without Cirrhosis


Chronic hepatitis
Proteinenergy malnutrition is unusual in patients with
chronic liver disease without cirrhosis. Patients with
chronic viral hepatitis may experience anorexia and nausea
that limit their food intake, but PEM is rare. Most commonly, precirrhotic patients may present with vitamin deficiencies. Thiamine and folate deficiencies are well-known
in patients with alcoholic liver disease. Other water-soluble-vitamin deficiencies in patients with chronic liver
disease include deficiencies of pyridoxin, niacin, riboflavin, and B12. Cholestatic liver diseases with steatorrhea are
associated with a high prevalence of deficiencies to lipidsoluble vitamins A, D, E, and K. Other than vitamin supplementation, no formal nutritional recommendations are
available for patients with noncirrhotic chronic liver
diseases. A diet of 1.0 to 1.5 g of protein/kg/d and 126 to
147 J/kg/d is recommended for healthy individuals.
Neither protein nor sodium restriction is necessary.
Fatty liver
Another common chronic liver disease is hepatic steatosis,
or fatty liver. This is a relatively benign liver condition that
occasionally leads to chronic inflammation (steatohepatitis)
and fibrosis similar to that seen in alcoholic liver disease.
The pathogenesis of fatty liver appears to be disproportionate between the uptake and oxidation of fatty acids versus
their synthesis and release as lipoproteins by the liver [28].
Causes of increased uptake of lipids by the liver include
diabetes mellitus, hyperlipidemia, and obesity. Alcohol
abuse promotes the hepatic synthesis of fatty acids. Causes
for decreased release of lipids from the liver include severe
protein malnutrition as seen in cases of kwashiorkor, jejunoileal bypass operations for morbid obesity, and alcohol
abuse. In patients with fatty liver related to obesity, calorie
restriction is recommended. Otherwise, hepatic steatosis
should be treated according to its cause, including tighter
control of diabetes and hyperlipidemia and abstinence from
alcoholic beverages. A low-fat diet is recommended.
Parenteral nutritioninduced liver disease
An iatrogenic cause of fatty liver with or without inflammation occurs in patients treated with long-term total
parenteral nutrition (TPN). In early stages, an increase in
serum transaminases occurs. Later, cholestasis becomes
more important, as shown by increases of alkaline
phosphatase and direct bilirubin. Follow-up studies have
shown that as early as 6 months after initiation of TPN,
hepatic fibrosis may be present in the liver, and cirrhosis
may develop fully in 1 year, especially in patients with

short-bowel syndrome. Biliary sludge and gallstones are


common in chronic TPN patients and should be excluded
as a cause of cholestasis. Cholecystokinin injections and
oral feedings have been useful in preventing biliary disease.
Findings from noncontrolled studies include improvements of TPN-induced cholestasis with oral metronidazole,
glutamine supplements, fat restriction, or introduction of
oral or enteral feedings [29]. More recently, choline
supplementation has proven effective in both oral and
parenteral form [30]. The pathogenesis of long-term TPN
liver disease is still under investigation. Attention to the
amount of calories and the proportion of carbohydrates
and lipids in TPN is essential to prevent this problem,
which frequently results from overfeeding. In this setting,
indirect calorimetry can be extremely helpful in estimating
nutritional requirements and avoiding overfeeding.

Acute Liver Diseases


Alcoholic hepatitis
Cytokine-mediated metabolic abnormalities are found in
alcoholic hepatitis that are similar to those of cirrhosis and
other catabolic states [31]. Severe anorexia, nausea, and
vomiting limit the intake of patients who experience these
abnormalities. Proteinenergy malnutrition has been
shown to worsen the prognosis of alcoholic hepatitis [32].
One large controlled trial has shown benefits of short-term
enteral feeding in patients with alcoholic hepatitis, including improved liver function tests and shorter hospital stay
[33]; however, no decrease in mortality has been reported.
During the anorectic phase of alcoholic hepatitis, enteral
nutrition should be started to provide sufficient protein and
energy to support these catabolic patients.
Fulminant hepatic failure
Fulminant hepatic failure results from a severe acute injury to
the liver and represents a great nutritional challenge. On one
hand, patients are hypercatabolic mainly from increased
intracranial pressure, which triggers the release of hormones
such as cortisol and catecholamines. On the other hand, the
lack of hepatic function severely limits the patients tolerance
of nutritional support. Fluid intake must be limited to a minimum in order to prevent worsening of brain edema. Although
the calorie and protein requirements of these patients are high,
nutritional support must be started slowly. Initially an infusion of 10% dextrose should be provided to prevent hypoglycemia and limit catabolism. A nasoenteric tube can be safely
placed and used if there is no intestinal ileus. If paralytic ileus
is present, then TPN becomes necessary [23]. The goal of this
treatment is to provide sufficient energy in the form of carbohydrates and lipids and to limit the patients protein intake in
cases of severe encephalopathy. Branched-chain amino-acid
formulas have not been supported by clinical studies for use in
hepatic encephalopathy. Our practice is to slowly increase protein intake to about 0.6 g/kg/d. As the clinical picture declares
itself, patients who spontaneously improve can be given

Nutrition and Liver Diseases Teran

increased amounts of parenteral or enteral nutrition, while


those who require liver transplantation can be started at fullstrength parenteral nutrition in the postoperative period.

Conclusions
Nutritional problems in liver diseases are very prevalent.
They are brought about by a combination of factors including metabolic abnormalities, poor oral intake, and
malabsorption. Although nutritional assessment is difficult in liver disease, results from most studies indicate that
poor nutritional status based on anthropometric parameters correlates with a bad prognosis. Decompensated
cirrhosis and severe acute hepatitis should be considered
catabolic states similar to sepsis or trauma. Efforts to
improve the nutritional status of patients with cirrhosis,
alcoholic hepatitis, and fulminant hepatic failure are warranted, preferably through enteral nutrition or, when
needed, by parenteral nutrition. Branched-chain aminoacid formulas offer no advantages over standard amino
acids in the treatment of hepatic encephalopathy. Protein
restriction is not necessary except in cases of refractory
chronic encephalopathy or fulminant hepatic failure. Most
patients with cirrhosis tolerate a diet with normal amounts
of protein. Unnecessary protein restriction may cause iatrogenic malnutrition. For patients with noncirrhotic chronic
liver disease, a normal diet is recommended, and vitamin
and mineral supplements may also be needed. Dietary
manipulation and correction of the specific cause are recommended for the management of patients with fatty liver.
Patients receiving long-term parenteral nutrition may benefit from precise assessment of their energy requirements by
indirect calorimetry as well as choline supplementation.

References and Recommended Reading


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