English Report
English Report
English Report
OF HEPATOLOGY
encephalopathy”, ‘‘osteoporosis”, ‘‘liver transplantation” for peer-reviewed by external expert reviewers and approved by
each specific topic of the guideline. The selection of references the EASL Governing Board.
was then based on appropriateness of study design, number of These guidelines are directed at consultant hepatologists,
patients, and publication in peer-reviewed journals. Original specialists in training, and general practitioners and refer specif-
data were prioritised. The resulting literature database was ically to adult patients with cirrhosis. Their purpose is to pro-
made available to all members of the panel. vide guidance on the best available evidence to deal with
All recommendations were discussed and approved by all nutritional problems in patients with chronic liver disease. A
participants. The Committee met on two occasions during inter- few schemes were produced by the panel and are included in
national meetings with experts who were available to partici- these guidelines to help with the management of nutritional
pate, two ad hoc teleconferences also took place for discussion problems in patients with liver cirrhosis.
and voting. For clarity, the terms and definitions used in the present
The evidence and recommendations in these guidelines have CPGs are summarised (Box 1).
been graded according to the Grading of Recommendations
Assessment, Development and Evaluation (GRADE) system.16
The classifications and recommendations are therefore based Screening and assessment for malnutrition and
on three categories: the source of evidence in levels I through obesity in liver cirrhosis: Who, when and how
III; the quality of evidence designated by high (A), moderate Given the worse prognosis associated with malnutrition, all
(B), or low quality (C); and the strength of recommendations patients with advanced chronic liver disease, and in particular
classified as strong (1) or weak (2) (Table 1). All recommenda- patients with decompensated cirrhosis are advised to undergo
tions based on expert opinion because of the lack of available a rapid nutritional screen. Those at risk of malnutrition should
data were graded as III. The recommendations were complete a more detailed nutritional assessment to confirm
Muscle wasting The active, progressive loss of muscle mass due to an underlying disease, ultimately leading to muscle atrophy. Most inflammatory
diseases, malnutrition and increased catabolism induce muscle wasting
Sarcopenia A generalised reduction in muscle mass and function due to aging (primary sarcopenia), acute or chronic illness (secondary
sarcopenia), including chronic liver disease
Frailty Loss of functional, cognitive, and physiologic reserve leading to a vulnerable state. Frailty may be considered a form of
nutrition-related disorder
Immunonutrition Use of specific nutrients in an attempt to modulate the immune system (not necessarily in the presence of malnutrition) and function
to improve health state. Examples include enteral nutritional formulas enriched with ω-3 fatty acids, arginine, glutamine and
nucleotides
Deconditioning Deterioration of muscle functional capacity related to immobility and chronic debilitating disease
Measures of frailty, defined as patient’s vulnerability to implement in those with advanced disease. Therefore, repeated
stress, decreased physiologic reserve and functional status 24 h dietary recalls are also optional.51 The 24 h recall technique
deficits39,40 can also be used in the assessment of cirrhotic requires short-term recall, is less burdensome, less likely to alter
patients. There are several measures of frailty that are used in eating behaviour than food diary, and can be used across diverse
geriatrics and were also demonstrated to have predictive value populations because it does not require a high level of literacy.52
in cirrhotic patients. The Fried frailty phenotype is characterised At a minimum, patients should be asked if their relative food
by five domains: unintentional weight loss, self-reported intake has changed and, if so, by how much (by half etc.) and
exhaustion, weakness (grip strength), slow walking speed, and over what period of time (for example, as indicated in the
low physical activity.39 An increase in the Fried frailty score SGA – nutritional assessment tool).53
was demonstrated to be associated with increased risk of liver
transplant waitlist mortality, even when adjusting for MELD.40 Obesity in cirrhosis: Assessment and interpretation
The short physical performance battery (SPPB) consists of timed With the increasing prevalence of obesity and NASH-related cir-
repeated chair stands, balance testing, and a timed 13-ft walk rhosis, attention needs to be paid to obesity in patients with cir-
and takes 2–3 mins to complete. Although the SPPB does not rhosis. Obesity does not rule out malnutrition. The combination
correlate with CT-based muscle mass in men or women,38 it of loss of skeletal muscle and gain of adipose tissue is termed
predicts liver transplant waitlist mortality.38,40 At present, there sarcopenic obesity and is observed in a significant number of
are no standardised or universally accepted criteria to diagnose patients with cirrhosis.14,54,55 Moreover, post-transplant obesity
frailty in cirrhosis. and metabolic syndrome are common and weight gain after
transplantation is considered to be primarily due to an increase
Global assessment tools in cirrhosis in the adipose tissue, with concomitant loss in skeletal mus-
The technique of subjective global assessment (SGA) uses data cle.55,56 Therefore, malnutrition needs to be estimated routinely
collected during clinical evaluation to determine nutritional sta- and treated in the obese cirrhotic patient. In clinical practice,
tus without recourse to objective measurements.32 Overall, SGA BMI is adequate to recognise obesity (defined as BMI equal or
has fair to good inter-observer reproducibility41 and is associ- greater than 30 kg/m2) in cirrhotic patients, in the absence of
ated with various clinical and prognostic variables of liver trans- fluid retention. In the case of fluid retention, BW needs to be
plantation.42 However, agreement of SGA with other methods of corrected by evaluating the patient’s dry weight, commonly
assessment of nutritional status (total lymphocyte count, estimated by post-paracentesis BW or weight recorded before
MAMC, MAMA, TSF, subscapular skinfold thickness, BMI and fluid retention if available, or by subtracting a percentage of
handgrip measurement) is low (K <0.26).43 Furthermore, SGA weight based upon the severity of ascites (mild 5%; moderate
underestimates the prevalence of muscle loss in liver disease 10%; severe 15%), with an additional 5% subtracted if bilateral
patients, compared with other objective measures.36,44–47 pedal oedema is present, as performed in several studies.21,30
The Royal Free Hospital-global assessment (RFH-GA),32 for This is still not validated but excellent inter-observer agreement
determining nutritional status in patients with cirrhosis is has been demonstrated. The dry-weight BMI is then calculated
reproducible, correlates with other measures of body composi- by dividing the patient’s estimated dry weight (kg) by the
tion and predicts survival and post-transplant complica- square of the patient’s height (m).
tions.32,48,49 Patients are stratified into one of three categories The proposed process for nutritional screening and assess-
based on their dry weight-based BMI and their MAMC: ade- ment in patients with chronic liver disease is summarised
quately nourished, moderately malnourished (or suspected to (Fig. 1).
be), or severely malnourished. The limitations of this tool
include the time required, and the need for trained personnel
for consistent results. Recommendations
Reported dietary intake Perform a rapid nutritional screen in all patients with
Dietary interviews provide practical information for nutritional cirrhosis and complete a detailed assessment in those
interventions by identifying what and how much the patient is at risk of malnutrition, to confirm the presence and
willing and capable of eating and determining specific nutrient severity of malnutrition. (Grade II-2, B1)
deficiencies that need to be corrected. A detailed assessment of
Assume risk for malnutrition to be high if BMI
dietary intake is suggested to include: food, fluids, supplements,
<18.5 kg/m2 or Child-Pugh C. Utilise nutritional screen-
number of meals and their timing throughout the day (e.g. inter-
ing tools to assess the risk of malnutrition in all other
val between meals, breakfast and late-night meals as recom-
instances. (Grade II-2, B1)
mended), as well as calories and quality and quantity of
protein intake. It should also include barriers to eating: nausea, In the diagnosis of obesity (BMI >30 kg/m2) always
vomiting, aversion to certain foods, taste, low-sodium diet, early consider the confounding effect of fluid retention and
satiety, gastrointestinal pain and diarrhoea or constipation. The estimate dry BW, even though the accuracy is low.
symptoms section of the abridged scored patient-generated (Grade II-2, B2)
subjective global assessment (abPG-SGA) can be used to con- Include an assessment of sarcopenia within the nutri-
struct the questions.50 tional assessment. (Grade II-2, B1)
Evaluation of dietary intake is time consuming, requires
skilled personnel and relies on patient recall and cooperation. Whenever a CT scan has been performed, assess muscle
The best method that relies the least on patient recall is a mass on images by this method. Anthropometry, DEXA
three-day food diary. However, it requires patients to cooperate or BIA are possible alternatives, which also allow for
and follow detailed instructions, which may make it difficult to serial measurements. (Grade II-2, B1)
18.5-29.9 kg/m2
Follow up re-screen
High risk Medium risk Low risk at least 1/year
Treat:
Nutrition supplementation and appropriate follow-up
(repeat assessment every 1-3 months in the 1st year)
Fig. 1. Nutritional screening and assessment in patients with cirrhosis. All patients should undergo a rapid screening of malnutrition using validated,
accepted tools. A liver specific screening tool which takes into consideration fluid retention may be advisable (Royal Free Hospital Nutritional Prioritizing Tool
(RFH-NPT). Patients found to be at high risk of malnutrition should undergo a detailed nutritional assessment, and based on the findings they should receive
either supplementation or regular follow-up. yIn a case of fluid retention, body weight should be corrected by evaluating the patient’s dry weight by post-
paracentesis body weight or weight recorded before fluid retention if available, or by subtracting a percentage of weight based upon severity of ascites (mild,
5%; moderate, 10%; severe, 15%), with an additional 5% subtracted if bilateral pedal oedema is present. BIA, bioelectrical impedance analysis; BMI, body mass
index; CT, computed tomography; DEXA; dual-energy X-ray absorptiometry.
ideally with doubly labelled water or in a respiratory chamber, period of fasting are therefore recommended in cirrhotic
but these methods are not feasible in the clinical setting. Phys- patients.
ical activity is reduced in patients with decompensated cirrhosis Protein needs are based on the minimum protein intake
and negligible when patients are hospitalised. In cirrhotic required to maintain nitrogen balance. In alcoholic
patients, TEE varies between 28 to 37.5 kcal/kg.BW/d.63,67–70 cirrhosis, nitrogen balance was achieved with intakes of
Some studies evaluated whether decompensated liver cirrhosis 0.8 g/kg.BW/d.81 This cut-off was confirmed in studies wherein
affected REE. One small longitudinal study suggested that cirrhotic patients received diets with increasing protein con-
ascites increases REE.71 However, a cross-sectional study found tent.70,82 These studies also showed that cirrhotic patients are
no difference in REE between patients with varying levels of able to utilise up to 1.8 g/kg.BW/d of protein.70 In the past, there
liver disease severity and fluid retention.72–74 Measured REE has been controversy about whether patients suffering from HE
may be higher than predicted, a situation termed hyperme- should undergo a transient restriction in protein intake, in order
tabolism. However, hypermetabolism cannot be identified by to limit the synthesis of ammonium and the deamination of
clinical or laboratory parameters,75 the severity and the aetiol- protein to aromatic amino acids. However, normal to high pro-
ogy of liver cirrhosis and the presence of ascites.25 REE may tein intake does not precipitate HE83,84 and may even improve
be estimated by predictive formulae but these are inaccurate mental status85,86 (see paragraph on hepatic encephalopathy).
in advanced cirrhotic patients, and thus measurement by indi- The recommended protein intake in patients with a
rect calorimetry is advisable whenever possible.61,62 The avail- diagnosis of liver cirrhosis is 1.2–1.5 g/kg.BW/d to prevent loss
ability of the hand held calorimeter at the bedside is a of muscle mass and reverse muscle loss in those who are sar-
possible alternative to determine a patient’s daily caloric copenic. Indeed, sarcopenia, as previously stated, contributes
needs.76 to worse clinical outcomes, independent of the severity of liver
The approach of most nutritional intervention studies in liver disease.27,63 Options for the treatment of sarcopenia will be
cirrhosis is to supply at least 35 kcal/kg.BW/d. The use of actual discussed in the next section.
BW, corrected for ascites (see previous section), is considered Short dietary advice for use when treating a cirrhotic patient
safe. This can be achieved primarily by tailoring the oral dietary at bedside or during an outpatient visit is provided (Box 2).
intake, even though this goal is frequently difficult to accom-
plish. The role of a nutrition support team has recently been
underlined by a retrospective study showing that nutritional Approach to sarcopenia in patients with liver cirrhosis
intervention, led by a multidisciplinary team, and in which cir- Factors related with sarcopenia in patients with cirrhosis
rhotic patients participated in teaching sessions about the rele- Skeletal muscle mass is the largest protein store in the body. A
vance of appropriate nutrition in chronic liver disease, was able balance between skeletal muscle protein synthesis and break-
to improve survival rates and quality of life.77 down is responsible for protein homeostasis (or proteostasis)
Whether frequent feeding can help prevent accelerated star- that maintains skeletal muscle mass.66,87,88 In the past, whole
vation and the related proteolysis has also been extensively body protein turnover studies have yielded conflicting results
evaluated. Since the longest inter-meal duration is at night, with unaltered, increased or decreased protein synthesis and
strategies to shorten nocturnal fasting with a late evening snack breakdown in cirrhosis.3,89 Skeletal muscle mass depends on a
have been explored, achieving an improvement in metabolic number of physiological factors including age, gender and eth-
profile and quality of life, although muscle mass did not show nicity. The severity and aetiology of liver disease also affects
consistent improvement.78 The adoption of a breakfast contain- muscle mass, with cholestatic and alcoholic liver disease lead-
ing some proteins79 and a late evening snack80 to shorten the ing to the most severe muscle loss independently of the severity
Box 2. Short, practical dietary advice for bedside or outpatient clinic use.
• Most of what you have heard/read on the relationship between food and the liver has limited scientific evidence to support it. Generally, healthy eating of a
variety of foods is advisable for all patients.
• Virtually no food other than alcohol actually damages the liver and/or is genuinely contraindicated in patients with chronic liver disease.
• In most patients with chronic liver disease, eating an adequate number of calories and protein is much more important than avoiding specific types of food,
so it is important that you have a good, varied diet that you enjoy.
• You should try to split your food intake into 3 main meals (breakfast, lunch and dinner) and 3 snacks (mid-morning, mid-afternoon, late evening). The
late-evening snack is the most important, as it covers the long interval between dinner and breakfast.
• You should try to eat as many fruit and vegetables as you can. If you feel that this makes you feel bloated, and that it makes you eat less, please report to
your doctor or dietician.
• You should try not to add too much salt to your food. It may take some time to adjust, but it usually gets easier with time. However, if you keep feeling that
this makes your food unpleasant to eat, and that it makes you eat less, please report to your doctor or dietician.
• A limited proportion of patents with liver disease have a complication called hepatic encephalopathy, which may make them tolerate animal protein (meat)
less well than vegetable protein (beans, peas etc.) and dairy proteins. Before you make any changes to your protein intake, you should always ask your
doctor or dietician. Please do not reduce your total protein intake as it is not advisable in cirrhosis.
• Some patients with liver disease have other diseases, for example diabetes or overweight/obesity, which require dietary adjustments. Please remember to
tell your doctor about all your illnesses and about any dietary advice you have already received from other doctors, nurses or dieticians.
Transplantation
Mitochondrial ↓ ATP
Proteostasis
dysfunction ↑ ROS
Mitoprotective Structured
agents exercise
programme
Muscle mass Muscle contractile
function
Fig. 2. Mechanisms and potential targets for anabolic resistance and dysregulated proteostasis resulting in sarcopenia and/or failure to respond to
standard supplementation. Adapted from Dasarathy S. et al. 2016.65 BCAA, branched chain amino acid; ROS, reactive oxygen species; Tx, treatment.
necessarily muscle mass.116 Resistance exercise promotes an quality data are lacking, particular attention must be paid to
increase in skeletal muscle mass.116 However, exercise also the protein intake needed to maintain muscle mass, because
increases muscle ammonia generation and portal pres- of the potential risk of exacerbating sarcopenia during weight
sure,117,118 both of which can have adverse effects in cirrhotic loss interventions.
patients. Despite these potential adverse responses, beneficial No clear-cut data is available regarding the best type of phys-
effects have been reported.103,104 Since both muscle loss and ical exercise (aerobic vs. anaerobic; endurance vs. resistance/
impaired contractile function are components of sarcopenia in strength training) and its duration in this population. In patients
cirrhosis, a combination of resistance and endurance exercise with portal hypertension, avoidance of abdominal pressure
would probably be appropriate and beneficial, as confirmed by seems reasonable even though there is some data suggesting
emerging data indicating the benefit of a moderate intensity that resistance exercise is probably safe.126 Exercise needs to
exercise regimen in cirrhosis.104 be tailored to the patient’s ability, beginning with moderate
Nutrient supplementation following physical activity is ben- intensity and maintained for the long-term.
eficial in physiological states, but whether such an intervention
is beneficial in cirrhosis is currently unknown.119,120 Continued
impaired functional capacity and reduced peak oxygen con- Recommendations
sumption are associated with decreased survival and poor
post-transplant outcomes.121,122 Hence measures to increase Nutritional counselling should be performed in cirrhotic
functional capacity are likely to improve long-term clinical out- patients with malnutrition, when possible by a multidis-
comes in cirrhosis.102 ciplinary team, helping patients to achieve adequate
caloric and protein intake. (Grade II-2, C2)
Other strategies
Optimal daily energy intake should not be lower than
Hormone replacement therapy utilising growth hormone or
the recommended 35 kcal/kg. actual BW/d (in non-
testosterone has been proposed but has not been consistently
obese individuals). (Grade II-2, B1)
effective.91,92,123,124 Furthermore caution is needed when using
testosterone because of the possibility of increasing the risk of Optimal daily protein intake should not be lower than
hepatocellular carcinoma.105 the recommended 1.2–1.5 g/kg. actual BW/d. (Grade
A number of reports in preclinical models have shown that II-2, B1)
hyperammonaemia results in impaired protein synthesis and Include late evening oral nutritional supplementation
increased autophagy, both of which result in loss of muscle and breakfast in dietary regimen of malnourished
mass.99,100 decompensated cirrhotic patients. (Grade II-1, B1)
Long-term ammonia-lowering strategies may result in
increased muscle mass and contractile strength but the data BCAA supplements and leucine enriched amino acid sup-
are derived from preclinical studies and require validation in plements should be considered in decompensated cir-
human studies.109 rhotic patients when adequate nitrogen intake is not
achieved by oral diet. (Grade II-1, C1)
Nutritional approach and management of obesity in In patients with malnutrition and cirrhosis who are
unable to achieve adequate dietary intake with the oral
patients with liver cirrhosis
diet (even with oral supplements), a period of enteral
Two studies have shown that obesity is at least as frequent in
nutrition is recommended. (Grade II-1, B1)
compensated cirrhosis as it is in the general population, ranging
from 20 to 35%,13,125 regardless of the origin of liver disease. In Patients with cirrhosis, whenever possible, can be
NASH-related cirrhosis obesity is present in most cases. More- encouraged to avoid hypomobility and to progressively
over, a sedentary lifestyle is highly prevalent in patients with increase physical activity to prevent and/or ameliorate
cirrhosis and might be seen as a cofactor, leading to an increase sarcopenia. (Grade II-1, C2)
in BW in this population. In the HALT-C trial125 the risk of his- Implement a nutritional and lifestyle programme to
tological progression or decompensation increased by 14% for achieve progressive weight loss (>5–10%) in obese cir-
each increase in BMI quartile, and the risk of progression rhotic patients (BMI >30 kg/m2 corrected for water
increased by 35% in patients whose BW increased by >5% at retention). (Grade II-2, C1)
one year.
In a randomised controlled trial comparing the use of timolol A tailored, moderately hypocaloric (-500–800 kcal/d)
or placebo to prevent the onset of gastroesophageal varices, BMI diet, including adequate protein intake (>1.5 g pro-
was associated with clinical decompensation, independently of teins/kg.ideal BW/d) can be adopted to achieve weight
portal hypertension and albumin, in patients with no varices loss without compromising protein stores in obese cir-
and an hepatic venous pressure gradient ≥6 mmHg.13 rhotic patients. (Grade II-1, C2)
Data from different studies suggest that a reduction in BW
improves outcomes in obese patients with compensated cirrho-
sis.102,125,126 This was achieved by a programme of lifestyle New research should address the following topics
intervention including nutritional therapy and supervised mod-
erate intensity physical exercise. A weight decrease ≥5–10% is 1. Does the improvement in muscle mass and/or muscle func-
considered an adequate goal, associated with a reduced rate of tion improve clinical outcomes (lower the risk of first decom-
disease progression in patients included in the HALT-C trial.125 pensation, ascites, infection and encephalopathy, reduce
Dietary intake is aimed to guarantee both moderate caloric hospital readmissions, decrease length of hospital stay,
restriction and adequate protein intake. Indeed, although good reduce risk of falls, improve survival)?
2. Do ammonia-lowering strategies in decompensated cirrhosis Wernicke’s encephalopathy, even in the absence of a history/
reverse muscle loss and improve clinical outcomes? clinical signs during life.135 If Wernicke’s encephalopathy is sus-
pected, generous parenteral thiamine supplementation is
3. Does a gradual increase in physical activity delay or mandatory. Deficiencies in pyridoxine (B6), folate (B9) and
reverse muscle loss and contractile dysfunction? What cobalamin (B12) may also develop rapidly in chronic liver dis-
type and duration of exercise are beneficial in cirrhotic ease resulting from diminished hepatic storage.136 However,
patients? good quality data on their prevalence and/or need for supple-
mentation are scarce. As vitamin status is not easily assessed
4. Is the addition of supplements (leucine, isoleucine or other and multivitamin supplementation is cheap and substantially
nutrient supplements) needed to lower ammonia and side effect free, a course of oral multivitamin supplementation
increase mitochondrial intermediates during training? could be justified in decompensated patients.
Hyponatraemia is common in patients with cirrhosis and is
5. How can therapies targeting the muscle protein synthesis more likely to occur when the intake of sodium is low, and that
pathway or dysregulated muscle autophagy be of water unchanged or increased.137 Thus, careful monitoring of
implemented? both sodium and water intake is required. If severe hypona-
traemia is corrected, this needs to be done slowly, to avoid the
6. How can anabolic resistance be overcome, or the underlying risk of central pontine myelinolysis.138 A reduction in dietary
causes of anabolic resistance in cirrhotic patients be sodium intake is recommended in patients with ascites,139
reversed? although evidence in this respect is limited and conflicting.140
Sodium intake should certainly not be reduced below 60
mmol/d, as this makes the diet unpalatable, potentially compro-
Micronutrients mising energy and protein intake.141 Reductions in circulating
In general, vitamin deficiencies in liver disease are related to levels of calcium, magnesium, and iron need to be considered
hepatic dysfunction, diminished reserves and, with increasing and corrected.142 Tissue zinc concentrations are reduced in
disease severity, inadequate dietary intake and malabsorption. patients with cirrhosis and zinc has been implicated in the
Fat-soluble vitamin deficiencies are common. A retrospective pathogenesis of HE. However, data on the effects of zinc supple-
study reported that the majority of liver disease patients being mentation on mental performance have been conflicting.143–145
considered for transplantation presented with vitamin A and D Selenium deficiency has been related to the severity of hepatic
deficiencies.127 fibrosis in patients with hepatitis C and identified as one of the
The prevalence of vitamin D deficiency in the general pop- factors contributing to insulin resistance in these patients.146
ulation ranges from 20 to 100% when referring to serum 25- Patients with cirrhosis have elevated total body manganese
hydroxyvitamin D (25(OH)D) concentrations <20 ng/ml, and levels, which may result in selective manganese accumulation
affects all age groups.128 In patients with chronic liver disease in the basal ganglia.147 While there is no clear relationship
vitamin D (25(OH)D) levels below 20 ng/ml have been between such a phenomenon and HE, it is probably reasonable
reported in between 64 and 92% of patients, predominantly to avoid nutritional supplements containing manganese.
in chronic cholestatic conditions, and usually inversely corre- Specific evidence about the beneficial effect of micronutri-
lated with more advanced disease and Child-Pugh score.129,130 ents and vitamin supplementation in cirrhotic patients is not
Although low vitamin D levels might, in part, be due to available. However, confirmed or clinically suspected deficiency
decreased plasma binding proteins in the presence of liver should be treated based on accepted general recommendations
insufficiency, some evidence in pre-cirrhotic stages provide and common practice.
support for a true nutritional deficit. Recent data suggest a
close correlation between vitamin D levels and response to Recommendations
treatment in patients with hepatitis C virus infection, non-
alcoholic fatty liver disease and those who develop hepatocel-
lular carcinoma.130–132 In cirrhotic patients, administer micronutrients and vita-
Based on these data, it is advisable to assess plasma vitamin mins to treat confirmed or clinically suspected defi-
D (25(OH)D) levels in all patients with chronic liver disease, par- ciency. (Grade II-1, C1)
ticularly in those with advanced disease,128,130 non-alcoholic Assess vitamin D levels in cirrhotic patients, as defi-
fatty liver and cholestatic disorders.133 Although there are no ciency is highly prevalent and may adversely affect clin-
specific recommendations in patients with chronic liver disease ical outcomes. (Grade II-3, B1)
except for those with chronic cholestasis, it seems reasonable to
Supplement vitamin D orally in cirrhotic patients with
supplement all chronic liver disease patients with vitamin D
vitamin D levels <20 ng/ml, to reach serum vitamin D
levels below 20 ng/ml with oral vitamin D until reaching a
(25(OH)D) >30 ng/ml. (Grade II-1, B1)
serum vitamin D level above 30 ng/ml. Higher doses may be
necessary in patients with non-alcoholic fatty liver disease.134 In cirrhotic patients with ascites under sodium restric-
Vitamin K deficiency should always be considered in patients tion (recommended intake of sodium 80 mmol day =
who are jaundiced or whose liver disease is cholestatic in origin, 2 g of sodium corresponding to 5 g of salt added daily
and parenteral supplementation might be needed. to the diet according to EASL guidelines) take care to
Patients with both alcohol and non-alcohol related cirrhosis improve diet palatability as this regime may cause a
are prone to deficiencies in water-soluble vitamins, particularly reduction in caloric intake. (Grade II-2, B1)
thiamine (B1). They often exhibit evidence at autopsy of
Nutritional treatment options for hepatic ammonia levels in 150 patients with overt HE.85 One of the
encephalopathy advantages of vegetable diets may be due to their fibre content
The relationship between malnutrition and HE has been known rather than protein content, as fibre has both prebiotic and lax-
since the seminal observation that decreased energy intake ative properties. While increased dietary fibre may be of value
determines weight loss and coma in Eck’s fistula dogs.148 in patients with HE, the available literature is limited,165 and
Human studies also support this association. HE occurs more increasing fibre consumption is difficult even in the healthy
frequently in malnourished patients with cirrhosis, and there population. Notably, support from a multidisciplinary nutrition
is an inverse relationship between muscle mass and blood team has been shown to be useful in patients with cirrhosis77
ammonia levels.149,150 Sarcopenia, as assessed by the skeletal and should be considered in patients with HE.
muscle index, is an independent risk factor for the development A decreased serum ratio of BCAA to aromatic amino acids has
of HE after transjugular intrahepatic portosystemic shunt place- been associated with a poor prognosis,166 but there is limited
ment.151 Muscle plays an important role in ammonia evidence that the original assumptions behind BCAA supple-
removal152 by increasing glutamine synthesis, a reaction that mentation in HE are correct. However, BCAA supplements, in
is catalysed by the enzyme glutamine synthetase.153 This has daily divided doses, may facilitate the provision of an adequate
generally been thought of as a straightforward, benign process nitrogen intake in patients who are intolerant to meat pro-
of ammonia disposal but evidence is accumulating that hyper- tein.167,168 The replacement of meat with dairy/vegetable pro-
ammonaemia may impair muscle function and contribute to tein plus BCAA supplements is likely to be preferable to a
muscle loss,154 thus establishing a vicious circle. There is also reduction in total protein intake. Long-term, oral BCAA supple-
evidence that lowering ammonia levels can reverse sarcopenia mentation may also have nutritional value.110,169 Palatability
in animal models.155 Recently a randomised clinical trial has proven to be a significant issue. In addition, costs and the
showed that nutritional intervention (30–35 kcal/kg.BW/d, possibility to prescribe BCAA as a drug (vs. a food supplement)
1.0–1.5 g vegetable protein/kg.BW/d for six months) was able vary considerably between countries.
to improve neuropsychiatric performance in patients with min- It has also been shown that L-leucine alone can reverse the
imal HE, and decrease their risk of developing overt HE com- decrease in disturbed muscle protein homeostasis (proteostasis)
pared to no nutritional intervention.114 due to hyperammonaemia.170 A Cochrane meta-analysis
Energy requirements in patients with cirrhosis and HE are included 16 randomised clinical trials, comparing oral or intra-
thought to be the same as those of patients with cirrhosis per venous BCAA supplementation vs. a control intervention in 827
se.156 Patients with HE need to avoid long periods of fasting, and patients with HE.171 Oral BCAA had a positive impact on HE.
should be encouraged to split their caloric and protein intake into However, oral or intravenous BCAA did not influence mortality,
small, frequent meals. It is advisable that breakfast79 and a late quality of life or nutritional status. No firm conclusions could be
evening snack80 also include some proteins (see also paragraph: reached on their nutritional effects and on how they compare
Energy and protein requirements in patients with liver cirrhosis). with non-absorbable disaccharides/antibiotics.172 Their use
Dysregulated nitrogen metabolism plays a major role in the intravenously for episodic overt HE is not supported by the
development of HE and its modulation is key to HE manage- available evidence.
ment. Up until the middle of the 20th century, meat protein In patients with HE grade III-IV, as oral dietary intake is
was administered to patients with cirrhosis to avoid unfeasible or impossible, in keeping with common practice in
catabolism.157 Then, a few uncontrolled studies showed that patients with neurologic coma, nutrition should be provided
decreased protein intake was associated with better mental sta- by nasogastric tube or parenterally.
tus in patients with HE and porto-systemic shunts,158 leading to
a widespread practice of chronic protein restriction.159 Protein
restriction is now considered detrimental, except perhaps, for
Recommendations
very short periods of time, in patients with severe overt HE
and gastrointestinal bleeding. There is sufficient evidence that, Nutritional status and the presence of sarcopenia should
in general, patients with HE tolerate diets with a normal protein be evaluated in patients with HE. (Grade II-3, B1)
content,86 and their nitrogen requirements are the same as
Avoid protein restriction in patients with HE. (Grade
those of patients with cirrhosis per se.160
II-1, A1)
The type of protein ingested may be important. The original
demonstration that Eck’s fistula dogs fed with fish/milk protein Optimal daily protein and energy intake should not be
rather than meat developed fewer/no behavioural abnormali- lower than the general recommendations for cirrhotic
ties161 led to the idea that patients with HE may benefit from patients (recommendations 14 and 15). (Grade II-1, A1)
the replacement of meat with dairy/vegetable protein. Subse- Encourage the consumption of vegetables and dairy pro-
quent uncontrolled, human studies showed that dairy protein tein. (Grade II-3, B1)
is better tolerated than protein from mixed sources and that
BCAA supplementation should be considered to improve
vegetable protein is better tolerated than meat protein.83,162,163
neuropsychiatric performance and to reach the recom-
While there is a good pathophysiological basis for the use of
mended nitrogen intake. (Grade I-1, A1)
dairy/vegetable diets in patients with HE, the results of the clin-
ical studies undertaken remain unconvincing.164 In addition, Oral dietary intake is preferred in patients who can tol-
concerns have been raised in relation to tolerability/palatability, erate it. In patients with grade III-IV encephalopathy,
and thus potential negative effects on overall caloric intake.156 who are unable to eat, provide nutrition by nasogastric
This is likely to depend on the features of the staple diet. Inter- tube (in patients with protected airways) or parenterally.
estingly, a 14-day casein-vegetable, high-protein, high-calorie (Grade II-1, B1)
diet was shown to improve mental performance and to decrease
Nutritional treatment options in cirrhotic patients in transplanted patients have reduced the incidence of
with bone diseases fractures.203
‘Hepatic osteodystrophy’, including osteoporosis and osteoma- According to the WHO, bone densitometry of the lumbar
lacia, has been used for years to describe the bone disease of spine and hip is the gold standard procedure for the diagnosis
patients with liver damage. Osteoporosis, characterised by loss of osteoporosis and osteopenia. Lateral X-rays of dorsal and
of bone mass and quality that leads to fragility fractures, is com- lumbar spine should also be performed to disclose vertebral
mon in patients with chronic liver disease.173 Osteomalacia fractures.204 Laboratory measurements to identify abnormal
resulting from poor bone mineralisation is uncommon and only calcium and vitamin D metabolism are also appropriate. The
present when associated with persistent vitamin D deficiency in biochemical markers of bone turnover can be determined, but
individuals with severe and long-lasting cholestasis and intesti- they are most helpful for monitoring the response to therapy.
nal malabsorption.174 Nutritional, hormonal, metabolic, genetic, Undecalcified transiliac bone biopsy is recommended only in
and inflammatory factors play a significant role in the patho- the exceptional cases with presumed osteomalacia.
genesis of osteoporosis in patients with chronic liver disease, The diagnosis and management of bone disease in patients
mainly because of decreased bone formation. with chronic liver disease is summarised in (Fig. 3). Bone densit-
The diagnosis of osteoporosis is based on bone mineral den- ometry should be evaluated in patients with previous fragility
sity (BMD) that is generally measured by DEXA. According to fractures and those treated with corticosteroids and before liver
World Health Organization, osteoporosis is considered when transplantation.180,204 Bone densitometry needs to be assessed
BMD is 2.5 standard deviations below the young average value in patients with cholestatic diseases or if any of the described
(T-score ≤2.5) and osteopenia when the T-score is between 1 risk factors are found, and in cirrhotics. In patients within nor-
and 2.5, and severe or ‘established’ osteoporosis refers to indi- mal BMD, it is advisable to repeat DEXA after two to three years,
viduals who meet densitometric criteria and have one or more as is suggested in the non-cirrhotic population. In conditions
fragility fractures.175 associated with rapid bone loss, such as in cholestatic patients
Prevalence of osteoporosis in patients with chronic liver dis- with more than one risk factor for osteoporosis, and in those
ease depends mostly on patient selection and diagnostic crite- in whom high-dose corticosteroid therapy has recently been ini-
ria. In summary, about 30% of patients have osteoporosis, with tiated, DEXA can be repeated in a shorter interval of approxi-
higher prevalence in patients with cholestasis including pri- mately one year. This schedule is also recommended for
mary biliary cholangitis (PBC) and primary sclerosing cholangi- patients with advanced cirrhosis, particularly in those eligible
tis.176–188 In patients eligible for liver transplantation the for transplantation. Inaccuracies in BMD and bone marker mea-
prevalence of osteoporosis is 30%.188–191 Fracture prevalence surements in patients with cirrhosis or chronic cholestasis need
ranges between 7% and 35%,176–188,192–198 being more frequent to be taken into consideration.205,206 Recognition of the risk fac-
in postmenopausal women than in young women and men,182 tors for bone loss including those for osteoporosis and fractures
and in patients receiving corticosteroid therapy.199 Vertebral in patients with chronic liver disease is recommended, as in
fractures are associated with osteoporosis and osteopenia with general population and in postmenopausal women (Table 2).204
a T-score lower than 1.5 in patients with PBC and primary A balanced diet is recommended because patients with
sclerosing cholangitis.180. Patients with a T-score below 1.5 chronic liver disease are often malnourished. Supplements of
have a high risk of hip and vertebral fractures, supporting this calcium (1,000–1,500 mg/d) and 25(OH)D (400–800 IU/d or
T-score as a practical guide for starting specific therapy. 260 lg every two weeks) or the dose required to preserve nor-
Osteoporosis is frequently observed in transplanted mal levels should be provided. However, there is no definite
patients,200 and associated with a high incidence of fractures data confirming the efficacy of these supplements in preventing
(25 to 35%) within the first year after liver transplanta- bone loss in patients with liver disease.134 Physical activity is
tion.201,202 Improvements in the management of bone health recommended, in particular with exercises designed to improve
Diagnosis Management
DEXA Treatment
Fig. 3. Diagnosis and management of bone disease in patients with chronic liver disease. *Calcium (1,000–1,500 mg/d) and 25(OH)D (400–800 IU/d or
260 lg every two weeks) to preserve normal levels. **According to the severity of liver disease and cholestasis, and in patients taking corticosteroids.
***Depending on additional risk factors. 25(OH)D, 25-hydroxyvitamin D. DEXA; dual-energy X-ray absorptiometry.
Table 2. Risk factors for the development of osteoporosis in chronic liver therapy for osteoporosis in these patients223 as well as deno-
disease. sumab, a human monoclonal IgG antibody that binds to RANKL
Risk factors and inhibits bone resorption.
Alcohol abuse
Smoking
Body mass index lower than 19 kg/m2
Recommendations
Male hypogonadism
Early menopause
Secondary amenorrhea of more than 6 months Evaluate BMD in cirrhotic patients and in patients with
Family history of osteoporotic fracture cholestatic liver diseases, those receiving long-term cor-
Treatment with corticosteroids (5 mg/d or more of prednisone for 3
ticosteroid treatment, and before liver transplantation.
months or longer)
(Grade II-2, A1)
Advanced age
Utilise lumbar and femoral densitometry (DEXA) to diag-
nose osteoporosis and osteopenia. Lateral X-rays of dor-
sal and lumbar spine for diagnosing vertebral fractures.
the mechanics of the spine. Factors that contribute to bone loss (Grade II-3, A1)
need to be reduced to a minimum, including alcohol and tobacco
use. Corticosteroids ought to be minimised whenever possible. Repeat DEXA after two to three years in patients within
Different pharmacological therapies have been proposed for normal BMD, and within one year when rapid bone loss
improving bone mass in patients with chronic liver disease, but is expected. (Grade II-1, B1)
most studies have included small numbers of patients, and Include supplements of calcium (1,000–1,500 mg/d) and
therefore it is difficult to reach any definite conclusions. Fur- 25(OH)D (400–800 IU/d or 260 lg every two weeks) in
thermore, no clear anti-fracture effect has been demonstrated, patients with chronic liver disease and a T-score below
and except for osteoporosis in PBC and after liver transplanta- -1.5. (Grade II-3, A1)
tion, no systematic studies have been reported.
Utilise bisphosphonates in cirrhotic patients with osteo-
There is no general agreement concerning the appropriate
porosis and in those waiting for liver transplantation.
time to start treatment, but patients with established osteo-
(Grade I, A1)
porosis, and therefore with fragility fractures, should be treated
to reduce the risk of further fractures. Since patients with PBC Consider testosterone supplementation and venesection
with a lumbar or a proximal femur T-score lower than <1.5 in males with hemochromatosis and hypogonadism.
have a high risk of vertebral fracture, it seems reasonable to (Grade II-2, B1)
consider specific therapy in these patients,180 and in all patients
with osteoporosis before transplantation.
Bisphosphonates are anti-catabolic drugs which increase New research should address the following topics
bone mass and reduce the incidence of fractures in post-
menopausal osteoporosis. Their effects in chronic liver disease 1. The use and safety of anabolic drugs, such as PTH 1–34 and
are not entirely defined, mostly because of the very limited num- denosumab as potential new therapies for osteoporosis in
ber of studies and small numbers of patients.207–212 Nonetheless, patients with cirrhosis.
etidronate, alendronate and ibandronate increase bone mass in
patients with PBC, resulting in these patients achieving similar Clinical scenarios requiring special considerations
bone mass as patients with osteoporosis associated with other Malnutrition in patients undergoing liver transplantation
causes.208,211 Serious adverse events have not been observed and liver surgery
and potential harmful effects of bisphosphonates have not been Preoperative nutrition
reported in liver patients. Moreover, bisphosphonates appear to Both severe under nutrition (BMI <18.5 kg/m2) and severe obe-
be well tolerated, although it would be reasonable to exercise sity (BMI >40 kg/m2) prior to liver transplantation are associ-
caution in using the drug in cirrhotics with recent oesophageal ated with increased mortality and morbidity.224–227 Severe
banding/sclerotherapy to avoid oesophageal injury. Bisphospho- obesity prior to liver transplantation is associated with a higher
nates may also have a role in transplanted patients.213–215 prevalence of comorbidities (diabetes, hypertension), crypto-
Favourable effects have been reported using zoledronic acid,216 genic cirrhosis and increased mortality from infectious compli-
and weekly alendronate.217 Moreover, zoledronic acid reduces cations, cardiovascular disease and cancer.226,227 Some
bone turnover and results in lower fracture rates.216 investigators found that severe obesity was associated with
In patients with liver disease, hormonal replacement therapy increased morbidity and mortality even when patients were
was limited for many years as it was considered harmful. Trans- classified according to ‘‘dry BMI”227 while others have reported
dermal oestrogens prevent bone loss or even increase BMD in that the amount of ascites and not BMI contributes to the
patients with PBC or autoimmune cirrhosis and in post- increased mortality risk.228
menopausal women after liver transplantation, with no adverse Numerous descriptive studies have shown higher morbidity
effects on the liver.218–221 In males with hemochromatosis and and mortality in cirrhotic patients with protein malnutrition
hypogonadism, treatment with testosterone and venesection is when such patients undergo liver transplantation.57,229–231
also effective.222 One concern about restoring testosterone Recently, sarcopenia and frailty have been shown to confer an
levels in cirrhotic patients is the increased risk of hepatocellular increased risk of morbidity and mortality on the waiting list
carcinoma.105 and after transplantation.58,232–241 Patients on the waiting list
There are no studies assessing the effects of anabolic drugs in are at risk because of an inadequate food or caloric intake,242
liver patients with osteoporosis, but PTH 1–34 is a potential and those consuming a low protein diet (<0.8 g/kg.BW/d) have
Sarcopenic cirrhotic patients undergoing non-transplant sur- ill cirrhotic patients more frequently require enteral or par-
gery like resection for hepatocellular carcinoma have an enteral nutrition. Nutritional guidelines exist, proposed by dif-
increased mortality risk.284,285 In cirrhotic patients undergoing ferent medical societies, for patients with chronic liver disease
non-transplant visceral surgery, the complication rate and in different settings (Table S1).
nitrogen economy can be improved when nutrition support is
provided instead of just fluid and electrolytes.286,263 It may be Alcoholic liver disease and severe/acute alcoholic hepatitis
safely assumed that enteral nutrition in the early postoperative Nielsen et al. focussed on patients with alcoholic cirrhosis and
period would yield at least equally beneficial results. However, found a mean TEE of 32 ± 7 kcal/kg.BW/d70 and, in another study,
there are no studies comparing the two regimens in cirrhotic a median TEE of 28 kcal/kg.BW/d,81 similar to that in patients with
patients. There are data to suggest a beneficial effect on gut per- cirrhosis of different aetiologies. However patients with active
meability of sequential parenteral/enteral nutrition (via alcohol abuse may have a higher REE than healthy controls.288,289
jejunostomy), compared to parenteral nutrition alone or no An early study in alcoholic hepatitis showed that the intra-
postoperative nutrition at all.263 venous addition of 70 to 85 g of amino acids to a diet containing
In cirrhotic patients undergoing liver resection, oesophageal 3,000 kcal and 100 g of protein over four weeks, was safe and
transection and splenectomy or splenorenal shunt, the rate of associated with a lower mortality rate.290 A low protein intake
HE was not increased when a conventional amino acid solution was also shown to worsen HE in 136 patients with alcoholic
(50 g/d) was used for postoperative parenteral nutrition instead hepatitis and HE.291
of a BCAA-enriched amino acid solution (40 g/d).286 Tang and Two meta-analyses evaluated the impact of nutritional sup-
colleagues reported improved immune function and preserved plementation in patients with alcoholic liver disease.12,112 The
gut mucosal integrity when parenteral nutrition supplemented first included seven randomised controlled studies testing oral
with glutamine and human growth hormone was used in cir- or intravenous nutritional supplementation vs. a hospital diet
rhotic patients.287 in 262 patients, for 21 to 28 days. Nutritional support improved
the resolution of clinical encephalopathy but did not influence
mortality, ascites or laboratory parameters.112 The second
Recommendations included studies comparing parenteral nutrition, enteral nutri-
tion and ONS with no nutritional support.12 No benefits of nutri-
After liver transplantation initiate normal food and/or tional support were observed but a trend towards a better
enteral tube feeding preferably within 12–24 h postop- nitrogen balance with parenteral nutrition was noted.
eratively, or as soon as possible, to reduce infection rates. It was hypothesised that enteral nutrition improves survival
(Grade II-2, B1) to the same extent as corticosteroids. One study found no differ-
ence in mortality in 71 patients with severe alcoholic hepatitis
When oral or enteral nutrition are not possible or are
(71% with cirrhosis) randomised to prednisone or enteral nutri-
impracticable, parenteral nutrition should be used
tion for 28 days.292 In another study, 136 patients with alcoholic
instead of no feeding in order to reduce complication
hepatitis were randomised to methylprednisolone and enteral
rates, time on mechanical ventilation and ICU stay.
nutrition or methylprednisolone with conventional nutrition.
(Grade II-2, B1)
No difference in the six-month mortality was observed but calo-
After the acute postoperative phase, provide an energy ric intake lower than 21.5 kcal/kg.BW/d was associated with
intake of 35 kcal/kg.BW/d and a protein intake of 1.5 g/ higher mortality.293
kg.BW/d. (Grade II-2, C1)
After other surgical procedures, patients with chronic Immunonutrition
liver disease can be managed according to the ERAS pro- Immunonutrition, i.e. nutritional solutions enriched with x-3
tocol. (Grade III, C2) fatty acids, arginine and nucleotides, has also been proposed.
One retrospective study examined patients undergoing elec-
Consider parenteral nutrition in patients with unpro- tive liver resection, who received preoperative oral immunonu-
tected airways and HE when cough and swallow reflexes trition for seven days (n = 84; 14 patients with cirrhosis) vs. no
are compromised, or enteral nutrition is contraindicated oral supplementation (n = 63, 5 patients with cirrhosis). The
or impractical. (Grade II-2, C1) authors found no impact on postoperative complications.294
Enteral tube feeding and/or parenteral nutrition with a When considering the components of immunonutrition sepa-
reduced target energy intake (25 kcal/kg.BW/d) and an rately, oral x-3 fatty acids administered to cirrhotic patients
increased target protein intake (2.0 g/kg.BW/d) can be with ascites and renal failure did not improve renal function
utilised in obese patients. (Grade III, C2) but increased bleeding time and arterial blood pressure, leading
the authors to argue against their use in cirrhotic patients.295
Nutrition in the critically ill cirrhotic patient Nutritional support in gastrointestinal bleeding
In critically ill cirrhotic patients (patients hospitalised for severe In a randomised study, 22 patients with liver cirrhosis were
complications of the disease, acute-on-chronic liver failure, administered enteral nutrition by a nasogastric tube or no oral
patients in an intensive care unit, those with acute alcoholic intake during the first four days after acute bleeding from oeso-
hepatitis), maintenance of an adequate nutritional support is a phageal varices.296 No difference in re-bleeding, nutritional sta-
relevant target. Direct measurement of REE by indirect tus, liver function, duration of hospital stay and mortality was
calorimetry is advisable in these patients whenever possible. observed between the groups after a follow-up of 35 days. Nev-
Of note, as in all critically ill patients, tight glucose control is ertheless, experts recommend withholding enteral nutrition for
indicated to prevent hyper- and hypoglycaemia.29,113 Critically 48–72 h after acute bleeding,297,298 because enteral nutrition
Conclusion References
[1] Nutritional status in cirrhosis. Italian multicentre cooperative project
Nutrition in chronic liver disease is a rapidly evolving field and
on nutrition in liver cirrhosis. J Hepatol 1994;21:317–325.
the object of growing clinical interest. These Clinical Practice [2] Caregaro L, Alberino F, Amodio P, Merkel C, Bolognesi M, Angeli P, et al.
Guidelines have been produced with the aim of summarising Malnutrition in alcoholic and virus-related cirrhosis. Am J Clin Nutr
current knowledge in this field. Nutritional impairment and 1996;63:602–609.
sarcopenia have been recognised as crucial complications of [3] Dasarathy S. Consilience in sarcopenia of cirrhosis. J Cachexia Sarcope-
nia Muscle 2012;3:225–237.
[4] Huisman EJ, Trip EJ, Siersema PD, van Hoek B, van Erpecum KJ. Protein [27] Carey EJ, Lai JC, Wang CW, Dasarathy S, Lobach I, Montano-Loza AJ, et al.
energy malnutrition predicts complications in liver cirrhosis. Eur J A multicenter study to define sarcopenia in patients with end-stage
Gastroenterol Hepatol 2011;23:982–989. liver disease. Liver Transpl 2017;23:625–633.
[5] Merli M, Lucidi C, Giannelli V, Giusto M, Riggio O, Falcone M, et al. [28] van Vugt JL, Levolger S, de Bruin RW, van Rosmalen J, Metselaar HJ,
Cirrhotic patients are at risk for health care-associated bacterial IJzermans JN. Systematic review and meta-analysis of the impact of
infections. Clin Gastroenterol Hepatol 2010;8:979–985. computed tomography-assessed skeletal muscle mass on outcome in
[6] Merli M, Giusto M, Lucidi C, Giannelli V, Pentassuglio I, Di Gregorio V, patients awaiting or undergoing liver transplantation. Am J Transplant
et al. Muscle depletion increases the risk of overt and minimal hepatic 2016;16:2277–2292.
encephalopathy: results of a prospective study. Metab Brain Dis [29] Plauth M, Cabre E, Riggio O, Assis-Camilo M, Pirlich M, Kondrup J, et al.
2013;28:281–284. ESPenteral nutrition guidelines on enteral nutrition: liver disease. Clin
[7] Gunsar F, Raimondo ML, Jones S, Terreni N, Wong C, Patch D, et al. Nutr 2006;25:285–294.
Nutritional status and prognosis in cirrhotic patients. Aliment Pharma- [30] Tandon P, Low G, Mourtzakis M, Zenith L, Myers RP, Abraldes JG, et al. A
col Ther 2006;24:563–572. model to identify sarcopenia in patients with cirrhosis. Clin Gastroen-
[8] Montano-Loza AJ, Meza-Junco J, Prado CM, Lieffers JR, Baracos VE, terol Hepatol 2016;14:e1473.
Bain VG, et al. Muscle wasting is associated with mortality in [31] Alberino F, Gatta A, Amodio P, Merkel C, Di Pascoli L, Boffo G, et al.
patients with cirrhosis. Clin Gastroenterol Hepatol 2012;10:166–173, Nutrition and survival in patients with liver cirrhosis. Nutrition
173 e161. 2001;17:445–450.
[9] Englesbe MJ, Patel SP, He K, Lynch RJ, Schaubel DE, Harbaugh C, et al. [32] Morgan MY, Madden AM, Soulsby CT, Morris RW. Derivation and
Sarcopenia and mortality after liver transplantation. J Am Coll Surg validation of a new global method for assessing nutritional status in
2010;211:271–278. patients with cirrhosis. Hepatology 2006;44:823–835.
[10] Ney M, Vandermeer B, van Zanten SJ, Ma MM, Gramlich L, Tandon P. [33] Giusto M, Lattanzi B, Albanese C, Galtieri A, Farcomeni A, Giannelli V,
Meta-analysis: oral or enteral nutritional supplementation in cirrhosis. et al. Sarcopenia in liver cirrhosis: the role of computed tomography
Aliment Pharmacol Ther 2013;37:672–679. scan for the assessment of muscle mass compared with dual-energy X-
[11] Fialla AD, Israelsen M, Hamberg O, Krag A, Gluud LL. Nutritional therapy ray absorptiometry and anthropometry. Eur J Gastroenterol Hepatol
in cirrhosis or alcoholic hepatitis: a systematic review and meta- 2015;27:328–334.
analysis. Liver Int 2015;35:2072–2078. [34] Wu LW, Lin YY, Kao TW, Lin CM, Liaw FY, Wang CC, et al. Mid-arm
[12] Koretz RL, Avenell A, Lipman TO. Nutritional support for liver disease. muscle circumference as a significant predictor of all-cause mortality in
Cochrane Database Syst Rev 2012 CD008344. male individuals. PLoS One 2017;12 e0171707.
[13] Berzigotti A, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Morillas R, [35] Morgan MY, Madden AM, Jennings G, Elia M, Fuller NJ. Two-component
et al. Obesity is an independent risk factor for clinical decompensation models are of limited value for the assessment of body composition in
in patients with cirrhosis. Hepatology 2011;54:555–561. patients with cirrhosis. Am J Clin Nutr 2006;84:1151–1162.
[14] Montano-Loza AJ, Angulo P, Meza-Junco J, Prado CM, Sawyer MB, [36] Alvares-da-Silva MR, Reverbel da Silveira T. Comparison between
Beaumont C, et al. Sarcopenic obesity and myosteatosis are associated handgrip strength, subjective global assessment, and prognostic nutri-
with higher mortality in patients with cirrhosis. J Cachexia Sarcopenia tional index in assessing malnutrition and predicting clinical outcome
Muscle 2016;7:126–135. in cirrhotic outpatients. Nutrition 2005;21:113–117.
[15] Nishikawa H, Nishiguchi S. Sarcopenia and sarcopenic obesity are [37] Tandon P, Tangri N, Thomas L, Zenith L, Shaikh T, Carbonneau M, et al. A
prognostic factors for overall survival in patients with cirrhosis. Intern rapid bedside screen to predict unplanned hospitalization and death in
Med 2016;55:855–856. outpatients with cirrhosis: a prospective evaluation of the clinical
[16] Andrews J, Guyatt G, Oxman AD, Alderson P, Dahm P, Falck-Ytter Y, frailty scale. Am J Gastroenterol 2016;111:1759–1767.
et al. GRADE guidelines: 14. Going from evidence to recommendations: [38] Wang CW, Feng S, Covinsky KE, Hayssen H, Zhou LQ, Yeh BM, et al. A
the significance and presentation of recommendations. J Clin Epidemiol comparison of muscle function, mass, and quality in liver transplant
2013;66:719–725. candidates: results from the functional assessment in liver transplan-
[17] Tandon P, Raman M, Mourtzakis M, Merli M. A practical approach to tation study. Transplantation 2016;100:1692–1698.
nutritional screening and assessment in cirrhosis. Hepatology [39] Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J,
2017;65:1044–1057. et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol
[18] Teitelbaum D, Guenter P, Howell WH, Kochevar ME, Roth J, Seidner DL. Sci Med Sci 2001;56:M146–M156.
Definition of terms, style, and conventions used in A.S.P.E.N. guidelines [40] Lai JC, Feng S, Terrault NA, Lizaola B, Hayssen H, Covinsky K. Frailty
and standards. Nutr Clin Pract 2005;20:281–285. predicts waitlist mortality in liver transplant candidates. Am J Trans-
[19] Charney P. Nutrition screening vs. nutrition assessment: how do they plant 2014;14:1870–1879.
differ? Nutr Clin Pract 2008;23:366–372. [41] Hasse J, Strong S, Gorman MA, Liepa G. Subjective global assessment:
[20] Cederholm T, Bosaeus I, Barazzoni R, Bauer J, Van Gossum A, Klek S, alternative nutrition-assessment technique for liver-transplant candi-
et al. Diagnostic criteria for malnutrition – An ESPenteral nutrition dates. Nutrition 1993;9:339–343.
Consensus Statement. Clin Nutr 2015;34:335–340. [42] Bakshi N, Singh K. Nutrition assessment and its effect on various clinical
[21] Tandon P, Ney M, Irwin I, Ma MM, Gramlich L, Bain VG, et al. Severe variables among patients undergoing liver transplant. Hepatobiliary
muscle depletion in patients on the liver transplant wait list: its Surg Nutr 2016;5:358–371.
prevalence and independent prognostic value. Liver Transpl [43] Ferreira LG, Anastacio LR, Lima AS, Correia MI. Assessment of nutri-
2012;18:1209–1216. tional status of patients waiting for liver transplantation. Clin Trans-
[22] Borhofen SM, Gerner C, Lehmann J, Fimmers R, Gortzen J, Hey B, et al. plant 2011;25:248–254.
The royal free hospital-nutritional prioritizing tool is an independent [44] Figueiredo FA, Dickson ER, Pasha TM, Porayko MK, Therneau TM,
predictor of deterioration of liver function and survival in cirrhosis. Dig Malinchoc M, et al. Utility of standard nutritional parameters in
Dis Sci 2016;61:1735–1743. detecting body cell mass depletion in patients with end-stage liver
[23] Booi AN, Menendez J, Norton HJ, Anderson WE, Ellis AC. Validation of a disease. Liver Transpl 2000;6:575–581.
screening tool to identify undernutrition in ambulatory patients with [45] Fernandes SA, Bassani L, Nunes FF, Aydos ME, Alves AV, Marroni CA.
liver cirrhosis. Nutr Clin Pract 2015;30:683–689. Nutritional assessment in patients with cirrhosis. Arq Gastroenterol
[24] Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, 2012;49:19–27.
et al. Sarcopenia: European consensus on definition and diagnosis: [46] Figueiredo FA, Perez RM, Freitas MM, Kondo M. Comparison of three
report of the European Working Group on Sarcopenia in Older People. methods of nutritional assessment in liver cirrhosis: subjective global
Age Ageing 2010;39:412–423. assessment, traditional nutritional parameters, and body composition
[25] Peng S, Plank LD, McCall JL, Gillanders LK, McIlroy K, Gane EJ. Body analysis. J Gastroenterol 2006;41:476–482.
composition, muscle function, and energy expenditure in patients with [47] Naveau S, Belda E, Borotto E, Genuist F, Chaput JC. Comparison of
liver cirrhosis: a comprehensive study. Am J Clin Nutr clinical judgment and anthropometric parameters for evaluating
2007;85:1257–1266. nutritional status in patients with alcoholic liver disease. J Hepatol
[26] Martin L, Birdsell L, Macdonald N, Reiman T, Clandinin MT, McCargar LJ, 1995;23:234–235.
et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is [48] Sasidharan M, Nistala S, Narendhran RT, Murugesh M, Bhatia SJ, Rathi
a powerful prognostic factor, independent of body mass index. J Clin PM. Nutritional status and prognosis in cirrhotic patients. Trop
Oncol 2013;31:1539–1547. Gastroenterol 2012;33:257–264.
amino acid supplementation in the skeletal muscle of alcoholic [118] Garcia-Pagan JC, Santos C, Barbera JA, Luca A, Roca J, Rodriguez-Roisin
cirrhosis. Hepatology 2015;61:2018–2029. R, et al. Physical exercise increases portal pressure in patients with
[96] Nishikawa H, Enomoto H, Ishii A, Iwata Y, Miyamoto Y, Ishii N, et al. cirrhosis and portal hypertension. Gastroenterology
Elevated serum myostatin level is associated with worse survival in 1996;111:1300–1306.
patients with liver cirrhosis. J Cachexia Sarcopenia Muscle [119] Schoenfeld BJ, Aragon AA, Krieger JW. The effect of protein timing on
2017;8:915–925. muscle strength and hypertrophy: a meta-analysis. J Int Soc Sports Nutr
[97] Holecek M. Branched-chain amino acid supplementation in treatment of 2013;10:53.
liver cirrhosis: Updated views on how to attenuate their harmful effects [120] Beale DJ et al. Evidence inconclusive – comment on article by
on cataplerosis and ammonia formation. Nutrition 2017;41:80–85. Schoenfeld. J Int Soc Sports Nutr 2016;13:37.
[98] Dasarathy S, McCullough AJ, Muc S, Schneyer A, Bennett CD, Dodig M, [121] Jones JC, Coombes JS, Macdonald GA. Exercise capacity and muscle
et al. Sarcopenia associated with portosystemic shunting is reversed by strength in patients with cirrhosis. Liver Transpl 2012;18:146–151.
follistatin. J Hepatol 2011;54:915–921. [122] Dharancy S, Lemyze M, Boleslawski E, Neviere R, Declerck N, Canva V,
[99] Qiu J, Thapaliya S, Runkana A, Yang Y, Tsien C, Mohan ML, et al. et al. Impact of impaired aerobic capacity on liver transplant candi-
Hyperammonemia in cirrhosis induces transcriptional regulation of dates. Transplantation 2008;86:1077–1083.
myostatin by an NF-kappaB-mediated mechanism. Proc Natl Acad Sci U [123] Matsumoto R, Fukuoka H, Iguchi G, Nishizawa H, Bando H, Suda K, et al.
S A 2013;110:18162–18167. Long-term effects of growth hormone replacement therapy on liver
[100] Qiu J, Tsien C, Thapalaya S, Narayanan A, Weihl CC, Ching JK, et al. function in adult patients with growth hormone deficiency. Growth
Hyperammonemia-mediated autophagy in skeletal muscle contributes Horm IGF Res 2014;24:174–179.
to sarcopenia of cirrhosis. Am J Physiol Endocrinol Metab 2012;303: [124] Sinclair M, Gow PJ, Grossmann M, Angus PW. Review article: sarcope-
E983–E993. nia in cirrhosis–aetiology, implications and potential therapeutic
[101] Thapaliya S, Runkana A, McMullen MR, Nagy LE, McDonald C, Naga interventions. Aliment Pharmacol Ther 2016;43:765–777.
Prasad SV, et al. Alcohol-induced autophagy contributes to loss in [125] Everhart JE, Lok AS, Kim HY, Morgan TR, Lindsay KL, Chung RT, et al.
skeletal muscle mass. Autophagy 2014;10:677–690. Weight-related effects on disease progression in the hepatitis C
[102] Zenith L, Meena N, Ramadi A, Yavari M, Harvey A, Carbonneau M, et al. antiviral long-term treatment against cirrhosis trial. Gastroenterology
Eight weeks of exercise training increases aerobic capacity and muscle 2009;137:549–557.
mass and reduces fatigue in patients with cirrhosis. Clin Gastroenterol [126] Macias-Rodriguez RU, Ilarraza-Lomeli H, Ruiz-Margain A, Ponce-de-
Hepatol 2014;12:e1922. Leon-Rosales S, Vargas-Vorackova F, Garcia-Flores O, et al. Changes in
[103] Berzigotti A, Saran U, Dufour JF. Physical activity and liver diseases. hepatic venous pressure gradient induced by physical exercise in
Hepatology 2016;63:1026–1040. cirrhosis: results of a pilot randomized open clinical trial. Clin Transl
[104] Berzigotti A, Albillos A, Villanueva C, Genesca J, Ardevol A, Augustin S, Gastroenterol 2016;7:e180.
et al. Effects of an intensive lifestyle intervention program on portal [127] Venu M, Martin E, Saeian K, Gawrieh S. High prevalence of vitamin A
hypertension in patients with cirrhosis and obesity: the SportDiet deficiency and vitamin D deficiency in patients evaluated for liver
study. Hepatology 2017;65:1293–1305. transplantation. Liver transpl 2013;19:627–633.
[105] Nagasue N, Yukaya H, Chang YC, Ogawa Y, Kohno H, Ito A. Active uptake [128] Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA,
of testosterone by androgen receptors of hepatocellular carcinoma in Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D
humans. Cancer 1986;57:2162–2167. deficiency: an Endocrine Society clinical practice guideline. J Clin
[106] Gorostiaga EM, Navarro-Amezqueta I, Calbet JA, Sanchez-Medina L, Endocrinol Metab 2011;96:1911–1930.
Cusso R, Guerrero M, et al. Blood ammonia and lactate as markers of [129] Trautwein C, Possienke M, Schlitt HJ, Boker KH, Horn R, Raab R, et al.
muscle metabolites during leg press exercise. J Strength Cond Res Bone density and metabolism in patients with viral hepatitis and
2014;28:2775–2785. cholestatic liver diseases before and after liver transplantation. Am J
[107] Takeda K, Takemasa T. Expression of ammonia transporters Rhbg and Gastroenterol 2000;95:2343–2351.
Rhcg in mouse skeletal muscle and the effect of 6-week training on [130] Stokes CS, Volmer DA, Grunhage F, Lammert F. Vitamin D in chronic
these proteins. Physiol Rep 2015:3. liver disease. Liver Int 2013;33:338–352.
[108] McDaniel J, Davuluri G, Hill EA, Moyer M, Runkana A, Prayson R, et al. [131] Barchetta I, Angelico F, Del Ben M, Baroni MG, Pozzilli P, Morini S, et al.
Hyperammonemia results in reduced muscle function independent of Strong association between non alcoholic fatty liver disease (NAFLD)
muscle mass. Am J Physiol Gastrointest Liver Physiol 2016;310: and low 25(OH) vitamin D levels in an adult population with normal
G163–G170. serum liver enzymes. BMC Med 2011;9:85.
[109] Kumar A, Davuluri G, Silva RNE, Engelen M, Ten Have GAM, Prayson R, [132] Petta S, Camma C, Scazzone C, Tripodo C, Di Marco V, Bono A, et al. Low
et al. Ammonia lowering reverses sarcopenia of cirrhosis by restoring vitamin D serum level is related to severe fibrosis and low responsive-
skeletal muscle proteostasis. Hepatology 2017;65:2045–2058. ness to interferon-based therapy in genotype 1 chronic hepatitis C.
[110] Nakaya Y, Harada N, Kakui S, Okada K, Takahashi A, Inoi J, et al. Severe Hepatology 2010;51:1158–1167.
catabolic state after prolonged fasting in cirrhotic patients: effect of [133] European Association for the Study of the. L. EASL Clinical Practice
oral branched-chain amino-acid-enriched nutrient mixture. J Gastroen- Guidelines: management of cholestatic liver diseases. J Hepatol
terol 2002;37:531–536. 2009;51:237–267.
[111] Yoshida T, Muto Y, Moriwaki H, Yamato M. Effect of long-term oral [134] Dasarathy J, Varghese R, Feldman A, Khiyami A, McCullough AJ,
supplementation with branched-chain amino acid granules on the Dasarathy S. Patients with nonalcoholic fatty liver disease have a low
prognosis of liver cirrhosis. Gastroenterol Jpn 1989;24:692–698. response rate to vitamin D supplementation. J Nutr 2017.
[112] Antar R, Wong P, Ghali P. A meta-analysis of nutritional supplemen- [135] Kril JJ, Butterworth RF. Diencephalic and cerebellar pathology in
tation for management of hospitalized alcoholic hepatitis. Can J alcoholic and nonalcoholic patients with end-stage liver disease.
Gastroenterol 2012;26:463–467. Hepatology 1997;26:837–841.
[113] Plauth M, Cabre E, Campillo B, Kondrup J, Marchesini G, Schutz T, et al. [136] Bemeur C, Butterworth RF. Nutrition in the management of cirrhosis
ESPenteral nutrition Guidelines on Parenteral Nutrition: hepatology. and its neurological complications. J Clin Exp Hepatol 2014;4:141–150.
Clin Nutr 2009;28:436–444. [137] Cosgray RE, Hanna V, Davidhizar RE, Smith J. The water-intoxicated
[114] Maharshi S, Sharma BC, Sachdeva S, Srivastava S, Sharma P. Efficacy of patient. Arch Psychiatr Nurs 1990;4:308–312.
nutritional therapy for patients with cirrhosis and minimal hepatic [138] Kleinschmidt-DeMasters BK, Norenberg MD. Rapid correction of
encephalopathy in a randomized trial. Clin Gastroenterol Hepatol hyponatremia causes demyelination: relation to central pontine myeli-
2016;14:454–460. nolysis. Science 1981;211:1068–1070.
[115] Liao CD, Tsauo JY, Wu YT, Cheng CP, Chen HC, Huang YC, et al. Effects of [139] European Association for the Study of the L. EASL clinical practice
protein supplementation combined with resistance exercise on body guidelines on the management of ascites, spontaneous bacterial
composition and physical function in older adults: a systematic review peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol
and meta-analysis. Am J Clin Nutr 2017;106:1078–1091. 2010;53:397–417.
[116] Baar K. Training for endurance and strength: lessons from cell [140] Gu XB, Yang XJ, Zhu HY, Xu BY. Effect of a diet with unrestricted sodium
signaling. Med Sci Sports Exerc 2006;38:1939–1944. on ascites in patients with hepatic cirrhosis. Gut Liver 2012;6:355–361.
[117] Dietrich R, Bachmann C, Lauterburg BH. Exercise-induced hyperam- [141] Morando F, Rosi S, Gola E, Nardi M, Piano S, Fasolato S, et al. Adherence
monemia in patients with compensated chronic liver disease. Scand J to a moderate sodium restriction diet in outpatients with cirrhosis and
Gastroenterol 1990;25:329–334. ascites: a real-life cross-sectional study. Liver Int 2015;35:1508–1515.
[188] Monegal A, Navasa M, Peris P, Colmenero J, Cuervo A, Muxi A, et al. [211] Guanabens N, Monegal A, Cerda D, Muxi A, Gifre L, Peris P, et al.
Bone disease in patients awaiting liver transplantation. Has the Randomized trial comparing monthly ibandronate and weekly alen-
situation improved in the last two decades? Calcif Tissue Int dronate for osteoporosis in patients with primary biliary cirrhosis.
2013;93:571–576. Hepatology 2013;58:2070–2078.
[189] Sinigaglia L, Fargion S, Fracanzani AL, Binelli L, Battafarano N, Varenna [212] Zein CO, Jorgensen RA, Clarke B, Wenger DE, Keach JC, Angulo P, et al.
M, et al. Bone and joint involvement in genetic hemochromatosis: role Alendronate improves bone mineral density in primary biliary cirrho-
of cirrhosis and iron overload. J Rheumatol 1997;24:1809–1813. sis: a randomized placebo-controlled trial. Hepatology
[190] Guggenbuhl P, Deugnier Y, Boisdet JF, Rolland Y, Perdriger A, Pawlotsky 2005;42:762–771.
Y, et al. Bone mineral density in men with genetic hemochromatosis [213] Ninkovic M, Love S, Tom BD, Bearcroft PW, Alexander GJ, Compston JE.
and HFE gene mutation. Osteoporos Int 2005;16:1809–1814. Lack of effect of intravenous pamidronate on fracture incidence and
[191] Valenti L, Varenna M, Fracanzani AL, Rossi V, Fargion S, Sinigaglia L. bone mineral density after orthotopic liver transplantation. J Hepatol
Association between iron overload and osteoporosis in patients with 2002;37:93–100.
hereditary hemochromatosis. Osteoporos Int 2009;20:549–555. [214] Monegal A, Guanabens N, Suarez MJ, Suarez F, Clemente G, Garcia-
[192] Guanabens N, Pares A, Navasa M, Martinez de Osaba MJ, Hernandez ME, Gonzalez M, et al. Pamidronate in the prevention of bone loss after liver
Munoz J, et al. Cyclosporin A increases the biochemical markers of bone transplantation: a randomized controlled trial. Transpl Int
remodeling in primary biliary cirrhosis. J Hepatol 1994;21:24–28. 2009;22:198–206.
[193] Springer JE, Cole DE, Rubin LA, Cauch-Dudek K, Harewood L, Evrovski J, [215] Millonig G, Graziadei IW, Eichler D, Pfeiffer KP, Finkenstedt G,
et al. Vitamin D-receptor genotypes as independent genetic predictors Muehllechner P, et al. Alendronate in combination with calcium and
of decreased bone mineral density in primary biliary cirrhosis. vitamin D prevents bone loss after orthotopic liver transplantation: a
Gastroenterology 2000;118:145–151. prospective single-center study. Liver Transpl 2005;11:960–966.
[194] Newton J, Francis R, Prince M, James O, Bassendine M, Rawlings D, et al. [216] Crawford BA, Kam C, Pavlovic J, Byth K, Handelsman DJ, Angus PW,
Osteoporosis in primary biliary cirrhosis revisited. Gut et al. Zoledronic acid prevents bone loss after liver transplantation: a
2001;49:282–287. randomized, double-blind, placebo-controlled trial. Ann Intern Med
[195] Solerio E, Isaia G, Innarella R, Di Stefano M, Farina M, Borghesio E, et al. 2006;144:239–248.
Osteoporosis: still a typical complication of primary biliary cirrhosis? [217] Atamaz F, Hepguler S, Akyildiz M, Karasu Z, Kilic M. Effects of
Dig Liver Dis 2003;35:339–346. alendronate on bone mineral density and bone metabolic markers in
[196] Bonkovsky HL, Hawkins M, Steinberg K, Hersh T, Galambos JT, patients with liver transplantation. Osteoporos Int 2006;17:942–949.
Henderson JM, et al. Prevalence and prediction of osteopenia in chronic [218] Olsson R, Mattsson LA, Obrant K, Mellstrom D. Estrogen-progestogen
liver disease. Hepatology 1990;12:273–280. therapy for low bone mineral density in primary biliary cirrhosis. Liver
[197] Ninkovic M, Love SA, Tom B, Alexander GJ, Compston JE. High 1999;19:188–192.
prevalence of osteoporosis in patients with chronic liver disease prior [219] Pereira SP, O’Donohue J, Moniz C, Phillips MG, Abraha H, Buxton-
to liver transplantation. Calcif Tissue Int 2001;69:321–326. Thomas M, et al. Transdermal hormone replacement therapy improves
[198] Sokhi RP, Anantharaju A, Kondaveeti R, Creech SD, Islam KK, Van Thiel vertebral bone density in primary biliary cirrhosis: results of a 1-year
DH. Bone mineral density among cirrhotic patients awaiting liver controlled trial. Aliment Pharmacol Ther 2004;19:563–570.
transplantation. Liver Transpl 2004;10:648–653. [220] Ormarsdottir S, Mallmin H, Naessen T, Petren-Mallmin M, Broome U,
[199] Olsson R, Johansson C, Lindstedt G, Mellstrom D. Risk factors for bone Hultcrantz R, et al. An open, randomized, controlled study of transder-
loss in chronic active hepatitis and primary biliary cirrhosis. Scand J mal hormone replacement therapy on the rate of bone loss in primary
Gastroenterol 1994;29:753–756. biliary cirrhosis. J Intern Med 2004;256:63–69.
[200] Monegal A, Navasa M, Guanabens N, Peris P, Pons F, Martinez de Osaba [221] Isoniemi H, Appelberg J, Nilsson CG, Makela P, Risteli J, Hockerstedt K.
MJ, et al. Bone disease after liver transplantation: a long-term Transdermal oestrogen therapy protects postmenopausal liver trans-
prospective study of bone mass changes, hormonal status and histo- plant women from osteoporosis. A 2-year follow-up study. J Hepatol
morphometric characteristics. Osteoporos Int 2001;12:484–492. 2001;34:299–305.
[201] Leidig-Bruckner G, Hosch S, Dodidou P, Ritschel D, Conradt C, Klose C, [222] Diamond T, Stiel D, Posen S. Effects of testosterone and venesection on
et al. Frequency and predictors of osteoporotic fractures after cardiac or spinal and peripheral bone mineral in six hypogonadal men with
liver transplantation: a follow-up study. Lancet 2001;357:342–347. hemochromatosis. J Bone Miner Res 1991;6:39–43.
[202] Navasa M, Monegal A, Guanabens N, Peris P, Rimola A, Munoz-Gomez J, [223] Dresner-Pollak R, Gabet Y, Steimatzky A, Hamdani G, Bab I, Ackerman Z,
et al. Bone fractures in liver transplant patients. Br J Rheumatol et al. Human parathyroid hormone 1–34 prevents bone loss in
1994;33:52–55. experimental biliary cirrhosis in rats. Gastroenterology
[203] Compston JE. Osteoporosis after liver transplantation. Liver Transpl 2008;134:259–267.
2003;9:321–330. [224] Keeffe EB, Gettys C, Esquivel CO. Liver transplantation in patients with
[204] Pares A, Guanabens N. Treatment of bone disorders in liver disease. J severe obesity. Transplantation 1994;57:309–311.
Hepatol 2006;45:445–453. [225] Sawyer RG, Pelletier SJ, Pruett TL. Increased early morbidity and
[205] Guanabens N, Pares A, Alvarez L, Martinez de Osaba MJ, Monegal A, mortality with acceptable long-term function in severely obese patients
Peris P, et al. Collagen-related markers of bone turnover reflect the undergoing liver transplantation. Clin Transplant 1999;13:126–130.
severity of liver fibrosis in patients with primary biliary cirrhosis. J [226] Nair S, Verma S, Thuluvath PJ. Obesity and its effect on survival in
Bone Miner Res 1998;13:731–738. patients undergoing orthotopic liver transplantation in the United
[206] Guanabens N, Monegal A, Muxi A, Martinez-Ferrer A, Reyes R, States. Hepatology 2002;35:105–109.
Caballeria J, et al. Patients with cirrhosis and ascites have false values [227] Dick AA, Spitzer AL, Seifert CF, Deckert A, Carithers RL, Reyes JD, et al.
of bone density: implications for the diagnosis of osteoporosis. Liver transplantation at the extremes of the body mass index. Liver
Osteoporos Int 2012;23:1481–1487. Transpl 2009;15:968–977.
[207] Guanabens N, Pares A, Monegal A, Peris P, Pons F, Alvarez L, et al. [228] Leonard J, Heimbach J, Malinchoc M, Watt K, Charlton M. the impact of
Etidronate versus fluoride for treatment of osteopenia in primary obesity on long-term outcomes in liver transplant recipients—results of
biliary cirrhosis: preliminary results after 2 years. Gastroenterology the NIDDK liver transplant database. Am J Transplant 2008;8:667–672.
1997;113:219–224. [229] Pikul J, Sharpe MD, Lowndes R, Ghent CN. Degree of preoperative
[208] Guanabens N, Pares A, Ros I, Alvarez L, Pons F, Caballeria L, et al. malnutrition is predictive of postoperative morbidity and mortality in
Alendronate is more effective than etidronate for increasing bone mass liver transplant recipients. Transplantation 1994;57:469–472.
in osteopenic patients with primary biliary cirrhosis. Am J Gastroen- [230] Harrison J, McKiernan J, Neuberger JM. A prospective study on the
terol 2003;98:2268–2274. effect of recipient nutritional status on outcome in liver transplanta-
[209] Lindor KD, Jorgensen RA, Tiegs RD, Khosla S, Dickson ER. Etidronate for tion. Transpl Int 1997;10:369–374.
osteoporosis in primary biliary cirrhosis: a randomized trial. J Hepatol [231] Selberg O, Bottcher J, Tusch G, Pichlmayr R, Henkel E, Muller M-J.
2000;33:878–882. Identification of high-and low-risk patients before liver transplanta-
[210] Wolfhagen FH, van Buuren HR, den Ouden JW, Hop WC, van Leeuwen tion: a prospective cohort study of nutritional and metabolic param-
JP, Schalm SW, et al. Cyclical etidronate in the prevention of bone loss eters in 150 patients. Hepatology 1997;25:652–657.
in corticosteroid-treated primary biliary cirrhosis. A prospective, [232] Tandon P, Ney M, Irwin I, Ma MM, Gramlich L, Bain VG, et al. Severe
controlled pilot study. J Hepatol 1997;26:325–330. muscle depletion in patients on the liver transplant wait list: its
[277] Richards J, Gunson B, Johnson J, Neuberger J. Weight gain and obesity portal hypertension surgery. World J Gastroenterol
after liver transplantation. Transpl Int 2005;18:461–466. 2007;13:2223–2228.
[278] Laryea M, Watt KD, Molinari M, Walsh MJ, McAlister VC, Marotta PJ, [288] Addolorato G, Capristo E, Greco AV, Caputo F, Stefanini GF, Gasbarrini G.
et al. Metabolic syndrome in liver transplant recipients: prevalence and Three months of abstinence from alcohol normalizes energy expendi-
association with major vascular events. Liver Transpl ture and substrate oxidation in alcoholics: a longitudinal study. Am J
2007;13:1109–1114. Gastroenterol 1998;93:2476–2481.
[279] Bianchi G, Marchesini G, Marzocchi R, Pinna AD, Zoli M. Metabolic [289] Levine JA, Harris MM, Morgan MY. Energy expenditure in chronic
syndrome in liver transplantation: relation to etiology and immuno- alcohol abuse. Eur J Clin Invest 2000;30:779–786.
suppression. Liver Transpl 2008;14:1648–1654. [290] Nasrallah SM, Galambos JT. Aminoacid therapy of alcoholic hepatitis.
[280] Schutz T, Hudjetz H, Roske AE, Katzorke C, Kreymann G, Budde K, et al. Lancet 1980;2:1276–1277.
Weight gain in long-term survivors of kidney or liver transplantation– [291] Morgan TR, Moritz TE, Mendenhall CL, Haas R. Protein consumption
another paradigm of sarcopenic obesity? Nutrition 2012;28:378–383. and hepatic encephalopathy in alcoholic hepatitis. VA Cooperative
[281] Krasnoff JB, Vintro AQ, Ascher NL, Bass NM, Dodd MJ, Painter PL. Study Group #275. J Am Coll Nutr 1995;14:152–158.
Objective measures of health-related quality of life over 24 months [292] Cabre E, Rodriguez-Iglesias P, Caballeria J, Quer JC, Sanchez-Lombrana
post-liver transplantation. Clin Transplant 2005;19:1–9. JL, Pares A, et al. Short- and long-term outcome of severe alcohol-
[282] Krasnoff JB, Vintro AQ, Ascher NL, Bass NM, Paul SM, Dodd MJ, et al. A induced hepatitis treated with steroids or enteral nutrition: a multi-
randomized trial of exercise and dietary counseling after liver trans- center randomized trial. Hepatology 2000;32:36–42.
plantation. Am J Transplant 2006;6:1896–1905. [293] Moreno C, Deltenre P, Senterre C, Louvet A, Gustot T, Bastens B, et al.
[283] Roman E, Torrades MT, Nadal MJ, Cardenas G, Nieto JC, Vidal S, et al. Intensive enteral nutrition is ineffective for patients with severe
Randomized pilot study: effects of an exercise programme and leucine alcoholic hepatitis treated with corticosteroids. Gastroenterology
supplementation in patients with cirrhosis. Dig Dis Sci 2016;150:e908.
2014;59:1966–1975. [294] Zacharias T, Ferreira N, Carin AJ. Preoperative immunonutrition in liver
[284] Harimoto N, Shirabe K, Yamashita YI, Ikegami T, Yoshizumi T, Soejima resection-a propensity score matched case-control analysis. Eur J Clin
Y, et al. Sarcopenia as a predictor of prognosis in patients following Nutr 2014;68:964–969.
hepatectomy for hepatocellular carcinoma. Br J Surg [295] Badalamenti S, Salerno F, Salmeron JM, Lorenzano E, Rimola A, Gines P,
2013;100:1523–1530. et al. Lack of renal effects of fish oil administration in patients with
[285] Voron T, Tselikas L, Pietrasz D, Pigneur F, Laurent A, Compagnon P, et al. advanced cirrhosis and impaired glomerular filtration. Hepatology
Sarcopenia impacts on short- and long-term results of hepatectomy for 1997;25:313–316.
hepatocellular carcinoma. Ann Surg 2015;261:1173–1183. [296] de Ledinghen V, Beau P, Mannant PR, Borderie C, Ripault MP, Silvain C,
[286] Kanematsu T, Koyanagi N, Matsumata T, Kitano S, Takenaka K, et al. Early feeding or enteral nutrition in patients with cirrhosis after
Sugimachi K. Lack of preventive effect of branched-chain amino acid bleeding from esophageal varices? A randomized controlled study. Dig
solution on postoperative hepatic encephalopathy in patients with Dis Sci 1997;42:536–541.
cirrhosis: a randomized, prospective trial. Surgery 1988;104: [297] Hebuterne X, Vanbiervliet G. Feeding the patients with upper gastroin-
482–488. testinal bleeding. Curr Opin Clin Nutr Metab Care 2011;14:197–201.
[287] Tang ZF, Ling YB, Lin N, Hao Z, Xu RY. Glutamine and recombinant [298] McClave SA, Chang WK. When to feed the patient with gastrointestinal
human growth hormone protect intestinal barrier function following bleeding. Nutr Clin Pract 2005;20:544–550.