Best Practice & Research Clinical GastroenterologyVol. 20, No. 3, pp. 547–560, 2006

7

Nutrition in end stage liver disease

Jens Kondrup*Professor, Senior Physician, Dr Med Sci

Department of Human Nutrition, Royal Veterinary and Agricultural University, 30 Rolighedsvej, 1958 Frederiksberg C,

Denmark

Nutrition Unit 5711, Rigshospitalet University, 9 Blegdamsvej, 2100 Copenhagen, Denmark

This chapter will focus on studies within the last 5 years of nutrition in end stage liver disease, butearlier studies illustrating the present state of affairs will also be mentioned. The first part willfocus on descriptive epidemiological studies that help to set the scene for the interventionstudies, which will be described in the second part. Each part will discuss liver cirrhosis, acuteliver failure and liver transplantation separately.The aim is to provide the reader with sufficient background for the decision in clinical practiceabout when to see nutrition support as an important part of treatment of the patient.

Key words: liver cirrhosis; acute liver failure; liver transplantation; nutrition support; branched-chain amino acids.

PREVALENCE OF MALNUTRITION AND ITS RELATION TO CLINICALOUTCOME AND PHYSIOLOGICAL FUNCTION

Cirrhosis

Malnutrition is common in chronic liver disease and should be seen as a complication inline with ascites, esophageal varices, hepatic encephalopathy (HE), and treated as such.

In an Italian multicenter study of more than 1400 patients with cirrhosis, theprevalence of low body weight relative to height was only 5%, but 20% of the patientshad a recent weight loss O10% of usual body weight and malnutrition, as measured bymid-arm-muscle-area (MAMA) or mid-arm-fat-area, was present in 30% of thepatients.1 In a follow-up to that study, it was found that within the Child–Pugh classes A

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* Corresponding author. Address: Department of Human Nutrition, Royal Veterinary and Agricultural

University, 30 Rolighedsvej, 1958 Frederiksberg C, Denmark. Tel.: C45 3528 2491; fax: C45 3528 2483.

E-mail address: jens.kondrup@kvl.dk

548 J. Kondrup

and B, survival was related to MAMA, but not in class C, suggesting that nutritionalstatus is more important in patients with a better prognosis.2 Another study found thatmid-arm-circumference (MAC) was independently associated with survival andimproved the prognostic accuracy when combined with the Child–Pugh score.3

Even in mild disease, Child–Pugh class A, 25% of the patients were found to bemalnourished.2 A study which employed total body neutron activation analysis, amethod considered by many to be the gold standard for measuring nutritional status,also showed low total body nitrogen content in patients with Child-Pugh class A.4

A more recent study, employing calculation of Body Cell Mass (BCM) frommeasurement of total body water and extracellular water (by isotope dilution), alsofound a reduction in BCM in Child–Pugh class A patients.5 Concomitant with impairednutritional status in Child–Pugh class A patients, measured as MAC, it was alsoobserved that 48 and 34% of these patients had a low energy intake (!30 kcal/kg perday) and protein intake (!1 g/kg per day), respectively.6

Even at this early stage of disease, the impaired nutritional status is related to clinicaloutcome. Child–Pugh class A patients who were categorised as malnourished, either bySubjective Global Assessment (SGA)7 or by hand grip strength, had a higher 1 year-rateof major complications and/or death.8

In most of the studies mentioned, nutritional status was further aggravated withincreasing severity of disease, Child–Pugh class B and C, but it is noticeable thatnutritional problems are already prominent and related to clinical outcome with milddisease. Also, in many of these studies, patients with different etiologies have beenincluded, such as alcohol, virus and cryptogenic cirrhosis and there seems to be nomajor difference in prevalence or functional impact of malnutrition among the differentcauses of cirrhosis.

In addition to the clinical outcome variables mentioned above, nutritional status hasbeen associated with impaired measures of physiological function. Knee and anklemuscle strength were decreased in alcoholic cirrhosis, and it was related to Lean BodyMass, as measured by 24 creatinine excretion, rather than to Child–Pugh score orpolyneuropathy.9 Hand grip strength was related to BCM, as determined bymeasurement of total body water and extracellular water.10 In a study of mainlyChild–Pugh class A patients, all patients who were malnourished according to SGA alsohad decreased hand grip strength.8

Malnutrition is also associated with immuno-incompetence in liver cirrhosis, such asskin test anergy,11–13 but the independent association between immuno-incompetenceand liver function versus nutritional status has not been explicitly investigated. In one ofthese studies,12 it was shown that with increasing severity of disease, i.e. Child–Pughscore, there was a parallel increase in malnutrition and also anergy.

Malnutrition may also impair mental function in cirrhotic patients, since it wassuggested that increased degradation of endogenous proteins contributed aromaticamino acids that would increase HE.14 However, the possible association betweennutritional status and HE has not been examined.

It should be emphasised that there is no ‘Gold Standard’ for routine clinicalscreening or assessment of nutritional problems in patients with cirrhosis. It is oftenstressed that BMI may be unreliable for nutritional evaluation due to the accumulationof fluid in patients with cirrhosis. This is a problem only in patients who may have afalsely normal BMI due to the accumulation of fluid. In most cases, a clinical judgment ofthe amount of ascites is possible which can be subtracted from the measured bodyweight. Patients with ascites who have a low BMI are of course malnourished. As analternative to BMI, it has been suggested to use bioimpedance analysis or other more

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sophisticated methods, but it should be stressed that the simple methods, such as SGAor anthropometrics methods including MAC do provide information on clinical courseas related to nutritional status (see above). A low MAC combined with low hand gripstrength has a high sensitivity and specificity of identifying patients with a low BCM, asdetermined by isotope dilution, while SGA was not associated with BCM.10 Thissuggests that a combination of simple objective measurements of MAC and hand gripstrength give a better reflection of BCM than the SGA which is limited by being amultivariate subjective method.

The use of bioimpedance analysis for calculating body cell compartments byequations that are not validated in patients with cirrhosis is dubious. Direct use ofresults from bioimpedance analysis (resistance and phase angle) may be moreappropriate. It has been shown that phase angle is more closely related to survival thanMAMA, total body potassium or lean body mass estimated from 24 hours creatinine inpatients with cirrhosis.15 The approach of vector analysis based on resistance and phaseangle, as a functional measure of cell mass and/or cell function16 may become of value inthe future.

In the guideline for nutrition screening17 published by the European Society forClinical Nutrition and Metabolism (ESPEN), it is emphasised that the tool used fornutritional screening should have a high degree of predictive validity, i.e. that thepatients identified to be malnourished/at nutritional risk should expect to benefit fromnutritional intervention by an improved clinical outcome. None of the methods usedfor evaluation of nutritional status mentioned above have been validated in this way inpatients with cirrhosis (see further in the section on Intervention). The ESPENguidelines also stress that screening for nutritional risk should include quantitativeinformation on BMI (or MAC when body weight is unreliable/unobtainable), recentweight loss and recent dietary intake and, for hospitalised patients, an evaluation ofseverity of disease as an index of nutritional requirements. For patients with cirrhosis,such a complete screening process has not yet been undertaken, although the SGAdoes contain most of these elements in a non-quantitative form. The ESPEN guidelinealso underlines that plasma albumin is not useful for nutritional screening, since manyfactors related to the disease process and hydration status, rather than nutritionalstatus, influence plasma albumin levels. This certainly also applies to patients withcirrhosis.

Acute liver failure and transplantation

In patients with acute liver failure, no studies are available demonstrating thatnutritional status plays an independent role for the clinical course.

Several studies have shown that the risk of postoperative complications is high inmalnourished cirrhotic patients.18 In liver transplantation, the nutritional status at thetime of operation, as evaluated clinically, was suggested to be the only variable amongthose related to survival after liver transplantation that could be treated.19 In an analysiswith an extensive set of variables related to liver function and nutritional status, it wasdetermined that a low BCM, as measured with bioimpedance analysis, combinedwith increased resting energy expenditure (REE), predicted mortality irrespective ofChild–Pugh classification.20 In a later study there was no association between outcomeand nutritional status, measured as BCM by isotope dilution or MAC, but as the authorspointed out, their malnourished recipients had received nutritional supplements while

550 J. Kondrup

waiting for transplantation.21 The presence of malnutrition has been estimated toincrease cost of liver transplantation by 40%.22

CAUSES OF MALNUTRITION IN CIRRHOSIS

The liver plays a central role in the metabolism of most nutrients. In chronic liverdisease, glucose intolerance or frank diabetes mellitus is frequent, alterations in aminoacid metabolism play a role for the development of HE, decreased hepatic proteinsynthesis contribute to hypoalbuminemia and ascites and reduced bile acid synthesis isresponsible for fat malabsorption. Ascites, and inflammatory processes in the diseasedliver, cause decreased appetite. In alcoholic liver disease, alcohol by itself changeshepatic metabolism of some vitamins. All these changes were listed in an early review.23

For more recent reviews, see.24–26 It remains impossible, however, to name one or afew functions that are quantitatively of major importance for the impaired nutritionalstate. In the following, recent studies related to macronutrients, minerals and vitaminswill be discussed.

Energy

The average REE was found to normal in a study of 473 patients, as compared tovalues predicted by the Harris–Benedict equation, but 34% the patients had an REE O120% of the expected value. In these hypermetabolic patients, total body potassiumwas lower, suggesting an association between increased REE and malnutrition, at leastin some patients.27 Exercise-induced increase in oxygen uptake was found to benormal in patients with cirrhosis.28 With a different approach, REE was comparedbetween well-nourished or malnourished cirrhotic patients and it was found that REEwas lower in absolute terms in the malnourished patients, that energy expenditureassociated with physical activity was equal in the two groups and that both groupswere in energy balance.29 Only 2 of 50 cirrhotic patients were hypermetabolic in thatstudy. This study concluded that the state of malnutrition is not associated with anegative energy balance, confirming a similar previous study in malnourished cirrhoticpatients.30 In both studies,29,30 REE and dietary intake were decreased in proportionto body size and both REE and dietary intake were lower than those of the healthypopulation. Therefore, hypermetabolism may contribute to the development ofmalnutrition, but when the state of malnourishment is reached, it appears that a newsteady state is reached, i.e. that REE, mainly determined by lean body mass, is adaptedto the new condition. In young healthy individuals, however, intake exceedsexpenditure (hyperphagia) after an experimental weight loss.31 The same studyshowed that elderly did not show hyperphagia after weight loss. The biochemical basisof this abnormality is not known, and it seems that patients with cirrhosis also have adefect in the signalling between being underweight and compensatory excess dietaryintake.

Protein

Protein requirement is increased in clinically stable patients with cirrhosis, to an averagerequirement of about 0.8 g/kg per day. With the customary addition of 2 SD’s, arecommendation of about 1.2 g/kg per days is reached.32–34 Protein requirement can be

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increased due to decreased absorption, decreased synthesis of body protein, increaseddegradation of body protein, or increased hepatic urea production with increasedurinary nitrogen excretion and/or increased intestinal protein loss. In these studies,faecal nitrogen excretion was not increased, i.e. neither malabsorption nor increasedintestinal loss was responsible. Investigations with stable isotopes suggested that thereis an increased rate of endogenous protein degradation both in the fasting state35 and inthe diurnal fasting/fed state.36 The increase in breakdown of body protein wasassociated with an increase in plasma amino acids, suggesting that the primary event isincreased protein breakdown rather than increased hepatic urea formation.36 Theincreased degradation in the fasting state may be due to low glycogen reserves,prompting an early switch to gluconeogenesis from amino acids origination from bodyprotein stores,35 as based on the observations in Owen’s study.37 The increase in thediurnal fasting/fed state, as based on preliminary data, may be due to a relative lack ofbranched-chain amino acids (BCAA—see further on BCAA below), e.g. for removal ofammonia,38 based on the observations in the study by Hayashi.39 A single meal does notincrease whole body protein synthesis in patients with cirrhosis, in contrast to theincrease seen in healthy volunteers.40 This defect was suggested to be due to theinsulin-insensitivity also observed in the study.

Together, these studies indicate that the increased protein requirement is due toboth a defect in meal-induced protein synthesis and increased protein degradationduring feeding as well as fasting. However, a note of caution is warranted since themethods for measuring protein metabolism are still being debated, not the least inpatients with cirrhosis.

Despite the increased requirement for protein, stable malnourished patients withcirrhosis are in nitrogen balance at an intake lower than that of the healthypopulation,33 suggesting that they have reached a steady state with the low intake andthe same considerations a those given above about the lack of excess energy intake inan underweight state apply to protein intake.

In situations when acute exacerbations further decrease the intake, e.g. due toinfections, tense ascites, bleeding, encephalopathic episodes, the possible increase inREE and the increase in protein requirement will of course aggravate the nutritionalstatus rapidly.

Vitamins and minerals

Patients with liver cirrhosis often have low plasma levels of vitamins and trace minerals,but the specific causes and specific functional implications of these abnormalities arenot known in detail. Magnesium depletion, now also determined as urinary excretionafter a magnesium load, is common in end stage liver disease.41 Zink deficiency is alsocommon and seems to be caused by decreased absorption and a diuretics-inducedincrease in urinary excretion.42 Supplementation with zinc increases glucosetolerance.43,44 One study reported that zinc supplementation reduced the increasein plasma ammonia after an alanine load, and this was accompanied by an improvementin psychometric tests, liver function tests and Child–Pugh score.45 However, the effecton psychometric tests was not confirmed in another study.46

Thiamine deficiency is common in alcoholism and in alcoholic cirrhosis, but it hasbeen found to be equally frequent in hepatitis C virus related cirrhosis.47 The deficiencywas not due to decreased erythrocyte phosphorylation of thiamine in that study, but

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other potential causes were not investigated. It was recommended to give thiaminesupplements to all patients with cirrhosis.

INTERVENTION STUDIES

Standard nutrition support in patients with cirrhosis

There is no specific meta-analysis available which can guide the reader as to when togive nutrition support to patients with liver cirrhosis. Recently, a meta-analysis wasperformed of about 30 randomised controlled trials with a total of about 3000 patientsgiven oral supplements or tube feeding. The meta-analysis included a large variety ofdiagnoses: neurology, gastrointestinal disease, liver disease, malignant disease, elderly,abdominal surgery, orthopaedic surgery, critical illness/injury, burns. The resultsshowed that the rate of complications was reduced from 46 to 28%, that the rate ofinfections was reduced from 44 to 24% and that mortality was reduced from 24 to17%.48 It may therefore be inferred that nutrition support will also improve clinicaloutcome in patients with cirrhosis, being a part of the malnourished population inhospitals.

The latest systematic review of nutrition support in patients with cirrhosis49 aimedat defining more precisely in clinical terms when to give nutrition support to thesepatients. This was based on the information supplied in the randomised controlledstudies available, some of which showed an effect on clinical outcome while others didnot. It was noted that the positive and no-effect trials had included patients withapproximately the same degree of impaired liver function and impaired nutritionalstatus, whereas the studies differed in amount and type of exclusion criteria. Thestudies with few exclusion criteria, and with a positive effect on outcome, includedpatients that had a low spontaneous energy and protein intake while the studies with alarge number of exclusion criteria, an no effect on outcome, included patients who hada fairly adequate spontaneous intake of energy and protein. It was therefore suggestedthat nutrition support is indicated in patients with a low spontaneous intake, i.e. below50 g protein per day, for example due to complications of the disease (infections, tenseascites, bleeding, encephalopathic episodes). It seems rather obvious that nutritionsupport only works when the spontaneous intake is low. In these studies there was noindication that adequate dietary intake, including protein, aggravated HE. The point ofkeeping track of dietary intake has been re-emphasised in a study showing that intake ofenergy and protein during hospital stay is related to mortality and septic complications.6

The consensus report of ESPEN on nutrition support in liver disease50 gaverecommendations for various clinical conditions of the patients: malnourished patientswho have an inadequate dietary intake and are at risk of fatal complications shouldreceive nutrition support. This recommendation was based on the same evidence asreviewed above. The intervention studies available, which suggest a positive effect onclinical outcome in such patients, gave energy in amounts of 35–40 kcal/kg per day andprotein in amounts up to 1.6 g/kg per day and these doses were recommended byESPEN to be used as a guideline.

A more recent systematic review of all studies of nutrition support also showed thatin studies of patients with cirrhosis who fulfil the criteria for being nutritionally at-riskby the ESPEN screening tool NRS-2002,17 there is a positive effect of nutrition supporton clinical outcome.51

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The ESPEN consensus report50 also stated, based on the intervention trials available,that in malnourished patients who have an inadequate dietary intake and are at risk offatal complications, low grade HE (grade I–II) should not be considered acontraindication to nutrition support, including an adequate protein supply. This laststatement aimed at changing the clinical routine of reducing protein intake inencephalopathic patients, based on an ill-defined suspicion of encephalopathic patientsbeing protein-intolerant. Iatrogenic protein restriction will of course aggravatemalnutrition, in particular when considering the increased protein requirements. Thisnew policy was not immediately accepted.52,53

For patients with HE as their main problem, rather than disease-related anorexia andmalnutrition, the ESPEN guideline advised a few days of protein restriction if otherobvious causes of HE had been ruled out and protein-intolerance was possible, butafter a few days adequate nutrition should be reinstituted.

The need for caution has now been formally investigated in an intervention trial.54 Inthis trial, malnourished encephalopathic patients in stage 1–4, median stage 2, wererandomised to follow the advice of a gradual increase in protein intake or to adequateprotein intake via tube feeding, 1.2 g/kg per day, from the beginning. At the same timeprecipitating factors were treated when identified: infection or electrolyte disturb-ances. In 4 out of 10 patients in each group the precipitating factor was not identified.All patients received standard therapy for HE (lactulose followed by neomycin).Outcome of HE and mortality were identical in both groups. The normal protein grouphad a positive nitrogen balance from day 2, associated with a lower rate of proteindegradation compared to the low protein group, at similar rates of protein synthesis.Plasma ammonia at the end of the study was similar in both groups. This study clearlyshows that no harm is done when treating malnourished encephalopathic patients withadequate amounts of protein. In addition, the study demonstrates that tube feeding cansafely be applied in these patients, since none of the patients developed aspirationpneumonia or significant gastric retention. These conclusions have already receivedconsiderable support.55,56

A novel approach is to add pre- and probiotics to a standard tube feeding in order toreduce intestinal bacterial translocation and to improve gut immune function. In a studyof patients after liver transplantation, the addition of lactic acid bacteria and fibresindeed resulted in a dramatic reduction in postoperative infections.57

Evening meals

The study of Owen37 showed that after an overnight fast, the splanchnic metabolism inpatients with cirrhosis had changed to a metabolic state similar to that of healthyvolunteers after a 3 days’ fast, in particular with respect to increased gluconeogenesisfrom peripheral amino acids derived from body protein. It was suggested that lowhepatic glycogen reserves in cirrhotic liver prompt this rapid shift to gluconeogenesisduring night hours. It was therefore investigated whether the same amount of proteindivided into 4–6 meals including a late evening meal would improve nitrogen balancecompared to the usual three main meals pattern. This was indeed found to be thecase.58 The same group later reported that a similar improvement could be achieved bya late evening oral dose of glucose.59 This approach has been extended to giving BCAA(see further on BCAA below) after breakfast and at night compared to the usualprocedure: after breakfast and after dinner.60 With the night dose of BCAA, the urinaryexcretion of 3-methylhistidine decreased, both absolute and relative to urinarycreatinine excretion. This indicates a lower muscle protein breakdown with the evening

554 J. Kondrup

dose of BCAA. It has also been found that one late evening snack with carbohydrate andBCAA improves glucose tolerance to the same degree as the same snack given twiceduring the daytime.61 These studies all point to the importance of reducing the length ofevening-night time starvation in patients with cirrhosis. Future studies are needed tocompare the relative efficiency of the methods described, meal, carbohydrate orcarbohydrate with BCAA, for clinical outcome.

BCAA in cirrhosis

BCAA is still under investigation as a method to treat HE and/or as a nutritionalsupplement to improve nutritional status and clinical outcome. For recent reviews,see.62–65 BCAA, especially leucine, appear to have a special anabolic role as a co-regulator of the rate of protein breakdown, and in experimental animals, also of the rateof protein synthesis.65,66 BCAA compete with the serotonin precursor tryptophane forthe same amino acid transporter in the blood–brain barrier. The ratio of BCAA/tryptophane is decreased in most patients with cirrhosis, probably due tohyperinsulinemia and/or decreased postabsorptive removal of non-BCAA by the failingliver, and it is therefore believed that a supplement with BCAAmay reduce brain uptakeof tryptophane.63,64

In a meta-analysis of studies using BCAA for treatment of HE, BCAA was effectivewhen including all studies, but when excluding studies with a low quality (unknownrandomisation method, unknown blinding), the effect was neither seemingly norstatistically significant. It was also noted that too few studies were available to carry outa meta-analysis of the effect of BCAA as a nutritional supplement.67

Sine this meta-analysis, a large multicenter 1-year trial investigated the role of BCAAas a nutritional supplement.68 The 174 cirrhotic patients were included on the basis ofsevere liver disease, defined as a Child–Pugh score B or C and evidence of portalhypertension. Neither malnourishment nor encephalopathy were entry criteria. Thepatients included were not malnourished as determined by MAC or bioimpedance norovertly encephalopathic. Therefore, the purpose of the study was not to treatmalnourishment or encephalopathy, but rather to investigate whether BCAA would beof clinical benefit in cirrhotic patients with moderate–severe disease. The patients wererandomised to three groups given different supplements containing either 14 g BCAAor isonitrogenousCisoenergetic lactalbumin or isoenergetic maltodextrin. It is a strongmethodological feature of this study to include both control groups. BCAA reducedrate of death and further severe progression of liver disease and rate of hospitaladmissions, increased appetite rating and Quality of Life. The low grade encephalopathypresent in some of the included patients did not improve. BCAA increased tricepsskinfold thickness, results for MAC were not reported and bioimpedance analysis wasnot improved. The main problem with the study was a rather large rate of drop-outs inthe BCAA group, mainly due to palatability/acceptance issues. This led to a non-significant intention-to-treat analysis for the main outcome variable, death and furthersevere progression of liver disease. The study does suggest, however, that BCAA has apositive effect on outcome, more than the lactalbumin-based supplement, which in itscomposition may be more similar to a standard oral supplement. Still, it does remain tobe shown that a BCAA supplement is superior to standard products in a successfulintention-to-treat analysis.

One of the first studies to employ BCAA was carried out in patients who wereprotein-intolerant, i.e. tolerating less than 40 g of protein. They were randomised toincrease their protein intake to 70 g, either in the form of casein or with a BCAA

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supplement.69 When encephalopathy worsened, it was considered a treatment failureand the patient was withdrawn from the study. Seven out of 12 patients in the caseingroup were treatment failures, but only 1 out of 14 in the BCAA group was a treatmentfailure. This study combines the two potential uses of BCAA: treatment/prevention ofHE in malnourished patients who cannot be refed because of protein-intolerance. Thisis the only study available with this design, and it was the basis of the ESPENrecommendation to use BCAA in this particular situation.50 This study of course needsto be verified in other centres, but until more studies are available, this situationremains to be the only clear indication for the use of BCAA in treatment of patientswith cirrhosis.

Hepatic coma and acute liver failure

There are no recent studies available on nutrition support in hepatic coma. Theconclusions from the meta-analysis70 still seem to hold: that parenteral nutritionprobably improves survival in these patients but the heterogeneity among the studiesmakes firm conclusions impossible. It should be stressed that most of the trials hadtested BCAA containing products, but in most cases they used control treatmentwithout amino acids and therefore it cannot be concluded that it is BCAA, rather astandard amino acid mixture, that may be effective.

For acute liver failure there are no intervention studies available to define thebest practice. A survey in Europe showed a surprising variation in feeding techniques(enteral or parenteral) and in composition of feeds.71 A large number of centresused standard TPN containing amino acids, despite the fact that these patients haveplasma amino acid concentrations that are increased three–fourfold above normalvalues.

In acute liver failure, the splanchnic area produces large amounts of ammonia, mostlikely derived from glutamine removed from the circulation by the portally drainedviscera. Ammonia produced in the splanchnic region is taken up in muscle and brain andprobably contributes to the production of glutamine in these organs. However, bothmuscle and brain produce more glutamine than can be accounted for by ammonia andamino acid uptake in these tissues, indicating a severe protein catabolic state.72,73 Thesestudies also confirmed earlier studies showing decreased levels of BCAA, despite theincrease in total amino acids. It does not seem rational to supply a standard mixture ofamino acids to these patients. Future trials on clinical outcome may show clinical benefitfrom correction of the amino acid pattern by supplying BCAA.

Transplantation

Two studies have examined the effect of nutrition support after liver transplantation.Early postoperative enteral nutrition, within 12 hours after transplantation, reducedthe rate of viral infections74 and showed a tendency to reduced bacterial infections.Postoperative parenteral nutrition reduced the length of stay in the ICU.75

The concept of pre- and postoperative immunonutrition has now also beenintroduced in liver transplantation,76 inspired by the positive results obtained in othertypes of gastrointestinal surgery.77 The study by Plank et al76 is a feasibility study with ahistoric control group and therefore the promising outcome results can only be seen asa stimulus to perform a prospective study. However, it is worth noting from this studythat the immunostimulatory effect did not seem to cause an increase in the rate of

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rejections and it will be highly interesting to see the results of the prospective trialpresently being carried by the authors.

SUMMARY

It has become increasingly clear during the last 10 years that malnutrition by itself isassociated with worsened clinical outcome in patients with liver cirrhosis. Simplemethods, such as SGA, MAC or the ESPEN screening tool, NRS-2002, may be used toidentify patients who are at risk of nutrition-related complications. Inadequate intake inpatients with complications raises the alert to initiate nutrition support. In suchpatients, nutrition support will improve clinical outcome, as a best possibleinterpretation of the randomised studies available. Standard products can be used inmost situations, despite the disturbances in absorption and metabolism of glucose andprotein/amino acids. A new study demonstrates that adequate protein intake can safelybe given to encephalopathic patients via tube feeding.

In acute liver failure, no intervention studies can govern towards the best practice,but it should be considered that plasma amino acid concentrations are already greatlyelevated due to the absent liver function and the increased protein catabolic rate andtherefore it does not seem rational to administer standard amino acid solutions in thiscondition.

In liver transplantation, studies employing standard preparations have also showedimproved clinical outcome. A recent feasibility study suggests that immunonutrition iswell tolerated after liver transplantation and the results of an ongoing intervention trialare expected with great interest.

Finally, the reader is encouraged to read the ESPEN Guidelines for Enteral Nutrition,which are expected to be published early in 2006. These guidelines also contain anextensive update of enteral nutrition in liver disease.

FUTURE RESEARCH

The effect of nutrition support is based on a systematic review of studies available49 andhighly influenced by one study showing improved survival by tube feeding in severely illpatients.78 More intervention studies with standard composition or disease specificcompositions are needed before recommendations can be based on a formal meta-analysis.

The role of BCAA is still uncertain. It seems that BCAA is not a useful treatment inpatients with HE in general.67 A recent study showed that BCAA improved clinicaloutcome in not-malnourished cirrhotic patients with moderate–severe liver disease,68

but compliance was unsatisfactory due to palatability problems and therefore a moreacceptable formulation of BCAA is needed. It also remains to be settled whether BCAAwill improve clinical outcome in malnourished patients, since the disease spectrum ofthese patients is probably not the same as in not-malnourished cirrhotic patients. Thepossible role of BCAA in nutrition support of patients with protein-intolerance69 needsto be verified and, in particular, a clinical test for diagnosing protein-intolerance shouldbe developed.

Practice points

† nutrition problems are prominent and related to clinical course already inpatients with mild disease, i.e. Child–Pugh class A

† nutrition problems can be identified by simple means, such as mid-arm-circumference, recent weight loss, recent dietary intake, or BMI when allowingfor amount of ascites

† survival after liver transplantation and cost are both related to nutritionalstatus

† nutrition support improves clinical outcome in patients who have a lowspontaneous intake due to acute complications of cirrhosis, or in the earlyposttransplantation phase

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REFERENCES

1. Anonymous. Nutritional status in cirrhosis. Italian multicentre cooperative project on nutrition in liver

cirrhosis. J Hepatol 1994; 21: 317–325.

2. Merli M, Riggio O, Dally L et al. Does malnutrition affect survival in cirrhosis? Hepatology 1996; 23: 1041–

1046.

3. Alberino F, Gatta A, Amodio P et al. Nutrition and survival in patients with liver cirrhosis. Nutrition 2001;

17: 445–450.

4. Prijatmoko D, Strauss BJ, Lambert JR et al. Early detection of protein depletion in alcoholic cirrhosis: role

of body composition analysis. Gastroenterology 1993; 105: 1839–1845.

5. Figueiredo FA, De Mello Perez R & Kondo M. Effect of liver cirrhosis on body composition: evidence of

significant depletion even in mild disease. J Gastroenterol Hepatol 2005; 20: 209–216.

6. Campillo B, Richardet JP, Scherman E et al. Evaluation of nutritional practice in hospitalized cirrhotic

patients: results of a prospective study. Nutrition 2003; 19: 515–521.

7. Detsky AS, Baker JP, Mendelson RA et al. Evaluating the accuracy of nutritional assessment techniques

applied to hospitalized patients: methodology and comparisons. J Par Ent Nutr 1984; 8: 153–159.

8. Alvares-da-Silva MR & Reverbel da Silveira T. Comparison between handgrip strength, subjective global

assessment, and prognostic nutritional index in assessing malnutrition and predicting clinical outcome in

cirrhotic outpatients. Nutrition 2005; 21: 113–117.

9. Andersen H, Borre M, Jakobsen J et al. Decreased muscle strength in patients with alcoholic liver cirrhosis

in relation to nutritional status, alcohol abstinence, liver function, and neuropathy. Hepatology 1998; 27:

1200–1206.

10. Figueiredo FA, Dickson ER, Pasha TM et al. Utility of standard nutritional parameters in detecting body

cell mass depletion in patients with end-stage liver disease. Liver Transpl 2000; 6: 575–581.

11. O’Keefe SJ, El-Zayadi AR, Carraher TE et al. Malnutrition and immuno-incompetence in patients with

liver disease. Lancet 1980; 2: 615–617.

12. Roongpisuthipong C, Sobhonslidsuk A, Nantiruj K et al. Nutritional assessment in various stages of liver

cirrhosis. Nutrition 2001; 17: 761–765.

13. Caly WR, Strauss E, Carrilho FJ et al. Different degrees of malnutrition and immunological alterations

according to the aetiology of cirrhosis: a prospective and sequential study. Nutr J 2003; 2: 10.

14. O’Keefe SJ, Abraham R, El-Zayadi A et al. Increased plasma tyrosine concentrations in patients with

cirrhosis and fulminant hepatic failure associated with increased plasma tyrosine flux and reduced hepatic

oxidation capacity. Gastroenterology 1981; 81: 1017–1024.

15. Selberg O & Selberg D. Norms and correlates of bioimpedance phase angle in healthy human subjects,

hospitalized patients, and patients with liver cirrhosis. Eur J Appl Physiol 2002; 86: 509–516.

16. Piccoli A, Pillon L & Dumler F. Impedance vector distribution by sex, race, body mass index, and age in the

United States: standard reference intervals as bivariate Z scores. Nutrition 2002; 18: 153–167.

17. Kondrup J, Allison SP, Elia M et al. ESPEN guidelines for nutrition screening 2002. Clin Nutr 2003; 22: 415–

421.

558 J. Kondrup

18. Merli M, Nicolini G, Angeloni S et al. Malnutrition is a risk factor in cirrhotic patients undergoing surgery.

Nutrition 2002; 18: 978–986.

19. Shaw BW,Wood RP, Gordon RDet al. Influence of selected patient variables and operative blood loss on

six-month survival following liver transplantation. Semin Liver Dis 1985; 5: 385.

20. Selberg O, Bottcher J, Tusch G et al. Identification of high- and low-risk patients before liver

transplantation: a prospective cohort study of nutritional and metabolic parameters in 150 patients.

Hepatology 1997; 25: 652–657.

21. Figueiredo F, Dickson ER, Pasha T et al. Impact of nutritional status on outcomes after liver

transplantation. Transplantation 2000; 70: 1347–1352.

22. O’Grady JG. Clinical economics review: liver transplantation. Aliment Pharmacol Ther 1997; 11: 445–451.

23. Sherlock S. Nutrition and the alcoholic. Lancet 1984; 1: 436–439.

24. Lieber CS. Alcohol: its metabolism and interaction with nutrients. Annu Rev Nutr 2000; 20: 395–430.

25. Campos AC, Matias JE & Coelho JC. Nutritional aspects of liver transplantation. Curr Opin Clin Nutr Metab

Care 2002; 5: 297–307.

26. Cabre E & Gassull MA. Nutrition in liver disease. Curr Opin Clin Nutr Metab Care 2005; 8: 545–551.

27. Muller MJ, Bottcher J, Selberg Oet al. Hypermetabolism in clinically stable patients with liver cirrhosis. Am

J Clin Nutr 1999; 69: 1194–1201.

28. Muller MJ, Dettmer A, Tettenborn M et al. Metabolic, endocrine, haemodynamic and pulmonary

responses to different types of exercise in individuals with normal or reduced liver function. Eur J Appl

Physiol 1996; 74: 246–257.

29. Riggio O, Angeloni S, Ciuffa L et al. Malnutrition is not related to alterations in energy balance in patients

with stable liver cirrhosis. Clin Nutr 2003; 22: 553–559.

30. Nielsen K, Kondrup J, Martinsen L et al. Nutritional assessment and adequacy of dietary intake in

hospitalized patients with alcoholic liver cirrhosis. Br J Nutr 1993; 69: 665–679.

31. Roberts SB, Fuss P, Heyman MB et al. Control of food intake in older men. JAMA 1994; 272: 1601–1606.

32. Swart GR, van den Berg JWO, van Vuure JK et al. Minimun protein requirements in liver cirrhosis

determined by nitrogen balance measurements at three levels of protein intake. Clin Nutr 1989; 8:

329–336.

33. Nielsen K, Kondrup J, Martinsen L et al. Long-term oral refeeding of patients with cirrhosis of the liver. Br

J Nutr 1995; 74: 557–567.

34. Kondrup J & Nielsen K. Protein requirement and protein utilization in patients with liver cirrhosis.

Z Gastroenterol 1996; 34: 26–31.

35. Swart GR, van den Berg JWO, Wattimena JLD et al. Elevated protein requirement in cirrhosis of the liver

investigated by whole body protein turnover studies. Clin Sci 1988; 75: 101–107.

36. Kondrup J, Nielsen K & Juul A. Effect of long-term refeeding on protein metabolism in patients with

cirrhosis of the liver. Br J Nutr 1997; 77: 197–212.

37. Owen OE, Reichle FA, Mozzoli MA et al. Hepatic, gut, and renal substrate flux rates in patients with

hepatic cirrhosis. J Clin Invest 1981; 68: 240–252.

38. Kondrup J. Metabolic basis of increased protein requirement in patients with liver cirrhosis (abstract). Clin

Nutr 2000; 19: 40.

39. Hayashi M, Ohnishi H, Kawade Y et al. Augmented utilization of branched-chain amino acids by skeletal

muscle in decompensated liver cirrhosis in special relation to ammonia detoxication. Gastroenterologia

Japonica 1981; 16: 64–70.

40. Tessari P, Barazzoni R, Kiwanuka E et al. Impairment of albumin and whole body postprandial protein

synthesis in compensated liver cirrhosis. Am J Physiol Endocrinol Metab 2002; 282: E304–E311.

41. Koivisto M, Valta P, Hockerstedt K et al. Magnesium depletion in chronic terminal liver cirrhosis. Clin

Transplant 2002; 16: 325–328.

42. Yoshida Y, Higashi T, Nouso K et al. Effects of zinc deficiency/zinc supplementation on ammonia

metabolism in patients with decompensated liver cirrhosis. Acta Med Okayama 2001; 55: 349–355.

43. Marchesini G, Bugianesi E, Ronchi M et al. Zinc supplementation improves glucose disposal in patients

with cirrhosis. Metabolism 1998; 47: 792–798.

44. Samman S. Zinc supplementation improves glucose disposal in patients with cirrhosis. Metabolism 1999;

48: 1069–1070.

45. Marchesini G, Fabbri A, Bianchi G et al. Zinc supplementation and amino acid-nitrogen metabolism in

patients with advanced cirrhosis. Hepatology 1996; 23: 1084–1092.

Nutrition in liver failure 559

46. Bresci G, Parisi G & Banti S. Management of hepatic encephalopathy with oral zinc supplementation:

a long-term treatment. Eur J Med 1993; 2: 414–416.

47. Levy S, Herve C, Delacoux E et al. Thiamine deficiency in hepatitis C virus and alcohol-related liver

diseases. Dig Dis Sci 2002; 47: 543–548.

48. Stratton RJ, Green CJ, & Elia M. Combined analysis of the effects of oral nutritional supplements and

enteral tube feeding. In Disease-related malnutrition: an evidence-based approach to treatment. Wallingford:

CABI Publishing, 2003, pp. 276–87.

49. Kondrup J & Muller MJ. Energy and protein requirements of patients with chronic liver disease. J Hepatol

1997; 27: 239–247.

50. Plauth M, Merli M, Kondrup J et al. ESPEN guidelines for nutrition in liver disease and transplantation. Clin

Nutr 1997; 16: 43–55.

51. Kondrup J, Rasmussen HH, Hamberg Oet al. Nutritional risk screening (NRS 2002): a new method based

on an analysis of controlled clinical trials. Clin Nutr 2003; 22: 321–336.

52. Plauth M, Merli M & Kondrup J. Management of hepatic encephalopathy. N Engl J Med 1997; 337: 1921–

1922.

53. Riordan SM &Williams R. Reply to Management of hepatic encephalopathy. N Engl J Med 1997; 337: 1922.

54. Cordoba J, Lopez-Hellin J, Planas M et al. Normal protein diet for episodic hepatic encephalopathy: results

of a randomized study. J Hepatol 2004; 41: 38–43.

55. Mullen KD& Dasarathy S. Protein restriction in hepatic encephalopathy: necessary evil or illogical dogma?

J Hepatol 2004; 41: 147–148.

56. Shawcross D & Jalan R. Dispelling myths in the treatment of hepatic encephalopathy. Lancet 2005; 365:

431–433.

57. Rayes N, Seehofer D, Theruvath T et al. Supply of pre- and probiotics reduces bacterial infection rates

after liver transplantation—a randomized, double-blind trial. Am J Transplant 2005; 5: 125–130.

58. Swart GR, Zillikens MC, van Vuure JK et al. Effect of a late evening meal on nitrogen balance in patients

with cirrhosis of the liver. Br Med J 1989; 299: 1202–1203.

59. Zillikens MC, van den Berg JW, Wattimena JL et al. Nocturnal oral glucose supplementation. The effects

on protein metabolism in cirrhotic patients and in healthy controls. J Hepatol 1993; 17: 377–383.

60. Yamauchi M, Takeda K, Sakamoto K et al. Effect of oral branched chain amino acid supplementation in the

late evening on the nutritional state of patients with liver cirrhosis. Hepatol Res 2001; 21: 199–204.

61. Tsuchiya M, Sakaida I, Okamoto M et al. The effect of a late evening snack in patients with liver cirrhosis.

Hepatol Res 2005.

62. Marchesini G, Marzocchi R, Noia M et al. Branched-chain amino acid supplementation in patients with

liver diseases. J Nutr 2005; 135: 1596S–1601S.

63. Bianchi G, Marzocchi R, Agostini F et al. Update on branched-chain amino acid supplementation in liver

diseases. Curr Opin Gastroenterol 2005; 21: 197–200.

64. Bianchi G, Marzocchi R, Agostini F et al. Update on nutritional supplementation with branched-chain

amino acids. Curr Opin Clin Nutr Metab Care 2005; 8: 83–87.

65. Laviano A, Muscaritoli M, Cascino A et al. Branched-chain amino acids: the best compromise to achieve

anabolism? Curr Opin Clin Nutr Metab Care 2005; 8: 408–414.

66. Garlick PJ. The role of leucine in the regulation of protein metabolism. J Nutr 2005; 135: 1553S–1556S.

67. Als-Nielsen B, Koretz RL, Kjaergard LL et al. Branched-chain amino acids for hepatic encephalopathy.

Cochrane Database Syst Rev 2003; CD001939.

68. Marchesini G, Bianchi G, Merli M et al. Nutritional supplementation with branched-chain amino acids in

advanced cirrhosis: a double-blind, randomized trial. Gastroenterology 2003; 124: 1792–1801.

69. Horst D, Grace ND, Conn HOet al. Comparison of dietary protein with an oral, branched chain-enriched

amino acid supplement in chronic portal-systemic encephalopathy: a randomized controlled trial.

Hepatology 1984; 4: 279–287.

70. Naylor CD, O’Rourke K, Detsky AS et al. Parenteral nutrition with branched-chain amino acids in hepatic

encephalopathy. A meta-analysis. Gastroenterology 1989; 97: 1033–1042.

71. Schutz T, Bechstein WO, Neuhaus P et al. Clinical practice of nutrition in acute liver failure—a European

survey. Clin Nutr 2004; 23: 975–982.

72. Clemmesen JO, Kondrup J & Ott P. Splanchnic and leg exchange of amino acids and ammonia in acute liver

failure. Gastroenterology 2000; 118: 1131–1139.

560 J. Kondrup

73. Strauss GI, Knudsen GM, Kondrup J et al. Cerebral metabolism of ammonia and amino acids in patients

with fulminant hepatic failure. Gastroenterology 2001; 121: 1109–1119.

74. Hasse JM, Blue LS, Liepa GU et al. Early enteral nutrition support in patients undergoing liver

transplantation. J Par Ent Nutr 1995; 19: 437–443.

75. Reilly J, Mehta R, Teperman L et al. Nutritional support after liver transplantation: a randomized

prospective study. J Par Ent Nutr 1990; 14: 386–391.

76. Plank LD, McCall JL, Gane EJ et al. Pre- and postoperative immunonutrition in patients undergoing liver

transplantation: a pilot study of safety and efficacy. Clin Nutr 2005; 24: 288–296.

77. Heyland DK, Novak F, Drover JW et al. Should immunonutrition become routine in critically ill patients?

A systematic review of the evidence. JAMA 2001; 286: 944–953.

78. Cabre E, Gonzalez-Huix F, Abad-Lacruz A et al. Effect of total enteral nutrition on the short-term

outcome of severely malnourished cirrhotics. A randomized controlled trial. Gastroenterology 1990; 98:

715–720.