Nutritional support in patients with chronic liver disease · " Nutritional support in patients with chronic liver disease Anne S Henkel and Alan L Buchman* SUMMARY Malnutrition is

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" Nutritional support in patients with chronicliver diseaseAnne S Henkel and Alan L Buchman*

SUMMARY

Malnutrition is highly prevalent among patients with chronic liver diseaseand is nearly universal among patients awaiting liver transplantation.Malnutrition in patients with cirrhosis leads to increased morbidity andmortality rates. Furthermore, patients who are severely malnourishedbefore transplant surgery have a higher rate of complications and adecreased overalI survival rate after liver transplantation. In light of thehigh incidence of malnutrition among patients with chronic liver diseaseand the complications that result from malnutrition in these patients, itis essential to assess the nutritional status of alI patients with liver disease,

and to initiate treatment as indicated. This review addresses the etiologiesof malnutrition, methods used to assess nutritional status, and appropriate

treatment strategies.

KEYWORDScirrhosis, liver disease, nutrient deficiency, nutritional status,protei~alorie malnutrition

REVIEW CRITERIA

PubMed was searched in June 2005 using the terms "liver disease", "cirrhosis","Iiver transplant", "nutritional status", "malnutrition", "protein-caloriemalnutrition", "nutrient deficiency", "enteral nutrition'; "parenteral nutrition",and "branched-chain amino acid" in various combinations. The search was

restricted to full papers published in English-language journals. Papers in theauthors' own collections were also included in the search. The reference list was

updated in November 2005.

AS Henkel isa Fellowin theDivision ofHepat%gy, and AL BuchmanisAssociate Professor of Medicine in the Division of Gastroenterology,Department of Medicine, Northwestern University Feinberg Schoo/of Medicine, Chicago, IL, USA.

Correspondence'Northwestem University Feinberg School of Medicine, 676 N St Clair St, Suite 1400, Chicago,IL60611, [email protected]

Received 24 July2005 Accepted 6 January 2006www.nature.com/clinicalpractice

doi:1 0.1 O38Incpgasthep0443

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INTRODUCTION

Malnutrition is an increasingly recognizedcomplication of chronic liver disease thathas important prognostic implications.Malnourished patients with cirrhosis have ahigher rate of complications and, overalI, anincreased mortality rate.1,2 Malnutrition hassignificant implications for livertransplantation;it has been shown that patients with poornutritional status before transplantation haveincreased complications and higher mortalityrates postoperatively. 3~ Screening alI patientswith chronic liver disease for nutritional abnor-

malities can identify those at risk of developingpreventable complications.7 The initiation ofnutritional therapy has the potential to reducethe risk of such complications, and to improvethe overalI mortality rate.

PREVALENCEProtein-calorie malnutrition (PCM)-a condi-tion of body wasting related to dietary deficiencyof calories and protein-is found in 65-90%of patients with advanced liver disease and inalmost 100%of candidates for livertransplanta-tion.8,9 Patients with chronic liver disease also

frequently develop micronutrient deficiencies,which can have a more insidious presentationthan the overt cachexia seen in patients withPCM. There is a direct correlation between

the progression of the liver disease and theseverity of malnutrition.lO,11 Malnutritiondevelops in patients with cirrhosis irrespectiveof the etiology of their disease12and occurswithroughly equal incidence in patients with alco-holic and nonalcoholic liver disease.13Patients

with cholestatic liverdiseaseare subject to caloriedepletion, whereas patients with noncholestaticdiseasepredominantly experience protein deple-tion.14 Additionally, cholestatic disease is morefrequently associated with a deficiency in fat-soluble vitamins than noncholestatic disease.15

Malnutrition is not typicalIy a complication ofacute liverinjury, but manifests with progressionto liver failure.

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SEQUELAEMalnutrition is associated with increased

morbidity and mortality rates in patients withchronic liver disease. Patients with cirrhosis

who are malnourished have a higher rate ofhepatic encephalopathy, infection, and varicealbleeding.3,16They are also twice as likelyto haverefractory ascites.8Although numerous studieshave found a correlation between poor nutri-tional status and a decreased survival rate, thereis debate as to whether the increased mortalityrate iscaused by malnutrition or by the advancedliver disease itself. Alberino et ai. identified

malnutrition as an independent predictor ofmortality in patients with cirrhosis.1

Nutritional status has prognostic implicationsin livertransplant candidates.Malnutrition beforetransplantation is associatedwith a higher rate ofpost-transplant complications, including infec-tion and variceal bleeding.;4,16,17Patients whoare severely malnourished require more bloodproducts intraoperatively, remain on ventila-tory support longer postoperatively,and have anincreasedlength ofhospital star,4,9 and a higherincidence of graft failure.18Ultimately, patientswith poor nutritional status before transplantsurgery have a decreased survival rate after livertransplantation.5,6,9

ETIOLOGIES

The primary etiology of malnutrition is poororal intake, stemming from multiple factors.Manypatients with advanced liver disease havean altered sense of taste, which might be relatedto vitamin A and/or zinc deficiency.19Patientswith cirrhosis often experience eariy satietythat is related to mechanical compression frommassiveascites.Eariysatiety can also result froman increased serum concentration of leptin,whichhas been found in patients with advancedliver disease.20The dietary restrictions that arecommonly recommended to these patients, suchas restriction of sodium, protein, and fluids, candiscourage adequate oral intake. In addition,weakness,fatigue,and low-gradeencephalopathycan contribute to decreased oral intake.

Malabsorption is another important factor inthe development of malnutrition in this patientpopulation.A number of mechanisms contributeto malabsorption. There might be a reductionin the bile-salt pool in patients with advancedliver disease, leading to fat malabsorption,21which is particulariy problematic in patientswith cholestatic liver disease. Another potential

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mechanism that contributes to malabsorption inpatients with advanced liver disease is bacterialovergrowth resulting from impaired small-bowelmotility.22The presenceof portal hypertensionhasalso been implicated as a cause of malabsorptionand gastrointestinal protein loss.23,24An addi-tional factor isthe administration of medications

that lead to malabsorption, such as neomycin,which is used in the treatment ofhepatic enceph-alopathy.25Fat malabsorption not only contrib-utes to undernourishment, but also results in adeficiencyin fat-soluble vitamins.

Another factor that might contribute tomalnutrition, around which there has beenconsiderable debate, is increased energy expend-iture. Although several studies have suggestedthat cirrhosis does not significantly alter restingenergy expenditure (REE),26,27other studiessuggest that patients with cirrhosis are actu-ally hypermetabolic when measurements ofREE are corrected for lean body mass.28,29Hypermetabolism is found in as many as a thirdof patients with stable cirrhosis; however, itseems that there is significant variability in REEamong patients with cirrhosis. In fact, it hasbeen suggested that up to 30% of patients withcirrhosis are actually hypometabolic.30,31

The exact cause of hypermetabolism remainsunclear, but certain predisposing factors havebeen identified. Infection, a common compli-cation in patients with advanced liver disease,tends to induce a state of hypermetabolism.Ascites has also been shown to increase energyexpenditure; this effect tends to be reversedwith the removal of ascitic fluid.32Muller et ai.

demonstrated that hypermetabolism cannotbe readily identified by clinical or biochemicalmarkers of liver disease, suggesting thathypermetabolism might be an extrahepaticmanifestation of liver disease.31 It has also

been demonstrated that an increase in energyexpenditure caused by hypermetabolism seemsto be matched by a reduction in activity-relatedenergy expenditure.33 Successful treatment ofportal hypertension with transjugular intra-hepatic portosystemic shunt placement resultsin a reduction of the hypermetabolic state.34

Patients with advanced liver disease also

have an altered pattern of fuel consumption, inwhich there is a more rapid transition from theuse of carbohydrates to the use of fat stores asa substrate for metabolismo This increased use

of lipids is a metabolic pattern that is seen instarvation.6,35,36Chang et aI.showed that, after

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GLOSSARY

THIRD-SPACINGA shift of fluid from lheinlravascular space 10lheinlerslilium

ISOTOPE DILUTlON

A melhod of assessing bodycomposilion using a Iracerdose of slable isolope,which is adminislered orallyand analyzed in body fluidsusing mass speclroscopy

WHOLE-BODYPOTASSIUMThe measuremenl of whole-body radiolabeled isolopeof polassium can be used10calculale fal-free mass byslandardlzed formulas

BIOELECTRICALIMPEDANCE

An assay of lolal bodywaler, whereby a weakcurrenl is passed Ihroughlhe body: lhe vollage dropbetween two eleclrodesis measured and isproportional 10lhe body'sfluid volume in Ihal region

an overnight fast, 58% of the energy used bypatients with cirrhosis was derived from fatoxidation, whereas control participants derived55% of their energy from carbohydrates.36

NUTRITIONALASSESSMENT

Considering the complications created bymalnutrition, a thorough nutritional assess-ment should be performed for everypatient withchronic liverdisease.This,however,might not beeasilyaccomplished.

There are several factors that complicate theevaluation of nutritional status in patients withcirrhosis. Many of the commonly used markersof malnutrition are not usefui parameters forthe prediction of malnutrition in this patientpopulation. Weight, for example, is not a reli-able indicator of malnutrition, because thepresence of ascites and edema will increasethe measured weight, whereas lean body massmight actually be reduced. AIso, many of thelaboratory tests that are typical markers ofnutritional status are less reliable in patientswith cirrhosis. For example, concentrations ofalbumin and prealbumin could be low becauseof low levelsof synthesis, rather than because ofpoor nutritional status. Other parameters mustbe used in the evaluation of these patients. Acommonly used method is anthropometry.Anthropometric measurements include tricepsskin-fold thickness and midarm circumference,which assess fat storage and skeletal musclemass, respectively. This method is, however,aiso not without its problems. Potentiallimi-tations of anthropometry include poor inter-observer reproducibility and overestimationof these values because of the THIRD-SPACINGof fluidoII

Subjective global assessment (SGA) is atechnique that combines multiple elements ofnutritional assessment to classifythe severity ofmalnutrition.37 These components are weightloss during the previous 6 months, changesin dietary intake, gastrointestinal symptoms,functional capacity, metabolic demands, signsof muscle wasting, and the presence of presacralor pedal edema. SGAhas been shown to have aninterobserver reproducibility rate of 80%,38andis useful in predicting outcome following livertransplantation.3

The assessment of muscle function measuringhand-grip strength and respiratory-musclestrength has also been used in nutritional evalu-ation; however, these measurements tend to be

more usefui when taken serially.39Hand-gripstrength is a highly sensitivetest and might actu-allyoverestimate the prevalence of malnutrition.Nonetheless, hand-grip strength seems to be agood predictor of complications in patients withadvanced liver disease.A recent study comparedSGA, the prognostic nutritional index, andhand-grip strength as predictors of outcome inpatients with cirrhosis.40In this study,decreasedhand-grip strength accurately predicted a poorclinical outcome that was related to a higherrate of complications, including ascites, hepaticencephalopathy, spontaneous bacterial peri-tonitis, and hepatorenal syndrome, whereasSGA and the prognostic nutritional indexdid noto The prevalence of malnutrition washighest when measured by hand-grip strength,suggesting that hand-grip strength could bethe most sensitive technique. Figueiredo et aI.showed that decreased handgrip strength beforetransplantation is associated with longer staysinthe intensive-care unit and more postoperativeinfections.17

Depletion ofbody cellmass (BCM) is a usefulestimation of nutritional status.41 DecreasedBCM before transplantation has been shown tocorrelate with a threefold increase in post-trans-plant mortality rates.5,6 ISOTOPEDILUTION,measurement of WHOLE-BODYPOTASSIUM,and in vivo neutron activation analysis arearguably the most accurate methods currentlyavailable to assess body composition; however,these techniques are costly and labor intensive,making them less practical for routine nutri-tional screening. BIOELECTRICAL IMPEDANCE

is a more readilyavailable tool for estimatingBCM. Although this is a reliable tool in manypatient populations, the accuracy of thesemeasurements in patients with cirrhosis canbe affected by fluid retention.42 Pirlich et aI.,however, showed that estimation of BCM usingbioelectrical impedance correlated closelywithBCM measured by total body potassium inpatients with and without ascites.43Figueiredoet aI.studied whether the traditionally measurednutritional parameters correia te with BCM.Although depleted BCM correlated most closelywith arm-muscle circumference and hand-gripstrength, most parameters, nonetheless, did notcorrelate well with depleted BCM.44

An evaluation of the status of energy metab-olism might be a reasonable component of anutritional assessment, because there seemsto be a correlation between hypermetabolism

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and malnutrition.6.31 This evaluation can

be accomplished using indirect calorimetry,a widely accepted tool that is used to esti-mate REE. Indirect calorimetry measures theconsumption of oxygen and production ofcarbon dioxide, and REE is calculated usingthe Weir equation: [kcal/d= [3.941 xV02(l/day)] + 1.l06 xVC02(l/day) ].45 The meas-ured REEis compared with the predicted energyexpenditure, as calculated using the Harris-Benedict equation.46 A patient is generallyconsidered to be hypermetabotic if the meas-ured REEis more than 10-20% greater than thepredicted REE.30.31In transplant recipients,hypermetabolism is associated with a decreasedsurvival rate after transplantation.5 The use ofindirect calorimetry enables the calculationof the nonprotein respiratory quotient, definedas the ratio of energy produced by carbohydratemetabolism to energy generated by fat oxida-tion, which confirms whether a patient has analtered pattern of fuel consumption.

TREATMENT

The goals of nutritional therapy are to improvePCM and correct nutrient deficiencies.This can

be accomplished via oral, enteral, or parenteralmethods, or a combination of these modalities.

Intervention in the earlystagesof malnutritioncan improve outcome. Hirsch et aI. studiedthe effects of nutritional supplementationin patients with alcoholic cirrhosis.47 Theyfound that patients receiving a daily supple-ment of 1,000kcal and 34g of protein (given asa casein-based enteral nutrition product) hadbetter outcomes compared with those in thecontrol group; the number of hospitalizationswas significantly fewer in the treated group,and additional parameters, including midarmcircumference, serum albumin concentration,and hand-grip strength, also improved earlierin the treated group than in the control group.Mendenhall et ai. studied the effects of oral

nutritional support in patients with alcoholichepatitis. In patients with severe malnutrition,inadequate caloric intake was associated with51% mortality compared with 19% mortalityin patients who received adequate oral nutri-tion (greater than 2,500 kcal/day).48 Onerandomized, controlled trial demonstratedthat providing nutritional supplementationto pretransplant candidates did not increaseoverall dietary energy or protein intake, anddid not significantly improve post-transplant



outcome. It is thought that the patients whoreceived a nutritional supplement might havecompensated for taking the supplement bydecreasing their intake of food. This studyconcluded that regular dietary counseling is aseffectivein increasing energy intake as providinga nutritional supplement.49

Enteral nutrition

As a general guidetine, oral intake should beencouraged; if patients are unable to maintainadequate intakeorally,a nasogastrictube should beinserted for enteral feeding.Cabre et aI.found that,in severelymalnourished patients with cirrhosis,enteral feeding improved serum albumin levelsand Child- Turcotte-Pugh scores, and decreasedin-hospital mortality rates, compared with thestandard oral diet.50 Hasse et ai. demonstrated

the benefit of early initiation of enteral feedingafter transplantation.51 Patients who receivedenteral feeds had an improved nitrogen balanceand fewer viral infections after transplantation.Kearns et ai. showed that aggressive nutritionalintervention with enteral feeding acceleratedimprovement in alcoholic liver disease; patientswho receivedenteral feeds demonstrated a morerapid decrease in bilirubin levels and improve-ment in hepatic encephalopathy compared withcontrol participants.52

Parenteral nutrition

Parenteral nutrition is a less desirable optionthan enteral nutrition and should be reserved

for patients in whom enteral feeding cannotbe achieved.53Wicks et ai. showed that enteral

feeding is as effective as parenteral feeding formaintaining nutritional status after tiver trans-plantation, and has the benefit of decreasingcomplications and cost. 54 There is someevidence to suggest that parenteral feedingmight be superior to enteral feeding in patientswith portosystemic shunting, because enteralfeeding might worsen hyperammonemia in thisspecific patient population.55

Guidelinesfor meetingnutritionalgoalsIn 1997, the European Society for ClinicalNutrition and Metabolism created guidelinesfor meeting nutri tionaI goals in patients withend-stage liver disease.53 They recommendinitiation of enteral feeding when oral intakeis inadequate. In patients with compensatedcirrhosis, the guidelines recommend that patientsconsume 25-35 kcal/kg body weight per day of

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nonprotein energy and 1-1.2 glkg body weightper day of protein or amino acids. In patientswith complicated cirrhosis associated withmalnutrition, nonprotein energy should beincreased to 35-40 kcal/kg body weight per dayand protein intake should increase to 1.5glkgbody weight per day.Accordingto the guidelines,protein intake should decrease to 0.5-1.5 glkgbody weight/day if stage I or 11encephalopathyis present, and to 0.5 glkg body weight/day ifstage III or IV encephalopathy is present. Morerecent evidence suggests that protein restrictionshould not be recommended, even in the settingof episodic hepatic encephalopathy.56

Distribution of calorie intake

The distribution of calorie intake throughout theday has also been studied. It has been proposedthat eating a late evening snack could alleviatethe shift towards lipid oxidation by reducing thelength of time a patient fasts overnight. Indeed,a late evening meal has been shown to improvethe nitrogen balance57and raise the nonproteinrespiratory quotient.58 A typical recommenda-tion for patients with advanced liverdisease is toconsume four to fivesmall meals per day,as wellas a late evening snack.

Supplementationwith branched-chainamino acidsThe usefulness of branched-chain amino

acid (BCAA) supplementation in patientswith cirrhosis has long been debated. It wasproposed that depletion of BCAAs,as seen inmany patients with advanced liverdisease,mightpromote the development of hepatic encepha-lopathy by enhancing the passage of aromaticamino acids across the blood-brain barrier,resulting in the synthesis of false neurotrans-mitters. For this reason, it was hypothesized thatBCAAsupplementationmightimprovehepaticencephalopathy. Early investigations, therefore,focused on BCAAs as a potential treatmentfor hepatic encephalopathy. Although somecontrolled trials showed no benefit of BCAAswith respect to mental function,59 several trialsshowed a significant improvement in hepaticencephalopathy with BCAA treatment.60,61 A2003 review of 11 randomized trials concluded

that BCAAs improve hepatic encephalopathy,particu]ar]y when administered enteraJJy topatients with chronic encephalopathy.62

Although there are conflicting data, thereis more evidence of the beneficial effects of

BCAAs to support their use in the treatment

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of malnutrition in patients with advancedcirrhosis. Marchesini et ai. performed a multi-center, randomized trial examining the role oforal BCAA supplementation in patients withadvanced liver disease.63 The trial consisted

of 174 patients with advanced cirrhosis whoreceived 1 year of nutritional supplementationwith BCAAs, lactoalbumin, or maltodextrins.BCAA administration wasadvantageouswithregard to rates of mortality, progression of liverfailure, and hospital admission. The most signif-icant limitation that the investigators found waspoor compliance with the BCAA-enriched diet;in the BCAA group, 15% of patients did notcomplete the treatment course. Poor compli-ance was attributed to poor palatability ofthe BCAA supplement.A recent multicenter,randomized, nutrient-intake-controlled trialdemonstrated that oral supplementation withBCAAs for 2 years improved survival, serumalbumin concentration, and quality of life inpatients with decompensated cirrhosis.64

Recent studies advocate the use of nocturnalBCAA administration.65 It is believed that

BCAAs that are consumed during the day areprimarily used as a source of energy for physicalexercise, whereas when administered at night,BCAAsmight be preferentially used for proteinsynthesis.

Correctingnutrient deficienciesNutritional therapy in patients with chronicliver disease shouJd not only focus on treatmentof PCM, but should also aim to correct specificnutrient deficiencies. Patients with advanced

liver disease commonly develop micronutrientdeficiencies.For example,patients with alcoholicliver disease who continue to consume alcohol

are particularly at risk for deficiency of thia-mine, folate, and magnesium.66 Most patientswith advanced liver disease, but particularlythose with cholestatic liver disease, develop adeficiency of fat-soluble vitamins.67

Decreased serum vitamin A levels result from

fat malabsorption, as well as defective mobi-lization of vitamin A from the liver.68 One

of the common complications of vitamin Adeficiency is night blindness, which has beenshown to improve with vitamin A supplemen-tation, generaJJy at a dose of 25,000 units/dayfor 4-12 weeks.69Persistent problems with darkadaptation, despite adequate supplementation,might result from concomitant zinc deficiency.70Vitamin A deficiency typically resolves within

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2 weeks of liver transplantation.69 Vitamin Atoxicity is a potential risk of vitamin A supple-mentation. Vitamin A toxicity typically causeselevated transaminase levelsand can eventuallylead to cirrhosis, chronic hepatitis, or portalhypertension.70 Although it was tradition-ally thought that the development of vitaminA toxicity requires doses well in excess of therecommended range, data now suggest thatcirrhosis can develop at therapeutic doses ofvitamin A (e.g. 25,000 IU/day for 6 years).71Liver disease resulting from vitamin A toxicitycan persist for up to 1 year after discontinuationof the supplement.

Vitamin D deficiency is another complica-tion of chronic liver disease, resulting primarilyfrom malabsorption; decreased UV light expo-sure and inadequate dietary intake might alsobe contributing factors to vitamin D deficiency.Impaired hepatic 25-hydroxylation of vitamin Dis alsoseen in patients with alcoholiccirrhosis.72Calcium deficiency, and eventually oste6-malacia or osteoporosis, results from decreasedintestinal calcium absorption. Up to 43% ofpatients undergoing transplant evaluation haveosteoporosis.73 There are conflicting data onwhether vitamin D supplementation improvesosteoporosis in patients with advanced liverdisease. It has been suggested that osteoporosisdoes not respond to vitamin D supplementationin patients with primary biliary cirrhosis,62butit can improve in patients with alcoholic liverdiseasewhen 25-hydroxyvitamin D supplemen-tation (25-50mglday) is taken.74 A proposedguideline is to supplement alipatients who havechronic liver disease with calcium (1 glday) andvitamin D3 (8001U/day).75,76

Zinc deficiency commonly occurs in patientswith cirrhosis and has been implicated in thepathogenesis ofhepatic encephalopathy.77Zincsupplementation at doses of 600mglday for3 months has been shown to improve mentalfunctioning in patients with hepatic encephalo-pathy,78although other studies show conflictingfindings, and the role of zinc in treating hepaticencephalopathy remains controversial.

CONCLUSION

Malnutrition is a well-known complication ofadvanced liver disease and is associated with

detrimental consequences if left untreated. Itis, therefore, of critical importance to assessthenutritional status of alipatients with chronic liverdisease and to optimize nutritional support in



these patients. Treatment should focus on main-taining adequate protein and caloric intake andcorrecting nutrient deficiencies.Strategiesincludethe consumption of frequent small meals and alate evening snack to reduce protein breakdown.When oral intake is insufficient, eariy implemen-tation of enteral feeding should be considered.The use of BCAAs remains controversial, butthe most recent data promote their therapeuticpotential. Malnutrition is a potentially revers-ible condition that, when identified and treatedappropriately, can lead to improved outcomes.

KEY POINTS

Malnutrition is an increasingly recognizedcomplication ot chronic liver disease that hasimportant prognostic implications

Etiologies include poor oral intake,malabsorption, increased energy expenditure, andan altered pattem ot tuel consumption

The nutritional status ot ali patients with liverdisease should be assessed to identify those at riskot developing preventable complications

Initiating nutritional therapy can reduce the risk otcomplications and improve the overall mortality rate

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Competing interestsThe authors declaredthey have no competinginterests.

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Reprinted with pennission from Nature Clinical Practice Gastroenterology and Hepatology 2006; 3(4):202-9.HenkelAS, Buchman AL. Nutritional support in patients with chronic liver disease. Copyright ~ 2006 NaturePublishing Group, a division ofMacmillan Publishers Limited. Ali rights reserved.


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Nutritional support in patients with chronic liver disease · " Nutritional support in patients with chronic liver disease Anne S Henkel and Alan L Buchman* SUMMARY Malnutrition is