Nutritional Therapy in Liver Transplantation

25 Pages·2017·1.47 MB·English

nutrients
Review
Nutritional Therapy in Liver Transplantation
AhmedHammad1,2,ToshimiKaido1,*,VusalAliyev1 ID,ClaudiaMandato3and
ShinjiUemoto1
1 DivisionofHepato-Biliary-PancreaticandTransplantSurgery,DepartmentofSurgery,
GraduateSchoolofMedicine,KyotoUniversity,Kyoto606-8501,Japan;
[email protected](A.H.);[email protected](V.A.);[email protected](S.U.)
2 DepartmentofGeneralSurgery,MansouraUniversity,Mansoura35516,Egypt
3 L’AORNChildren’sHospitalSantobonoandPausilipon,Napoli80122,Italy;[email protected]
* Correspondence:[email protected];Tel.:[phone];Fax:[phone]
Received:23August2017;Accepted:12October2017;Published:16October2017
Abstract: Protein-energy malnourishment is commonly encountered in patients with end-stage
liver disease who undergo liver transplantation. Malnutrition may further increase morbidity,
mortalityandcostsinthepost-transplantationsetting.Theimportanceofcarefullyassessingthe
nutritional status during the work-up of patients who are candidates for liver replacement is
widelyrecognized. Themetabolicabnormalitiesinducedbyliverfailurerendertheconventional
assessmentofnutritionalstatustobechallenging. Preoperativelossofskeletalmusclemass,namely,
sarcopenia, has a significant detrimental impact on post-transplant outcomes. It is essential to
provide sufficient nutritional support during all phases of liver transplantation. Oral nutrition
is preferred, but tube enteral nutrition may be required to provide the needed energy intake.
Herein, the latest currently employed perioperative nutritional interventions in liver transplant
recipientsarethoroughlyillustratedincludingsynbiotics,micronutrients,branched-chainaminoacid
supplementation,immunonutritionformulas,fluidandelectrolytebalance,theofferingofnocturnal
meals,dietarycounselling,exerciseandrehabilitation.
Keywords: livertransplantation;immunonutrition;synbiotics;nutritionalintervention;sarcopenia;
branched-chainaminoacids;nutraceuticals
1. Introduction
Theliveristhelargestandmostcrucialmetabolicorgan,playingapivotalroleinintegrating
severalbiochemicalpathwaysofcarbohydrate,fat,protein,andvitaminmetabolismaswellasthe
transportoflipidsandthesecretionandexcretionofbile,allofwhichareprocessesinvolvedinmuscle
andproteinmetabolismandcentralforwell-nourishedstatus[1–3].
Advances in post-transplant care and management of graft rejection have greatly improved
outcomesforpatientsafterorthotopiclivertransplantation(LT).However,malnutritionisarelevant
factorwhendeterminingtheprogressofhepaticdisease,asitcontributestohypoalbuminemiaand
intensifiesthehydroelectrolyticimbalancedeterminedbyrenalalterations[3–7].
Protein energy malnutrition (PEM) is a common problem in patients with end-stage liver
disease(ESLD)awaitingLT[5]. ThisappliestonearlyeveryetiologyofESLDwiththeexceptionof
fulminanthepaticfailure.ThediagnosisofPEMinESLDisestablishedbymarkedmusclewasting
andsubcutaneousfatloss[5,6]. PEMismoreprevalentinthosewithdecompensatedliverdisease
i.e.,thosewithascites,portosystemichepaticencephalopathy(HE),portalhypertensivebleedingand
patientshospitalizedforalcoholicliverdiseasethaninpatientswithnonalcoholicliverdisease[7].
ClinicalfeaturesofdeterioratedliverfunctiontendtonormalizefollowingsuccessfulLT.However,
PEMcansignificantlyincreasetheoperativeriskatthetimeofsurgeryandisariskfactorformorbidity,
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Nutrients2017,9,1126 2of25
short-andlong-termmortalityinpatientsundergoingLT[7,8]anddecreasedgraftsurvivalafterLT[9].
Moreover, PEMpredisposesapatienttocomplicationssuchascompromisedrespiratoryfunction,
wound-healing problems, longer dependency on mechanical ventilation, increased rates of septic
complications, useofantibiotics, bloodproductsusage, lengthofhospitalstay, intensivecareunit
admissions, delayed physical rehabilitation, with substantially higher cost of the transplant [8,9].
Prolongedwaitingtimesworsenoutcomeswhenpatientsarealreadymalnourished[10].
A patient’s nutritional status can worsen rapidly in the immediate postoperative period due
to perioperative malnutrition, surgical stress, immunosuppressive therapy, post-interventional
complications, postoperativeproteincatabolism, andfastingperiods[5,6]. Thissuggeststheneed
forpreemptivenutritionalsupportwithliver-adaptedformulascontainingadditionalcarbohydrates,
fatandproteinsespeciallybranched-chainaminoacids(BCAAs)[7,8].
Bodycellmass(BCM)isdefinedasthesumofintracellularwaterandfat-freemass,including
skeletal muscle and viscera, without bone mineral mass. BCM comprises the metabolically active
andprotein-richcompartmentsinthebodyresponsibleforbasalenergyexpenditure(BEE)andis
knowntobedepletedinpatientswithPEM[9]. Lossofskeletalmusclemass(SMM)orsarcopenia,
reflecting preoperative malnutrition is a common complication of liver cirrhosis (LC). Sarcopenia
couldinterferewithearlypostoperativemobilizationandhasbeenfoundtobecloselyassociatedwith
post-LTmortalityinpatientsundergoinglivingdonorLT(LDLT)[9].Sarcopeniaconfersavulnerability
topreoperativeinfection,includingspontaneousbacterialperitonitis,pneumonia,post-LTbacteremia,
sepsisandwounddehiscenceandpulmonarycomplications,includingaspirationpneumoniaand
atelectasis secondary to deteriorated immune functions [10,11]. Although less apparent, muscle
wasting may be present in obese patients, which is identified as “sarcopenic obesity” [10,11] and
underscores the importance of considering muscle depletion in such patients. This observation is
relevant because the number of obese patients, with ESLD due to Non-alcoholic steato-hepatitis,
isincreasingamongthoseawaitingLT[11,12].
Anaggressiveapproachtoensureadequatenutritionalrepletion,aswellascorrectingvitamin
andmicronutrientdeficienciesiscentraltomaintainremaininghepaticfunction,improvethepatient’s
metabolicreserves,andtheoutcomesafterLT[1]. Hence,timelynutritionassessmentandpatient
tailoredinterventionforanticipatedrecipientsorthoseonthewaitinglistmayimproveoutcomes
surroundingLT[1–3].
1.1. EtiologyofMalnutrition
1.1.1. DecreasedEnergyIntake
Patients with liver disease have decreased energy intake due to anorexia caused by zinc
deficiency,hyperglycemiaandincreasedpro-inflammatorycytokinelevels;tumornecrosisfactor-alpha
(TNF-α),interleukin(IL)-6andleptin[12–15]. Othercausesoflossofappetiteinthosepatientsare
the unpalatable specialized diets; low-salt and low-protein diets for ascites and HE, respectively,
andalteredgustatorysensationduetohypomagnesemiaandautonomicneuropathyinLC,whichalso
causesgastroparesisanddelayedboweltransittime,togetherwithconditionalbacterialovergrowthon
topoftenseascites,earlysatietyduetolessgastrointestinalperistalsisandgastricrestrictiveexpansion
due to large volume ascites, maldigestion, impaired hepato-intestinal extraction, malabsorption
and intestinal mucosal atrophy associated with portal hypertensive gastroenteropathy [12–16].
Increasedproteinlossesduetogastrointestinalbleedingandfrequentlargevolumeparacentesisalso
contributetomalnutrition,whichmayfurtherbeworsenedbyprotein-losingenteropathy,exacerbating
hypoalbuminemia. In liver cirrhosis, up to 45% of patients may have a coexisting infection with
Helicobacter pylori may cause dyspepsia and a decreased desire for food [13]. Moreover, limited
intakeduetodiagnosticproceduraleventscanleadtoprolongednilperosmayfurthercontributeto
PEM[14–17].
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1.1.2. HypercatobolicStatus
Nutrients 2017, 9, 1126 3 of 24
AnumberofcirrhoticpatientsmayalsohaveincreasedBEEthatmayberelatedtoincreased
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19a]n. dvisceralproteinsdemonstratingmuscledepletionanddecreaseinsubcutaneousfat[17–19].
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anantitmimeteatabbooliltietes,s c,hchoolelsetsrtyryaammininee) )[1[122,2,233].] F.Fata tmmalaalbabsosorprptitoionn inin alaclochoohloilci canadnd chcohloelsetsattaitci clivlievre dridsiesaesaesse,s ,
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Figure1. EtiologyofMalnutritioninEndStageLiverDisease. BEE:basalenergyexpenditure;IBD:
Figure 1. Etiology of Malnutrition in End Stage Liver Disease. BEE: basal energy expenditure; IBD:
inflammatoryboweldisease;IGF1:insulingrowthfactor1;IL6:interleukin-6;GI:gastrointestinaltract;
inflammatory bowel disease; IGF1: insulin growth factor 1; IL6: interleukin-6; GI: gastrointestinal
GH:growthhormone;LD:liverdisease;NS:nervoussystem;TNF-α:tumournecrosisfactoralpha.
tract; GH: growth hormone; LD: liver disease; NS: nervous system; TNF-α: tumour necrosis factor
alpha.
1.2. AssessmentofNutritionalStatus
1.2. AsAselslspmaetnietn otfs Nbueitnrigtiponreapl Sartaetdufso rLTshouldundergoathoroughnutritionalevaluation. Traditional
assessmenttoolsasBMIandanthropometryarenotaccurateinpatientswithliverdiseaseduetofluid
All patients being prepared for LT should undergo a thorough nutritional evaluation.
Traditional assessment tools as BMI and anthropometry are not accurate in patients with liver disease
due to fluid retention and organomegaly found in a significant number of patients. No gold-standard
evaluation exists to determine the extent of malnutrition in patients with ESLD [6,24].
Nutrients2017,9,1126 4of25
retentionandorganomegalyfoundinasignificantnumberofpatients. Nogold-standardevaluation
existstodeterminetheextentofmalnutritioninpatientswithESLD[6,24].
1.2.1. SubjectiveGlobalAssessment
The initial assessment should begin with a careful history to document weight loss, nausea,
anorexia,andspecializeddietsandsupplements. Acompletephysicalexaminationshouldsearch
for changes in oral mucosa, skin and hair, loss of subcutaneous fat, muscle-wasting and stigmata
of chronic liver disease. Subjective global assessment (SGA) combines a thorough history-taking
andphysicalexaminationandratespatientseither“well-nourished”,“moderatelymalnourished”,
or “severely malnourished” [6]. This test has shown high specificity with very low sensitivity for
diagnosingmalnutritioninpatientswithalcoholicliverdisease. However,ithasnotbeenfoundtobe
areliabletoolforevaluatingnutritionalstatusinLTpatients[6,24]. First,SGAdependsonpersonal
informationthatcanbedifficulttoobtainfrompatientswithcognitiveimpairmentorsomnolence.
Second, the only anthropometric measure utilized is the body weight, which is often changed by
ascitesandedema[6,24].
1.2.2. BiochemicalParametersandImmune-Competence
Biochemicaltestsusedasnutritionalindicatorsincludeserumtransferrinandretinolbinding
protein levels [25,26]. A reduced level of serum transferrin is additionally indicative of decreased
energyproteinintakerelatedtoLTpatients[25]. However,suchparametershavenotbeenshownto
beaccurateindicesofnutritionalstatusgiventhefactthattheirlevelscorrelatewithseverityofliver
damageandinflammatorystatesratherthanmalnutritionduetothecatabolicnatureofliverdisease
andassociatedproteinturnover.
Serumalbuminfrequentlyservesasanimportantindicatorofliverfunction. However,ithas
alonghalf-life(17–21days)andbecauseexogenousalbuminsupplementsarefrequentlyadministered
inclinicalpractice,serumalbuminlevelscannotsensitivelyordynamicallyreflectearlyliverdamage.
Theshorterhalf-life(2–3days)ofprealbumin(transthyretin)rendersitamoresensitiveindicatorof
damagedsynthesisfunctioningintheliverandfluctuationsinnutritionalstatusthanalbumin[27].
Creatinine-heightindex,24-hurinenitrogenand3-methylhistidineexcretionweresuggestedasindirect
measureofbodymusclemass,as1gofexcretedcreatinineequals18.5kgofmusclemass[26].
Immunecompetence,whichisconsideredafunctionaltestofnutritionalstatus,maybeaffected
byhypersplenism,abnormalimmunologicreactivityandalcoholabuse[26]. Lowtotallymphocyte,
CD8 cell counts, and abnormal response to skin anergy tests; delayed cutaneous hypersensitivity
response(≥5mmindurationtotwoormoreskintests)weresuggestedparametersformalnutrition[27].
The measurement of lean cell mass with total body potassium has been postulated for nutritional
assessmentofchildrenbutitisnotapartofroutinenutritionalassessmentofchildren[28].
1.2.3. Anthropometry
Anthropometricmeasurements,suchasbodymassindex,mid-armmusclecircumference,triceps
skinfoldthickness,bicepsorsubscapularskinfoldthicknessaresimple,quick,cheapandnoninvasive
assessmentmethodsinpatientswithliverdisease[25–27,29]. However,thesemeasureshavebeen
questionedregardingtheirreliabilityinpatientswithascitesandperipheraledemabutcorrection
by subtracting estimated amounts of ascites and other fluid collections may compensate for this
disadvantagetosomeextent[25–27,29]. Tricepsskinfoldthicknessremainedinadequatein70%of
malnourishedpatientsattheendofthefirstyear[30]. Inaprospectivecohortstudy,cirrhoticpatients
whowereseverelymalnourishedwhileonthewaitinglistshowedfurtherdeteriorationat3months
aftertransplantation;however,theyimprovedat6and12months. Onceagain,primarychangeswere
observedforfatmass(mediantricepsskinfold: basal10.8mmvs. 15.2mm,12mmp=0.03)[30].
Nutrients2017,9,1126 5of25
1.2.4. HandGripDynamometry
Functionalassessmentsuchashandgripstrengthdynamometryandthesix-minutewalktest
havebeenadvocatedaspotentialgoodparametersnotonlytoassessbutalsotofollowupnutritional
interventions[27]. Handgripstrengthisgoodreflectorofupperlimbstrengthandcanusedserially
inconjunctionwithbioelectricalimpedanceanalysis(BIA)tofollowupadoptednutritionaltherapy
regimen[29–32].
1.2.5. IndirectCalorimetry
The BEE can be predicted with several formulas such as the Harris-Benedict or Schofield
equations[33]. TheREEisanestimatedvalueofBEEaccountingfortheeffectsoffood,temperature,
stressandactivityfactors[19,30]. Thenon-proteinrespiratoryquotient(npRQ),aunitlessnumber
measuredby24hurinaryureanitrogen,bodycarbondioxideproductionandoxygenconsumption
wasusedtoevaluatethenutritionalstatusofpatientswithLC[34]. Moreover,npRQprovidesuseful
informationregardingsubstrateutilizationinthepost-operativeperiodwhichcanbeveryhelpfulin
thedevelopmentofanutritionsupportstrategy[34].
1.2.6. BioelectricalImpedance
InnutritionalassessmentforpatientsundergoingLDLT,Kaidoetal.[10–12]useddirectsegmental
multi-frequencyBIAwiththeInBody720(Biospace,Tokyo,Japan)device,bywhichbodymassindex,
intra-andextracellularwater,andbodyfatpercentagecouldbeautomaticallyandmeasuredwithin
2min. SMMwasmeasuredandshownasapercentagainststandardSMMcalculatedbysexand
heightofeachpatient.BCMwasautomaticallycalculatedbytheInBody720anddisplayedasanormal
range(e.g.,23.0–28.1kg).
TheBIAmeasuresthebody’sresistancetoflow(impedance)ofalternatingelectricalcurrentat
adesignatedfrequencybetweenpointsofcontactonthebody. Waterinbodytissueisconductive;
therefore,BIAcanindirectlyprovideinformationonthebody’stissuecontentincludingtotalbody
water, fat-free mass, and SMM [7,9]. BIA is increasingly being used because it is easy to perform,
portable,non-invasive,andquickdespitesomelimitationsinpatientswithascites. Ithasbeenhighly
correlatedwithhydrostaticweighing,dualenergyX-rayabsorptiometry,invivo-neutronactivation
analysis,anddeuteriumisotopedilution,withouttheradiationexposurehazards[35–38]. BIAmight
beconsideredcomparabletomeasuringthepsoasmusclecrosssectionalareaattheL vertebrallevel
3
bycomputedtomography(CT)scanormagneticresonanceimaging(MRI)asitmightbeappropriate
toevaluatenotonlythepsoasmusclemass,butalsothewholebodySMM[39–41].
Consideringfeasibility,thecurrentguidelinesoftheEuropeanSocietyforClinicalNutritionand
Metabolism(ESPEN)recommendonlySGAand/oranthropometryparameterstoidentifypatientsat
riskforpoornutritionalstatus,andBIAtoquantifyundernutritioninspiteofthelimitationsofall
techniquesinpatientswithasciticdecompensation[40–42]. AccordingtotheESPEN,othercomposite
nutritionscoresprovidenoadditionalprognosticinformation[42–44](Figure2).
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Figure2.AssessmentofnutritionalstatusinEndStageLiverDiseasePatients.
Figure 2. Assessment of nutritional status in End Stage Liver Disease Patients.
2. NutritionalTherapybeforeLiverTransplantation
2. Nutritional Therapy before Liver Transplantation
Themaingoalsofpre-LTnutritionaltherapyaretopreventfurthernutrientandmuscledepletion
The main goals of pre-LT nutritional therapy are to prevent further nutrient and muscle
andtocorrectanyvitaminandmineraldeficienciespresentinordertominimizetheriskofinfections
depletion and to correct any vitamin and mineral deficiencies present in order to minimize the risk
anddebility[23].
of infections and debility [23].
Because in deceased donor transplantation (DDLT), no one can predict when a patient will
Because in deceased donor transplantation (DDLT), no one can predict when a patient will
receive a transplant [2], an aggressive early post-operative nutritional support (by enteral route if
receive a transplant [2], an aggressive early post-operative nutritional support (by enteral route if
possible)shouldbeallocatedtothosepatientswithhighestMELDscores,especiallywhentheyare
possible) should be allocated to those patients with highest MELD scores, especially when they are
undernourishedand,ifitisanticipatedthatpatientswillbeunabletoeatwithinformorethantwo
undernourished and, if it is anticipated that patients will be unable to eat within for more than two
days. Also, this approach should be considered when patients cannot maintain oral intake above
days. Also, this approach should be considered when patients cannot maintain oral intake above 60%
60%oftherecommendedintakeformorethan10days[18]. Ontheotherhand,anearly,planned,
of the recommended intake for more than 10 days [18]. On the other hand, an early, planned,
preoperativenutritionalinterventioncanbeperformedinmostcasesofLDLT,sincethedateofLTis
preoperative nutritional intervention can be performed in most cases of LDLT, since the date of LT
knowninadvance,unlikeinDDLT.Nutritionaltherapy,aswellasrehabilitationatthetimeofreferral
is known in advance, unlike in DDLT. Nutritional therapy, as well as rehabilitation at the time of
ofapotentialrecipient,startsapproximatelyafewmonthsbeforeLTtomosteffectivelyincreaseSMM
referral of a potential recipient, starts approximately a few months before LT to most effectively
andBCM[7].
increase SMM and BCM [7].
2.1. RouteofNutritionalSupport
2.1. Route of Nutritional Support
Enteralnutrition(EN)withagastricorjejunalsmall-borefeedingtubeisthepreferableroute
Enteral nutrition (EN) with a gastric or jejunal small-bore feeding tube is the preferable route of
of delivery of nutrition for all patients who are not able to maintain adequate oral intake to still
delivery of nutrition for all patients who are not able to maintain adequate oral intake to still benefit
benefitfromtopicalnutritionalfactorsinthegut,andmaintaintheintegrityofthegastricmucosa
from topical nutritional factors in the gut, and maintain the integrity of the gastric mucosa and gut
andgutbarrier. Itisalsolesscostly,withfewercomplicationsanddecreasedhospitallengthofstay
barrier. It is also less costly, with fewer complications and decreased hospital length of stay compared
comparedwithparenteralnutrition(PN)whichcarriesriskofinfection,fluidoverloadandelectrolyte
with parenteral nutrition (PN) which carries risk of infection, fluid overload and electrolyte
imbalance[45]. ESPENguidelines(2006)onenteralnutritioninorgantransplantationrecommended
imbalance [45]. ESPEN guidelines (2006) on enteral nutrition in organ transplantation recommended
useofnutritionalsupportinpatientswithseverenutritionalriskfor10–14dayspriortomajorsurgery
use of nutritional support in patients with severe nutritional risk for 10–14 days prior to major surgery
evenifsurgeryhastobedelayed[41,42].
even if surgery has to be delayed [41,42].
ENprovidesantigenicstimulationtothegut-associatedlymphoidtissueandisastimulusfor
EN provides antigenic stimulation to the gut-associated lymphoid tissue and is a stimulus for
biliarysecretionofimmunoglobulinA[10,46]. Thesefactorsmaintainthebarrieragainsttranslocation
biliary secretion of immunoglobulin A [10,46]. These factors maintain the barrier against
translocation of luminal bacteria to the portal circulation, thus decreasing infectious complications
indicated by the differential urinary excretion of carbohydrates of varying molecular weights [10,47].
Nutrients2017,9,1126 7of25
ofluminalbacteriatotheportalcirculation,thusdecreasinginfectiouscomplicationsindicatedbythe
differentialurinaryexcretionofcarbohydratesofvaryingmolecularweights[10,47].
WithEN,excessivefeedingwillleadtointolerancewithdiarrhea,bloating,andvomiting.Because
thegutprovidesa“gate-keeper”role,majorcomplicationsrelatedtoexcessivetubefeedadministration
aregenerallykepttoaminimum. WithPNhowever,therearenomeansofregulationandthepatient
isforcedtoassimilatetheentiresubstrateload[10,45].
Feedingtubesdonotincreasetheriskforesophagealvaricealhemorrhage,butmaybeassociated
withanincreasedriskofepistaxis,sinusitis,impairedgastricemptyingandtubefeeding-associated
diarrheaonlong-termuseaswellastuberetraction,cloggingandsmallintestinalobstruction.However,
complicationsrelatedtomal-positionedfeedingtubesareusuallypreventableifplacementiscorrectly
achievedandregularlymonitored[10,47].
Feedingtubesarepreoperativelyplacedendoscopicallybytransilluminationacrosstheabdominal
wall. Thepresenceofascitesmayincreasethedifficultyinfindingasafewindowfortubeplacement.
Fluid in the peritoneal cavity can prevent proper apposition of the gastric body to the abdominal
walltoensurethehealingofapropertubetract. Ascitesthataccumulatescanalsodrainthroughthe
tractandincreasetheriskofinfection.Particularlyinthesettingofhypocomplementemiaincirrhosis,
thedecreasedopsonizationandtheopencommunicationfromtheskintosubcutaneoustissueand
ascitic fluid could further increase the risk of bacterial peritonitis. The concern is for puncture of
a variceal vessel during the procedure. In addition, portal hypertension can lead to many small
collateralvesselssubcutaneouslythatalsoelevatebleedingrisk[18,43].
The indications for PN use in liver disease have recently been reviewed and published by
ESPENforpatientswithfulminanthepaticfailureandcoma,andforpatientswhoaremoderatelyor
severelymalnourishedandcannotachieveadequateenergyintake,eitherorallyorthroughENdueto
gastrointestinaldysfunctionsuchasesophagealbleeding,ileusorintestinalobstructionorthosewho
shouldbe[41,48].Giventhelowglycogenstoresinpatientswithliverdisease,itisimportanttoprovide
aglucoseinfusioninpatientswhorequirefastingandarenotabletotakeoralnutrientsorENfor
morethan12h[41,42]. Useof“standardized”formulasshouldberestrictedtostablepatientswithno
fluidoverloadwhoneedmaintenancefluidadministrationonly[48]. Asforstablepatients,theoption
existstousefluidmaintenancecontainingwater,electrolytes,water-andfat-solublevitaminsorthe
liver-adaptedsolutionscontaininghigherBCAAandlowercontentofaromaticaminoacids[49].
2.2. ConsiderationsforCarbohydrateSupplementation
Carbohydrateintakeshouldexclusivelybeprovidedbyglucoseandcover50–60%ofnon-protein
energy requirements. Glucose infusion should supply 2–3 g/kg body weight per day of glucose.
Administrationofglucoseinexcesswillresultinseverehyperglycemia,lipogenesisandincreased
carbon dioxide production [47,48]. Patients with liver failure can have alterations in glucose
homeostasis; therefore, careful monitoring of serum glucose is needed to avoid complications
associated with hyperglycemia [48]. In the early postoperative phase, a dysfunction of glucose
metabolismassociatedwithinsulinresistanceisoftenprevalent. Increasedischemia-relateddamage
ofneuronsandgliacells,dysfunctionalleukocytefunctionoroxidativestresshavebeenfoundtobe
associatedwithhyperglycaemia. Thus,hyperglycaemiashouldbetreatedbyreducingtheglucose
intaketo2.0g/kg/day,andupto4IU/hinsulin,ifneeded,tomaintaineuglycaemiabecausehigher
insulindosesdonotimproveglucoseoxidation. Whentacrolimusisusedforimmunosuppression,
its diabetogenic potential can be lowered by reducing the dose and aiming for trough levels of
3–8ng/mLwithoutundueriskofrejection[49].
2.3. ConsiderationsforLipidSupplementation
Patients with advanced LC have decreased plasma levels of essential fatty acids and their
polyunsaturated derivatives such as arachidonate levels that have been associated with lower
survival. Botharecellmembranecomponentsandprecursorsofawidearrayofbiologicallyactive
Nutrients2017,9,1126 8of25
compounds. Lipidshouldbeprovidedbyusingemulsionswithareducedcontentofpolyunsaturated
fatty acids, as compared to pure soy bean oil emulsions, and cover 40–50% of non-protein energy
requirements[22,50].
Becausefatisimportantinnutrientrepletionofthemalnourishedpatient,dietaryfatshouldnotbe
restrictedunlesstruefatmalabsorptionhasbeendiagnosedusingafecalfattest.Incorporatingmedium
chain triglycerides; an alternative form of fat not requiring bile salts for absorption, can provide
aconcentratedsourceofcaloriestopatientswithfatmalabsorptionandareavailableinbothENand
PNformulations[22,50].
ManyENformulasprovideawiderangeoflipiddosagesfromavarietyofsourcesforfattyacids.
When prescribing total parenteral nutrition (TPN) many hospitals compound “three-in-one” TPN
solutionscontainingaminoacids,dextrose,andlipids. Theminimumlipiddoseinsuchcombinations
shouldbe20g/Lor2%finalconcentration. Moredilutelipidformulasareunstableinthepresence
of hypertonic dextrose and amino acids, resulting in separation of the lipid emulsion into oil and
water [50]. However, Clinical essential fatty acid deficiency takes approximately 5 to 6 weeks to
developwithoutlinoleicacidorlinolenicacidintake,soitisnotlikelytobecomeanissueformost
patientswithliverfailureexceptinthoseseverelymalnourished. Therefore,ashortcourseof“fat-free”
TPNmightbeused[22,51].
Otherhospitalsfavorseparate“piggyback”lipidinfusionwhichmaybepreferredduetoincreased
infectionriskthatcomesfromTPNsolutionshangingforupto24handtheuseofmulti-doselipid
vialsforcompoundingTPN[40,52]. AlargedoseofPNlipidcanresultinreticuloendothelialsystem
blockingwhichaggravatesinfectionriskandisexacerbatedbyrapid“piggyback”infusiontechniques,
andamelioratedbyslowercontinuousinfusion. Lipidadministrationshouldnotexceed1g/kg/day
usingpre-hospitaldryweightandshouldbegivenover24hifpossible[49,52].
The use of an omega-3 fatty acid-predominant lipid emulsion can prevent the occurrence
of dietary-induced and parenteral nutrition-induced steatosis and improves the resolution of
cholestasis. Omega-3candecreasedenovolipogenesis,interferewiththearachidonicacidpathwayof
inflammationtherebyreducingtheavailabilityforeicosanoid-synthesizingenzymesandinflammation.
Itisthoughtthatappropriateintakeofomega-3fattyacidswouldimproveimmunologicalresistance
andoffersomeprotectionagainstinflammatorytissuedamageandcapillarypermeability[52,53].
2.4. ConsiderationsforProteinSupplementation
The dilemma of sarcopenic chronically malnourished hepatopathic patients with ESLD and
cirrhosis,havingasubtleborderbetweentheneedforhypercaloricdietsrichinproteinsandtheriskof
hyperammoniemiaandHEisstilltobesolved. Inthesepatients,theneedforsevereproteinrestriction,
however,maybealleviatedbymeasures,suchaslactuloseandneomycinorprobioticstodecrease
intestinalammoniogenesisandBCAAs[54].
Hyperammonemia results from the production of ammonia in the gut and kidneys and the
decreasedbreakdownbyliverandskeletalmuscle,causedbysarcopeniainmalnourishedpatients
withliverdisease. Itiswellknownthatammoniahasadirecttoxicityonbrainastrocytes. Thiseffect
definitely contributes to HE. In addition, inflammation, infection, and oxidative stress also play
arole[54].
Proteinintakeshouldnotbelimitedasthismayaggravateproteindeficiency,andimprovement
innitrogenbalancemaybeachievedwithoutaggravatingHE[55]. Supplementationwithvegetable,
ratherthananimal,sourceproteinmaybeadvantageous[56].
Inpractice,whole-proteinformulasaregenerallyrecommended,andBCAA-enrichedformulas
should be used in patients who develop HE during re-feeding. Protein intake should be at least
1g/kg/dayinitially,andthen24-hurinaryureanitrogencanbemeasuredtoassessthecatabolicrate
inpatientswithnormalrenalfunction. Furtherincreasesinproteinintakecanbeadjustedaccordingly.
Progressiveincrementsinproteinsupplementationshouldbeimplemented,upto1.8–2.0g/kg/day
astolerated[52,56].
Nutrients2017,9,1126 9of25
Nutrients 2017, 9, 1126 9 of 24
2.5. Branched-ChainAminoAcidSupplementation
2.5. Branched-Chain Amino Acid Supplementation
BCAAs (leucine, isoleucine and valine) do not require the liver for metabolism, and thus are
BCAAs (leucine, isoleucine and valine) do not require the liver for metabolism, and thus are
preferentiallyusedinliverfailure. Ontheotherhand,aromaticaminoacids(AAAs)(phenylalanine,
preferentially used in liver failure. On the other hand, aromatic amino acids (AAAs) (phenylalanine,
tryptophanandtyrosine)arenotmetabolizedeffectivelyinliverfailureandthusaccumulate[52–57].
tryptophan and tyrosine) are not metabolized effectively in liver failure and thus accumulate [52–57].
The expected ratio, the so-called Fisher’s ratio, or the BCAAs/tyrosine ratio (BTR) should be
The expected ratio, the so-called Fisher’s ratio, or the BCAAs/tyrosine ratio (BTR) should be 3.5:1;
3.5:1; however, this ratio falls to 1:1 in patients with ESLD, allowing preferential transport of
however, this ratio falls to 1:1 in patients with ESLD, allowing preferential transport of the AAAs to
the AAAs to occur across the blood-brain barrier [58]. These are metabolized to octopamine,
occur across the blood-brain barrier [58]. These are metabolized to octopamine, phenylethylamine,
phenylethylamine,andphenylethanolamine,whichareweakfalseneurotransmittersthatcompete
and phenylethanolamine, which are weak false neurotransmitters that compete with endogenous
with endogenous neurotransmitters, inhibit excitatory stimulation of the brain, competing with
neurotransmitters, inhibit excitatory stimulation of the brain, competing with endogenous
endogenousneurotransmitters,thusaggravatingHE[57,58]. Inaddition,tryptophanismetabolizedto
neurotransmitters, thus aggravating HE [57,58]. In addition, tryptophan is metabolized to 5-
5-hydroxytryptophan(serotonin),whichcanproducefurtherlethargy[55,56](Figure3).
hydroxytryptophan (serotonin), which can produce further lethargy [55,56] (Figure 3).

Figure3.AminoAcidsAlteredinLiverDisease.TheexpectedBCAAs/tyrosineratio(Fisher’sratio),
Figure 3. Amino Acids Altered in Liver Disease. The expected BCAAs/tyrosine ratio (Fisher’s ratio),
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aimlbupmroivne, palrbeuamlbuinm, pinr,etaolbtaulmlyimn, ptohtoacly ltyemcpouhnoct,yBteT cRo,ugnlut,c BoTseRi,n gtloulecorasne cien,tolilveerranrecge,e nlievreart iroeng,enimermatuionne,
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[7,65I,n67it]i.a tionoforalBCAAsinpatientsintheearlystageofliverdiseasemaycontributetosolving
currenIntiLtiTatpioronb olef morsa,ls uBcChAaAsst hine dpoantioerntssh ionr ttahgee ,eathrleya svtaaiglaeb oilfi tlyivoefr odnislyeassme amllalyiv ceorngtrraibftustfeo trop saotlivenintsg
acwurarietinntg LTL DprLoTb.lTemhes,u ssuecho faso rthale BdConAoAr sshmorigtahgtea, ltshoe pavlaayilaabrioliltey ionf oimnlpyr somvianllg lipvoesrt g-LraTftms foorrt aplaittyienbtys
parwesaeirtivnign gLtDhLeTh.e pTahtei cursees eorfv eoroafl sBcCheAdAusle mdLigThrt eaclispoie pnltasy[ 6a8 ,r6o9l]e. in improving post-LT mortality by
preseBrCvAinAg tshuep hpelepmateicn rtaetsieornvep oofs ts-cehxeedrcuilseeda LttTe nruecaitpeidenthtse [6d8e,c6l9in].e inmyofibrillarproteinsynthesis,
whichBCisAvAita sluinppplreemseernvtiantgiolne apnomst-aesxsedrcuirsien gatwteneiugahttedlo sths.eT dheucsli,nthe eina dmdyitoiofinbroilflaBrC pArAotesiunp spylenmtheensitss,
mwahyichha ivs eviatalllo iwn epdrefsoerrvthineg mleaainn tmenaassn cdeuroifngle waneimghuts lcolses.m Tahsussb, tehcea uasdedoitfioints opf oBtCenAtAia lsutoppelnehmaennctes
lmeaany mhauvsec laellopwroetde ifnors tyhnet hmeasiinste[6n5a,n7c0e]. oOf lreaaln imnguessctlieo nmaosfs abeBcaCuAseA ofs uitps pploetmenetniatl btoe feonrehaonrcea lfetaern
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bimrepakrodvoewdn t[h6e4 ,6r6e,c7o0v].ery of damaged muscles by suppressing the endogenous muscle-protein
breakdown [64,66,70].
Nutrients2017,9,1126 10of25
2.6. MicronutrientSupplementation
PatientswithESLDaresusceptibletoseveredeficienciesinfolateandpyridoxal-5(cid:48)-phosphate,
thebiologicallyactivevitaminB6.ThiamineliverstoresaredepletedinalcoholicandhepatitisC-related
LC[71–73].Thisdepletionisassociatedwithincreasedbrainammoniaconcentrationsduetodecreased
activity of a-ketoglutarate dehydrogenase, a rate-limiting tricarboxylic acid cycle enzyme [71,72].
Deficienciesinantioxidantmicronutrients(selenium,vitaminE,vitaminC)arerelatedtooxidative
stresscommoninsuchpatients[73].
Atypicalfeatureofalcoholicorcholestaticliverdiseasesisanincreasinglyseverereductionin
hepaticvitaminAstores,whichsometimesleadstoinfertilityandnightblindness[73–75]. Invitamin
A-deficientcirrhoticpatients,thesupplementationofvitaminA,evenatrelativelymoderatedoses,
mayfurtheraggravateliverinjurysincehigh-dosevitaminApreparationsmaybehepatotoxicdueto
polarretinoidmetabolitesthatcausehepatocellularapoptosisandmaypromotefibrogenesis[74,75].
Decreasedlevelsoffolate,B12,calcium,phosphorusandvitaminKwithsubsequentcoagulopathyare
alsocommon[75–78].
MagnesiumandzincdeficiencyarecommoninpatientswithdecompensatedLCduetodecreased
absorptionanddiuretic-inducedincreasedurinaryexcretion[31,32].Clinically,zincdeficiencypresents
withalterationsofsmellandtaste,alterationsinproteinmetabolism,andHE.Zincsupplementation
improvesglucoseintoleranceanddecreasesammonialevels[31,32,76].
Bitettoetal.[79]observedthatvitaminDmayactasanimmunemodulatorinLT,favoringimmune
toleranceofliverallograft. Additionally,Bitettoetal. foundthatearlyvitaminDsupplementation,
inadditiontopreventingosteoporosis,wasindependentlyassociatedwithalackofacuterejection,
whichisimportantbecauselowvitaminDlevelsareprevalentamongLTcandidates.
Ontheotherhand,anexcessofmicronutrientscanalsobedangerous. Serumferritinisassociated
withincreasedbodyironorcanbeaconsequenceofsystemicnecro-inflammatorystates. Thelevelof
serumferritinactsasapredictorofmortalityinLCpatients[77].
2.7. CorrectionofLiverOsteodystrophy
Osteopenia and osteoporosis are highly prevalent in patients with ESLD, and represent
a major cause of morbidity before and after LT [80]. They can be caused by hormonal changes
inparathormoneandcalcitonin,increasedcirculatinglevelsofbilirubinandcytokines,corticosteroids,
andimmunosuppressivetherapyincholestaticdiseases[81–83]. Ingestionofalcoholcandirectlyand
indirectlypromoteboneloss. However,poordiet,physicalinactivity,anddegreeofliverinsufficiency
furthercontributetodeteriorationofbone[81,82].
LT candidates should be encouraged to consume foods high in calcium and vitamin D.
If consumption is low, calcium and vitamin D supplementation (1200–1500 mg/day) is highly
recommendedforpatientswithosteopeniaandincombinationwithbisphosphonatesforpatients
withestablishedosteoporosisand/orhistoryoffractures. Ifsteatorrheaisdiagnosed,asincholestatic
diseaseswater-miscibleformsoffat-solublevitaminsincludingvitaminDshouldbeprescribed[81].
Proteinmetabolismgeneratesalargeamountofacid,whichmustbebufferedbytheskeletonand
kidneys. Theskeletonrespondstohighserumaciditybyreleasingabufferingagentcalciumintothe
bloodstream,activatingboneresorption. Withmorecalciumenteringthebloodstream,thekidneys
respondbyincreasingurinaryexcretion,resultinginanetlossofcalcium. Thereisalsoalinkbetween
high-fatdietsandboneloss,asfatissuggestedtoinhibitosteoblastformation[80–83].
2.8. Over-SupplementationandPhysicalRehabilitationProgram
Patientswithliverdiseasecommonlysufferfromobesitybecauseofcontinuedoralintakealong
withlimitationsinphysicalactivitythatareoftenrecommendedduetofearthatexertionwouldhasten
theprogressofESLDprogressionorworsencomplications. However,exerciseisdocumentednotto
adverselyaffectliverfunctiontestsorworsensymptoms. Infact,theadverseeffectsofinactivityand