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Nutrition in Clinical Care Roleofnutritioninlivertransplantation for end-stage chronic liver disease Felix Stickel, Daniel Inderbitzin, and Daniel Candinas Patients with end-stage liver disease often reveal significant protein-energy malnutrition, which may deteriorate after listing for transplantation. Since malnutrition affects post-transplant survival, precise assessment must be an integral part of pre- and post-surgical management.Whilethereiswideagreement that aggressive treatment of nutritional deficiencies is required, strong scientific evidence supporting nutritional therapy is sparse. In practice, oral nutritional supplementsarepreferredoverparenteralnutrition,butenteraltubefeedingmaybe necessarytomaintainadequatecalorieintake.Proteinrestrictionshouldbeavoided and administration of branched-chain amino acids may help yield a sufficient protein supply. Specific problems such as micronutrient deficiency, fluid balance, cholestasis, encephalopathy, and comorbid conditions need attention in order to optimize patient outcome. ©2008International Life Sciences Institute INTRODUCTION its failure to accurately predict survival in approximately 15–20%ofpotentialtransplantrecipientsrelatestothefact Orthotopic liver transplantation (OLT) has greatly that malnutrition does not influence MELD figures. improved the prognosis of patients with chronic liver Nocontroversycurrentlyexistsregardingtheimpor- failure, and clinical features of declining liver function tance of nutritional status as an important predictor of largelynormalizefollowingsuccessfulorganreplacement. post-transplant outcome and the benefits of its therapeu- Amongthemostprevalentcomplicationsofchronicliver tic improvement, although evidence from randomized failure is a marked impairment of the nutritional status clinical trials is limited. The present review aims to sum- due to both primary and secondary malnutrition. The marizethecurrentevidenceonnutritionalaspectsinliver | downloaded: 5.1.2023degree of malnutrition has been a parameter of the oldtransplantation both in the pre- and post-transplant version of the Child-Pugh index; however, the lack of setting in order to highlight the importance of sufficient universally applicable diagnostic tools to precisely diag- nutritional support as a valuable intervention to improve nosemalnutritioninclinicalpracticehasleftthediagnosis patients overall prognosis and quality of life. based on clinical signs of encephalopathy and ascites as well as the laboratory parameters serum bilirubin, serum 1 albumin, and prothrombin time (index). Interestingly, PREVALENCEANDSIGNIFICANCEOFMALNUTRITION the model for end-stage liver disease (MELD), initially INEND-STAGELIVERDISEASE developedforpredictionofsurvivalofpatientswithcom- plications of portal hypertension scheduled for a trans- With the exception of patients with fulminant hepatic jugular intrahepatic portosystemic shunt, is now widely failure, most candidates for OLT present with significant usedfororganallocationinlivertransplantprogrammes, malnutrition, and nutritional deficiencies usually evolve 2 butit does not consider nutritional status at all. Possibly, prior to clinical signs of hepatic insufficiency. Protein Affiliations: F Stickel is with the Institute of Clinical Pharmacology, Inselspital, University of Berne, Berne, Switzerland. D Inderbitzin and DCandinasarewiththeDepartmentofVisceralandTransplant Surgery, Inselspital, University of Berne, Berne, Switzerland. https://doi.org/10.7892/boris.28346Correspondence: F Stickel, Institute of Clinical Pharmacology, University of Berne, Murtenstrasse 35, 3010 Berne, Switzerland. E-mail: felix.stickel@ikp.unibe.ch, Phone: +41-31-632 8715, Fax: +41-31-632 4997 Keywords:branched-chainaminoacids,livertransplantation,nutritionaltherapy, protein malnutrition source: doi:10.1111/j.1753-4887.2007.00005.x Nutrition Reviews® Vol. 66(1):47–54 47 energy malnutrition (PEM), in particular, is frequently drates, lipids, proteins, vitamins, and trace minerals; it is encountered in patients with cirrhosis of nearly every also an importantpartof theimmunesystem.Literallyall 3 functionalpropertiesof theliverareprofoundlyimpaired etiology. Even in stable cirrhotic patients, who are com- monly referred to as having Child A cirrhosis, protein in end-stage liver disease (ESLD). Malnutrition in 4 patients with ESLD has numerous causes,some of which depletion is prevalent in approximately 20% of patients. This figure rises sharply as liver insufficiency progresses, relate to the underlying etiology of liver damage while and a majority of patients with Child C cirrhosis have others are universal features of declining liver function 5–8 significant nutritional deficiencies. PEMclinically pre- irrespective of the type of liver disease.Both primary and sents with weakness,muscle wasting,weight loss,nausea, secondary factors contribute to poor nutritional status and anorexia; its prevalence is similar in advanced alco- and must be accounted for in the management of these 7,9 holic liver disease and other causes of liver cirrhosis. In patients. The most relevant causes of malnutrition in alcoholic cirrhosis, PEM is closely associated with com- patients with ESLD are as follows: 1) Dietary insuffi- plications of cirrhosis including infections, encephalopa- ciency:a)anorexia,nausea,vomiting;b)earlysatiety,taste 10,11 abnormalities, poor palatability of diets (protein and salt thy, development of ascites, and variceal bleeding, as well as with reduced patient and graft survival after restriction);c) reflux disease (ascites,abnormalgutmotil- OLT.12,13 ity): 2) Malabsorbtion: a) pancreatic insufficiency; b) Patients with end-stage liver disease are often defi- cholestasis (fat soluble vitamins); c) drug-related diar- 14 rhoea(lactulose,antibiotics,diuretics,cholestyramine):3) cient in various vitamins and other micronutrients. Cirrhotic alcoholics are especially susceptible to severe Metabolicdisturbances:a)hypermetabolismduringcom- vitamin depletion, particularly that of folate and plications (infections, haemorrhage, ascitic decompensa- pyridoxal-5′-phosphate,the biologically active coenzyme tion);b)proteincatabolism(inflammation,impairedliver 15 synthesis); c) impairment of glucose homeostasis due to of vitaminB6,withbothoccurringinupto70%ofcases. Thiamine levels are also frequently decreased in patients hepatic insulin resistance (altered gluconeogenesis, low with alcoholic and hepatitis C-related cirrhosis, which glycogen stores, impaired glycogenolysis); d) increased may elicit the Wernicke-Korsakoff syndrome and Beri- lipolysis, enhanced lipid oxidation; e) proinflammatory 16 Beri cardiomyopathy. A typical feature of early and cytokines (TNFa, interleukins, leptin): 4) Iatrogenic: a) advanced alcoholic liver disease is an increasingly severe investigativeprocedure-relatedfastingperiods;b)protein reduction of hepatic vitamin A stores, which sometimes restriction during periods of encephalopathy; c) large leads to infertility and night blindness.17 In vitamin volume paracentesis. A-deficient cirrhotics, its supplementation, even at rela- Notably, the majority of patients with ESLD have tively moderate doses, may further aggravate liver injury no increased resting energy expenditure (REE).A recent since high-dose vitamin A preparations may be hepato- study found a normal energy balance in clinically toxic due to polar retinoid metabolites that cause hepato- stable cirrhotic patients with malnutrition as assessed 18,19 25 cellular apoptosis and may promote fibrogenesis. Zinc by anthropometry. Seventy-four consecutive cirrhotic deficiency is common in patients with decompensated patients and nine healthy controls were investigated cirrhosis and likely relates to decreased absorption and a using indirect calorimetry adjusted according to the diuretics-induced increase in its urinary excretion.Clini- patients physical activity. Thirty-two patients in the cir- cally, zinc deficiency presents with alterations of smell rhoticgroupwereclassifiedasseverelymalnourished,but and taste, protein metabolism, and encephalopathy. basal energy expenditure (BEE) was similar in all three Regarding the latter, one study showed that zinc supple- groups; the non-protein respiratory quotient was lower mentationresulted in lower ammonia levels following an in cirrhotics notwithstanding their nutritional status. alanine challenge, and improvements of psychometric In addition, no difference in the estimated daily energy 20 but another tests, liver function, and Child-Pugh score, expenditure and energy intake was observed among 21 study did not replicate these findings. groups. Reduced nutritional status has been identified as Amajorreasonforprimarymalnutrition in patients an independent predictor of poor prognosis in patients priortotransplantationisreducedfoodconsumptiondue 22,23 26 with liver cirrhosis and an indicator of unfavorable to anorexia. Low calorie intake may also be traced to 24 outcome after liver transplantation. several other reasons including unpalatable diet compo- 23 sition due to salt and protein restriction, early satiety 27 CAUSESOFMALNUTRITIONIN because of ascites and portal gastropathy, and loss of END-STAGELIVERDISEASE appetite due to upregulated mediators of inflammation and mediators of appetite such as tumor necrosis factor- The liver is the largest metabolic organ of the human alpha and leptin.28,29 In addition, in up to 45% of cirrhot- body and plays a prime role in the turnover of carbohy- ics coexistinginfectionwithHelicobacterpylorimaycause 48 Nutrition Reviews® Vol. 66(1):47–54 30 values for triceps skin fold thickness and MAMC as dyspepsia and a decreased desire for food. Significant malnutrition may be the result of maldigestion related to simple bedside tests for nutritional assessment are given pancreatic or biliary abnormalities such as exocrine pan- in Table 1.BMI in particular has been criticized for yield- creatic insufficiency or primary biliary liver disorders, ing falsely high values,but correction by subtracting esti- while malabsorbtion can result from applied medications matedamountsof ascites and other fluid collections may 31 8 such as lactulose or antibiotics causing diarrhea. compensate for this disadvantage to some extent. Impaired glucose tolerance due to insulin resistance Biochemical markers of malnutrition include serum and established diabetes has an important impact on albumin concentration and measurements of 24-hour nutritional status in many cirrhotic patients. Due to creatinine excretion related to a reference population. impaired glyconeogenesis,the cirrhotic liver fails to store While the former obviously varies significantly due to sufficient amounts of glycogen; this results in glyconeo- hepatic function,the latter has been suggested as an indi- genesis from protein catabolism and lipid oxidation.32 rect measure of body muscle mass, as 1 g of excreted Therefore, periods of fasting should be avoided in cir- creatinine equals 18.5 kg of muscle mass.37 A more rhotic patients, and frequent meals should be imple- sophisticated, but less widely available, examination tool mented to prevent protein catabolism. In fact, late for assessing body composition is bioelectric impedance evening meals and nocturnal glucose supplementation analysis(BIA).BIAisapreciseandnoninvasivetechnique has been shown to improve nitrogen balance in cirrhotic that measures lean body mass and fat stores; however, 33,34 patients. it also becomes inaccurate when patients retain fluid. Another noninvasive method is dual x-ray absorptiom- NUTRITIONALASSESSMENT etry(DEXA),whichprovidesexactmeasurementsoftotal bodycomposition.Again,itsaccuracydeclinesinpatients For assessing nutritional status in patients with ESLD with ascites and edema. These shortcomings may be on the transplant waiting list no accepted diagnostic bypassed with more precise approaches such as in vivo- “gold standard” exists; in fact, several surrogate markers neutron activation analysis and isotope dilution tech- 38 but since application of these methods is of an individuals nutritional status are usually necessary niques, to obtain valid data on the severity and pattern of time-consuming and costly, their use is restricted to malnutrition. research purposes. Oneuseful,easily applicable,and validated approach Considering these feasibility issues, the European is subjective global assessment (SGA). This method inte- Society for Parenteral and Enteral Nutrition (ESPEN) has grates a detailed medical and dietary history,body weight publishedupdatedguidelinesonenteralnutritioninliver 39 and height, coexisting medical conditions, and physical transplant candidates. The current guidelines recom- activity to rate patients either “well-nourished”,“moder- mend simple bedside methods such as SGA and/or ately malnourished”, or “severely malnourished”. The anthropometry parameters to identify patients at risk for dietary history is ideally recorded by an experienced poor nutritional status and BIA to quantify undernutri- dietician.SGAishighlyspecific(96%)forthedetectionof tion despite the limitations of all techniques in patients 39 35 with ascitic decompensation. According to the ESPEN malnutrition in liver transplant candidates, butitlacks expertpanel,othercompositenutritionscoresprovideno 36 sensitivity in patients with severe alcoholic liver disease. additional prognostic information. Easily applicable techniques include anthropometric measurements such as body mass index (BMI), triceps skin fold thickness, and mid-arm muscle circumference NUTRITIONALINTERVENTION–THERAPEUTICAIMS (MAMC). Unfortunately, most of the easily applicable methods are confounded by significant fluid retention in Patients with ESLD on the transplant waiting list cirrhotics with ascites and peripheral edema. Reference frequently display a gradual decline of their nutritional Table 1 Bedside tests for simple assessment of malnutrition. Anthropometric test Normal Moderate Severe Triceps skin fold thickness Men 7.5–12.5mm 4–6mm <4mm Women 10–16.5mm 5–8mm <5mm Mid-armmusclecircumference Men 23.0–25.5cm 18–20cm <18cm Women 21–23cm 6–18.5cm <16cm 22 AdaptedfromSelbergetal. (Hepatology 1997;25:652–657). Nutrition Reviews® Vol. 66(1):47–54 49 Table 2 Harris-Benedict equation. tures, calcium and vitamin D supplementation should be 23 Gender Resting energy expenditure combined with bisphosphonates. Female 66.5+(9.56¥bodyweight[kilogram])+ (1.85 ¥ height [centimetres]) – ROUTEOFNUTRITIONALSUPPORT 4.676¥age(years) Male 66.5+(13.75¥bodyweight[kilogram])+ (5.0 ¥ height [centimetres]) – Nutritional supplements should,ideally, be administered 6.75¥age(years) enterally, either by oral supplements or,if active eating is hampered,throughagastricorjejunaltubesincepatients appear to benefit from topical nutritional factors in the condition. As a result, the major goals of pre-transplant gut. Another argument favoring oral nutrition is the nutritional therapy are to prevent further nutrient and lower rate of infections that may occur with central protein depletion and to correct macro- and micronutri- venous catheters.Concerns such as precipitating variceal ent deficiencies. Nutritional support should include the hemorrhage while inserting the feeding tube have not been confirmed in clinical trials.44 However, reports of administrationof sufficientamountsof calories,proteins, complications related to malpositioned feeding tubes vitamins,minerals,andtraceelementswithoutexacerbat- continue to surface; most are due to inadvertent disloca- ing liver disease-related complications such as portosys- tion in the respiratory tract causing aspiration, especially temic encephalopathy, fluid retention, and electrolyte when the tube is placed in the esophagus. Other imbalances. Determining the extent of nutritional complications observed occasionally with nasogastric/ supplementation requires calculation of the individuals nasoduodenal tubes include epistaxis, sinusitis, tube energy needs; this can be done by calculating BEE using removal or retraction, tube clogging, and tube-feeding- the Harris Benedict equation while considering the ideal associated diarrhea.45,46 However, complications related body weight rather than the patients actual weight to malpositioned feeding tubes are usually preventable (Table 2).As a rule of thumb, the total calories should be if correct placement is safely achieved and regularly aminimumof1.2timestheBEE,equalling35–40kcal/kg monitored. body weight daily, and 60–70% should derive from car- Totalparenteralnutrition(TPN)shouldberestricted 40 bohydrates. to patients who are unable to eat or those for whom Portosystemic encephalopathy is frequent in OLT enteral feeding is contraindicated. In cases of severe gas- candidates with ESLD, and many clinicians implement trointestinal dysfunction, such as esophageal bleeding or protein restriction to treat it. However, this should be intestinal obstruction, TPN remains an option to ensure avoided as a routine measure since it aggravates PEM. adequate caloric intake.However,TPN is associated with Instead, encephalopathy should be treated aggressively higher risks of infection and electrolyte imbalance, it is with standard therapy using lactulose and treatment of moreexpensive,and since evidence supporting its use in precipitating causes such as infections and gastrointesti- ESLD stems from studies focused on the treatment of nal hemorrhage. Usually, standard amino acid formulas severe alcoholic liver disease, it may not apply to patients are well tolerated and should provide at least 1g 9,23 protein/kg body weight per day, which can be increased waiting for liver transplantation. 23,40,41 to 1.2–2.0 g/kg daily when tolerated. Theusefulness of branched-chain amino acids (BCAA) has not been NUTRITIONALTHERAPYBEFORELIVER specifically investigated in patients with ESLD on the TRANSPLANTATION transplant waiting list, but it can be assumed that the supportive evidence from two recent randomized trials Until now,only two prospective controlled trials investi- suggesting that long-term (<12 months) nutritional gated the effect of pre-transplant nutritional therapy on 47 supplementation with oral BCAA is beneficial in slowing the outcome of patients undergoing OLT. Chin et al. the progression of hepatic failure and prolonging event- prospectively included 19 children with ESLD, with a free survival in liver cirrhotics also applies for OLT median age of 1.25 years, to compare a high-energy, 42,43 candidates. In practice, whole-protein formulas are isoenergetic and isonitrogenous BCAA-enriched semi- generally recommended, and BCAA-enriched formulas elemental formulation with a matched standard semi- should be used in patients who develop encephalopathy elemental formation. Only 12 of 19 patients completed during refeeding. the study before OLT, and only 10 of 19 completed a full Osteopenia and osteoporosis is frequent in patients crossover study. Both regimens improved weight and withESLD;therefore,calciumandvitaminDsupplemen- height, whereas the BCAA formula resulted in signifi- tation is recommended for all patients on the waiting list. cantly more pronounced improvements of total body Inthosewithestablishedosteoporosisorahistoryoffrac- potassium,mid-upper-armcircumference,andsubscapu- 50 Nutrition Reviews® Vol. 66(1):47–54
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