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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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