Gastroenterology Nutrition and liver disease

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Nutrition in End-Stage Liver Disease: Principles and Practice

Alastair OBrien Roger Will iams

Institute of Hepatology, Royal Free and University College Medical School, University College London, London, England

Malnutrition is commonly seen in both alcoholicand nonalcoholic liver disease13 and has been

shown to adversely affect outcome (see Figure 1).4,5 Bydefinition, it occurs when diet does not provide adequatecalories and protein to maintain nutritional status or thebody is unable to fully absorb or utilize food eatensecondary to liver disease. Despite the obvious relevance,clinical research in this field is surprisingly limited andmalnutrition is frequently underdiagnosed in clinicalpractice.6

The prevalence of malnutrition in cirrhosis is as highas 65%90%.13 Evidence concerning the impact of etiol-ogy (of cirrhosis) on malnutrition is conflicting. Somestudies have shown no difference in prevalence and se-

verity of malnutrition in patients with viral- and alcohol-related cirrhosis who were abstinent.2,7,8 Others haveshown that alcoholic cirrhosis was associated with apoorer nutritional state compared with virus-associatedcirrhosis.9 Active alcoholism is a major cause of malnu-trition per se and could contribute to the earlier devel-opment observed.10 Protein depletion and reduced mus-cle function are common in cirrhosis, particularly in menand patients with alcoholic liver disease.11 The reason forthe male preponderance is unknown and is not related tohypermetabolism or reduced energy and protein intake.11

The reduced levels of testosterone observed in male pa-

tients with cirrhosis12 may contribute to decreased pro-tein anabolism, but this requires further investigation.The largest studies on prevalence and severity have beenthe Veterans Affairs Cooperative Studies in 1984 and1993, which focused on alcoholic hepatitis.13,14 Theseand other studies showed that the severity of malnutri-tion correlated with that of the liver disease and thedevelopment of serious complications such as hepaticencephalopathy, ascites, hepatorenal syndrome, post-transplantation outcome, and mortality.1518Also, short-term survival is reduced in parallel with severity of mal-nutrition.19 The majority of patients in these pivotal

studies had advanced liver disease; however, more sophis-ticated methods of analysis (neutron activation analysis

or intracellular/extracellular body water) have shown thatsignificant losses of body cell mass may occur in Child Acirrhosis.20

In this review, we examine the mechanisms underlyingmalnutrition in chronic liver disease, the assessmentmethods available, and the role of nutritional therapy(advice, supplementation, enteral or parenteral) in thevarious stages of chronic liver disease. Acute liver failureand transplantation and the emerging data on probioticsare considered separately.

Mechanisms of Malnutrition inCirrhosis

A variety of mechanisms are considered to con-tribute to malnutrition in cirrhosis: poor dietary intake,malabsorption, increased intestinal protein losses, lowprotein synthesis, disturbances in substrate utilization,and hypermetabolism. Many of these are not fully under-stood.

In advanced liver disease, patients often have poordietary intake. Recommended diets may be unpalatablebecause of the sodium restriction needed for control ofascites and peripheral edema. A distortion or decrease intaste sensation (dysgeusia) associated with zinc or mag-nesium deficiency is well described and may contribute.21

Nausea and early satiety are well recognized, secondary togastroparesis, tense ascites, small bowel dysmotility, andbacterial overgrowth.22,23 When admitted to the hospital,malnutrition is paradoxically further worsened as pa-tients are often starved, for instance, for endoscopy. Inaddition, as glucose storage is reduced in alcohol-inducedcirrhosis,24 gluconeogenesis is active and can cause mus-cle mass breakdown to provide amino acids for glucose

Abbreviations used in this paper: BCAA, branched-chain amino acid;

DEXA, dual-energy x-ray absorptiometry; PUFA, polyunsaturated fatty

acid; SAMe, S-adenosylmethionine.

2008 by the AGA Institute

0016-5085/08/$34.00doi:10.1053/j.gastro.2008.02.001

GASTROENTEROLOGY 2008;134:17291740


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formation.25 Patients need frequent meals to protectmuscle mass, which are not always provided. However,even when inpatients receive specific attention to nutri-tion, as in the Veterans Affairs Cooperative Studies, only67% were found to consume the recommended 2500-kcaldiet.13,14 In severe cholestasis, intraluminal bile salts arereduced with consequent malabsorption of fat and fat-soluble vitamins. This can be further worsened by neo-mycin, which may blunt intestinal villi, and the use ofcholestyramine for pruritus, which may induce bile saltdeficiency.26

The metabolic disturbances consequent to liver dis-ease, such as increased energy expenditure,27,28 insulinresistance,29 and low respiratory quotient (indicating re-duced glucose and increased lipid oxygenation),30 maycontribute to malnutrition even in the early stages. Hy-permetabolic patients tend to weigh less, are more fre-quently malnourished, and have a higher mortality than

normometabolic patients.31 The estimated prevalence ofhypermetabolism varies considerably, with the largeststudy of 473 cirrhotic patients reporting 34%.32A smallerstudy of 50 cirrhotic patients found only 2 hypermeta-bolic patients,33 whereas a more recent study of 268patients found 15%.11 The cause of hypermetabolism isunclear, with one group finding no association with sex,etiology, severity of disease, protein depletion, and pres-ence of ascites or tumor.11 Indirect evidence suggests that25% of hypermetabolism in cirrhosis may be explained byincreased sympathetic nervous system activity, possiblyas part of the commonly observed hyperdynamic circu-

lation.34

Sepsis is common in liver disease and is likely toincrease energy expenditure further. The use of-block-

ade for variceal bleeding prophylaxis, which will reducemetabolic rate, is likely to be a confounding variable.Measurement of energy expenditure by indirect calorim-etry is not straightforward or frequently available, andestimates such as the HarrisBenedict equation are com-

monly applied.35

It should be noted that significant dif-ferences have been shown between resting energy expen-diture values measured by indirect calorimetry and suchestimations.36

Polyunsaturated fatty acid (PUFA) deficiency is com-mon in cirrhosis, especially alcoholic cirrhosis, becausePUFA synthesis from essential fatty acid precursors oc-curs in the liver.37 PUFA deficiency has been found inplasma lipids, erythrocytes, platelets, and adipocytes.37

Parenchymal cells are most likely deficient, although nodata exist. The consequences of PUFA deficiency are un-clear, and supplementation is controversial.38 PUFA con-tributes to the fluidity of cell membranes and the releaseof an array of secondary messengers (including eico-sanoids), and PUFA deficiency is an independent predic-tive factor of mortality in alcoholic cirrhosis.37 However,attempts to reverse deficiency have been disappointing;for example, parenteral nutrition containing Intralipid (asoybean oil, linoleic acidbased lipid emulsion; FreseniusKabi, Uppsala, Sweden) failed to improve long-chainPUFA deficiency in 9 malnourished alcoholic patients.39

Intriguingly, in alcohol-fed rats, a PUFA-enriched diet ledto more severe liver injury than a diet enriched in satu-rated fatty acids.40Also, PUFA deficiency has been shownto reverse alcohol-related mitochondrial dysfunction in

rodents via an increase in phospholipid arachidonic overlinoleic ratio, which raises cytochrome oxidase activity.41

Thus, PUFA deficiency may be an adaptive phenomenonto counteract the decline in adenosine triphosphate syn-thesis flux.

Micronutrient Deficiencies in Cirrhosis

Deficiencies in water-soluble vitamins (vitamin Bcomplex and C) are common in alcoholic cirrhosis inparticular but also occur in nonalcoholic liver disease.42

The risks of Wernickes encephalopathy and Korsakoffsdementia are well described in alcoholic patients deficient

in thiamine.43 Thiamine deficiency has also been shownin hepatitis Crelated cirrhosis,44 and administration ofthiamine to all cirrhotic patients has been recommended.Fat-soluble vitamin deficiencies occur more commonly inthe cholestatic liver syndromes. Vitamin A (retinol) defi-ciency has been described in cirrhosis and is considered arisk factor for development of cancer, including hepato-cellular carcinoma.45 Vitamin E, an antioxidant, is re-duced in cholestasis and alcoholic liver disease. Low levelsof trace elements such as selenium and zinc have beendescribed.46 Zinc deficiency in patients with chronic al-coholism is attributed to decreased intake and absorp-

tion and diuretic-induced increased urinary excretion.47

Supplementation with zinc has been shown to improve

Figure 1. Malnutrition is predictive of survival in patients with liver

cirrhosis. Survival rates in patients with midarm muscle circumferences

below the 5th (group 1), 10th (group 2), and 75th (group 3) percentiles

and above the 75th percentile (group 4). P .001 at 6, 12, and 24

months between patients with severe and moderate malnutrition

(groups 1 and2, respectively) andthose withnormal andovernourished

nutrition (groups 3 and 4, respectively). Patients with transplants were

screened at the time of transplantation. Reprinted with permission from

Alberino et al.5

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glucose disposal in cirrhotic patients,48 and deficiencymay contribute to the impaired glucose tolerance anddiabetes commonly observed. Zinc deficiency is consid-ered to precipitate hepatic encephalopathy49; however,trials of supplementation have shown conflicting re-

sults.50,51

Zinc is also used in alcoholic patients for treat-ment of night blindness not responsive to vitamin A.47

Magnesium deficiency occurs in alcoholic liver disease,and muscle magnesium is an independent predictor ofmuscle strength.52 This is probably related to the reducedcontent of sodium-potassium pumps in skeletal musclethat accompanies magnesium deficiency. However, sup-plementation did not restore muscle magnesium or im-prove muscle function in patients with alcoholic liverdisease.53 Interestingly, patients treated with spironolac-tone had higher contents of sodium-potassium pumps;the underlying mechanism is unclear and the subject ofongoing investigation.

Studies have shown that serum levels of 25-hydroxyvi-tamin D are low in patients with liver disease54 and fallwith disease progression.55 The likely causes include re-duced exposure to UV light, dietary insufficiency, andmalabsorption. A high prevalence of osteoporosis is re-ported in both cholestatic and noncholestatic cirrhosis.56

Treatment with corticosteroids as part of immunosup-pressive regimens for autoimmune hepatitis and follow-ing liver transplantation is a risk factor. Few randomizedcontrolled trials have assessed the role of intervention inprevention of osteoporosis in chronic liver disease.57

However, it is reasonable to recommend correction of

vitamin D insufficiency with vitamin D3 and calcium inconditions where osteoporosis is likely. In addition, hor-mone replacement therapy increases bone mineral den-sity in primary biliary cirrhosis and should always beconsidered for postmenopausal women.58 All patientswith chronic liver disease should undergo a dual-energyx-ray absorptiometry (DEXA) scan to assess bone mineraldensity.57 Treatment with bisphosphonates is recom-mended in those with osteoporosis, as for noncirrhoticpatients. Oral alendronate (not risedronate) may causeesophageal ulceration and should be avoided in view ofthe risk of precipitating variceal hemorrhage; cyclical

etidronate appears safe.

Diagnosis and Assessment

It is not difficult to diagnose malnutrition in acachectic patient with advanced liver disease, but in ear-lier stages of the disease diagnosis is more challenging.20

In addition, the cachexia of liver disease may developinsidiously and be masked by edema. Early diagnosis isimportant to allow appropriate intervention, becausemalnutrition is predictive of complications of liver dis-ease and mortality.6 There is no gold standard for clinicalassessment. Body weight can be misleading in patients

with ascites and peripheral edema, although one studyhas validated body mass index in cirrhotic patients with

cut-off values of 22 kg/m2 in nonascitic patients, 23kg/m2 for patients with mild ascites, and 25 kg/m2 forpatients with tense ascites.59 The creatinine height indexcan be unreliable owing to frequent disturbances in renalfunction in patients with liver disease.60

Protein catabolism is a hallmark of critical illness. Onecan assess protein requirement by measuring the nitro-gen balance, intake excretion, in which intake representsnutritional nitrogen and excretion, the sum of measuredurinary nitrogen plus an estimate of cutaneous and gas-trointestinal losses.61 Achievement of a positive nitrogenbalance is widely considered to be the primary goal ofnutritional support, and several studies of nutrition inliver disease have reported clinical improvements associ-ated with increases in nitrogen balance.62,63 Indeed, im-proved nitrogen balance calculations of improvementover time in response to nutrition is the single nutri-

tional variable most consistently associated with im-proved outcome during critical illness.63 However, nitro-gen balance is rarely measured outside clinical trials andis not routine practice at the authors hospital.

The 2 common bedside assessments, plasma proteinconcentration and anthropometry, both have significantdrawbacks. Plasma protein concentration correlates bet-ter with the severity of liver disease than with malnutri-tion.64 Anthropometric techniques such as midarm mus-cle circumference assess body composition. Fat-free mass(lean body weight; water, protein, and mineral) and fatmass are measured, and these techniques are referred toas 2-compartment systems. Anthropometric techniques

may be affected by edema65 and have been shown in onestudy to classify up to 20%30% of healthy controls asundernourished.66 However, several other studies haveshown that anthropometric measurements and handgripstrength correlate well with more sophisticated assess-ments such as DEXA in cirrhotic patients.67,68 Indeed,midarm muscle circumference was shown to be an inde-pendent predictor of mortality in advanced cirrhosis.69 Inan Italian multicenter study of more than 1000 patients,survival was related to midarm muscle circumference forChild A and B but not C.70 Midarm muscle circumferencehas also been shown to be independently associated with

survival and improve prognostic accuracy when com-bined with the Child score.5 The measurement of phaseangle by bioimpedance analysis as an indicator of bodycell mass has been shown to be of prognostic significancein cirrhosis71; however, most, but not all, investigatorsdeem it unreliable in patients with ascites.72-74 Subjectiveglobal assessment uses clinical information obtained dur-ing history taking and examination to determine nutri-tional status without objective measurements and candetermine outcome in patients with cirrhosis.75 However,when compared with nutritional prognostic index andhandgrip strength, handgrip strength was the only

method that predicted a poorer clinical outcome.69

TheEuropean Society for Clinical Nutrition and Metabolism

May 2008 NUTRITION IN END-STAGE LIVER DISEASE 1731


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guidelines state that bedside methods such as subjectiveglobal assessment, anthropometry, or handgrip strengthare adequate for identification of undernutrition andthat composite scores do not add value. For quantitativeanalysis, the determination of phase angle or body cellmass using bioimpedance analysis is recommendedrather than anthropometry, despite limitations with as-cites.76 The authors current practice is to use subjectiveglobal assessment or handgrip strength.

Although anthropometrical methods are useful forinitial assessment, they are of much less value for mon-itoring treatment effects because of their high coefficient

of variation and interobserver variability. Thus, moresophisticated methods are often used in research studies,such as DEXA and in vivo neutron activation analysis.

The limitations of 2-compartment assessment meth-ods that distinguish fat mass from fat-free mass havebeen recently highlighted.77 This study compared a4-component model (data obtained from densitometry,deuterium dilution, and DEXA) with reference and bed-side 2-component techniques, such as anthropometry,DEXA, and bioimpedance analysis. Significant differ-ences were found between 2-compartment and 4-com-partment techniques, and the authors concluded that

assumptions relating to the density and hydration frac-tion of fat-free mass were violated in cirrhosis and thusstandard 2-component techniques are inaccurate. Theyadvocate multicomponent models for research or whenprecise data are required. In a separate study, they de-scribed a new method for assessing nutritional status incirrhosis using midarm muscle circumference, dietaryintake, and a subjective override. This method was foundto be reproducible, valid against a 4-component model,and a significant predictor of survival78 (see Figure 2).

Treatment

Patients with cirrhosis should have a full assess-ment of nutritional status at presentation (see previous

text and Table 1). An intake of 3540 kcal kg1 day1

(dry body weight) and 1.21.5 g kg1 day1 of proteinis desirable.79 Conventional diet therapy combined withsupplementation is the mainstay of long-term nutri-tional support in the majority. The first report showingthe benefit of a nutritious diet in alcoholic cirrhosis waspublished as long ago as 1948,80 and several studies sincehave shown that a modified eating pattern with 4 7small meals, including at least one late evening carbohy-drate-rich snack, improves nitrogen economy and par-tially reverses the abnormal substrate oxidation of cir-rhotic patients.81,82

Restriction of sodium, the main extracellular compart-ment electrolyte, is crucial to minimize the diuretic dose

Figure 2. Scheme for determining nutritional status in patients with cirrhosis. Patients are categorized in relation to their body mass index (BMI),

midarm muscle circumference (MAMC), and dietary intake into one of 3 categories: adequately nourished, moderately malnourished (or suspected

to be), andseverely malnourished. A subjectiveoverridebased on factors such as profound weightloss or recentsignificant improvementsin appetite

and dietary intake can be used to modify the classification by one category only. Reprinted with permission from Morgan et al.78

Table 1. Standard Approach

1. Assess nutritional statusBody mass index subjective global assessment or handgrip

strength2. Teach

Frequent meals (47/day with 1 late evening snack)Low-sodium diet (2 g or 88 mmol/day) if ascites or edema

3. If moderate-severe malnourishmentEncourage oral intake

Add oral nutritional supplementProspective calorie count every 23 daysProvide multivitamins and correct specific deficiencies (eg,

vitamin D, zinc)Fluid restriction only when hyponatremia present (sodium level120 mmol/L)

Consider patients for indirect calorimetric studiesConsider DEXA scan for bone mineral density and treatment if

osteoporotic4. If intake 3540 kcal kg1 day1 and protein 1.21.5

g kg1 day1

Start enteral nutrition to provide above requirements5. If hepatic encephalopathy or protein intolerantMaximize encephalopathy treatment (lactulose, rifaximin, and

so on)

Consider BCAAs



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necessary to control ascites, peripheral edema, and he-patic hydrothorax. A 2-g (88 mmol/L) sodium-restricteddiet is recommended rather than the previous 0.5 g,which is very unpalatable.

In severely malnourished patients with cirrhosis, feed-

ing approximately 40 kcal kg1

day1

orally over 1month increases body fat mass, irrespective of the degreeof liver damage.83 When counseling is insufficient tomaintain an intake of 3540 kcal kg1 day1 and 1.21.5 g kg1 day1 protein, as documented by caloriecount, chemically defined nutritional oral supplementsshould be added.79 A controlled trial with a daily supple-ment of 1000 kcal and 34 g protein for 1 year in alcoholiccirrhosis showed a reduction in hospitalization due tofewer infective episodes and a trend to improved surviv-al.84 Additionally, 3 months of treatment with a dailysupplement containing 500 kcal, 32 g protein, 11 g fat,

and 70 g carbohydrate improved nutritional and biolog-ical parameters in malnourished cirrhotic patients.85

If nutritional supplementation is insufficient to main-tain desired intake, then artificial nutrition should becommenced, either via a nasogastric feeding tube (enter-ally) or intravenously (parenterally). A nasoenteric (naso-duodenal or nasojejunal) feeding tube is considered abetter option; however, insertion requires an endoscopicprocedure, and thus nasogastric tubes are used morecommonly. Although mostly used for inpatients becauseof practical considerations, both forms of artificial nutri-tion may be tolerated at home, with appropriate support.

A whole protein formula providing 35 40

kcal kg1 day1 energy and 1.21.5 g kg1 day1 pro-tein is recommended for enteral feeding.77 Standard prep-arations contain approximately 100 kcal energy, 4 g protein,and 3.5 mmol of sodium and potassium per 100 mL. Con-centrated high energy (1.5 kcal/mL) and protein formulasare available in many countries and may be preferable inpatients with hyponatremia and ascites to regulate fluidbalance. This may also improve treatment adherence be-cause less volume needs to be consumed. For patients whodevelop steatorrhea, it is important to limit long-chain fattyacids and increase short-chain and medium-chain fatty ac-ids in the formula. Pancreatic enzymes should be supple-

mented, especially in patients with alcohol-related cirrhosisin whom pancreatic insufficiency is common. As these en-zymes are inactivated by gastric acid, proton pump inhibi-tors are necessary. Four randomized trials concerning totalenteral nutrition in cirrhosis have been reported.8689 Threeshowed an increased dietary intake over conventional oraldiet,8789 and 2 showed improvements in liver function.88,89

One showed lower hospital mortality compared with con-ventional diet.87 The fourth was performed in well-nour-ished patients admitted with variceal bleeding and failed toshow benefit in nutritional status or disease-related mor-bidity and mortality.89 However, most of these patients were

able to eat 2000 kcal/day from day 4. In hospitalized pa-tients with an inadequate dietary intake, enteral nutrition

should be commenced as soon as possible, ideally within2448 hours of admission.90 This is illustrated by a pro-spective study in 396 patients showing that a decrease indietary intake was an independent predictor of hospitalmortality and corresponded with a deterioration of liver

function.91

Two important considerations during nasogastricfeeding are hepatic encephalopathy and variceal bleed-ing. Hepatic encephalopathy must be treated aggres-sively with lactulose or rifaximin and attention givento possible precipitating causes (eg, electrolyte status,hypoxemia, sedative use, and presence of sepsis orvariceal bleed). Traditionally, a restricted protein diethas been considered a mainstay of treatment92; how-ever, cirrhotic patients exhibit increased protein re-quirements to achieve balanced nitrogen metabo-lism,93 and normal protein diets have been given safely

to patients with hepatic encephalopathy.94

Thus, re-striction is rarely required but, if necessary, usually forno more than 48 hours. It should be noted that therecommended protein supplementation is based ondry body weight and may need alteration in edema-tous patients. Importantly, the risk of aspiration pneu-monia in patients with advanced hepatic encephalop-athy during tube feeding must be weighed against thepotential complications of parenteral nutrition (seebelow). The European Society for Parenteral and En-teral Nutrition guidelines support insertion of fine-bore nasogastric tubes in patients with esophagealvarices.77 This has been addressed in only one study, in

which 22 patients with esophageal varices after bleed-ing and endoscopic treatment were randomized toeither nasogastric feeding or no oral diet for 3 days.89

Recurrent bleeding occurred in 3 patients from thenasogastric tube group but none of the controls. Inlight of these findings, it has been suggested that theguidelines should state that tube feeding is dangerousin patients with esophageal varices that have bledbefore and that in patients without former bleeding,there is a tendency for an adverse effect.95 The Euro-pean Society for Clinical Nutrition and Metabolismauthors responded that endoscopic therapies in this

study were unbalanced between the 2 groups, whichmight have influenced outcome, with a higher propor-tion of injection sclerotherapy in the feeding group asopposed to a greater number of band ligations incontrols.96 They also referred to a small series of tube-fed cirrhotic patients in which fine-bore tubes did notprovoke variceal hemorrhage97 and a trial of low/nor-mal protein diets via fine-bore tube in hepatic enceph-alopathy in which gastrointestinal bleeding occurredin only one of 30 patients.83 They concluded if pa-tients are unable to maintain adequate oral intake,tube feeding is recommended (even when esophageal

varices are present) .96

They acknowledged that there isconcern in the immediate days following a bleed. In-



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deed, our current practice is to wait at least 24 hoursfollowing endoscopic therapy for a bleed and theninsert a nasogastric tube and commence feeding.

Total parenteral nutrition (containing Intralipid,amino acids, dextrose, electrolytes, vitamins, and miner-

als) in severe alcoholic hepatitis has shown benefit in liverfunction but not (short-term) survival.98,99 One study inpatients with transjugular intrahepatic portosystemicshunts concluded that small intestinal metabolism con-tributes to postfeeding (enteral) hyperammonemia,which may worsen hepatic encephalopathy, and that, insuch cases, parenteral nutrition may be superior to en-teral nutrition.100 Further supportive evidence comesfrom a meta-analysis of studies performed in the 1980susing parenteral nutrition in hepatic coma. This showedprobable improved survival, but the studies were veryheterogeneous and so firm conclusions are difficult to

draw.101

However, the risks of mechanical complications(eg, pneumothorax) and catheter-related sepsis are highin malnourished cirrhotic patients; it is essential thatparenteral nutrition is administered via a dedicated lineto reduce the incidence of sepsis. Also, the osmoticstrength of parenteral mixtures requires the infusion oflarge amounts of fluid that may be excessive for patientswith ascites. Thus, enteral feeding is the preferred modeof artificial nutrition in liver disease, and the parenteralroute is reserved for intensive care patients with multi-organ failure and subsequent paralytic ileus that preventssuccessful enteral feeding. It should be mentioned that a

randomized trial comparing the two in liver disease hasnever been performed.

Severe alcoholic hepatitis, defined by a Maddreyscore 32, has a significant mortality rate. Althoughcorticosteroids remain the mainstay of treatment,102

there have been several studies of nutritional support.A multicenter, randomized, controlled trial that com-pared 4 weeks of treatment with total enteral nutritionor corticosteroids showed no difference in mortalityduring treatment between the 2 groups.103 Deaths werefound to occur earlier in the enteral nutrition group.However, 10 of the survivors treated with corticoste-

roids died in the first year of follow-up compared with2 of 24 who received enteral nutrition. The majority ofthese deaths were due to sepsis. The investigators hy-pothesized that the increase in infection seen withprolonged immunosuppression could be reduced byimproving gut barrier function and thus reducing bac-terial translocation. They went on to examine the com-bination of enteral nutrition with corticosteroid treat-ment in a pilot study in 13 patients and found nodeaths related to infection.104

Finally, insertion of a percutaneous feeding gastros-tomy may be indicated in patients with an esophageal/

upper gastrointestinal stricture, but ascites, impairmentof the coagulation system, and portosystemic collateral

circulation due to portal hypertension are significant riskfactors.105

Value of Branched-Chain Amino Acids

Over the years, the use of the branched-chain

amino acids (BCAAs) leucine, isoleucine, and valine hasbeen the subject of continued interest. These are essentialamino acids, meaning that they cannot be synthesized denovo, must be obtained from the diet, and are largelymetabolized by muscle rather than liver. In cirrhosis,there is a likely reduced total body pool of BCAAs due toreduced lean muscle mass and defective use secondary tohyperinsulinemia.106 Conversely, amino acids metabo-lized by the liver are elevated in cirrhosis (eg, the circu-lating aromatic amino acids phenylalanine, tryptophan,and tyrosine).106 BCAAs compete with the serotonin pre-cursor tryptophan for the same amino acid transporter in

the blood-brain barrier, and the imbalance between thetwo in cirrhosis probably influences brain ammonia lev-els directly or indirectly.107 This is considered to be animportant mechanism underlying the development ofhepatic encephalopathy, and so supplementation withBCAAs may reduce brain uptake of tryptophan and im-prove encephalopathy.108 Additionally, both enteral andparenteral BCAA supplementation improved cerebralperfusion in cirrhotic patients, which again may improveencephalopathy; the underlying mechanism is un-clear.109,110

Oral BCAAs have been shown to benefit patients withhepatic encephalopathy111,112; moreover, a large multi-center study showed that oral BCAAs given for 1 yearimproved the Child score, reduced hospital admissions,and prolonged event-free survival.113 A further large trialshowed improved event-free survival and quality of life inJapanese patients treated with BCAAs for 2 years com-pared with controls.114 However, a Cochrane analysisbased on 11 trials of oral supplementation and 556patients found no convincing evidence of benefit.115 Al-though no toxicity was reported, many patients stopsupplementation because of the taste and amount ofwater required. Importantly, no benefit of BCAA supple-mentation was observed in protein-tolerant patients.

Parenteral administration of BCAAs to patients withacute liver failurerelated encephalopathy within intensivecare units has been advocated because these patients haveincreased total amino acids but reduced BCAAs.116,117 How-ever, there have been no controlled studies.

The timing of BCAA supplementation was addressedby one crossover study of 12 cirrhotic patients.118 Day-time administration improved nitrogen balance andFischers ratio; however, both were further significantlyimproved with nocturnal administration. At 3 months,a significant increase in serum albumin level was ob-served in patients administered nocturnal BCAAs but

not daytime BCAAs. It is possible that daytime BCAAsare used primarily as calories, whereas nocturnal



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BCAAs may be preferentially used for protein synthe-sis.

The use of BCAAs remains controversial, and they arenot widely available in many centers due to their expenseand unpalatability.106 The authors currently follow the

European Society for Parenteral and Enteral Nutritionguidelines,77 which recommend that enteral feed en-riched with BCAAs be reserved for patients who developencephalopathy with enteral feeding despite appropriatetreatment. This represents a very small proportion ofpatients.

Additional Nutritional Supplements

Nutritional supplements containing S-adenosyl-methionine (SAMe), a coenzyme involved in methylgroup transfers, are postulated to improve gut or sys-temic defenses to infection and injury.119 Experimental

models have shown that SAMe protects against tumornecrosis factor hepatotoxicity.120 Patients with alcohol-induced liver disease have reduced SAMe levels that maypredispose to mitochondrial glutathione depletion anddysfunction, and oral administration resulted in signifi-cantly decreased liver transplantation and liver mortalityin patients with alcoholic liver disease compared withplacebo.121 Supplementation also reduced pruritus andelevated serum bilirubin levels in gestational cholesta-sis.122 However, a Cochrane analysis concluded that therewas no evidence supporting or refuting the use of SAMeand high-quality randomized trials were needed before

they could be recommended.123

Another frequently takensupplement is polyenylphosphatidylcholine (lecithin), amixture of glycolipids, triglycerides, and phospholipidsand an essential component of the plasma membrane.Lecithin has been shown to prevent cirrhosis in alcohol-fed baboons,124 but in humans it did not improve clinicaloutcome in heavy drinkers.125

Acute Liver Failure

Because there is usually no preceding illness inacute liver failure, the patient is not generally malnour-ished at presentation. The aim of treatment is to main-

tain a nutritional balance in the face of the markedlyincreased catabolic state that occurs both as a result ofsevere hepatic impairment and frequently coexistent sep-sis. Hypoglycemia is commonly seen in the initial stagesdue to impaired gluconeogenesis, depletion of hepaticglycogen, and hyperinsulinism, and hence administrationof intravenous glucose at 1.52 g kg1 day1 has beenwidely adopted. At a later stage, often secondary to sepsis,hyperglycemia related to insulin resistance may be ob-served. In general intensive care patients, 2 large random-ized trials have shown that intensive insulin therapy tomaintain normoglycemia produced an absolute reduc-

tion in risk of hospital death of 3%4% and an improve-ment in morbidity.126 Strict blood glucose control (110

mg/dL) is required to obtain the most clinical benefit,but this inherently increases the risk of hypoglycemia.These studies did include patients with hepatic disorders;however, no study has formally addressed strict glycemiccontrol in acute liver failure. Because hypoglycemia is

more frequent in these patients, great care must be takenwith insulin regimens.

A recent European survey was answered by 33 hepatol-ogy units attending 2170 cases of acute liver failure peryear. All units used specific nutrition regimens, but thesevaried considerably and mostly resembled those used incritically ill patients with near-normal liver function.127

Eight units preferentially used enteral feeding and 25parenteral. Two thirds used standard parenteral regimenscontaining amino acids, although plasma amino acidlevels are already greatly elevated due to liver failure andincreased protein catabolic rate.128

Liver Transplantation

Several studies have examined the impact of pre-operative malnutrition on outcome posttransplantation.A series of 100 patients 6 months posttransplantationfound that muscle wasting was one of 6 variables asso-ciated with reduced survival.129 Other studies have shownthat preoperative malnutrition impacts negatively onposttransplantation outcome.15,27,31 These include a pro-spective study of 150 patients who underwent transplan-tation for cirrhosis and who could be divided into high-risk and low-risk groups, with survival rates of 54% and88%, respectively, based on preoperative nutrition andresting energy expenditure.31 Other studies have shownhigher rates of complications and mortality in cirrhoticpatients with malnutrition compared with those withadequate nutrition who undergo transplantation.129,130

More recently, however, this has been questioned. A pro-spective series of 53 patients from the Mayo Clinic whounderwent transplantation failed to show an associationbetween any preoperative nutritional parameters and sur-vival or global resource utilization.131 In this series, thepostoperative mortality was quite low after 1 year (7.5%),as was the frequency of preoperative malnutrition (9.4%),and patients were offered preoperative nutritional sup-

port. Thus, this study could be interpreted as showingeither that adverse outcome after transplantation is as-sociated with factors other than preoperative nutritionalstate, or that preoperative nutritional support can over-come the adverse effect of malnutrition on outcome. Anolder study used a prognostic nutritional index based onserum albumin and transferrin levels, triceps skinfoldthickness, and delayed hypersensitivity responses to as-sess malnutrition and outcome posttransplantation. Allpatients were found to be malnourished pretransplanta-tion, but there was no correlation between this index andmortality or morbidity posttransplantation.132 A further

prospective series of 61 candidates for transplantationshowed poor correlation between nutritional parameters



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and the Child score and Model of End-Stage Liver Dis-ease score.133 Interestingly, a retrospective study in 121patients examined risk factors for acute rejection andfound that the only significant predictor on multivariateanalysis of a reduction in acute cellular rejection was

decreased midarm muscle circumference, that is, mal-nourished patients had a lower incidence of acute rejec-tion.134

To date, no controlled trial has shown that preopera-tive intervention improves clinically relevant outcomes. Astudy of 82 patients randomized to enteral supplemen-tation (750 kcal, 20 g protein, and 34 g fat) and conven-tional diet or conventional diet alone showed an im-provement in handgrip strength and midarm musclecircumference but not outcome.135 The difference inoverall survival at 6 months posttransplantation almostreached significance, and a larger sample size might haveshown benefit. Two studies have examined nutritionalsupport following transplantation. Early postoperativeenteral nutrition, within 12 hours, reduced the rate ofviral infections and showed a trend toward a lower rate ofbacterial infections.136 Postoperative parenteral nutritioncompared with intravenous administration of fluid andelectrolytes reduced the length of intensive care stay.137

Obesity has a negative impact on outcome after non-liver surgery.138 However, the published reports on obe-sity in liver transplantation are inconclusive.139141 Mostrecently, a case-control study from John Hopkins Univer-sity Hospital examined 121 patients undergoing trans-plantation. Although postoperative complications, hos-

pital stay, and cost were higher in severely obese patients(body mass index 32.3 kg/m2 for women, 31.1 kg/m2

for men) compared with nonobese patients, there was nodifference in overall survival rates.142

Immunonutrition, supplementation with nutrientsthat have been shown to beneficially influence immuno-logic or inflammatory parameters in clinical or laboratorystudies (eg, glutamine), has shown positive results inother gastrointestinal surgery.143 A pilot study of 15patients given an immunomodulatory diet containingarginine, n-3 fatty acids, and nucleotides (Impact; Novar-tis Consumer Health, Nyon, Switzerland) before and af-

ter transplantation showed an increase in total bodyprotein and a trend to reduction in infections comparedwith historical controls receiving standard nutrition.144

Use of Probiotics and Synbiotics

Although not directly related to nutrition andliver disease, the use of probiotics and synbiotics along-side nutritional supplements merits consideration in thetreatment of the frequent septic episodes that accompanyliver decompensation. Probiotics are living microorgan-isms, prebiotics are indigestible carbohydrates that stim-ulate the growth and activity of beneficial bacteria within

the intestinal flora, and synbiotics are a combination ofthe two.145 There is increasing evidence that bacterial

translocation of intestinal flora combined with failure ofantibacterial defense mechanisms plays a key role in thedevelopment of sepsis.146 Probiotic or prebiotic treat-ment aims to augment the intestinal content of lacticacidtype bacteria at the expense of other species with

more pathogenic potential and thus reduce the incidenceof sepsis.

A randomized study compared postoperative infec-tions in 95 liver transplant recipients treated with anearly supply of standard enteral feed supplemented witheither a synbiotic regimen including Lactobacillus planta-rum and fermentable fiber, a heat-inactivated Lactobacillus

plantarum and fiber, or selective intestinal decontamina-tion.147 The patients who received the synbiotic regimendeveloped significantly fewer bacterial infections (13%)than those undergoing intestinal decontamination (48%).The mean duration of antibiotic therapy, hospital stay,and intensive care unit stay was also shorter in the syn-biotic group but did not reach significance. The samegroup compared the postoperative use of a mixture of 4prebiotics versus the same mixture plus a probiotic prep-aration containing lactic acid bacteria (synbiotic) in 66patients.148 The incidence of postoperative bacterial in-fections was significantly reduced (48% given prebioticscompared with 3% given synbiotics), and the duration ofantibiotic therapy was significantly shorter in the latter.

There is also evidence that synbiotic/probiotic supple-mentation improves hepatic function. Synbiotic treat-ment improved the Child score in 55 cirrhotic patientswith minimal hepatic encephalopathy, with significant

improvements in bilirubin level, albumin level, and pro-thrombin time.149 Also, supplementation with the probi-otic VSL#3 (lactobacillus and bifidobacterium bacteria: VSLPharmaceuticals, Inc, Fort Lauderdale, FL) improved he-patic function and serum alanine transferase level inpatients with alcohol-related and hepatitis Crelated cir-rhosis.150

Conclusions

In summary, malnutrition is common in end-stage liver disease and adversely affects prognosis. Nutri-tional support improves outcome in patients unable to

maintain an intake of 3540 kcal kg1 day1 and 1.21.5 g kg1 day1 protein. Simple methods of assess-ment such as subjective global assessment, midarm mus-cle circumference, and calorie counting are useful, andstandard enteral products may be used in the majority ofpatients.

However, considerable difficulties remain concerningthe treatment modalities. Enteral nutrition is usuallyconsidered first line, but the parenteral route may berequired if the patient is intolerant due to nausea andvomiting or develops increasing encephalopathy. How-ever, there is a significant risk of catheter-related sepsis.

The value of BCAAs remains uncertain despite a consid-erable number of studies, and a more palatable form



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would help clarify their value. There is very little infor-mation concerning nutrition in acute liver failure andconflicting data regarding the effect of preoperative mal-nutrition and intervention on outcome in liver transplan-tation, although early postoperative nutrition seems to

be of benefit. Synbiotics may provide additional benefitsover dietary supplementation in reducing infective epi-sodes, which impact malnutrition. Future researchshould be aimed at answering these questions. In partic-ular, disease-specific nutritional therapy should be con-sidered for acute liver failure, sepsis, transplantation, andencephalopathy. Further large-scale intervention studiesare required before treatment guidelines can be based ona formal meta-analysis. The implementation of thesecrucial studies will be extremely difficult, and researcherswill need to collaborate on a national or internationalscale.

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Received November 28, 2007. Accepted February 1, 2008.

Address requests for reprints to: Alastair OBrien, BSc, MBBS, PhD,Institute of Hepatology, Royal Free and University College Medical

School, University College London, 69 - 75 Chenies Mews, London

WC1E 6HX, England. e-mail: [email protected]; fax: (44) 207 380

0405.

mailto:a.o%E2%80%[email protected]:a.o%E2%80%[email protected]:a.o%E2%80%[email protected]

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Gastroenterology Nutrition and liver disease