Nutrition in CH

8/12/2019 Nutrition in CH

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Prevalence and Mechanisms of Malnutrition in Patients With AdvancedLiver Disease, and Nutrition Management Strategies

KALLY CHEUNG,* SAMUEL S. LEE, and MAITREYI RAMAN

*Alberta Health Services, Calgary, Alberta, Canada; Liver Unit, and Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary,

Alberta, Canada

This article has an accompanying continuing medical education activity on page e18. Learning ObjectiveAt the endof this activity, the learner will appreciate that morbidity and mortality is related to nutritional status in patients withadvanced liver disease; recognize the multifactorial nature of malnutrition in patients with cirrhosis; and appreciate theimportance of the liver in the many derangements of nutritional status in patients with cirrhosis.

Malnutrition is prevalent among cirrhotic patients and isan important prognostic factor. Etiologic factors includehypermetabolism, malabsorption, altered nutrient metabo-lism, and anorexia. It is a challenge to manage nutrition incirrhotic patients because of alterations to metabolic andstorage functions of the liver; use of traditional assessmenttools, such as anthropometric and biometric measures, isdifficult because of complications such as ascites and in-flammation. In addition to meeting macro- and micronutri-ent requirements, the composition and timing of supplementshave been proposed to affect efficacy of nutrition support.Studies have indicated that branched chain aromatic acid canbe given as therapeutic nutrients, and that probiotics andnocturnal feeding improve patient outcomes.

Keywords: Liver Disease; Nutrient Therapies; Diet; Cirrhosis;Malnutrition.

Nutrition status is recognized as a predictor of morbidityand mortality in patients with advanced liver disease. 13The liver is an important regulator of metabolism, storage,synthesis, and absorption of nutrients. Accordingly, the severityof malnutrition increases with decreases in liver function. 4 Themechanisms involved in the pathogeneses of malnutrition arenot fully understood, though it is important to continue toexplore this relationship; improvements in nutritional statuscan improve outcomes of patients with advanced liver disease.

We review the prevalence and mechanisms of malnutrition andprovide recommendations for nutrition management.

Prevalence of Malnutrition

Patients with chronic diseases frequently become mal-nourished; they have an inability to meet macronutrient andmicronutrient requirements through oral intake.5 Inadequateintake and/or associated malabsorption alters body composi-tion and diminishes biological functions.5 Parameters used toassess malnutrition in patients with liver disease include an-thropometric and serum measurements and qualitative data onweight history and food intake.6,7

Malnutrition is common in patients with advanced liver

disease; the prevalence is reported to be 50%90% among cir-rhotic patients.711 In a study of 300 patients, more than 75% of

those with advanced liver disease presented with some degree ofmalnutrition, and almost 40% presented with moderate or se-

vere malnutrition, based on anthropometric and serum mea-surements.7 In the same study, 95% of patients of ChildPughclass C presented with malnutrition, compared with 84% and46% of classes B and A, respectively.7

The prevalence of malnutrition among patients with evenearly-stage cirrhosis is concerning, given that nutrition status isassociated with mortality and complications.12,13 In a largenationwide analysis of hospitalized patients with cirrhosis andportal hypertension, patients with protein calorie malnutritionhad greater incidences of complications such as ascites (65%,compared with 48% without malnutrition) and hepatorenalsyndrome (5% vs 3%).12 Malnourished patients also had longerhospital stays and had a 2-fold increase in in-hospital mortality,

compared with well-nourished patients.12 The incidence of mal-nutrition in this study was 6% among patients with cirrhosis,compared with 2% of general medical patientscaptured usingInternational Classification of Diseases, 9th Version (ICD-9)coding, which might have led to underreporting of malnutri-tion; rates of malnutrition were significantly lower comparedwith those reported in other studies.12 The impact of malnu-trition on mortality and complications might have been largerin magnitude if a more sensitive measure of malnutrition wasused.

A study of patients of ChildPugh class A demonstrated thatmalnutrition, even in early stages of cirrhosis, had large effectson patient outcomes. Among a cohort of patients that were

primarily ChildPugh class A, those that were malnourishedhad a 1-year mortality rate of about 20%, whereas none of thepatients that received sufficient amounts of nutrients diedwithin the 1-year period.13 Complications such as infections,hepatic encephalopathy, ascites, and hepatorenal syndrome also

Abbreviations used in this paper: AAA, aromatic amino acid; ASPEN,

American Society of Parenteral and Enteral Nutrition; BCAA, branched

chain aromatic acid; ESPEN, European Society of Clinical Nutrition and

Metabolism; HE, hepatic encephalopathy; MHE, minimal hepatic en-

cephalopathy; PBC, primary biliary cirrhosis; REE, resting energy ex-

penditure; SGA, subjective global assessment; TPN, total parenteral

nutrition.

2012 by the AGA Institute

1542-3565/$36.00doi:10.1016/j.cgh.2011.08.016

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10:117125


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increased with malnutrition; in the same study, 65% of mal-nourished patients developed complications compared with11% of well-nourished patients.13

After liver transplantation, malnutrition has been associatedwith higher rates of infectious complications, longer stays inthe intensive care unit, and higher mortality.6,8 Additionally,patients with more severe malnutrition have longer postopera-tive hospital stays.6

Etiology of Malnutrition

The etiology of malnutrition is multifactorial and pri-

marily related to reduced liver function; poor oral intake andcomplications of cirrhosis such as ascites and hepatic enceph-alopathy also contribute.

Hypermetabolism

Resting energy expenditure (REE) is the amount ofenergy an individual uses to perform vital organ functions, freeof activity and digestion.14 A commonly used predictive equa-tion for REE is the Harris Benedict Equation, which factorsweight, height, and sex in the calculation. Whereas most cir-rhotic patients have a REE that is similar to predicted values,15%30% of patients are hypermetabolic.15,16 Hypermetabolism isdefined as REE120% compared with the predicted value.15,16 The

causes of hypermetabolism are unclear; a recent study of 268patients did not associate hypermetabolism with sex, etiology,

severity of disease, protein depletion, presence of ascites, ortumors.16 This finding is inconsistent with results from olderstudies that reported that energy expenditure increased amongpatients with ascites or hepatocellular carcinoma.17,18

The increase in REE among patients with cirrhosis might resultfrom infections or immune compromise. Plasma concentrationsof catecholamines are increased in cirrhotic patients, indicatingactivation of the sympathetic nervous system.19 Sympathetic over-activity could induce systemic responses such as tachycardia and

increases in cardiac output and blood glucose levels,20 which couldall increase energy expenditure.15 Proposed causes for the increased

levels of catecholamine include gastrointestinal bacterial translo-cation, an inflammatory phenotype of chronic liver failure, orcentral neural dysregulation of the circulation.21,22

Malabsorption

There are multiple mechanisms that can lead to mal-absorption of nutrientsparticularly of fatin cirrhotic pa-tients (Figure 1). One complication that affects nutrient absorp-tion in patients with cirrhosis is portosystemic shunting. Ascirrhosis progresses, portosystemic shunting causes nutrients tobypass the liver, without metabolic processing.2,23 In addition,

many patients with cirrhosis that is secondary to alcohol abusehave chronic pancreatitis, which contributes to malabsorption.

An analysis of autopsy results found that 18% of cirrhoticpatients also had chronic pancreatitis.24

Figure 1. Possible factors

contributing to lipid maldiges-

tion or malabsorption in pa-

tients with cirrhosis or chronic

pancreatitis.

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Another factor that leads to fat malabsorption in patientswith cirrhosis is intraluminal bile acid deficiency, which resultsfrom the decreased capacity for bile production and portosys-temic shunting; intraluminal bile acid deficiency impairs for-mation of micelles and absorption of long chain fatty acidsthrough the usual lymphatic route.25 Portal absorption of longchain fatty acids might also occur in patients with cirrhosis;Cabre et al showed that the incorporation of radiolabeled fattyacid in chylomicron and very-low-density lipoprotein (VLDL)-associated plasma tricylglycerols was lower and less sustained incirrhotic patients compared with healthy controls.26 This find-ing is consistent with reports of impaired lipoprotein exportin cirrhotic patients, probably from decreased synthesis of tri-aclyglycerols.27,28 The findings of Cabre et al indicate an alter-nate route for fat absorption in cirrhotic patients, which by-passes standard lymphatic transport. A portal route for fatabsorption has pathophysiologic implications; it could result inexcess hepatic storage of fat, which can reduce liver functionand the systemic availability of fat for organic functions.

Altered Macronutrient Metabolism

Glucose metabolism has been well studied in patientswith liver disease. Those with cirrhosis have increased levels ofgluconeogenesis and protein catabolism and decreased levels ofglycogenlysis, compared with healthy individuals.29,30 The al-tered rates of metabolism reflect a significant depletion inprotein and fat reserves, reported in about 50% of cirrhoticpatients.6,16

Patients with chronic liver disease have increased rates ofgluconeogenesisa number of factors contribute to this. First,cirrhosis reduces the ability of hepatocytes to store, synthesize,and break down glycogen. These defects promote gluconeogen-

esis from fats and protein as alternate fuel sources. Following ashort overnight fast, the rate of fat and protein catabolism inpatients with cirrhosis is similar to that of healthy subjects whounderwent 2 to 3 days of starvation.31

Second, cirrhosis and insulin resistance are related; patientswith cirrhosis have high serum levels of insulin after fasting andpostprandial levels of glucose.32 Fasting plasma levels of insulin,among 31 patients with cirrhosis, were 3-fold higher than thoseof healthy individuals.32 Insulin resistance decreases peripheralglucose utilization and contributes to decreased hepatic glucoseproduction and hepatic glycogen reserves.33 Increased serumlevels of glucagon, which result from impaired degradation bythe liver, increases the rate of gluconeogenesis.

Third, infection can increase rates of protein catabolism. The

production of cytokines and other infection mediators activateproteolysis and increase oxidation of branched chain aromaticacids (BCAAs). This can promote the breakdown of muscle cellsfor substrates, if dietary protein intake is insufficient. In pa-tients with cirrhosis, the utilization of oxidative fuels is associ-ated with an increased rate of lipid oxidationparticularly inthe fasting state.34

Anorexia

As in other chronic illnesses, anorexia makes a signifi-cant contribution to malnutrition. Anorexia can be caused byphysical symptoms of discomfort such as nausea, bloating,fatigue, and vomiting. Patients with ascites often experience

early satiety resulting from the mechanical effects of asciticfluid, which compress the stomach.35

Additionally, loss of appetite can be related to the up-regu-lation of inflammation and appetite mediators.16,36 Levels oftumor necrosis factor (TNF)-and leptin correlate with satietyand energy expenditure; patients with cirrhosis have increasedserum levels of this cytokine.37 Tumor necrosis factor- mightaffect appetite and metabolism by acting on the central nervoussystem, altering the release and function of neurotransmitters.38

Leptin is an appetite-regulating hormone that is secreted byadipose tissue.39 Cirrhotic patients had a 2-fold increase infasting levels of leptin compared with healthy individuals; thismight contribute to anorexia in these patients.32

Ghrelin, which stimulates appetite, is produced primarily bythe stomach. Although some cirrhotic patients have been ob-served to have abnormal fasting levels of this hormone, therelationship between ghrelin and anorexia is unclear; somestudies have reported increases and others reported de-creases.32,40 Changes in ghrelin levels might be related to thesystemic response to liver disease and state of anorexia or aconsequence of the livers role in hormone regulation.32,40

Aside from hormonal influences and physical discomfort,disinterest in food can result from dietary restrictions and tastealterations. Dietary limitations, such as sodium restriction forascites management, preoperative fasting, and limitation ofprotein intake for severe hepatic encephalopathy can reducefood variety; many patients do not accept the allowable foods.

Although taste alterations have been commonly attributed tomicronutrient deficiencies, researchers have questioned whetherthey are a consequence of cirrhosis itself.41,42

It is also important to consider alcohol-related anorexia.According to the American Liver Foundation, 10%20% ofchronic users of alcohol develop cirrhosis. Poor and irregularfeeding is common among patients with alcoholic cirrhosis.Before hospital admission, 53% of alcoholic patients reportedanorexia, 40% reported irregular feeding, and 36% ate only 1meal per day.43 In a study of middle-income patients withalcoholic cirrhosis, although their energy intake was similar tothat of nonalcoholics, their overall intake of nutrients waslower, because they acquired most of their energy from alcoholrather than nutrient-rich foods.44 The socioeconomic status ofpatients can also affect oral intake; patients who have alcoholiccirrhosis and low socioeconomic status are prone to poor andirregular feeding. As a result, they develop nutrient deficiencies,such as low serum levels of folate, B12, and B6, and macronu-trient deficiencies.45

Micronutrient Status

Patients with advanced liver disease have an increasedrisk of micronutrient deficiencies that arise from anorexia,diuretic use, fat malabsorption, and hepatitis C. Because pa-tients with ascites have restricted intake of animal protein andare treated with diuretics, they commonly acquire zinc defi-ciency.46 Similarly, magnesium deficiency can result from de-creased oral intake of nutrients and use of diuretics.

Although rates of deficiencies in fat-soluble vitamins varyamong studies, vitamin A and vitamin D deficiencies are mostcommonly reported.47 More than 90% of patients with cirrhosishave some level of vitamin D deficiency and 29% have severe

vitamin D deficiency (17.5 nmol/L).48 Low serum levels offat-soluble vitamins can impair absorption of other nutrients,

such as vitamin D and calcium. In patients with primary biliarycirrhosis (PBC), reduced concentrations of intraluminal bile

February 2012 MALNUTRITION IN ADVANCED LIVER DISEASE 119


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increase the risk of malabsorption and deficiencies in fat andfat-soluble vitamins (A, D, E, and K).23,4749 In a study of 180patients with PBC, 33%, 13%, 2%, and 8% had deficiencies in

vitamins A, D, E, or K, respectively.47Although these differenceswere not statistically significant (likely due to the small samplesize), the authors associated the stage of PBC with the degree of

vitamin deficiency.47

Hepatitis C virus (HCV) infection has been associated withdecreased levels of vitamin B6 and folate; therapy with pegy-lated interferon and ribavirin further decreased the levels of

vitamin B6 and reduced plasma levels of vitamins B1 and B2.Many B-complex vitamins are cofactors for enzymatic reactions,so standard antiviral therapy for hepatitis C might impairphysiological functions and cause complications.50 In thisstudy, dietary intake of B-complex vitamins did not differ be-tween patients with hepatitis C and healthy individuals, indi-cating that hepatitis C virus might compete with human cellsfor vitamins; therapy might therefore affect nutrient utilization.

Nutrition AssessmentBecause nutrition is correlated with outcome of pa-

tients with liver disease, it is important to accurately assessnutritional status and provide timely nutritional support. Thistask is challenging, due to the complications of altered rates ofprotein metabolism and presence of ascites and edema. TheEuropean Society of Clinical Nutrition and Metabolism(ESPEN) 2006 guideline recommends the use of the subjectiveglobal assessment (SGA), anthropometry analysis, or the hand-

grip strength test to identify patients with cirrhosis who are at

risk of malnutrition.51

SGA is a bedside assessment tool used to collect information

on dietary intake, weight change, and gastrointestinal symp-

toms; it includes an examination for subcutaneous fat loss,

muscle wasting, edema, and ascites.

14

The SGA is commonlyused to assess patients with liver disease because it is simple and

cost-effective.14

Although traditional anthropometric measures such as

weight, midarm circumference, and triceps skin-fold thickness

are considered to be adequate for determination of nutritional

status of cirrhotic patients, efforts to document these parame-

ters in patients with advanced liver disease should be made on

a regular basis. Determination of body mass with weight scales,

or body composition with bioelectric impedance analysis, is not

always accurate, due to the prevalence of ascites or edema in

this population.51 Albumin levels are poor nutritional markers

because they are typically reduced in patients with advanced

liver disease and fluctuate during periods of inflammation.14

The handgrip strength test measures the strength of hand

and forearm muscles. Subjects are classified as malnourished if

their grip strength is less than 2 standard deviations from the

mean of the age and sex groups.13 This is a simple and quick

tool to assess nutritional status, though its use as a sole assess-

ment technique is not widespread. The handgrip test has been

compared with the SGA in patients with cirrhosis and found to

be a superior predictor of clinical complications such as uncon-

trolled ascites, hepatic encephalopathy, spontaneous bacterial

peritonitis, and hepatorenal syndrome.13 Complications devel-

oped in 65% of patients who were classified as malnourished

using the handgrip strength test, compared with 35.7% of

patients classified as malnourished using the SGA.13

Dual-energy x-ray absorptiometry, in vivo neutron activation

analysis, and isotope dilution are other methods used to mea-

sure nutritional status.51 Though they provide relevant and

accurate information, their widespread application has been

limited by cost and technical complexity.52 So, the SGA, anthro-

pometric measures, and the handgrip test are most commonly

used in routine nutritional assessments.

Although the SGA is adequate as a stand-alone nutrition as-

sessment tool, some studies have shown it can underestimate the

frequency and severity of malnutrition of patients in the initial

stages of the disease.14,52,53 Figueiredo et al52 suggested that nutri-

tional intervention should be automatically initiated in patients

with cirrhosis of ChildPugh class B or C, due to the prevalence ofmalnutrition in these groups, with more extensive nutritional

assessment for patients of class A, to provide timely support.

Therefore, a combination of subjective and objective data indicate the

need for a comprehensive analysis of patients nutritional status.52,54

Diabetes is associated with poor prognoses for cirrhotic

patients; because of the prevalence of impaired glucose toler-

ance among these patients, physicians should consider screen-

ing them for glucose intolerance.55 Often, diabetes presents in

patients with subclinical cirrhosis who have normal fasting

glucose levels; the 75 g oral glucose tolerance test might be a

better diagnostic tool.55 Studies do not support routine assess-

ment of serum levels of insulin or glucagon, or use of homeo-

stasis model assessment scores, to identify patients with im-paired glucose tolerance or hepatogenous diabetes.

Table 1. Nutrition Recommendations

Energy requirement, based on dry weightor determined ideal body weight,

for patients with ascites

2540 kcal per d

ASPEN

Without encephalopathy 2535 kcal/kg per d

With acute encephalopathy 35 kcal/kg per d

Stable and malnourished 3040 kcal/kg per d

ESPEN

All stable cirrhosis patients 3540 kcal/kg per d

Macronutrients

Carbohydrate 45%65% of daily caloric

intake per DRI

Protein

All patients, except acute

encephalopathy

1.01.5 g/kg per d

Acute encephalopathy 0.60.8 g/kg per dFat 25%30% of daily caloric

intake per DRI

Micronutrients

Fat-soluble vitamins (vitamins A, D, E,

and K); all patients with

compensated liver disease

Up to RDA levelsa

Zinc Up to RDA levelsa

Selenium Up to RDA levelsa

Folic acid and thiamine; patients with

history of alcohol abuse

Up to RDA levelsa

Sodium; patients with ascites and

edema

Restricted to 2 g per d

DRI, daily recommended intake; RDA, recommended dietary allow-

ance.aFor patients without signs of deficiency.



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Nutrition Recommendations

Current nutritional recommendations aim to providepatients with cirrhosis with sufficient energy intake for dailyactivities, the increased energy requirements associated withliver disease, to prevent further protein catabolism for energy,

and to meet nutritional requirements, based on recommendeddaily intake. The recommendations proposed in the literaturereflect the higher nutritional needs of patients with advancedliver disease, who have impaired nutrient absorption, and al-tered micro- and macronutrient metabolism (Table 1). Theseare the basic recommendations for patientschanges might benecessary based on trends in body composition, deficienciesdetected in serologic analyses, and further deterioration of liverfunction.

Energy requirements determined for patients are based onthe severity of cirrhosis and the presence of ascites, hyperme-tabolism, or malnutrition.56 It is important to continuouslymonitor weight trends and maintain nutritional status. Theenergy recommendation, based on the American Society of

Parenteral and Enteral Nutrition (ASPEN) and ESPEN guide-lines, ranges from 25 to 40 kcal/kg per day.51,56 The ASPENguideline recommends 25 to 35 kcal/kg per day for patientswithout encephalopathy and 35 kcal/kg per day in those withacute encephalopathy. The 2006 ESPEN guidelines recommenda much higher energy intake, at 35 to 40 kcal/kg per day for allpatients with stable cirrhosis.51 The ESPEN recommendationappears to focus on prevention and treatment, due to theprevalence of malnutrition among cirrhotic patients; the AS-PEN guideline also recommends 30 to 40 kcal/kg per day forstable and malnourished patients.51,56

Energy recommendations are created based on patients dryweight or, in the presence of ascites, their determined ideal body

weight. The ESPEN guideline recommends use of oral supple-ment or overnight enteral feeds if patients cannot maintainadequate intake from food.51

Carbohydrate restriction is not recommended for patientswith cirrhosis despite the high prevalence of insulin resistanceand diabetes in this population.51 With impaired glycogen syn-thesis and limited glycogen stores in the liver, regular intake ofcarbohydrates can help prevent hypoglycemia. Patients are ad-

vised to have frequent meals and snacks to reduce the risk ofhypoglycemia, which might subsequently improve oral intakeamong patients with poor appetites.56,57 Some studies investi-gated the use of low glycemic and high-fiber carbohydratesources to manage hyperinsulinemia and hyperglycemia; thesewere either small or case studies, so their findings cannot be

generalized to all cirrhotic patients.5860 It has been recom-mended that carbohydrates account for 45% 65% of caloricintake, based on the dietary reference intake.61

Historically, protein restriction was recommended in pa-tients with liver disease. The practice originated from the 1970sand 1980s, when uncontrolled observational studies reportedimprovements in hepatic encephalopathy following protein re-striction.62 Studies have shown that high-protein diets are notonly well-tolerated in patients with cirrhosis and/or moderatehepatic encephalopathy, but can also improve their prognosisand mental status.63 Conversely, protein restriction can lead toincreased protein catabolism, which worsens hepatic encepha-lopathy, because of the release of ammonia, a by-product of

catabolism. A randomized study showed that patients withprotein intake of 0.5 g/kg per day had an increase in muscle

breakdown compared with patients with 1.2 g/kg per day pro-tein intake.63

The current protein recommendation for patients with cir-rhosis is 1.0 to 1.5 g/kg per day.51,56 This amount is higher thanthe 0.8 g/kg per day recommended for healthy individuals,because of increases in gluconeogenesis, muscle catabolism, anddecreased absorption as in cirrhotic patients. Patients withacute encephalopathy are placed on temporary protein restric-tion (0.6 0.8 g/kg per day) until the cause of encephalopathy isdiagnosed and eliminated; then normal protein intake can beresumed.56

Although several mechanisms appear to contribute to fatmalabsorption, there are no guidelines to support the use ofmedium chain triglycerides for patients with cirrhosis. How-ever, if patients appear to have overt fat malabsorption, basedon an abnormal, 72-hour fecal fat test result following a chal-lenge with 100 g fat, it is reasonable to consider this approach.

For patients with advanced liver disease, diet supplementa-tion with fat-soluble vitamins (A, D, E, and K), zinc, and

selenium are recommended; deficiencies in these nutrients arefrequently observed in patients with compensated liver dis-ease.49,56 The recommended intake levels of fat-soluble vitaminsare substantially higher for patients with chronic cholestasis;when these patients are suspected of having deficienciesin fat-soluble vitamins, serum levels of vitamin A and 25-hydroxyvitamin D [25(OH)D] should be checked, at baselineand then annually.47,64 For patients with a history of alcoholabuse, administration of folic acid and thiamin is also advised.56

Because of the increased risks of micronutrient deficienciesamong most patients with advanced liver disease, they shouldtake a multivitamin routinely.

Patients with edema and ascites are usually placed onsodium-restricted diets (2 g per day).65 Hospitalized pa-tients with refractory or diuretic-resistant ascites might ben-efit temporarily from more stringent restrictions in sodium.It is generally not recommended to discharge patients onsevere sodium restriction dietstheir poor palatability usu-ally leads to poor compliance.66

Probiotics

Patients with cirrhosis have disruptions in the compo-sition of the gastrointestinal microflora, due to medical thera-pies and abnormal intestinal motility;67 25% have small bowelbacterial overgrowth, which can promote intestinal wall perme-ability that results in bacteria translocation, secondary infec-tions, and fat malabsorption with associated consequences.67

Changes in microflora observed in patients with gastrointesti-nal bacterial overgrowth have been associated with minimalhepatic encephalopathy (MHE).6769 MHE is the mildest formof hepatic encephalopathy, in which patients do not necessarilyhave recognizable symptoms but can exhibit mild cognitive andpsychomotor deficits that impact health-related quality of life.MHE can be treated with lactulose and antibiotics, but use ofthese agents is limited by the development of resistant strains ofbacteria and low levels of patient adherence, because of sideeffects such as abdominal pain, flatulence, bloating, and diar-rhea.68,70

Probiotics are being investigated for their ability to restoreintestinal integrity. They could improve or reverse MHE by

lowering intestinal levels of ammonia and decreasing pH, whichwould inhibit growth of pathogenic bacteria and decrease in-



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testinal permeability.68,71,72 Results from several randomizedcontrol trials have demonstrated that they lead to significantimprovements, based on psychometric tests results.68,69,73 How-ever, the application of probiotics to treatment of MHE is arelatively new area of study; more research is required to deter-mine the most effective probiotic strain and therapeutic dose. 68

Probiotics appear to be a safe, natural, and well-tolerated formof therapy for long-term use in patients with mild hepaticencephalopathy (HE).68

Branched-Chain Amino Acids

BCAA are amino acids that are essential for proteinsynthesis, protein turnover, and regulation of energy metabo-lism.2 The use of BCAA in the treatment of HE has been wellstudied. Ammonia and aromatic amino acids (AAAs) are nor-mally metabolized and/or detoxified by the liver. However, inpatients with advanced liver disease, AAAs accumulate as aresult of impaired hepatocyte function and portal shunting.

Patients with cirrhosis have a low ratio of BCAA:AAA; BCAA

levels decrease because they are taken up by skeletal musclecells, as a substrate for energy or ammonia degradation. 2 AAAlevels increase due to the impaired capacity of hepatocytes indeamination.74 BCAA and AAA compete for the same blood-brain barrier transporter, so decreased serum concentrations ofBCAA increase brain uptake of tryptophan, an AAA. 2 Greateruptake of tryptophan has been proposed to cause an imbalanceof neurotransmitter synthesis in the brain, leading to the con-fusion and altered consciousness that are characteristic of HE.75

BCAA supplementation might help restore the balance betweenBCAA and AAA transport in the brain.

Increased serum concentration of ammonia might also affectneurotransmission and interfere with the normal flow of nu-

trients, fluids, substrates, and hormones, and with neurotrans-mitter function, to lead to HE.75 BCAA supplementation canreduce hyperammonemia, because ammonia is detoxified aspart of the skeletal muscle metabolism of BCAA for energy. 76

The ESPEN 2006 consensus that supports the use of oralBCAA supplement to improve clinical outcomes was basedlargely on results from 2 randomized trials.52 Marchesini et alconducted a 1-year, double-blind study of 174 patients withadvanced cirrhosis who were randomly assigned to a group thatwas given BCAA (14 g per day; 59 patients) or control groupsthat were given equicaloric amounts of lactoalbumin or malto-dextrin.77 The primary end point was a combination of deathand liver decompensation, defined by worsening hepatic en-cephalopathy, refractory ascites, or a ChildPugh score 12.

Even though the rates of death or decompensation, when con-sidered individually, did not differ significantly between groups,the combined rate of death and decompensation was signifi-cantly lower in the group given BCAAs, compared with thosegiven lactoalbumin (but not maltodextrin). However, the BCAAformulation had a poor taste, which contributed to a higherdropout rate in that group; it is likely that the study wastherefore not actually blinded.77

Muto et al performed a multicenter, randomized, controlledtrial of 646 patients; they reported an increase in serum levels ofalbumin and reduced rate of liver failure (ie, decreased furtherdecompensating events) among subjects with decompensatedcirrhosis who were given 12 g of BCAA per day, compared with

controls, and followed for 2 years.78

Again, BCAAs did notimprove survival or other important end points such as rates of

variceal bleeding. Instead, the rate of decompensation, whichincluded potentially subjective criteria such as development ofrefractory ascites or encephalopathy, was the parameter thatdiffered between groups.65,79 This study had a high rate ofpatient compliance (85%) because the authors used a better-tasting, granulated form of BCAAs.

Although we can propose a biological mechanism for theefficacy of BCAAs in patients with advanced liver disease, theirpoor palatability in commercial formulas and high cost remaina barrier to patient acceptance.57,75,78

Nocturnal Supplements

Nocturnal oral supplements have been investigated as amethod to reduce gluconeogenesis and protein catabolism. A12-month randomized control trial followed 108 patients whoreceived either daytime or bedtime oral nutritional supplemen-tation with 700 calories.80 The study reported a significantincrease in total body protein stores over 3-, 6-, and 12-monthperiods in the group given bedtime supplementation, which the

authors attributed to the decreased length of the overnight fastand associated progression of nocturnal gluconeogenesis.80 Thedifference between the 2 groups was equivalent to a gain of 2 kgof lean muscle tissue, sustained over 12 months.80 Compara-tively, there were no significant changes in total body proteinstores over the 12-month period in the group that receiveddaytime supplements. Improvements in protein stores might bedependent on the type of nutrients provided, as opposed to thetiming of supplementation.57 For example, a BCAA-rich snacksignificantly improved serum levels of albumin, nitrogen bal-ance, and respiratory quotients, compared with the controlgroup, which was given carbohydrate for 3 months.57 These 2studies indicate that bedtime supplementation can shorten the

length of overnight fasts and improve protein stores.

What About Parenteral Nutrition?

Total parenteral nutrition (TPN) should be restricted topatients that have contraindications to oral or enteral nutritionand to situations whereby adequate oral or enteral caloric in-take is not being met despite best efforts. Patients who receiveparenteral nutrition are at risk for infectionsparticularlycatheter-related infections. Patients with advanced liver diseaseare also at risk for infections, because of alterations in intestinalpermeability and endotoxemia; the presence of foreign bodiessuch as indwelling catheters, combined with the high dextrosemilieu, could significantly increase the risk of infectious com-

plications in this immunocompromised population. Addition-ally, when TPN is used for an extended period of time, liverfunction can worsen.

However, TPN might meet metabolic needs of hospitalized,malnourished patients when enteral requirements cannot bemet. For the critically ill and patients who have received livertransplantation, the combined effects of preoperative malnutri-tion, surgical stress, and postoperative protein catabolism,could lead to a need for early nutritional therapy.

TPN was reported to be reasonably well tolerated in patientsafter liver transplantation, compared with those given enteralnutrition.81 Recent ESPEN guidelines (grade C) recommendthat TPN should be considered after surgery for patients who

cannot tolerate oral and/or enteral nutrition; following livertransplantation, nutrition support is indicated, with TPN as a



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clear second choice to enteral nutrition.82 Recommended nu-trient intake includes provision of carbohydrate to cover 50%60% of nonprotein energy, with lipid provision to cover 40%50% of nonprotein energy requirements. Amino acid provisionshould amount to 1.2 g/kg per day in patients with compen-sated cirrhosis and to a dose of 1.5 g/kg per day in those withdecompensated disease.

Conclusions

Many different factors contribute to malnutrition inpatients with chronic liver disease. Impaired hepatocyte func-tions disrupt the nutrient balance and metabolism, which (inaddition to ascites, protein catabolism, and nutrient deficien-cies) can lead to hepatic encephalopathy. Studies have shownthat early detection and treatment of malnutrition is imperativeto improve patient outcomes. In addition to current recommen-dations for macro- and micronutrient supplementation, thetherapeutic uses of nutrients such as BCAA and probioticscontinue to be investigated.

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Reprint requests

Address requests for reprints to: Maitreyi Raman, MD, MSc, 6D26TRW Building, 3280 Hospital Drive, Calgary, Alberta T2N 4N1, Canada.

e-mail:[email protected];fax: (403) 592-5090.

Conflicts of interest

The authors disclose no conflicts.

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