Normal protein diet for episodic hepatic encephalopathy:results of a randomized study

7/27/2019 Normal protein diet for episodic hepatic encephalopathy:results of a randomized study

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Normal protein diet for episodic hepatic encephalopathy:results of a randomized study

Juan Cordoba 1, *, Juan Lopez-Hell n2 , Merce Planas 3 , Pilar Sabn4 , Francesc Sanpedro 1 ,Francisco Castro 1 , Rafael Esteban 1 , Jaume Guardia 1

1 Servei de Medicina Interna-Hepatologia, Hospital Universitari Vall dHebron, Barcelona, Universitat Auto `noma de Barcelona, Barcelona, Spain2 Centre dInvestigacions en Bioqu mica i Biologia Molecular, Hospital Universitari Vall dHebron, Barcelona, Universitat Auto `noma de Barcelona,

Barcelona, Spain3 Unitat de Suport Nutricional, Hospital Universitari Vall dHebron, Barcelona, Universitat Auto `noma de Barcelona, Barcelona, Spain

4Servei de Farmacia, Hospital Universitari Vall dHebron, Barcelona, Universitat Auto `noma de Barcelona, Barcelona, Spain

See Editorial, pages 147148

Background/Aims : Protein-restricted diets are usually prescribed for cirrhotic patients with hepatic encephalopathy.However, protein restriction may worsen the nutritional status without resulting in an improvement of hepaticencephalopathy. We designed a study to assess the effects of the amount of protein in the diet on the evolution of episodichepatic encephalopathy.

Methods : Cirrhotics admitted to the hospital because of an episode of encephalopathy ( n 5 30) were randomized to

receive a low-protein diet with progressive increments or a normal protein diet for 14 days, in addition to standardmeasures to treat hepatic encephalopathy. Protein synthesis and breakdown were studied at day 2 and day 14 with theglycine-N 15 infusion method.

Results : The outcome of hepatic encephalopathy was not signicantly different between both groups of treatment.Protein synthesis was similar for low and normal protein diet, but those of the low-protein diet group showed higherprotein breakdown.

Conclusions : Diets with a normal content of protein, which are metabolically more adequate, can be administeredsafely to cirrhotic patients with episodic hepatic encephalopathy. Restriction of the content of protein of the diet doesnot appear to have any benecial effect for cirrhotic patients during an episode of encephalopathy.q 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Keywords : Encephalopathy; Low-protein diet; Ammonia

1. Introduction

Hepatic encephalopathy is a common complication of cirrhosis that accounts for a large number of hospitaladmissions. Treatment of encephalopathy is based on thecorrection of precipitating factors and administration of drugs to decrease intestinal generation of ammonia [1].Protein restriction has classically been considered amainstay of treatment in hepatic encephalopathy [2].

However, this recommendation has been contested due tothe lack of scientic proof [3]. The inclusion of proteinrestriction as a component of therapy for hepatic encephalo-pathy has been based on old uncontrolled observations, mostof them anecdotal [4]. There have been no prior studies of cirrhotic patients admitted to the hospital because of anepisode of hepatic encephalopathy in which patients wererandomized to receive different amounts of protein in thediet.

Cirrhotic patients exhibit increased protein requirementsto achieve balanced nitrogen metabolism [5]. In thesepatients, malnutrition has been associated with decreasedsurvival [6]. Thus, limiting the amount of protein mayworsen their clinical condition. Indeed, in severe alcoholic

Journal of Hepatology 41 (2004) 3843www.elsevier.com/locate/jhep

0168-8278/$30.00 q 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.doi:10.1016/j.jhep.2004.03.023

Received 29 October 2003; received in revised form 17 February 2004;

accepted 5 March 2004; available online 20 April 2004* Corresponding author. Tel.: 34-93-274-6140; fax: 34-93-274-6068.E-mail address: [email protected] (J. Co rdoba).
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liver disease, high-protein diets may result in a betteroutcome [7]. These data have led the European Society forParenteral and Enteral Nutrition (ESPEN) to acknowledgethe importance that an adequate amount of protein may haveon the outcome of cirrhotic patients [8]. The currentrecommendation is to limit protein restriction during anepisode of hepatic encephalopathy to a moderate intake(0.5 g/kg/day) and to shortly thereafter return to a normal-to-high protein intake (1 1.5 g/kg/day). For all thesereasons we designed a randomized study to assess theeffects of the amount of protein in the diet on theevolution of the mental state during an episode of hepaticencephalopathy.

2. Methods

2.1. Participants

We selected our patients from subjects presenting to the emergencyroom of Hospital Vall dHebron, Barcelona, Spain. Patients wereconsidered eligible if they were cirrhotic patients showing clear signs of episodic hepatic encephalopathy. The diagnosis of cirrhosis was based onprior liver biopsy or on a combination of clinical and imaging datademonstrating liver failure, portal hypertension and cirrhotic appearance of the liver. Episodic hepatic encephalopathy was diagnosed on the basis of asudden change in mental state from a previously normal consciousness thatcould not be attributed to another cause. Exclusion criteria to participate inthe study were: impossibility to provide nasogastric feeding (e.g. gastro-intestinal bleeding, intestinal ileum), contraindications for low-protein diets(e.g. acute alcoholic hepatitis), terminal disease (e.g. advanced hepato-carcinoma, hepatorenal syndrome), clinical instability requiring respiratoryor cardiovascular support and neurological comorbidities (e.g. priorcerebrovascular disease, dementia) or intake of toxins (e.g. alcohol toxicity,benzodiazepines) that would make the assessment of mental state difcult.

The study was approved by the Institutional Review Board. Informedconsent was initially given by next of kin and later conrmed by the patient.Insertion of a nasogastric tube was justied by the need to provide adequatenutritional support in patients that could show a worse outcome if insufciently nourished [9].

2.2. Interventions

All patients followed a systematic protocol in order to assess criteria of eligibility and search for precipitating factors. The protocol included thefollowing assessment: prior history, standard blood and urinary tests,qualitative determination of benzodiacepines in blood, chest X-ray,paracentesis if ascites, blood cultures, urinary cultures, fecal exam in

search for melenas and assessment of focal neurological signs. Those withadvanced encephalopathy (Glasgow , 13) or with focal neurological signsunderwent computed tomography of the brain.

After the initial workup, those who fullled entry criteria were invitedto participate in the study. Acute alcoholic hepatitis was excludedaccording to clinical data (heavy alcohol abuse, jaundice, leukocytosis,fever, tender hepatomegaly) [10]; liver biopsies were not performed. Theinterval of time between admission in the hospital and initiation of theenteric formula was in all cases less than 24 h (group A: 14.2 ^ 2.7 h;group B: 13.5 ^ 3.1 h). During this period of time the patients completedthe clinical workup, a nasogastric tube was inserted to deliver the entericdiet, and therapeutic measures for hepatic encephalopathy were initiated.

Patients were randomized to two groups of treatment: A) a low-proteingroup and B) a normal protein group. Enteric nutrition was delivered by anasogastric tube for 2 weeks with the aid of a peristaltic pump that wasadjusted to deliver the complete amount ( < 1500 ml) for 24 h (from 4 pm to4 pm). The enteric formula contained 30 kcal/kg/day and a 3:1 ratio of

glycids to lipids. The low-protein group (group A) followed a progressiveincrease in the dose of protein in the diet, because this regimen is commonin many centers, has been recommended by several experts [2,11] and is in

accordance with the recommendations of the ESPEN [8]. They received 0 gof protein for the rst 3 days, then the amount of protein was increasedprogressivelyevery 3 days (12, 24 and 48 g) up to 1.2 g/kg/dayfor the last 2days. The normal protein group (group B) received 1.2 g/kg/day from therst day. Both groups received the same amount of calories to control forthis variable. Prior studies in alcoholic liver disease have shown a pooreroutcome for patients that received low amount of protein and calories [5]; itis not possible to differentiate which one of the two factors determined theclinical outcome. Due to difculties in estimating dry body weight (withoutascites or edema), ideal body weight was used for all calculations. Idealbody weight was calculated from height, gender and frame size, accordingto standard values of the Spanish population. Gastric retention was assessedevery 6 h, and the velocity of the pump was adjusted according to theamount of retention in order to minimize the risk of aspiration.Metoclorpramide and omeprazole were systematically administered toimprove enteric tolerance and to prevent gastrointestinal bleeding.

Hepatic encephalopathy was treated similarly in all patients. Correctionof precipitating factors consisted of the administration of broad-spectrumantibiotics when infection was suspected or conrmed and intravenousadministration of saline infusions when signs of dehydration were present.Initially, an enema of lactulose was administered, irrespective of theprecipitating factor, and was followed by treatment with neomycin (3 g/dayduring the rst 3 days, followed by 1 g/day thereafter). We chose treatmentwith neomycin instead of lactulose because we were concerned about thedifculties in differentiating the effects of lactulose from the possibledevelopment of diarrhea complicating enteric nutrition. Furthermore, bothdrugs have been shown to be equally effective [12] . All patients receivedsupportive therapy and special nursing care was provided for patients withdepressed consciousness. Concomitant drugs were allowed as needed if they did not interfere with the assessment of mental status. For the durationof the study the patients did not receive any oral diet apart from the entericformula.

2.3. Objectives

The objective of the study was to assess whether there would besignicant differences in the outcome of hepatic encephalopathy between

both groups of therapy over a period of 14 days following inclusion into thestudy. Due to the lack of standardized measures to assess outcome, wedecided to compare the degree of hepatic encephalopathy between eachgroup at each day during the study period. The hypothesis of the study wasthat there would not be signicant differences in the outcome of hepaticencephalopathy, but those treated with a low-protein diet would experiencea negative protein balance.

2.4. Outcomes

Hepatic encephalopathy was assessed, quantifying the mental state witha scale that was an adaptation of the West Haven criteria, according to therecommendations of a consensus conference [13]. Due to the lack of a cleardenition of the different stages, we decided to dene them as shown inTable 1 . The same evaluator (F. S. or F. C.) assessed the same patient for theduration of the study at the same time every day (4 pm). We did not performneuropsychological tests, such as Trail A or Symbol Digit, because tointerpret them correctly the patient needs to be collaborative and shownormal consciousness.

Protein synthesis and degradation were evaluated with the glycine-N 15

infusion method [14] at day 2 and at day 14. Essentially, patients received a50-mg bolus dose of glycine-N 15 followed by a continuous infusion(4.475 10

2 7 mol/kg2 1 /h

2 1) for 24 h. Urinary samples were taken atbaseline and after 12 h of infusion, and N 15 urinary enrichment wasdetermined with an isotope ratio mass spectrometer. Standard laboratoryblood tests and anthropometric indexes were determined at day 1 andday 14.

2.5. Sample size

Due to the lack of prior studies, the sample size was calculated on theassumption that the detection of a clinically relevant effect would requirethe inclusion of 20 patients that survive the episode of hepatic

encephalopathy. The inclusion of this number of patients in a randomizedstudy demonstrated the superiority of lactulose over placebo [15] . Althoughthe efcacy of lactulose has been questioned, a large clinical experience

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supports its use. The analysis was intentionally directed to assess patientsthat survived to 14 days of therapy to avoid the bias that could be introducedby including patients with terminal liver failure.

2.6. Randomization

Allocation was performed following a randomization scheme con-trolled by the Hospital pharmacy. The allocation sequence was generatedby a computer and kept concealed until the end of the study. Enrolment wasnished after the inclusion of 20 patients who completed the 14 days of

treatment. The physicians in charge of the patients (J.C., F.C., F.S.) did notknow treatment allocation. The pharmacist (P.S.), who was also responsiblefor the preparation of the enteric formula, was not informed about theevolution of patients. To favor blinding of assessment, the enteric productswere prepared to have a similar appearance and were kept in dark, codedbags that were distributed by the pharmacy.

2.7. Statistical methods

Although several variables followed a normal distribution, due to thesmall number of patients the results are expressed as median (rst quartile).The non-parametric MannWhitney rank sum test was used forcomparisons between both groups of treatment. Calculations wereperformed with the Sigma Stat v3.0 statistic software.

3. Results

The enrolment period started on March 2001 and nishedon November 2002. The ow of participants through eachstage of the trial is shown in Fig. 1. During this period 62patients were considered eligible; of them, 30 patients wererandomized. The reasons for exclusion were: acute alco-holic hepatitis n 6, gastrointestinal bleeding n 10,hepatocellular carcinoma n 3, previous intake of benzodiacepines n 2, neurological comorbiditiesn 3, respiratory failure requiring ventilatory supportn 2, refusal to participate n 2, and other n 4.

The baseline demographic and clinical characteristics of patients included in the study or those that nished

Table 1Stages of hepatic encephalopathy (adapted from Ref. [13] )

Stage Neurological manifestations

0 Alert and attentive (in time and space) without signs of encephalopathy (neither dysarthria, ataxia, apping tremor orobvious decrease in the speed of mental processing)

1 Alert and attentive, but with at least one of the following signs:dysarthria, ataxia, apping tremor or obvious decrease in thespeed of mental processing

2 Awake but inattentive: disoriented, somnolent, easy to distract,unable to perform easy mental tests (addition, subtraction,remember a list of numbers). Patients speech is easy tounderstand

3 Marked somnolence or psychomotor agitation. Speech isdifcult to understand

4 Coma. The patient does not speak and does not follow simple

commands (such as raising an arm or opening the mouth)

Table 2Clinical characteristics of patients included in the study

Low protein n 10 Normal protein n 10

DemographicsAge (years) 67 (55) 68 (58)Gender (male/female) 4/6 7/3

Etiology of cirrhosisAlcohol 5 4Hepatitis C 4 4Other 1 2

DecompensationPrior encephalopathy 9 7Ascites at admission 5 3

Precipitating factorInfection 4 5Disturbance of electrolytes 2 1Unknown 4 4

Blood testsProthrombin activity (%) 51 (41) 57 (46)Bilirubin (mg/dl) 1.7 (1.2) 2.2 (1.5)Albumin (mg/dl) 2.2 (1.9) 2.5 (2.4)Ammonia (mcM/l) 92 (66) 108 (76)

Anthropometrical dataBody weight (kg) 60 (58) 69 (61)TSF (mm) 8 (7) 9 (9)MAC (cm) 25 (23) 26 (24)MAMC (cm) 22 (21) 21 (20)Malnutrition 5 8

Results in medians (rst quartile). There were non-statistically signicant differences between both groups. TSF: Triceps skin fold thickness; MAC:Midarm circumference; MAMC: Midarm muscle circumference. Malnutrition (severe): TSF, MAC or MAMC , 5th percentile.

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treatment ( Table 2 ) were similar in both groups. All patientsreceived the allocated intervention. During follow-up 10patients nished treatment before the end of the study. Thereasons for discontinuation were equally distributed amongboth groups of treatment and corresponded to: deathn 8, gastrointestinal bleeding n 1 or voluntaryabandon n 1. None of the patients developed aspirationpneumonia. Some patients required repeated introduction of nasogastric tubes due to unconscious removal; none of themdeveloped signicant gastric retention. The administrationof the enteric feeding along the 14-day period of treatmentwas over 80% of the prescribed dose in all the cases. Twentypatients, 10 in each group, completed the 14 days of therapy.All patients nishing the study were discharged alive fromthe hospital.

There were no signicant differences in the course

of hepatic encephalopathy between the two groups of treatment, neither among all patients enrolled in the study(Fig. 2) nor those who nished the 14 days of treatment(Fig. 3).

The analysis of protein metabolism was limited to thosepatients completing the study. During the second day onenteric nutrition, protein breakdown was exacerbated in thelow protein group ( Fig. 4; group A: 4.1 (3.6), group B: 2.5(2.4) g protein kg/day; p 0:04), but without differences inprotein synthesis (group A: 3.5 (3.1), group B: 3.1 (3.0) gprotein kg/day). However, at the end of the study, when bothgroups received the same amount of protein, there were nodifferences either in protein synthesis (group A: 4.8 (3.4),group B: 3.9 (3.2) g protein kg/day) or breakdown (group A:4.8 (3.1), group B: 3.7 (3.1) g protein kg/day).

At the end of the study, both groups showed similarvalues of plasma ammonia (group A: 59 (34), group B: 61(46) mcm/l), prothrombin activity (group A: 51 (39), groupB: 59 (47) %), bilirubin (group A: 2 (1.1), group B: 1.6(0.9) mg/dl) and albumin (group A: 2 (1.9), group B: 1.6(0.9) mg/dl).

4. Discussion

The main nding of this study is that there is no majorbenet of limiting protein intake on the evolution of episodic hepatic encephalopathy, while the administrationof a low-protein diet exacerbates protein breakdown. In theshort term, protein restriction did not have major conse-

quences on liver function or plasma ammonia, as indicatedby the evolution of blood tests. However, favoring proteinbreakdown for more prolonged periods may have detri-mental consequences on the nutritional status and may resultin adverse consequences.

Our results suggest that patients with episodic hepaticencephalopathy can safely receive a normal protein diet.The current recommendation advocates limiting proteinrestriction to short periods of time and early initiation of anormal protein diet [1,8] . We designed the study accordingto this recommendation. Patients in group A underwentprotein restriction followed by progressive increments,while those in group B followed a normal protein diet

from the beginning. The lack of difference in the evolutionof encephalopathy between both groups indicates thattolerance to a normal protein diet is higher than previouslythought [4]. In practice, most of the patients can be treatedwith intravenous solutions for the rst days. The majoritywould then be able to reinitiate oral intake. Our data supportthat at that time patients can receive a diet with a normalamount of protein. In case of difculties in regaining oralintake, naso-gastric feeding should then be considered.

Ammonia has been classically recognized as the mainculprit for the development of hepatic encephalopathy [16].Protein restriction was promoted as a simple way todecrease the nitrogenous load, which could lead to lowervalues of plasma ammonia [17]. However, this approachdoes not take into consideration the effects of limitingprotein intake on protein metabolism. Kinetic studies instable cirrhotics show that skeletal muscle removes largeamounts of ammonia from circulation [18]. In muscle,ammonia is trapped and released as the ammonia carrierglutamine. In splanchnic viscera, glutamine is deaminated,resulting in ammonia production in portal drained viscera.An increase in protein breakdown causes a release of aminoacids from the skeletal muscle. In cirrhotics, this nitrogen-ous load could cause an increase in plasma ammonia due toa decrease in the capacity to synthesize urea [19].

Most stable cirrhotics exhibit increased protein require-ments that appear to be secondary to increased proteinbreakdown [20,21] and may explain why they are prone to

Fig. 1. Flow-chart of participants through each stage of the trial.Reasons for not meeting inclusion criteria are reported in the section of results.



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rapid protein wasting in periods of metabolic stress, fastingor reduced caloric intake. Whole-body protein turnover hasnot been studied before in cirrhotic patients with encephalo-pathy. In spite of limitations of the method [22], our data arein accordance with results from prior studies [20,21] . Weobserved high values of protein synthesis in patients withhepatic encephalopathy. Those fed a low-protein dietexhibited higherprotein breakdown.Thedifferences in proteinbreakdown can be explained by an increase in substraterequirements to maintain critical metabolic processes such asprotein synthesis. Those differences disappeared at the end of the study, when the same group ofpatients received a dietwithnormal protein content (1.2 g/kg/d).

The main drawback of this study is small sample size;hence, a larger study is required to validate our ndings.However, this kind of study is difcult to conduct, as shownby the lack of similar studies in the past. In spite of samplesize limitations, our data are more solid than those provided

by uncontrolled observations. Our results are in accordancewith the current view that maintaining an adequatenutritional status is benecial for patients with cirrhosis[23,24] . This appears to be especially critical for those whoare to undergo liver transplantation [25]. Furthermore,avoiding protein breakdown may decrease the production of ammonia derived from amino acid release from skeletalmuscle. Thus, administering enough protein to attain proteinrequirements could improve hepatic encephalopathy.

In conclusion, the rst controlled study randomizingcirrhotic patients with hepatic encephalopathy to receivedifferent amounts of protein suggests that low-protein dietsshould be abandoned. Contrary to current recommendations[1,8] , manycenters stillprescribe low-protein diets to cirrhoticpatientswho havehad prior episodesof encephalopathy [26], a

Fig. 2. Evolution of hepatic encephalopathy in all patients randomizedto follow the low-protein diet (upper panel) or the normal protein diet(lower panel). The asterisks identify those patients who died during thestudy.

Fig. 3. Stage of hepatic encephalopathy (box plot: median, 10th90thpercentile, 25th 75th percentile, dashed line: mean) at inclusion (day0), day 7 and end of the study (day 14) in the patients that nished the

study (per-protocol analysis), grouped according to treatment. Therewere no statistical differences between the low-protein diet (whiteboxes) and the normal protein diet (gray boxes).

Fig. 4. Protein metabolism (medians) estimated with the glycine-N15

method in patients who nished the study and followed the low-proteindiet (group A) or the normal protein diet (group B). Protein breakdownat day 2 was higher in the low protein diet group p 5 0:04. There wereno statistically signicant differences between baseline and nal resultsin either groups. The gure shows the normal range observed in aprevious group of healthy individuals [14] as a reference.

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practice that has been severely criticized [27]. The presentstudy may help to implement these recommendations.

Acknowledgements

Study supported by FIS 99/809 and Instituto de SaludCarlos III (projects G03/155 and C03/02). Dr. FranciscoCastro was supported by an educational grant of InstitutoDanone.

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Normal protein diet for episodic hepatic encephalopathy:results of a randomized study