The Treatment of Patients With Hepatic Encephalopathy

8/3/2019 The Treatment of Patients With Hepatic Encephalopathy

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The Treatment of Patients

With Hepatic Encephalopathy:

Review of the Latest Data

from EASL 2010

u l y 2 0 1 0 V o l u m e 6 , I s s u e 7 , S u p p l e m e n t 1 1w w w . c l i n i c a l a d v a n c e s . c o m

A Review of Selected Presentations

From the 45th Annual Meeting of the

European Association for the Study of the Liver

April 1418, 2010

Vienna, Austria

With commentary by

Kevn D. Mullen, MD

Professor of Medicine

Case Western Reserve University

Director, Gastroenterology Fellowship Program

Department of Gastroenterology

MetroHealth Medical Center

Cleveland, Ohio A CME ActvtyApproved for1.0 AMA PRA

Category 1 Credit(s)TM

Release date: July 2010

Expiration date: July 31, 2011

Estimated time to complete activity: 1.0 hour

Sponsored by Postgraduate Institute for Medicine

Supported through an educational grant from

Salix Pharmaceuticals, Inc.


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Maria T. Abreu, MDUniversity of MiamiSchool of Medicine

Nezam H. Afdhal, MDBeth Israel Deaconess

Medical CenterHarvard Medical School

Leonard Baidoo, MDUniversity of Pittsburgh

Robert N. Baldassano, MDChildrens Hospital of Philadelphia

University of Pennsylvania

Theodore Bayless, MDJohns Hopkins Hospital

Manoop S. Bhutani, MDUniversity of Texas

M. D. Anderson Cancer Center

Athos Bousvaros, MD, MPHChildrens Hospital Boston

Thomas D. Boyer, MDUniversity of Arizona

Joel V. Brill, MDPredictive Health, LLC

Robert S. Brown, Jr., MD, MPHColumbia University

Medical Center

Brooks D. Cash, MDNational Naval Medical Center

Lin Chang, MDDavid Geffen School of MedicineUniversity of California,

Los Angeles

William D. Chey, MDUniversity of Michigan

Medical Center

Russell D. Cohen, MDUniversity of Chicago

Scott J. Cotler, MD

University of Illinois at Chicago

Douglas Dieterich, MDMount Sinai Medical Center

Adrian M. Di Bisceglie, MDSaint Louis University

Jack A. Di Palma, MDUniversity of South Alabama

David B. Doman, MDGeorge Washington University

School of Medicine

Herbert L. DuPont, MDUniversity of TexasHouston

School of Public Health andBaylor College of Medicine

Gary W. Falk, MDCleveland Clinic Foundation

Ronnie Fass, MDUniversity of Arizona

M. Brian Fennerty, MDOregon Health & Science

University

Steven L. Flamm, MDNorthwestern University

Feinberg School of Medicine

Robert Gish, MD

California PacificMedical Center

Tarek Hassanein, MDUniversity of California,

San Diego

Colin W. Howden, MDNorthwestern University

Feinberg School of Medicine

Ira M. Jacobson, MDWeill Medical College of

Cornell University

David L. Jaffe, MDUniversity of Pennsylvania

School of Medicine

EDITORIAL ADVISORY BOARD

EDito-in-ChiEf:

Gary . Lcese, MD

Director, Inammatory BowelDisease ProgramProfessor of MedicineUniversity of Pennsylvania

SECtion EDitoS:

J Balle, MB CB, fCP Professor of MedicineDirector of PancreatobiliaryDisorders ServiceWake Forest University HealthSciences Center

Sepe B. haauer, MDProfessor of Medicineand Clinical PharmacologyDirector, Section of

Gastroenterology and NutritionUniversity of Chicago

Jel E. cer, MD, fACP, MACGProfessor of MedicineChairman, Department of MedicineTemple University School ofMedicine

Eugee . Sc, MDProfessor of MedicineDirector, Schiff Liver InstituteDirector, Center for Liver DiseasesUniversity of Miami Schoolof Medicine

Lennox J. Jeffers, MDUniversity of Miami

Maureen M. Jonas, MDChildrens Hospital Boston

Sunanda V. Kane, MD, MSPHMayo Clinic

Philip O. Katz, MDAlbert Einstein Medical Center

Seymour Katz, MD, FACG, MACGNew York University

Emmet B. Keeffe, MDStanford University

Asher Kornbluth, MDMount Sinai Medical Center

Joshua Korzenik, MDMassachusetts General Hospital

Brian E. Lacy, MD, PhDDartmouth-Hitchcock Medical Center

Bret A. Lashner, MDCleveland Clinic Foundation

Jonathan A. Leighton, MDMayo Clinic

Anthony J. Lembo, MDBeth Israel Deaconess

Medical Center

Richard MacDermott, MD

Albany Medical Center

Willis C. Maddrey, MDUniversity of Texas Southwestern

Medical Center

Uma Mahadevan-Velayos, MDUniversity of California,

San Francisco

Paul Martin, MDUniversity of Miami

Philip B. Miner Jr., MDOklahoma School of Medicine

Kevin D. Mullen, MD

Metrohealth Medical Center

Guy Neff, MD, MBAUniversity of Cincinnati

Marion G. Peters, MDUniversity of California,

San Francisco

Mark Pimentel, MD, FRCP(C)Cedars-Sinai Medical Center

Paul J. Pockros, MDScripps Clinic

Fred Poordad, MDCedars-Sinai Medical Center

Daniel H. Present, MDMount Sinai School of Medicine

Eamonn M. M. Quigley, MDNational University of Ireland, Cork

K. Rajender Reddy, MDUniversity of Pennsylvania

Douglas K. Rex, MDIndiana University Medical Center

David T. Rubin, MDUniversity of Chicago

Paul Rutgeerts, MDKatholieke Universiteit Leuven

Sammy Saab, MD, MPHDavid Geffen School of Medicine

University of California,Los Angeles

Seymour M. Sabesin, MDRush University Medical Center

Richard E. Sampliner, MDUniversity of Arizona

Ellen J. Scherl, MD

Weill Medical CollegeCornell UniversityNew York-Presbyterian Hospital

Philip S. Schoenfeld, MD, MEd, MScUniversity of Michigan

Bo Shen, MD

The Cleveland Clinic

Mitchell Shiffman, MDVirginia Commonwealth

University

Corey A. Siegel, MDDartmouth-HitchcockMedical Center

Jerome H. Siegel, MDBeth Israel Medical Center

Mark Sulkowski, MDJohns Hopkins University

School of Medicine

Nicholas J. Talley, MD, PhDMayo Clinic

Michael F. Vaezi, MD, PhDVanderbilt University

Medical Center

Fernando Velayos, MDUniversity of California,

San Francisco

Nizar Zein, MDCleveland Clinic Foundation


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Target Audience: Tis activity has been designed to meet theeducational needs of gastroenterologists involved in the management

of patients with hepatic encephalopathy (HE).

Statement of Need/Program Overview: An abundance of newinformation has recently come to light in the treatment of patients

with HE regarding quality of life (QOL), pharmacokinetic data,

ammonium reduction, etc. and a distinct educational need existsin the gastroenterology and hepatology community for an updated

understanding of the latest treatment strategies. Te abstract review

monograph will present the most current data emerging within this

therapeutic area.

Educational Objectives: After completing this activity, theparticipant should be better able to:

1. Outline challenges in the detection and treatment of various stages

of HE.

2. Describe the signicance of using rifaximin to reduce risk of HE-

related hospitalization and breakthrough HE.

3. Review the latest information from the EASL 2010 on the use of

targeted agents as treatment options for HE.

4. Describe QOL, pharmacokinetic, and ammonia reduction data in

patients with HE.

Accreditation Statement: Tis activity has been planned andimplemented in accordance with the Essential Areas and policies of the

Accreditation Council for Continuing Medical Education (ACCME)

through the joint sponsorship of Postgraduate Institute for Medicine

(PIM) and Gastroenterology & Hepatology.

Credit Designation: Postgraduate Institute for Medicine designatesthis educational activity for a maximum of 1.0 AMA PRA Category 1Credit(s). Physicians should only claim credit commensurate with theextent of their participation in the activity.

Disclosure of Conflicts of Interest:Postgraduate Institute for Medicine (PIM) assesses conict of interest with its instructors, planners, managers, and other individuals who

are in a position to control the content of CME activities. All relevant

conicts of interest that are identied are thoroughly vetted by PIM for

fair balance, scientic objectivity of studies utilized in this activity, and

patient care recommendations. PIM is committed to providing its learn-

ers with high-quality CME activities and related materials that promote

improvements or quality in healthcare and not a specic proprietary

business interest of a commercial interest.

Te faculty reported the following nancial relationships or relation-

ships to products or devices they or their spouse/life partner have with

commercial interests related to the content of this CME activity:

DisclosuresKevin D. Mullen, MDconsulting fees: Salix Pharmaceuticals; fees for

nonCME services: Homan-La Roche.

Te planners and managers reported the following nancial relation-

ships or relationships to products or devices they or their spouse/life

partner have with commercial interests related to the content of this

CME activity:

Te following PIM planners and managers, Jan Hixon, RN, BSN, MA,

race Hutchison, PharmD, Julia Kirkwood, RN, BSN, Samantha Mat-

tiucci, PharmD, Jan Schultz, RN, MSN, CCMEP, and Patricia Staples,MSN, NP-C, CCRN, hereby state that they or their spouse/life partner

do not have any nancial relationships or relationships to products or

devices with any commercial interest related to the content of this acti-

vity of any amount during the past 12 months.

Method of Participation: Tere are no fees for participating andreceiving CME credit for this activity. During the period July 15, 2010

through July 31, 2011, participants must read the learning objectives

and faculty disclosures and study the educational activity.

PIM supports Green CE by oering your Request for Credit online. If

you wish to receive acknowledgment for completing this activity, please

complete the post-test and evaluation on www.cmeuniversity.com. On

the navigation menu, click on Find Post-test/Evaluation by Course and

search by course ID 7281. Upon registering and successfully completingthe post-test with a score of 70% or better and the activity evaluation,

your certicate will be made available immediately. Processing credit

requests online will reduce the amount of paper used by nearly 100,000

sheets per year.

Media: Monograph

Disclosure of Unlabeled Use: Tis educational activity maycontain discussion of published and/or investigational uses of agents

that are not indicated by the FDA. Postgraduate Institute for Medicine

(PIM), Gastroenterology & Hepatology, and Salix Pharmaceuticals,Inc. do not recommend the use of any agent outside of the labeled

indications.

Te opinions expressed in the educational activity are those of thefaculty and do not necessarily represent the views of PIM, Gastro-Hep

Communications, and Salix Pharmaceuticals, Inc. Please refer to the

ocial prescribing information for each product for discussion of

approved indications, contraindications, and warnings.

Disclaimer: Participants have an implied responsibility to use thenewly acquired information to enhance patient outcomes and their

own professional development. he information presented in this

activity is not meant to serve as a guideline for patient management.

Any procedures, medications, or other courses of diagnosis or

treatment discussed or suggested in this activity should not be

used by clinicians without evaluation of their patients conditions

and possible contraindications or dangers in use, review of any

applicable manufacturers product information, and comparison

with recommendations of other authorities.


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Gastroenterology & Hepatology Volume 6, Issue 7, Supplement 11 July 2010 5

Recent Advances in the Diagnosis andTreatment of Hepatic Encephalopathy

being most severe and 7 being least severe. Higher scoresindicate a better quality of life. CLDQ overall score andindividual domain scores were subjected to longitudinalanalysis; calculated area under the curve was normalizedby exposure time (time-weighted average [WA]) foreach patient. Since fatigue subdomain scores were foundto be highly correlated with disease severity, it was chosenas a key secondary endpoint. Rifaximin treatment led tosignicantly higher mean WA score for fatigue versusthat for placebo (3.2 vs 2.5, P=.0087) and for the overallCLDQ score (3.7 vs 2.9, P=.0093). Mean WA scoreswere also signicantly higher for the other 5 domains withrifaximin treatment compared with placebo (able 1).

Te investigators found that rifaximin safety wascomparable to placebo with an 80% and 79.9% incidenceof adverse events in each treatment group, respectively.Te most commonly reported events (occurring in 12%of patients in either treatment group) included peripheraledema (15.0% vs 8.2%), nausea (14.3% vs 13.2%), diz-ziness (12.9% vs 8.2%), fatigue (12.1% vs 11.3%), anddiarrhea (10.7% vs 13.2%), for rifaximin and placebo,respectively. A total of 20 patients, 9 patients in the

rifaximin group and 11 patients in the placebo group,died during the trial; disease progression was the primaryreason for most of the deaths.

Te results of this analysis indicate that rifaximinsignicantly improves the quality of life for patients withhepatic cirrhosis and recurrent, overt HE.

A Review of Selected Presentations from

the 45th Annual Meeting of the European

Association for the Study of the Liver

April 1418, 2010

Vienna, Austria

15 Rifaximin Treatment Improved Quality ofLife in Patients with Hepatic Encephalopathy:Results of a Large, Randomized, Placebo-Controlled Trial1

A Sanyal, N Bass, K Mullen, F Poordad, A Shaw,K Merchant, E Bortey, WP Forbes, S Huang

Rifaximin, a broad-spectrum, gut-selective, minimallyabsorbed oral antibiotic, has demonstrated ecacy inthe treatment of acute hepatic encephalopathy (HE)and more recently in the prevention of overt HE recur-rence.2 In the randomized phase III RFHE3001 trialconducted over a 6-month period, rifaximin (550 mgtwice daily) reduced the risk of breakthrough overt HEby 57.9% compared with placebo (hazard ratio, 0.421;95% condence interval [CI], 0.2760.641; P


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A B S T R A C T S U M M A R Y

6 Gastroenterol ogy & Hepatology Volume 6, Issue 7, Supplement 11 July 2010

149 Persistent Deficit in Learning of ResponseInhibition Following Onset of Overt HepaticEncephalopathy in Cirrhosis3

J Bajaj, DM Heuman, C Schubert, DP Gibson,

JB Wade, A Topaz, D Bell, RT Stravitz, RK Sterling,AJ Sanyal

Episodes of overt HE lead to acute mental status changesthat are usually reversible. However, for some patients,chronic neurologic damage may occur. o determineif cognitive function deteriorates after overt HE, Bajajand colleagues evaluated the psychometric performanceof patients with or without prior overt HE in 2 trials.Te rst was a cross-sectional analysis of 226 patients inwhich the mean age was 57 years, 75% of participantsbeing male, and 69% having a hepatic C virus (HCV)infection; the model for end-stage liver disease (MELD) was 9, with overt (n=52), minimal (n=120), and nominimal HE (n=54). Te second was a prospective studyof 59 patients with liver cirrhosis and no prior episodesof overt HE, who later developed overt HE (n=15; meanage, 54 years; male, 80%; HCV infection, 80%) or whodid not develop overt HE (n=44; mean age, 55 years;male, 73%; HCV infection, 74%). Psychometric perfor-mance was evaluated by a psychometric battery, includ-ing number connection test A+B, digit symbol test, andblock design test. Tese tests were given in conjunctionwith an inhibitor control test (IC) where high lures

indicate poor response inhibition. Since IC has identi-cal halves, the ability to learn response inhibition wasstudied by measuring the improvement (or reduction) inlures between the rst and second IC halves (DL12).All overt HE patients were adherent to lactulose treat-ment and had a normal mental status as determined bya mini-mental score greater than 25.

In the cross-sectional analysis, the study authorsfound that patients with overt HE and minimal HEperformed the worst on all psychometric measures com-pared with patients who had no minimal HE (P25). Mean duration of follow-up was 1312months and patients had a median of 2 HE episodes

Table 2. Mean Psychometric Test Scores

Mean scores (SEM)

NC-A, seconds 48 (22)

NC-B, seconds 149 (87)

DS 41 (13)

BD 26 (15)

IC Lures 15 (9)

IC argets, % correct 89 (12)


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T R E A T M E N T O F P AT I E N T S W I T H H E P AT I C E N C E P H A L O P AT H Y


(range, 113) requiring at least 1 hospitalization (range,17). Infection (n=18) was the predominant reason for therst hospitalization, followed by transjugular intrahepaticportosystemic shunt (IPS; n=10), medication (n=7), andspontaneous reasons for the remaining patients.

All patients underwent a psychomotor test bat-tery including number connection test (NC) A+B,digit symbol test (DS), block design test (BD), andIC (lures and targets). Poor cognitive performance isindicated by high IC lure and NC scores and lowDS, BD, and IC target scores. All patients hadhighly abnormal test scores after HE onset (able 2).Worse psychometric performance was highly correlated with the number of HE episodes, the number of HEhospitalizations, and the duration between the rst HE

episode to testing (able 3).In patients with cirrhosis, decits in working mem-

ory, psychomotor speed, attention and response inhibi-tion worsen with the number and severity of overt HEepisodes. Te study investigators conclude that thesedecits likely resulted from chronic neurologic injurydue to the metabolic perturbations that led to HE thatwas slow to reverse.

161 THDP-17 Inhibits the Glutaminase Activityin Caco-2 Cell Cultures5

MM Diaz-Herrero, JA del Campo, P Carbonero,M Jover, J Vega Perez, F Ig lesias Guerra, I Perin,

JD Bautista, M Romero Gmez

Hyperammonemia plays a key role in the pathogenesisof HE. Ammonia that reaches the brain is thought tobe neurotoxic.6 wo likely sources of ammonia produc-tion include: 1) the breakdown of urea by intestinalbacteria, and 2) glutaminase activity in gut enterocytes

that is increased in patients with liver cirrhosis andcorrelates with minimal HE.7 Tus, inhibition of glu-taminase activity in gut enterocytes is a potential targetfor therapeutic intervention in patients with cirrhosisand HE. Te study investigators have previously dem-onstrated in vitro inhibition of glutaminase activity bythe compound HDP-17.5 Te aim of the current studywas to assess the ability of HDP-17 to inhibit K-typeglutaminase activity in colon carcinoma cell (Caco-2)cultures. Caco-2 cells were cultured using standardgrowth conditions at a density of 50,000 cells per wellin 12-well plates. Culture medium contained 2 mM ofL-glutamine. Glutaminase activity was assayed using aprotocol previously described by Heini and colleagues.8

Following 48 hours of treatment with 100 mM

HDP-17, 42% of the initial glutaminase activity inCaco-2 cells was inhibited.5 Tis is in comparison withthe 48% inhibition of Caco-2 cell glutaminase activityfound after 48 hours of treatment with 100 mM 6-diazo-5-oxo-norleucina, a known inhibitor of glutaminase.

Given the inhibitory activity of HDP-17 in Caco-2cells and its ability to cross cell and mitochondrialmembranes, investigators found that HDP-17 oers apotential new therapeutic option for patients with hepaticencephalopathy.

185 Minimal Hepatic Encephalopathy (MHE):Simplified Diagnosis and Relationships withthe Development of Overt HepaticEncephalopathy (OHE)9

C Pasquale, L Ridola, I Pentassuglio, S Nardelli,M Trezza, C Marzano, O Riggio

Patients with liver cirrhosis can have cognitive decits,or minimal HE, that may reduce their quality of lifeand ability to operate a motorized vehicle. Importantly,

Table 3. Correlation between Psychometric Performance and the Number of Overt HE Episodes, Hospitalizations,and Duration Between the First HE Episode and Testing

Number of HE EpisodesNumber of

Hospitalizations for HEDuration Between First HE

Episode and Testing

Correlationcoecient Pvalue



NC-B 0.35 .047 0.35 .05

DS -0.46 .009 0.46 .009 -0.36 .04

IC Lures -0.50 .002 -0.59 .0001 0.48 .007

IC argets -0.43 .009 -0.44 .015


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189 Mild Hepatic Encephalopathy (HE) Assessedby the Repeatable Battery for the Assessmentof Neuropsychological Status (RBANS) is HighlyPrevalent in Ambulatory Patients with Cirrhosis

C Randolph, J Bajaj, MY Sheikh, R Vemuru,G Morelli, LA Balart, M Chojkier, MS Harris,

JD Bornstein, K Mullen

While patients with mild (or minimal) HE typicallyhave no outward symptoms of HE, they often have mildcognitive and psychomotor decits that can reduce theirquality of life and increase their risk for negative out-comes such as job loss and motor vehicle accidents. Teprevalence of mild HE in patients with cirrhosis rangesfrom 3084%.10-15 Te International Society for HepaticEncephalopathy and Nitrogen Metabolism (ISHEN)recommends that detection of mild HE be assessed usingthe Repeatable Battery for the Assessment of Neuropsy-chological Status (RBANS). Tis recommendation isbased on the nding that RBANS correlates with qual-ity of life issues, including impaired daily functioningand job loss, and has well-established population norms.In this analysis, Randolph and colleagues used RBANSto qualify subjects for the ASUE trial, a phase 2bstudy designed to test the ecacy of AS-120 (spheri-cal absorbent carbon) in the treatment of patients withmild HE.16

A total of 206 subjects who met the specied inclu-sion criteria (cirrhosis, age 1870 years, MELD 25, noIPS or surgical shunt, no overt HE within 3 months,no use of lactulose, rifaximin or neomycin within 7 days) were screened by RBANS for participation in the ran-domized trial. Screened patients were mostly male (61%)with a mean age of 55.4 years. Hepatitis C infection wasthe most common underlying liver disease. More thanhalf (56%) of the patients screened scored below the 10thpercentile on the RBANS total scale, after adjusting forage and education and were eligible for randomizationin the ASUE trial. Qualifying RBANS scores were

similar among education levels: 54% of college attendees,57% of high school graduates, and 59% of high schooldropouts qualied.

Te results of this analysis indicate that mild HE ishighly prevalent among patients with well-compensatedcirrhosis and is not predicted by age, education, MELDscore, or indicators of portal hypertension.

patients with minimal HE are at a heightened risk fordeveloping overt HE. In clinical practice, however, thesepatients are often overlooked, due to a lack of a simpleand standardized technique to help identify patients withminimal HE. Te Psychometric Hepatic Encephalopathy

Score (PHES) is currently considered the gold standardfor assessing minimal HE in patients with cirrhosis. Tefollowing 5 tests are included in the PHES, the DS, trailmaking test A and B, serial dotting test (SD), and linetracing test (L). Te goal of the current study was tosimplify the PHES and determine if a correlation existsbetween PHES or simplied PHES (sPHES) and thedevelopment of HE.

Of the 79 patients (male, 62%; mean age, 6013years; Child-Pugh Classication A/B, 81%; Model forend-stage liver disease score, 146) with liver cirrhosis whowere studied, 45 patients were diagnosed with minimalHE by PHES. Psychometric test outcomes were expressedas z-scores of an Italian population standardized for ageand education. Backward logistic regression analysis wasused to simplify PHES. Tis involved incorporating thez-scores of the 5 tests in PHES at the rst step of the logis-tic regression and then eliminating variables in a stepwisefashion, such that removal did not impair the regression.Tis resulted in a simplied model that contained 3 tests:DS, SD, and L. Tis simplied model was not sig-nicantly dierent than a model containing all 5 tests inits ability to identify patients with minimal HE. For bothmodels, PHES and sPHES, the rate of patients correctlyclassied as having minimal HE was 94%.

In total, 20 patients developed overt HE duringfollow-up. Te probability of developing overt HE wassignicantly higher in patients with minimal HE com-pared with those who did not have minimal HE (PHES,P=.012 and sPHES, P=.019). According to Coxs analysis,development of overt HE during follow-up was indepen-dently associated with Child-Pugh class, MELD score,the presence of large porto-systemic shunt and PHES(simplied, relative risk=3.17; P=.04; or not simplied,relative risk=3.75; P=.03).

In summary, the study authors found that a simpli-ed psychometric measure including DS, SD, and

L was equally able to identify patients with minimalHE as the whole PHES, which also includes trail mak-ing test A and B. Both PHES and the simplied PHEScorrelated with development of overt HE and werefound to be independent factors for the occurrence ofovert HE. Given these results, further validation of thesimplied PHES in an independent group of patientsis warranted.


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P=.0079). A signicant and positive correlation was foundbetween mean venous ammonia WA and breakthroughHE (Spearman correlation coecient of 0.22, P=.0005).Te ability of venous ammonia concentrations to predictbreakthrough HE was found to be good as determined by

a Receiver Operating Characteristic curve analysis, 0.64(95% CI, 0.570.72).In conclusion, rifaximin was found to signicantly

decrease venous ammonia concentrations and protectagainst breakthrough episodes of overt HE. Given theability of WA of venous ammonia concentrations toindependently predict breakthrough HE, the studyinvestigators asserted that the Conn score is a reliable andclinically relevant measure of breakthrough HE episodes.

202 A Case Control Study of IMPACT: A Brief

and Effective Web-Based NeuropsychologicalAssessment Battery to Diagnose Minimal HepaticEncephalopathy (MHE)19

M Tsushima, W Tsushima, V Tsushima, N Lim,E Madrigal, C Jackson, M Mendler

Eorts are currently aimed to nd a simplied psycho-metric performance test battery for the diagnosis of mini-mal HE in patients with cirrhosis. ImPAC (ImmediatePost-concussion Assessment and Cognitive esting) is a

short, user-friendly, internet-based neuropsychologicaltest battery that includes 6 modules resulting in 4 com-posite scores: verbal memory, visual memory, visual motorspeed, and reaction time. In this case control study, theauthors compared the ability of ImPAC with traditionaltesting (paper-and-pencil tests [PP]), which includednumber connection A and B tests and DSs to evaluatepatients at risk for minimal HE versus a control cohort ofhealthy volunteers.

Included in this study were 90 patients (meanage, 54.3 years; male, 69%) with cirrhosis (MELD,10.393.42) and no evidence of overt HE, and 131

age-, gender-, and education-matched controls thatwere free of liver disease and otherwise healthy. Patientsand controls were compared on traditional PP and the4 ImPAC composite scores. Participants were excludedfrom the study if they were currently using treatmentsapplicable to overt HE or sedatives, narcotics, or anti-depressants. A positive PP score was dened by a score2 standard deviations below the normative mean on 1or less PP. A patient was determined to have a positiveImPAC score if their score was 2 standard deviationsfrom the control mean.

195 Rifaximin Decreases Venous AmmoniaConcentrations and Time-Weighted AverageAmmonia Concentrations Correlate with OvertHepatic Encephalopathy (HE) as Assessed byConn Score in a 6-Month Study17

A Sanyal, N Bass, F Poordad, MY Sheikh, K Mullen,S Sigal, T Frederick, R Brown Jr., B Bhandari,S Sedghi, K Merchant, S Huang, A Shaw, E Bortey,WP Forbes

Elevated blood ammonia concentrations play a key role inthe pathogenesis of overt HE and are quantitatively asso-ciated with central nervous system eects. Tus, ammonialevels may be a useful marker for severity of overt HE.reatments for HE, such as lactulose and probiotics, aimto lower intestinal ammonia production and absorption.In the multinational, double-blind, randomized phase IIItrial RFHE3001, rifaximin (n=140) reduced the risk ofbreakthrough overt HE over a 6-month period by 57.9%compared with placebo (n=159) in patients with cirrhosis(MELD 25) and a history of recurrent (2 HE episodesas indicated by a Conn score 2 within past 6 months),overt episodic HE.2

wo objectives were sought in this subanalysis ofRFHE3001 presented by Sanyal and colleagues. First,the eect of rifaximin treatment on concentrations of

venous ammonia was determined. Second, the cor-relation between venous ammonia concentrations andbreakthrough HE was assessed by Conn score (scale 04,with more severe impairment indicated by a higher score)which is currently recommended by the Working Partyon Hepatic Encephalopathy for the assessment of overtHE in clinical trials.2,18,17 Venous ammonia concentra-tions were measured at baseline and during treatmenton days 24, 84, and 168. Ammonia concentrations wereexpressed using WA (area under the curve for ammoniaconcentrations over time normalized by exposure time).

Of the 299 patients randomized in RFHE3001, 104

patients (35%) experienced breakthrough HE dened asan increase in Conn score to 2 or greater or an increasein Conn score to 1 and an asterixis grade increase by 1unit if the baseline Conn score was equal to 0.2. Overall,194 patients remained in remission. Rifaximin treatmentsignicantly decreased venous ammonia concentrationscompared with placebo (-5.7 mg/dL vs -0.3 mg/dL,respectively; P=.0391). Patients with breakthrough HEhad signicantly higher venous ammonia concentra-tions (mean WA, 102.4 mmol/L) compared with thosepatients who remained in remission (85.4 mmol/L;


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10 Gastroentero logy & Hepatology Volume 6, Issue 7, Supplement 11 July 2010

Among the 90 patients at risk for minimal HE, 16had a positive PP, and 25 had a positive ImPAC score.Compared with controls, patients had worse scores on 3of 4 ImPAC composite scores (able 4). Patients whohad a positive PP also performed worse on ImPACcompared with patients who had a negative PP (P


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Gastroentero logy & Hepatology Volume 6, Issue 7, Supplement 11 July 2010 11

compared with controls after liver transplantation (278ms vs 244 ms, respectively; P


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investigators found that having both conditions appearsto cause loss of brain tissue and irreversible brain damage.Tey suggested that optimal management of HE prior toliver transplant may help improve cognitive function aftertransplant. Te results of this trial may also inuence how

patients are prioritized for liver transplant.

References

1. Sanyal A, Bass N, Mullen K, et al. Rifaximin treatment improved quality

of life in patients with hepatic encephalopathy: results of a large, randomized,

placebo-controlled trial. Program and abstracts of the 45th Annual Meeting of

the European Association for the Study of the Liver; April 14-18, 2010; Vienna,

Austria 2010; Abstract 15.

2. Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encepha-

lopathy. N Engl J Med. 2010; 362: 1071-1081.

3. Bajaj J, Heuman DM, Schubert C, et al. Persistent decity in learning of

response inhibition following onset of overt hepatic encephalopathy in cirrhosis.

Program and abstracts of the 45th Annual Meeting of the European Association

for the Study of the Liver; April 14-18, 2010; Vienna, Austria 2010; Abstract 149.

4. Bajaj J, Schubert C, Sanyal AJ, Bell D, Pisney L, Heuman DM. Severity of

chronic cognitive impairment in cirrhosis increases with number of episodes of

overt hepatic encephalopathy. Program and abstracts of the 45th Annual Meeting

of the European Association for the Study of the Liver; April 14-18, 2010; Vienna,


5. Diaz-Herrero MM, del Campo JA, Carbonero P, et al. HDP-17 inhibits the

glutaminase activity in Caco-2 cell cultures. Program and abstracts of the 45th

Annual Meeting of the European Association for the Study of the Liver; April

14-18, 2010; Vienna, Austria 2010; Abstract 161.

6. Romero-Gomez M. Pharmacotherapy of hepatic encephalopathy in cirrhosis.

Expert Opin Pharmacother. 2010; 11: 1317-1327.

7. Romero-Gomez M, Ramos-Guerrero R, Grande L, et al. Intestinal glutaminase

activity is increased in liver cirrhosis and correlates with minimal hepatic encepha-

lopathy.J Hepatol. 2004; 41: 49-54.8. Heini HG, Gebhardt R, Brecht A, Mecke D. Purication and characterization

of rat liver glutaminase. Eur J Biochem. 1987; 162: 541-546.

9. Pasquale C, Ridola L, Pentassuglio I, et al. Minimal hepatic encephalopathy

(MHE): Simplied diagnosis and relationships with the development of overthepatic encephalopathy (OHE). Program and abstracts of the 45th Annual Meet-

ing of the European Association for the Study of the Liver; April 14-18, 2010;

Vienna, Austria 2010; Abstract 185.

10. Das A, Dhiman RK, Saraswat VA, Verma M, Naik SR. Prevalence and natural

history of subclinical hepatic encephalopathy in cirrhosis.J Gastroenterol Hepatol.

2001; 16: 531-535.

11. Groeneweg M, Quero JC, De B, I, et al. Subclinical hepatic encephalopathy

impairs daily functioning. Hepatology. 1998; 28: 45-49.12. Hartmann IJ, Groeneweg M, Quero JC, et al. Te prognostic signicance

of subclinical hepatic encephalopathy.Am J Gastroenterol. 2000; 95: 2029-2034.

13. Kircheis G, Wettstein M, immermann L, Schnitzler A, Haussinger D.

Critical icker frequency for quantication of low-grade hepatic encephalopathy.

Hepatology. 2002; 35: 357-366.

14. Quero JC, Schalm SW. Subclinical hepatic encephalopathy. Semin Liver Dis.1996; 16: 321-328.

15. Romero-Gomez M, Boza F, Garcia-Valdecasas MS, Garcia E, Aguilar-Reina

J. Subclinical hepatic encephalopathy predicts the development of overt hepatic

encephalopathy.Am J Gastroenterol. 2001; 96: 2718-2723.16. Randolph C, Bajaj J, Sheikh MY, et al. Mild hepatic encephalopathy (HE)

assessed by the Repeatable Battery for the Assessment Neuropscyological Status

(RBANS) is highly prevalent in ambulatory patients with cirrhosis. Program and

abstracts of the 45th Annual Meeting of the European Association for the Study of

the Liver; April 14-18, 2010; Vienna, Austria 2010; Abstract 189.

17. Sanyal A, Bass N, Poordad F, et al. Rifaximin decreases venous ammonia

concentrations and time-weighted average ammonia concentrations correlate with

overt hepatic encephalopathy (HE) as assessed by Conn Score in a 6-months study.



18. Ferenci P, Lockwood A, Mullen K, arter R, Weissenborn K, Ble i A. Hepatic

encephalopathy--denition, nomenclature, diagnosis, and quantication: nal

report of the working party at the 11th World Congresses of Gastroenterology,

Vienna, 1998. Hepatology. 2002; 35: 716-721.

19. sushima M, sushima W, sushima V, et al. A case control study of

IMPAC: a brief and eective web-based neuropsychological assessment battery

to diagnose minimal hepatic encephalopathy (MHE). Program and abstracts of the

45th Annual Meeting of the European Association for the Study of the Liver; April


20. Grande L, Jover M, Fobelo M, et al. Double-blind crossover trial analyz ing

the usefulness of rifaximin in the treatment of minimal hepatic encephalopathy

(MHE): an interim analysis. Program and abstracts of the 45th Annual Meeting of



21. Schranz M, Krismer F, Roos J, et al. Saccadic latency as an objective and

quantitative marker of hepatic encephalopathy. Program and abstracts of the 45th



22. Montagnese S, Gordon HM, Jackson C, et al. Disruption of smooth pursuiteye movements in cirrhosis: relationship to hepatic encephalopathy and its treat-

ment. Hepatology. 2005; 42: 772-781.23. Garcia-Mart inez R, Jacas C, Alonso J, Vargas V, Simon-alero M, Cordoba J.

Prior hepatic encephalopathy and alcohol etiology determine cognitive function

after liver transplantation. Program and abstracts of the 45th Annual Meeting of




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Gastroentero logy & Hepatology Volume 6, Issue 7, Supplement 11 July 2010 13

Commentary

Kevin D. Mullen, MDProfessor of Medicine

Case Western Reserve UniversityDirector, Gastroenterology Fellowship ProgramDepartment of GastroenterologyMetroHealth Medical CenterCleveland, OH

Tere has been quite a bit of activity in the area of diag-nosis and treatment of hepatic encephalopathy (HE) inthe last few years. Te 2010 European Association forthe Study of Liver (EASL) meeting in Vienna illustratedthis point well. Many very interesting abstracts weresubmitted on the topic of HE. Before specically com-menting on the abstracts included in this summary, it isworth considering a number of issues to put the eld ofHE into perspective.

Te rst is the major imperative to develop test sys-tems to detect minimal HE. Te Psychometric HepaticEncephalopathy Score (PHES) has been declared the

gold standard for the diagnosis of minimal HE by theWorld Congress consensus working party. Te completelack of normative data in the United States and somecopyright concerns largely prevented the use of thePHES system, except in a few countries. Multiple alter-native psychometric testing systems are being evaluatedand will be available in the coming years for what we aregoing to call covert rather than minimal HE. Tename change is primarily needed because minimal HEsounds like something unimportant. Despite its subtlepresence, we have growing evidence that this covert formof HE signicantly reduces the quality of life (QOL) for

cirrhotic patients. It was formerly thought that QOLreduction in cirrhosis was related directly to the eect ofcirrhosis. Studies now clearly implicate HE as the causeof this reduction of QOL.

urning our attention to the abstracts, the rst onecited by Sanyal and colleagues,1 of which I am also co-author, provoked some interest in light of the commentsmade above. Tis is a follow-up paper on the eect ofrifaximin on HE, which was presented at the EASLmeeting in Copenhagen in 2009.2 Tis presentation reit-erated the data showing the reduction (58%) in recurrent

bouts of overt HE in a large group of cirrhotic patients(n=299) at risk for recurrent bouts of HE. However, thenew analysis describes the signicant improvement inthe disease-specic Chronic Liver Disease Questionnaire(CLDQ), designed for liver patients by Younossi, when

treated with rifaximin. As data accumulate that QOLcan be improved by specic HE treatments, there willbe major pressure to treat HE at its earliest stages, sinceminimal/covert HE clearly reduces QOL.

Another issue that has worried hepatologist for yearsis whether single or multiple episodes of overt HE leadto permanent loss of discrete domains of brain function.Bajaj and colleagues have 2 abstracts that address thispoint.3,4 Te rst raised the concept that response inhibi-tion testing can also be a measure of learning becausethe testing system has 2 identical halves. Tis is a trickypoint because multiple factors eect learning, not theleast of which is motivation to perform the test well inthe rst place. Nonetheless, the normal learning eectseemed to be absent after patients had bouts of overtHE. Likewise in the other abstracts where multipledefects in many domains of brain function were notedto increase with the number and severity of bouts ofovert HE in patients. Before dismissing this idea, it isimportant to note that detailed neurologic evaluationsare rarely done on patients emerging from bouts ofovert HE. Literally, we have not documented recoveryfrom overt HE very well. One major study on this topicsuggested that neurologic signs were present in manycirrhotic patients recovering or recovered from a bout

of HE. What has been observed is recovery from severeHE to either absent, minimal, or low-grade overt HE;none of this has been sought specically. Regardless, the2 provocative abstracts of Bajaj and colleagues raise thepossibility that bouts of overt HE lead, in some patients,to a potentially progressive neurologic degeneration.Te more orid hepatocerebral degeneration syndromeshave largely been thought to be irreversible even afterliver transplantation, but a few reports of recovery offunction and even reversal of severe brain atrophy makesone wonder if brain injury due to chronic liver disease/overt HE is uniformly irreversible.

Te abstract of Diaz-Herrero and colleagues comesfrom the Seville unit, which has studied intestinal glu-taminase in great detail.5 Tis enzyme system releasesthe majority of the ammonia found in the portal vein. Itprovides an energy source for intestinal mucosa cells, andthe enzyme is upregulated after creation of a portosystemshunt. Neomycin is known to inhibit this enzyme, butits toxicity has reduced its use as a treatment for HE. Itis worth noting that most of the activity of neomycinagainst HE is mediated by inhibitor of glutaminase ratherthan its antibacterial properties. Tis abstract describes


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a new inhibitor of intestinal glutaminase. HDP-17inhibited glutaminase enzyme activity in an in vitro cellsystem. Tis report may be followed by others on this newtherapeutic approach to the treatment of HE.

Te abstract of Pasquale and colleagues addresses the

issue discussed earlier about developing minimal/covertHE.6 It examined the accuracy of reduced content psy-chometric test proles to diagnose minimal/covert HE.Instead of the full set of tests in the PHES system, theyfound that a combination of just the digit symbol, linetracing, and serial dotting test was as sensitive in diagnos-ing minimal HE as the more elaborate full PHES system.

Following in the same vein, Randolph and col-leagues, including myself, looked at another battery ofneuropsychologic status tests called Repeatable Batteryfor the Assessment of Neurological Status (RBANS).7Minimal or mild HE (a term not generally used thesedays) was found in more than half the patients using thiswell-known diagnostic tool. As mentioned, these dier-ent attempts to develop and validate tests for the detec-tion of minimal HE are ongoing in multiple centers.

Te second abstract of Sanyal and colleagues, ofwhich I am again coauthor, basically showed that accu-rately measured venous ammonia levels predicted thelikelihood of HE recurrence.8 It is important to note thatthe ammonia tests were done at set points during studyfollow-up. Terefore, they are not being done after a boutof overt HE has occurred. Instead, higher levels indicatedthat HE reoccurrence in the coming time period is likely.

sushima and colleagues looked at yet another bat-

tery of tests to detect minimal/covert HE.9 ImPAC(Immediate Post-concussion Assessment and Cognitiveesting) was used in 90 patients at risk for minimal HEand compared to a paper and pencil battery of tests(number connector A and B, and digital symbol test).Te test system generates scores for verbal memory,visual motor speed, and reactor time. As noted above, intime, we will potentially reduce the number of tests forminimal HE based on cost, convenience, and sensitivity.

Grande and colleagues reported the eect of 4 weeksof rifaximin treatment (1,200 mg/daily) or placebo.10Psychometric tests improved in the patients randomized

to receive rifaximin in the second 4-week period. Moredata in manuscript form would help in analyzing thesignicance of this study.

Schranz and colleagues reminded us that saccadiclatency can be measured with relative ease in patients withHE and could be an objective measure of HE to employin the future.11 Tese are not saccadic ocular pursuits, butmore a measure of eye movement response times.

Finally, Garcia-Martinez and colleagues remindedus that brain atrophy is more prominent in patients with

cirrhosis of an alcoholic etiology.12 More specically,this important study found a lack of full psychometricfunction return after liver transplant in these patients.Te authors propose that more aggressive and earlytreatment of HE in patients with alcoholic cirrhosis

may improve cognitive function in these patients afterliver transplantation.

References

1. Sanyal A, Bass N, Mullen K, et al. Rifaximin treatment improved quality

of life in patients with hepatic encephalopathy: results of a large, randomized,

placebo-controlled trial. Program and abstracts of the 45th Annual Meeting of



2. Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encepha-

lopathy. N Engl J Med2010; 362: 1071-1081.3. Bajaj J, Heuman DM, Schubert C, et al. Persistent decity in learning of

response inhibition following onset of overt hepatic encephalopathy in cirrhosis.


for the Study of the Liver; April 14-18, 2010; Vienna, Austria 2010; Abstract 149.4. Bajaj J, Schubert C, Sanyal AJ, Bell D, Pisney L, Heuman DM. Severity of

chronic cognitive impairment in cirrhosis increases with number of episodes of

overt hepatic encephalopathy. Program and abstracts of the 45th Annual Meeting

of the European Association for the Study of the Liver; April 14-18, 2010; Vienna,


5. Diaz-Herrero MM, del Campo JA, Carbonero P, et al. HDP-17 inhibits the

glutaminase activity in Caco-2 cell cultures. Program and abstracts of the 45th



6. Pasquale C, Ridola L, Pentassuglio I, et al. Minimal hepatic encephalopathy

(MHE): Simplied diagnosis and relationships with the development of overt

hepatic encephalopathy (OHE). Program and abstracts of the 45th Annual Meet-

ing of the European Association for the Study of the Liver; April 14-18, 2010;

Vienna, Austria 2010; Abstract 185.

7. Randolph C, Bajaj J, Sheikh MY, et al. Mild hepatic encephalopathy (HE)

assessed by the Repeatable Battery for the Assessment Neuropscyological Status

(RBANS) is highly prevalent in ambulatory patients with cirrhosis. Program and

abstracts of the 45th Annual Meeting of the European Association for the Study of

the Liver; April 14-18, 2010; Vienna, Austria 2010; Abstract 189.

8. Sanyal A, Bass N, Poordad F, et al. Rifaximin decreases venous ammonia con-

centrations and time-weighted average ammonia concentrations correlate with

overt hepatic encephalopathy (HE) as assessed by Conn Score in a 6-months study.



9. sushima M, sushima W, sushima V, et al. A case control study of IMPAC:

a brief and eective web-based neuropsychological assessment battery to diagnose

minimal hepatic encephalopathy (MHE). Program and abstracts of the 45th



10. Grande L, Jover M, Fobelo M, et al. Double-blind crossover trial analyz ing

the usefulness of rifaximin in the treatment of minimal hepatic encephalopathy

(MHE): an interim analysis. Program and abstracts of the 45th Annual Meeting of

the European Association for the Study of the Liver; April 14-18, 2010; Vienna,Austria 2010; Abstract 513.

11. Schranz M, Krismer F, Roos J, et al. Saccadic latency as an objective and

quantitative marker of hepatic encephalopathy. Program and abstracts of the 45th



12. Garcia-Mart inez R, Jacas C, Alonso J, Vargas V, Simon-alero M, Cordoba J.

Prior hepatic encephalopathy and alcohol etiology determine cognitive function

after liver transplantation. Program and abstracts of the 45th Annual Meeting of




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The Treatment of Patients With Hepatic Encephalopathy

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