Assesment of Hepatic Encephalopathy

Review

New assessment of hepatic encephalopathy

Juan Córdoba⇑

Servei de Medicina Interna-Hepatologia, Hospital Vall d’Hebron, Universitat Autònoma de Barcelona and Centro de Investigación Biomédica enRed de Enfermedades Hepáticas y Digestivas (CIBEREHD), Paseo Vall d’Hebron 119, Barcelona 08035, Spain

Hepatic encephalopathy (HE) is a common complication of cir- hepatocarcinoma, hepatorenal syndrome), the management of
rhosis that requires careful appraisal of the clinical manifesta-tions, evaluation of the underlying neurological disorders, andassessment of liver function and the portal-systemic circulation.This article reviews recent developments in the assessment ofHE and discusses the controversy regarding the use of a categor-ical or a continuous approach in measuring the severity of thiscondition. New scales facilitate effective monitoring and assess-ment of episodic HE. Neuropsychological test batteries andneurophysiological tests are of value for evaluating cognitivefunction in outpatients and can establish the diagnosis of mini-mal HE, and the severity of low-grade HE. These tools allow bet-ter evaluation of the origin of cognitive complaints and help inestimating the risk of accidents. It is now possible to completethe evaluation with measurement of the effects of cognitiveimpairment on daily living. In difficult cases, imaging of the brainand portal-systemic circulation with magnetic resonance imag-ing is especially helpful. Based on these studies, neurologicalsigns and symptoms can be attributed to HE in patients with mildliver disease and in those with complex neurological manifesta-tions. The new methods presented are also valuable for investi-gating the neurological manifestations occurring after livertransplantation.� 2010 European Association for the Study of the Liver. Publishedby Elsevier B.V. All rights reserved.
Introduction

Hepatic encephalopathy (HE) is a common complication of cir-rhosis, characterized by a myriad of neurological manifestations,diverse underlying liver disorders, and a variety of precipitatingfactors [1]. The importance of these elements, which determinethe approach to the patient, is recognized in the classification(Table 1). As to the other complications of cirrhosis (e.g. jaundice,

Journal of Hepatology 20

Keywords: Hepatic encephalopathy; Diagnostic methods; Neuropsychology;Magnetic resonance; Cirrhosis.Received 25 July 2010; received in revised form 22 November 2010; accepted 23November 2010⇑ Tel.: +34 649877726; fax: +34 932746068.E-mail address: [email protected]: HE, hepatic encephalopathy; HESA, Hepatic Encephalopathy Scal-ing Algorithm; CHESS, Clinical Hepatic Encephalopathy Staging Scale; PHES, Ps-ychometric Hepatic Encephalopathy Score; RBANS, Repeatable Battery for theAssessment of Neuropsychological Status; MR, magnetic resonance; FLAIR, fluid-attenuation inversion recovery; CT, computed tomography.

HE patients is not uniform and requires precise assessment ofthe neurological and hepatic function [2]. The last decade haswitnessed the development of several new tools that enable:(a) HE grading, (b) assessment of cognitive performance, (c) diag-nosis of minimal HE, (d) evaluation of the consequences in dailyliving, (e) imaging of the brain, and (f) evaluation of the portal-systemic circulation. This article reviews the characteristics ofthese methods and discusses their use in several clinical scenar-ios: (a) during an episode of HE, (b) in asymptomatic outpatients,(c) in determining the origin of cognitive complaints, (d) in attrib-uting neurological manifestations to HE, and (e) in post-trans-plantation follow-up.

New tools

Clinical scales for grading episodic HE

The neurological manifestations of episodic HE are typically fluc-tuating and have multiple expressions, which have beendescribed in detail elsewhere [3]. In clinical practice, these man-ifestations should be quantified and summarized into a simplescore to facilitate monitoring of the clinical course and the effectof therapeutic interventions. Clinical scales that evaluate thepresence of a series of neurological manifestations are effectivetools for this purpose. Neurophysiological methods can providea more objective assessment and are useful for investigatingthe effect of new treatments [4,5].

Standardization of neurological scales for HE is still in the ini-tial phases [6]. The West Haven scale is an arbitrary method thatestablishes four stages of HE based on alterations in the state ofconsciousness, intellectual function, and behavior, and on neuro-muscular signs [7]. The scale includes several manifestations foreach stage, but lacks specific definitions (supplementary Table1). In clinical practice, doctors do not check for the presence ofall the manifestations listed; instead, they use the scale in anintuitive way (0 = absence of HE, 1 = mild manifestations,2 = moderate manifestations, 3 = severe manifestations, 4 =coma). This makes HE grading subjective, a fact that does notinvalidate the scale in individual cases, but causes discrepanciesbetween different assessors. This limitation, which is especiallyrelevant in clinical trials, has been overcome in the various adap-tations of the West Haven scale [8,9].

The Hepatic Encephalopathy Scaling Algorithm (HESA) imple-ments objective ways of measuring the parameters of the West

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mailto:[email protected]

Table 1. Classification of hepatic encephalopathy associated with cirrhosis.

sepytbuSsepyT Features

Precipitated Acute change in mental state induced by: gastrointestinal bleeding, constipation, excessive protein, intake, infection, renal failure, dehydratation, electrolyte disturbance.

.

Episodic

Spontaneous Without recognized precipitating factors. Usually associated with large portosystemic shunts (spontaneous, surgical, TIPS)

Minimal Cognitive disturbances that are not obvious in the standard neurological exam and are detected byneuropsychological or neurophysiological tests

dliM Chronic cognitive or motor manifestations that impact negatively on social and occupational activities but do not cause dependency

Persistent

ereveS Chronic manifestations that cause dependency (dementia, paraplegia, parkinsonism....)

The classification is based on the consensus of Vienna [1].Patients with HE in the context of acute liver failure, portosystemic shunting in the absence of intrinsic liver disease and acute-on-chronic liver failure are classifiedseparately.

JOURNAL OF HEPATOLOGY

Haven scale [10]. The HESA utilizes clinical indicators combinedwith validated neuropsychological tools and well-defined criteriafor each stage (supplementary Table 2). The use of the HESA isstill limited and its metric characteristics have not been fully ana-lyzed [11]. One good favorable characteristic of the HESA is that itidentifies low grades of HE (grade I and II) more precisely, but ithas the drawback of requiring training for proper use.

Another new method is the Clinical Hepatic EncephalopathyStaging Scale (CHESS) [12]. In comparison to other clinical scales,the CHESS was developed without a previous arbitrary definitionof the severity of HE. The authors assessed the presence orabsence of 48 items in a group of 36 patients with episodic HE.The items were selected by a group of experts and were finallyreduced to 9 after applying principal component analysis. Thefinal CHESS is a linear scale that scores HE from 0 (unimpaired)to 9 (deep coma) (supplementary Table 3). The CHESS showsgood metric characteristics in terms of internal consistency,reproducibility, criterion-related validity, and external respon-siveness, but it needs to be validated in other patient samplesand other centers.

The HESA and the CHESS, complemented with the GlasgowComa Score (1), are adequate for clinical trials. The CHESS is sim-pler to use, but since direct comparisons with the HESA have notbeen performed, it is unknown whether the sensitivity of the twoinstruments is similar. For clinical purposes, it may not be neces-sary to establish many grades. House officers usually employ twolevels of severity of the West Haven instrument, referred to asWest Haven I–II, and West-Haven III–IV. These levels of severityreflect as to what extent the patient needs support (e.g. preven-tion of bronchial aspiration, need for artificial nutrition, physicalrestraint) and clinical resources (e.g. admission to intensive care,specialized nursing, intensive monitoring).

Assessment of cognitive performanceThe diagnosis of HE is based on the presence of neurological man-ifestations that are obvious on clinical examination [13]. There isa good agreement between observers in grading patients whoexhibit severe manifestations or are completely alert, but catego-rization often varies between raters in patients who exhibit milddisturbances [11]. The term overt is used to emphasize the pres-ence of clear neurological manifestations and the term covert


refers to disturbances that can only be recognized with special-ized tests.

The traditional view is that HE progress from unimpaired cog-nition (normal psychometric tests and normal clinical examina-tion), to minimal HE (abnormal psychometric tests and normalclinical examination), to grade I–II HE (abnormal psychometrictests and abnormal clinical examination), and to grade III–IV HE(psychometric tests cannot be applied due to decreased con-sciousness). However, the current trend is to interpret the neuro-cognitive impairment as a continuum and promote the use ofcognitive ratings instead of categorical divisions [14]. As repre-sented in Fig. 1, patients may exhibit cognitive impairment inthe context of an acute confusional syndrome (episodic HE).Those with chronic cognitive impairment can be classified byseverity as having low-grade HE [15], which may be covert orovert, or dementia (if the deficit is severe and lasts long enough).The terms used for those with dementia are severe persistent HEor acquired hepatocerebral degeneration (when associated withmotor disturbances: parkinsonism, chorea, myelopathy. . .).

In patients with apparently unimpaired mental status or chroniclow-grade HE, assessment of cognition can benefit from the appli-cation of neuropsychological tests that quantify brain dysfunctionand evaluate various cognitive domains [16]. These instrumentsare preferred over neurophysiological tests and other biologicalmarkers, as they directly measure cognitive functions (e.g. memory,attention, or visuospatial skills) that are relevant to the activities ofdaily living. Psychometric tests are not adequate for patients with adecreased level of consciousness; hence, confusion should beexcluded before beginning neuropsychological testing. This iseasily done with the four questions provided in the ConfusionAssessment Method (CAM) [17] (supplementary Table 4).

Extended neuropsychological assessment is the best way todemonstrate cognitive deficits. Patients complete a series of tests,the results of which are compared to normative standards andinterpreted by a neuropsychologist. Ideally, scores are adjustedfor age, gender, and education level. Usually, the examiner selectsa basic battery of psychometric tests attending to cultural andsocial parameters, available normative data, and prior experience.Additional tests are brought in, to further explore the domainsthat appear impaired in the basic assessment. The final diagnosis(presence or absence of cognitive impairment) depends on inter-

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Continuous approach

MINIMAL

GRADE I

NORMAL

GRADE II

GRADE III

GRADE IV

SEVERITY

CHRONIC LOW-GRADE HE

EPISODIC HE

UNIMPAIRED

PERSISTENT SEVERE HE/ ACQUIRED HEPATOCEREBRAL

DEGENERATION

UNSTABLE STABLE

Categorical approach

Acute confusional syndrome

Coma

Covert

OvertSeve

rity

Fig. 1. Cognitive function assessment in HE can be performed with a categorical or a continuous approach. In the categorical approach, the criteria that define the categoriesare arbitrary and vary between raters. In the continuous approach, patients may be unimpaired (lack of cognitive impairment) or impaired (unstable or stable), and may movefrom one situation to another or remain stable for long periods of time. Those that are unstable exhibit an acute confusional syndrome (that can progress to coma). Those that areimpaired, but stable, show chronic low-grade HE that may be covert (only revealed by psychometric tests) or overt (obvious on clinical exam). Patients with prolonged and severecognitive deficits (dementia) are diagnosed as having persistent severe HE or acquired hepatocerebral degeneration (when associated with motor manifestations). There is someoverlapping between the grades of the categorical approach and the situations defined in the continuous approach, but there is no direct correspondence.

Review

pretation of the test results and observation of the patient’sbehavior. The pattern of neuropsychological impairment suggeststhe type of disorder, but the neuropsychological profile alone isnot diagnostic of a specific disease.

Short neuropsychological test batteries, developed to facilitatethe diagnosis of the cognitive status in several neurological dis-eases, are an alternative to extended neuropsychological assess-ment. These batteries include a limited number of tests thatcan be given by trained technicians, and typically take less than30 min to complete. The tests examine those cognitive domainsthat are expected to be abnormal in a certain disease. It is com-mon practice to consider abnormal scores as those >1.5–2 SDbelow the reference population mean.

A series of short neuropsychological batteries [18,19] areavailable to assess patients with cirrhosis (Table 2); some of themhave computerized versions [20]. Short batteries are more heav-ily weighted to detect deficits that characterize low-grade HE:impairment in attention, executive function, psychomotor abili-ties, and speed of information processing. They are typically per-formed in patients in a chronic non-fluctuating situation, inwhom confusion has been excluded. These batteries can quantifythe cognitive impairment present in minimal HE and in mild per-sistent HE, but they do not differentiate between these situations,because it depends on the threshold that is chosen to distinguishcovert from overt HE. Recommendations and therapeutic mea-sures can be established based on the results [21]. Whenrepeated testing is performed (e.g. to monitor the effect of ther-apy) it is important to control for learning effects. Parallel ver-sions of the same test could lessen this effect, but few testshave well-standardized parallel versions. The choice of which

1032 Journal of Hepatology 2011

battery to use should be based on the availability of local trans-lations and normative data [16].

Screening tests for minimal HE

Minimal HE is a highly prevalent asymptomatic disturbance,especially in patients with advanced disease (Child-Pugh B/C)[22]. The fact that minimal HE can have important consequenceson daily living even though patients are asymptomatic [23] hasled to the need for screening tests. These tests should be easyto use, and quantifiable in a few minutes. Several simple comput-erized tests have been developed for this purpose, and they arereliable in repeated testing (Table 2). Most of them essentiallyassess one cognitive domain: attention deficit and slow informa-tion processing, which are the most prominent disturbances inminimal HE [24].

Various authors have proposed that an abnormal test result issufficient to establish the diagnosis of minimal HE [25–27]. How-ever, the tests are not specific and can be easily affected by sev-eral factors, such as patient anxiety or fatigue, and othercircumstantial elements that act as distracters. Few studies havecompared this group of tests to short neuropsychological batter-ies [22] or extended neuropsychological assessment. Further-more, the use of these tests in populations different from theone included in the original description has yielded conflictingresults, with a high number of abnormal results in control groups[28]. For this reason, it is recommendable to confirm the cogni-tive impairment with additional neuropsychological assessmentsbefore making clinical decisions, such as initiating treatment forminimal HE.

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Table 2. Neuropsychological tools for the diagnosis of cognitive deficits in patients with cirrhosis.

Methods Characteristics Validation

Extended neuropsychological assessment “in-house” selection of tests that examine multiple domains

Difficult Diagnosis based on expert

RBANS [18] Short battery (paper-pencil tests) Large normative data Available in multiple languages Most studies in Alzheimer’s diseasesFew data in cirrhosis Parallel versions available for repeated testing

PHES [19] Short battery (paper-pencil tests) Several studies in cirrhosis Normative data in several countries Parallel versions available for repeated testing

Cognitive Drug Research [20] Computerized neuropsychological battery

Large normative data in United Kingdom Few data in cirrhosis Parallel versions available for repeated testing

Critical Flicker Frequency [25] Psychophysical measurement Not affected by education or age Measures general arousal Identifies patients with abnormal PHES

Inhibitory Control Test [26] Computerized neuropsychological test

Highly demanding test Studies in USA support its use in cirrhosis Needs to be standardized to each population

Scan test [27] Computerized neuropsychological test

mgidarapgrebnretSehtnodesabksatnoitingoceRStudies in Italy support its use in cirrhosis

RBANS: Repeatable Battery for the Assessment of Neuropsychological Status.PHES: Psychometric Hepatic Encephalopathy Score.


Functional scales for assessing the impact of chronic low-grade HE

One important aspect of the neuropsychological assessment is todetermine as to what extent the cognitive deficits affect daily life[29]. This can be done in a systematic manner with the aid ofquestionnaires. The SF-36 and the Chronic Liver Disease Ques-tionnaire have been extensively used in patients with cirrhosis.These easily administered questionnaires can detect a decreasein quality of life associated with minimal HE [30]. They are, how-ever, probably less sensitive than the Sickness Impact Profile, along questionnaire (136 items) that covers numerous aspects ofdaily living and has been shown to detect the benefits of thera-peutic interventions [31].

Patient interview alone does not suffice to determine the con-sequences of cognitive deficits on daily living [32]. The patients’relatives perceive cognitive deficits better than they themselvesdo, and for this reason relatives of patients with dementia areinterviewed with tools such as the Informant Questionnaire onCognitive Decline in the Elderly (IQCODE). Another of these, theClinical Global Assessment of HE (CGA-HE), is an attractiveapproach developed by Dr. C. Randolph that is currently undervalidation. The CGA-HE obtains information on cognitive, motor,and functional status by interviewing the patient and a caregiveror family member, and provides a final score.

Magnetic resonance of the brain

Magnetic resonance (MR) of the brain has become a standard tech-nique for assessing patients with neurological manifestations. Inpatients with cirrhosis, MR is useful to exclude alternative diagno-


ses, such a Wernicke’s encephalopathy, viral encephalitis, andstroke. In addition, MR can detect a series of abnormalities [33]that are characteristically present in the brain of cirrhosis patientswho develop HE:

(a) Deposition of paramagnetic substances in the basalganglia. These substances cause a high signal intensity onT1-weighted imaging, characteristically at the globuspallidus [34]. The hyperintensity probably corresponds tomanganese deposition secondary to portosystemic shunt-ing, and it may be present in the absence of cirrhosis orsecondary to other causes of manganese deposition [35].The intensity of the signaI is not related to the severityof HE [36], but the absence of T1 hyperintensity in apatient with cirrhosis and neurological manifestationssuggests that the neurological symptoms are not causedby HE.

(b) A decrease in the size of the brain. Brain atrophy has beencharacteristically associated with cirrhosis, particularlycases in which the etiology is related to alcohol abuse[37]. The decrease in brain parenchyma is more pro-nounced in specific areas, such as the frontal lobes and cer-ebellum. The mechanism by which cirrhosis induces brainatrophy is not known, but appears to be related to chronicportosystemic shunting and ammonia exposure [38]. Thedecrease in brain volume caused by alcohol recovers(at least partially) after abstinence. The coexistence oflow-grade brain edema may make recognition of atrophydifficult, but it can become more evident after liver trans-plantation [39].

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Fig. 2. MR of the brain in a patient exhibiting grade II HE, and repeated 6 weeks later when the patient exhibited minimal HE. (A) (fast-FLAIR) shows hyperintensefocal white matter lesions (leukoaraiosis) that decrease in volume after the resolution of HE. (B) (MR-spectroscopy) at follow-up shows decrease of the high glutamine-containing (Glx) peak and increase of the low of myo-inositol (mIns) peak. The other peaks correspond to choline-containing compounds (Cho), n-acetyl-aspartate (NAA),and creatine (Cr).

Review

(c) An increase in brain water. Brain edema has been demon-strated using sophisticated MR techniques in patients withchronic liver failure [40] and by laboratory methods inexperimental models [41]. The location and severity ofedema seems to differ according to the duration of liverfailure and the degree of hyperammonemia. Chronic liverfailure induces low-grade interstitial brain edema [42],whereas acute liver failure causes intracellular edema thatcan be severe and lead to brain herniation [43]. In conven-tional MR techniques, brain water changes are reflected asan increase in signal intensity on fast-FLAIR imaging inperiventricular regions, and as focal white matter lesions(Fig. 2-A) or lesions along the corticospinal tract [33]. Diffu-sion-weighted maps typically show an increase in theapparent diffusion coefficient in chronic liver failure and adecrease during episodic HE that is more apparent in certainareas [44].

(d) Changes in organic osmolytes and ammonia related-metab-olites. MR-spectroscopy of the brain shows a typical pattern


in HE patients: an increase in the glutamine peak and adecrease in the choline-containing and myo-inositol peaks(Fig. 2-B) [45]. This pattern is attributed to ammonia metab-olism to glutamine in astrocytes, which induces astrocyteswelling, and to a compensatory osmotic response(decrease in organic osmolytes: myo-inositol and choline-containing compounds)[46]. The severity of HE has beenassociated with the intensity of this abnormality [47]. Nev-ertheless, cut-off values have not been established and thediagnostic accuracy of this pattern is uncertain.

Assessment of portosystemic shunting

The importance of portosystemic shunting in inducing HE is wellknown from the experience with surgical shunts and transjugularintrahepatic portosystemic shunts (TIPS) [48]. The developmentof HE is rare in the absence of significant liver disease, but notexceptional [49]. Portosystemic shunts can be visualized by

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Fig. 3. Dynamic helical CT scanning discloses a splenorenal shunt (arrow) during the arterial phase (left image) that becomes more evident in the venous phase(right image).


various imaging techniques, the most valuable being helical com-puted tomography (CT) (Fig. 3), MR, and endoscopic ultrasonog-raphy. Portal flow steal is a critical mechanism in the inductionof HE in these patients [50]. The arterial concentration of sub-stances with a high first-pass metabolism, such as ammonia, ishighly dependent on portal flow. This fact offers the possibilityof exploring the functional consequences of the shunts. The oralglutamine challenge test consists in the measurement of plasmaammonia after ingestion of glutamine in a fasting state [51]. Thetest has not been standardized and normal values are based onthe experience of independent investigators [49,52]. In our expe-rience, oral glutamine challenge is very helpful for assessing com-plex clinical situations. We have observed flat ammonia curves insome patients with cirrhosis and abnormal psychometric tests,and interpret this finding as a strong argument against attribut-ing cognitive disturbances to HE. This interpretation is supportedby the theoretical basis and the outcomes in cases where we hadthe opportunity to assess.

Approach to patients

Episodic HE

Patients with cirrhosis and an acute change in mental stateshould be managed following a protocol that will exclude alter-native neurological disorders, search for precipitating factors,and assess predisposing conditions (Fig. 4). HE episodes havebeen traditionally related to the occurrence of a precipitatingfactor, which can be defined as a clinical event that does notcause direct injury to the liver or portal-systemic circulationand is responsible for the acute change in mental status. Precip-itating factors appear to act by increasing the generation ofputative toxins or enhancing the effects of toxins on the centralnervous system. They are temporally related to the develop-ment of HE, and their correction to re-establishment of con-sciousness. Several factors are commonly considered underthis category (gastrointestinal bleeding, constipation, excessiveprotein intake, dehydration, electrolyte disturbances, renal fail-ure, and infection), and are thought to explain the majority ofHE episodes. However, a significant number of episodes arenot related to a precipitating factor [53].


Patients that have experienced an episode of HE shouldundergo liver function testing and imaging of the liver and por-tal-systemic circulation to investigate the presence of predispos-ing conditions. These may be defined as disturbances in liverfunction and portal-systemic circulation that facilitate the devel-opment of episodic HE. These conditions are present for a longertime than the precipitating factor, and they may be difficult torelate to the acute episode. Liver function disturbances candevelop over a short period of time (weeks) in relation to an insult(e.g. alcohol) that usually causes a severe, but potentially revers-ible, inflammatory injury. This situation has been proposed to betermed acute-on-chronic liver failure [54] and should be managedseparately from episodic HE. Multiple factors that may interferedirectly with mental status are involved (e.g. sepis, circulatorydysfunction, respiratory failure, etc. . .). These factors require spe-cific therapeutic approaches in addition to measures for HE. Onother occasions (e.g. advanced hepatocarcinoma), liver functiondisturbances develop slowly to a terminal stage that is suspectedby progressive deterioration of the performance status, which pre-cedes the appearance of HE. Portal-systemic circulation distur-bances can either be caused by the presence of a TIPS or asurgically induced portosystemic shunt, as well as by the existenceof large, spontaneous portosystemic shunts [55]. Recognition ofspontaneous shunts is important, because occlusion is a treatmentoption in patients with recurrent HE and good hepatocellular func-tion (low bilirubin) [56]. One interesting recent observation is theidentification of specific polymorphisms in the glutaminase genethat may increase intestinal glutaminase activity and predisposeaffected individuals to the development of episodic HE [57]. Ifthese findings are confirmed, genetic polymorphism should beincluded in the group of predisposing conditions. Apart from iden-tifying high-risk patients, polymorphism assessment may initiatean era of personalized medicine in the field of HE.

Asymptomatic outpatient with cirrhosis

Neuropsychological impairment, which is common amongoutpatients with cirrhosis, is frequently asymptomatic and inmany cases not perceived by the physician (minimal or covertHE). Assessment of cognitive function requires the use of psycho-metric tests under neuropsychological supervision. In many cen-

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Exclusion of alternative neurological disorders

1. Medical history + physical exam: presence of headache, focal neurological signs, meningeal signs

2. Basic analysis: glycemia, PCO23. Toxics in blood or urine:

benzodiacepines (consider flumazenil if suspicous), alcohol…

4. Assess B1 deficit in blood (or give thiamine if suspicion)

5. Neuroimaging (CT, MR) if any abnormality in 1 or coma (unless rapid improvement).

6. EEG if suspicion of seizures or non- .sutats evisluvnoc

Cirrhosis + acute change in mental state

Search of precipitating factors 1. Medical history + physical exam: explore signs of gastrointestinal

bleeding, constipation, dehydration, infection (fever, localized signs) 2. Basic analysis: Hemoglobin, leukocytes, creatinine, Na, K, pH, 3. Leukocytes in urine and ascites (if present) 4. X-rays (thorax and abdomen). 5. Cultures of blood, urine, ascites or other body fluids (if abnormal)

Liver function and portal-systemic circulation 1. Medical history+physical exam: signs of complications of cirrhosis 2. Blood test: bilirubin, albumin, prothrombin, AST, ALT

…RM ,TC :noitalucric cimetsys-latrop dna revil fo gnigamI.3

Acute-on-chronic liver failure Factor that induces injury (alcohol, infection..), usually “inflammatory”-mediated Recent decompensation (2-4 weeks) Jaundice (bilirubin > 5 mg/dl) Circulatory dysfunction (hypotension, renal failure…)

Episodic HE Prior to HE: good performance status. Underlying: precipitating factor or large portosystemic shunts

Terminal Prior to HE: low performance status Underlying: advanced hepatocarcinoma or severe cirrhosis

Fig. 4. Evaluation of a patient with cirrhosis and an acute change in mental status should be initiated by excluding toxic, metabolic, and structuralencephalopathies. In parallel, the patient should be assessed following a protocol to investigate precipitating factors and undergo blood tests and imaging studies toevaluate liver function and portal-systemic circulation. According to the results, patients are classified as episodic HE, acute-on-chronic liver failure, or terminal liverdisease, and are managed accordingly.

Review

ters, this assessment is not easily available and is limited topatients with cognitive complaints. The main reason for limitingneuropsychological assessment to symptomatic patients is theuncertainty about the implications of establishing a diagnosis ofminimal HE [58]. Although one study has shown that treatmentimproves the patients’ quality of life [31], the actual benefit oftreating mild cognitive impairment is still uncertain [21].

Several studies have shown that the decline in cognitive func-tion that characterizes minimal HE worsens the ability to drive acar [59] and increases the risk of automobile accidents [60].Impaired visuo-motor coordination and working memory isreflected by insufficient navigation skills [61], a key element forproper driving. Attention disturbance and slow mental process-ing reduces the ability to react to unexpected traffic conditions,such as an illegal incursion by another vehicle at an intersection.

Establishing the diagnosis of minimal HE helps to identifypatients at a higher risk of incurring accidents, but does not inval-idate the patient to drive a car [62]. One study observed that thepercentage of patients with minimal HE that experienced trafficaccidents was small (8–16%, depending on the diagnostic test)[60]. Driving is a complex activity that depends on many factors,especially pre-morbid skills. Experienced drivers may compen-sate for the cognitive decline by taking additional precautions[63]. It is recommendable to investigate the presence of minimalHE in cirrhotic patients who drive, but general advice based onthe presence or absence of this condition cannot be given. The


evaluation cannot rely on the patients’ judgment because theyoverestimate their driving abilities [59,32]. A history of recenttraffic violations or minor accidents and the observation ofchanges in driving performance by relatives are important clues.Unfortunately, computer-based tests cannot reliably predict fit-ness to drive and a final recommendation may require consulta-tion with specialized experts [59].

In asymptomatic patients, medical advice about the risk ofaccidents may be more important than treatment for minimalHE. The risk extends to accidental falls [64] and injury when han-dling machinery [21]. It is recommendable (Fig. 5) to screen forcognitive defects that may increase risk, and take preventiveactions. Patients should be asked about their habits when drivingand using machinery. The interview should address recent acci-dents and falls, and include queries to relatives about whetherthey have observed a decline in performance. Some data supportthe value of screening tests [60] for this purpose, but they do notsuffice [28] to recommend a specific test [14]. Each center shoulddecide what test to apply according to the available resources andexperience (Table 2). One easily performed test commonly usedin geriatrics to estimate the risk of falls, the timed ‘‘up and gotest’’, can be helpful [65]. According to the results of the interviewand cognitive testing, general recommendations can be given(e.g. avoid doing other tasks while walking, avoid slipperyground). However, avoiding risk situations is not always possibleor acceptable to the patient. This is often the case when patients

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Asymptomatic patient with cirrhosis

Possible risk of accidents 1. Drivers 2. Handling machinery 3. History of falls

Screening tests for the presence of minimal HE

Consider preventive measures with the patient

Positive results

Additional assessment to confirm risks of driving

Driving issues

Fig. 5. Asymptomatic outpatients with cirrhosis at risk of experiencing an accident should undergo additional tests to investigate the presence of low-grade HE.Preventive measures should be recommended for those with abnormal results. Neuropsychological assessment should be more detailed and may require expert advice inpatients who want to keep on driving.


are advised to quit driving; at this stage, additional evaluation byexperts may be needed.

Cognitive complaints in patients with cirrhosis

Some cirrhosis patients request consultation for cognitive com-plaints or because relatives or coworkers have observed a declinein their performance of social activities. The impact of minimal HEon daily living depends on the cognitive demands [32]. Manypatients, particularly those of advanced age, decrease their activitiesor receive the help of caregivers, and accept the decline as part of thegeneral effects of the disease or the consequence of aging. Althoughthe effect of minimal HE on working performance has not beenstudied directly, cirrhotic patients with minimal HE are more likelyto not be working than those without this condition [66].

Unless cognitive impairment is severe, it is difficult to per-ceive in the clinical examination and requires psychometric test-ing. Common deficits are usually mild and do not interfere ininstrumental activities (shopping, answering the phone, takingpublic transportation) or basic daily life activities (dressing,personal hygiene, eating) [14]. However, deficits in attention,executive function, and psychomotor skills may impair complexactivities (planning a trip, handling finances, gardening, perform-ing a job) and can elicit a consultation. One study in patients withminimal HE related their complaints to a decrease in psychomo-tor performance (‘‘I have difficulty doing handwork. . .’’), impairedattention (‘‘I am confused. . .’’) and poor memory (‘‘I forget alot. . .’’) [66]. The study also found that an important number ofpatients reporting cognitive complaints did not exhibit neuropsy-


chological or neurophysiological abnormalities. The complaintscan have multiple origins and may reflect psycho-affective orhealth problems unrelated to cognition [67]. Discrepanciesbetween complaints and cognitive function are not infrequentin other clinical situations [68]. For this reason, additional assess-ment is needed before low-grade HE can be interpreted as thecause of cognitive complaints.

In most cases, psychometric tests will suffice to establish theorigin of cognitive complaints. However, the results may be diffi-cult to interpret in some cases, because of a low education levelon the part of patients, linguistic barriers, and sensorial defects(sight, hearing) or other handicaps. Furthermore, since neuropsy-chological scores are calculated in relation to normative data,they may not detect a decline in patients who had above-averagepre-morbid performance. In these cases, the best option is to per-form neurophysiological tests, such as electroencephalography orevoked potentials [69]. Normal results are helpful to reassurethat cognitive complaints are not secondary to minimal HE.

Attributing neurological manifestations to HE in complex cases

The diagnosis of HE is based on the presence of neurological man-ifestations that can be attributed to liver failure or portosystemicshunting. In practice, this is done without major difficulties byidentifying the characteristic manifestations, excluding otherneurological disorders, and judging whether the liver disease issevere enough to explain HE. However, in some cases the diag-nosis is difficult, as occurs in patients with normal or onlyslightly abnormal liver tests [70], and those that exhibit unusual

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Review
neurological manifestations or neurological co-morbidities. Thislatter situation is critical when contemplating liver transplanta-tion, a treatment that resolves neurological manifestations sec-ondary to HE [71], but is ineffective for other neurologicaldisorders, such as vascular cognitive impairment and earlyAlzheimer’s disease.
The most common error that occurs when evaluating patientswith prominent neurological manifestations and almost normalliver tests is to miss cirrhosis associated with large portosystemicshunts. A valuable diagnostic test in these cases is CT scanning ofthe liver. Once the condition is properly diagnosed, patientsshould receive adequate treatment for HE [72], which includesavoidance of diuretics, and possibly, occlusion of the shunts.

The best option in patients with cirrhosis and complex neuro-logical manifestations (e.g. behavioral and personality changes,paraparesis, chorea, ataxia) in whom alternative diagnoses havebeen excluded (e.g. hypothyroidism, vitamin B1 deficiency, hypo-glycemia) and psychiatric and neurological consultation has beenobtained, is to perform MR imaging and spectroscopy. The evalua-tion may be completed by searching for portosystemic shunts withabdominal CT scanning and performing an oral glutamine chal-lenge test. As was indicated above, a lack of the typical featuresassociated with HE is a strong argument against the diagnosis.

MR can identify white matter lesions secondary to small-ves-sel cerebral disease. These findings prompt the diagnosis of vascu-lar cognitive impairment [73], which has a pattern of cognitivedeterioration similar to low-grade HE. The lesions show a markedreduction in size with reversal of HE [74]. Thus, their presence,even when extensive, does not imply that the cognitive impair-ment will not improve with transplantation. Similarly, mild tomoderate brain atrophy is found in most patients with persistentHE [75] and does not necessarily indicate progressive dementia. Inpatients with these findings on MR imaging, our practice is toattribute the neurological manifestations to HE if they have a fluc-tuating course and if magnetic resonance spectroscopy of thebrain shows high levels of glutamine and normal or only slightlydecreased levels of n-acetyl-aspartate (a neuronal marker).

Neurological manifestations after liver transplantation

Neurological complications are common after liver transplanta-tion, mainly in the early postoperative period [76]. A frequentmanifestation is acute confusional syndrome (‘‘delirium’’). Neuro-imaging and microbiological investigation are helpful to excludevascular disorders and central nervous system infections, but itis more difficult to ascertain the origin of the syndrome whenthese tests are normal, and the patient has several metabolic dis-turbances or is taking certain drugs. Metabolic encephalopathy isusually considered multifactorial, and treatment is directedtoward correcting the derangements and the judicious use ofpotentially neurotoxic drugs. This condition is more common inpatients with cirrhosis of alcoholic etiology, prior HE, or a severepreoperative situation [77]; the presence of these factors mayhelp to support the diagnosis of a metabolic origin. An unresolvedissue is to what extent an acute confusional syndrome in the post-operative period may be caused by HE. The metabolic distur-bances identified by brain MR spectroscopy take several monthsto normalize [78]. Similarly, portosystemic shunts may persistdespite a normally functioning graft and can be responsible foracute changes in the mental state [79].


Liver transplantation improves HE, even in patients withsevere manifestations [73,80]. Nevertheless, studies that haveassessed neuropsychological function following liver transplanta-tion have challenged the notion of complete reversibility [81].Some sequelae may persist, but most of the patients exhibit nor-mal cognitive function [82]. In a prospective assessment ofpatients up to nine years after liver transplantation, long-termcognitive function was associated with vascular risk factors andsigns of small-vessel cerebral disease on MR imaging [39]. Thus,it is important to prevent ‘‘premature aging’’ of the brain by iden-tifying and treating vascular risk factors, such as diabetes melli-tus and arterial hypertension, and prescribing the smallestpossible dose of immunosuppressive drugs.

Financial support

CIBEREHD is supported by Instituto de Salud Carlos III, Madrid,Spain. The data used to generate the figures in the article wereobtained with the support of a grant from the Spanish Ministryof Health (FIS 07/06419).

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Conflict of interest
The authors who have taken part in this study declared that theydo not have anything to disclose regarding funding or conflict ofinterest with respect to this manuscript.

Acknowledgments

I am indebted to Dr. Alex Rovira and Dr. Juli Alonso, neuroradiol-ogists, Dr. Carlos Jacas, neuropsychologist, and Dr. Rita García-Martinez, hepatologist, for their critical review of the manuscriptand helpful discussions on the diagnosis of HE during severalyears of collaborative work.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.jhep.2010.11.015.

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