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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 en
Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Paseo Vall d’Hebron 119, Barcelona 08035, Spain

Hepatic encephalopathy (HE) is a common complication of cirrhosis that requires careful appraisal of the clinical manifestations, evaluation of the underlying neurological disorders, and
assessment of liver function and the portal-systemic circulation.
This article reviews recent developments in the assessment of
HE and discusses the controversy regarding the use of a categorical or a continuous approach in measuring the severity of this
condition. New scales facilitate effective monitoring and assessment of episodic HE. Neuropsychological test batteries and
neurophysiological tests are of value for evaluating cognitive
function in outpatients and can establish the diagnosis of minimal HE, and the severity of low-grade HE. These tools allow better evaluation of the origin of cognitive complaints and help in
estimating the risk of accidents. It is now possible to complete
the evaluation with measurement of the effects of cognitive
impairment on daily living. In difficult cases, imaging of the brain
and portal-systemic circulation with magnetic resonance imaging is especially helpful. Based on these studies, neurological
signs and symptoms can be attributed to HE in patients with mild
liver disease and in those with complex neurological manifestations. The new methods presented are also valuable for investigating the neurological manifestations occurring after liver
Ó 2010 European Association for the Study of the Liver. Published
by Elsevier B.V. All rights reserved.

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

Keywords: Hepatic encephalopathy; Diagnostic methods; Neuropsychology;
Magnetic resonance; Cirrhosis.
Received 25 July 2010; received in revised form 22 November 2010; accepted 23
November 2010
⇑ Tel.: +34 649877726; fax: +34 932746068.
E-mail address:
Abbreviations: HE, hepatic encephalopathy; HESA, Hepatic Encephalopathy Scaling Algorithm; CHESS, Clinical Hepatic Encephalopathy Staging Scale; PHES, Psychometric Hepatic Encephalopathy Score; RBANS, Repeatable Battery for the
Assessment of Neuropsychological Status; MR, magnetic resonance; FLAIR, fluidattenuation inversion recovery; CT, computed tomography.

hepatocarcinoma, hepatorenal syndrome), the management of
HE patients is not uniform and requires precise assessment of
the neurological and hepatic function [2]. The last decade has
witnessed the development of several new tools that enable:
(a) HE grading, (b) assessment of cognitive performance, (c) diagnosis of minimal HE, (d) evaluation of the consequences in daily
living, (e) imaging of the brain, and (f) evaluation of the portalsystemic circulation. This article reviews the characteristics of
these methods and discusses their use in several clinical scenarios: (a) during an episode of HE, (b) in asymptomatic outpatients,
(c) in determining the origin of cognitive complaints, (d) in attributing neurological manifestations to HE, and (e) in post-transplantation follow-up.

New tools
Clinical scales for grading episodic HE
The neurological manifestations of episodic HE are typically fluctuating and have multiple expressions, which have been
described in detail elsewhere [3]. In clinical practice, these manifestations should be quantified and summarized into a simple
score to facilitate monitoring of the clinical course and the effect
of therapeutic interventions. Clinical scales that evaluate the
presence of a series of neurological manifestations are effective
tools for this purpose. Neurophysiological methods can provide
a more objective assessment and are useful for investigating
the effect of new treatments [4,5].
Standardization of neurological scales for HE is still in the initial phases [6]. The West Haven scale is an arbitrary method that
establishes four stages of HE based on alterations in the state of
consciousness, intellectual function, and behavior, and on neuromuscular signs [7]. The scale includes several manifestations for
each stage, but lacks specific definitions (supplementary Table
1). In clinical practice, doctors do not check for the presence of
all the manifestations listed; instead, they use the scale in an
intuitive 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 not
invalidate the scale in individual cases, but causes discrepancies
between different assessors. This limitation, which is especially
relevant in clinical trials, has been overcome in the various adaptations of the West Haven scale [8,9].
The Hepatic Encephalopathy Scaling Algorithm (HESA) implements objective ways of measuring the parameters of the West

Journal of Hepatology 2011 vol. 54 j 1030–1040

Table 1. Classification of hepatic encephalopathy associated with cirrhosis.






Acute change in mental state induced by: gastrointestinal bleeding,, constipation, excessive protein
intake, infection, renal failure, dehydratation, electrolyte disturbance.
Without recognized precipitating factors. Usually associated with large portosystemic shunts
(spontaneous, surgical, TIPS)


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

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


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 classified

Haven scale [10]. The HESA utilizes clinical indicators combined
with validated neuropsychological tools and well-defined criteria
for each stage (supplementary Table 2). The use of the HESA is
still limited and its metric characteristics have not been fully analyzed [11]. One good favorable characteristic of the HESA is that it
identifies low grades of HE (grade I and II) more precisely, but it
has the drawback of requiring training for proper use.
Another new method is the Clinical Hepatic Encephalopathy
Staging Scale (CHESS) [12]. In comparison to other clinical scales,
the CHESS was developed without a previous arbitrary definition
of the severity of HE. The authors assessed the presence or
absence of 48 items in a group of 36 patients with episodic HE.
The items were selected by a group of experts and were finally
reduced to 9 after applying principal component analysis. The
final CHESS is a linear scale that scores HE from 0 (unimpaired)
to 9 (deep coma) (supplementary Table 3). The CHESS shows
good metric characteristics in terms of internal consistency,
reproducibility, criterion-related validity, and external responsiveness, but it needs to be validated in other patient samples
and other centers.
The HESA and the CHESS, complemented with the Glasgow
Coma Score (1), are adequate for clinical trials. The CHESS is simpler to use, but since direct comparisons with the HESA have not
been performed, it is unknown whether the sensitivity of the two
instruments is similar. For clinical purposes, it may not be necessary to establish many grades. House officers usually employ two
levels of severity of the West Haven instrument, referred to as
West Haven I–II, and West-Haven III–IV. These levels of severity
reflect as to what extent the patient needs support (e.g. prevention of bronchial aspiration, need for artificial nutrition, physical
restraint) and clinical resources (e.g. admission to intensive care,
specialized nursing, intensive monitoring).
Assessment of cognitive performance
The diagnosis of HE is based on the presence of neurological manifestations that are obvious on clinical examination [13]. There is
a good agreement between observers in grading patients who
exhibit severe manifestations or are completely alert, but categorization often varies between raters in patients who exhibit mild
disturbances [11]. The term overt is used to emphasize the presence of clear neurological manifestations and the term covert

refers to disturbances that can only be recognized with specialized tests.
The traditional view is that HE progress from unimpaired cognition (normal psychometric tests and normal clinical examination), to minimal HE (abnormal psychometric tests and normal
clinical examination), to grade I–II HE (abnormal psychometric
tests and abnormal clinical examination), and to grade III–IV HE
(psychometric tests cannot be applied due to decreased consciousness). However, the current trend is to interpret the neurocognitive impairment as a continuum and promote the use of
cognitive ratings instead of categorical divisions [14]. As represented in Fig. 1, patients may exhibit cognitive impairment in
the context of an acute confusional syndrome (episodic HE).
Those with chronic cognitive impairment can be classified by
severity as having low-grade HE [15], which may be covert or
overt, or dementia (if the deficit is severe and lasts long enough).
The terms used for those with dementia are severe persistent HE
or acquired hepatocerebral degeneration (when associated with
motor disturbances: parkinsonism, chorea, myelopathy. . .).
In patients with apparently unimpaired mental status or chronic
low-grade HE, assessment of cognition can benefit from the application of neuropsychological tests that quantify brain dysfunction
and evaluate various cognitive domains [16]. These instruments
are preferred over neurophysiological tests and other biological
markers, as they directly measure cognitive functions (e.g. memory,
attention, or visuospatial skills) that are relevant to the activities of
daily living. Psychometric tests are not adequate for patients with a
decreased level of consciousness; hence, confusion should be
excluded before beginning neuropsychological testing. This is
easily done with the four questions provided in the Confusion
Assessment Method (CAM) [17] (supplementary Table 4).
Extended neuropsychological assessment is the best way to
demonstrate cognitive deficits. Patients complete a series of tests,
the results of which are compared to normative standards and
interpreted by a neuropsychologist. Ideally, scores are adjusted
for age, gender, and education level. Usually, the examiner selects
a basic battery of psychometric tests attending to cultural and
social parameters, available normative data, and prior experience.
Additional tests are brought in, to further explore the domains
that appear impaired in the basic assessment. The final diagnosis
(presence or absence of cognitive impairment) depends on inter-

Journal of Hepatology 2011 vol. 54 j 1030–1040



Continuous approach

Categorical approach
















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 categories
are arbitrary and vary between raters. In the continuous approach, patients may be unimpaired (lack of cognitive impairment) or impaired (unstable or stable), and may move
from 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 are
impaired, 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 severe
cognitive deficits (dementia) are diagnosed as having persistent severe HE or acquired hepatocerebral degeneration (when associated with motor manifestations). There is some
overlapping between the grades of the categorical approach and the situations defined in the continuous approach, but there is no direct correspondence.

pretation of the test results and observation of the patient’s
behavior. The pattern of neuropsychological impairment suggests
the type of disorder, but the neuropsychological profile alone is
not diagnostic of a specific disease.
Short neuropsychological test batteries, developed to facilitate
the diagnosis of the cognitive status in several neurological diseases, are an alternative to extended neuropsychological assessment. These batteries include a limited number of tests that
can be given by trained technicians, and typically take less than
30 min to complete. The tests examine those cognitive domains
that are expected to be abnormal in a certain disease. It is common practice to consider abnormal scores as those >1.5–2 SD
below the reference population mean.
A series of short neuropsychological batteries [18,19] are
available to assess patients with cirrhosis (Table 2); some of them
have computerized versions [20]. Short batteries are more heavily weighted to detect deficits that characterize low-grade HE:
impairment in attention, executive function, psychomotor abilities, and speed of information processing. They are typically performed in patients in a chronic non-fluctuating situation, in
whom confusion has been excluded. These batteries can quantify
the cognitive impairment present in minimal HE and in mild persistent HE, but they do not differentiate between these situations,
because it depends on the threshold that is chosen to distinguish
covert from overt HE. Recommendations and therapeutic measures can be established based on the results [21]. When
repeated testing is performed (e.g. to monitor the effect of therapy) it is important to control for learning effects. Parallel versions of the same test could lessen this effect, but few tests
have well-standardized parallel versions. The choice of which

battery to use should be based on the availability of local translations 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 consequences
on daily living even though patients are asymptomatic [23] has
led to the need for screening tests. These tests should be easy
to use, and quantifiable in a few minutes. Several simple computerized tests have been developed for this purpose, and they are
reliable in repeated testing (Table 2). Most of them essentially
assess one cognitive domain: attention deficit and slow information processing, which are the most prominent disturbances in
minimal HE [24].
Various authors have proposed that an abnormal test result is
sufficient to establish the diagnosis of minimal HE [25–27]. However, the tests are not specific and can be easily affected by several factors, such as patient anxiety or fatigue, and other
circumstantial elements that act as distracters. Few studies have
compared this group of tests to short neuropsychological batteries [22] or extended neuropsychological assessment. Furthermore, the use of these tests in populations different from the
one included in the original description has yielded conflicting
results, with a high number of abnormal results in control groups
[28]. For this reason, it is recommendable to confirm the cognitive impairment with additional neuropsychological assessments
before making clinical decisions, such as initiating treatment for
minimal HE.

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




Extended neuropsychological assessment

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

Diagnosis based on expert

RBANS [18]

Short battery (paper-pencil tests)

Large normative data
Available in multiple languages
Most studies in Alzheimer’s diseases
Few 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

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

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

Scan test [27]

Computerized neuropsychological

Recognition task based on the Sternberg paradigm
Studies 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 to
determine as to what extent the cognitive deficits affect daily life
[29]. This can be done in a systematic manner with the aid of
questionnaires. The SF-36 and the Chronic Liver Disease Questionnaire have been extensively used in patients with cirrhosis.
These easily administered questionnaires can detect a decrease
in quality of life associated with minimal HE [30]. They are, however, probably less sensitive than the Sickness Impact Profile, a
long questionnaire (136 items) that covers numerous aspects of
daily living and has been shown to detect the benefits of therapeutic interventions [31].
Patient interview alone does not suffice to determine the consequences of cognitive deficits on daily living [32]. The patients’
relatives perceive cognitive deficits better than they themselves
do, and for this reason relatives of patients with dementia are
interviewed with tools such as the Informant Questionnaire on
Cognitive Decline in the Elderly (IQCODE). Another of these, the
Clinical Global Assessment of HE (CGA-HE), is an attractive
approach developed by Dr. C. Randolph that is currently under
validation. The CGA-HE obtains information on cognitive, motor,
and functional status by interviewing the patient and a caregiver
or family member, and provides a final score.
Magnetic resonance of the brain
Magnetic resonance (MR) of the brain has become a standard technique for assessing patients with neurological manifestations. In
patients with cirrhosis, MR is useful to exclude alternative diagno-

ses, such a Wernicke’s encephalopathy, viral encephalitis, and
stroke. In addition, MR can detect a series of abnormalities [33]
that are characteristically present in the brain of cirrhosis patients
who develop HE:
(a) Deposition of paramagnetic substances in the basal
ganglia. These substances cause a high signal intensity on
T1-weighted imaging, characteristically at the globus
pallidus [34]. The hyperintensity probably corresponds to
manganese deposition secondary to portosystemic shunting, and it may be present in the absence of cirrhosis or
secondary to other causes of manganese deposition [35].
The intensity of the signaI is not related to the severity
of HE [36], but the absence of T1 hyperintensity in a
patient with cirrhosis and neurological manifestations
suggests that the neurological symptoms are not caused
by HE.
(b) A decrease in the size of the brain. Brain atrophy has been
characteristically associated with cirrhosis, particularly
cases in which the etiology is related to alcohol abuse
[37]. The decrease in brain parenchyma is more pronounced in specific areas, such as the frontal lobes and cerebellum. The mechanism by which cirrhosis induces brain
atrophy is not known, but appears to be related to chronic
portosystemic shunting and ammonia exposure [38]. The
decrease in brain volume caused by alcohol recovers
(at least partially) after abstinence. The coexistence of
low-grade brain edema may make recognition of atrophy
difficult, but it can become more evident after liver transplantation [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 hyperintense
focal white matter lesions (leukoaraiosis) that decrease in volume after the resolution of HE. (B) (MR-spectroscopy) at follow-up shows decrease of the high glutaminecontaining (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).

(c) An increase in brain water. Brain edema has been demonstrated using sophisticated MR techniques in patients with
chronic liver failure [40] and by laboratory methods in
experimental models [41]. The location and severity of
edema seems to differ according to the duration of liver
failure and the degree of hyperammonemia. Chronic liver
failure induces low-grade interstitial brain edema [42],
whereas acute liver failure causes intracellular edema that
can be severe and lead to brain herniation [43]. In conventional MR techniques, brain water changes are reflected as
an increase in signal intensity on fast-FLAIR imaging in
periventricular regions, and as focal white matter lesions
(Fig. 2-A) or lesions along the corticospinal tract [33]. Diffusion-weighted maps typically show an increase in the
apparent diffusion coefficient in chronic liver failure and a
decrease during episodic HE that is more apparent in certain
areas [44].
(d) Changes in organic osmolytes and ammonia related-metabolites. MR-spectroscopy of the brain shows a typical pattern

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

Assessment of portosystemic shunting
The importance of portosystemic shunting in inducing HE is well
known from the experience with surgical shunts and transjugular
intrahepatic portosystemic shunts (TIPS) [48]. The development
of HE is rare in the absence of significant liver disease, but not
exceptional [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 computed tomography (CT) (Fig. 3), MR, and endoscopic ultrasonography. Portal flow steal is a critical mechanism in the induction
of HE in these patients [50]. The arterial concentration of substances with a high first-pass metabolism, such as ammonia, is
highly dependent on portal flow. This fact offers the possibility
of exploring the functional consequences of the shunts. The oral
glutamine challenge test consists in the measurement of plasma
ammonia after ingestion of glutamine in a fasting state [51]. The
test has not been standardized and normal values are based on
the experience of independent investigators [49,52]. In our experience, oral glutamine challenge is very helpful for assessing complex clinical situations. We have observed flat ammonia curves in
some patients with cirrhosis and abnormal psychometric tests,
and interpret this finding as a strong argument against attributing cognitive disturbances to HE. This interpretation is supported
by the theoretical basis and the outcomes in cases where we had
the opportunity to assess.
Approach to patients
Episodic HE
Patients with cirrhosis and an acute change in mental state
should be managed following a protocol that will exclude alternative neurological disorders, search for precipitating factors,
and assess predisposing conditions (Fig. 4). HE episodes have
been traditionally related to the occurrence of a precipitating
factor, which can be defined as a clinical event that does not
cause direct injury to the liver or portal-systemic circulation
and is responsible for the acute change in mental status. Precipitating factors appear to act by increasing the generation of
putative toxins or enhancing the effects of toxins on the central
nervous system. They are temporally related to the development of HE, and their correction to re-establishment of consciousness. Several factors are commonly considered under
this category (gastrointestinal bleeding, constipation, excessive
protein intake, dehydration, electrolyte disturbances, renal failure, and infection), and are thought to explain the majority of
HE episodes. However, a significant number of episodes are
not related to a precipitating factor [53].

Patients that have experienced an episode of HE should
undergo liver function testing and imaging of the liver and portal-systemic circulation to investigate the presence of predisposing conditions. These may be defined as disturbances in liver
function and portal-systemic circulation that facilitate the development of episodic HE. These conditions are present for a longer
time than the precipitating factor, and they may be difficult to
relate to the acute episode. Liver function disturbances can
develop over a short period of time (weeks) in relation to an insult
(e.g. alcohol) that usually causes a severe, but potentially reversible, inflammatory injury. This situation has been proposed to be
termed acute-on-chronic liver failure [54] and should be managed
separately from episodic HE. Multiple factors that may interfere
directly with mental status are involved (e.g. sepis, circulatory
dysfunction, respiratory failure, etc. . .). These factors require specific therapeutic approaches in addition to measures for HE. On
other occasions (e.g. advanced hepatocarcinoma), liver function
disturbances develop slowly to a terminal stage that is suspected
by progressive deterioration of the performance status, which precedes the appearance of HE. Portal-systemic circulation disturbances can either be caused by the presence of a TIPS or a
surgically induced portosystemic shunt, as well as by the existence
of large, spontaneous portosystemic shunts [55]. Recognition of
spontaneous shunts is important, because occlusion is a treatment
option in patients with recurrent HE and good hepatocellular function (low bilirubin) [56]. One interesting recent observation is the
identification of specific polymorphisms in the glutaminase gene
that may increase intestinal glutaminase activity and predispose
affected individuals to the development of episodic HE [57]. If
these findings are confirmed, genetic polymorphism should be
included in the group of predisposing conditions. Apart from identifying high-risk patients, polymorphism assessment may initiate
an era of personalized medicine in the field of HE.
Asymptomatic outpatient with cirrhosis
Neuropsychological impairment, which is common among
outpatients with cirrhosis, is frequently asymptomatic and in
many cases not perceived by the physician (minimal or covert
HE). Assessment of cognitive function requires the use of psychometric tests under neuropsychological supervision. In many cen-

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Cirrhosis + acute change in mental state

Exclusion of alternative
neurological disorders

Medical history + physical exam:
presence of headache, focal
neurological signs, meningeal signs
Basic analysis: glycemia, PCO2
Toxics in blood or urine:
benzodiacepines (consider
flumazenil if suspicous), alcohol…
Assess B1 deficit in blood (or give
thiamine if suspicion)
Neuroimaging (CT, MR) if any
abnormality in 1 or coma (unless
rapid improvement).
EEG if suspicion of seizures or nonconvulsive status.

Search of precipitating factors

Medical history + physical exam: explore signs of gastrointestinal
bleeding, constipation, dehydration, infection (fever, localized signs)
Basic analysis: Hemoglobin, leukocytes, creatinine, Na, K, pH,
Leukocytes in urine and ascites (if present)
X-rays (thorax and abdomen).
Cultures of blood, urine, ascites or other body fluids (if abnormal)


Medical history+physical exam: signs of complications of cirrhosis
Blood test: bilirubin, albumin, prothrombin, AST, ALT
Imaging of liver and portal-systemic circulation: CT, MR…

Liver function and portal-systemic circulation

Acute-on-chronic liver failure

Episodic HE


Factor that induces injury (alcohol, infection..), usually
Recent decompensation (2-4 weeks)
Jaundice (bilirubin > 5 mg/dl)
Circulatory dysfunction (hypotension, renal failure…)

Prior to HE: good performance
precipitating factor or
large portosystemic shunts

Prior to HE: low performance
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 structural
encephalopathies. In parallel, the patient should be assessed following a protocol to investigate precipitating factors and undergo blood tests and imaging studies to
evaluate liver function and portal-systemic circulation. According to the results, patients are classified as episodic HE, acute-on-chronic liver failure, or terminal liver
disease, and are managed accordingly.

ters, this assessment is not easily available and is limited to
patients with cognitive complaints. The main reason for limiting
neuropsychological assessment to symptomatic patients is the
uncertainty about the implications of establishing a diagnosis of
minimal HE [58]. Although one study has shown that treatment
improves the patients’ quality of life [31], the actual benefit of
treating mild cognitive impairment is still uncertain [21].
Several studies have shown that the decline in cognitive function that characterizes minimal HE worsens the ability to drive a
car [59] and increases the risk of automobile accidents [60].
Impaired visuo-motor coordination and working memory is
reflected by insufficient navigation skills [61], a key element for
proper driving. Attention disturbance and slow mental processing 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 identify
patients at a higher risk of incurring accidents, but does not invalidate the patient to drive a car [62]. One study observed that the
percentage of patients with minimal HE that experienced traffic
accidents 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 compensate for the cognitive decline by taking additional precautions
[63]. It is recommendable to investigate the presence of minimal
HE in cirrhotic patients who drive, but general advice based on
the presence or absence of this condition cannot be given. The

evaluation cannot rely on the patients’ judgment because they
overestimate their driving abilities [59,32]. A history of recent
traffic violations or minor accidents and the observation of
changes in driving performance by relatives are important clues.
Unfortunately, computer-based tests cannot reliably predict fitness to drive and a final recommendation may require consultation with specialized experts [59].
In asymptomatic patients, medical advice about the risk of
accidents may be more important than treatment for minimal
HE. The risk extends to accidental falls [64] and injury when handling machinery [21]. It is recommendable (Fig. 5) to screen for
cognitive defects that may increase risk, and take preventive
actions. Patients should be asked about their habits when driving
and using machinery. The interview should address recent accidents and falls, and include queries to relatives about whether
they have observed a decline in performance. Some data support
the value of screening tests [60] for this purpose, but they do not
suffice [28] to recommend a specific test [14]. Each center should
decide what test to apply according to the available resources and
experience (Table 2). One easily performed test commonly used
in geriatrics to estimate the risk of falls, the timed ‘‘up and go
test’’, can be helpful [65]. According to the results of the interview
and cognitive testing, general recommendations can be given
(e.g. avoid doing other tasks while walking, avoid slippery
ground). However, avoiding risk situations is not always possible
or acceptable to the patient. This is often the case when patients

Journal of Hepatology 2011 vol. 54 j 1030–1040

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
Positive results
Consider preventive measures
with the patient

Additional assessment to
confirm risks of driving

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 in
patients who want to keep on driving.

are advised to quit driving; at this stage, additional evaluation by
experts may be needed.
Cognitive complaints in patients with cirrhosis
Some cirrhosis patients request consultation for cognitive complaints or because relatives or coworkers have observed a decline
in their performance of social activities. The impact of minimal HE
on daily living depends on the cognitive demands [32]. Many
patients, particularly those of advanced age, decrease their activities
or receive the help of caregivers, and accept the decline as part of the
general effects of the disease or the consequence of aging. Although
the effect of minimal HE on working performance has not been
studied directly, cirrhotic patients with minimal HE are more likely
to not be working than those without this condition [66].
Unless cognitive impairment is severe, it is difficult to perceive in the clinical examination and requires psychometric testing. Common deficits are usually mild and do not interfere in
instrumental activities (shopping, answering the phone, taking
public transportation) or basic daily life activities (dressing,
personal hygiene, eating) [14]. However, deficits in attention,
executive function, and psychomotor skills may impair complex
activities (planning a trip, handling finances, gardening, performing a job) and can elicit a consultation. One study in patients with
minimal HE related their complaints to a decrease in psychomotor performance (‘‘I have difficulty doing handwork. . .’’), impaired
attention (‘‘I am confused. . .’’) and poor memory (‘‘I forget a
lot. . .’’) [66]. The study also found that an important number of
patients reporting cognitive complaints did not exhibit neuropsy-

chological or neurophysiological abnormalities. The complaints
can have multiple origins and may reflect psycho-affective or
health problems unrelated to cognition [67]. Discrepancies
between complaints and cognitive function are not infrequent
in other clinical situations [68]. For this reason, additional assessment is needed before low-grade HE can be interpreted as the
cause of cognitive complaints.
In most cases, psychometric tests will suffice to establish the
origin of cognitive complaints. However, the results may be difficult to interpret in some cases, because of a low education level
on the part of patients, linguistic barriers, and sensorial defects
(sight, hearing) or other handicaps. Furthermore, since neuropsychological scores are calculated in relation to normative data,
they may not detect a decline in patients who had above-average
pre-morbid performance. In these cases, the best option is to perform neurophysiological tests, such as electroencephalography or
evoked potentials [69]. Normal results are helpful to reassure
that 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 manifestations that can be attributed to liver failure or portosystemic
shunting. In practice, this is done without major difficulties by
identifying the characteristic manifestations, excluding other
neurological disorders, and judging whether the liver disease is
severe enough to explain HE. However, in some cases the diagnosis is difficult, as occurs in patients with normal or only
slightly abnormal liver tests [70], and those that exhibit unusual

Journal of Hepatology 2011 vol. 54 j 1030–1040


neurological manifestations or neurological co-morbidities. This
latter situation is critical when contemplating liver transplantation, a treatment that resolves neurological manifestations secondary to HE [71], but is ineffective for other neurological
disorders, such as vascular cognitive impairment and early
Alzheimer’s disease.
The most common error that occurs when evaluating patients
with prominent neurological manifestations and almost normal
liver tests is to miss cirrhosis associated with large portosystemic
shunts. A valuable diagnostic test in these cases is CT scanning of
the liver. Once the condition is properly diagnosed, patients
should receive adequate treatment for HE [72], which includes
avoidance of diuretics, and possibly, occlusion of the shunts.
The best option in patients with cirrhosis and complex neurological manifestations (e.g. behavioral and personality changes,
paraparesis, chorea, ataxia) in whom alternative diagnoses have
been excluded (e.g. hypothyroidism, vitamin B1 deficiency, hypoglycemia) and psychiatric and neurological consultation has been
obtained, is to perform MR imaging and spectroscopy. The evaluation may be completed by searching for portosystemic shunts with
abdominal CT scanning and performing an oral glutamine challenge test. As was indicated above, a lack of the typical features
associated with HE is a strong argument against the diagnosis.
MR can identify white matter lesions secondary to small-vessel cerebral disease. These findings prompt the diagnosis of vascular cognitive impairment [73], which has a pattern of cognitive
deterioration similar to low-grade HE. The lesions show a marked
reduction in size with reversal of HE [74]. Thus, their presence,
even when extensive, does not imply that the cognitive impairment will not improve with transplantation. Similarly, mild to
moderate brain atrophy is found in most patients with persistent
HE [75] and does not necessarily indicate progressive dementia. In
patients with these findings on MR imaging, our practice is to
attribute the neurological manifestations to HE if they have a fluctuating course and if magnetic resonance spectroscopy of the
brain shows high levels of glutamine and normal or only slightly
decreased levels of n-acetyl-aspartate (a neuronal marker).

Liver transplantation improves HE, even in patients with
severe manifestations [73,80]. Nevertheless, studies that have
assessed neuropsychological function following liver transplantation have challenged the notion of complete reversibility [81].
Some sequelae may persist, but most of the patients exhibit normal cognitive function [82]. In a prospective assessment of
patients up to nine years after liver transplantation, long-term
cognitive function was associated with vascular risk factors and
signs of small-vessel cerebral disease on MR imaging [39]. Thus,
it is important to prevent ‘‘premature aging’’ of the brain by identifying and treating vascular risk factors, such as diabetes mellitus and arterial hypertension, and prescribing the smallest
possible 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 were
obtained with the support of a grant from the Spanish Ministry
of Health (FIS 07/06419).

Neurological manifestations after liver transplantation
Neurological complications are common after liver transplantation, mainly in the early postoperative period [76]. A frequent
manifestation is acute confusional syndrome (‘‘delirium’’). Neuroimaging and microbiological investigation are helpful to exclude
vascular disorders and central nervous system infections, but it
is more difficult to ascertain the origin of the syndrome when
these tests are normal, and the patient has several metabolic disturbances or is taking certain drugs. Metabolic encephalopathy is
usually considered multifactorial, and treatment is directed
toward correcting the derangements and the judicious use of
potentially neurotoxic drugs. This condition is more common in
patients with cirrhosis of alcoholic etiology, prior HE, or a severe
preoperative situation [77]; the presence of these factors may
help to support the diagnosis of a metabolic origin. An unresolved
issue is to what extent an acute confusional syndrome in the postoperative period may be caused by HE. The metabolic disturbances identified by brain MR spectroscopy take several months
to normalize [78]. Similarly, portosystemic shunts may persist
despite a normally functioning graft and can be responsible for
acute changes in the mental state [79].


Journal of Hepatology 2011 vol. 54 j 1030–1040

Conflict of interest
The authors who have taken part in this study declared that they
do not have anything to disclose regarding funding or conflict of
interest with respect to this manuscript.
I am indebted to Dr. Alex Rovira and Dr. Juli Alonso, neuroradiologists, Dr. Carlos Jacas, neuropsychologist, and Dr. Rita GarcíaMartinez, hepatologist, for their critical review of the manuscript
and helpful discussions on the diagnosis of HE during several
years of collaborative work.

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