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New assessment of hepatic encephalopathy

  • Juan Córdoba
    Correspondence
    Tel.: +34 649877726; fax: +34 932746068.
    Affiliations
    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
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Open AccessPublished:December 09, 2010DOI:https://doi.org/10.1016/j.jhep.2010.11.015
      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 transplantation.

      Keywords

      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 (fluid-attenuation inversion recovery), CT (computed tomography)

      Introduction

      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 [
      • Ferenci P.
      • Lockwood A.
      • Mullen K.
      • Tarter R.
      • Weissenborn K.
      • Blei A.T.
      Hepatic encephalopathy–definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998.
      ]. 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, hepatocarcinoma, hepatorenal syndrome), the management of HE patients is not uniform and requires precise assessment of the neurological and hepatic function [
      • Cordoba J.
      • Minguez B.
      Hepatic encephalopathy.
      ]. 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 portal-systemic 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.
      Table 1Classification of hepatic encephalopathy associated with cirrhosis.
      The classification is based on the consensus of Vienna
      • Ferenci P.
      • Lockwood A.
      • Mullen K.
      • Tarter R.
      • Weissenborn K.
      • Blei A.T.
      Hepatic encephalopathy–definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998.
      .
      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 separately.

      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 [
      • Adams R.D.
      • Foley J.M.
      The neurological disorder associated with liver disease.
      ]. 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 [
      • Weissenborn K.
      • Scholz M.
      • Hinrichs H.
      • Wiltfang J.
      • Schmidt F.W.
      • Kunkel
      Neurophysiological assessment of early hepatic encephalopathy.
      ,
      • Amodio P.
      • Gatta A.
      Neurophysiological investigation of hepatic encephalopathy.
      ].
      Standardization of neurological scales for HE is still in the initial phases [
      • Mullen K.D.
      Review of the final report of the 1998 Working Party on definition, nomenclature and diagnosis of hepatic encephalopathy.
      ]. 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 [
      • Conn H.O.
      The hepatic encephalopathies.
      ]. 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 [
      • Gyr K.
      • Meier R.
      • Haussler J.
      • Bouletreau P.
      • Fleig W.E.
      • Gatta A.
      • et al.
      Evaluation of the efficacy and safety of flumazenil in the treatment of portal systemic encephalopathy: a double blind, randomised, placebo controlled multicentre study.
      ,
      • Cordoba J.
      • Lopez-Hellin J.
      • Planas M.
      • Sabin P.
      • Sanpedro F.
      • Castro F.
      • et al.
      Normal protein diet for episodic hepatic encephalopathy: results of a randomized study.
      ].
      The Hepatic Encephalopathy Scaling Algorithm (HESA) implements objective ways of measuring the parameters of the West Haven scale [
      • Hassanein T.I.
      • Hilsabeck R.C.
      • Perry W.
      Introduction to the Hepatic Encephalopathy Scoring Algorithm (HESA).
      ]. 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 [
      • Hassanein T.
      • Blei A.T.
      • Perry W.
      • Hilsabeck R.
      • Stange J.
      • Larsen F.S.
      • et al.
      Performance of the hepatic encephalopathy scoring algorithm in a clinical trial of patients with cirrhosis and severe hepatic encephalopathy.
      ]. 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) [
      • Ortiz M.
      • Cordoba J.
      • Doval E.
      • Jacas C.
      • Pujadas F.
      • Esteban R.
      • et al.
      Development of a clinical hepatic encephalopathy staging scale.
      ]. 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 [
      • Lockwood A.H.
      “What is in a name?” Improving the care of cirrhotics.
      ]. 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 [
      • Hassanein T.
      • Blei A.T.
      • Perry W.
      • Hilsabeck R.
      • Stange J.
      • Larsen F.S.
      • et al.
      Performance of the hepatic encephalopathy scoring algorithm in a clinical trial of patients with cirrhosis and severe hepatic encephalopathy.
      ]. 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 [
      • Bajaj J.S.
      • Wade J.B.
      • Sanyal A.J.
      Spectrum of neurocognitive impairment in cirrhosis: Implications for the assessment of hepatic encephalopathy.
      ]. 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 [
      • Haussinger D.
      • Cordoba J.
      • Kircheis G.
      • Vilstrup H.
      • Blei A.T.
      Definition and assessment of low grade hepatic encephalopathy.
      ], 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…).
      Figure thumbnail gr1
      Fig. 1Cognitive 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.
      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 [
      • Randolph C.
      • Hilsabeck R.
      • Kato A.
      • Kharbanda P.
      • Li Y.Y.
      • Mapelli D.
      • et al.
      Neuropsychological assessment of hepatic encephalopathy: ISHEN practice guidelines.
      ]. 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) [
      • Inouye S.K.
      • van Dyck C.H.
      • Alessi C.A.
      • Balkin S.
      • Siegal A.P.
      • Horwitz R.I.
      Clarifying confusion: the confusion assessment method. A new method for detection of delirium.
      ] (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 interpretation 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 [
      • Mooney S.
      • Hasssanein T.I.
      • Hilsabeck R.C.
      • Ziegler E.A.
      • Carlson M.
      • Maron L.M.
      • et al.
      Utility of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in patients with end-stage liver disease awaiting liver transplant.
      ,
      • Weissenborn K.
      • Ennen J.C.
      • Rückert N.
      • Hecker H.
      Neuropsychological characterization of hepatic encephalopathy.
      ] are available to assess patients with cirrhosis (Table 2); some of them have computerized versions [
      • Mardini H.
      • Saxby B.K.
      • Record C.O.
      Computerized psychometric testing in minimal encephalopathy and modulation by nitrogen challenge and liver transplant.
      ]. 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 [
      • Ortiz M.
      • Jacas C.
      • Cordoba J.
      Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations.
      ]. 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 [
      • Randolph C.
      • Hilsabeck R.
      • Kato A.
      • Kharbanda P.
      • Li Y.Y.
      • Mapelli D.
      • et al.
      Neuropsychological assessment of hepatic encephalopathy: ISHEN practice guidelines.
      ].
      Table 2Neuropsychological tools for the diagnosis of cognitive deficits in patients with cirrhosis.
      RBANS: Repeatable Battery for the Assessment of Neuropsychological Status.
      PHES: Psychometric Hepatic Encephalopathy Score.

      Screening tests for minimal HE

      Minimal HE is a highly prevalent asymptomatic disturbance, especially in patients with advanced disease (Child-Pugh B/C) [
      • Romero-Gomez M.
      • Cordoba J.
      • Jover R.
      • del Olmo J.A.
      • Ramirez M.
      • Rey R.
      • et al.
      Value of the critical flicker frequency in patients with minimal hepatic encephalopathy.
      ]. The fact that minimal HE can have important consequences on daily living even though patients are asymptomatic [
      • Quero J.C.
      • Schalm S.W.
      Subclinical hepatic encephalopathy.
      ] 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 [
      • McMcrea M.
      • Cordoba J.
      • Vessey G.
      • Blei A.T.
      • Randolph C.
      Neuropsychological characterization and detection of subclinical hepatic encephalopathy.
      ].
      Various authors have proposed that an abnormal test result is sufficient to establish the diagnosis of minimal HE [
      • Kircheis G.
      • Wettstein M.
      • Timmermann L.
      • Schnitzler A.
      • Haussinger D.
      Critical flicker frequency for quantification of low-grade hepatic encephalopathy.
      ,
      • Bajaj J.S.
      • Saeian K.
      • Verber M.D.
      • Hischke D.
      • Hoffmann R.G.
      • Franco J.
      • et al.
      Inhibitory control test is a simple method to diagnose minimal hepatic encephalopathy and predict development of overt hepatic encephalopathy.
      ,
      • Amodio P.
      • Marchetti P.
      • Del Piccolo F.
      • Rizzo C.
      • Iemmolo R.
      • Caregaro L.
      • et al.
      Study on the Sternberg paradigm in cirrhotic patients without hepatic encephalopathy.
      ]. 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 [
      • Romero-Gomez M.
      • Cordoba J.
      • Jover R.
      • del Olmo J.A.
      • Ramirez M.
      • Rey R.
      • et al.
      Value of the critical flicker frequency in patients with minimal hepatic encephalopathy.
      ] 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 [

      Amodio P, Ridola L, Schiff S, Montagnese S, Pasquale C, Nardelli S et al. Improving detection of minimal hepatic encephalopathy using the inhibitory control task. Gastroenterology 2010.

      ]. 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.

      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 [
      • Groeneweg M.
      • Quero J.C.
      • de Bruijn I.
      • Hartmann I.J.
      • Essink-Bot M.L.
      • Hop W.C.
      • et al.
      Subclinical hepatic encephalopathy impairs daily functioning.
      ]. 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 [
      • Les I.
      • Doval E.
      • Flavia M.
      • Jacas C.
      • Cardenas G.
      • Esteban R.
      • et al.
      Quality of life in cirrhosis is related to potentially treatable factors.
      ]. 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 [
      • Prasad S.
      • Dhiman R.K.
      • Duseja A.
      • Chawla Y.K.
      • Sharma A.
      • Agarwal R.
      Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy.
      ].
      Patient interview alone does not suffice to determine the consequences of cognitive deficits on daily living [
      • Bajaj J.S.
      • Saeian K.
      • Hafeezullah M.
      • Hoffmann R.G.
      • Hammeke T.A.
      Patients with minimal hepatic encephalopathy have poor insight into their driving skills.
      ]. 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 diagnoses, such a Wernicke’s encephalopathy, viral encephalitis, and stroke. In addition, MR can detect a series of abnormalities [
      • Rovira A.
      • Alonso J.
      • Cordoba J.
      MR imaging findings in hepatic encephalopathy.
      ] 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 [
        • Kulisevsky J.
        • Pujol J.
        • Balanzo J.
        • Junque C.
        • Deus J.
        • Capdevila A.
        • et al.
        Pallidal hyperintensity on magnetic resonance imaging in cirrhotic patients: clinical correlations.
        ]. 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 [
        • Morgan M.Y.
        Noninvasive neuroinvestigation in liver disease.
        ]. The intensity of the signaI is not related to the severity of HE [
        • Spahr L.
        • Butterworth R.F.
        • Fontaine S.
        • Bui L.
        • Therrien G.
        • Milette P.C.
        • et al.
        Increased blood manganese in cirrhotic patients: relationship to pallidal magnetic resonance signal hyperintensity and neurological symptoms.
        ], 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 [
        • Thuluvath P.J.
        • Edwin D.
        • Yue N.C.
        • deVilliers C.
        • Hochman S.
        • Klein A.
        Increased signals seen in globus pallidus in T1-weighted magnetic resonance imaging in cirrhotics are not suggestive of chronic hepatic encephalopathy.
        ]. 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 [
        • Butterworth R.F.
        Neuronal cell death in hepatic encephalopathy.
        ]. 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 [
        • Garcia M.R.
        • Rovira A.
        • Alonso J.
        • Aymerich F.X.
        • Huerga E.
        • Jacas C.
        • et al.
        A long-term study of changes in the volume of brain ventricles and white matter lesions after successful liver transplantation.
        ].
      • (c)
        An increase in brain water. Brain edema has been demonstrated using sophisticated MR techniques in patients with chronic liver failure [
        • Shah N.J.
        • Neeb H.
        • Kircheis G.
        • Engels P.
        • Haussinger D.
        • Zilles K.
        Quantitative cerebral water content mapping in hepatic encephalopathy.
        ] and by laboratory methods in experimental models [
        • Chavarria L.
        • Oria M.
        • Romero J.
        • Alonso J.
        • Lope-Piedrafita S.
        • Cordoba J.
        Diffusion tensor imaging supports the cytotoxic origin of brain edema in a rat model of acute liver failure.
        ]. 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 [
        • Kale R.A.
        • Gupta R.K.
        • Saraswat V.A.
        • Hasan K.M.
        • Trivedi R.
        • Mishra A.M.
        • et al.
        Demonstration of interstitial cerebral edema with diffusion tensor MR imaging in type C hepatic encephalopathy.
        ], whereas acute liver failure causes intracellular edema that can be severe and lead to brain herniation [
        • Rai V.
        • Nath K.
        • Saraswat V.A.
        • Purwar A.
        • Rathore R.K.
        • Gupta R.K.
        Measurement of cytotoxic and interstitial components of cerebral edema in acute hepatic failure by diffusion tensor imaging.
        ]. 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 [
        • Rovira A.
        • Alonso J.
        • Cordoba J.
        MR imaging findings in hepatic encephalopathy.
        ]. 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 [
        • McKinney A.M.
        • Lohman B.D.
        • Sarikaya B.
        • Uhlmann E.
        • Spanbauer J.
        • Singewald T.
        • et al.
        Acute hepatic encephalopathy: diffusion-weighted and fluid-attenuated inversion recovery findings, and correlation with plasma ammonia level and clinical outcome.
        ].
        Figure thumbnail gr2
        Fig. 2MR 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 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).
      • (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) [
        • Kreis R.
        • Ross B.D.
        • Farrow N.A.
        • Ackerman Z.
        Metabolic disorders of the brain in chronic hepatic encephalopathy detected with H-1 MR spectroscopy.
        ]. 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 choline-containing compounds) [
        • Laubenberger J.
        • Haussinger D.
        • Bayer S.
        • Gufler H.
        • Hennig J.
        • Langer M.
        Proton magnetic resonance spectroscopy of the brain in symptomatic and asymptomatic patients with liver cirrhosis.
        ]. The severity of HE has been associated with the intensity of this abnormality [
        • Lee J.H.
        • Seo D.W.
        • Lee Y.-S.
        • Kim S.-T.
        • Mun C.-W.
        • Lim T.-H.
        • et al.
        Proton magnetic resonance spectroscopy (1H-MRS) findings for the brain in patients with liver cirrhosis reflect the hepatic functional reserve.
        ]. 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) [
      • Hassoun Z.
      • Deschenes M.
      • Lafortune M.
      • Dufresne M.P.
      • Perreault P.
      • Lepanto L.
      • et al.
      Relationship between pre-TIPS liver perfusion by the portal vein and the incidence of post-TIPS chronic hepatic encephalopathy.
      ]. The development of HE is rare in the absence of significant liver disease, but not exceptional [
      • Minguez B.
      • Garcia-Pagan J.C.
      • Bosch J.
      • Turnes J.
      • Alonso J.
      • Rovira A.
      • et al.
      Noncirrhotic portal vein thrombosis exhibits neuropsychological and MR changes consistent with minimal hepatic encephalopathy.
      ]. Portosystemic shunts can be visualized by 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 [
      • Ohnishi K.
      • Saito M.
      • Terabayashi H.
      • Nomura F.
      • Okuda K.
      Development of portal vein thrombosis complicating idiopathic portal hypertension. A case report.
      ]. 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 [
      • Romero-Gomez M.
      • Grande L.
      • Camacho I.
      Prognostic value of altered oral glutamine challenge in patients with minimal hepatic encephalopathy.
      ]. The test has not been standardized and normal values are based on the experience of independent investigators [
      • Minguez B.
      • Garcia-Pagan J.C.
      • Bosch J.
      • Turnes J.
      • Alonso J.
      • Rovira A.
      • et al.
      Noncirrhotic portal vein thrombosis exhibits neuropsychological and MR changes consistent with minimal hepatic encephalopathy.
      ,
      • Masini A.
      • Efrati C.
      • Merli M.
      • Attili A.F.
      • Amodio P.
      • Ceccanti M.
      • et al.
      Effect of lactitol on blood ammonia response to oral glutamine challenge in cirrhotic patients: evidence for an effect of nonabsorbable disaccharides on small intestine ammonia generation.
      ]. 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.
      Figure thumbnail gr3
      Fig. 3Dynamic helical CT scanning discloses a splenorenal shunt (arrow) during the arterial phase (left image) that becomes more evident in the venous phase (right image).

      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 [
      • Bass N.M.
      • Mullen K.D.
      • Sanyal A.
      • Poordad F.
      • Neff G.
      • Leevy C.B.
      • et al.
      Rifaximin treatment in hepatic encephalopathy.
      ].
      Figure thumbnail gr4
      Fig. 4Evaluation 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.
      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 [
      • Sarin S.K.
      • Kumar A.
      • Almeida J.A.
      • Chawla Y.K.
      • Fan S.T.
      • Garg H.
      • et al.
      Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL).
      ] 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 [
      • Riggio O.
      • Efrati C.
      • Catalano C.
      • Pediconi F.
      • Mecarelli O.
      • Accornero N.
      • et al.
      High prevalence of spontaneous portal-systemic shunts in persistent hepatic encephalopathy: a case-control study.
      ]. Recognition of spontaneous shunts is important, because occlusion is a treatment option in patients with recurrent HE and good hepatocellular function (low bilirubin) [
      • Uflacker R.
      • Silva A.
      • d’Albuquerque L.A.
      • Piske R.L.
      • Mourao G.S.
      Chronic portosystemic encephalopathy: embolization of portosystemic shunts.
      ]. 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 [
      • Romero-Gómez M.
      • Jover M.
      • Del Campo J.A.
      • Royo J.L.
      • Hoyas E.
      • Galán J.J.
      • et al.
      Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis: A cohort study.
      ]. 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 centers, 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 [
      • Bajaj J.S.
      • Etemadian A.
      • Hafeezullah M.
      • Saeian K.
      Testing for minimal hepatic encephalopathy in the United States: an AASLD survey.
      ]. Although one study has shown that treatment improves the patients’ quality of life [
      • Prasad S.
      • Dhiman R.K.
      • Duseja A.
      • Chawla Y.K.
      • Sharma A.
      • Agarwal R.
      Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy.
      ], the actual benefit of treating mild cognitive impairment is still uncertain [
      • Ortiz M.
      • Jacas C.
      • Cordoba J.
      Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations.
      ].
      Several studies have shown that the decline in cognitive function that characterizes minimal HE worsens the ability to drive a car [
      • Kircheis G.
      • Knoche A.
      • Hilger N.
      • Manhart F.
      • Schnitzler A.
      • Schulze H.
      • et al.
      Hepatic encephalopathy and fitness to drive.
      ] and increases the risk of automobile accidents [
      • Bajaj J.S.
      • Saeian K.
      • Schubert C.M.
      • Hafeezullah M.
      • Franco J.
      • Varma R.R.
      • et al.
      Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test.
      ]. Impaired visuo-motor coordination and working memory is reflected by insufficient navigation skills [
      • Bajaj J.S.
      • Hafeezullah M.
      • Hoffmann R.G.
      • Varma R.R.
      • Franco J.
      • Binion D.G.
      • et al.
      Navigation skill impairment: another dimension of the driving difficulties in minimal hepatic encephalopathy.
      ], 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 [
      • Cordoba J.
      • Lucke R.
      Driving under the influence of minimal hepatic encephalopathy.
      ]. One study observed that the percentage of patients with minimal HE that experienced traffic accidents was small (8–16%, depending on the diagnostic test) [
      • Bajaj J.S.
      • Saeian K.
      • Schubert C.M.
      • Hafeezullah M.
      • Franco J.
      • Varma R.R.
      • et al.
      Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test.
      ]. 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 [
      • Srivastava A.
      • Mehta R.
      • Rothke S.P.
      • Rademaker A.W.
      • Blei A.T.
      Fitness to drive in patients with cirrhosis and portal-systemic shunting: a pilot study evaluating driving performance.
      ]. 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 [
      • Kircheis G.
      • Knoche A.
      • Hilger N.
      • Manhart F.
      • Schnitzler A.
      • Schulze H.
      • et al.
      Hepatic encephalopathy and fitness to drive.
      ,
      • Bajaj J.S.
      • Saeian K.
      • Hafeezullah M.
      • Hoffmann R.G.
      • Hammeke T.A.
      Patients with minimal hepatic encephalopathy have poor insight into their driving skills.
      ]. 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 [
      • Kircheis G.
      • Knoche A.
      • Hilger N.
      • Manhart F.
      • Schnitzler A.
      • Schulze H.
      • et al.
      Hepatic encephalopathy and fitness to drive.
      ].
      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 [

      Roman E, Cordoba J, Torrens M, Torras X, Villanueva C, Vargas V et al. Minimal hepatic encephalopathy is associated with falls. Am J Gastroenterol 2010.

      ] and injury when handling machinery [
      • Ortiz M.
      • Jacas C.
      • Cordoba J.
      Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations.
      ]. 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 [
      • Bajaj J.S.
      • Saeian K.
      • Schubert C.M.
      • Hafeezullah M.
      • Franco J.
      • Varma R.R.
      • et al.
      Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test.
      ] for this purpose, but they do not suffice [

      Amodio P, Ridola L, Schiff S, Montagnese S, Pasquale C, Nardelli S et al. Improving detection of minimal hepatic encephalopathy using the inhibitory control task. Gastroenterology 2010.

      ] to recommend a specific test [
      • Bajaj J.S.
      • Wade J.B.
      • Sanyal A.J.
      Spectrum of neurocognitive impairment in cirrhosis: Implications for the assessment of hepatic encephalopathy.
      ]. 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 [
      • Podsiadlo D.
      • Richardson S.
      The timed “Up & Go”: a test of basic functional mobility for frail elderly persons.
      ]. 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 are advised to quit driving; at this stage, additional evaluation by experts may be needed.
      Figure thumbnail gr5
      Fig. 5Asymptomatic 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.

      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 [
      • Bajaj J.S.
      • Saeian K.
      • Hafeezullah M.
      • Hoffmann R.G.
      • Hammeke T.A.
      Patients with minimal hepatic encephalopathy have poor insight into their driving skills.
      ]. 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 [
      • Groeneweg M.
      • Moerland W.
      • Quero J.C.
      • Hop W.C.J.
      • Krabbe P.
      • Schalm S.W.
      Screening of subclinical hepatic encephalopathy.
      ].
      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) [
      • Bajaj J.S.
      • Wade J.B.
      • Sanyal A.J.
      Spectrum of neurocognitive impairment in cirrhosis: Implications for the assessment of hepatic encephalopathy.
      ]. 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…”) [
      • Groeneweg M.
      • Moerland W.
      • Quero J.C.
      • Hop W.C.J.
      • Krabbe P.
      • Schalm S.W.
      Screening of subclinical hepatic encephalopathy.
      ]. The study also found that an important number of patients reporting cognitive complaints did not exhibit neuropsychological or neurophysiological abnormalities. The complaints can have multiple origins and may reflect psycho-affective or health problems unrelated to cognition [
      • Comijs H.C.
      • Deeg D.J.
      • Dik M.G.
      • Twisk J.W.
      • Jonker C.
      Memory complaints; the association psychoactive and health problems and the role of personality charactheristics. A 6-year follow-up study.
      ]. Discrepancies between complaints and cognitive function are not infrequent in other clinical situations [
      • Schofield P.W.
      • Marder K.
      • Dooneief G.
      • Jacobs D.M.
      • Sano M.
      • Stern Y.
      Association of subjetive memory complaints with subsequent cognitive decline in community-dwelling elderly individuals with baseline cognitive impairment.
      ]. 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 [
      • Guerit J.M.
      • Amantini A.
      • Fischer C.
      • Kaplan P.W.
      • Mecarelli O.
      • Schnitzler A.
      • et al.
      Neurophysiological investigations of hepatic encephalopathy: ISHEN practice guidelines.
      ]. 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 [
      • Cordoba J.
      • Hinojosa C.
      • Sanpedro F.
      • Alonso J.
      • Rovira A.
      • Quiroga S.
      • et al.
      Usefulness of magnetic resonance spectroscopy for diagnosis of hepatic encephalopathy in a patient with relapsing confusional syndrome.
      ], and those that exhibit unusual neurological manifestations or neurological co-morbidities. This latter situation is critical when contemplating liver transplantation, a treatment that resolves neurological manifestations secondary to HE [
      • Weissenborn K.
      • Tietge U.J.
      • Bokemeyer M.
      • Mohammadi B.
      • Bode U.
      • Manns M.P.
      • et al.
      Liver transplantation improves hepatic myelopathy: evidence by three cases.
      ], 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 [
      • Blei A.T.
      • Cordoba J.
      Hepatic encephalopathy. Practice guidelines of the American College of Gastroenterology.
      ], 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 [
      • O’Brien J.T.
      • Erkinjuntti T.
      • Reisberg B.
      • Roman G.
      • Sawada T.
      • Pantoni L.
      • et al.
      Vascular cognitive impairment.
      ], which has a pattern of cognitive deterioration similar to low-grade HE. The lesions show a marked reduction in size with reversal of HE [
      • Rovira A.
      • Minguez B.
      • Aymerich F.X.
      • Jacas C.
      • Huerga E.
      • Cordoba J.
      • et al.
      Decreased white matter lesion volume and improved cognitive function after liver transplantation.
      ]. 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 [
      • Zeneroli M.L.
      • Cioni G.
      • Crisi G.
      • Vezzelli C.
      • Ventura E.
      Globus pallidus alterations and brain atrophy in liver cirrhosis patients with encephalopathy: an MR imaging study.
      ] 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).

      Neurological manifestations after liver transplantation

      Neurological complications are common after liver transplantation, mainly in the early postoperative period [

      Amodio P, Biancardi A, Montagnese S, Angeli P, Iannizzi P, Cillo U et al. Neurological complications after orthotopic liver transplantation. Dig Liver Dis 2007.

      ]. 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 [
      • Kanwal F.
      • Chen D.
      • Ting L.
      • Gornbein J.
      • Saab S.
      • Durazo F.
      • et al.
      A model to predict the development of mental status changes of unclear cause after liver transplantation.
      ]; 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 [
      • Cordoba J.
      • Alonso J.
      • Rovira A.
      • Jacas C.
      • Sanpedro F.
      Castells Ll et al. The development of low-grade cerebral edema in cirrhosis is supported by the evolution of 1H-magnetic resonance abnormalities after liver transplantation.
      ]. Similarly, portosystemic shunts may persist despite a normally functioning graft and can be responsible for acute changes in the mental state [
      • Herrero J.I.
      • Bilbao J.I.
      • Diaz M.L.
      • Alegre F.
      • Inarrairaegui M.
      • Pardo F.
      • et al.
      Hepatic encephalopathy after liver transplantation in a patient with a normally functioning graft: Treatment with embolization of portosystemic collaterals.
      ].
      Liver transplantation improves HE, even in patients with severe manifestations [
      • O’Brien J.T.
      • Erkinjuntti T.
      • Reisberg B.
      • Roman G.
      • Sawada T.
      • Pantoni L.
      • et al.
      Vascular cognitive impairment.
      ,
      • Larsen F.S.
      • Ranek L.
      • Hansen B.A.
      • Kirkegaard P.
      Chronic portosystemic hepatic encephalopathy refractory to medical treatment successfully reversed by liver transplantation.
      ]. Nevertheless, studies that have assessed neuropsychological function following liver transplantation have challenged the notion of complete reversibility [
      • Mechtcheriakov S.
      • Graziadei I.W.
      • Mattedi M.
      • Bodner T.
      • Kugener A.
      • Hinterhubert H.H.
      • et al.
      Incomplete improvement of visuo-motor deficits in patients with minimal hepatic encephalopathy after liver transplantation.
      ]. Some sequelae may persist, but most of the patients exhibit normal cognitive function [
      • Sotil E.U.
      • Gottstein J.
      • Ayala E.
      • Randolph C.
      • Blei A.T.
      Impact of preoperative overt hepatic encephalopathy on neurocognitive function after liver transplantation.
      ]. 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 [
      • Garcia M.R.
      • Rovira A.
      • Alonso J.
      • Aymerich F.X.
      • Huerga E.
      • Jacas C.
      • et al.
      A long-term study of changes in the volume of brain ventricles and white matter lesions after successful liver transplantation.
      ]. 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.

      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.

      Acknowledgments

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

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