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EASL Clinical Practice Guidelines on the management of hepatic encephalopathy

      Summary

      The EASL Clinical Practice Guidelines (CPGs) on the management of hepatic encephalopathy (HE) present evidence-based answers to a set of relevant questions (where possible, formulated in PICO [patient/population, intervention, comparison and outcomes] format) on the definition, diagnosis, differential diagnosis and treatment of HE. The document does not cover the pathophysiology of HE and does not cover all available treatment options. The methods through which it was developed and any information relevant to its interpretation are also provided.

      Introduction and methods

      The Governing Board of the European Association for the Study of the Liver (EASL) selected a panel of experts to prepare these Clinical Practice Guideline (CPGs) with the purpose of providing the best available evidence on diagnosis and management of hepatic encephalopathy (HE). The EASL Governing Board and the CPG panel went on to identify a Delphi panel of 36 reviewers including 24 hepatologists/gastroenterologists/internists, 5 nurses, 2 methodologists, 1 neurologist, 1 neurophysiologist, 1 neuropsychologist, 1 neuroradiologist, 1 neuroscientist and 1 patient with a background in psychology, all with an interest in HE; 24 participated in all review steps. The CPG panel was first assigned the task of identifying the most relevant topics, in the form of PICO [P Patient, Population, or Problem; I Intervention, Prognostic Factor, or Exposure; C Comparison or Intervention (if appropriate), O Outcome] questions, which resulted in 29 questions; on first Delphi panel review, some of these questions were modified/removed and some added, resulting in the 31 final questions which are presented in the current document. While the panel agreed to the PICO format, for a number of topics the format was not applicable and/or the evidence insufficient. Therefore, intermediate format questions were accepted and treated as such.
      An extensive literature search of publications in English was performed by an experienced research librarian (Helene Sognstrup, Royal Danish Library Aarhus) using PubMed, Embase and the Cochrane Library.
      Features and limits: Language: English (not possible in Cochrane); Publication year: All years; Publication type: Clinical, trials, Randomized controlled trials.
      ((“Hepatic Encephalopathy”[MeSH Terms] OR “Hepatic Encephalopathy”[Text Word] OR neuropsycholog∗[Text Word] OR “Psychometrics”[Mesh] OR “Cognition Disorders”[MeSH Terms] OR “Cognition”[MeSH Terms]) AND (((“Liver Diseases”[MeSH Terms] OR “liver diseas∗”[Text Word]) AND (“Chronic Disease"[MeSH Terms] OR "chronic disease∗"[Text Word])) OR ("Liver Cirrhosis"[MeSH Terms] OR "Liver Cirrhosis”[Text Word])) AND (“clinical trial”[Title] OR “randomi∗”[Title])) OR ((“Hepatic Encephalopathy”[MeSH Terms] OR "Hepatic Encephalopathy”[Text Word] OR neuropsycholog∗[Text Word] OR “Psychometrics”[Mesh] OR “Cognition Disorders”[MeSH Terms] OR "Cognition"[MeSH Terms]) AND ((("Liver Diseases"[MeSH Terms] OR "liver diseas∗"[Text Word]) AND ("Chronic Disease"[MeSH Terms] OR "chronic disease∗"[Text Word])) OR ("Liver Cirrhosis"[MeSH Terms] OR "Liver Cirrhosis"[Text Word])) AND ("clinical trial"[Publication Type] OR "Randomized Controlled Trials as Topic"[MeSH Terms] OR "Clinical Trials as Topic"[MeSH Terms]))
      Four hundred and sixteen references were retrieved from PubMed, 326 from Embase and 257 from the Cochrane Library, for a total of 999 references, which were then reduced to 726 after deduplication. All panellists read the retrieved literature and searched for further literature, where appropriate. Each panellist chose a number of PICO questions based on their specific expertise; where overlap/disparities were present agreement was sought and easily reached.
      The evidence was evaluated and scored, and the recommendations produced following EASL’s methodological recommendations for CPGs (Table 1, Table 2)
      • Cornberg M.
      • Tacke F.
      • Karlsen T.H.
      European Association for the Study of the Liver
      Clinical Practice Guidelines of the European Association for the Study of the Liver - advancing methodology but preserving practicability.
      ; definitions and statements were not graded. After a first in-person meeting, due to the COVID-19 pandemic, all subsequent meetings were held by teleconference. All recommendations were discussed and approved by all panellists. The Delphi panel examined the recommendations. Returning scores were graded as follows: less than 50% approval: re-write recommendation and resubmit to the Delphi panel; 50%-75% approval: re-write/improve the recommendation, but no resubmission to the Delphi panel; 75-90% approval: no need to re-write the recommendation but the document will take into account the comments; ≥90% approval: assumed as consensus, no change needed but small corrections possible. To consider a question approved, an agreement from at least 75% of Delphi panel members was required.
      Table 1Level of evidence based on the Oxford Centre for Evidence-based Medicine.
      LevelCriteriaSimple model for high, intermediate and low evidence
      1Systematic Reviews (SR) (with homogeneity) of Randomised controlled trials (RCT)Further research is unlikely to change our confidence in the estimate of benefit and risk
      2Randomised controlled trials (RCT) or observational studies with dramatic effects;

      Systematic Reviews (SR) of lower quality studies (i.e. non-randomised, retrospective)
      3Systematic Reviews (SR) of lower quality studies (i.e. non-randomised, retrospective)Further research (if performed) is likely to have an impact on our confidence in the estimate of benefit and risk and may change the estimate
      4Case-series, case-control, or historically controlled studies (systematic review is generally better than an individual study)
      5Expert opinion (Mechanism-based Reasoning)Any estimate of effect is uncertain
      Table 2Grades of recommendation.
      GradeWordingCriteria
      StrongMust, shall, should, is recommended

      Shall not, should not, is not recommended
      Evidence, consistency of studies, risk-benefit ratio, patient preferences, ethical obligations, feasibility
      Weak or openCan, may, is suggested

      May not, is not suggested
      When neutral answers were excluded, all questions received a score above 75%, thus there was no formal need for revision. However, several specific comments on the recommendations and the free comments provided by the Delphi panel were extremely useful and important, so the recommendations and the overall document were modified accordingly, and 2 further Delphi reviews performed, together with a review by the EASL Governing Board.
      Despite constant debate on HE classification, the panel felt that there were no grounds nor any actual need to revise the classification previously proposed in the joint 2014 EASL-AASLD guideline,
      American Association for the Study of Liver DiseasesEuropean Association for the Study of the Liver
      Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases.
      with particular reference to the indication that HE should be described by type, grade, time course and precipitant (when identified). As for grade and, again, despite ongoing discussions on the semantics and appropriateness of the term Covert as raised by Jalan and Rose,
      • Jalan R.
      • Rose C.F.
      Heretical thoughts into hepatic encephalopathy.
      this was maintained for 3 main reasons: i) continuous changes in HE nomenclature seem to have been more damaging than useful in the past, making it difficult for the community at large to become familiar with the meaning/use of the different terms proposed over time
      • Lockwood A.H.
      “What's in a name?” Improving the care of cirrhotics.
      ; ii) the 2014 definition of overt as ≥ West Haven grade II (thus excluding the vague and operator-dependent grade I)
      • Conn H.O.
      • Leevy C.M.
      • Vlahcevic Z.R.
      • Rodgers J.B.
      • Maddrey W.C.
      • Seeff L.
      • et al.
      Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial.
      was undoubtedly a step forward for the purposes of both clinical research and multicentre trials; iii) as the diagnosis of grade I HE is vague and operator-dependent, the border between minimal HE and covert HE has always, by definition, been difficult to trace, making the literature on minimal HE largely relevant to both terms.
      • Amodio P.
      • Marchetti P.
      • Del Piccolo F.
      • de Tourtchaninoff M.
      • Varghese P.
      • Zuliani C.
      • et al.
      Spectral vs. visual EEG analysis in mild hepatic encephalopathy.
      Hence our decision to use the term covert also with reference to evidence and literature produced in years where the most commonly used terms were minimal and/or subclinical HE. Finally, as several of the Delphi panel experts highlighted in their free comments, some more specific topics (for example sedation recommendations during endoscopy in patients with HE) and, more importantly, a number of drugs which have shown promise in HE are not covered by this guideline, as they were not the subject of specific PICO questions. A short, pragmatic review on these drugs has recently been published.
      • Mangini C.
      • Montagnese S.
      New therapies of liver diseases: hepatic encephalopathy.

      Questions and recommendations

      In patients with HE, can pre-defined classification criteria improve diagnostic accuracy and the effects of treatment?

      Recommendation
      • HE should be qualified as type A in patients with acute liver failure, type B in those with portosystemic shunt, and type C in those with cirrhosis. Overt HE should be qualified as recurrent if ≥2 bouts occur within 6 months and persistent if the patient does not return to her/his baseline performance between bouts. The severity of mental alterations, any identified precipitants and the presence of portosystemic shunts should also be recorded as these factors impact upon both diagnostic accuracy and treatment (LoE 5, strong recommendation, 96% consensus).
      The currently recommended classification of HE is based on the severity of the underlying liver disease and/or presence of portosystemic shunting, the severity and time course of mental alterations and any identified precipitating events. Thus “type A” HE is due to acute liver failure, “type B” to portosystemic shunt without significant liver disease and “type C” to cirrhosis with or without portosystemic shunt.
      American Association for the Study of Liver DiseasesEuropean Association for the Study of the Liver
      Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases.
      In terms of its severity, HE is qualified as covert (minor or no signs/symptoms but abnormalities on neuropsychological and/or neurophysiological tests) or overt (grades II or over according to the West Haven criteria
      American Association for the Study of Liver DiseasesEuropean Association for the Study of the Liver
      Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases.
      ). Finally, in terms of its time course, overt HE is classified as episodic, recurrent (more than one episode over a period of 6 months) or persistent (no return to normal/baseline neuropsychiatric performance in between episodes).
      American Association for the Study of Liver DiseasesEuropean Association for the Study of the Liver
      Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases.
      Recognised precipitating events are constipation, gastrointestinal bleeding, infections, hyponatremia, and dehydration/diuretic overdose.
      • Strauss E.
      • da Costa M.F.
      The importance of bacterial infections as precipating factors of chronic hepatic encephalopathy in cirrhosis.
      The presence of portosystemic shunts facilitates the occurrence of HE and is associated with more severe forms.
      • 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.
      All such information should be recorded when an episode of HE occurs, as it has both therapeutic and prognostic implications. It is reasonable to assume that a classification based on the above criteria may improve diagnostic accuracy and treatment outcome.

      In patients with HE, are the West Haven criteria and Glasgow coma scale appropriate for grading?

      Recommendation
      • The West Haven criteria should be used for HE grading when at least temporal disorientation is present (i.e. from West Haven grades ≥2). In patients with no or mild neuropsychiatric abnormalities (i.e. not meeting the criteria for the diagnosis of HE grades ≥2 based on the West Haven criteria), a neuropsychological/neurophysiological or therapeutic test should be used to diagnose covert HE. In patients with grades III-IV West Haven criteria, the Glasgow coma scale should be added (LoE 5, strong recommendation, 96% consensus).
      The diagnosis of overt HE is usually straightforward in clinical practice. However, grading and staging is mandatory, mainly for monitoring. West Haven and Glasgow coma scales have been utilised for many years.
      • Conn H.O.
      • Leevy C.M.
      • Vlahcevic Z.R.
      • Rodgers J.B.
      • Maddrey W.C.
      • Seeff L.
      • et al.
      Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial.
      ,
      • Teasdale G.
      • Jennett B.
      Assessment of coma and impaired consciousness. A practical scale.
      No comparative analysis has been published yet. The West Haven scale is easy to use in clinical practice, at least from grade II upwards and especially with its semi-quantitative equivalents.
      American Association for the Study of Liver DiseasesEuropean Association for the Study of the Liver
      Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases.
      ,
      • Montagnese S.
      • Russo F.P.
      • Amodio P.
      • Burra P.
      • Gasbarrini A.
      • Loguercio C.
      • et al.
      Hepatic encephalopathy 2018: a clinical practice guideline by the Italian Association for the Study of the Liver (AISF).
      However, in the clinical setting, it has often been used in an intuitive way, leading to discrepancies in grading between observers. In patients with HE and impaired consciousness, including those managed in an intensive care unit, the Glasgow coma scale should be added.

      How does the term “brain failure” in patients with acute-on-chronic liver failure relate to HE?

      Recommendation
      • The term “Brain Failure” should be replaced with the term “acute encephalopathy”, in accordance with international guidelines on delirium. Acute encephalopathy should not be used as a synonym for HE in patients with acute-on-chronic liver failure because while it may be accounted for by HE, there may be alternative or concomitant causes for its development (LoE 4, strong recommendation, 91% consensus).
      The term “brain failure” first appeared in hepatology in 2014 as one of the organ failures defining patients with acute-on-chronic liver failure.
      • Jalan R.
      • Saliba F.
      • Pavesi M.
      • Amoros A.
      • Moreau R.
      • Ginès P.
      • et al.
      Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure.
      The term is descriptive, it has no pathophysiological connotation, it does not exist in standard neurological terminology, and it may be considered an equivalent of the more correct and more commonly utilised term acute encephalopathy.
      • Slooter A.J.C.
      • Otte W.M.
      • Devlin J.W.
      • Arora R.C.
      • Bleck T.P.
      • Claassen J.
      • et al.
      Updated nomenclature of delirium and acute encephalopathy: statement of ten societies.
      Acute encephalopathy refers to a pathophysiological process, and can translate clinically speaking into subdelirium, delirium or coma, depending on the severity of symptoms. Since the current definition of HE implies that HE is caused by and not only associated with liver failure,
      American Association for the Study of Liver DiseasesEuropean Association for the Study of the Liver
      Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases.
      the terms HE and acute encephalopathy are not interchangeable. Acute encephalopathy may be accounted for by HE, either on its own or in association with other forms of encephalopathy.
      • Weiss N.
      • Saint Hilaire P.B.
      • Colsch B.
      • Isnard F.
      • Attala S.
      • Schaefer A.
      • et al.
      Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy.
      • Montagnese S.
      • Schiff S.
      • Amodio P.
      Quick diagnosis of hepatic encephalopathy: fact or fiction?.
      • Weissenborn K.
      Minimal/covert hepatic encephalopathy - impact of comorbid conditions.
      It remains important for management purposes that each form of acute encephalopathy is treated according to its underlying cause.
      • Amodio P.
      • Montagnese S.
      Lights and shadows in hepatic encephalopathy diagnosis.
      By contrast, taking a simplistic approach to the neuropsychiatric alterations exhibited by patients with liver failure
      • Weiss N.
      • Saint Hilaire P.B.
      • Colsch B.
      • Isnard F.
      • Attala S.
      • Schaefer A.
      • et al.
      Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy.
      may stand in the way of validating the results of clinical trials of novel drugs, because no drug can be expected to target a large number of pathophysiological processes and/or to be tested reliably within a context of unclear diagnoses.

      In patients with cirrhosis, do the features and prognosis of HE depend on aetiology of cirrhosis?

      Recommendation
      • Patients with HE should not be classified based on the aetiology of their underlying liver disease (LoE 4, strong recommendation, 93% consensus).
      The definition of HE does not consider the underlying cause of liver failure. However, aetiologies such as alcohol, viral hepatitis, and metabolic dysfunction-associated fatty liver disease (MAFLD) can impact brain function through mechanisms different from those directly linked to liver failure.
      • Balzano T.
      • Forteza J.
      • Borreda I.
      • Molina P.
      • Giner J.
      • Leone P.
      • et al.
      Histological features of cerebellar neuropathology in patients with alcoholic and nonalcoholic steatohepatitis.
      • Forton D.M.
      • Allsop J.M.
      • Main J.
      • Foster G.R.
      • Thomas H.C.
      • Taylor-Robinson S.D.
      Evidence for a cerebral effect of the hepatitis C virus.
      • Mosher V.A.L.
      • Swain M.G.
      • Pang J.X.Q.
      • Kaplan G.G.
      • Sharkey K.A.
      • MacQueen G.M.
      • et al.
      Magnetic resonance imaging evidence of hippocampal structural changes in patients with primary biliary cholangitis.
      Furthermore, conditions such as diabetes and age could influence the risk of HE. Alcohol is neurotoxic in itself, making it difficult to distinguish the contribution of aetiology vs. liver dysfunction. Likewise, MAFLD is becoming the most common cause of cirrhosis and such patients may show impaired neurocognitive function and lower brain volume even in non-cirrhotic stages.
      • Weinstein G.
      • Zelber-Sagi S.
      • Preis S.R.
      • Beiser A.S.
      • DeCarli C.
      • Speliotes E.K.
      • et al.
      Association of nonalcoholic fatty liver disease with lower brain volume in healthy middle-aged adults in the Framingham study.
      Some patients with MAFLD can exhibit hyperammonaemia and astrocytic and microglial activation in the absence of cirrhosis.
      • Weinstein G.
      • Zelber-Sagi S.
      • Preis S.R.
      • Beiser A.S.
      • DeCarli C.
      • Speliotes E.K.
      • et al.
      Association of nonalcoholic fatty liver disease with lower brain volume in healthy middle-aged adults in the Framingham study.
      • VanWagner L.B.
      • Terry J.G.
      • Chow L.S.
      • Alman A.C.
      • Kang H.
      • Ingram K.H.
      • et al.
      Nonalcoholic fatty liver disease and measures of early brain health in middle-aged adults: the CARDIA study.
      • De Chiara F.
      • Heebøll S.
      • Marrone G.
      • Montoliu C.
      • Hamilton-Dutoit S.
      • Ferrandez A.
      • et al.
      Urea cycle dysregulation in non-alcoholic fatty liver disease.
      • Seo S.W.
      • Gottesman R.F.
      • Clark J.M.
      • Hernaez R.
      • Chang Y.
      • Kim C.
      • et al.
      Nonalcoholic fatty liver disease is associated with cognitive function in adults.
      • Kjærgaard K.
      • Mikkelsen A.C.D.
      • Wernberg C.W.
      • Grønkjær L.L.
      • Eriksen P.L.
      • Damholdt M.F.
      • et al.
      Cognitive dysfunction in non-alcoholic fatty liver disease-current knowledge, mechanisms and perspectives.
      In viral hepatitis, neuropsychiatric patient-reported outcomes, such as depression or loss of attention, are independent of disease severity. The abnormalities on brain imaging differ from other aetiologies, possibly relating to viral replication in endothelial cells, astroglia and microglia, causing neuroinflammation.
      • Grover V.P.B.
      • Pavese N.
      • Koh S.-B.
      • Wylezinska M.
      • Saxby B.K.
      • Gerhard A.
      • et al.
      Cerebral microglial activation in patients with hepatitis C: in vivo evidence of neuroinflammation.
      Lastly, patients with porto-sinusoidal hypertension can suffer from HE in the absence of liver dysfunction, mainly owing to large portosystemic shunts. In conclusion, aetiology probably does have an impact on brain function together with medications, ageing and comorbidities, and formulating a differential diagnosis is challenging. Nevertheless, in multivariate analysis, aetiology has not emerged as an independent variable predicting risk of overt HE in the majority of studies.
      • Gil-Gómez A.
      • Ampuero J.
      • Rojas Á.
      • Gallego-Durán R.
      • Muñoz-Hernández R.
      • Rico M.C.
      • et al.
      Development and validation of a clinical-genetic risk score to predict hepatic encephalopathy in patients with liver cirrhosis.

      In patients with suspected HE, can the exclusion or identification of alternative or additional causes of neuropsychiatric impairment improve prognostic accuracy and the results of treatment?

      Recommendation
      • In patients with suspected HE, alternative or additional causes of neuropsychiatric impairment should be identified to improve prognostic accuracy and the results of treatment (LoE 4, strong recommendation, 100% consensus).
      There is no clinical study to answer this question. However, a correct diagnosis is the precondition for rational therapeutic and prognostic evaluation. It should be emphasised that HE might occur on top of a pre-existing disease such as, for example, dementia. Patients with suspected HE should therefore undergo the same standardised diagnostic evaluation as any other patient with altered consciousness. This is emphasised by the finding of extrahepatic causes for acute encephalopathy in 22% of patients with liver disease suspected of HE.
      • Akhtar A.J.
      • Alamy M.E.
      • Yoshikawa T.T.
      Extrahepatic conditions and hepatic encephalopathy in elderly patients.
      These causes included infections (urinary infection, pneumonia), perfusion disorders (stroke, myocardial infarction), other neurological causes (subdural haematoma) and several others. The diagnostic work-up might include blood tests for glucose, electrolytes, inflammatory markers (e.g. C-reactive protein), full blood count, blood alcohol level and ammonia, thyroid-stimulating hormone, brain imaging, as well as screening for psychoactive drugs, lumbar puncture to rule out meningitis or encephalitis, and an electroencephalogram (EEG) to exclude non-convulsive seizures. Concomitant disorders that may present with HE-like symptoms must be considered, as well as HE precipitating factors. Concomitant disorders that must be considered are infections, hyponatremia, renal dysfunction, hypo- or hyperglycaemia, alcohol or drug abuse, intracranial bleeding, thiamine deficiency, malnutrition or hypothyroidism, as reported.
      • Amodio P.
      Hepatic encephalopathy: diagnosis and management.
      • Weissenborn K.
      Challenges in diagnosing hepatic encephalopathy.
      • Díaz-Fontenla F.
      • Castillo-Pradillo M.
      • Díaz-Gómez A.
      • Ibañez-Samaniego L.
      • Gancedo P.
      • Guzmán-de-Villoria J.A.
      • et al.
      Refractory hepatic encephalopathy in a patient with hypothyroidism: another element in ammonia metabolism.
      Differential diagnosis is even more important within the context of a poor or partial response to anti-HE treatment.

      Does mild cognitive impairment (MCI) of an aetiology other than liver dysfunction show features that are different from those of covert HE in patients with cirrhosis?

      Statement
      • Features of covert HE and MCI of an aetiology other than liver dysfunction show significant overlap (LoE 2, 90% consensus).
      MCI is an intermediate state between normal ageing and dementia.
      • Sachdev P.S.
      • Lipnicki D.M.
      • Crawford J.
      • Reppermund S.
      • Kochan N.A.
      • Trollor J.N.
      • et al.
      Risk profiles of subtypes of mild cognitive impairment: the sydney memory and ageing study.
      The differential diagnosis of covert HE is especially relevant in patients with liver disease over the age of 60 years. The prevalence of MCI in this age group is up to 20%
      • Petersen R.C.
      Mild cognitive impairment.
      but daily functioning in the presence of MCI is largely preserved,
      • Sachdev P.S.
      • Blacker D.
      • Blazer D.G.
      • Ganguli M.
      • Jeste D.V.
      • Paulsen J.S.
      • et al.
      Classifying neurocognitive disorders: the DSM-5 approach.
      in stark contrast to the severe daily functional impairment of patients with covert HE. MCI may present with memory dysfunction or alterations of complex attention, executive function, learning, language, perceptual–motor function, or social cognition and has usually been noticeable for at least 6 months, in contrast to the cognitive impairment of covert HE which is often fluctuating. Considering the features of covert HE – deficits in attention, concentration, visuo-spatial orientation and coordination, motor speed and accuracy –
      • Weissenborn K.
      • Ennen J.C.
      • Schomerus H.
      • Rückert N.
      • Hecker H.
      Neuropsychological characterization of hepatic encephalopathy.
      there is an obvious overlap in symptomatology with MCI, but there are also some differences. Language, for example, is preserved in patients with covert HE as is memory, while an alteration of motor speed and accuracy is not typical of MCI.
      • Sachdev P.S.
      • Lipnicki D.M.
      • Crawford J.
      • Reppermund S.
      • Kochan N.A.
      • Trollor J.N.
      • et al.
      Risk profiles of subtypes of mild cognitive impairment: the sydney memory and ageing study.
      Since comorbidities are frequent in patients with cirrhosis, especially the elderly, abnormal psychometric test results cannot be interpreted solely as an indication of covert HE. A possible overlap of comorbidities has to be considered, and finally a diagnosis of covert HE should be reconsidered in the context of response to HE therapy.

      In patients with delirium, is ammonia measurement useful for purposes of diagnosis, differential diagnosis, treatment and prognosis?

      Recommendation
      • In patients with delirium/encephalopathy and liver disease, plasma ammonia measurement should be performed, as a normal value brings the diagnosis of HE into question (LoE 4, strong recommendation, 95% consensus).
      Ammonia plays a central role in the pathophysiology of HE. In principle, if a patient is normoammonaemic, they do not have a sufficient degree of hepatic failure and/or portosystemic shunting to justify a working diagnosis of HE. However, there has been much debate on the use of ammonia measurement in clinical practice.
      Diagnosis. Blood ammonia levels correlate with the severity of HE, but patients without manifest HE and even without liver disease can display hyperammonaemia.
      • Nicolao F.
      • Efrati C.
      • Masini A.
      • Merli M.
      • Attili A.F.
      • Riggio O.
      Role of determination of partial pressure of ammonia in cirrhotic patients with and without hepatic encephalopathy.
      ,
      • Shalimar
      • Sheikh M.F.
      • Mookerjee R.P.
      • Agarwal B.
      • Acharya S.K.
      • Jalan R.
      Prognostic role of ammonia in patients with cirrhosis.
      Moreover, ammonia may remain elevated after clinical HE resolution.
      • Poo J.L.
      • Góngora J.
      • Sánchez-Avila F.
      • Aguilar-Castillo S.
      • García-Ramos G.
      • Fernández-Zertuche M.
      • et al.
      Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study.
      ,
      • Rahimi R.S.
      • Safadi R.
      • Thabut D.
      • Bhamidimarri K.R.
      • Pyrsopoulos N.
      • Potthoff A.
      • et al.
      Efficacy and safety of ornithine phenylacetate for treating overt hepatic encephalopathy in a randomized trial.
      However, a normal blood ammonia level has negative predictive value,
      • Nicolao F.
      • Efrati C.
      • Masini A.
      • Merli M.
      • Attili A.F.
      • Riggio O.
      Role of determination of partial pressure of ammonia in cirrhotic patients with and without hepatic encephalopathy.
      ,
      • Gundling F.
      • Zelihic E.
      • Seidl H.
      • Haller B.
      • Umgelter A.
      • Schepp W.
      • et al.
      How to diagnose hepatic encephalopathy in the emergency department.
      and normal ammonia in a patient with cirrhosis and delirium should prompt renewed or further differential diagnostic work-up for other causes of delirium. Hence, plasma ammonia measurement, when measured correctly, should be performed in patients with acute encephalopathy and liver disease and is considered to have a high negative predictive value in relation to a working diagnosis of HE.
      Treatment. The role of ammonia measurement in guiding HE treatment has not been well studied. In clinical trials, patients are often not categorised by hyperammonaemia, and ammonia analyses are often not systematically performed or timed.
      • Rahimi R.S.
      • Safadi R.
      • Thabut D.
      • Bhamidimarri K.R.
      • Pyrsopoulos N.
      • Potthoff A.
      • et al.
      Efficacy and safety of ornithine phenylacetate for treating overt hepatic encephalopathy in a randomized trial.
      This is debatable if one is using drugs which are expected to lower ammonia levels. Ammonia lowering is inconsistently associated with clinical treatment response, and ammonia levels are not used to monitor therapy. A post hoc analysis of patients with cirrhosis and 2 episodes of overt HE showed that the level of ammonia after recovery was predictive of the onset of new episodes of HE, even with mild hyperammonaemia. Hospitalisation rates were shown to increase in patients with ammonia 1.5x the upper limit of normal.
      • Vierling J.M.
      • Mokhtarani M.
      • Brown Jr., R.S.
      • Mantry P.
      • Rockey D.C.
      • Ghabril M.
      • et al.
      Fasting blood ammonia predicts risk and frequency of hepatic encephalopathy episodes in patients with cirrhosis.
      However, these findings were not confirmed in a recent study.
      • Haj M.
      • Rockey D.C.
      Ammonia levels do not guide clinical management of patients with hepatic encephalopathy caused by cirrhosis.
      Hence, tailoring HE therapy using ammonia monitoring cannot be routinely recommended.
      Prognosis. Hyperammonaemia is associated with decreased transplant-free survival from acute decompensation of cirrhosis, although the prognostic value of ammonia in patients with cirrhosis and acute encephalopathy remains unclear. A recent study in acute-on-chronic liver failure suggested a prognostic role of ammonia in patients with overt HE.
      • Shalimar
      • Sheikh M.F.
      • Mookerjee R.P.
      • Agarwal B.
      • Acharya S.K.
      • Jalan R.
      Prognostic role of ammonia in patients with cirrhosis.

      Should patients with cirrhosis and delirium undergo cerebral imaging for the purposes of diagnosis, differential diagnosis and treatment?

      Recommendation
      • In patients with delirium/encephalopathy and liver disease, brain imaging by CT scan or MRI should be performed in case of diagnostic doubts or non-response to treatment (LoE 5, strong recommendation, 96% consensus).
      Diagnosis. There is no specific radiological diagnostic sign of HE on a cerebral CT scan in patients with delirium. However, the technique may provide other relevant information, especially of the low-grade diffuse brain oedema related to hyperammonaemia. The CT scan can measure the gravity of cerebrospinal fluid and thus contribute towards differential diagnosis.
      • Weiss N.
      • Rosselli M.
      • Mouri S.
      • Galanaud D.
      • Puybasset L.
      • Agarwal B.
      • et al.
      Modification in CSF specific gravity in acutely decompensated cirrhosis and acute on chronic liver failure independent of encephalopathy, evidences for an early blood-CSF barrier dysfunction in cirrhosis.
      ,
      • Liotta E.M.
      • Romanova A.L.
      • Lizza B.D.
      • Rasmussen-Torvik L.J.
      • Kim M.
      • Francis B.
      • et al.
      Osmotic shifts, cerebral edema, and neurologic deterioration in severe hepatic encephalopathy.
      A CT scan can also reveal brain atrophy, which participates in deteriorating neurological status in patients with liver disease,
      • Amodio P.
      • Pellegrini A.
      • Amistà P.
      • Luise S.
      • Del Piccolo F.
      • Mapelli D.
      • et al.
      Neuropsychological-neurophysiological alterations and brain atrophy in cirrhotic patients.
      ,
      • Chavarria L.
      • Cordoba J.
      Magnetic resonance imaging and spectroscopy in hepatic encephalopathy.
      although atrophy is more closely related to the cause of liver disease – alcohol and metabolic syndrome – than to HE. Multimodal brain magnetic resonance imaging (MRI), including at least magnetic resonance spectroscopy, can identify a metabolic profile with relatively high specificity for HE (see below). However, accessibility to the modality is restricted to large units. Moreover, the examination usually requires general anaesthesia in patients with delirium. Hence, brain MRI is not recommended for the diagnosis of HE in patients with delirium.
      Differential diagnostics. Brain imaging is always warranted if there is clinical suspicion of a cerebral lesion or haemorrhage as is often the case in alcohol-related cirrhosis (relative risk for intracerebral bleeding at alcohol overuse above 5).
      • Grønbaek H.
      • Johnsen S.P.
      • Jepsen P.
      • Gislum M.
      • Vilstrup H.
      • Tage-Jensen U.
      • et al.
      Liver cirrhosis, other liver diseases, and risk of hospitalisation for intracerebral haemorrhage: a Danish population-based case-control study.
      Treatment. Brain CT or MRI have not been evaluated for guiding or monitoring treatment of HE. This may change with the emergence of improved techniques and software that may serve as surrogate markers in the future.

      In patients with cirrhosis, do any brain imaging methods provide results proving HE?

      Statement
      • No cerebral imaging proves a diagnosis of HE (LoE 4, 96% consensus).
      CT scan. There are no specific features of HE on brain CT scan.
      Structural MRI. Most patients with cirrhosis or portosystemic shunts present with bilateral symmetric pallidal hyperintensities in the T1-weighted MR spin echo sequence, while the T2-weighted images are normal
      • Weissenborn K.
      • Ehrenheim C.
      • Hori A.
      • Kubicka S.
      • Manns M.P.
      Pallidal lesions in patients with liver cirrhosis: clinical and MRI evaluation.
      ,
      • Rovira A.
      • Alonso J.
      • Córdoba J.
      MR imaging findings in hepatic encephalopathy.
      . The signal intensity is probably related to manganese accumulation resulting from the shunt, which does not seem to have a pathophysiological role in HE itself.
      • Weissenborn K.
      • Ehrenheim C.
      • Hori A.
      • Kubicka S.
      • Manns M.P.
      Pallidal lesions in patients with liver cirrhosis: clinical and MRI evaluation.
      Hyperintensities may increase after transjugular intrahepatic portosystemic shunt (TIPS) placement and reverse following improvement of liver function, occlusion of congenital portosystemic shunts, or liver transplantation. This suggests that pallidal intensity may be related to portal hypertension rather than HE. Conventional brain MRI techniques do not show T2-weighted signal-intensity abnormalities representing the slight cerebral oedema that may be present in patients with type C HE. 1H-magnetic resonance spectroscopy
      • Córdoba J.
      • Sanpedro F.
      • Alonso J.
      • Rovira A.
      1H magnetic resonance in the study of hepatic encephalopathy in humans.
      • Kreis R.
      • Farrow N.
      • Ross B.D.
      Localized 1H NMR spectroscopy in patients with chronic hepatic encephalopathy. Analysis of changes in cerebral glutamine, choline and inositols.
      • Ross B.D.
      • Jacobson S.
      • Villamil F.
      • Korula J.
      • Kreis R.
      • Ernst T.
      • et al.
      Subclinical hepatic encephalopathy: proton MR spectroscopic abnormalities.
      • Weissenborn K.
      • Ahl B.
      • Fischer-Wasels D.
      • van den Hoff J.
      • Hecker H.
      • Burchert W.
      • et al.
      Correlations between magnetic resonance spectroscopy alterations and cerebral ammonia and glucose metabolism in cirrhotic patients with and without hepatic encephalopathy.
      has been shown to be useful in the differential diagnosis of HE. Low levels of myoinositol and choline with high glutamine content have been associated with HE.
      • Zeng G.
      • Penninkilampi R.
      • Chaganti J.
      • Montagnese S.
      • Brew B.J.
      • Danta M.
      Meta-analysis of magnetic resonance spectroscopy in the diagnosis of hepatic encephalopathy.

      In patients with cirrhosis, should covert HE be screened for in the clinic and/or ward, and how?

      Recommendation
      • In patients with cirrhosis and no history of overt HE, screening for covert HE should be performed with tests for which experience/tools and local norms are available. As the only bedside test available to date, the Animal Naming Test is worthy of further study and validation (LoE 4, strong recommendation, 83% consensus).
      The diagnosis of covert HE is relevant because the condition occurs in 30-70% of patients with cirrhosis (to some extent depending on test methods and cut-off values), is associated with poor quality of life,
      • Hartmann I.J.
      • Groeneweg M.
      • Quero J.C.
      • Beijeman S.J.
      • de Man R.A.
      • Hop W.C.
      • et al.
      The prognostic significance of subclinical hepatic encephalopathy.
      • Schomerus H.
      • Hamster W.
      Quality of life in cirrhotics with minimal hepatic encephalopathy.
      • Marchesini G.
      • Bianchi G.
      • Amodio P.
      • Salerno F.
      • Merli M.
      • Panella C.
      • et al.
      Factors associated with poor health-related quality of life of patients with cirrhosis.
      reduced socio-economic potential,
      • Bajaj J.S.
      • Cordoba J.
      • Mullen K.D.
      • Amodio P.
      • Shawcross D.L.
      • Butterworth R.F.
      • et al.
      International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN). Review article: the design of clinical trials in hepatic encephalopathy--an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement.
      and, most importantly, with an increased risk of developing overt HE over time.
      • Hartmann I.J.
      • Groeneweg M.
      • Quero J.C.
      • Beijeman S.J.
      • de Man R.A.
      • Hop W.C.
      • et al.
      The prognostic significance of subclinical hepatic encephalopathy.
      ,
      • Romero-Gómez M.
      • Boza F.
      • García-Valdecasas M.S.
      • García E.
      • Aguilar-Reina J.
      Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy.
      • Patidar K.R.
      • Thacker L.R.
      • Wade J.B.
      • Sterling R.K.
      • Sanyal A.J.
      • Siddiqui M.S.
      • et al.
      Covert hepatic encephalopathy is independently associated with poor survival and increased risk of hospitalization.
      • Flud C.R.
      • Duarte-Rojo A.
      Prognostic implications of minimal/covert hepatic encephalopathy: large-scale validation cohort studies.
      Patients with covert HE have been shown not to drive as safely as unimpaired patients with cirrhosis,
      • Kircheis G.
      • Knoche A.
      • Hilger N.
      • Manhart F.
      • Schnitzler A.
      • Schulze H.
      • et al.
      Hepatic encephalopathy and fitness to drive.
      although driving ability is difficult to establish at a single patient level. Lastly, covert HE could impact on cirrhosis progression
      • Ampuero J.
      • Montoliú C.
      • Simón-Talero M.
      • Aguilera V.
      • Millán R.
      • Márquez C.
      • et al.
      Minimal hepatic encephalopathy identifies patients at risk of faster cirrhosis progression.
      and overall survival.
      • Ampuero J.
      • Simón M.
      • Montoliú C.
      • Jover R.
      • Serra M.Á.
      • Córdoba J.
      • et al.
      Minimal hepatic encephalopathy and critical flicker frequency are associated with survival of patients with cirrhosis.
      In patients without previous overt HE episodes, covert HE may predict overt HE, while in those with previous overt HE episodes, subsequent overt HE episodes depend more on the severity of liver dysfunction and/or portosystemic shunting.
      • Formentin C.
      • Zarantonello L.
      • Mangini C.
      • Frigo A.C.
      • Montagnese S.
      • Merkel C.
      Clinical, neuropsychological and neurophysiological indices and predictors of hepatic encephalopathy (HE).
      A genetic risk score combining previous bouts of overt HE, genetic profile and liver dysfunction has been used to calculate the risk of HE during follow-up.
      • Gil-Gómez A.
      • Ampuero J.
      • Rojas Á.
      • Gallego-Durán R.
      • Muñoz-Hernández R.
      • Rico M.C.
      • et al.
      Development and validation of a clinical-genetic risk score to predict hepatic encephalopathy in patients with liver cirrhosis.
      How to screen covert HE? Covert HE affects multiple facets of mental functioning, which may or may not be impaired to the same degree at any given time. Thus, the diagnosis is often better based on more than one test, to be chosen depending on available local norms/expertise.
      • Bajaj J.S.
      • Riggio O.
      • Allampati S.
      • Prakash R.
      • Gioia S.
      • Onori E.
      • et al.
      Cognitive dysfunction is associated with poor socioeconomic status in patients with cirrhosis: an international multicenter study.
      However, there is no gold standard, and very little data on how to combine and interpret different tests and their outcomes. Concordance between tests is low because they assess different pathways.
      • Ampuero J.
      • Simón M.
      • Montoliú C.
      • Jover R.
      • Serra M.Á.
      • Córdoba J.
      • et al.
      Minimal hepatic encephalopathy and critical flicker frequency are associated with survival of patients with cirrhosis.
      Tests can be neuropsychological (paper & pencil or computerised) or neurophysiological.
      • Montagnese S.
      • Russo F.P.
      • Amodio P.
      • Burra P.
      • Gasbarrini A.
      • Loguercio C.
      • et al.
      Hepatic encephalopathy 2018: a clinical practice guideline by the Italian Association for the Study of the Liver (AISF).
      Neuropsychological tests have the advantage of being closer to the disability one is attempting to measure. However, they are prone to learning effects and affected by both age and educational attainment; thus, the availability of pertinent local norms is crucial. The neuropsychological Animal Naming Test (i.e. the number of animals listed in 60 seconds, no equipment required) has recently been shown to compare favourably with more established covert HE measures,
      • Weissenborn K.
      • Ennen J.C.
      • Schomerus H.
      • Rückert N.
      • Hecker H.
      Neuropsychological characterization of hepatic encephalopathy.
      and to predict overt HE.
      • Campagna F.
      • Montagnese S.
      • Ridola L.
      • Senzolo M.
      • Schiff S.
      • De Rui M.
      • et al.
      The animal naming test: an easy tool for the assessment of hepatic encephalopathy.

      In patients with cirrhosis, does screening for covert HE enable treatment initiation and overt HE prevention?

      Recommendation
      • Patients with covert HE should be treated with non-absorbable disaccharides (LoE 3, strong recommendation, 92% consensus).
      Covert HE is a strong risk factor for overt HE and responds well to anti-HE interventions.
      • Mittal V.V.
      • Sharma B.C.
      • Sharma P.
      • Sarin S.K.
      A randomized controlled trial comparing lactulose, probiotics, and L-ornithine L-aspartate in treatment of minimal hepatic encephalopathy.
      It is therefore expected, but not yet proven in randomised-controlled trials (RCTs), that treatment will result in a reduction of overt HE episodes, which would add to the arguments for screening. The pathophysiology of any degree of HE is believed to be the same; covert HE is a risk factor for overt HE and, by and large, there is a progression in neuropsychological and neurophysiological abnormalities when moving from covert to overt HE. The difference between clinically detectable minor cognitive abnormalities (grade I) and abnormalities that require tests to detect (minimal) is often difficult to establish. This may speak in favour of considering both conditions as one entity (covert HE), including for the purposes of treatment initiation. There is evidence of beneficial effects of anti-HE strategies on neuropsychological and neurophysiological performance in several studies
      • Mittal V.V.
      • Sharma B.C.
      • Sharma P.
      • Sarin S.K.
      A randomized controlled trial comparing lactulose, probiotics, and L-ornithine L-aspartate in treatment of minimal hepatic encephalopathy.
      • Egberts E.H.
      • Schomerus H.
      • Hamster W.
      • Jürgens P.
      Branched chain amino acids in the treatment of latent portosystemic encephalopathy. A double-blind placebo-controlled crossover study.
      • Morgan M.Y.
      • Alonso M.
      • Stanger L.C.
      Lactitol and lactulose for the treatment of subclinical hepatic encephalopathy in cirrhotic patients. A randomised, cross-over study.
      • Malaguarnera M.
      • Gargante M.P.
      • Cristaldi E.
      • Vacante M.
      • Risino C.
      • Cammalleri L.
      • et al.
      Acetyl-L-carnitine treatment in minimal hepatic encephalopathy.
      • Malaguarnera M.
      • Greco F.
      • Barone G.
      • Gargante M.P.
      • Malaguarnera M.
      • Toscano M.A.
      Bifidobacterium longum with fructo-oligosaccharide (FOS) treatment in minimal hepatic encephalopathy: a randomized, double-blind, placebo-controlled study.
      • Pratap Mouli V.
      • Benjamin J.
      • Bhushan Singh M.
      • Mani K.
      • Garg S.K.
      • Saraya A.
      • et al.
      Effect of probiotic VSL#3 in the treatment of minimal hepatic encephalopathy: a non-inferiority randomized controlled trial.
      • Sidhu S.S.
      • Goyal O.
      • Parker R.A.
      • Kishore H.
      • Sood A.
      Rifaximin vs. lactulose in treatment of minimal hepatic encephalopathy.
      • Li X.
      • Gan D.
      • Li Y.
      • Zhang P.
      • Li Z.
      • Du H.
      • et al.
      JianPi HuaZhuo XingNao formula (Chinese herbal medicine) for the treatment of minimal hepatic encephalopathy: a protocol for a randomized, placebo-controlled pilot trial.
      • Xia X.
      • Chen J.
      • Xia J.
      • Wang B.
      • Liu H.
      • Yang L.
      • et al.
      Role of probiotics in the treatment of minimal hepatic encephalopathy in patients with HBV-induced liver cirrhosis.
      and some network meta-analyses.
      • Goh E.T.
      • Stokes C.S.
      • Sidhu S.S.
      • Vilstrup H.
      • Gluud L.L.
      • Morgan M.Y.
      L-ornithine L-aspartate for prevention and treatment of hepatic encephalopathy in people with cirrhosis.
      • Dhiman R.K.
      • Thumburu K.K.
      • Verma N.
      • Chopra M.
      • Rathi S.
      • Dutta U.
      • et al.
      Comparative efficacy of treatment options for minimal hepatic encephalopathy: a systematic review and network meta-analysis.
      • Gluud L.L.
      • Vilstrup H.
      • Morgan M.Y.
      Non-absorbable disaccharides vs. placebo/no intervention and lactulose vs. lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis.
      • Zacharias H.D.
      • Zacharias A.P.
      • Gluud L.L.
      • Morgan M.Y.
      Pharmacotherapies that specifically target ammonia for the prevention and treatment of hepatic encephalopathy in adults with cirrhosis.
      However, there are no robust data to confirm that treatment of covert HE also results in a reduction of overt HE risk. On the other hand, in a situation where covert HE is suspected, even if not confirmed, treatment with non-absorbable disaccharides (and/or rifaximin) could be initiated and, if beneficial, also used as confirmation of the diagnosis (ex juvantibus).

      In patients with liver failure and HE, are liver-support systems of proven benefit for HE?

      Statement
      • In patients with liver failure and overt HE, albumin dialysis ameliorates HE and can be considered. The impact on prognosis is, however, uncertain and further study is warranted (LoE 2, 77% consensus).
      An artificial liver assist device would be valuable to resolve HE by removing neurotoxins when liver function is impaired, especially if it also improves the prospects of survival. Several studies show that high-volume plasma exchange improves the grade of HE and confers a survival benefit in patients with acute liver failure, but this is not demonstrated in patients with cirrhosis.
      • Larsen F.S.
      • Schmidt L.E.
      • Bernsmeier C.
      • Rasmussen A.
      • Isoniemi H.
      • Patel V.C.
      • et al.
      High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial.
      The removal of both water-soluble and lipophilic substances from the blood by albumin dialysis, i.e. the molecular adsorbent recirculating system (MARS) device, has been shown in 3 RCTs and a meta-analysis (on raw data of these trials) to result in a faster reduction in the grade of HE in cirrhosis
      • Hassanein T.I.
      • Tofteng F.
      • Brown Jr., R.S.
      • McGuire B.
      • Lynch P.
      • Mehta R.
      • et al.
      Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis.
      ,
      • Bañares R.
      • Nevens F.
      • Larsen F.S.
      • Jalan R.
      • Albillos A.
      • Dollinger M.
      • et al.
      Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial.
      but with only a modest impact on survival.
      • Bañares R.
      • Ibáñez-Samaniego L.
      • Torner J.M.
      • Pavesi M.
      • Olmedo C.
      • Catalina M.V.
      • et al.
      Meta-analysis of individual patient data of albumin dialysis in acute-on-chronic liver failure: focus on treatment intensity.

      In patients with overt HE, does the prevention of further decompensation/worsening of the underlying liver disease improve prognosis?

      Recommendation
      • In patients with HE, all measures to control progression of the underlying liver disease should be undertaken (LoE 4, strong recommendation, 100% consensus).
      All of the classical signs of decompensation of cirrhosis, including HE, are individually and additively associated with increased mortality, although the association is strongest for HE.
      • Jepsen P.
      • Ott P.
      • Andersen P.K.
      • Sørensen H.T.
      • Vilstrup H.
      Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study.
      Decompensation usually accompanies progression of the underlying liver disease which determines short- and long-term prognosis.
      • Jepsen P.
      • Vilstrup H.
      • Ott P.
      • Keiding S.
      • Andersen P.K.
      • Tygstrup N.
      The galactose elimination capacity and mortality in 781 Danish patients with newly diagnosed liver cirrhosis: a cohort study.
      ,
      • Laursen T.L.
      • Sandahl T.D.
      • Kazankov K.
      • Eriksen P.L.
      • Kristensen L.H.
      • Holmboe C.H.
      • et al.
      Normalization of reduced urea synthesis capacity in patients with hepatitis C cirrhosis by successful direct-acting antiviral therapy.
      Management of non-HE decompensations, e.g. acute variceal bleeding, also improves prognosis even if the liver function remains unchanged. In the case of HE, it has not been studied specifically whether such interventions have the same positive effects on prognosis. However, despite the negative prognostic importance of HE, there is no basis for the assumption that management of other decompensations is without effect. It follows that management of non-HE decompensations and attempts to arrest liver disease progression, e.g. cessation of alcohol misuse in those with alcohol-related cirrhosis, will have a significant impact on the prognosis of patients with HE.

      In patients with overt HE, do the identification, prevention, and management of precipitating events, if any, improve treatment outcomes and prognosis?

      Recommendation
      • In patients with HE, precipitating factors should be sought and managed (LoE 2, strong recommendation, 100% consensus).
      The primary intervention in patients with overt HE is a search for, and correction of, any precipitating factors. This exercise always precedes specific anti-HE treatment and up to 90% of the patients can be expected to recover from episodic overt HE by correction of one or more precipitating factors.
      • Strauss E.
      • Tramote R.
      • Silva E.P.
      • Caly W.R.
      • Honain N.Z.
      • Maffei R.A.
      • et al.
      Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy.
      Specific treatment of HE has little prospect of success without management of precipitating factors. It remains uncertain if successful treatment of an episode of HE in itself improves prognosis. However, several HE-precipitating factors, e.g. infection and bleeding, are associated with increased mortality and effective management of such factors may improve prognosis in patients with overt HE. Finally, rapid removal of blood from the gastrointestinal tract
      • Tromm A.
      • Griga T.
      • Greving I.
      • Hilden H.
      • Huppe D.
      • Schwegler U.
      • et al.
      Orthograde whole gut irrigation with mannite vs. paromomycine + lactulose as pro-phylaxis of hepatic encephalopathy in patients with cirrhosis and upper gastrointestinal bleeding: results of a controlled randomized trial.
      and rapid resolution of constipation
      • Rahimi R.S.
      • Singal A.G.
      • Cuthbert J.A.
      • Rockey D.C.
      Lactulose vs. polyethylene glycol 3350—electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial.
      ,
      • Naderian M.
      • Akbari H.
      • Saeedi M.
      • Sohrabpour A.A.
      Polyethylene glycol and lactulose vs. lactulose alone in the treatment of hepatic encephalopathy in patients with cirrhosis: a non-inferiority randomized controlled trial.
      have been shown to improve recovery from an episode of overt HE.

      In patients with overt HE, which criteria should be used to guide admission to an intensive care unit (ICU) to improve outcome?

      Recommendation
      • Patients with overt HE grade 3 and 4 are at risk of aspiration and should be treated in the ICU. No single marker can identify patients who will benefit from ICU admission, and referral relies on clinical judgement (LoE 4, strong recommendation, 96% consensus).
      The clinical course of patients with HE stage 3-4 is unpredictable and often calls for a rapid decision regarding escalating monitoring and treatment, a clinical setting that speaks in favour of care in a high dependency or intensive care environment.
      • Romero-Gómez M.
      • Montagnese S.
      • Jalan R.
      Hepatic encephalopathy in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure.
      Relatively old studies showed a reluctance towards admitting such patients to the ICU.
      • Shellman R.G.
      • Fulkerson W.J.
      • DeLong E.
      • Piantadosi C.A.
      Prognosis of patients with cirrhosis and chronic liver disease admitted to the medical intensive care unit.
      ,
      • Wehler M.
      • Kokoska J.
      • Reulbach U.
      • Hahn E.G.
      • Strauss R.
      Short-term prognosis in critically ill patients with cirrhosis assessed by prognostic scoring systems.
      However, several prognostic scores, i.e. model for end-stage liver disease (MELD), APACHE II (Acute Physiology and Chronic Health Evaluation II) and CLIF-C (Chronic Liver Failure consortium) organ failure, are now available and can help identify patients with an unacceptably high predicted mortality, in whom ICU care is not warranted due to futility.
      • Durand F.
      • Nadim M.K.
      Management of acute-on-chronic liver failure.
      • Drolz A.
      • Horvatits T.
      • Rutter K.
      • Landahl F.
      • Roedl K.
      • Meersseman P.
      • et al.
      Lactate improves prediction of short-term mortality in critically ill patients with cirrhosis: a multinational study.
      • Campbell J.
      • McPeake J.
      • Shaw M.
      • Puxty A.
      • Forrest E.
      • Soulsby C.
      • et al.
      Validation and analysis of prognostic scoring systems for critically ill patients with cirrhosis admitted to ICU.
      • McPhail M.J.
      • Shawcross D.L.
      • Abeles R.D.
      • Chang A.
      • Patel V.
      • Lee G.H.
      • et al.
      Increased survival for patients with cirrhosis and organ failure in liver intensive care and validation of the chronic liver failure-sequential organ failure scoring system.
      Thus, overt HE in a patient with cirrhosis is not an absolute contraindication for admission to the ICU as it is potentially fully reversible. In patients with HE grade 3-4, and a Glasgow coma score less than 7, respiratory function is endangered as the patient is unable to protect their airways. In such cases, management in the ICU is recommended unless other factors speak against it.

      In patients with overt HE, which criteria should be used to guide referral to a liver transplantation centre?

      Recommendation
      • Patients with recurrent or persistent HE should be considered for liver transplantation and a first episode of overt HE should prompt referral to a transplant centre for evaluation (LoE 5, strong recommendation, 85% consensus).
      Liver transplantation represents the ultimate treatment for HE, but HE is not a transplantation indication in most countries, unless associated with liver failure. Emergency liver transplantation in patients with severe HE in the setting of acute liver failure is commonly indicated and results in rapid resolution of HE together with marked survival improvement.
      European Association for the Study of the Liver
      EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure.
      Liver transplantation in patients with overt HE due to cirrhosis may also be considered if associated with other signs of advanced liver failure, as determined by clinical condition and Child-Pugh and MELD scores.
      • Martin P.
      • DiMartini A.
      • Feng S.
      • Brown Jr., R.
      • Fallon M.
      Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation.
      ,
      • Cholongitas E.
      • Marelli L.
      • Shusang V.
      • Senzolo M.
      • Rolles K.
      • Patch D.
      • et al.
      A systematic review of the performance of the model for end-stage liver disease (MELD) in the setting of liver transplantation.
      Such patients, however, cannot be listed for emergency liver transplantation. Instead, the goal is to stabilise the patient and treat decompensation episodes including an overt HE episode, and then consider liver transplantation following recovery. However, this approach is not possible in all patients. Some patients with HE deteriorate and develop multiorgan failure, requiring treatment in the ICU and ultimately transplantation for survival. In highly selected patients with acute-on-chronic liver failure, liver transplantation results in acceptable outcomes.
      • Artru F.
      • Louvet A.
      • Ruiz I.
      • Levesque E.
      • Labreuche J.
      • Ursic-Bedoya J.
      • et al.
      Liver transplantation in the most severely ill cirrhotic patients: a multicenter study in acute-on-chronic liver failure grade 3.
      • Sundaram V.
      • Jalan R.
      • Wu T.
      • et al.
      Factors associated with survival of patients with severe acute-on-chronic liver failure before and after liver transplantation.
      • Thuluvath P.J.
      • Thuluvath A.J.
      • Hanish S.
      • Savva Y.
      Liver transplantation in patients with multiple organ failures: feasibility and outcomes.
      However, this approach is not widely used in Europe because of the limited availability of donor livers and strict allocation policies. The development of overt HE has been associated with poor transplant-free survival
      • Jepsen P.
      • Ott P.
      • Andersen P.K.
      • Sørensen H.T.
      • Vilstrup H.
      Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study.
      ,
      • Bustamante J.
      • Rimola A.
      • Ventura P.J.
      • Navasa M.
      • Cirera I.
      • Reggiardo V.
      • et al.
      Prognostic significance of hepatic encephalopathy in patients with cirrhosis.
      ; thus, a first episode of overt HE should prompt referral to a transplant centre for an initial evaluation.

      In patients who have had a first episode of overt HE, should secondary prophylaxis be initiated to prevent further episodes?

      Recommendations
      • Lactulose is recommended as secondary prophylaxis following a first episode of overt HE, and should be titrated to obtain 2-3 bowel movements per day (LoE 1, strong recommendation, 96% consensus).
      • Rifaximin as an adjunct to lactulose is recommended as secondary prophylaxis following ≥1 additional episodes of overt HE within 6 months of the first one (LoE 2, strong recommendation, 92% consensus).
      An open-label RCT showed that patients who had recovered from an episode of overt HE and were receiving lactulose had a 14-month HE recurrence risk of 20% vs. 47% among those who did not receive lactulose.
      • Sharma B.C.
      • Sharma P.
      • Lunia M.K.
      • Srivastava S.
      • Goyal R.
      • Sarin S.K.
      A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy.
      A recent systematic review and network meta-analysis of a total of 1,828 participants demonstrated that lactulose was effective at preventing overt episodes of HE with only mild gastrointestinal adverse effects.
      • Dhiman R.K.
      • Thumburu K.K.
      • Verma N.
      • Chopra M.
      • Rathi S.
      • Dutta U.
      • et al.
      Comparative efficacy of treatment options for minimal hepatic encephalopathy: a systematic review and network meta-analysis.
      An updated Cochrane review,
      • Gluud L.L.
      • Vilstrup H.
      • Morgan M.Y.
      Non-absorbable disaccharides vs. placebo/no intervention and lactulose vs. lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis.
      evaluating 38 trials, demonstrated a beneficial effect of lactulose on preventing overt episodes of HE (risk ratio [RR] 0.58, 95% CI 0.50 to 0.69; 1,415 participants; 22 RCTs) but only 2 of these RCTs specifically addressed the effectiveness of lactulose in the secondary prophylaxis of overt HE.
      • Sharma B.C.
      • Sharma P.
      • Lunia M.K.
      • Srivastava S.
      • Goyal R.
      • Sarin S.K.
      A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy.
      ,
      • Agrawal A.
      • Sharma B.C.
      • Sharma P.
      • Sarin S.K.
      Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy.
      Rifaximin compared to placebo decreased the risk of recurrence of overt HE in patients with cirrhosis and ≥2 episodes of overt HE within the previous 6 months, with HE episodes occurring in 22.1% of patients in the rifaximin group vs. 45.9% in the placebo group (number needed to treat 4) (hazard ratio 0.42; 95% CI 0.28 to 0.64; p <0.001). Rifaximin also decreased the risk of hospitalisation (13.6%) vs. placebo (22.6%), with a number needed to treat of 9; of these patients, 91% were on concurrent lactulose therapy, supporting the use of rifaximin in addition to lactulose for the prevention of HE after a second overt HE episode.
      • Bass N.M.
      • Mullen K.D.
      • Sanyal A.
      • Poordad F.
      • Neff G.
      • Leevy C.B.
      • et al.
      Rifaximin treatment in hepatic encephalopathy.
      In a systematic review and meta-analysis including this trial and one further smaller RCT which did not show benefit,
      • Ali B.
      • Zaidi Y.A.
      • Alam A.
      • Anjum H.S.
      Efficacy of Rifaximin in prevention of recurrence of hepatic encephalopathy in patients with cirrhosis of liver.
      overall, rifaximin had a beneficial effect on the secondary prevention of overt HE (RR 1.32; 95% CI 1.06 to 1.65).
      • Kimer N.
      • Krag A.
      • Møller S.
      • Bendtsen F.
      • Gluud L.L.
      Systematic review with meta-analysis: the effects of rifaximin in hepatic encephalopathy.
      Due to the very low overall quality of published trials, there is no evidence for the use of probiotics compared with lactulose and no RCT has examined probiotics in the secondary prevention of overt HE.
      • Dalal R.
      • McGee R.G.
      • Riordan S.M.
      • Webster A.C.
      Probiotics for people with hepatic encephalopathy.
      Branched-chain amino acids have a beneficial effect on HE (RR 0.73, 95% CI 0.61 to 0.88; 827 participants; 16 trials; high quality of evidence)
      • Gluud L.L.
      • Dam G.
      • Les I.
      • Marchesini G.
      • Borre M.
      • Aagaard N.K.
      • et al.
      Branched-chain amino acids for people with hepatic encephalopathy.
      but, in the only high quality RCT to date, they did not prevent recurrence in patients with a previous episode of overt HE.
      • Les I.
      • Doval E.
      • García-Martínez R.
      • Planas M.
      • Cárdenas G.
      • Gómez P.
      • et al.
      Effects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study.

      Should prophylaxis of HE be used in an acute bleeding episode in patients with cirrhosis?

      Recommendation
      • In patients presenting with gastrointestinal bleeding, rapid removal of blood from the gastrointestinal tract (lactulose or mannitol by naso-gastric tube or lactulose enemas) can be used to prevent HE (LoE 1, strong recommendation, 85% consensus).
      Gastrointestinal bleeding often precipitates HE, and HE is generally multifactorial in nature (liver failure, hyperammonaemia, systemic inflammation and infection). The relationship between gastrointestinal bleeding and increase in blood ammonia is well established.
      • Bessman A.N.
      • Hawkins R.
      The relative effects of enterically administered plasma and packed cells on circulating blood ammonia.
      ,
      • Jalan R.
      • Olde Damink S.W.
      • Lui H.F.
      • Glabus M.
      • Deutz N.E.
      • Hayes P.C.
      • et al.
      Oral amino acid load mimicking hemoglobin results in reduced regional cerebr. Oral amino acid load mimicking hemoglobin results in reduced regional cerebral perfusionand deterioration in memory tests in patients with cirrhosis of the liver.
      A recent open-label single-centre randomised study showed that lactulose treatment significantly reduced the incidence of HE in patients with gastrointestinal bleeding (14% vs. 40 %, p <0.03), without any effect on survival (8.5% vs. 14%, p = n.s.).
      • Sharma P.
      • Agrawal A.
      • Sharma B.C.
      • Sarin S.K.
      Prophylaxis of hepatic encephalopathy in acute variceal bleed: a randomized controlled trial of lactulose vs. no lactulose.
      Another single-centre open-label randomised study also suggested that lactulose significantly reduced HE incidence (3.2% vs. 16.9 %, p <0.02); the factors independently associated with the occurrence of HE were Child-Pugh score and lactulose treatment.
      • Wen J.
      • Liu Q.
      • Song J.
      • Tong M.
      • Peng L.
      • Liang H.
      Lactulose is highly potential in prophylaxis of hepatic encephalopathy in patients with cirrhosis and upper gastrointestinal bleeding: results of a controlled randomized trial.
      The meta-analysis of those 2 trials confirmed the beneficial effect of lactulose on the prevention of HE during gastrointestinal bleeding (7% vs. 28%, p <0.01), though it was not associated with any survival benefit.
      • Aires F.T.
      • Ramos P.T.
      • Bernardo W.M.
      Efficacy of lactulose in the prophylaxis of hepatic encephalopathy in cirrhotic patients presenting gastrointestinal bleeding.
      Mannitol by mouth has also been shown to work in this context, also by comparison with paromomycin plus lactulose.
      • Rolachon A.
      • Zarski J.P.
      • Lutz J.M.
      • Fournet J.
      • Hostein J.
      Is the intestinal lavage with a solution of mannitol effective in the prevention of post-hemorrhagic hepatic encephalopathy in patients with liver cirrhosis? Results of a randomized prospective study.
      ,
      • Li M.
      • Zhang Z.
      • Chen Q.
      • Zhou X.
      • Shui D.
      • Huang J.
      Comparative effectiveness and safety of polyethylene glycol electrolyte solution vs. lactulose for treatment of hepatic encephalopathy: a systematic review and meta-analysis.
      In patients with gastrointestinal bleeding, broad-spectrum antibiotic prophylaxis also had a beneficial effect on survival, especially in patients with Child-Pugh C cirrhosis. However, the efficacy of antibiotic prophylaxis on HE occurrence has not been studied.

      Should prophylaxis of HE be used before TIPS placement in patients with cirrhosis?

      Recommendation
      • In patients with cirrhosis and previous episodes of overt HE, rifaximin can be considered for prophylaxis of HE prior to non-urgent TIPS placement. Non-absorbable disaccharides, as a stand-alone or in combination, are worthy of further study in this context (LoE 2, strong recommendation, 82% consensus).
      One of the main drawbacks of TIPS for the treatment of portal hypertension-related complications is the increased risk of HE. On average, an episode of overt HE occurs in 35% to 50% of patients after TIPS.
      • Riggio O.
      • Merlli M.
      • Pedretti G.
      • Servi R.
      • Meddi P.
      • Lionetti R.
      • et al.
      Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt. Incidence and risk factors.
      • Zuo L.
      • Lv Y.
      • Wang Q.
      • Yin Z.
      • Wang Z.
      • He C.
      • et al.
      Early-recurrent overt hepatic encephalopathy is associated with reduced survival in cirrhotic patients after transjugular intrahepatic portosystemic shunt creation.
      • Bai M.
      • Qi X.S.
      • Yang Z.P.
      • Yang M.
      • Fan D.M.
      • Han G.H.
      TIPS improves liver transplantation-free survival in cirrhotic patients with refractory ascites: an updated meta-analysis.
      Mortality is more than doubled in patients with early overt HE (hazard ratio 2.75; 95% CI 1.75-4.32; p <0.001),
      • Zuo L.
      • Lv Y.
      • Wang Q.
      • Yin Z.
      • Wang Z.
      • He C.
      • et al.
      Early-recurrent overt hepatic encephalopathy is associated with reduced survival in cirrhotic patients after transjugular intrahepatic portosystemic shunt creation.
      which was confirmed in a meta-analysis.
      • Bai M.
      • Qi X.S.
      • Yang Z.P.
      • Yang M.
      • Fan D.M.
      • Han G.H.
      TIPS improves liver transplantation-free survival in cirrhotic patients with refractory ascites: an updated meta-analysis.
      This risk of HE after TIPS may be nearly halved using a smaller diameter covered stent.
      • Wang Q.
      • Lv Y.
      • Bai M.
      • Wang Z.
      • Liu H.
      • He C.
      • et al.
      Eight millimetre covered TIPS does not compromise shunt function but reduces hepatic encephalopathy in preventing variceal rebleeding.
      HE developed in significantly more of those with a stent >8 mm compared to 6-7 mm (54% vs. 27%; p = 0.015),
      • Schepis F.
      • Vizzutti F.
      • Garcia-Tsao G.
      • Marzocchi G.
      • Rega L.
      • De Maria N.
      • et al.
      Under-dilated TIPS associate with efficacy and reduced encephalopathy in a prospective, non-randomized study of patients with cirrhosis.
      but the benefit of placing smaller stents has not been confirmed in all studies.
      • Riggio O.
      • Ridola L.
      • Angeloni S.
      • Cerini F.
      • Pasquale C.
      • Attili A.F.
      • et al.
      Clinical efficacy of transjugular intrahepatic portosystemic shunt created with covered stents with different diameters: results of a randomized controlled trial.
      Whilst a previous RCT comparing lactitol 60 g/day with rifaximin 1,200 mg/day and no treatment did not show pharmacological therapy to be effective for prophylaxis during the first month after TIPS placement,
      • Riggio O.
      • Masini A.
      • Efrati C.
      • Nicolao F.
      • Angeloni S.
      • Salvatori F.M.
      • et al.
      Pharmacological prophylaxis of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled study.
      a large double-blind placebo-controlled RCT supports the use of rifaximin to prevent post-TIPS HE
      • Bureau C.
      • Thabut D.
      • Jezequel C.
      • Archambeaud I.
      • D'Alteroche L.
      • Dharancy S.
      • et al.
      The use of rifaximin in the prevention of overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled trial.
      : in 197 patients with cirrhosis undergoing TIPS for intractable ascites or prevention of variceal rebleeding, rifaximin 600 mg twice daily significantly reduced the incidence of an overt HE episode over the following 168 days (53% vs. 34%) (post hoc RCT analysis). In this trial, rifaximin was started 14 days prior to TIPS placement and continued for approximately 6 months. The potential benefit of rifaximin 6 months after TIPS and beyond remains to be investigated. Human albumin solution has no impact on HE occurrence after TIPS.
      • Riggio O.
      • Nardelli S.
      • Pasquale C.
      • Pentassuglio I.
      • Gioia S.
      • Onori E.
      • et al.
      No effect of albumin infusion on the prevention of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt.

      When should prophylactic therapy for HE be discontinued in patients with cirrhosis?

      Recommendation
      • In patients with a history of overt HE with improvement of liver function and nutritional status and in whom precipitant factors have been controlled, discontinuation of anti-HE therapy should be considered on an individual basis (LoE 5, weak recommendation, 77% consensus).
      No RCT is available to demonstrate the beneficial impact of stopping prophylactic therapy. In patients with a history of overt HE whose liver function
      • Montagnese S.
      • De Rui M.
      • Schiff S.
      • Ceranto E.
      • Valenti P.
      • Angeli P.
      • et al.
      Prognostic benefit of the addition of a quantitative index of hepatic encephalopathy to the MELD score: the MELD-EEG.
      and/or nutritional status
      • Maharshi S.
      • Sharma B.C.
      • Sachdeva S.
      • Srivastava S.
      • Sharma P.
      Efficacy of nutritional therapy for patients with cirrhosis and minimal hepatic encephalopathy in a randomized trial.
      has improved, or in those patients whose history of overt HE was due to a precipitant factor which will not recur (for example a patient with a history of overt HE precipitated by gastrointestinal bleeding whose varices have been obliterated) discontinuation of therapy can be considered on a case-by-case basis.

      In patients with HE, is zinc supplementation a treatment option to improve mental status?

      Recommendation
      • In patients with HE, routine zinc supplementation is not recommended (LoE 2, strong recommendation, 95% consensus).
      Tissue zinc concentrations have been shown to be reduced in patients with cirrhosis and zinc has been implicated in the pathogenesis of HE.
      • Grüngreiff K.
      • Reinhold D.
      • Wedemeyer H.
      The role of zinc in liver cirrhosis.
      ,
      • Miwa T.
      • Hanai T.
      • Maeda T.
      • Ogiso Y.
      • Imai K.
      • Suetsugu A.
      • et al.
      Zinc deficiency predicts overt hepatic encephalopathy and mortality in liver cirrhosis patients with minimal hepatic encephalopathy.
      However, data on the effects of zinc supplementation on mental performance are conflicting
      • Grüngreiff K.
      • Reinhold D.
      • Wedemeyer H.
      The role of zinc in liver cirrhosis.
      ,
      • Reding P.
      • Duchateau J.
      • Bataille C.
      Oral zinc supplementation improves hepatic encephalopathy. Results of a randomised controlled trial.
      • Riggio O.
      • Ariosto F.
      • Merli M.
      • Caschera M.
      • Zullo A.
      • Balducci G.
      • et al.
      Short-term oral zinc supplementation does not improve chronic hepatic encephalopathy. Results of a double-blind crossover trial.
      • Bresci G.
      • Parisi G.
      • Banti S.
      Management of hepatic encephalopathy with oral zinc supplementation: a long-term treatment.
      • Chavez-Tapia N.C.
      • Cesar-Arce A.
      • Barrientos-Gutiérrez T.
      • Villegas-López F.A.
      • Méndez-Sanchez N.
      • Uribe M.
      A systematic review and meta-analysis of the use of oral zinc in the treatment of hepatic encephalopathy.
      • Katayama K.
      • Saito M.
      • Kawaguchi T.
      • Endo R.
      • Sawara K.
      • Nishiguchi S.
      • et al.
      Effect of zinc on liver cirrhosis with hyperammonemia: a preliminary randomized, placebo-controlled double-blind trial.
      • Mousa N.
      • Abdel-Razik A.
      • Zaher A.
      • Hamed M.
      • Shiha G.
      • Effat N.
      • et al.
      The role of antioxidants and zinc in minimal hepatic encephalopathy: a randomized trial.
      and supplementation, as a rule, cannot be recommended as part of HE management.

      Is vitamin/micronutrient supplementation a treatment option to improve mental status in patients with HE?

      Recommendation
      • In patients with HE, demonstrated or suspected vitamin/micronutrient deficiencies should be treated, as they can compound HE (LoE 4, weak recommendation, 88% consensus).
      Patients with both alcohol- and non-alcohol-related cirrhosis are prone to deficiencies in water-soluble vitamins, particularly thiamine. Post-mortem evidence of Wernicke’s encephalopathy is often observed, even in the absence of a history/clinical signs during life.
      • Kril J.J.
      • Butterworth R.F.
      Diencephalic and cerebellar pathology in alcoholic and nonalcoholic patients with end-stage liver disease.
      If Wernicke’s encephalopathy is suspected, high-dose parenteral thiamine supplementation is mandatory. Deficiencies in pyridoxine, folate and cobalamin may also develop rapidly in chronic liver disease due to diminished hepatic storage.
      • Bemeur C.
      • Butterworth R.F.
      Nutrition in the management of cirrhosis and its neurological complications.
      However, good-quality data on their prevalence and/or need for correction are limited, as routine vitamin/micronutrient status is not easily assessed in patients with cirrhosis. Nevertheless, a course of oral multivitamin supplementation could be justified in patients with decompensated liver disease.
      • Amodio P.
      • Bemeur C.
      • Butterworth R.
      • Cordoba J.
      • Kato A.
      • Montagnese S.
      • et al.
      The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.
      Finally, one should always be reminded that vitamin/micronutrient deficiencies may cause a metabolic encephalopathy which can accompany but should not be confused with HE.

      In patients with recurrent/persistent HE, is the identification and, where possible, the obliteration of portal-systemic shunts a treatment option to improve outcome?

      Recommendation
      • Obliteration of accessible portal-systemic shunts in patients with cirrhosis with recurrent or persistent HE (despite adequate medical treatment) can be considered in stable patients with a MELD score <11 (LoE 4, weak recommendation, 100% consensus).
      Large spontaneous portal-systemic shunts are associated with recurrent or persistent HE in cirrhosis. Up to one-third of patients with cirrhosis have large (>8 mm) or smaller portal-systemic shunts on imaging. Almost 50% of these are splenorenal shunts. HE was reported in 48% of patients with large portal-systemic shunts and 34% of patients with small portal-systemic shunts.
      • Simón-Talero M.
      • Roccarina D.
      • Martínez J.
      • Lampichler K.
      • Baiges A.
      • Low G.
      • et al.
      Association between portosystemic shunts and increased complications and mortality in patients with cirrhosis.
      Portal-systemic shunts with a total surface area >83 mm2 increase the risk of overt HE and mortality in patients with cirrhosis.
      • Praktiknjo M.
      • Simón-Talero M.
      • Römer J.
      • Roccarina D.
      • Martínez J.
      • Lampichler K.
      • et al.
      Total area of spontaneous portosystemic shunts independently predicts hepatic encephalopathy and mortality in liver cirrhosis.
      Only 2 small retrospective cohort studies including a total of 58 patients have examined the utility of shunt obliteration.
      • Laleman W.
      • Simon-Talero M.
      • Maleux G.
      • Perez M.
      • Ameloot K.
      • Soriano G.
      • et al.
      Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicenter survey on safety and efficacy.
      ,
      • Philips C.A.
      • Kumar L.
      • Augustine P.
      Shunt occlusion for portosystemic shunt syndrome related refractory hepatic encephalopathy-A single-center experience in 21 patients from Kerala.
      Shunt embolisation in patients with recurrent or persistent HE who were diagnosed with a single large portal-systemic shunt resulted in almost 60% of patients being free of HE at 100 days and almost 50% remaining free of HE for 2 years in a European multicentre cohort study.
      • Laleman W.
      • Simon-Talero M.
      • Maleux G.
      • Perez M.
      • Ameloot K.
      • Soriano G.
      • et al.
      Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicenter survey on safety and efficacy.
      Hospitalisation rate and HE severity were also decreased. MELD score was the strongest positive predictive factor of HE recurrence, with a cut-off of 11 used for patient selection to ensure safe embolisation without an increase in de novo development or aggravation of pre-existing varices, portal hypertensive gastropathy, or ascites. The success of this intervention therefore seems to be dependent on whether there is sufficient functional liver mass to accommodate redirected portal flow.
      • Laleman W.
      • Simon-Talero M.
      • Maleux G.
      • Perez M.
      • Ameloot K.
      • Soriano G.
      • et al.
      Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicenter survey on safety and efficacy.
      ,
      • Philips C.A.
      • Kumar L.
      • Augustine P.
      Shunt occlusion for portosystemic shunt syndrome related refractory hepatic encephalopathy-A single-center experience in 21 patients from Kerala.
      A trial of shunt obliteration by coil-assisted retrograde transvenous obliteration has also shown extremely promising results and limited side-effects in patients with highly recurrent or persistent HE.
      • Lee E.W.
      • Saab S.
      • Kaldas F.
      • Fletcher S.
      • Busuttil R.W.
      • Durazo F.
      • et al.
      Coil-assisted retrograde transvenous obliteration (CARTO): an alternative treatment option for refractory hepatic encephalopathy.
      In conclusion, obliteration of accessible portal-systemic shunts in patients with cirrhosis with recurrent or persistent HE can be considered in stable patients with a low MELD score and no obvious contraindications.

      In patients with recurrent/persistent HE, is the replacement of animal protein with vegetable and dairy protein a treatment option to improve outcome?

      Recommendation
      • In patients with recurrent/persistent HE, replacement of animal protein with vegetable and dairy protein can be considered, provided that overall protein intake is not compromised and that patient’s tolerance is considered (LoE 4, weak recommendation, 83% consensus).
      While the rationale for the replacement of animal protein with vegetarian and dairy protein in patients with HE is compelling, the evidence base to support it is scarce and controversial.
      • Amodio P.
      • Bemeur C.
      • Butterworth R.
      • Cordoba J.
      • Kato A.
      • Montagnese S.
      • et al.
      The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.
      ,
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines on nutrition in chronic liver disease.
      In short-term analysis in patients with chronic HE shifting from animal to vegetable proteins was associated with slight improvements in psychometric tests and ammonia balance.
      • Bianchi G.P.
      • Marchesini G.
      • Fabbri A.
      • Rondelli A.
      • Bugianesi E.
      • Zoli M.
      • et al.
      Vegetable vs. animal protein diet in cirrhotic patients with chronic encephalopathy. A randomized cross-over comparison.
      ,
      • Keshavarzian A.
      • Meek J.
      • Sutton C.
      • Emery V.M.
      • Hughes E.A.
      • Hodgson H.J.
      Dietary protein supplementation from vegetable sources in the management of chronic portal systemic encephalopathy.
      However, changes in dietary habits are not easy to implement, and tolerance and adherence to vegetarian proteins could be reduced, impacting on overall nutritional status. Furthermore, unmonitored use of vegetarian and dairy diets can lead to decreased overall protein and calorie intake and should therefore: i) be confined to patients in whom standard treatment has failed and who seem truly intolerant to animal protein
      • Shaw S.
      • Worner T.M.
      • Lieber C.S.
      Comparison of animal and vegetable protein sources in the dietary management of hepatic encephalopathy.
      ; and ii) performed by expert centres under very close dietary monitoring to avoid inducing weight loss and sarcopenia.
      • Amodio P.
      • Bemeur C.
      • Butterworth R.
      • Cordoba J.
      • Kato A.
      • Montagnese S.
      • et al.
      The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.
      ,
      • Counsell C.
      • Warlow C.
      Failure of presumed hepatic myelopathy to improve after liver transplantation.

      In patients with recurrent/persistent HE, is liver transplantation a treatment option to improve outcome?

      Recommendation
      • Patients with end-stage liver disease and recurrent or persistent HE not responding to other treatments should be assessed for liver transplantation (LoE 4, strong recommendation, 100% consensus).
      The development of HE in patients with cirrhosis is associated with reduced quality of life and a poor prognosis.
      • Bustamante J.
      • Rimola A.
      • Ventura P.J.
      • Navasa M.
      • Cirera I.
      • Reggiardo V.
      • et al.
      Prognostic significance of hepatic encephalopathy in patients with cirrhosis.
      Recurrent or persistent HE is frequently driven by spontaneous portosystemic shunting; dominant shunts should be identified, and obliteration considered in those with MELD scores <11. Post-TIPS HE can be treated by shunt reduction or closure. If no shunts can be identified or the patient does not respond to occlusion or if liver function is poor, liver transplantation is the last treatment option. In patients with HE as the primary driver for transplantation, it can be difficult to determine the right time to consider transplantation as the allocation of donor organs in many transplantation centres relies on the MELD score, which does not include HE.
      • Acharya C.
      • Bajaj J.S.
      Hepatic encephalopathy and liver transplantation: the past, present, and future toward equitable access.
      A pragmatic solution is to consider liver transplantation i) once the patient has experienced an index complication, including HE, with a MELD score above 15, and ii) when a patient has a history of recurrent hospitalisation for overt HE.
      • Martin P.
      • DiMartini A.
      • Feng S.
      • Brown Jr., R.
      • Fallon M.
      Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation.
      Patients with chronic persistent HE with only a mild degree of hepatic insufficiency may be considered for liver transplantation if all other treatments have failed. This requires careful work-up and the patient, family and other health professionals should be aware that the manifestations of HE are not always resolved as quickly as expected after liver transplantation.
      • Hopp A.E.
      • Dirks M.
      • Petrusch C.
      • Goldbecker A.
      • Tryc A.B.
      • Barg-Hock H.
      • et al.
      Hepatic encephalopathy is reversible in the long term after liver transplantation.
      ,
      • Albhaisi S.A.M.
      • Bajaj J.S.
      Cognitive function in liver transplantation.
      Great attention should be paid to closure of all shunts during the transplantation procedure.

      In patients with hepatic myelopathy, is liver transplantation a treatment option to improve outcome?

      Recommendation
      • In patients with hepatic myelopathy, liver transplantation should be considered as soon as possible since there is no other therapeutic option (LoE 4, strong recommendation, 94% consensus).
      Hepatic myelopathy is a rare complication of cirrhosis that is most often (>80%) accompanied by extensive portosystemic shunts.
      • Nardone R.
      • Buratti T.
      • Oliviero A.
      • Lochmann A.
      • Tezzon F.
      Corticospinal involvement in patients with a portosystemic shunt due to liver cirrhosis: a MEP study.
      ,
      • Koo J.E.
      • Lim Y.S.
      • Myung S.J.
      • Suh K.S.
      • Kim K.M.
      • Lee H.C.
      • et al.
      Hepatic myelopathy as a presenting neurological complication in patients with cirrhosis and spontaneous splenorenal shunt.
      It is characterised by rapidly progressing spastic paraparesis without sensory deficit or sphincter dysfunction and does not respond to standard therapies for HE. After months of progression patients either depend on walking aids or become wheelchair-dependent.
      • Campellone J.V.
      • Lacomis D.
      • Giuliani M.J.
      • Kroboth F.J.
      Hepatic myelopathy. Case report with review of the literature.
      For differential diagnosis spinal MRI should be performed to exclude other possible causes of a myelopathy including vitamin B12-, thiamine, and copper deficiency. In a short case series,
      • Troisi R.
      • Debruyne J.
      • de Hemptinne B.
      Improvement of hepatic myelopathy after liver transplantation.
      ,
      • 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.
      patients with clinical signs of hepatic myelopathy who underwent liver transplantation had similar outcomes as patients transplanted due to other forms of HE.
      • Baccarani U.
      • Zola E.
      • Adani G.L.
      • Cavalletti M.
      • Schiff S.
      • Cagnin A.
      • et al.
      Reversal of hepatic myelopathy after liver transplantation: fifteen plus one.
      • Caldwell C.
      • Werdiger N.
      • Jakab S.
      • Schilsky M.
      • Arvelakis A.
      • Kulkarni S.
      • et al.
      Use of model for end-stage liver disease exception points for early liver transplantation and successful reversal of hepatic myelopathy with a review of the literature.
      • Qu B.
      • Liu C.
      • Guo L.
      • Yang Y.
      • Li J.H.
      • Yu L.
      • et al.
      The role of liver transplantation of hepatic myelopathy: case report with review of the literature.

      In patients with cirrhosis-related Parkinsonism, are dopaminergic drugs a treatment option to improve outcome?

      Recommendation
      • In patients with cirrhosis-related Parkinsonism, dopaminergic treatment should be tested (LoE 2, strong recommendation, 95% consensus).
      There are a few case reports on the effect of dopaminergic drugs in cirrhosis-related Parkinsonism, but only 2 controlled studies. In contrast to the case reports and case series which showed contradictory results, the 2 controlled studies point to a possible benefit of dopaminergic treatment for patients with cirrhosis-related Parkinsonism. A RCT included 6 patients treated for 8-12 weeks with 15 mg bromocriptine/day after increasing the daily dose from 2.5 mg to 15 mg over a time period of 16 days. The patients were assessed by physicians unaware of the trial drug. All patients showed an improvement in their mental state and speech, impaired gait was improved in 2 of 4, as was tremor in 4 of 4. After the initial phase, 5 of the patients were further treated in a double-blind cross-over design for 16 weeks. Those patients who received placebo during the first 8 weeks of this cross-over trial rapidly deteriorated to their former functional status but improved again when bromocriptine was re-started. Those who crossed to placebo after another 8 weeks of bromocriptine therapy deteriorated as well, but only after about 1 week of placebo therapy.
      • Morgan M.Y.
      • Jakobovits A.W.
      • James I.M.
      • Sherlock S.
      Successful use of bromocriptine in the treatment of chronic hepatic encephalopathy.
      In 2018, another double-blind, randomised, placebo-controlled study to assess the efficacy of bromocriptine in patients with cirrhosis-related Parkinsonism was reported. Twenty-two were randomised to receive placebo, 24 to receive bromocriptine. The bromocriptine dose was increased from 2.5 mg to 15 mg within 4 weeks. The primary endpoint was response to treatment at 12 weeks. Response to treatment was defined as a >30% reduction in the baseline UPDRS motor score at 12 weeks of therapy. Partial response was defined as reduction in the score of 10%-30% at 12 weeks of therapy and non-response was defined as a reduction in Unified Parkinson Disease Rating Scale (UPDRS) motor score of <10% at 12 weeks of therapy. Response was seen in 7 patients (29%) in the bromocriptine group compared to none in the placebo group. Twelve patients in the treatment group (50%) compared to 1 in the placebo group (4.5%) showed partial response. No major adverse events occurred in either treatment group. Of note, non-responders were more severely affected, had significant postural instability and a longer history of Parkinsonian clinical symptoms, indicating that treatment should be started early in the development of the disease.
      • Sahney A.
      • Sharma B.C.
      • Jindal A.
      • Anand L.
      • Arora V.
      • Vijayaraghavan R.
      • et al.
      A double-blind randomized controlled trial to assess efficacy of bromocriptine in cirrhotic patients with hepatic parkinsonism.
      In conclusion, there is evidence for a benefit of bromocriptine treatment in patients with cirrhosis-related Parkinsonism.

      In patients with recurrent/persistent HE, is faecal microbiota transplantation (FMT) a treatment option to improve outcome?

      Recommendation
      • In patients with recurrent/persistent HE, FMT is not routinely recommended as a treatment option but its validation in large randomised placebo-controlled trials powered for clinical outcomes is warranted (LoE 2, weak recommendation, 93% consensus).
      Gut microbiome changes have prime importance in the pathogenesis of cirrhosis and HE.
      • Bajaj J.S.
      • Heuman D.M.
      • Hylemon P.B.
      • Sanyal A.J.
      • White M.B.
      • Monteith P.
      • et al.
      Altered profile of human gut microbiome is associated with cirrhosis and its complications.
      FMT is a well-established treatment to modify the gut microbiome and has been shown to be safe and efficacious in disease states resulting from gut dysbiosis including Clostridium difficile infection.
      • Baxter M.
      • Colville A.
      Adverse events in faecal microbiota transplant: a review of the literature.
      Patients with cirrhosis have an imbalance between healthy and pathogenic gut bacteria with skewed microbiota populations in favour of increased numbers of pro-inflammatory and ammoniagenic species including Enterobacteriaceae, Firmicutes, Archaea and Prevotella.
      • Qin N.
      • Yang F.
      • Li A.
      • Prifti E.
      • Chen Y.
      • Shao L.
      • et al.
      Alterations of the human gut microbiome in liver cirrhosis.
      In an open-label randomised phase I safety trial of 10 patients treated with FMT via rectal enema, FMT was shown to be safe and potentially efficacious in treating HE.
      • Bajaj J.S.
      • Kassam Z.
      • Fagan A.
      • Gavis E.A.
      • Liu E.
      • Cox I.J.
      • et al.
      Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial.
      However, patients were treated with broad-spectrum antibiotics prior to FMT and the favourable impact may have been related to the antibiotic administration (not given to the standard of care arm). This would still support FMT as having possible utility in restoring antibiotic-induced disruption in microbial diversity and function in the context of HE.
      • Bajaj J.S.
      • Kakiyama G.
      • Savidge T.
      • Takei H.
      • Kassam Z.A.
      • Fagan A.
      • et al.
      Antibiotic-associated disruption of microbiota composition and function in cirrhosis is restored by fecal transplant.
      The long-term safety and efficacy of FMT was studied within this population between 12 and 15 months. The FMT cohort had no adverse effects on long-term follow-up.
      • Bajaj J.S.
      • Fagan A.
      • Gavis E.A.
      • Kassam Z.
      • Sikaroodi M.
      • Gillevet P.M.
      Long-term outcomes of fecal microbiota transplantation in patients with cirrhosis.
      Encapsulated FMT offers a more practically feasible modality of treatment. Bajaj et al. have recently published a phase I study demonstrating that oral FMT capsules are safe and well tolerated in 10 patients with cirrhosis and recurrent HE.
      • Bajaj J.S.
      • Salzman N.H.
      • Acharya C.
      • Sterling R.K.
      • White M.B.
      • Gavis E.A.
      • et al.
      Fecal microbial transplant capsules are safe in hepatic encephalopathy: a phase 1, randomized, placebo-controlled trial.
      FMT was associated with improved duodenal mucosal diversity, anti-microbial peptide expression, lipopolysaccharide-binding protein and improved cognitive performance. Preliminary data is encouraging, but further validation in larger randomised placebo-controlled trials focusing on clinical endpoints are warranted before it can be recommended as a treatment option.

      In patients with cirrhosis and covert HE, is it useful to institute treatment for the purposes of differential diagnosis and to reduce the likelihood of developing overt HE?

      Recommendation
      • In patients with covert HE, anti-HE treatment should be considered for the purposes of differential diagnosis and to prevent overt HE (LoE 5, strong recommendation, 89% consensus).
      While there is evidence of varying strengths that show treatment can reverse covert HE, improve quality of life and reduce the likelihood of overt HE,
      • Dhiman R.K.
      • Thumburu K.K.
      • Chopra M.
      • Dutta U.
      • Duseja A.
      • Chawla Y.K.
      Comparative effectiveness of different pharmacological interventions for the treatment of minimal hepatic encephalopathy: a systematic review with network meta-analysis.
      there are no RCTs to show that treatment of covert HE prevents overt HE; these studies need to be performed. It is however true that covert and overt HE share the same pathophysiology, and therefore it can be argued that treatment of covert HE should be considered. Similarly, a course of anti-HE treatment for the purposes of differential diagnosis is also reasonable.
      • Amodio P.
      Hepatic encephalopathy: diagnosis and management.

      Should patients with a history of, or with, overt HE be provided with advice in relation to driving for the purposes of their own and public safety?

      Recommendation
      • Patients who have had an episode of overt HE should be provided with information on the risks associated with driving and on the appropriateness of formal driving assessment with the relevant authorities (LoE 5, strong recommendation, 100% consensus).
      During driving simulation studies and on-road driving tests, patients with cirrhosis and HE have been shown to exhibit problems with vehicle handling, adaptation, cautiousness, lane-keeping, brake usage, and are more likely to need intervention from an instructor to avoid accidents.
      • Wein C.
      • Koch H.
      • Popp B.
      • Oehler G.
      • Schauder P.
      Minimal hepatic encephalopathy impairs fitness to drive.
      • Kircheis G.
      • Knoche A.
      • Hilger N.
      • Manhart F.
      • Schnitzler A.
      • Schulze H.
      • et al.
      Hepatic encephalopathy and fitness to drive.
      • Lauridsen M.M.
      • Bajaj J.S.
      Hepatic encephalopathy treatment and its effect on driving abilities: a continental divide.
      • Felipo V.
      • Urios A.
      • Valero P.
      • Sánchez M.
      • Serra M.A.
      • Pareja I.
      • et al.
      Serum nitrotyrosine and psychometric tests as indicators of impaired fitness to drive in cirrhotic patients with minimal hepatic encephalopathy.
      Patients with cirrhosis and cognitive impairment have more documented traffic accidents and violations compared to unimpaired patients with cirrhosis
      • Bajaj J.S.
      • Hafeezullah M.
      • Hoffmann R.G.
      • Saeian K.
      Minimal hepatic encephalopathy: a vehicle for accidents and traffic violations.
      and may overestimate their driving competence.
      • 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.
      • Franco J.
      • Thompson A.
      • Anderson R.
      Patients with minimal hepatic encephalopathy have poor insight into their driving skills.
      Two studies found no increased rate of accidents in patients with cirrhosis and covert HE
      • Subasinghe S.K.
      • Nandamuni Y.
      • Ranasinghe S.
      • Niriella M.A.
      • Miththinda J.K.
      • Dassanayake A.
      • et al.
      Association between road accidents and low-grade hepatic encephalopathy among Sri Lankan drivers with cirrhosis: a prospective case control study.
      ,
      • 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.
      and patients with covert HE may not be unsafe drivers in reality.
      • 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.
      Nevertheless, treatment with rifaximin in a randomised trial has been shown to improve driving simulator performance in patients with covert HE.
      • Bajaj J.S.
      • Heuman D.M.
      • Wade J.B.
      • Gibson D.P.
      • Saeian K.
      • Wegelin J.A.
      • et al.
      Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy.
      ,
      • Lauridsen M.M.
      • Thacker L.R.
      • White M.B.
      • Unser A.
      • Sterling R.K.
      • Stravitz R.T.
      • et al.
      In patients with cirrhosis, driving simulator performance is associated with real-life driving.
      There are no clear published guidelines on driving for patients with covert HE with or without recent overt HE. Expert consensus recommends avoidance of driving after an episode of overt HE
      • Kircheis G.
      • Knoche A.
      • Hilger N.
      • Manhart F.
      • Schnitzler A.
      • Schulze H.
      • et al.
      Hepatic encephalopathy and fitness to drive.
      as most patients with HE experience significant “lapses of consciousness” following a recent or current episode.
      • Cohen S.M.
      • Kim A.
      • Metropulos M.
      • Ahn J.
      Legal ramifications for physicians of patients who drive with hepatic encephalopathy.
      Verbal and written advice to avoid driving following an episode of overt HE should be given to patients and caregivers. If patients want to resume driving, they should schedule a formal driving re-assessment with the local authorities based on local regulations.
      Attempts to draw up international guidelines on whether patients with cirrhosis and HE can continue to drive have been fraught, owing to different regulatory and legal approaches with respect to HE in different jurisdictions, both within and between countries. Clinicians should be aware of their local responsibilities and be mindful that they are not trained to assess fitness to drive. No single psychometric test has the ability to reliably divide patients into safe and unsafe drivers.
      • Tapper E.B.
      • Romero-Gómez M.
      • Bajaj J.S.
      Hepatic encephalopathy and traffic accidents: vigilance is needed!.

      In patients with cirrhosis who are considered for TIPS, which neurologic work-up should take place to assess risk of post-TIPS HE?

      Recommendation
      • In patients scheduled for non-urgent TIPS, the presence and/or history of overt and covert HE should be thoroughly assessed. One single episode of HE is not an absolute contraindication, especially if precipitated by bleeding (LoE 5, strong recommendation, 89% consensus).
      To date, no method is available to reliably identify patients who will go on to develop HE after TIPS. The psychometric hepatic encephalopathy score
      • Nardelli S.
      • Gioia S.
      • Pasquale C.
      • Pentassuglio I.
      • Farcomeni A.
      • Merli M.
      • et al.
      Cognitive impairment predicts the occurrence of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt.
      • Senzolo M.
      • Zarantonello L.
      • Formentin C.
      • Orlando C.
      • Beltrame R.
      • Vuerich A.
      • et al.
      Predictive value of induced hyperammonaemia and neuropsychiatric profiling in relation to the occurrence of post-TIPS hepatic encephalopathy.
      • Berlioux P.
      • Robic M.A.
      • Poirson H.
      • Métivier S.
      • Otal P.
      • Barret C.
      • et al.
      Pre-transjugular intrahepatic portosystemic shunts (TIPS) prediction of post-TIPS overt hepatic encephalopathy: the critical flicker frequency is more accurate than psychometric tests.
      studied before TIPS placement could not indicate cut-offs that predicted a high risk for post-TIPS HE. Ammonia determination, and its time course after amino acid challenge, have recently been studied as predictive factors of post-TIPS HE. Low ammonia levels before TIPS placement, higher increases in blood ammonia, as well as increased response regarding neuropsychiatric indices (sleepiness and psychometric tests after amino acid challenge) were associated with more frequent HE occurrence after TIPS.
      • Senzolo M.
      • Zarantonello L.
      • Formentin C.
      • Orlando C.
      • Beltrame R.
      • Vuerich A.
      • et al.
      Predictive value of induced hyperammonaemia and neuropsychiatric profiling in relation to the occurrence of post-TIPS hepatic encephalopathy.
      If confirmed, these results could help to improve the stratification of patients at risk of post-TIPS HE. Brain MRI, and especially diffusion tensor imaging, are recommended only for research purposes.
      • Rudler M.
      • Weiss N.
      • Perlbarg V.
      • Mallet M.
      • Tripon S.
      • Valabregue R.
      • et al.
      Combined diffusion tensor imaging and magnetic resonance spectroscopy to predict neurological outcome before transjugular intrahepatic portosystemic shunt.
      In summary, we recommend, in the context of non-urgent TIPS, a careful assessment of medical history, with particular reference to overt HE history
      • Bai M.
      • Qi X.
      • Yang Z.
      • Yin Z.
      • Nie Y.
      • Yuan S.
      • et al.
      Predictors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in cirrhotic patients: a systematic review.
      ; liver and kidney function, focusing on bilirubin levels, international normalised ratio and urea levels
      • Fürschuß L.
      • Rainer F.
      • Effenberger M.
      • Niederreiter M.
      • Portugaller R.H.
      • Horvath A.
      • et al.
      A novel score predicts mortality after transjugular intrahepatic portosystemic shunt: MOTS - modified TIPS Score.
      ; a neurological and neuropsychological examination to detect HE, to rule out and manage large spontaneous porto-systemic shunts
      • Lv Y.
      • Chen H.
      • Luo B.
      • Bai W.
      • Li K.
      • Wang Z.
      • et al.
      Concurrent large spontaneous portosystemic shunt embolization for the prevention of overt hepatic encephalopathy after TIPS: a randomized controlled trial.
      ; and, finally, microbiome analysis could also help with decision-making in patients with TIPS at risk of overt HE.
      • Li M.
      • Li K.
      • Tang S.
      • Lv Y.
      • Wang Q.
      • Wang Z.
      • et al.
      Restoration of the gut microbiota is associated with a decreased risk of hepatic encephalopathy after TIPS.
      In summary, new bouts of post-TIPS HE could be modulated by using covered stents
      • Bureau C.
      • Thabut D.
      • Oberti F.
      • Dharancy S.
      • Carbonell N.
      • Bouvier A.
      • et al.
      Transjugular intrahepatic portosystemic shunts with covered stents increase transplant-free survival of patients with cirrhosis and recurrent ascites.
      and promoting early placement of TIPS.
      • Nicoară-Farcău O.
      • Han G.
      • Rudler M.
      • Angrisani D.
      • Monescillo A.
      • Torres F.
      • et al.
      Effects of early placement of transjugular portosystemic shunts in patients with high-risk acute variceal bleeding: a meta-analysis of individual patient data.
      ,
      • Thabut D.
      • Pauwels A.
      • Carbonell N.
      • Remy A.J.
      • Nahon P.
      • Causse X.
      • et al.
      Cirrhotic patients with portal hypertension-related bleeding and an indication for early-TIPS: a large multicentre audit with real-life results.

      Abbreviations

      APACHE II, acute physiology and chronic health evaluation II; CLIF-C, chronic liver failure consortium; CPGs, clinical practice guidelines; EASL, European Association for the Study of the Liver; FMT, faecal microbiota transplantation; HE, hepatic encephalopathy; ICU, intensive care unit; MAFLD, metabolic dysfunction-associated fatty liver disease; MARS, molecular adsorbent recirculating system; MCI, mild cognitive impairment; MELD, model for end-stage liver disease; MRI, magnetic resonance imaging; PICO, P Patient, Population, or Problem; I Intervention, Prognostic Factor, or Exposure; C Comparison or Intervention (if appropriate), O Outcome; RCTs, randomised-controlled trials; RR, risk ratio; TIPS, transjugular intrahepatic portosystemic shunt; UPDRS, Unified Parkinson Disease Rating Scale.

      Conflict of interest

      Please refer to the accompanying EASL disclosure forms for details.

      Acknowledgements

      The authors would like to thank the members of the Delphi Panel of this Clinical Practice Guideline for their valuable contribution: Javier Ampuero, Palle Bager, Jasmohan Bajaj, William Bernal, Christophe Bureau, Rita Garcia, Lise-Lotte Gluud, Linda Greenslade, Peter Jepsen, Nina Kimer, Christian Labenz, Mette M Lauridsen, Giulio Marchesini, Manuela Merli, Peter Nissen Bjerring, Peter Ott, Oliviero Riggio, Marika Rudler, Antoine Santiago, Macarena Simon-Talero, German Soriano, Elliot Tapper, Nicolas Weiss, Cihan Yurdaydin, Ane Zamalloa. The authors would also like to thank the Governing Board for their valuable contribution to the review process.

      Appendix. Delphi round agreement on the statements and recommendations of the present CPGs.

      Tabled 1
      Recommendation/statementConsensus
      HE should be qualified as type A in patients with acute liver failure, type B in those with portosystemic shunt, and type C in those with cirrhosis. Overt HE should be qualified as recurrent if ≥2 bouts occur within 6 months and persistent if the patient does not return to her/his baseline performance between bouts. The severity of mental alterations, any identified precipitants and the presence of portosystemic shunts should also be recorded as these factors impact upon both diagnostic accuracy and treatment (LoE 5, strong recommendation).96%
      The West Haven criteria should be used for HE grading when at least temporal disorientation is present (i.e. from West Haven grades ≥2). In patients with no or mild neuropsychiatric abnormalities (i.e. not meeting the criteria for the diagnosis of HE grades ≥2 based on the West Haven criteria), a neuropsychological/neurophysiological or therapeutic test should be used to diagnose covert HE. In patients with grades III-IV West Haven criteria, the Glasgow coma scale should be added (LoE 5, strong recommendation).96%
      The term “Brain Failure” should be replaced with the term “acute encephalopathy”, in accordance with international guidelines on delirium. Acute encephalopathy should not be used as a synonym for hepatic encephalopathy in patients with acute-on-chronic liver failure because while it may be accounted for by HE, there may be alternative or concomitant causes for its development (LoE 4, strong recommendation).91%
      Patients with HE should not be classified based on the aetiology of their underlying liver disease (LoE 4, strong recommendation).93%
      In patients with suspected HE, alternative or additional causes of neuropsychiatric impairment should be identified to improve prognostic accuracy and the results of treatment (LoE 4, strong recommendation).100%
      Features of covert HE and MCI of an aetiology other than liver dysfunction show significant overlap (LoE 2).90%
      In patients with delirium/encephalopathy and liver disease, plasma ammonia measurement should be performed, as a normal value brings the diagnosis of HE into question (LoE 4, strong recommendation).95%
      In patients with delirium/encephalopathy and liver disease, brain imaging by CT scan or MRI should be performed in case of diagnostic doubts or non-response to treatment (LoE 5, strong recommendation).96%
      No cerebral imaging proves a diagnosis of HE (LoE 4).96%
      In patients with cirrhosis and no history of overt HE, screening for covert HE should be performed with tests for which experience/tools and local norms are available. As the only bedside test available to date, the Animal Naming Test is worthy of further study and validation (LoE 4, strong recommendation).83%
      Patients with covert HE should be treated with non-absorbable disaccharides (LoE 3, strong recommendation).92%
      In patients with liver failure and overt HE, albumin dialysis ameliorates HE and can be considered. The impact on prognosis is, however, uncertain and further study is warranted (LoE 2).77%
      In patients with HE, all measures to control progression of the underlying liver disease should be undertaken (LoE 4, strong recommendation).100%
      In patients with HE, precipitating factors should be sought and managed (LoE 2, strong recommendation).100%
      Patients with overt HE grade 3 and 4 are at risk of aspiration and should be treated in the ICU. No single marker can identify patients who will benefit from ICU admission, and referral relies on clinical judgement (LoE 4, strong recommendation).96%
      Patients with recurrent or persistent HE should be considered for liver transplantation and a first episode of overt HE should prompt referral to a transplant centre for evaluation (LoE 5, strong recommendation).85%
      Lactulose is recommended as secondary prophylaxis following a first episode of overt HE, and should be titrated to obtain 2-3 bowel movements per day (LoE 1, strong recommendation).96%
      Rifaximin as an adjunct to lactulose is recommended as secondary prophylaxis following ≥1 additional episodes of overt HE within 6 months of the first one (LoE 2, strong recommendation).92%
      In patients presenting with gastrointestinal bleeding, rapid removal of blood from the gastrointestinal tract (lactulose or mannitol by naso-gastric tube or lactulose enemas) can be used to prevent HE (LoE 1, strong recommendation).85%
      In patients with cirrhosis and previous episodes of overt HE, rifaximin can be considered for prophylaxis of HE prior to non-urgent TIPS placement. Non-absorbable disaccharides, as a stand-alone or in combination, are worthy of further study in this context (LoE 2, strong recommendation).82%
      In patients with a history of overt HE with improvement of liver function and nutritional status and in whom precipitant factors have been controlled, discontinuation of anti-HE therapy should be considered on an individual basis (LoE 5, weak recommendation).77%
      In patients with HE, routine zinc supplementation is not recommended (LoE 2, strong recommendation).95%
      In patients with HE, demonstrated or suspected vitamin/micronutrient deficiencies should be treated, as they can compound HE (LoE 4, weak recommendation).88%
      Obliteration of accessible portal-systemic shunts in patients with cirrhosis with recurrent or persistent HE (despite adequate medical treatment) can be considered in stable patients with a MELD score <11 (LoE 4, weak recommendation).100%
      In patients with recurrent/persistent HE, replacement of animal protein with vegetable and dairy protein can be considered, provided that overall protein intake is not compromised and that patient’s tolerance is considered (LoE 4, weak recommendation).83%
      Patients with end-stage liver disease and recurrent or persistent HE not responding to other treatments should be assessed for liver transplantation (LoE 4, strong recommendation).100%
      In patients with hepatic myelopathy, liver transplantation should be considered as soon as possible since there is no other therapeutic option (LoE 4, strong recommendation).94%
      In patients with cirrhosis-related Parkinsonism, dopaminergic treatment should be tested (LoE 2, strong recommendation).95%
      In patients with recurrent/persistent HE, faecal transplantation is not routinely recommended as a treatment option but its validation in large randomised placebo-controlled trials powered for clinical outcomes is warranted (LoE 2, weak recommendation).93%
      In patients with covert HE, anti-HE treatment should be considered for purposes of differential diagnosis and to prevent overt HE (LoE 5, strong recommendation).89%
      Patients who have had an episode of overt HE should be provided with information on the risks associated with driving and on the appropriateness of formal driving assessment with the relevant authorities (LoE 5, strong recommendation).100%
      In patients scheduled for non-urgent TIPS, the presence and/or history of overt and covert HE should be thoroughly assessed. One single episode of HE is not an absolute contraindication, especially if precipitated by bleeding (LoE 5, strong recommendation).89%

      Supplementary data

      The following are the supplementary data to this article:

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