Advertisement

Heretical thoughts into hepatic encephalopathy

  • Rajiv Jalan
    Correspondence
    Corresponding authors. Addresses: Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom.
    Affiliations
    Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
    Search for articles by this author
  • Christopher F. Rose
    Correspondence
    Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada.
    Affiliations
    Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada
    Search for articles by this author
Published:March 27, 2022DOI:https://doi.org/10.1016/j.jhep.2022.03.014

      Summary

      Clinical progress in the development of new diagnostic modalities and therapeutic strategies for the management of patients with hepatic encephalopathy has lagged behind the vast knowledge that has been generated from basic studies. In this article, we critically assess matters that should be revisited, such as definition, classification, diagnosis and grading of hepatic encephalopathy, which are difficult to apply reproducibly using the current criteria. Many lines of investigation have confirmed that hepatic encephalopathy is irreversible in many patients and suggest the need for further studies focussing on mechanisms of neuronal injury and death, to guide future drug development for these patients. The clinical evidence behind using lactulose for all severities of hepatic encephalopathy, which is currently considered the standard of care, is poor and placebo-controlled trials for hepatic encephalopathy should be considered ethically sound. This expert opinion identifies current challenges in hepatic encephalopathy and highlights areas which require further debate and investigation in order to help advance the field both scientifically and clinically.

      Keywords

      Introduction

      Hepatic encephalopathy (HE) research, including the development of diagnostic tests and treatments, remains rudimentary despite many advances in our understanding of the basic biology of this condition. Unfortunately, many remaining issues need to be addressed to improve the clinical management and outcomes of this debilitating syndrome. In this article, we highlight matters that we believe need attention if we are to reduce the morbidity and mortality of patients with HE. We attempt to identify areas and concerns which we believe require further investigation. We have chosen the title carefully to reflect the objective of this paper which includes the deliberate attempt to be provocative. The manuscript will focus on definition, classification, diagnosis, irreversibility, and treatment.

      Definition

      Currently, the term ‘hepatic encephalopathy’ is defined as ‘brain dysfunction caused by liver insufficiency and/or portosystemic shunting (PSS)’.
      • Vilstrup H.
      • Amodio P.
      • Bajaj J.
      • Cordoba J.
      • Ferenci P.
      • Mullen K.D.
      • et al.
      Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American association for the study of liver diseases and the European association for the study of the liver.
      There are many problems with this definition. First, it is incorrect to refer to patients with PSS and no liver disease (currently classified as Type B HE) with brain dysfunction as having ‘HE’ since the liver is normal. Clearly, the prognosis, pathophysiology, and management options for PSS are distinct from patients with advanced liver disease. Moreover, infants born with urea cycle disorders (UCDs) that develop hyperammonaemia-induced neurological dysfunction are not diagnosed as having HE since liver disease is not present.
      • Weiss N.
      • Mochel F.
      • Rudler M.
      • Demeret S.
      • Lebray P.
      • Conti F.
      • et al.
      Peak hyperammonemia and atypical acute liver failure: the eruption of an urea cycle disorder during hyperemesis gravidarum.
      Hyperammonemia leads to brain dysfunction, a commonality in all 3 conditions: liver disease, PSS and UCDs. However, since patients with PSS and UCDs do not have underlying liver disease, brain dysfunction in these patients should not be described as HE. Instead, this term should be reserved for patients with brain dysfunction induced by liver disease-related hyperammonemia. Second, ‘liver insufficiency’ is a broad term that is poorly quantified and can range from trivial abnormalities of liver function (based on plasma liver enzyme levels, transient elastography; non-functional analysis) to fulminant liver failure. Third, the causes of liver injury such as alcohol abuse, obesity and metabolic associated fatty liver disease, hepatitis C and co-morbidities (e.g. hypertension and diabetes) may impact brain function independently of the severity of liver disease.
      • Rose C.F.
      • Amodio P.
      • Bajaj J.S.
      • Dhiman R.K.
      • Montagnese S.
      • Taylor-Robinson S.D.
      • et al.
      Hepatic encephalopathy: novel insights into classification, pathophysiology and therapy.
      Since these disorders can induce neurological dysfunction, independent of the impact of severity of liver disease, it is critical to define HE with a liver disease-specific neurotoxin. The best validated biomarker in this context is hyperammonaemia. Fourth, brain dysfunction arising during acute liver failure (ALF) (currently classified as Type A HE) is characterised by brain oedema and risk of intracranial hypertension, due to very different pathophysiological mechanisms and different clinical challenges than those observed in patients with HE on the background of cirrhosis.
      • Rose C.F.
      • Amodio P.
      • Bajaj J.S.
      • Dhiman R.K.
      • Montagnese S.
      • Taylor-Robinson S.D.
      • et al.
      Hepatic encephalopathy: novel insights into classification, pathophysiology and therapy.
      This entity, although under the umbrella of HE, should be considered separately. Furthermore, it is important to classify brain dysfunction in patients with acute-on-chronic liver failure (ACLF), which is clinically, pathophysiologically and prognostically distinct from that occurring in patients with decompensated cirrhosis and no ACLF.
      • Cordoba J.
      • Ventura-Cots M.
      • Simón-Talero M.
      • Amorós À.
      • Pavesi M.
      • Vilstrup H.
      • et al.
      Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF).
      Fifth, a small proportion of patients with cirrhosis develop overt motor disturbances (Parkinsonian features) while others develop paraplegia (hepatic myelopathy).
      • Tryc A.B.
      • Goldbecker A.
      • Berding G.
      • Rümke S.
      • Afshar K.
      • Shahrezaei G.H.
      • et al.
      Cirrhosis-related Parkinsonism: prevalence, mechanisms and response to treatments.
      ,
      • 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.
      These are extremely rare syndromes that are poorly characterised both clinically and pathophysiologically. Some early studies indicate that hepatic myelopathy is caused by demyelination of the corticospinal tract in the spinal cord with no clinical or pathophysiological link to HE.
      • Utku U.
      • Asil T.
      • Balcı K.
      • Uzunca İ.
      • Çelik Y.
      Hepatic myelopathy with spastic paraparesis.
      Likewise, Parkinsonian syndrome-like manifestations are very poorly understood; these manifestations do not respond to conventional treatments for HE and dopaminergic treatments are currently the preferred option.
      • Tryc A.B.
      • Goldbecker A.
      • Berding G.
      • Rümke S.
      • Afshar K.
      • Shahrezaei G.H.
      • et al.
      Cirrhosis-related Parkinsonism: prevalence, mechanisms and response to treatments.
      There are only isolated case reports showing their improvement with liver transplantation.
      • Weissenborn K.
      • Tietge U.J.F.
      • Bokemeyer M.
      • Mohammadi B.
      • Bode U.
      • Manns M.P.
      • et al.
      Liver transplantation improves hepatic myelopathy: evidence by three cases.
      Lumping them together with conventional HE is inappropriate, and we feel they should be classified as ‘variant forms’ of neurological dysfunction in patients with liver disease.
      The complexity of brain dysfunction in patients with liver disease is highlighted in Fig. 1. To navigate through some of the intricacies in relation to classifying HE, we believe minimum diagnostic criteria need to be developed to help define the syndrome. The term ‘HE’ should be reserved for dysfunction of the brain that is a consequence of cirrhosis or ALF and associated with hyperammonemia (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Proposed model for differential diagnosis of brain dysfunction in patients with liver disease.
      Brain dysfunction can occur under multiple conditions with or without liver disease. Therefore, hepatic encephalopathy should not be defined by specific symptom(s) but rather by the presence of cirrhosis or acute liver failure and, the presence of hyperammonemia, the causal agent. Many co-factors, as illustrated, can act synergistically with hyperammonemia to produce hepatic encephalopathy but by themselves do not cause hepatic encephalopathy in the absence of hyperammonemia.

      Staging and classification

      HE is currently staged according to the modified form of the West Haven criteria.
      • Vilstrup H.
      • Amodio P.
      • Bajaj J.
      • Cordoba J.
      • Ferenci P.
      • Mullen K.D.
      • et al.
      Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American association for the study of liver diseases and the European association for the study of the liver.
      Table 1 summarises this grading system and questions its relevance, emphasising the likelihood of a large variability in the way these criteria are clinically assessed. The hepatic encephalopathy staging tool was developed to assess the severity of HE as an end point and has been approved by the US FDA. It appears to be more objective and easier to apply,
      • 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.
      and provides a clearer distinction between grade 1 and 0 HE (Table 2). However, it does not consider minimal HE (mHE). Patients (without asterixis) who respond correctly to all 5 questions get defined as grade 0. Patients (without asterixis) who incorrectly answer 1 of the 5 questions, get defined as grade 1. Patients (with asterixis) who incorrectly answer 1 of the 5 questions, get defined as grade 2. However, this promising tool requires further validation.
      Table 1Modified West Haven criteria as described in the current guidelines and the problems with their assessment.
      GradeClinical criteriaRelevance to diagnosis and grading
      UnimpairedNo HE‘Normal’ needs to be defined. No pertinent tests have been identified
      No history of HENo data on whether all patients with previous HE will continue to have brain abnormalities
      MinimalPsychometric or neuropsychological alterations of tests exploring psychomotor speed/executive functions or neurophysiological alterations without clinical evidence of mental changeThe currently used tests to diagnose mHE, such as the PHES test and CFF, lack specificity. EEG is likely to be more specific but not as sensitive
      1Trivial lack of awareness, euphoria or anxietyThe terms such as ‘trivial’ ‘euphoria’ ‘anxiety’ ‘shortened attention span’ ‘impairment’ are extremely non-specific and subjective; therefore, they are not useful in clinical practice, research and drug development
      Shortened attention spanTests need to be specified
      Impairment of addition or subtractionNeed to clarify degree of complexity
      Altered sleep rhythmAltered sleep rhythm is likely due to altered ‘clock’ and is non-specific
      2Lethargy or apathy; obvious personality change, inappropriate behaviour; dyspraxiaThe terms ‘lethargy’, ‘apathy’ ‘personality change’, ‘inappropriate behaviour’ and ‘dyspraxia’ are non-specific and not quantitative
      Disorientation for time and asterixisDisorientation and asterixis are more specific but not sensitive
      3Somnolence to semistupor; responsive to stimuli; bizarre behaviourThe terms ‘somnolence’, ‘responsive to stimuli’ and ‘bizarre behaviour’ are non-specific and difficult to quantify
      Confused; gross disorientation‘Confused’ and ‘Gross disorientation’ are clearer yet their severity is not quantifiable
      4ComaAlthough this is clear, its degrees are not quantifiable
      CFF, critical flicker frequency; EEG, electroencephalography; HE, hepatic encephalopathy; mHE, minimal HE; PHES, psychometric HE score.
      Table 2Hepatic encephalopathy staging tool.
      StageCriteria
      0/1No asterixis
      Three or more flaps/30 s indicates asterixis. Modified from Rahimi et al. CGH 2020.
      and no disorientation based on the following 5 questions (i.e., patient provides a correct response to questions 1, 2, 3, 4 and 5):
      • 1.
        What is your name?
      • 2.
        What city are we in?
      • 3.
        What type of place is this? (correct answer: hospital)
      • 4.
        What is the year?
      • 5.
        What is the month?
      2Asterixis and disorientation based on the following 5 questions (i.e., any single incorrect response qualifies the patient as stage 2 for questions 1, 2, 3, 4, or 5):
      • 1.
        What is your name?
      • 2.
        What city are we in?
      • 3.
        What type of place is this? (correct answer: hospital)
      • 4.
        What is the year?
      • 5.
        What is the month?
      3Stupor, arousable out but falls asleep, responsive to verbal stimuli
      Obvious confusion
      Gross disorientation
      4Coma
      NOTE. Patients (without asterixis) who respond correctly to all 5 questions get defined as grade 0. Patients (without asterixis) who incorrectly answer 1 of the 5 questions, get defined as grade 1. To qualify for study entry as stage 2 hepatic encephalopathy, both asterixis and ≥1 error in the 5 sentinel questions must have been present at screening and baseline. For recording hepatic encephalopathy response after starting study drug infusion, patients were classified as improved to stages 0/1 only if asterixis resolved and all 5 questions were answered correctly.
      a Three or more flaps/30 s indicates asterixis. Modified from Rahimi et al. CGH 2020.
      As stated in the current guidelines, HE should be classified according to the type of underlying disease, severity of manifestations, time course, and precipitating factors (Fig. 2).
      • Vilstrup H.
      • Amodio P.
      • Bajaj J.
      • Cordoba J.
      • Ferenci P.
      • Mullen K.D.
      • et al.
      Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American association for the study of liver diseases and the European association for the study of the liver.
      However, classifying patients with ALF as having either covert or overt, episodic, recurrent or persistent and, spontaneous or precipitated is not clinically relevant.
      Figure thumbnail gr2
      Fig. 2Current classification of HE
      Classification of hepatic encephalopathy according to the type of underlying disease, severity of manifestations, time course, and precipitating factors (modified from Vilstrup et al. J Hep 2014). HE, hepatic encephalopathy; MHE, minimal HE.
      Furthermore, complexity and confusion have been created by the introduction of the term ’covert’, which encompasses all patients with mHE and Grade 1 HE under a single category (Fig. 2). The term ‘covert’ attempts to simplify the classification but in our view, this nomenclature is confusing and should be revisited. Literally, ‘covert’ means ‘hidden’. However, patients with Grade 1 HE are symptomatic and clinical signs can be elicited.
      • Thomsen K.L.
      • Macnaughtan J.
      • Tritto G.
      • Mookerjee R.P.
      • Jalan R.
      Clinical and pathophysiological characteristics of cirrhotic patients with grade 1 and minimal hepatic encephalopathy.
      Moreover, the risk of complications of cirrhosis, mortality and severity of systemic inflammation are significantly higher in patients with Grade 1 HE compared with those with mHE.
      • Thomsen K.L.
      • Macnaughtan J.
      • Tritto G.
      • Mookerjee R.P.
      • Jalan R.
      Clinical and pathophysiological characteristics of cirrhotic patients with grade 1 and minimal hepatic encephalopathy.
      Therefore, to combine these very disparate entities (non-symptomatic (mHE) with symptomatic (Grade 1)) under a single domain appears to be an oversimplification. The diagnosis of mHE is even more challenging. There are several psychological/psychometric tests presently available, which questionably evaluate different elements of brain function. Their widespread usability, clinical utility, specificity, prognostic and pathophysiological correlates remain unclear and require large multicentre studies to provide further clarity. Furthermore, the impact of previous episodes of overt HE on ongoing abnormalities in these tests remains unknown and should be further evaluated (see Fig. 2).

      Diagnosis of HE and the role of ammonia measurement

      For decades, hyperammonemia leading to neurotoxicity has been shown to be the cardinal pathogenic factor in the pathogenesis of HE in patients, animal models and cell systems.
      • Shawcross D.L.
      • Olde Damink S.W.M.
      • Butterworth R.F.
      • Jalan R.
      Ammonia and hepatic encephalopathy: the more things change, the more they remain the same.
      Undeniably, the diagnosis of HE is based on clinical judgment and subsequently the pathogenic factor should be identified and corrected. Remarkably, in 30% of cases of HE, precipitating and pathogenic factors are not identified. Many lines of investigation show that a diagnosis of HE is incompatible with normal ammonia levels although a direct relationship between grade of hyperammonemia and severity of HE is lacking. However, elevated blood ammonia can predict HE-related hospitalisations and established cut-offs of blood ammonia have been demonstrated to have prognostic value in many different studies.
      • Patwardhan V.R.
      • Jiang Z.G.
      • Risech-Neiman Y.
      • Piatkowski G.
      • Afdhal N.H.
      • Mukamal K.
      • et al.
      Serum ammonia in associated with transplant-free survival in hospitalized patients with acutely decompensated cirrhosis.
      • Vierling J.M.
      • Mokhtarani M.
      • Brown 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.
      • Shalimar
      • Sheikh M.F.
      • Mookerjee R.P.
      • Agarwal B.
      • Acharya S.K.
      • Jalan R.
      Prognostic role of ammonia in patients with cirrhosis.
      Furthermore, a change in the severity of hyperammonenia in patients with HE defines the risk of death, arguing for the value in serial measures of ammonia (Table 2). Therefore, it is inevitable that without an increase in blood ammonia, a diagnosis of HE is not tenable. However, despite the overwhelming evidence for the role of ammonia measurement in the diagnosis and prognosis of HE, it is not routinely measured, nor is its measurement recommended in the current guidelines. Rather, pragmatic treatment with lactulose and/or rifaximin is initiated. An inadequate clinical response to medical therapy signifies exclusion of the diagnosis of HE and the need to consider differential diagnoses. There are many challenges with this approach. First, treating HE without identifying the pathogenic factor reduces the potential effectiveness of current interventions.
      • Rose C.F.
      • Jalan R.
      Judging the value of ammonia measurement on lactulose dosing: apples and oranges?.
      Second, response to therapy should not be used as a diagnostic tool to define HE, particularly since lactulose has not been shown to be useful in overt HE in placebo-controlled clinical trials. Third, the time required to wait for a response to treatment can be vital as duration of HE episode (>48 hours) can have a significant impact on mortality.
      • Ventura-Cots M.
      • Carmona I.
      • Moreno C.
      • Ampuero J.
      • Simón-Talero M.
      • Sanpedro F.
      • et al.
      Duration of the acute hepatic encephalopathy episode determines survival in cirrhotic patients.
      The recently published Rahimi study (phase IIb trial assessing the efficacy of ornithine phenylacetate) was the first trial designed to randomise patients with HE and hyperammonemia and to demonstrate that ammonia is a valuable companion biomarker in HE.
      • 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.
      In this study, 231 patients with cirrhosis with overt HE (>grade 2) were randomised to receive ornithine phenylacetate or placebo.
      • 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.
      The protocol stipulated that randomisation was to take place if blood ammonia levels were elevated (>upper limit of normal). The primary endpoint was not reached as the drug did not lead to a significant reduction in time to improvement of overt HE. However, when the ammonia levels were measured in a central laboratory, the investigators showed that in 30 patients, ammonia levels were normal at the time of randomisation. Upon a post hoc analysis including the 201 patients with elevated ammonia levels, statistically significant results in time to clinical improvement in overt HE were observed in the group treated with the active agent. These data argue strongly for the use of ammonia as a companion biomarker to guide HE therapy with a drug known to target ammonia. This is particularly relevant for the development of new treatments for HE.
      As illustrated in Table 3, the existing data show very clearly that a diagnosis of HE cannot be sustained if ammonia levels are normal and that ammonia plays an important diagnostic and prognostic role. We believe minimum criteria are required to diagnose HE. Some of the elements that may be pertinent and applicable are the following.
      • Presence of cirrhosis or ALF
      • Pathophysiological basis (hyperammonemia)
      • Brain imaging to exclude other causes
      • Some measure of neurological dysfunction such as abnormal electroencephalography, which has shown specificity for HE or alternative psychological/psychometric tests used to detect mHE.
        • Bersagliere A.
        • Raduazzo I.D.
        • Schiff S.
        • Gatta A.
        • Merkel C.
        • Amodio P.
        • et al.
        Ammonia-related changes in cerebral electrogenesis in healthy subjects and patients with cirrhosis.
      Table 3Evidence for the importance of ammonia measurements in the diagnosis and prognosis of patients with hepatic encephalopathy.
      StudyAimStudy designNumber of patients includedMain resultsConclusion
      Clemmensenet al. 1999
      • Clemmesen J.O.
      • Larsen F.S.
      • Kondrup J.
      • Hansen B.A.
      • Ott P.
      Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration.
      To examine the hypotheses that high arterial ammonia is related to death by cerebral herniationProspective and retrospective single-centre study22 patients with ALF and 31 with HE (22 with ALF and 9 with ACLF)Ammonia levels were higher in patients with ALF who developed cerebral herniation. They identified a cut-off of 150 μmol/L.In ALF, high ammonia level is associated with cerebral herniation
      Jalan et al. 2004
      • Jalan R.
      • Olde Damink S.W.M.
      • Hayes P.C.
      • Deutz N.E.P.
      • Lee A.
      Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia and cerebral blood flow.
      To determine the role of inflammation in the pathogenesis of intracranial hypertension in patients with ALF and its interplay with cerebral blood flow and ammoniaProspective single-centre study. Measurements were made prior to any specific treatment for intracranial hypertension21 patients with ALF and grade IV HE divided into 2 groups: 1) ICP >20 mmHg and 2) ICP <20 mmHgInflammatory markers, ammonia and CBF were higher in those with ICP >20 mmHgAmmonia and inflammation play synergistic role in intracranial hypertension in patients with ALF
      Kundra et al. 2005
      • Kundra A.
      • Jain A.
      • Banga A.
      • Bajaj G.
      • Kar P.
      Evaluation of plasma ammonia levels in patients with acute liver failure and chronic liver disease and its correlation with the severity of hepatic encephalopathy and clinical features of raised intracranial tension.
      To compare plasma ammonia levels in patients with ALF or CLD with or without HE; to correlate ammonia levels with the severity of HE and with clinical features of intracranial hypertensionProspective single-centre study. Clinical criteria were used for diagnosis and staging of HE20 with ALF and 20 with CLD (8 with HE and 12 without HE)There was good correlation between severity of HE and ammonia. In ALF, ammonia levels of patients with intracranial hypertension/cerebral herniation were significantly higher than those withoutThere is good correlation between severity of HE and clinical features of intracranial hypertension or cerebral herniation and ammonia levels in ALF
      Bhatia et al. 2006
      • Bhatia V.
      • Singh R.
      • Acharya S.K.
      Predictive value of arterial ammonia for complications and outcome in acute liver failure.
      To evaluate the relationship of arterial ammonia levels at admission to complications and survivalProspective single-centre study80 patients with ALFNon-survivors had higher median ammonia than survivors. Hyperammonemia was associated with deeper encephalopathy, cerebral oedema, need for ventilation and seizures. A reduction in ammonia level was associated with better outcomes.Arterial ammonia at presentation is predictive of outcome and can be used for risk stratification. Serial measurement of ammonia provides important prognostic information
      Bernal et al. 2007
      • Bernal W.
      • Hall C.
      • Karvellas C.J.
      • Auzinger G.
      • Sizer E.
      • Wendon J.
      Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure.
      To evaluate the relation between the arterial ammonia concentrations on admission and survival, risk of subsequent HE and intracranial hypertensionProspective single-centre study165 patients with ALF and advanced HE, 50 with ALF in the absence of severe HE, 33 with decompensated CLD, and 9 admitted following hepatobiliary surgeryAmmonia was an independent risk factor for the development of severe HE and intracranial hypertension. After admission, ammonia levels remained high in those who developed intracranial hypertension and fell in those who did not.Ammonia is an independent risk factor for the development of both HE and intracranial hypertension
      Niranjan-Azadi et al. 2016
      • Niranjan-Azadi A.M.
      • Araz F.
      • Patel Y.A.
      • Alachkar N.
      • Alqahtani S.
      • Cameron A.M.
      • et al.
      Ammonia level and mortality in acute liver failure: a single-center experience.
      To evaluate the relationship between ammonia levels and mortality in ALF and to characterise the subgroup of patients who develop acute kidney injury and require replacement therapyRetrospective single-centre study. Patients who required haemodialysis were compared to those without acute kidney injury36 consecutive patients admitted to intensive care units with grade III and IV HEAdmission ammonia level (>120 μmol/L) was associated with higher mortality rate.Admission ammonia level is predictive of mortality in patients with ALF and grade 3–4 HE
      Ong et al. 2003
      • Ong J.P.
      • Aggarwal A.
      • Krieger D.
      • Easley K.A.
      • Karafa M.T.
      • Van Lente F.
      • et al.
      Correlation between ammonia levels and the severity of hepatic encephalopathy.
      To evaluate the relationship between ammonia levels and the severity of HE using venous, arterial and partial pressuresProspective single-centre study121 patients with cirrhosisEach of the 4 measures of ammonia increased with the severity of HEAmmonia levels correlate with the severity of hepatic encephalopathy. Venous ammonia levels are adequate
      Nicolao et al. 2003
      • 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.
      To compare venous, arterial and partial pressure of ammonia in patients with cirrhosis, with and without HE, and controlsProspective single-centre study. Clinical and psychometric evaluation were used to assess HE27 patients with cirrhosis and HE, 15 patients with cirrhosis without HE and 9 controlsHE was associated with higher levels of each form of ammonia. The correlation with the severity of HE was similar for venous, arterial ammonia and partial pressureVenous ammonia levels allow diagnosis of HE. Arterial levels do not add substantially
      Patwardhan et al. 2016
      • Patwardhan V.R.
      • Jiang Z.G.
      • Risech-Neiman Y.
      • Piatkowski G.
      • Afdhal N.H.
      • Mukamal K.
      • et al.
      Serum ammonia in associated with transplant-free survival in hospitalized patients with acutely decompensated cirrhosis.
      To determine whether ammonia is associated with transplant-free survival in patients with AD and ACLFRetrospective single-centre cohort study494 consecutive hospitalised patients (265 with HE)Every doubling of ammonia was associated with 30- and 90-day transplant or mortality. Patients with ammonia levels >60 μmol/L had higher 30- and 90-day risk of death or transplantationAn elevated ammonia on admission is independently associated with reduced 90-day transplant-free survival
      Sawhney et al. 2016
      • Sawhney R.
      • Holland-Fischer P.
      • Rosselli M.
      • Mookerjee R.P.
      • Agarwal B.
      • Jalan R.
      Role of ammonia, inflammation, and cerebral oxygenation in brain dysfunction of acute-on-chronic liver failure patients.
      To determine the role of ammonia, inflammation, and cerebral oxygenation in patients with ACLF with and without HEProspective study. Arterial ammonia, JVO2 and white blood cell count were measured consecutively101 with ACLF admitted to the intensive care unitHyperammonemia was associated with the presence and severity of HE; improvement in these parameters was associated with a reduction in HE severity whilst an increase in ammonia increased risk of deathAmmonia, is an important prognostic biomarker and change in its levels are prognostically important
      Vierling et al. 2016
      • Vierling J.M.
      • Mokhtarani M.
      • Brown 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.
      To determine the role of blood ammonia levels on mortality and risk of overt HERetrospective analysis from prospective multicentre study178 patients with cirrhosis and a history of 2 episodes of overt HE within the past 6 monthsFasting ammonia levels of >1.5xULN lead to an increased risk of developing an HE event and death within 16 weeksFasting ammonia is useful in predicting HE-related morbidity
      Ravi et al. 2017
      • Ravi S.
      • Bade K.S.
      • Hasanin M.
      • Singal A.K.
      Ammonia level at admission predicts in-hospital mortality for patients with alcoholic hepatitis.
      To study the impact of ammonia levels in alcoholic hepatitisRetrospective single-centre cohort study105 patients admitted with alcoholic hepatitis (51 with HE)Higher ammonia levels predicted risk of mortality. The addition of ammonia to the regression models improved their performance irrespective of the presence of HEAmmonia levels predict risk of mortality
      Shalimar et al. 2019
      • Shalimar
      • Sheikh M.F.
      • Mookerjee R.P.
      • Agarwal B.
      • Acharya S.K.
      • Jalan R.
      Prognostic role of ammonia in patients with cirrhosis.
      To determine the relationship between ammonia and severity of HE and its association with organ dysfunction and short-term mortalityProspective observational multicentre study498 patients with cirrhosis admitted with ADAmmonia correlated with severity of HE and was an independent predictor of 28-day mortality. Lack of improvement in baseline ammonia at day 5 was associated with high mortality (70.6%)Ammonia is an important prognostic biomarker and change in its levels are prognostically important
      Shalimar et al. 2020
      • Shalimar
      • Rout G.
      • Kumar R.
      • Singh A.D.
      • Sharma S.
      • Gunjan D.
      • et al.
      Persistent or incident hyperammonemia is associated with poor outcomes in acute decompensation and acute-on-chronic liver failure.
      To assess the effect of persistent or incident hyperammonemia on organ failure and outcomes in ACLFPaired ammonia on day 1 and 3 of admission. Persistent or incident hyperammonemia was defined as ≥79.5 μmol/L on day 3229 consecutive admissions with ACLF and 83 with no ACLFPersistent or incident hyperammonemia was associated with new-onset organ failure involving liver, kidney, brain, coagulation, circulation, and respiratory and had higher 28-day mortalityHyperammonemia independent of ACLF is associated with increased risk of organ failure and death
      Hu et al. 2020
      • Hu C.
      • Huang K.
      • Zhao L.
      • Zhang F.
      • Wu Z.
      • Li L.
      Serum ammonia is a strong prognostic factor for patients with acute-on-chronic liver failure.
      To determine the association between ammonia level and short-term prognosis in ACLFACLF according to the APASL definition (subanalyses in HBV reactivation)174 with ACLF (106 with HBV reactivation)Ammonia was higher in non-survivors and was related to ACLF grade and organ failure. Ammonia was a prognostic factor in HBV reactivation-induced ACLFAmmonia is correlated with organ failure and is an independent risk factor for mortality in ACLF and HBV reactivation-related ACLF
      Verma et al. 2021
      • Verma N.
      • Dhiman R.K.
      • Choudhury A.
      • Taneja S.
      • Duseja A.
      • Singh V.
      • et al.
      Dynamic assessments of hepatic encephalopathy and ammonia levels predict mortality in acute-on-chronic liver failure.
      To evaluate the dynamics of HE and ammonia estimation in ACLFPatients with ACLF recruited using APASL criteria3,009 ACLF, 1,315 (43.7%) with HE at presentationAmmonia was a predictor of HE occurrence, higher HE grades and 30-day mortality. The dynamic increase in ammonia over 7 days could predict non-survivors and progression of HEAmmonia is associated with the presence, severity and progression of HE and mortality in ACLF
      Chiriac et al. 2021
      • Chiriac S.
      • Stanciu C.
      • Cojocariu C.
      • Singeap A.-M.
      • Sfarti C.
      • Cuciureanu T.
      • et al.
      Role of ammonia in predicting the outcome of patients with acute-on-chronic liver failure.
      To assess the role of venous ammonia in predicting the outcome of patients with ACLFRetrospective observational study in patients with ACLF using APASL criteria446 with ACLFReceiver operating characteristic analysis showed good accuracy for the prediction of short-term mortality for ammoniaAmmonia can be used as a biomarker to predict mortality in patients with ACLF
      ACLF, acute-on-chronic liver failure; AD, acute decompensation; ALF, acute liver failure; APASL, Asia Pacific Association for the Study of Liver; CBF, cerebral blood flow; CLD, chronic liver disease; ICP, intracranial pressure; JVO2, jugular venous oxygen saturation; HE, hepatic encephalopathy; ULN, upper limit of normal. Studies in patients with ALF are italic. The table describes a selection of studies.
      This suggested approach will need to be validated in future studies.

      Lessons from other complications of cirrhosis

      Other main complications of liver disease have reliable clinical features or biomarkers.
      • Portal hypertension: hepatic venous pressure gradient; transient elastography combined with platelet count, presence of varices; splenomegaly
      • Renal dysfunction: creatinine
      • Ascites: ultrasound, clinical examination
      • Infection: cultures for bacteria, inflammatory markers
        • spontaneous bacterial peritonitis: neutrophil count in ascitic fluid
      Similarly, elevated glucose has high predictive value for the risk of diabetes and its complications.
      • Rhee M.K.
      • Ho Y.-L.
      • Raghavan S.
      • Vassy J.L.
      • Cho K.
      • Gagnon D.
      • et al.
      Random plasma glucose predicts the diagnosis of diabetes.
      The current predicament with ammonia and HE parallels what was previously the case with hepatorenal syndrome (HRS). Historically, all patients with cirrhosis who presented with acute kidney injury were indiscriminately diagnosed with HRS. Today, HRS has specific diagnostic criteria that could enable the introduction of new biomarkers.
      • Allegretti A.S.
      • Parada X.V.
      • Endres P.
      • Zhao S.
      • Krinsky S.
      • Hillien St., S.A.
      • et al.
      Urinary NGAL as a diagnostic and prognostic marker for acute kidney injury in cirrhosis: a prospective study.
      Although there is some degree of overlap with non-HRS acute kidney injury, HRS is a relatively specific entity.
      It is however, important to state that the measurement of ammonia is only clinically useful if measured meticulously using standardised protocols. We hope this article encourages clinicians to engage with their clinical and biochemical teams to develop appropriate standard operating procedures. Indeed, the false positives (30/231; 13%) observed in the Rahimi et al. study provide evidence that ammonia measurements can only be interpreted if performed properly. Implementation of methods to correctly analyse ammonia may well be challenging but are warranted to improve management and provide the appropriate therapy for patients.

      Irreversibility

      Since HE is defined as a neurological disorder due to liver disease, in theory it should be reversible with liver transplantation. However, many reports have shown that the neurological state of patients with a history of HE who receive a liver transplant does not normalise,
      • Sotil E.U.
      • Gottstein J.
      • Ayala E.
      • Randolph C.
      • Blei A.T.
      Impact of preoperative overt hepatic encephalopathy on neurocognitive function after liver transplantation.
      suggesting that HE is not always reversible. However, it remains unknown what pathophysiological factors and conditions (preoperative, operative, postoperative) precipitate neuronal cell death and contribute to this irreversibility.
      • Ochoa-Sanchez R.
      • Tamnanloo F.
      • Rose C.F.
      Hepatic encephalopathy: from metabolic to neurodegenerative.
      Interestingly, it is recognised that the duration of hyperammonemia and/or the concentration of blood ammonia can influence neuronal cell survival.
      • Braissant O.
      • McLin V.A.
      • Cudalbu C.
      Ammonia toxicity to the brain.
      The latter is difficult to explore in patients without serial (or home monitoring) ammonia measures. Based on these observations, one could argue that HE should be treated as a medical emergency in the same way as myocardial infarction and cerebrovascular accident are currently managed. Greater emphasis should be placed on attempts to prevent the first episode of HE.
      For decades, astrocyte swelling has been thought to be the central neurological marker in the pathology of HE.
      • Häussinger D.
      • Kircheis G.
      • Fischer R.
      • Schliess F.
      • Dahl S vom
      Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema?.
      However, the precise role of astrocyte swelling in the pathogenesis of HE remains undefined. Undoubtedly, a physiological or metabolically impaired swollen astrocyte will lead to weakened astrocyte-neuronal communication and compromise brain function.
      • Butterworth R.F.
      Altered glial-neuronal crosstalk: cornerstone in the pathogenesis of hepatic encephalopathy.
      However, the manifestations of HE are the result of multiple pathogenic factors which trigger changes in cerebral bioenergetics, mitochondrial dysfunction, oxidative stress and neuroinflammation. Future studies should explore interventions that target these newly discovered important pathophysiological pathways and better define the mechanisms underlying irreversibility.

      Treatment

      The current ‘standard of care’ for HE, independent of severity, is lactulose, a disaccharide proposed to have different mechanisms of action including reducing ammonia absorption, acting as a pre-biotic and altering the microbiome.
      • Morgan M.Y.
      Current state of knowledge of hepatic encephalopathy (part III): non-absorbable disaccharides.
      However, lactulose is a laxative and whether other laxatives are equally beneficial remains unknown. Although there are many controlled clinical trials which have investigated the effect of lactulose on the severity of HE, a great proportion of these studies are open to bias since most are single-centre studies that are neither double blinded nor placebo controlled. As illustrated in Table 4, 11 placebo-controlled clinical trials with lactulose have been conducted, each with an average of 22 patients (number of patients in individual studies ranging between 6-40). A total of 246 patients were studied between 1969 and 1997 with very different designs, type of placebo used, dose of lactulose administered, inclusion and exclusion criteria, and clinical outcomes. More importantly, the placebos used in all these studies were inappropriate as none of them produced a laxative effect, leading to inevitable unblinding. Moreover, there is lack of clarity on whether the trials were independently monitored (for the variables such as inclusion and exclusion criteria; end points) and compliance is not clearly documented. It is clear from existing clinical experience that lactulose is a difficult treatment to tolerate and is associated with many unfavourable side effects. Although serious adverse events are rare, flatulence, diarrhoea, dehydration are frequent, which occasionally result in hyponatremia and acute kidney injury.
      • Gluud L.L.
      • Vilstrup H.
      • Morgan M.Y.
      Nonabsorbable disaccharides for hepatic encephalopathy: a systematic review and meta-analysis.
      Table 4Characteristics of clinical trials of lactulose vs. placebo.
      Trial and yearTrial designNumber of patientsDefinition of HEAssessment of HEActive agent(s)PlaceboBlindingEnd pointsResult
      Elkington et al. 1969
      • Elkington S.G.
      • Floch M.H.
      • Conn H.O.
      Lactulose in the treatment of chronic portal-systemic encephalopathy. A double-blind clinical trial.
      Double-blind, cross-over, single-centre, inpatient trial7Persistent (25%) or previous overt HE (75%)Mental status (modified Parsons-Smith criteria), arterial ammonia, EEGLactulose, galactose, and lactoseSorbitolParticipants and personnelEfficacy5 out of 7 patients improved. Stool pH and arterial ammonia were reduced by lactulose; improvement in the EEG occurred in 4 patients
      Simmons et al. 1970
      • Simmons F.
      • Goldstein H.
      • Boyle J.D.
      A controlled clinical trial of lactulose in hepatic encephalopathy.
      Double-blind, parallel-arm, single-centre, inpatient trial26Episodic (81%), recurrent (19%)Mental status, venous ammoniaLactuloseGlucoseParticipants and personnelMortality, HE, adverse eventsNo significant differences
      Brown et al. 1971
      • Brown H.
      • Trey C.
      • McDermott W.V.
      Lactulose treatment of hepatic encephalopathy in outpatients.
      Double-blind, cross-over, single-centre inpatient/outpatient20PersistentMental status, blood ammonia, EEGLactuloseSorbitolParticipants and personnelLong-term efficacy11 patients responded favourably (2 of them had few months of follow-up), 6 were not taking the lactulose, 3 died early
      Germain et al. 1973
      • Germain L.
      • Frexinos J.
      • Louis A.
      • Ribet A.
      Double blind study of lactulose in 8 patients with chronic hepatic encephalopathy after portocaval shunt.
      Double-blind, parallel-arm, single-centre, outpatient trial18PersistentMental status (Parson-Smith criteria), psychometric tests, venous ammonia, EEGLactuloseSaccharose-basedParticipants and personnelMortality, HE, and adverse eventsNo significant differences
      Rodgers et al. 1973
      • Rodgers J.B.
      • Kiley J.E.
      • Balint J.A.
      Comparison of results of long-term treatment of chronic hepatic encephalopathy with lactulose and sorbitol.
      Double-blind, cross-over, single-centre, outpatient trial6PersistentMental status, blood ammonia, EEGLactuloseSorbitolParticipants and personnelLong-term efficacyNo significant differences
      Corazza et al. 1982
      • Corazza G.R.
      • Tacconi C.
      • Zoli G.
      Use of pyridoxine-alpha-ketoglutarate (PAK) in hepatic encephalopathy.
      Double-blind, parallel-arm, single-centre inpatient trial32PersistentMental status, blood ammonia, EEGLactuloseNot availableParticipants and personnelEfficacyLactulose was better than placebo in lowering ammonia levels.

      Improvement of HE not available
      McClain et al. 1984
      • McClain C.J.
      • Potter T.J.
      • Kromhout J.P.
      • Zieve L.
      The effect of lactulose on psychomotor performance tests in alcoholic cirrhotics without overt hepatic encephalopathy.
      Double-blind, parallel-arm, single-centre, outpatient trial32Not clinical evidence of HEPsychometric testsLactuloseSucroseParticipants and personnelPsychometric testImprovement in 3 of the 5 tests in the lactulose group (no improvement in any test in the sucrose group)
      Uribe et al. 1987
      • Uribe M.
      • Toledo H.
      • Perez F.
      • Vargas F.
      • Gil S.
      • Garcia-Ramos G.
      • et al.
      Lactitol, a second-generation disaccharide for treatment of chronic portal-systemic encephalopathy. A double-blind, crossover, randomized clinical trial.
      Double-blind, cross-over, single-centre, outpatient trial18Episodic, PersistentConn score, Number Connection Test, blood ammonia, EEGLactitolLactoseParticipants and personnelSafety and efficacyNo significant differences
      Horsmans et al. 1997
      • Horsmans Y.
      • Solbreux P.M.
      • Daenens C.
      • Desager J.P.
      • Geubel A.P.
      Lactulose improves psychometric testing in cirrhotic patients with subclinical encephalopathy.
      Double-blind, parallel-arm, single-centre, outpatient trial14Subclinical HEMental status, psychometric tests, venous ammonia, EEG20 g, orally, t.d.s.,

      lactulose
      LactoseParticipants and personnelEffect of lactulose on psychometric testLactulose therapy resulted in a significant improvement, assessed by the number connection test and the race track test.

      Improvement in number connection test (5 out of 7 vs. 1 out of 7) and race track test (24.5% vs. 9.8%)
      Quero et al. 1997
      • Quero
      • et al.
      Double-blind, parallel-arm, single-centre, outpatient trial40Minimal HE diagnosed with at least 2 psychometric testsMental status, psychometric tests, arterial ammonia, EEGLactuloseLactoseParticipants and personnelMortality, HE, adverse events, and quality of lifeNo significant differences
      Shi et al. 1997
      • Shi H.
      • Liu H.Y.
      • Fu Z.
      • Zhu L.
      • Chen W.Z.
      Lactitol in treatment of subclinical hepatic encephalopathy: a double blind placebo-controlled randomised trial [Chinese].
      Double-blind, parallel-arm, single-centre, outpatient trial31Minimal HEPsychometric tests, blood ammoniaLactuloseGlucoseParticipants and personnelEffect of lactulose on psychometric testNot available
      EEG, electroencephalography; HE, hepatic encephalopathy.
      Taken together, lactulose as a treatment for HE does not endure the rigour that is required for approval of new treatments. Even though lactulose can be useful in patients with cirrhosis who are admitted stuporous, particularly if they are constipated, lactulose is not an FDA-approved indication for either the treatment or prevention of HE. Therefore, we believe that lactulose should not be considered standard of care until more robust data from adequately powered, independently performed, monitored, placebo-controlled, randomised, double-blinded and multicentre studies are available. The choice of such a placebo for comparison with lactulose is complex but would require a laxative component to avoid unblinding. We, therefore, propose that placebo-controlled trials of lactulose are needed to confirm that this drug indeed should be considered standard of care. Also, placebo-controlled trials of potential new treatments should be considered ethically sound given the paucity of high-quality data showing superiority of lactulose compared with placebo. To achieve these aims, the regulators, governing boards of responsible societies and patient groups will need to be convinced.

      Conclusions

      With advances in the knowledge and understanding of what constitutes evidence, we believe a relook at the many aspects of HE is essential if we want to have a positive impact on this terrible complication of cirrhosis. There are important lessons to be learnt from how other liver-related complications such as renal dysfunction and HRS have been re-classified. Introducing clarity to the nomenclature, classification, diagnostic criteria, pathophysiology, and standard of care are crucial in designing clinical trials and identifying sound clinical end points, with the ultimate aim of improving patient care.

      Abbreviations

      ACLF, acute-on-chronic liver failure; ALF, acute liver failure; HE, hepatic encephalopathy; HRS, hepatorenal syndrome; mHE, minimal hepatic encephalopathy; PSS, portsystemic shunting; UCDs, urea cycle disorders.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      Both Prof Jalan and Prof Rose have contributed equally to scientific rationale, generation of the idea, data collection, data analysis, writing and critical review of the manuscript.

      Conflict of interest

      Rajiv Jalan is the inventor of OPA, which has been patented by UCL and licensed to Mallinckrodt Pharma. He is also the founder of Yaqrit Discovery, a spin out company from University College London, Hepyx Limited and Cyberliver. He has research collaborations with Takeda and Yaqrit Discovery. Christopher Rose has research collaborations with, and is an advisor for Aza Technologies, Axcella, Horizon Therapeutics, Lupin Pharma, Mallinckrodt, Morphocell Technologies and Neuractas.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgements

      The authors gratefully acknowledge the help of Dr Maria Pilar Ballester, MD, PhD, who helped with the generation of Table 2, Table 3.

      Supplementary data

      The following are the supplementary data to this article:

      References

        • Vilstrup H.
        • Amodio P.
        • Bajaj J.
        • Cordoba J.
        • Ferenci P.
        • Mullen K.D.
        • et al.
        Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American association for the study of liver diseases and the European association for the study of the liver.
        Hepatology. 2014; 60: 715-735https://doi.org/10.1002/hep.27210
        • Weiss N.
        • Mochel F.
        • Rudler M.
        • Demeret S.
        • Lebray P.
        • Conti F.
        • et al.
        Peak hyperammonemia and atypical acute liver failure: the eruption of an urea cycle disorder during hyperemesis gravidarum.
        J Hepatol. 2017; (S0168-8278(17)32289-4. https://doi.org/10.1016/j.jhep.2017.09.009)
        • Rose C.F.
        • Amodio P.
        • Bajaj J.S.
        • Dhiman R.K.
        • Montagnese S.
        • Taylor-Robinson S.D.
        • et al.
        Hepatic encephalopathy: novel insights into classification, pathophysiology and therapy.
        J Hepatol. 2020; 73: 1526-1547https://doi.org/10.1016/j.jhep.2020.07.013
        • Cordoba J.
        • Ventura-Cots M.
        • Simón-Talero M.
        • Amorós À.
        • Pavesi M.
        • Vilstrup H.
        • et al.
        Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF).
        J Hepatol. 2014; 60: 275-281https://doi.org/10.1016/j.jhep.2013.10.004
        • Tryc A.B.
        • Goldbecker A.
        • Berding G.
        • Rümke S.
        • Afshar K.
        • Shahrezaei G.H.
        • et al.
        Cirrhosis-related Parkinsonism: prevalence, mechanisms and response to treatments.
        J Hepatol. 2013; 58: 698-705https://doi.org/10.1016/j.jhep.2012.11.043
        • 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.
        Liver Transpl. 2010; 16: 1336-1337https://doi.org/10.1002/lt.22149
        • Utku U.
        • Asil T.
        • Balcı K.
        • Uzunca İ.
        • Çelik Y.
        Hepatic myelopathy with spastic paraparesis.
        Clin Neurol Neurosurg. 2005; 107: 514-516https://doi.org/10.1016/j.clineuro.2004.10.002
        • Weissenborn K.
        • Tietge U.J.F.
        • Bokemeyer M.
        • Mohammadi B.
        • Bode U.
        • Manns M.P.
        • et al.
        Liver transplantation improves hepatic myelopathy: evidence by three cases.
        Gastroenterology. 2003; 124: 346-351https://doi.org/10.1053/gast.2003.50062
        • 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.
        Clin Gastroenterol Hepatol. 2021; 19: 2626-2635.e7https://doi.org/10.1016/j.cgh.2020.10.019
        • Thomsen K.L.
        • Macnaughtan J.
        • Tritto G.
        • Mookerjee R.P.
        • Jalan R.
        Clinical and pathophysiological characteristics of cirrhotic patients with grade 1 and minimal hepatic encephalopathy.
        PLOS ONE. 2016; 11e0146076https://doi.org/10.1371/journal.pone.0146076
        • Shawcross D.L.
        • Olde Damink S.W.M.
        • Butterworth R.F.
        • Jalan R.
        Ammonia and hepatic encephalopathy: the more things change, the more they remain the same.
        Metab Brain Dis. 2005; 20: 169-179https://doi.org/10.1007/s11011-005-7205-0
        • Patwardhan V.R.
        • Jiang Z.G.
        • Risech-Neiman Y.
        • Piatkowski G.
        • Afdhal N.H.
        • Mukamal K.
        • et al.
        Serum ammonia in associated with transplant-free survival in hospitalized patients with acutely decompensated cirrhosis.
        J Clin Gastroenterol. 2016; 50: 345-350https://doi.org/10.1097/MCG.0000000000000443
        • Vierling J.M.
        • Mokhtarani M.
        • Brown 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.
        Clin Gastroenterol Hepatol. 2016; 14: 903-906.e1https://doi.org/10.1016/j.cgh.2015.11.018
        • Shalimar
        • Sheikh M.F.
        • Mookerjee R.P.
        • Agarwal B.
        • Acharya S.K.
        • Jalan R.
        Prognostic role of ammonia in patients with cirrhosis.
        Hepatology. 2019; 70: 982-994https://doi.org/10.1002/hep.30534
        • Clemmesen J.O.
        • Larsen F.S.
        • Kondrup J.
        • Hansen B.A.
        • Ott P.
        Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration.
        Hepatology. 1999; 29: 648-653https://doi.org/10.1002/hep.510290309
        • Jalan R.
        • Olde Damink S.W.M.
        • Hayes P.C.
        • Deutz N.E.P.
        • Lee A.
        Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia and cerebral blood flow.
        J Hepatol. 2004; 41: 613-620https://doi.org/10.1016/j.jhep.2004.06.011
        • Kundra A.
        • Jain A.
        • Banga A.
        • Bajaj G.
        • Kar P.
        Evaluation of plasma ammonia levels in patients with acute liver failure and chronic liver disease and its correlation with the severity of hepatic encephalopathy and clinical features of raised intracranial tension.
        Clin Biochem. 2005; 38: 696-699https://doi.org/10.1016/j.clinbiochem.2005.04.013
        • Bhatia V.
        • Singh R.
        • Acharya S.K.
        Predictive value of arterial ammonia for complications and outcome in acute liver failure.
        Gut. 2006; 55: 98-104https://doi.org/10.1136/gut.2004.061754
        • Bernal W.
        • Hall C.
        • Karvellas C.J.
        • Auzinger G.
        • Sizer E.
        • Wendon J.
        Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure.
        Hepatology. 2007; 46: 1844-1852https://doi.org/10.1002/hep.21838
        • Niranjan-Azadi A.M.
        • Araz F.
        • Patel Y.A.
        • Alachkar N.
        • Alqahtani S.
        • Cameron A.M.
        • et al.
        Ammonia level and mortality in acute liver failure: a single-center experience.
        Ann Transpl. 2016; 21: 479-483https://doi.org/10.12659/aot.898901
        • Ong J.P.
        • Aggarwal A.
        • Krieger D.
        • Easley K.A.
        • Karafa M.T.
        • Van Lente F.
        • et al.
        Correlation between ammonia levels and the severity of hepatic encephalopathy.
        Am J Med. 2003; 114: 188-193https://doi.org/10.1016/s0002-9343(02)01477-8
        • 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.
        J Hepatol. 2003; 38: 441-446https://doi.org/10.1016/s0168-8278(02)00436-1
        • Sawhney R.
        • Holland-Fischer P.
        • Rosselli M.
        • Mookerjee R.P.
        • Agarwal B.
        • Jalan R.
        Role of ammonia, inflammation, and cerebral oxygenation in brain dysfunction of acute-on-chronic liver failure patients.
        Liver Transpl. 2016; 22: 732-742https://doi.org/10.1002/lt.24443
        • Ravi S.
        • Bade K.S.
        • Hasanin M.
        • Singal A.K.
        Ammonia level at admission predicts in-hospital mortality for patients with alcoholic hepatitis.
        Gastroenterol Rep (Oxf). 2017; 5: 232-236https://doi.org/10.1093/gastro/gow010
        • Shalimar
        • Rout G.
        • Kumar R.
        • Singh A.D.
        • Sharma S.
        • Gunjan D.
        • et al.
        Persistent or incident hyperammonemia is associated with poor outcomes in acute decompensation and acute-on-chronic liver failure.
        JGH Open. 2020; 4: 843-850https://doi.org/10.1002/jgh3.12314
        • Hu C.
        • Huang K.
        • Zhao L.
        • Zhang F.
        • Wu Z.
        • Li L.
        Serum ammonia is a strong prognostic factor for patients with acute-on-chronic liver failure.
        Sci Rep. 2020; 10: 16970https://doi.org/10.1038/s41598-020-73603-1
        • Verma N.
        • Dhiman R.K.
        • Choudhury A.
        • Taneja S.
        • Duseja A.
        • Singh V.
        • et al.
        Dynamic assessments of hepatic encephalopathy and ammonia levels predict mortality in acute-on-chronic liver failure.
        Hepatol Int. 2021; 15: 970-982https://doi.org/10.1007/s12072-021-10221-7
        • Chiriac S.
        • Stanciu C.
        • Cojocariu C.
        • Singeap A.-M.
        • Sfarti C.
        • Cuciureanu T.
        • et al.
        Role of ammonia in predicting the outcome of patients with acute-on-chronic liver failure.
        World J Clin Cases. 2021; 9: 552-564https://doi.org/10.12998/wjcc.v9.i3.552
        • Rose C.F.
        • Jalan R.
        Judging the value of ammonia measurement on lactulose dosing: apples and oranges?.
        Can Liv J. 2021; 4: 72-74https://doi.org/10.3138/canlivj-2020-0036
        • Ventura-Cots M.
        • Carmona I.
        • Moreno C.
        • Ampuero J.
        • Simón-Talero M.
        • Sanpedro F.
        • et al.
        Duration of the acute hepatic encephalopathy episode determines survival in cirrhotic patients.
        Therap Adv Gastroenterol. 2018; 11 (1756283X17743419)https://doi.org/10.1177/1756283X17743419
        • Bersagliere A.
        • Raduazzo I.D.
        • Schiff S.
        • Gatta A.
        • Merkel C.
        • Amodio P.
        • et al.
        Ammonia-related changes in cerebral electrogenesis in healthy subjects and patients with cirrhosis.
        Clin Neurophysiol. 2013; 124: 492-496https://doi.org/10.1016/j.clinph.2012.08.014
        • Rhee M.K.
        • Ho Y.-L.
        • Raghavan S.
        • Vassy J.L.
        • Cho K.
        • Gagnon D.
        • et al.
        Random plasma glucose predicts the diagnosis of diabetes.
        PLoS ONE. 2019; 14e0219964https://doi.org/10.1371/journal.pone.0219964
        • Allegretti A.S.
        • Parada X.V.
        • Endres P.
        • Zhao S.
        • Krinsky S.
        • Hillien St., S.A.
        • et al.
        Urinary NGAL as a diagnostic and prognostic marker for acute kidney injury in cirrhosis: a prospective study.
        Clin Transl Gastroenterol. 2021; 12e00359https://doi.org/10.14309/ctg.0000000000000359
        • Sotil E.U.
        • Gottstein J.
        • Ayala E.
        • Randolph C.
        • Blei A.T.
        Impact of preoperative overt hepatic encephalopathy on neurocognitive function after liver transplantation.
        Liver Transpl. 2009; 15: 184-192https://doi.org/10.1002/lt.21593
        • Ochoa-Sanchez R.
        • Tamnanloo F.
        • Rose C.F.
        Hepatic encephalopathy: from metabolic to neurodegenerative.
        Neurochem Res. 2021; 46: 2612-2625https://doi.org/10.1007/s11064-021-03372-4
        • Braissant O.
        • McLin V.A.
        • Cudalbu C.
        Ammonia toxicity to the brain.
        J Inherit Metab Dis. 2013; 36: 595-612https://doi.org/10.1007/s10545-012-9546-2
        • Häussinger D.
        • Kircheis G.
        • Fischer R.
        • Schliess F.
        • Dahl S vom
        Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema?.
        J Hepatol. 2000; 32: 1035-1038https://doi.org/10.1016/S0168-8278(00)80110-5
        • Butterworth R.F.
        Altered glial-neuronal crosstalk: cornerstone in the pathogenesis of hepatic encephalopathy.
        Neurochem Int. 2010; 57: 383-388https://doi.org/10.1016/j.neuint.2010.03.012
        • Morgan M.Y.
        Current state of knowledge of hepatic encephalopathy (part III): non-absorbable disaccharides.
        Metab Brain Dis. 2016; 31: 1361-1364https://doi.org/10.1007/s11011-016-9910-2
        • Elkington S.G.
        • Floch M.H.
        • Conn H.O.
        Lactulose in the treatment of chronic portal-systemic encephalopathy. A double-blind clinical trial.
        N Engl J Med. 1969; 281: 408-412https://doi.org/10.1056/NEJM196908212810803
        • Simmons F.
        • Goldstein H.
        • Boyle J.D.
        A controlled clinical trial of lactulose in hepatic encephalopathy.
        Gastroenterology. 1970; 59: 827-832
        • Brown H.
        • Trey C.
        • McDermott W.V.
        Lactulose treatment of hepatic encephalopathy in outpatients.
        Arch Surg. 1971; 102: 25-27https://doi.org/10.1001/archsurg.1971.01350010027006
        • Germain L.
        • Frexinos J.
        • Louis A.
        • Ribet A.
        Double blind study of lactulose in 8 patients with chronic hepatic encephalopathy after portocaval shunt.
        Arch Francaises Des Maladies de l’appareil Digestif. 1973; 62: 293-302
        • Rodgers J.B.
        • Kiley J.E.
        • Balint J.A.
        Comparison of results of long-term treatment of chronic hepatic encephalopathy with lactulose and sorbitol.
        Am J Gastroenterol. 1973; 60: 459-465
        • Corazza G.R.
        • Tacconi C.
        • Zoli G.
        Use of pyridoxine-alpha-ketoglutarate (PAK) in hepatic encephalopathy.
        Int J Clin Pharmacol Res. 1982; 2: 7-13
        • McClain C.J.
        • Potter T.J.
        • Kromhout J.P.
        • Zieve L.
        The effect of lactulose on psychomotor performance tests in alcoholic cirrhotics without overt hepatic encephalopathy.
        J Clin Gastroenterol. 1984; 6: 325-329
        • Uribe M.
        • Toledo H.
        • Perez F.
        • Vargas F.
        • Gil S.
        • Garcia-Ramos G.
        • et al.
        Lactitol, a second-generation disaccharide for treatment of chronic portal-systemic encephalopathy. A double-blind, crossover, randomized clinical trial.
        Dig Dis Sci. 1987; 32: 1345-1353https://doi.org/10.1007/BF01296659
        • Horsmans Y.
        • Solbreux P.M.
        • Daenens C.
        • Desager J.P.
        • Geubel A.P.
        Lactulose improves psychometric testing in cirrhotic patients with subclinical encephalopathy.
        Aliment Pharmacol Ther. 1997; 11: 165-170https://doi.org/10.1046/j.1365-2036.1997.118289000.x
        • Quero
        • et al.
        Record C.O. Al-Mardini H. International Symposium on Ammonia. Advances in lepatic encephalopathy & metabolism in liver disease. Medical Faculty, University of Newcastle upon Tyne, Newcastle upon Tyne, England1997
        • Shi H.
        • Liu H.Y.
        • Fu Z.
        • Zhu L.
        • Chen W.Z.
        Lactitol in treatment of subclinical hepatic encephalopathy: a double blind placebo-controlled randomised trial [Chinese].
        Chin J Digestion. 1997; 17: 221-223
        • Gluud L.L.
        • Vilstrup H.
        • Morgan M.Y.
        Nonabsorbable disaccharides for hepatic encephalopathy: a systematic review and meta-analysis.
        Hepatology. 2016; 64: 908-922https://doi.org/10.1002/hep.28598