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Current Diagnosis and Classification of Hepatic Encephalopathy

  • Piero Amodio
    Correspondence
    Address for correspondence: Piero Amodio, MD, FRCP, Department of Medicine –DIMED- University of Padova, via Giustiniani, 2, 35128 Padova, Italy. Fax: +39 049 7960903.
    Affiliations
    Department of Medicine –DIMED- University of Padova, Italy
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Published:August 27, 2018DOI:https://doi.org/10.1016/j.jceh.2018.07.001
      Hepatic encephalopathy is a brain dysfunction caused by liver insufficiency and/or portal-systemic shunt; it manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma. It should be differentiated from other neurological/psychiatric disorders that can occur in patients with liver disease. Its classification needs to take into account the underlying condition, severity, course, precipitating factors, and—possibly—sensitivity to ammonia-lowering agents.

      Keywords

      Abbreviations:

      ACLF (acute-on-chronic liver failure), EEG (electroencephalogram), HE (Hepatic Encephalopathy), PSE (portal-systemic encephalopathy)
      The term ‘hepatic encephalopathy’ (HE) was used by Porter and Adams
      • Porter H.
      • Adams R.D.
      The copper content of brain and liver in hepatic encephalopathy.
      to refer to the condition that was previously called hepatic coma
      • Foley J.M.
      • Watson C.W.
      • Adams R.D.
      Significance of the electroencephalographic changes in hepatic coma.
      and was accurately described and named portal-systemic encephalopathy (PSE) by Sherlock et al.
      • Sherlock S.
      • Summerskill W.H.
      • White L.P.
      • Phear E.A.
      Portal-systemic encephalopathy; neurological complications of liver disease.
      The term PSE underlined the link between brain dysfunction (i.e., encephalopathy) and portal-systemic (PS) shunt occurring in cirrhosis, which causes a relevant increase in gut-derived ammonia and, possibly, other gut-derived toxins. In fact, ammonia is a substance with extensive first-pass effect, and thus, its plasma level is massively increased by PS blood shunting. The use of the term HE is preferable to the one of PSE because it underlines that at the basis of the condition, there is a lack of some functions of the liver, independent of this occurring because of PS blood shunting or because of pure liver failure, as it happens in acute hepatic failure.
      The observation that liver disease is associated to behavioral changes goes back to Hippocrates, but the first accurate description of the association of cirrhosis with delirium and coma was given by Morgagni in the 18th century.
      • Morgagni G.B.
      De sedibus, et causis morborum per anatomen indagatis.
      However, the fundamental pathophysiological insight into the condition was provided by Hann et al.
      • Hahn M.
      • Massen O.
      • Nencki M.
      Die Eck's Fistel zwischen der unteren Holvene und der Pfortader und ihre Folgen fuer den Organismus.
      who were able to induce brain dysfunction in dogs with the creation of PS shunt. They were also able to prove a link with nitrogen metabolism. The power of ammonia to induce coma or stupor in patients with cirrhosis was clearly established in humans in the 30s of the last century by van Coulert et al.,
      • Van Caulert C.
      • Deviller C.
      • Halff M.
      Troubles provoques par l'ingestion de sels ammoniacaux chez l'homme atteint de cirrhose de Laennec.
      who administered oral ammonia salt loads, and by the comatogenous side effect of the first diuretic substances that increased the ammonia level.
      • Gabuzda G.J.
      • Phillips G.B.
      • Davidson C.S.
      Reversible toxic manifestations in patients with cirrhosis of the liver given cation-exchange resins.
      Of note, the variability of the effect of the same amount of ammonia salt load in the same subjects
      • Nayrac P.
      Troubles neurologiques au cours des maladies du foie.
      clearly proved that the toxic effect of ammonia on the brain is not direct, but mediated by some metabolic processes within the brain and by the interaction with other factors.

      The diagnosis of HE

      The clear link with nitrogen metabolism and deficiency in ammonia detoxification, which depends on liver function and PS shunt, differentiates HE from other unspecific kinds of delirium (also called ‘encephalopathy’) which easily occur in many severe medical conditions, such as pneumonia, urinary infections, myocardial infarction, hip fractures, hyponatremia, drug toxicity, etc. and is easily seen in elderly people.
      • Inouye S.K.
      • Westendorp R.G.
      • Saczynski J.S.
      Delirium in elderly people.
      Of note, since the half of last century, Riddell
      • Riddell A.G.
      The mechanism of hepatic coma.
      stated that: ‘... among a group of patients with severe liver disease a number of neurological disturbances will be met with; not all of these are the disease known as hepatic coma. Among these other states are the psychoses associated with chronic alcoholism and nicotinic acid deficiency, electrolyte disturbances, septicaemia, increased response to narcotics and subdural haematoma’.
      Thus, despite its unspecific clinical expression, HE cannot be classified as mere delirium (or ‘encephalopathy’) occurring in patients with liver disease because of its peculiar causal link with liver insufficiency/PS shunt and with the consequently altered metabolism of gut-derived nitrogenous substances.
      This is the reason why the American Association for the Study of Liver Diseases/European Association for the Study of the Liver (AASLD/EASL) guidelines stated that ‘HE is a brain dysfunction caused by liver insufficiency and/or PS shunt; it manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma’.
      • Vilstrup H.
      • Amodio P.
      • Bajaj J.
      • 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.
      A Bayesian approach to the diagnosis of HE is based on the recognition of i) compatible clinical findings (Table 1), ii) high pretest probability (severe liver failure/PS shunt), iii) consideration of obvious alternative causes that can completely or partially explain the findings, and iv) at least some degree of reversibility with treatments improving the derangement of nitrogen metabolism (Figure 1).
      Table 1Clinical Patterns of HE Presentation—Modified From the Study by Amodio.
      • Amodio P.
      Hepatic encephalopathy.
      PatternDescription
      A) ComaThe patient's eyes are closed, unresponsive even to pain stimulation
      B) Rapidly developing confusion stateInhibitedThe patient is disoriented in time and/or space and/or identity and somnolent
      AgitatedThe patient is disoriented in time and/or space and/or identity and agitated/angry/restless
      C) Almost continuous mild mental dysfunction with interspersed recurrent episodes of more severe confusion than usualDementia-like pattern
      D) Predominant motor disorder with mild/moderate mental dysfunction/confusionExtrapyramidalParkinsonism or chorea or athetosis
      PyramidalSpastic paraparesis with hyperreflexia
      E) Mild brain dysfunctionThe patient is oriented, and his/her mental activity seems normal or near-normal; sometimes, caregivers or relatives refer a decay from the patient's standard in terms of behavior, irritability, or cognition.

      On psychometrical testing, alterations are detectable (they concern attention, working memory, visuo-practical ability, and inhibition). Other signs associated or independent of psychometrical alterations are the slowing of EEG activity and/or the reduction of critical flicker frequency.
      Note: In patterns B-D, usually asterixis is present.
      EEG, electroencephalogram; HE, hepatic encephalopathy.
      Figure 1
      Figure 1Flow chart for the diagnosis of HE—modified from the study by Amodio
      • Amodio P.
      Hepatic encephalopathy.
      —ALAs, ammonia-lowering agents; *high plasma ammonia level is a marker for liver insufficiency and/or portal-systemic blood shunting.
      Concerning the alternative causes, it should be noted that in single patients, HE can be superimposed to other medical or neurological disorders damaging the brain function because HE—a disorder depending on liver insufficiency/PS shunt—can be overlapped to other conditions damaging the brain function. In this case, proper diagnosis of each condition is mandatory to allow combined treatments.
      Of note, patients with low plasma ammonia levels lack the prerequisite for HE to occur; i.e., severe liver dysfunction and/or PS shunt both of which are reflected by high plasma ammonia levels.
      • Akahoshi T.
      • Nishizaki T.
      • Wakasugi K.
      • et al.
      Portal-systemic encephalopathy due to a congenital extrahepatic portosystemic shunt: three cases and literature review.
      • Watanabe A.
      Portal-systemic encephalopathy in non-cirrhotic patients: classification of clinical types, diagnosis and treatment.
      • Laleman W.
      • Simon-Talero M.
      • Maleux G.
      • et al.
      Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicenter survey on safety and efficacy.
      • Takahashi H.
      • Shigefuku R.
      • Yoshida Y.
      • et al.
      Correlation between hepatic blood flow and liver function in alcoholic liver cirrhosis.
       Patients with low plasma ammonia may suffer from delirium of any other origin (as any other patients without liver failure), so that accurate investigation of alternative causes is required. In contrast, patients with high ammonia may have i) normal brain function, ii) HE, iii) other brain disorders, and iv) overlapped brain disorders. Thus, high ammonia, although a risk factor for the development of HE,
      • Vierling J.M.
      • Mokhtarani M.
      • Brown Jr., R.S.
      • et al.
      Fasting blood ammonia predicts risk and frequency of hepatic encephalopathy Episodes in patients with cirrhosis.
      is not sufficient for the diagnosis of HE, just as hypercholesterolemia is not a criterion to diagnose myocardial infarction.
      Proper diagnosis is relevant for patient management because it is potentially dangerous to miss out the diagnosis of other potentially threatening conditions and treat them with drugs targeted to reduce gut dysbiosis/lower plasma ammonia, such as lactulose, oral antibiotics, l-ornithyne-l-aspartate, sodium and glycerol phenybutirrate, or ornithine-phenylacetate.

      The classification of HE

      The classification of HE is multiaxial because various dimensions are required for proper management of patients. HE should be qualified on the basis of 1) the underlying context, 2) the actual severity, 3) the time course, 4) the precipitating factors, if any, and—possibly—5) the response and dependence to hypoammonemic treatments.
      Consensus exists that the kind of disorder causing HE should be mentioned because this has pathophysiological, clinical, prognostic, and treatment implication.
      • Vilstrup H.
      • Amodio P.
      • Bajaj J.
      • 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.
      • Ferenci P.
      • Lockwood A.
      • Mullen K.
      • Tarter R.
      • Weissenborn K.
      • Blei A.T.
      Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998.
      The main distinction is between HE in the context of acute liver failure (ALF) vs. the one in the context of cirrhosis. More recently, it was found useful to distinguish between HE in cirrhosis vs. the one in patients with noncirrhotic PS blood shunting.
      • Vilstrup H.
      • Amodio P.
      • Bajaj J.
      • 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.
      • Ferenci P.
      • Lockwood A.
      • Mullen K.
      • Tarter R.
      • Weissenborn K.
      • Blei A.T.
      Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998.
      Clearly, HE in ALF (type ‘A’ HE) has distinct pathophysiological features because it occurs in a context without shunt, with massive systemic inflammation involving the brain, severe systemic and intracranial hemodynamic alterations, and intracranial hypertension that can lead to death because of brain herniation.
      • Bjerring P.N.
      • Eefsen M.
      • Hansen B.A.
      • Larsen F.S.
      The brain in acute liver failure. A tortuous path from hyperammonemia to cerebral edema.
      • Wendon J.
      • Cordoba J.
      • Dhawan A.
      • et al.
      EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure.
      Thus, it requires specific treatments that differ from those used in patients with chronic disease. In contrast, the distinction between HE in cirrhotic (type ‘C’ HE) and in noncirrhotic PS shunt (type ‘B’ HE) is less relevant because the pathophysiology, clinical picture, and treatments are similar. However, this distinction may be useful because i) the obliteration of shunt, if possible, resolves the problem in patients with noncirrhotic PS shunt and ii) the prognostic implications are clearly different because patients with noncirrhotic portal hypertension and shunt have better prognosis than cirrhotic patients.
      Recently, the opportunity to create a further distinction within the patients with cirrhosis between those with and those without acute-on-chronic liver failure (ACLF) was proposed.
      • Lee G.H.
      Hepatic encephalopathy in acute-on-chronic liver failure.
      The main reason behind this proposal is the more severe prognostic value of HE in the context of ACLF,
      • Cordoba J.
      • Ventura-Cots M.
      • Simon-Talero M.
      • et al.
      Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF).
      even if there is no proof of peculiar pathophysiological mechanisms.
      • Romero-Gomez M.
      • Montagnese S.
      • Jalan R.
      Hepatic encephalopathy in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure.
      The finding that the increased brain water content is parallel with the degree of HE
      • Gupta T.
      • Dhiman R.K.
      • Rathi S.
      • et al.
      Impact of hepatic and extrahepatic insults on the outcome of acute-on-chronic liver failure.
      is in line with the view of increased astrocyte hydration in HE.
      • Haussinger D.
      Low grade cerebral edema and the pathogenesis of hepatic encephalopathy in cirrhosis.
      It should be emphasized that the concept of brain hyperhydration (‘edema’) should not be confused with the one of intracranial hypertension. At any rate, in very severe cases of patients with HE and multiorgan failure in the intensive care unit, evidence of intracranial hypertension has been reported,
      • Wright G.
      • Sharifi Y.
      • Jover-Cobos M.
      • Jalan R.
      The brain in acute on chronic liver failure.
      despite autopsy-based evidence of death for cerebral herniation is scanty, if any.
      In the context of ACLF, the role of inflammation is greater in patients with ACLF than in patients without ACLF, as well as the role of other noxae in the brain deriving from multiorgan failure, such as hypoxia,
      • 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.
      renal failure, etc. Thus, the risk for mixed metabolic encephalopathy is reasonably higher in this context, so that probably both i) personalized treatments might be preferable and ii) specific trials might be implemented. Obviously, this might be difficult because ACLF is a syndrome (an umbrella term) combining different pathophysiological conditions. On the other hand, proliferation of headings in any classification should be avoided if their utility is unproven (Ockham's razor principle: “entities must not be multiplied beyond necessity”) (Table 2).
      Table 2Pros and Cons of the Introduction of the Label ‘Type D’ for HE in ACLF.
      ProsCons
      The higher the characterization of the underlying condition, the higher the likelihood of proper etiologic treatment.

      HE in ACLF is highly influenced by cytokine storm and MOF, and ICI was reported (despite very rarely).

      Brain hyperhydration is correlated with HE severity.
      Ockham's razor principle: ‘entities must not be multiplied beyond necessity’.

      No consensus/proof that further subdivision of HE improves the patient's management more than taking into account analytically all the mechanisms/treatments of delirium/coma in a subject with ACLF and MOF.

      Mixed metabolic encephalopathy is likely the actual condition.
      ACLF, acute-on-chronic liver failure; HE, hepatic encephalopathy.
      Thus, consensus about the utility to label HE in ACLF as a type (type ‘D’) separate from type ‘C’ will probably depend on the proof that it may require specific diagnostic and treatment procedure that differs from the ones used in patients without ACLF.
      The severity of symptoms of HE has an implication on patient care and possibly implies different therapeutic responses
      • Amodio P.
      • Ampuero J.
      Solving doubts about L-ornithine L-aspartate for overt hepatic encephalopathy: whom and how to treat.
      • Sidhu S.S.
      • Sharma B.C.
      • Goyal O.
      • Kishore H.
      • Kaur N.
      L-ornithine L-aspartate in bouts of overt hepatic encephalopathy.
      and prognosis.
      • Cordoba J.
      • Ventura-Cots M.
      • Simon-Talero M.
      • et al.
      Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF).
      This has been classified in various ways in the past (Table 2); other original and reasonable scoring systems are the Chess scale,
      • Ortiz M.
      • Cordoba J.
      • Doval E.
      • et al.
      Development of a clinical hepatic encephalopathy staging scale.
      the Log scale,
      • Salam M.
      • Matherly S.
      • Farooq I.S.
      • et al.
      Modified-orientation log to assess hepatic encephalopathy.
      and, more recently, a Delphi-based scoring system.
      • Bajaj J.S.
      • Frederick R.T.
      • Bass N.M.
      • et al.
      Overt hepatic encephalopathy: development of a novel clinician reported outcome tool and electronic caregiver diary.
      A not-recommendable tool is the hepatic encephalopathy scoring algorithm (HESA)
      • Hassanein T.I.
      • Tofteng F.
      • Brown Jr., R.S.
      • et al.
      Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis.
      because i) no operative definition of the terms is provided, ii) the number of items defining a grade is not defined, and iii) the progression of items to define a grade is arbitrary (e.g., why tremor cannot appear after slurred speech, or hyperactive reflexes after bizarre behavior?).
      A simple way is the one suggested by the AASLD/EASL practice guidelines that introduce operative criteria to improve the classic 4-degree system proposed by Conn and accept the dichotomy between asymptomatic or barely discernible HE (‘covert’) and highly symptomatic HE (‘overt’) proposed by an Iternational Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus.
      • Vilstrup H.
      • Amodio P.
      • Bajaj J.
      • 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.
      Each of the two conditions is heterogeneous and needs further staging. For overt HE, the classical criteria implemented by the operative definitions proposed by the AASLD/EASL practice guidelines (Table 3) are easily usable, while the Animal Naming Test
      • Campagna F.
      • Montagnese S.
      • Ridola L.
      • et al.
      The animal naming test: an easy tool for the assessment of hepatic encephalopathy.
      is a reasonably short and practical tool to detect and quantify the heterogeneity of the ‘covert’ condition. A recommendable tool to detect and quantify minimal hepatic encephalopathy (MHE) and, possibly, grade 1 HE is the portal hepatic encephalopathy score (PHES).
      • Morgan M.Y.
      • Amodio P.
      • Cook N.A.
      • et al.
      Qualifying and quantifying minimal hepatic encephalopathy.
      • Randolph C.
      • Hilsabeck R.
      • Kato A.
      • et al.
      Neuropsychological assessment of hepatic encephalopathy: ISHEN practice guidelines.
      More sensitive tools, such as computerized tests, might be inadequate to test grade 1 HE because patients may be unable to be tested. In contrast, a relatively easy and low-sensitive technique, such as critical flicker frequency (CFF), may be useful to detect patients with grade 1 HE but may fail to detect patients with MHE.
      • Kircheis G.
      • Wettstein M.
      • Timmermann L.
      • Schnitzler A.
      • Haussinger D.
      Critical flicker frequency for quantification of low-grade hepatic encephalopathy.
      This was also proved by the poorer prognosis of patients with altered CFF than patients with normal CFF vs. patients already having altered psychometric performance.
      • Ampuero J.
      • Simon M.
      • Montoliu C.
      • et al.
      Minimal hepatic encephalopathy and critical flicker frequency are associated with survival of patients with cirrhosis.
      Quantified electroencephalogram, which is independent of patient cooperation and has a good prognostic value,
      • Amodio P.
      • Del Piccolo F.
      • Petteno E.
      • et al.
      Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients.
      can detect different levels of brain suffering, but its use is limited until friendly equipment and quantifying procedures will be cheap and easily available.
      Table 3Grading of the Severity of HE (Modified From the AASLD/EASL Guidelines).
      ISHENWH modified with the insertion of MHEDescriptionOperative criteria
      UnimpairedNo encephalopathy at all, no history of HE
      CovertMinimalNeuropsychological alterations on tests exploring psychomotor speed/executive functions or neurophysiological alterations without clinical evidence of mental changeNeuropsychological alterations on tests exploring psychomotor speed/executive functions or neurophysiological/psychophysiological (CFF) alterations without clinical evidence of mental change
      Grade I
      • Trivial lack of awareness
      • Euphoria or anxiety
      • Shortened attention span
      • Impairment of addition or subtraction
      Despite oriented in time and space (see below), the patient appears to have some cognitive/behavioral decay with respect to his/her standard on clinical examination or to the caregivers
      Overt (i.e., undoubtedly symptomatic)Grade II
      • Lethargy or apathy
      • Disorientation for time
      • Obvious personality change
      • Inappropriate behavior
      Disoriented for time (at least three of the followings are wrong: day of the month, day of the week, month, season, year) ± the other mentioned symptoms
      Grade III
      • Somnolence to semi-stupor
      • Responsive to stimuli
      • Confused
      • Gross disorientation
      • Bizarre behavior
      Disoriented also for space (at least three of the followings are wrongly reported: country, state—or region, city, place, floor) ± the other mentioned symptoms
      Grade IVComaDo not respond even to pain stimuli
      HE, hepatic encephalopathy.
      The time course is relevant because the risk of future bouts of overt HE is higher in patients who had two bouts (∼40%) than in those who had only one bout of HE (∼25%) in the previous 6 months.
      • Bass N.M.
      • Mullen K.D.
      • Sanyal A.
      • et al.
      Rifaximin treatment in hepatic encephalopathy.
      • Sharma B.C.
      • Sharma P.
      • Agrawal A.
      • Sarin S.K.
      Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo.
      Furthermore, the latter have higher risk than those who did not have previous bouts of HE (9–35% in 5 years).
      • Sharma B.C.
      • Sharma P.
      • Agrawal A.
      • Sarin S.K.
      Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo.
      • Gentilini P.
      • Laffi G.
      • La V.G.
      • et al.
      Long course and prognostic factors of virus-induced cirrhosis of the liver.
      • Gines P.
      • Quintero E.
      • Arroyo V.
      • et al.
      Compensated cirrhosis: natural history and prognostic factors.
      Of note, the interval of 6 months was arbitrarily defined because no study proved that this is the optimal one, but it is reasonable that it is a good compromise between a too short interval in which the likelihood of a bout of overt HE is low and a too long interval in which the information about bouts of overt HE might be lost. At any rate, the qualification of HE concerning its time course is of fundamental importance because secondary prophylaxis is mandatory in subjects who had previous bouts of HE, and current consensus gives different suggestions depending on the frequency of recurrence.
      • Vilstrup H.
      • Amodio P.
      • Bajaj J.
      • 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.
      Precipitating factors should be mentioned because i) the occurrence of recognized precipitating factors increases the likelihood of prober diagnosis and ii) attention can be focused to prevent the recurrence of a specific precipitating factor. For instance, if the precipitating factor is constipation, treatment and education oriented to avoid constipation will be important, and if the precipitating factor is gastrointestinal bleeding, measures to avoid bleeding will be important, etc.
      The AASLD/EASL practice guidelines do not affirm the opportunity to report the response to ammonia-lowering treatments (disaccharides, oral antibiotic, L-Ornithine-L-Aspartate (LOLA), nonureic nitrogen-wasting products). At any rate, this information is useful both to confirm the diagnosis and to guide treatment, and thus, it should be added. The resulting classification grid is reported in Table 4.
      Table 4Grid Summarizing the Classification Criteria for HE.
      Table thumbnail fx1
      Note: *The utility to consider this subtype is under debate. Possibly it concerns patients with severe ACLF and severe metabolic encephalopathy—possibly of mixed etiology—in the context of MOF.
      ACLF, acute-on-chronic liver failure; HE, hepatic encephalopathy.

      Conflicts of interest

      The author has none to declare.

      Acknowledgements

      The author acknowleges the CIMANMEC of the University of Padova and the Hepatos Forin Foundation for their kind support.

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