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Hepatic encephalopathy in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure

Open AccessPublished:September 10, 2014DOI:https://doi.org/10.1016/j.jhep.2014.09.005

      Summary

      Hepatic encephalopathy in a hospitalized cirrhotic patient is associated with a high mortality rate and its presence adds further to the mortality of patients with acute-on-chronic liver failure (ACLF). The exact pathophysiological mechanisms of HE in this group of patients are unclear but hyperammonemia, systemic inflammation (including sepsis, bacterial translocation, and insulin resistance) and oxidative stress, modulated by glutaminase gene alteration, remain as key factors. Moreover, alcohol misuse, hyponatremia, renal insufficiency, and microbiota are actively explored. HE diagnosis requires exclusion of other causes of neurological, metabolic and psychiatric dysfunction. Hospitalization in the ICU should be considered in every patient with overt HE, but particularly if this is associated with ACLF. Precipitating factors should be identified and treated as required. Evidence-based specific management options are limited to bowel cleansing and non-absorbable antibiotics. Ammonia lowering drugs, such as glycerol phenylbutyrate and ornithine phenylacetate show promise but are still in clinical trials. Albumin dialysis may be useful in refractory cases. Antibiotics, prebiotics, and treatment of diabetes reduce systemic inflammation. Where possible and not contraindicated, large portal-systemic shunts may be embolized but liver transplantation is the most definitive step in the management of HE in this setting. HE in patients with ACLF appears to be clinically and pathophysiologically distinct from that of acute decompensation and requires further studies and characterization.

      Abbreviations:

      ACLF (acute-on-chronic liver failure), ALF (acute liver failure), HE (hepatic encephalopathy), GLS (glutaminase), ROS (reactive oxygen species), IL (interleukin), TNF (tumour necrosis factor), BT (bacterial translocation), SIBO (small intestinal bacterial overgrowth), DM (diabetes mellitus), IR (insulin resistance), COX (cyclooxygenase), OTC (ornithine transcarbamylase), OPE (ornithine-phenylacetate), LOLA (L-ornithine L-aspartate)

      Keywords

      Introduction

      Hepatic encephalopathy (HE) is a major complication of liver cirrhosis, affecting up to one third of cirrhotic patients and is classified into three types: Type A HE is due to acute liver failure (ALF); type B HE is due to portal-systemic shunting without intrinsic liver disease; and type C HE occurs in patients with underlying cirrhosis [
      • Ferenci P.
      • Lockwood A.
      • Mullen K.
      • Tarter R.
      • Weissenborn K.
      • Blei A.T.
      • et al.
      Hepatic encephalopathy-definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998.
      ]. HE manifests as a spectrum, ranging from minimal disturbances in mental function that impact on attention, cognition and quality of life to coma. In this review, patients with type C HE who require hospital admission will be discussed.
      Figure thumbnail fx2
      Figure thumbnail gr1
      Fig. 1Actuarial survival curve of hospitalized cirrhotic patients showing mortality of patients with or without ACLF in combination of with or without overt hepatic encephalopathy. Mortality rate was significantly higher in patients with ACLF and HE in comparison with non-HE patients with ACLF. In decompensated cirrhosis HE was also related to a raised mortality. Adapted from Cordoba J. et al.
      [
      • 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).
      ]
      .

      Pathophysiology of hepatic encephalopathy in hospitalized patients

      The pathophysiology of HE is multifactorial and complex but hyperammonemia, systemic inflammation and genetic factors are thought to be important. There are no human neuropathologic data but electron microscopic studies in animal models of ACLF show that the astrocytes are swollen with markedly vasoconstricted blood vessels [
      • Wright G.
      • Jalan R.
      Ammonia and inflammation in the pathogenesis of hepatic encephalopathy: Pandora’s box?.
      ]. Increased intracranial pressure is common in patients with ALF. In patients with ACLF, an overt increase in intracranial pressure and cerebral oedema-related deaths have been described in small case series [
      • Jalan R.
      • Bernuau J.
      Induction of cerebral hyperemia by ammonia plus endotoxin: does hyperammonemia unlock the blood-brain barrier?.
      ,
      • Donovan J.P.
      • Schafer D.F.
      • Shaw Jr., B.W.
      • Sorrell M.F.
      Cerebral oedema and increased intracranial pressure in chronic liver disease.
      ]. More recently, a retrospective study suggested that overt cerebral oedema was observed in about 5% patients with ACLF [
      • Joshi D.
      • O’Grady J.
      • Patel A.
      • Shawcross D.
      • Connor S.
      • Deasy N.
      • et al.
      Cerebral oedema is rare in acute-on-chronic liver failure patients presenting with high-grade hepatic encephalopathy.
      ], which was confirmed by imaging studies [
      • Nath K.
      • Saraswat V.A.
      • Krishna Y.R.
      • Thomas M.A.
      • Rathore R.K.
      • Pandey C.M.
      • et al.
      Quantification of cerebral edema on diffusion tensor imaging in acute-on-chronic liver failure.
      ]. Therefore, although brain swelling is a feature of ACLF, the relatively low incidence of deaths from cerebral herniation may be related to cerebral atrophy or reduced cerebral perfusion, which are known features of cirrhosis and HE [
      • García-Martínez R.
      • Córdoba J.
      Acute-on-chronic liver failure: the brain.
      ].

      Hyperammonemia

      In the brain, astrocytes are the only cells that metabolize ammonia by the enzyme glutamine synthetase, converting glutamate and ammonia into glutamine. Glutamine accumulation, as an osmolyte, promotes astrocyte swelling [
      • Romero-Gómez M.
      Role of phosphate-activated glutaminase in the pathogenesis of hepatic encephalopathy.
      ]. Ammonia also induces oxidative, cellular stress and energy failure.
      Data regarding a direct correlation between ammonia concentration and the severity of HE are limited. In a systematic review, a general correlation between higher levels of ammonia and more severe encephalopathy in cirrhosis was observed [
      • OldeDamink S.W.
      • Deutz N.E.
      • Dejong C.H.
      • Soeters P.B.
      • Jalan R.
      Interorgan ammonia metabolism in liver failure.
      ]. More recently, a retrospective study in cirrhotic patients with grade 3/4 HE showed that patients were hyperammonemic but the absolute levels did not correlate with the severity of HE [
      • Bosoi C.R.
      • Parent-Robitaille C.
      • Anderson K.
      • Tremblay M.
      • Rose C.F.
      AST-120 (spherical carbon adsorbent) lowers ammonia levels and attenuates brain edema in bile duct-ligated rats.
      ]. Studies in animal models have consistently shown that induction of hyperammonemia results in brain oedema and the reduction in ammonia translates into reduced brain swelling, firmly confirming the central role of ammonia as a therapeutic target [
      • Bosoi C.R.
      • Parent-Robitaille C.
      • Anderson K.
      • Tremblay M.
      • Rose C.F.
      AST-120 (spherical carbon adsorbent) lowers ammonia levels and attenuates brain edema in bile duct-ligated rats.
      ]. Interestingly, in a model of cirrhosis, reduction in ammonia concentration protected the brain from a subsequent challenge with lipopolysaccharide [
      • Wright G.
      • Vairappan B.
      • Stadlbauer V.
      • Mookerjee R.P.
      • Davies N.A.
      • Jalan R.
      Reduction in hyperammonaemia by ornithine phenylacetate prevents lipopolysaccharide-induced brain edema and coma in cirrhotic rats.
      ]. Thus, ammonia seems to sensitize the brain to a secondary inflammatory insult.

      Inflammation

      Inflammatory response, infections and sepsis

      The impact of the systemic inflammatory response on ammonia-induced brain dysfunction was described in cirrhotic patients admitted to the hospital with infection [
      • Shawcross D.L.
      • Davies N.A.
      • Williams R.
      • Jalan R.
      Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.
      ]. The main source of inflammation in cirrhotics was infection and sepsis. Ammonia-induced deterioration in neuropsychological dysfunction was prevented by antibiotics, supporting the notion of a synergy between ammonia and inflammation in the pathogenesis of HE. Merli et al. confirmed the presence of cognitive impairment (overt or subclinical) in 42% of cirrhotics without infection, in 79% with infection and in 90% with sepsis [
      • Merli M.
      • Lucidi C.
      • Pentassuglio I.
      • Giannelli V.
      • Giusto M.
      • Di Gregorio V.
      • et al.
      Increased risk of cognitive impairment in cirrhotic patients with bacterial infections.
      ]. Hung et al. observed that infections increase the mortality of HE cirrhotic patients, especially pneumonia and sepsis without specific focus [
      • Hung T.H.
      • Lay C.J.
      • Chang C.M.
      • Tsai J.J.
      • Tsai C.C.
      • Tsai C.C.
      The effect of infections on the mortality of cirrhotic patients with hepatic encephalopathy.
      ]. Lastly, in the CANONIC study described above, a clear role for systemic inflammation was demonstrated in patients with advanced HE, which correlated with mortality.

      Neuroinflammation, hyponatremia and oxidative stress

      Changes in the permeability of the blood-brain barrier (BBB) to water and other small molecules [
      • Jones E.A.
      • Mullen K.D.
      Theories of the pathogenesis of hepatic encephalopathy.
      ,
      • Scott T.R.
      • Kronsten V.T.
      • Hughes R.D.
      • Shawcross D.L.
      Pathophysiology of cerebral oedema in acute liver failure.
      ] together with hyponatremia [
      • Córdoba J.
      • García-Martinez R.
      • Simón-Talero M.
      Hyponatremic and hepatic encephalopathies: similarities, differences and coexistence.
      ] and oxidative stress have been implicated in HE [
      • Butterworth R.F.
      The liver-brain axis in liver failure: neuroinflammation and encephalopathy.
      ]. The BBB protects from common bacterial infections or toxins, and from the fluctuation of plasma components and neurotransmitters in the blood. During infection, microglial cells (the resident macrophages of the brain) and astrocytes may release pro-inflammatory cytokines (TNFα, IL-6), which enhance neuropsychological impairment induced by hyperammonemia [
      • Rodrigo R.
      • Cauli O.
      • Gomez-Pinedo U.
      • Agusti A.
      • Hernandez-Rabaza V.
      • Garcia-Verdugo J.M.
      • et al.
      Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy.
      ] but this observation remains controversial [
      • Wright G.A.
      • Sharifi Y.
      • Newman T.A.
      • Davies N.
      • Vairappan B.
      • Perry H.V.
      • et al.
      Characterisation of temporal microglia and astrocyte immune responses in bile duct-ligated rat models of cirrhosis.
      ,
      • RangrooThrane V.
      • Thrane A.S.
      • Wang F.
      • Cotrina M.L.
      • Smith N.A.
      • Chen M.
      • et al.
      Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering.
      ]. Nonetheless, TNFα levels correlate with HE severity [
      • Odeh M.
      • Sabo E.
      • Srugo I.
      • Oliven A.
      Serum levels of tumor necrosis factor-alpha correlate with severity of hepatic encephalopathy due to chronic liver failure.
      ] and some anti-TNFα drugs like etanercept and infliximab work on animal models of HE. Moreover, COX-1 inhibitors and NSAIDs have been found to be protective in animal models of HE, modulating neuroinflammation [
      • Jiang W.
      • Desjardins P.
      • Butterworth R.F.
      Direct evidence for central proinflammatory mechanisms in rats with experimental acute liver failure: protective effect of hypothermia.
      ,
      • Chang C.C.
      • Wang S.S.
      • Huang H.C.
      • Chan C.Y.
      • Lee F.Y.
      • Lin H.C.
      • et al.
      Selective cyclooxygenase inhibition improves hepatic encephalopathy in fulminant hepatic failure of rat.
      ]. However, these therapeutic approaches did not reach applicability in humans. Precipitating factors for HE, such as sepsis, hyponatraemia, gastrointestinal haemorrhage and renal failure are known to share different pathophysiological mechanisms beyond increasing TNFα production or COX-1 activity [
      • Odeh M.
      Pathogenesis of hepatic encephalopathy: the tumour necrosis factor-alpha theory.
      ].
      Hyponatremia is a major confounding factor in the pathophysiology of HE in patients with ACLF and it could be very difficult to differentiate between hepatic and hyponatremic encephalopathy. Hyperammonemia in ACLF would cause an increased intracellular content of glutamine and osmolality, due to glutamine synthase activity, resulting in astrocyte swelling and astrocyte dysfunction enhanced by oxidative stress. Astrocyte swelling triggers a signalling cascade, increasing formation of reactive nitrogen and oxygen species, mainly through activation of NADPH oxidase and nitric oxide synthase [
      • Carbonero-Aguilar P.
      • Diaz-Herrero M.M.
      • Cremades O.
      • Romero-Gómez M.
      • Bautista J.
      Brain biomolecules oxidation in portacaval-shunted rats.
      ]. Reactive nitrogen and oxygen species enhance protein tyrosine nitration, mobilization of zinc, oxidation of RNA, alterations in intra- and intercellular signalling and in gene transcription [
      • Görg B.
      • Schliess F.
      • Häussinger D.
      Osmotic and oxidative/nitrosative stress in ammonia toxicity and hepatic encephalopathy.
      ]. Whether the brain is directly involved in the inflammatory process in chronic liver failure or whether it is the systemic response that spills into the brain is not clear [
      • Bosoi C.R.
      • Rose C.F.
      Oxidative stress: a systemic factor implicated in the pathogenesis of hepatic encephalopathy.
      ,
      • Bosoi C.R.
      • Yang X.
      • Huynh J.
      • Parent-Robitaille C.
      • Jiang W.
      • Tremblay M.
      • et al.
      Systemic oxidative stress is implicated in the pathogenesis of brain edema in rats with chronic liver failure.
      ] (Fig. 2). Lastly, hyponatremia could represent a second osmotic hit to astrocytes that could aggravate the intracellular oedema. [
      • Ginès P.
      • Guevara M.
      Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management.
      ]. Renal ammoniagenesis increases during haemodynamic disturbances in cirrhotics characterized by effective hypovolemia secondary to splanchnic arterial vasodilation, similar to that associated with renal failure, hyponatremia, hypokalaemia, dehydration, or use of nephrotoxic agents, highlighting the key role of the kidneys on hepatic encephalopathy. In a large cohort of 562 cirrhotic patients, the main causes of renal insufficiency were infections, hypovolemic conditions, hepatorenal syndrome and nephrotoxic agents. Hepatic encephalopathy, hyponatremia and MELD predicted prognosis according to the different causes of AKI [
      • Martín-Llahí M.
      • Guevara M.
      • Torre A.
      • Fagundes C.
      • Restuccia T.
      • Gilabert R.
      • et al.
      Prognostic importance of the cause of renal failure in patients with cirrhosis.
      ].
      Figure thumbnail gr2
      Fig. 2Ammonia trafficking in hepatic encephalopathy (HE) from an organism (left panel) and an organ (right panel) perspective. A modified nitrogen balance and changes in ammonia production/disposal lead to hyperammonaemia. Hyperammonaemia, together with hyponatremia, increased levels of pro-inflammatory cytokines, an activated microglia and a number of other mechanisms lead to astrocyte swelling. In turn, this results in dysfunctional astrocyte-neuron interactions and, ultimately, in neuronal dysfunction. Other neurotoxins, such as cytokines, indoles and possibly mercaptans may also affect neurons directly. Adapted from Amodio P., Hepatic Encephalopathy in Cirrhosis: a practical guide to management [Moreau & Lee Eds, Oxford University Press (in press)].

      Bacterial translocation (BT) and microbiome

      Bacterial infections are well-known triggers for HE in patients with cirrhosis [
      • Gupta A.
      • Dhiman R.K.
      • Kumari S.
      • Rana S.
      • Agarwal R.
      • Duseja A.
      • et al.
      Role of small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhotic patients with minimal hepatic encephalopathy.
      ]. Multifactorial damage of the intestinal barrier results in a high rate of intestinal bacteria translocation in cirrhotics, resulting in systemic inflammation [
      • Albillos A.
      • de la Hera A.
      Multifactorial gut barrier failure in cirrhosis and bacterial translocation: working out the role of probiotics and antioxidants.
      ,
      • Bellot P.
      • Francés R.
      • Such J.
      Pathological bacterial translocation in cirrhosis: pathophysiology, diagnosis and clinical implications.
      ]. Therefore, BT may have a role in the pathogenic mechanisms involved in HE, due to circulating endotoxins, which activate macrophages to produce TNFα and other potentially cytotoxic pro-inflammatory mediators [
      • Lindros K.O.
      • Järveläinen H.A.
      Chronic systemic endotoxin exposure: an animal model in experimental hepatic encephalopathy.
      ]. Indeed, a high frequency of small-intestinal bacterial overgrowth (SIBO) in cirrhotic patients has been correlated with BT [
      • Jun D.W.
      • Kim K.T.
      • Lee O.Y.
      • Chae J.D.
      • Son B.K.
      • Kim S.H.
      • et al.
      Association between small intestinal bacterial overgrowth and peripheral bacterial DNA in cirrhotic patients.
      ]. On the other hand, microbiota could play a relevant role, irrespective of bacterial translocation. The dysbiosis rate, calculated as the ratio of autochthonous to non-autochthonous taxa, was related to hepatic encephalopathy. Patients developing overt HE during the follow-up demonstrated a lower rate of dysbiosis in comparison with compensated cirrhosis. Besides, the dysbiosis rate was associated with endotoxin levels; the higher the endotoxemia, the lower the dysbiosis rate [
      • Bajaj J.S.
      • Heuman D.M.
      • Hylemon P.B.
      • Sanyal A.J.
      • White M.B.
      • Monteith P.
      • et al.
      Altered profile of human gut microbiome is associated with cirrhosis and its complications.
      ,
      • Bajaj J.S.
      • Ridlon J.M.
      • Hylemon P.B.
      • Thacker L.R.
      • Heuman D.M.
      • Smith S.
      • et al.
      Linkage of gut microbiome with cognition in hepatic encephalopathy.
      ].

      Diabetes mellitus (DM) and insulin resistance (IR)

      Diabetes mellitus (DM) and insulin resistance (IR) was recently shown to be more frequently (59% vs. 43%) associated with the presence of HE [
      • Butt Z.
      • Jadoon N.A.
      • Salaria O.N.
      • Mushtaq K.
      • Riaz I.B.
      • Shahzad A.
      • et al.
      Diabetes mellitus and decompensated cirrhosis: risk of hepatic encephalopathy in different age groups.
      ], which was confirmed in another study [
      • Kalaitzakis E.
      • Olsson R.
      • Henfridsson P.
      • Hugosson I.
      • Bengtsson M.
      • Jalan R.
      • et al.
      Malnutrition and diabetes mellitus are related to hepatic encephalopathy in patients with liver cirrhosis.
      ]. The mechanisms underlying this may be related to increased glutaminase activity in the kidney, liver and small intestine [
      • Ampuero J.
      • Ranchal I.
      • del Mar Díaz-Herrero M.
      • del Campo J.A.
      • Bautista J.D.
      • Romero-Gómez M.
      Role of diabetes mellitus on hepatic encephalopathy.
      ]; increased pro-inflammatory cytokines such as TNFα and IL-6, resulting in systemic inflammatory response [
      • Basu S.
      • Zethelius B.
      • Helmersson B.
      • Berne C.
      • Larsson A.
      • Arnlov J.
      Cytokine-mediated inflammation is independently associated with insulin sensitivity measured by the euglycemic insulin clamp in a community-based cohort of elderly men.
      ]; increased protein catabolism and ammonia production [
      • Ampuero J.
      • Ranchal I.
      • Nuñez D.
      • Díaz-Herrero M.M.
      • Maraver M.
      • del Campo J.A.
      • et al.
      Metformin inhibits glutaminase activity and protects against hepatic encephalopathy.
      ] act upon the role of insulin to stimulate protein synthesis as well as on the inhibition of protein degradation; and a reduction in duodenum-cecal transit time due to autonomic neuropathy, resulting in constipation and SIBO [
      • Sigal S.H.
      • Stanca C.M.
      • Kontorinis N.
      • Bodian C.
      • Ryan E.
      Diabetes mellitus is associated with hepatic encephalopathy in patients with HCV cirrhosis.
      ].

      Alcohol misuse

      The CANONIC study demonstrated alcohol misuse was strongly related to HE in younger patients with ACLF. The disturbances in hepatic haemodynamics in alcohol-related ACLF have been found to associate with inflammation, multiorgan failure and marked activation of the sympathetic nervous system, supporting a specific role of alcohol in the development of HE, both in alcohol-related decompensation or alcohol-induced ACLF [
      • Mehta G.
      • Mookerjee R.P.
      • Sharma V.
      • Jalan R.
      Systemic inflammation is associated with increased intrahepatic resistance and mortality in alcohol-related acute-on-chronic liver failure.
      ].

      The GABA system

      The potential role of γ-aminobutyric acid-(GABA) or glutamate-mediated neurotransmission in the pathophysiology of HE, together with roles for neurosteroids or endogenous benzodiazepines or other neurotransmitters like serotonin, dopamine, adenosine and histamine have been recently revised [
      • Palomero-Gallagher N.
      • Zilles K.
      Neurotransmitter receptor alterations in hepatic encephalopathy: a review.
      ]. The high complexity of brain circuitries, controlled by multiples types of GABAergic interneurons and the large variety of GABA-A receptors precluded defining a more clear and specific role of GABA on HE [
      • Felipo V.
      Hepatic encephalopathy: effects of liver failure on brain function.
      ].

      Genetic factors

      The human glutaminase gene (OMIM: 138280) is located on chromosome 2 (2q32-q34) [
      • Elgadi K.M.
      • Meguid R.A.
      • Qian M.
      • Souba W.W.
      • Abcouwer S.F.
      Cloning and analysis of unique human glutaminase isoforms generated by tissue-specific alternative splicing.
      ]. In a prospective study (109 patients with cirrhosis in the estimation cohort, 177 patients in the validation cohort, and 107 healthy controls), Romero-Gómez et al. identified a microsatellite in the promoter region of the glutaminase gene (kidney type) containing between 8 and 29 GCA repeats. The longest microsatellite correlated with higher glutaminase activity in vivo. It increased the risk for overt HE in cirrhotic patients from 20% to 40% (hazard ratio 3.12 [CI: 1.39–7.02]; p = 0.006) [
      • Romero-Gómez M.
      • Jover M.
      • Del Campo J.A.
      • Royo J.L.
      • Hoyas E.
      • Galán J.J.
      • et al.
      Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis: a cohort study.
      ]. Furthermore, they carried out a functional analysis that showed how longer forms of the microsatellite repeat promoted higher activity in vitro, which may increase ammonia production [
      • Albrecht J.
      Hepatic encephalopathy in our genes?.
      ]. Therefore, the authors concluded that this genetic difference in the conversion rate of glutamine to ammonia, possibly explained at least in part the variability in the clinical presentation of HE (Fig. 3). Mayer et al. confirmed these results in a cohort of 158 patients with liver cirrhosis. The long-long homozygous form (also called major homozygous) was independently associated with HE [
      • Mayer L.B.
      • Gruenhage F.
      • Lammert F.
      A genetic variant in the promoter of Phosphate Activated Glutaminase (GLS) gene predicts the risk of developing Hepatic Encephalopathy.
      ].
      Figure thumbnail gr3
      Fig. 3Pathophysiology of hepatic encephalopathy. Hyperammonemia, systemic inflammation and oxidative and nitrosative stress in patients with liver dysfunction and/or portosystemic shunts modulated by glutaminase gene alterations are key factors and therapeutic targets on hepatic encephalopathy.

      Diagnosis and differential diagnosis of hepatic encephalopathy

      Definitions and general issues

      HE is characterized by a wide spectrum of nonspecific neurological and psychiatric abnormalities [
      • Sherlock S.
      • Summerskill W.H.
      • White L.P.
      • Phear E.A.
      Portal-systemic encephalopathy; neurological complications of liver disease.
      ]. In order for such abnormalities to be qualified as HE one should: (1) confirm that the degree of hepatic failure and/or portal-systemic shunting is severe enough to be able to cause HE, and (2) exclude other causes of neurological and psychiatric dysfunction. Basic as it may seem, this diagnostic procedure is neither routine nor necessarily straightforward. In relation to point 1, measurement of fasting ammonia levels is a reasonable start, because the absence of hyperammonemia makes it extremely unlikely that the observed neuropsychiatric abnormalities are due to HE. Therefore, finding normal ammonia levels in a confused, disorientated or comatose cirrhotic patient should prompt immediate search for alternative causes of neuropsychiatric dysfunction. Point 2 is more complicated, because patients with end-stage liver disease are prone to several types of metabolic encephalopathy (for example uremic and nutritional encephalopathy), and also to non-metabolic neuropsychiatric dysfunction (for example alcohol-related dementia and cerebrovascular disease). These can obviously co-exist with HE, somewhat hampering the ‘exclusion diagnosis’ procedure [
      • Montagnese S.
      • Schiff S.
      • Amodio P.
      A quick diagnosis of hepatic encephalopathy: fact or fiction?.
      ]. In addition, two common complications of end-stage liver disease, hyponatremia and inflammation/infection, are capable of causing neuropsychiatric dysfunction in the absence of cirrhosis. However, they have also been convincingly shown to act synergistically with gut-derived neurotoxins in determining neuropsychiatric dysfunction in experimental models of HE and in the clinical setting [
      • Merli M.
      • Lucidi C.
      • Pentassuglio I.
      • Giannelli V.
      • Giusto M.
      • Di Gregorio V.
      • et al.
      Increased risk of cognitive impairment in cirrhotic patients with bacterial infections.
      ,
      • Córdoba J.
      • Gottstein J.
      • Blei A.T.
      Chronic hyponatremia exacerbates ammonia-induced brain edema in rats after portacaval anastomosis.
      ,
      • Shawcross D.
      • Jalan R.
      The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.
      ]. For example, cognitive impairment (overt or subclinical) has been documented in 42% of patients with cirrhosis without infection, in 79% of those with infection and in 90% of those with sepsis [
      • Merli M.
      • Lucidi C.
      • Pentassuglio I.
      • Giannelli V.
      • Giusto M.
      • Di Gregorio V.
      • et al.
      Increased risk of cognitive impairment in cirrhotic patients with bacterial infections.
      ]. Thus, in patients with cirrhosis, the pathophysiological and clinical borders between hepatic and hyponatremic/septic encephalopathy may be less obvious than in healthy or other disease controls. In addition, in everyday practice it is reasonable and routine to treat them simultaneously. By contrast, one should be absolutely clear that neuropsychiatric abnormalities, related to hypoglycaemia, hypothyroidism, hypoxia, the desired or undesired effects of drugs, such as opioids or benzodiazepines should be qualified as such and not as HE, even when they occur in cirrhotic patients [
      • Montagnese S.
      • Merkel C.
      • Amodio P.
      Encephalopathy or hepatic encephalopathy?.
      ]. Differential diagnosis is crucial for two reasons: (i) the encephalopathy we refer to in order to define ALF or ACLF needs to be hepatic encephalopathy; (ii) the wrong attribution of neurological/psychiatric symptoms to HE might prevent the diagnosis and the correct management of other causes of neuropsychiatric dysfunction, which are unlikely to benefit from ammonia-lowering drugs or from transplantation. Multiple underlying mechanisms of altered mental status in a patient with cirrhosis should be sought for and treated individually.
      In order to tackle these diagnostic issues, it may be useful to draw suggestions from the more general literature. From a psychiatric perspective, episodic overt HE can be classified as a delirium [
      • Rosenberg R.
      • Renvillard S.G.
      • Hjerrild S.
      Organic delirious states and other psychiatric disorders: lessons for the hepatologists.
      ], an etiologically nonspecific syndrome, characterized by disturbances in cognition and consciousness, development over a short period time, and fluctuation over time [
      • American Psychiatric Association
      Diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV).
      ]. Delirium is common in hospitalized and critically ill patients. Within this context, its pathophysiology is largely unknown, and generally assumed to be mixed [
      • Reade M.C.
      • Finfer S.
      Sedation and delirium in the intensive care unit.
      ]. Interestingly, a recent review on delirium in the ICU does not indicate that efforts are, or should be made to establish the pathophysiology of a delirium episode [
      • Reade M.C.
      • Finfer S.
      Sedation and delirium in the intensive care unit.
      ]. It follows that treatment is empirical rather than aetiological [
      • van den Boogaard M.
      • Schoonhoven L.
      • van Achterberg T.
      • van der Hoeven J.G.
      • Pickkers P.
      Haloperidol prophylaxis in critically ill patients with a high risk for delirium.
      ]. Exactly as it happens with HE, it has also been estimated that non-specifically trained staff can miss the diagnosis of delirium in almost 70% of cases [
      • Van Eijk M.M.
      • van Marum R.J.
      • Klijn I.A.
      • de Wit N.
      • Kesecioglu J.
      • Slooter A.J.
      Comparison of delirium assessment tools in a mixed intensive care unit.
      ]. Efforts have recently been directed towards the prediction of delirium. A large study by van den Boogaard and co-workers defines the likelihood of developing delirium in the ICU based on 10 risk factors that are readily available within 24 h of admission: age, APACHE-II, urgent admission category, infection, coma, sedation, morphine use, urea level and metabolic acidosis [
      • van den Boogaard M.
      • Pickkers P.
      • Slooter A.J.
      • Kuiper M.A.
      • Spronk P.E.
      • van der Voort P.H.
      • et al.
      Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study.
      ]. This kind of research seems well directed, because a diagnosis of delirium has been associated with increased mortality [
      • Pisani M.A.
      • Kong S.Y.
      • Kasl S.V.
      • Murphy T.E.
      • Araujo K.L.
      • Van Ness P.H.
      Days of delirium are associated with 1-year mortality in an older intensive care unit population.
      ] and also with impaired long-term cognitive performance [
      • van den Boogaard M.
      • Schoonhoven L.
      • Evers A.W.
      • van der Hoeven J.G.
      • van Achterberg T.
      • Pickkers P.
      Delirium in critically ill patients: impact on long-term health related quality of life and cognitive functioning.
      ].

      Practical diagnostic recommendations

      Despite the highlighted difficulties, some practical recommendations for the diagnosis of overt HE in a hospitalized cirrhotic patient can be formulated (Table 1).
      Table 1Diagnosis and differential diagnosis of hepatic encephalopathy (HE).

      Clinical features and clinical scales

      Albeit non-specific, there is a neuropsychological profile to HE type A. Patients with mild overt HE may be inappropriate and euphoric, but higher grades tend to be almost invariably characterized by slowness (in mentation, motion and verbal production), disorientation, the presence of flapping tremor, excessive daytime sleepiness, all the way to lethargy and coma. Focal neurological signs are rare while bilateral Babinski may be observed. Obvious extrapyramidal signs and hepatic myelopathy are also rare but should be considered, especially in male patients with documented large shunts and a history of multiple, severe episodes of HE [
      • Caldwell C.
      • Werdiger N.
      • Jakab S.
      • Schilsky M.
      • Arvelakis A.
      • Kulkarni S.
      • et al.
      Use of model for end-stage liver disease exception points for early liver transplantation and successful reversal of hepatic myelopathy with a review of the literature.
      ]. While the patient is still awake and cooperative, verbal abilities tend to be preserved, thus obtainment of substantially adequate answers to simple questions (‘Good morning, how are you today?’) may lead to false reassurance. In contrast, questions should be aimed at specifically assessing orientation to time and space, possibly in a structured fashion [
      • Amodio P.
      • Montagnese S.
      • Gatta A.
      • Morgan M.Y.
      Characteristics of minimal hepatic encephalopathy.
      ,
      • Ortiz M.
      • Córdoba J.
      • Doval E.
      • Jacas C.
      • Pujadas F.
      • Esteban R.
      • et al.
      Development of a clinical hepatic encephalopathy staging scale.
      ]. Scales, such as CHESS and the Modified-orientation log have been suggested to be useful in this respect [
      • Salam M.
      • Matherly S.
      • Farooq I.S.
      • Stravitz R.T.
      • Sterling R.K.
      • Sanyal A.J.
      • et al.
      Modified-orientation log to assess hepatic encephalopathy.
      ]. Recording of the results of such evaluations in the notes may simplify monitoring, also across different nurses/physicians and over subsequent shifts. If the patient is not cooperative, the Glasgow Coma Scale should be utilized both at baseline and over the subsequent monitoring phases [
      • Bajaj J.S.
      • Cordoba J.
      • Mullen K.D.
      • Amodio P.
      • Shawcross D.L.
      • Butterworth R.F.
      • et al.
      International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN). Review article: the design of clinical trials in hepatic encephalopathy-an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement.
      ].

      History taking and patient profiling

      History taking from cooperative patients or from relatives/caregivers should be aimed at identifying obvious precipitants such as constipation, symptoms of chest, urinary tract or other infections, gastro-intestinal bleeding and dehydration. If identified, these should be corrected. A history of previous episodes of HE, especially if requiring hospitalization, increases the likelihood of the current episode being due to HE and should be recorded. Finally, it should be taken into account that HE associated with ACLF tends to occur in younger cirrhotics with alcohol-related disease and a systemic inflammatory reaction, bacterial infections, active alcohol misuse and/or dilutional hyponatremia [
      • 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).
      ].

      Laboratory tests

      A panel of laboratory tests to include full blood count, liver and kidney function, electrolytes, ammonia, TSH, CRP, vitamin B12 and a urine analysis should always be obtained, and abnormalities, such as anaemia, hypo/hyperglycemia or hyponatremia should be corrected. Active alcohol misusers can be considered thiamine/vitamin deficient by default and supplemented.
      Ammonia, given its central pathogenic role and known problems with its measurement, deserves further comment. There is probably limited advantage in measuring arterial compared to venous ammonia levels, which can be considered acceptable [
      • Kramer L.
      • Tribl B.
      • Gendo A.
      • Zauner C.
      • Schneider B.
      • Ferenci P.
      • et al.
      Partial pressure of ammonia versus ammonia in hepatic encephalopathy.
      ,
      • Drolz A.
      • Jäger B.
      • Wewalka M.
      • Saxa R.
      • Horvatits T.
      • Roedl K.
      • et al.
      Clinical impact of arterial ammonia levels in ICU patients with different liver diseases.
      ]. Venous blood should be preferably drawn when the patients is fasting, in a tube with a stabiliser, refrigerated on ice, sent to the lab immediately and analysed immediately. If arterial or capillary ammonia are utilized, the appropriate reference values should be obtained and utilized. Capillary ammonia is best measured on blood obtained from the earlobe, as sweat artefact leads to significant overestimation on blood drawn from the fingertip [
      • Huizenga J.R.
      • Gips C.H.
      • Conn H.O.
      • Jansen P.L.
      Determination of ammonia in ear-lobe capillary blood is an alternative to arterial blood ammonia.
      ,
      • 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.
      ]. Finally, it should be noted that ammonia measurements are problematic in terms of false positives and not false negatives, thus the exclusion of HE based on normal ammonia levels is unlikely to be fraught by measurement issues. Along these same lines, the recently published joint EASL/AASLD guidelines suggest that if ammonia levels are normal the diagnosis of HE is in question. In addition, they warn against the use of high ammonia levels alone for the purpose of diagnosing, staging and formulating prognosis [
      • 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.
      ].

      Imaging

      Cerebral imaging should be performed if the clinical profile is unusual, if the onset of the symptoms is abrupt and severe, if there are focal neurological signs and if there is limited or no response to treatment of the precipitant and/or to ammonia-lowering strategies. In most routine, practical conditions, a brain CT without contrast is sufficient, as it allows to diagnose/rule out cerebral and subdural haemorrhage. Structural MRI is probably more appropriate to better define dementia-like, prolonged confusional states and to diagnose/rule out encephalitis and Wernicke’s disease.

      Neurophysiological tools

      The EEG, although non-specific, provides information on the severity of HE in both cooperative and uncooperative patients, it may be useful to monitor them and may help for the inclusion of HE in indices aimed at transplant selection procedures [
      • Montagnese S.
      • De Rui M.
      • Schiff S.
      • Ceranto E.
      • Valenti P.
      • Angeli P.
      • et al.
      Prognostic benefit of the addition of a quantitative index of hepatic encephalopathy to the MELD score: the MELD-EEG.
      ]. The grading of the severity of EEG alterations in HE can be based on visual pattern recognition, which has limited reliability and reproducibility, on semi-quantitative evaluation of the frequency, or on automated, spectral analysis of the digitalized tracing. Spectral analysis is more accurate and less operator-dependent. Its value was recently confirmed [
      • Wunsch E.
      • Koziarska D.
      • Kotarska K.
      • Nowacki P.
      • Milkiewicz P.
      Normalization of the psychometric hepatic encephalopathy score in Polish population. A prospective, quantified electroencephalography study.
      ] and a large, validated observational study suggests that the addition of a spectrally derived EEG index improves the predictive value of MELD. The EEG can be recorded at any stage of the patient’s evolution, and it can be used to monitor the severity of HE over time and the response to treatment in an objective fashion, regardless of patient cooperation. As sedation, psychoactive drugs and hypothermia can produce EEG alterations not unlike those, which characterize HE, these should be considered as confounders in the diagnostic process. In severe coma, combinations of sensory evoked potential indices can contain information on residual cortical or sub-cortical activity [
      • Guerit J.M.
      • Amantini A.
      • Fischer C.
      • Kaplan P.W.
      • Mecarelli O.
      • Schnitzler A.
      • et al.
      Neurophysiological investigations of hepatic encephalopathy: ISHEN practice guidelines.
      ]. Neurophysiological monitoring of HE due to acute liver failure would seem reasonable but experience is limited.

      Response to treatment

      Unless contraindicated, an attempt at non-aggressive bowel cleansing and/or ammonia-lowering treatment can be considered part of the diagnostic armamentarium. A neuropsychiatric syndrome that responds to ammonia-lowering strategies is likely to be HE.

      Management of hepatic encephalopathy in a hospitalized cirrhotic patient

      Treatment of the acute episode

      General measures and monitoring

      Early risk stratification of patients with HE is required. This may be performed using the CLIF organ failure scoring system to determine whether the patient has ACLF or not [
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ]. If a patient has ACLF and associated HE, then he should be managed in an intensive care unit. Detailed description of organ support is outside the scope of this article and has been reviewed elsewhere [
      • Olson J.C.
      • Wendon J.A.
      • Kramer D.J.
      • Arroyo V.
      • Jalan R.
      • Garcia-Tsao G.
      • et al.
      Intensive care of the patient with cirrhosis.
      ]. The role of monitoring ammonia levels, jugular venous oxygen saturation, evoked potentials, EEG or intracranial pressure remains unascertained.

      Airway, breathing, and circulation

      Admission to the intensive care unit for close monitoring and airway protection should be considered in all patients with overt HE but particularly if this is associated with ACLF or if the airway is considered to be at risk. Short acting drugs should be used for sedation if needed because benzodiazepines can stay in the circulation for a long time. Hypercapnia and hypoxia should be avoided as they may alter cerebral blood flow. Supplemental oxygen or mechanical ventilation should be used as required. Inotropes should be used to maintain mean arterial pressure to ensure adequate cerebral perfusion [
      • Jalan R.
      Intracranial hypertension in acute liver failure: pathophysiological basis of rational management.
      ].

      Role of the precipitating event

      Although the prevalence of a precipitating event is more common in patients with ACLF compared to those without, in about 40% patients no precipitating event was found [
      • 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).
      ]. The most common causes were the use of diuretics suggesting intravascular volume depletion, bacterial infection and alcohol binge. Gastro-intestinal bleeding, as a precipitating event, was under-represented in patients with HE. Any identifiable precipitating event should be promptly treated, cultures performed from multiple sites and, appropriate and early antibiotics should be administered (Fig. 4).
      Figure thumbnail gr4
      Fig. 4An algorithm for the management of hepatic encephalopathy in a hospitalized cirrhotic patient.

      Glucose, nutrition, and electrolytes

      Hypoglycemia should be corrected and patients monitored to prevent further hypoglycemic episodes. Hyperglycemia should be prevented as this can make brain swelling worse but there is no evidence for a tight control of glucose [
      • Olson J.C.
      • Wendon J.A.
      • Kramer D.J.
      • Arroyo V.
      • Jalan R.
      • Garcia-Tsao G.
      • et al.
      Intensive care of the patient with cirrhosis.
      ]. Hyponatremia should be prevented by infusion of crystalloids as this can lead to worsening of HE. Hypernatremia can lead to cellular dysfunction and should be prevented. Vitamins, particularly thiamine should be administered to patients with underlying alcoholic liver disease to prevent occurrence of Wernicke’s encephalopathy, particularly when glucose containing fluids are administered. Low protein diets have not been shown to prevent recovery from HE and should be avoided as this can lead to protein breakdown. A restricted protein diet was compared with normal protein diet, which showed that the wake-up rate for the patients in both groups was similar but increased protein breakdown was observed in patients treated with a low protein diet [
      • Córdoba J.
      • López-Hellín J.
      • Planas M.
      • Sabín P.
      • Sanpedro F.
      • Castro F.
      • et al.
      Normal protein diet for episodic hepatic encephalopathy: results of a randomized study.
      ]. A detailed guidance on the nutritional management of patients with HE was recently published [
      • Amodio P.
      • Bemeur C.
      • Butterworth R.
      • Cordoba J.
      • Kato A.
      • Montagnese S.
      • et al.
      The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.
      ].

      Specific

      Ammonia

      Ammonia, a physiologic product of the intermediary metabolism, is composed of nitrogen and hydrogen. The human body has several sources of ammonia: (a) glutamine deamidation by glutaminase (GLS) in the small intestine; (b) urea and nitrogenous compound hydrolysis by gut bacteria [
      • Cichoż-Lach H.
      • Michalak A.
      Current pathogenetic aspects of hepatic encephalopathy and non cirrhotic hyperammonemic encephalopathy.
      ]; (c) ammonia production and excretion in the kidneys. In the healthy state, hepatic metabolism of ammonia takes place in two areas: (1) in periportal hepatocytes, through the urea cycle (the most important pathway); (2) in pericentral hepatocytes, transforming small quantities of ammonia into glutamine through the action of glutamine synthase [
      • Ciećko-Michalska I.
      • Szczepanek M.
      • Słowik A.
      • Mach T.
      Pathogenesis of hepatic encephalopathy.
      ]. In cirrhosis or in the presence of portosystemic shunts, the liver is by-passed and ammonia detoxification takes place in the muscle through glutamine synthesis by glutamine synthetase [
      • Jover-Cobos M.
      • Noiret L.
      • Lee K.
      • Sharma V.
      • Habtesion A.
      • Romero-Gomez M.
      • et al.
      Ornithine phenylacetate targets alterations in the expression and activity of glutamine synthase and glutaminase to reduce ammonia levels in bile duct ligated rats.
      ]. Furthermore, the kidney is an organ capable of synthesizing and degrading ammonia, depending upon the clinical situation [
      • Córdoba J.
      • Ventura-Cots M.
      Drug-induced removal of nitrogen derivatives in urine: a new concept whose time has come.
      ,
      • Perazzo J.C.
      • Tallis S.
      • Delfante A.
      • Souto P.A.
      • Lemberg A.
      • Eizayaga F.X.
      • et al.
      Hepatic encephalopathy: an approach to its multiple pathophysiological features.
      ].
      At present there is no drug that has been consistently shown to reduce ammonia by targeting its metabolism in hospitalized cirrhotic patients. Some new approaches to treat hyperammonemia combine potential ammonia-lowering agents together with products able to promote glutamine excretion. Ornithine phenylacetate (OP) is a drug that stimulates hepatic and muscle glutamine synthesis through the action of ornithine and traps ammonia in form of glutamine, which is then removed following conjugation with phenylacetate [
      • Jalan R.
      • Wright G.
      • Davies N.A.
      • Hodges S.J.
      L-Ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy.
      ]. In an open-label study, OP was shown to prevent the rise in ammonia concentration in cirrhotic patients presenting with a gastro-intestinal bleed [
      • Ventura-Cots M.
      • Arranz J.A.
      • Simón-Talero M.
      • Torrens M.
      • Blanco A.
      • Riudor E.
      • et al.
      Safety of ornithine phenylacetate in cirrhotic decompensated patients: an open-label, dose-escalating, single-cohort study.
      ]. A randomized study is underway. Another interesting approach that has not been tested in this population is a drug that has been used to treat urea cycle enzyme disorders, glycerol phenylbutyrate. This compound acts by scavenging glutamine, a precursor of ammonia and was shown to be useful in the secondary prophylaxis of HE in a phase 2b study [
      • Rockey D.C.
      • Vierling J.M.
      • Mantry P.
      • Ghabril M.
      • Brown Jr., R.S.
      • Alexeeva O.
      • et al.
      Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy.
      ]. Furthermore, L-ornithine-L-aspartate was found superior to placebo improving neuropsychiatric alterations and decreasing ammonia levels in a meta-analysis. The analysis omitted the results of some studies [
      • Pérez Hernández J.L.
      • Higuera de la Tijera F.
      • Serralde-Zúñiga A.E.
      • Abdo Francis J.M.
      Critical analysis of studies evaluating the efficacy of infusion of L-ornithine L-aspartate in clinical hepatic encephalopathy in patients with liver failure.
      ].

      Targeting the gut

      The mainstay of therapy of a hospitalized patient with cirrhosis is lactulose, which acts by reducing the absorption of ammonia by converting it to ammonium in the colon. It has recently been shown to prevent the occurrence of HE in patients with a gastrointestinal bleed [
      • Maharshi S.
      • Sharma B.C.
      • Srivastava S.
      • Jindal A.
      Prophylaxis of hepatic encephalopathy in acute variceal bleeding in patients with cirrhosis: an open label randomized controlled trial of lactulose versus rifaximin.
      ]. There is a lack of good data comparing lactulose against placebo in patients with advanced HE [
      • Als-Nielsen B.
      • Gluud L.L.
      • Gluud C.
      Nonabsorbable disaccharides for hepatic encephalopathy.
      ], but this approach remains to be thoroughly tested in clinical trials. The administration of enemas to clear the bowel is a useful adjunct to lactulose but the frequency of administration; type of enema to be used and clinical efficacy need to be better defined. A major advance in the management of HE was the introduction of rifaximin, a non-absorbable antibiotic. While its use has been confirmed in the secondary prophylaxis of HE [
      • Bass N.M.
      • Mullen K.D.
      • Sanyal A.
      • Poordad F.
      • Neff G.
      • Leevy C.B.
      • et al.
      Rifaximin treatment in hepatic encephalopathy.
      ], its role in the management of the hospitalized cirrhotic remains to be validated. A special population of patients are those undergoing insertion of a transjugular intrahepatic portosystemic stent-shunt. A randomized study comparing lactulose, rifaximin and placebo were unable to confirm the benefit of any these approaches to prevent the occurrence of HE [
      • Riggio O.
      • Masini A.
      • Efrati C.
      • Nicolao F.
      • Angeloni S.
      • Salvatori F.M.
      • et al.
      Pharmacological prophylaxis of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled study.
      ].

      Albumin and albumin dialysis

      Albumin is more than just a volume expander and may have important detoxification properties, modulating inflammatory response and endothelial function [
      • Garcia-Martinez R.
      • Caraceni P.
      • Bernardi M.
      • Gines P.
      • Arroyo V.
      • Jalan R.
      Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications.
      ]. In an early controlled study, the potential role of albumin in HE was observed in patients with diuretic-related HE [
      • Jalan R.
      • Kapoor D.
      Reversal of diuretic-induced hepatic encephalopathy with infusion of albumin but not colloid.
      ]. This approach was tested in a randomized controlled clinical trial [
      • Simón-Talero M.
      • García-Martínez R.
      • Torrens M.
      • Augustin S.
      • Gómez S.
      • Pereira G.
      • et al.
      Effects of intravenous albumin in patients with cirrhosis and episodic hepatic encephalopathy: a randomized double-blind study.
      ], which found that although there was no significant difference in the resolution of HE between the groups, survival was enhanced in the albumin group, suggesting that the trial was underpowered. The potential beneficial effects of albumin were translated into studies where the patient’s plasma was dialysed against albumin using the molecular adsorbent recirculating System (MARS). In an early randomized study, a beneficial effect on HE was observed without any significant effects on ammonia [
      • Sen S.
      • Davies N.A.
      • Mookerjee R.P.
      • Cheshire L.M.
      • Hodges S.J.
      • Williams R.
      • et al.
      Pathophysiological effects of albumin dialysis in acute-on-chronic liver failure: a randomized controlled study.
      ]. These observations were confirmed in a large randomized, multicentre clinical trial, showing incontrovertibly that those patients, not responding to the best standard of care, had significant improvement in HE and time to reduction in severity, when treated with MARS [
      • Hassanein T.I.
      • Tofteng F.
      • Brown Jr., R.S.
      • McGuire B.
      • Lynch P.
      • Mehta R.
      • et al.
      Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis.
      ]. These observations were confirmed in a multicentre randomized clinical trial in patients with ACLF, the RELIEF trial [
      • Bañares R.
      • Nevens F.
      • Larsen F.S.
      • Jalan R.
      • Albillos A.
      • Dollinger M.
      • et al.
      Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial.
      ]. Although overall survival was not improved, a significant effect on HE was observed in a subgroup analysis.

      The role of benzodiazepine antagonists

      Flumazenil, a benzodiazepine receptor antagonist has been trialled in patients with HE based upon the concept that endogenous benzodiazepines may contribute to hepatic encephalopathy. The data suggest that this approach is safe and may be particularly relevant in patients with HE related to iatrogenic administration of benzodiazepines. A further limitation is the short half-life of the drug [
      • Goulenok C.
      • Bernard B.
      • Cadranel J.F.
      • Thabut D.
      • Di Martino V.
      • Opolon P.
      • et al.
      Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a meta-analysis.
      ].

      Embolization of portacaval shunts

      One of the main contributors to the development of HE is portacaval shunting. Large spontaneous portacaval shunts, usually present with persistent HE, can result in hospital admission with advanced coma. In some patients with HE, large spontaneous shunts that are accessible to embolization, may benefit. In a retrospective cohort study this approach was shown to be of benefit in about 70% of patients, particularly if their MELD score was 11 or less [
      • Laleman W.
      • Simon-Talero M.
      • Maleux G.
      • Perez M.
      • Ameloot K.
      • Soriano G.
      • et al.
      Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicenter survey on safety and efficacy.
      ]. These data were confirmed in another retrospective controlled clinical study [
      • An J.
      • Kim K.W.
      • Han S.
      • Lee J.
      • Lim Y.S.
      Improvement in survival associated with embolisation of spontaneous portosystemic shunt in patients with recurrent hepatic encephalopathy.
      ]. Randomized controlled data are not available and it is clear that many patients will not benefit and also have portal hypertension related complications. Therefore, patient selection is extremely important.

      TIPSS-related hepatic encephalopathy

      De novo HE can affect up to 30–50% of patients who undergo TIPSS [
      • Riggio O.
      • Nardelli S.
      • Moscucci F.
      • Pasquale C.
      • Ridola L.
      • Merli M.
      Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt.
      ] and this can sometimes be severe enough to result in cerebral oedema and coma [
      • Jalan R.
      • Dabos K.
      • Redhead D.N.
      • Lee A.
      • Hayes P.C.
      Elevation of intracranial pressure following transjugular intrahepatic portosystemic stent-shunt for variceal haemorrhage.
      ]. The mechanism of this is complex and related to a combination of hyperammonemia, increased portosystemic shunting with resultant endotoxemia, and alterations in cerebral blood flow [
      • Jalan R.
      • Olde Damink S.W.
      • Ter Steege J.C.
      • Redhead D.N.
      • Lee A.
      • Hayes P.C.
      • et al.
      Acute endotoxemia following transjugular intrahepatic stent-shunt insertion is associated with systemic and cerebral vasodilatation with increased whole body nitric oxide production in critically ill cirrhotic patients.
      ]. Treatment options are limited and a randomized trial of lactulose or rifaximin, used prophylactically, was not shown to be useful [
      • Riggio O.
      • Masini A.
      • Efrati C.
      • Nicolao F.
      • Angeloni S.
      • Salvatori F.M.
      • et al.
      Pharmacological prophylaxis of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled study.
      ]. Patients with troublesome HE after TIPSS respond well to shunt occlusion, which remains the therapy of choice [
      • Riggio O.
      • Ridola L.
      • Angeloni S.
      • Cerini F.
      • Pasquale C.
      • Attili A.F.
      • et al.
      Clinical efficacy of transjugular intrahepatic portosystemic shunt created with covered stents with different diameters: results of a randomized controlled trial.
      ].

      Role of liver transplantation

      A hospitalized, critically ill cirrhotic patient with HE should be worked up from a transplant perspective. Transplantation itself and subsequent immunosuppressant treatment are risk factors for both neurological and psychiatric dysfunction, in the immediate and long-term post-transplant period, respectively [
      • American Psychiatric Association
      Diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV).
      ]. Patients that are transplanted with severe multiorgan failure, including severe HE, can have a good outcome with liver transplantation. Over 85% mortality was observed in patients with 3 or more organ failures without liver transplantation. This was reduced to a mortality of 20% with early liver transplantation [
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ]. However, at present there is no priority for severe HE patients on the waiting list for transplantation where organ allocation is based on the MELD score, which underestimates the risk of death [
      • 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.
      ]. A new scoring system has been developed and validated by the CLIF consortium, which needs further evaluation before it can be implemented for the clinical allocation of organs [
      • Jalan R.
      • Pavesi M.
      • Saliba F.
      • Amoros A.
      • Levesque E.
      • Moreau R.
      • et al.
      Validation of the CLIF-consortium (CLIF-C) score to predict mortality of patients with acute-on-chronic liver failure (ACLF) in an external cohort and for sequential measurements.
      ].

      Conclusions

      In conclusion, HE in a hospitalized patient, particularly when it is associated with ACLF, is associated with a high mortality rate independent of other organ failures. The mechanism of HE in ACLF is not clear but cerebral oedema affects a relatively small group of patients and although ammonia is important, the systemic inflammatory response plays an important part. Glutaminase gene alterations seem to modulate the HE risk and may allow selection of patients for prophylaxis. Treatment options are limited. It is clear that HE in ACLF patients is distinct clinically, prognostically and pathophysiologically to the conventional forms represented in type A, B and C. If the current observations are borne out by other ongoing studies, then it should perhaps be classified into a separate group, type D.

      Conflict of interest

      M. Romero-Gómez is the inventor of THDP-17, a glutaminase inhibitor, which was licensed by Janus Developments. He has ongoing research collaboration with Umecrine, Sweden. He has also received speaker fees from BAMA-GEVE, Merz, and Norgine. R. Jalan is the inventor of ornithine phenylacetate, which has been licensed to Ocera Therapeutics. He has ongoing research collaboration with Gambro and Grifols. He has also received speaker fees from Grifols and Norgine. S. Montagnese has received speaker fees from Merz and her institution has received funding from Merz to support research conducted by her team.

      Authors’ contributions

      M. Romero-Gómez, S. Montagnese, and R. Jalan shared writing of the manuscript.

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