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Management of Covert Hepatic Encephalopathy

  • Abhijeet Waghray
    Correspondence
    Address for correspondence: Abhijeet Waghray, Department of Medicine, MetroHealth Medical Center/Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH 44109, USA.
    Affiliations
    Department of Medicine, MetroHealth Medical Center/Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH 44109, USA
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  • Nisheet Waghray
    Affiliations
    Division of Gastroenterology, MetroHealth Medical Center/Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH 44109, USA
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  • Kevin Mullen
    Affiliations
    Division of Gastroenterology, MetroHealth Medical Center/Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH 44109, USA
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Published:February 27, 2014DOI:https://doi.org/10.1016/j.jceh.2014.02.007
      Hepatic encephalopathy is a reversible progressive neuropsychiatric disorder that encompasses a wide clinical spectrum. Covert hepatic encephalopathy is defined as patients with minimal hepatic encephalopathy and Grade I encephalopathy by West-Haven Criteria. Terminology such as “sub-clinical”, “latent”, and “minimal” appear to trivialize the disease and have been replaced by the term covert. The lack of clinical signs means that covert hepatic encephalopathy is rarely recognized or treated outside of clinical trials with options for therapy based on patients with episodic hepatic encephalopathy. This review discusses the current available options for therapy in covert hepatic encephalopathy and focuses on non-absorbable disacharides (lactulose or lactitol), antibiotics (rifaximin), probiotics/synbiotics and l-ornithine-l-aspartate.

      Keywords

      Abbreviations:

      HRQoL (health-related quality of life), CFF (critical flicker frequency), NCT-A (number connection tests A), NCT-B (number connection tests B), DST (digit symbol test), OCTT (orocecal transit time), FOS (fructo-oligosaccharides), BAEP (brain auditory evoked potential), BDT (block design test), LCT (line tracing test), RCT (race track test), ICT (inhibitory control test), SDMT (Symbol digit modalities test), TMT (Trail making test), SPT (standard psychometric test), NPE (neuropsychological exam), PCT (Picture completion test), FCT-A (Figure connection test-A), PSE (psychometric testing), SDT (serial-dotting test), APT (abnormal psychometric testing)
      Hepatic encephalopathy (HE) is a reversible progressive neuropsychiatric disorder occurring in patients with significant liver disease. It encompasses a clinical spectrum of symptoms involving psychomotor, intellectual, cognitive, and motor function.
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      • Schliess F.
      Pathogenetic mechanisms of hepatic encephalopathy.
      Minimal hepatic encephalopathy (MHE) presents with a normal neurologic examination and no obvious clinical signs, but subtle changes in attention, psychomotor speed, and executive decision making.
      • Zamora Nava L.E.
      • Torre Delgadillo A.
      Minimal hepatic encephalopathy.
      Prior terminology included “sub-clinical”, “latent”, and “minimal” appear to trivialize the condition. There is abundant evidence in the literature that MHE has a profound impact on quality of life, daily functioning, driving ability,
      • Arguedas M.R.
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      Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis.
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      Minimal hepatic encephalopathy: a vehicle for accidents and traffic violations.
      • Bajaj J.S.
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      • et al.
      Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test.
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      Hepatic encephalopathy and health-related quality of life.
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      • De Bruijn I.
      • et al.
      Subclinical hepatic encephalopathy impairs daily functioning.
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      • Torrens M.
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      Minimal hepatic encephalopathy is associated with falls.
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      Quality of life in cirrhotics with minimal hepatic encephalopathy.
      • Wein C.
      • Koch H.
      • Popp B.
      • Oehler G.
      • Schauder P.
      Minimal hepatic encephalopathy impairs fitness to drive.
      and nearly half of all patients with MHE may be unfit to maintain employment.
      • Schomerus H.
      • Hamster W.
      Quality of life in cirrhotics with minimal hepatic encephalopathy.
      Based on the current ISHEN guidelines,
      • Bajaj J.S.
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      • Mullen K.D.
      • et al.
      Review article: the design of clinical trials in hepatic encephalopathy–an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement.
      patients with MHE and Grade I encephalopathy by West-Haven Criteria were re-classified as having covert hepatic encephalopathy (CHE). Since the prevalence of MHE in patients with cirrhosis varies between 30 and 84%,
      • Bajaj J.S.
      Management options for minimal hepatic encephalopathy.
      • 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.
      • Hartmann I.J.
      • Groeneweg M.
      • Quero J.C.
      • et al.
      The prognostic significance of subclinical hepatic encephalopathy.
      • Ortiz M.
      • Jacas C.
      • Cordoba J.
      Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations.
      therapeutic strategies to prevent overt hepatic encephalopathy (OHE) are of major importance.
      Treatment options for CHE are derived from prior experience in patients with episodic HE. Given the lack of clinical signs, CHE is rarely recognized or treated outside of clinical trials. Many therapies have been tested based on theories of the pathogenesis of HE. These include N-methyl-d-aspartate antagonists, N-acetylcysteine, anti-inflammatories (cyclo-oxygenase inhibitors), flumazenil, and bromocriptine. However, all have been abandoned because of evidence of lack of efficacy or adverse safety profile. Circulating levels of ammonia and other gut derived toxins are central to the pathogenesis of HE and remain the target of therapy in CHE. The gut microbiota plays an integral role in the production of ammonia and other toxins resulting in oxidative stress/inflammation.
      • Chen Y.
      • Yang F.
      • Lu H.
      • et al.
      Characterization of fecal microbial communities in patients with liver cirrhosis.
      • Bajaj J.S.
      • Heuman D.M.
      • Sanyal A.J.
      • et al.
      Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.
      • Bajaj J.S.
      • Ridlon J.M.
      • Hylemon P.B.
      • et al.
      Linkage of gut microbiome with cognition in hepatic encephalopathy.
      • Butterworth R.F.
      Hepatic encephalopathy: a central neuroinflammatory disorder?.
      It would only seem natural that treatment modalities in CHE would focus on the modulation of the gut flora. Therapeutic strategies for CHE must be extrapolated from MHE trials as CHE is a relatively recent term and no studies on therapy are available at this time. This review discusses the currently available treatment options for CHE.

      Non-absorbable dissacharides

      Lactulose

      Lactulose or lactitol are synthetic non-absorbable disaccharides, that are extensively used in the management of OHE. Lactulose is fermented in the colon into acetic and lactic acid resulting in acidification of intestinal contents and conversion of ammonia (NH3) to ammonium (NH4+). Unlike ammonia, ammonium is not systemically absorbed and is excreted in stool. Lactulose also has a cathartic effect increasing nitrogen excretion by four fold.
      • Blei A.T.
      • Cordoba J.
      Practice Parameters Committee of the American College of Gastroenterology
      Hepatic encephalopathy.
      • Eroglu Y.
      • Byrne W.J.
      Hepatic encephalopathy.
      • Mullen K.D.
      • Ferenci P.
      • Bass N.M.
      • Leevy C.B.
      • Keeffe E.B.
      An algorithm for the management of hepatic encephalopathy.
      Recommendations supporting lactulose as the preferred therapeutic option in OHE are based on 2001 guidelines which were developed prior to a number of significant trials in alternative therapies such as rifaximin or probiotics.
      • Blei A.T.
      • Cordoba J.
      Practice Parameters Committee of the American College of Gastroenterology
      Hepatic encephalopathy.
      In a recent survey, 78% of gastroenterologists have extended the use of lactulose to first line therapy in the treatment of MHE.
      • Bajaj J.S.
      • Etemadian A.
      • Hafeezullah M.
      • Saeian K.
      Testing for minimal hepatic encephalopathy in the United States: an AASLD survey.
      In a randomized open label trial, lactulose therapy 30–60 mL/day was compared to no treatment in patients with cirrhosis and MHE.
      • Prasad S.
      • Dhiman R.K.
      • Duseja A.
      • Chawla Y.K.
      • Sharma A.
      • Agarwal R.
      Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy.
      Compared to the untreated group, there was a significant decrease in the number of abnormal psychometric tests in the group treated with lactulose (P < 0.0001). Treatment also demonstrated a significant improvement in the health-related quality of life (HRQoL) vs. those who did not receive lactulose [6.81 vs 0.17 (95% CI, 5.24–8.37) and (95% CI, −0.29 to 0.63), respectively; P < 0.001].
      • Prasad S.
      • Dhiman R.K.
      • Duseja A.
      • Chawla Y.K.
      • Sharma A.
      • Agarwal R.
      Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy.
      Sharma et al further reported the benefit of lactulose therapy for the primary prevention of OHE in patients with cirrhosis. A total of 120 cirrhotic patients with no prior episode of OHE were randomized to receive lactulose (55 patients, 32/55 with MHE) or no treatment (50 patients, 36/50 with MHE), with progression to OHE assessed over 12 months. MHE was diagnosed by psychometric and critical flicker frequency testing, while the West-Haven Criteria was used to grade OHE. Lactulose protected against the progression to OHE (11% of patient receiving lactulose and 28% in the control group developed OHE, P = 0.02) and 66% of the patients diagnosed with MHE responded to treatment. Therefore, lactulose was deemed to be effective in the primary prevention of overt hepatic encephalopathy.
      • Sharma P.
      • Sharma B.C.
      • Agrawal A.
      • Sarin S.K.
      Primary prophylaxis of overt hepatic encephalopathy in patients with cirrhosis: an open labeled randomized controlled trial of lactulose versus no lactulose.
      Congruent with prior results, several other studies have reported an improvement in neuropsychometric tests with various doses and durations of lactulose and lactitol treatment
      • Sharma P.
      • Sharma B.C.
      • Agrawal A.
      • Sarin S.K.
      Primary prophylaxis of overt hepatic encephalopathy in patients with cirrhosis: an open labeled randomized controlled trial of lactulose versus no lactulose.
      • Dhiman R.K.
      • Sawhney M.S.
      • Chawla Y.K.
      • Das G.
      • Ram S.
      • Dilawari J.B.
      Efficacy of lactulose in cirrhotic patients with subclinical hepatic encephalopathy.
      • Horsmans Y.
      • Solbreux P.M.
      • Daenens C.
      • Desager J.P.
      • Geubel A.P.
      Lactulose improves psychometric testing in cirrhotic patients with subclinical encephalopathy.
      • Watanabe A.
      • Sakai T.
      • Sato S.
      • et al.
      Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy.
      • Zeng Z.
      • Li Y.Y.
      [Effects of lactulose treatment on the course of subclinical hepatic encephalopathy].
      • Morgan M.Y.
      • Alonso M.
      • Stanger L.C.
      Lactitol and lactulose for the treatment of subclinical hepatic encephalopathy in cirrhotic patients. A randomised, cross-over study.
      (Table 1).
      Table 1Treatment options in MHE and significant findings.
      Treatment groupsStudyNumber of patients treated/durationPsychometric test usedTotal daily dosageSignificant findings with treatment
      LactuloseWantabe et al., 1997
      Sub-clinical HE.
      ,
      • Watanabe A.
      • Sakai T.
      • Sato S.
      • et al.
      Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy.
      22
      Lactulose.
      , 14
      Placebo/no treatment.
      /8 weeks
      NCT, DST, BDT45 mL↓ APT
      LactuloseHorsmans et al., 1997
      Sub-clinical HE.
      ,
      • Horsmans Y.
      • Solbreux P.M.
      • Daenens C.
      • Desager J.P.
      • Geubel A.P.
      Lactulose improves psychometric testing in cirrhotic patients with subclinical encephalopathy.
      7
      Lactulose.
      , 7
      Placebo/no treatment.
      /15 days
      NCT, RCT60 g↓ APT
      LactuloseDhiman et al., 2000
      Sub-clinical HE.
      ,
      • Dhiman R.K.
      • Sawhney M.S.
      • Chawla Y.K.
      • Das G.
      • Ram S.
      • Dilawari J.B.
      Efficacy of lactulose in cirrhotic patients with subclinical hepatic encephalopathy.
      14
      Lactulose.
      , 12
      Placebo/no treatment.
      /3 months
      NCT, FCT-A/B30–60 ml↓ APT
      LactulosePrasad et al., 2007
      • Prasad S.
      • Dhiman R.K.
      • Duseja A.
      • Chawla Y.K.
      • Sharma A.
      • Agarwal R.
      Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy.
      31
      Lactulose.
      , 30
      Placebo/no treatment.
      /3 months
      NCT-A/B, FCT-A/B30–60 ml↓ APT ↑ HRQoL
      LactuloseSharma et al., 2012
      • Sharma P.
      • Sharma B.C.
      • Agrawal A.
      • Sarin S.K.
      Primary prophylaxis of overt hepatic encephalopathy in patients with cirrhosis: an open labeled randomized controlled trial of lactulose versus no lactulose.
      60
      Lactulose.
      , 60
      Placebo/no treatment.
      /12 months
      CFF30–60 ml↓ Developed OHE ↓ APT
      LactuloseSharma et al., 2012
      • Sharma P.
      • Sharma B.C.
      Lactulose for minimal hepatic encephalopathy in patients with extrahepatic portal vein obstruction.
      30
      Lactulose.
      , 30
      Placebo/no treatment.
      /3 months
      NCT – A/B, DST, LCT, SDT. CFF30–60 ml↓ APT, ↓ arterial ammonia
      LactuloseJain et al., 2013
      • Jain L.
      • Sharma B.C.
      • Srivastava S.
      • Puri S.K.
      • Sharma P.
      • Sarin S.
      Serum endotoxin, inflammatory mediators, and magnetic resonance spectroscopy before and after treatment in patients with minimal hepatic encephalopathy.
      30
      Lactulose.
      , 30
      Placebo/no treatment.
      /3 months
      PHES, NCT-A/B, SDT, LCT30–60 ml↓ Serum endotoxins, ↓ APT, ↓ serum ammonia, ↓ IL-6/IL-8/TNF-α, ↓ glutamine, ↑ myoinositol, ↑ choline
      RifaximinGrande et al., 2010
      Abstract.
      ,
      • Grande L.J.M.
      • Fobelo M.
      • Figueruela B.
      • et al.
      Double-blinded crossover trial analyzing the usefulness of Rifaximin in the treatment of minimal hepatic encephalopathy (MHE): an interin analysis.
      4 weeksCFF1200 mg↓ APT
      RifaximinSidhu et al., 2011
      • Sidhu S.S.
      • Goyal O.
      • Mishra B.P.
      • Sood A.
      • Chhina R.S.
      • Soni R.K.
      Rifaximin improves psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (the RIME Trial).
      49
      Rifaximin.
      , 45
      Placebo/no treatment.
      /8 weeks
      NCT-A, FCT-A, DST, PCT, BDT1200 mg↓ APT, ↑ HRQoL
      RifaximinBajaj et al., 2011
      • Bajaj J.S.
      • Heuman D.M.
      • Wade J.B.
      • et al.
      Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy.
      21
      Rifaximin.
      , 21
      Placebo/no treatment.
      /8 weeks
      NCT-A/B, DST, BDT, ICT1100 mg↑ Driving performance (↓ speeding tickets, driving errors, illegal turns), ↓ APT
      Synbiotic
      Synbiotic.
      , fermentable fiber
      Fermentable fiber.
      Liu et al., 2004
      • Liu Q.
      • Duan Z.P.
      • Ha D.K.
      • Bengmark S.
      • Kurtovic J.
      • Riordan S.M.
      Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis.
      20
      Synbiotic.
      , 20
      Fermentable fiber.
      , 15
      Placebo/no treatment.
      /30 days
      NCT, BAEP1 sachetBoth groups: ↓fecal pH, ↓ venous ammonia, ↓ serum endotoxin, ↓ APT, ↓ Child-Turcotte Pugh classification
      ProbioticsMalaguarnera et al., 2007
      • Malaguarnera M.
      • Greco F.
      • Barone G.
      • Gargante M.P.
      • Malaguarnera M.
      • Toscano M.A.
      Bifidobacterium longum with fructo-oligosaccharide (FOS) treatment in minimal hepatic encephalopathy: a randomized, double-blind, placebo-controlled study.
      30
      Probiotics.
      , 30
      Placebo/no treatment.
      /90 days
      TMT, BDT, SDMT, MMSE1 packet↓ Serum ammonium, ↓ APT
      ProbioticsBajaj et al., 2008
      • Bajaj J.S.
      • Saeian K.
      • Christensen K.M.
      • et al.
      Probiotic yogurt for the treatment of minimal hepatic encephalopathy.
      17
      Probiotics.
      , 8
      Placebo/no treatment.
      /60 days
      NCT-A, DST, BDT1 yogurt↓ APT
      ProbioticsLunia et al., 2013
      Abstract.
      ,
      • Lunia M.K.
      • B. S.
      • Sachdeva
      • et al.
      An open label randomized controlled trial of probiotics for primary prophylaxsis of hepatic encephalopathy in patients with cirrhosis.
      42
      Probiotics.
      , 33
      Placebo/no treatment.
      /3 months
      CFF3 units↓ APT, ↓SIBO, ↓OCTT, ↓ arterial ammonia
      LOLAKircheis et al., 1997
      Sub-clinical HE.
      ,
      • Kircheis G.
      • Nilius R.
      • Held C.
      • et al.
      Therapeutic efficacy of l-ornithine-l-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study.
      63
      LOLA.
      , 63
      Placebo/no treatment.
      /7 days
      NCT-A20 g↓ APT, ↓ venous ammonia,
      LOLANdhaha et al., 2011
      • Ndraha S.
      • Hasan I.
      • Simadibrata M.
      The effect of l-ornithine l-aspartate and branch chain amino acids on encephalopathy and nutritional status in liver cirrhosis with malnutrition.
      17
      LOLA.
      , 17
      Placebo/no treatment.
      /2 weeks
      CFF18 g↓ APT, unchanged pre-albumin (nutritional status), unchanged urea–creatinine
      LOLASilva et al., 2013
      Abstract.
      ,
      • Alvares-da-Silva M.R.
      • de Araujo A.
      • Vicenzi J.R.
      • et al.
      Oral l-ornithine-l-aspartate in minimal hepatic encephalopathy: a randomized, double-blind, placebo-controlled trial.
      6 monthsNCT-A/B, DST, CFF, DST15 g↓ OHE events
      Lactulose
      Lactulose.
      , probiotics
      Probiotics.
      Sharma et al., 2008
      • Sharma P.
      • Sharma B.C.
      • Puri V.
      • Sarin S.K.
      An open-label randomized controlled trial of lactulose and probiotics in the treatment of minimal hepatic encephalopathy.
      35
      Lactulose.
      , 35
      Probiotics.
      , 35
      Lactulose.
      +
      Probiotics.
      /1 month
      NCT-A/B, FCT-A/B30–60 mL
      Lactulose.
      , 3 capsules
      Probiotics.
      All 3: ↓ APT, ↓ venous ammonia, ↓ Child-Pugh class
      LOLA
      LOLA.
      , lactulose
      Lactulose.
      , probiotics
      Probiotics.
      Mittal et al., 2011
      • Mittal V.V.
      • Sharma B.C.
      • Sharma P.
      • Sarin S.K.
      A randomized controlled trial comparing lactulose, probiotics, and l-ornithine l-aspartate in treatment of minimal hepatic encephalopathy.
      40
      LOLA.
      , 40
      Lactulose.
      , 40
      Probiotics.
      , 40
      Placebo/no treatment.
      /3 months
      NCT-A/B, PCT18 g
      LOLA.
      , 30–60 mL
      Lactulose.
      , 220 billion CFU
      Probiotics.
      All 3: ↓ APT, ↓ ammonia, ↑ HRQoL
      Probiotics
      Probiotics.
      , lactulose
      Lactulose.
      Ziada et al., 2013
      • Ziada D.H.
      • Soliman H.H.
      • El Yamany S.A.
      • Hamisa M.F.
      • Hasan A.M.
      Can Lactobacillus acidophilus improve minimal hepatic encephalopathy? A neurometabolite study using magnetic resonance spectroscopy.
      26
      Probiotics.
      , 24
      Lactulose.
      , 25
      Placebo/no treatment.
      /4 weeks
      NCTA, DST, SDT3 capsule
      Probiotics.
      , 30–60 mL
      Lactulose.
      Both: ↓ APT, ↓ venous ammonia
      ↓: decreased; ↑: increased.
      a Lactulose.
      b Rifaximin.
      c Probiotics.
      d Synbiotic.
      e Fermentable fiber.
      f LOLA.
      g Placebo/no treatment.
      h Sub-clinical HE.
      i Abstract.
      In a meta-analysis of five studies (total, N = 170 patients), lactulose treatment demonstrated a benefit for MHE (RR 0.34, 95% CI, 0.24–0.47; P < 0.0001).
      • Shukla S.
      • Shukla A.
      • Mehboob S.
      • Guha S.
      Meta-analysis: the effects of gut flora modulation using prebiotics, probiotics and synbiotics on minimal hepatic encephalopathy.
      Luo et al further corroborated these findings in a meta-analysis of 9 randomized studies (total, N = 434 patients). Analysis revealed a significant reduction in the mean number of abnormal neuropsychological tests, blood ammonia levels, progression to OHE (RR: 0.17, 95% CI, 0.06–0.52, P = 0.002), and improved HRQoL.
      • Luo M.
      • Li L.
      • Lu C.Z.
      • Cao W.K.
      Clinical efficacy and safety of lactulose for minimal hepatic encephalopathy: a meta-analysis.
      The results support the safety and efficacy of lactulose treatment for MHE.
      Diarrhea, abdominal pain/cramping, nausea, and flatulence are among the most common dose related adverse effects limiting adherence.
      • Sharma P.
      • Sharma B.C.
      • Agrawal A.
      • Sarin S.K.
      Primary prophylaxis of overt hepatic encephalopathy in patients with cirrhosis: an open labeled randomized controlled trial of lactulose versus no lactulose.
      • Watanabe A.
      • Sakai T.
      • Sato S.
      • et al.
      Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy.
      • Bajaj J.S.
      • Sanyal A.J.
      • Bell D.
      • Gilles H.
      • Heuman D.M.
      Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients.
      • Sharma P.
      • Sharma B.C.
      Lactulose for minimal hepatic encephalopathy in patients with extrahepatic portal vein obstruction.
      In a trial of 128 cirrhotic patients, Kalaitzakis et al reported that daily lactulose had a negative impact on HRQoL.
      • Kalaitzakis E.
      • Simren M.
      • Olsson R.
      • et al.
      Gastrointestinal symptoms in patients with liver cirrhosis: associations with nutritional status and health-related quality of life.
      The laxative effect and titration to 2–3 soft bowel movements per day make adherence to lactulose classically low.
      • Bajaj J.S.
      Management options for minimal hepatic encephalopathy.
      Paradoxically, overuse of lactulose can result in severe dehydration and hyponatremia leading to worsening of HE. Interestingly, a lower serum sodium (less than 132.5 mmol/L) and a higher ammonia level (greater than 93.5 mmol/L) were two parameters that correlated with lactulose failure.
      • Sharma P.
      • Sharma B.C.
      Rifaximin treatment in hepatic encephalopathy.
      Lastly, as stated earlier, all of the trials presented above were completed in MHE; therefore caution should be used when translating this data to CHE.

      Antibiotics

      The goal of antibiotic therapy remains the suppression of urease producing intestinal organisms, thereby reducing serum levels of ammonia and other gut derived toxins (eg, mercaptans, phenols, oxindole, and short chain fatty acids).
      • Mullen K.D.
      • Ferenci P.
      • Bass N.M.
      • Leevy C.B.
      • Keeffe E.B.
      An algorithm for the management of hepatic encephalopathy.
      • Riordan S.M.
      • Williams R.
      Gut flora and hepatic encephalopathy in patients with cirrhosis.
      • Seyan A.S.
      • Hughes R.D.
      • Shawcross D.L.
      Changing face of hepatic encephalopathy: role of inflammation and oxidative stress.
      Oral antibiotics (eg, neomycin, metronidazole, vancomycin, and paromycin) have demonstrated varying degrees of success in the treatment of OHE. However, systemic adverse events including nephrotoxicity, ototoxicity, peripheral neuropathy, antibiotic resistance, and the risk of Clostridium difficile colitis and vancomycin resistant enterocolitis (VRE) has limited their role in the treatment of MHE.

      Rifaximin

      Rifaximin is an oral non-systemic broad spectrum antibiotic that is structurally similar to Rifampin. By binding to bacterial DNA-dependent RNA polymerase, rifaximin inhibits bacterial RNA/protein synthesis. Structurally, the benzimidazole ring limits systemic absorption to 0.4%,
      • Huang D.B.
      • DuPont H.L.
      Rifaximin–a novel antimicrobial for enteric infections.
      with the primary mode of excretion via feces and low levels of drug excreted in urine or bile.
      • Verardi S.
      • Verardi V.
      Bile rifaximin concentration after oral administration in patients undergoing cholecystectomy.
      Concentrated in the gut, rifaximin is presumed to modulate intestinal bacteria, thereby reducing intestinal ammonia and toxin formation.
      • Maccaferri S.
      • Vitali B.
      • Klinder A.
      • et al.
      Rifaximin modulates the colonic microbiota of patients with Crohn's disease: an in vitro approach using a continuous culture colonic model system.
      In a recent open labeled trial, Bajaj et al performed a systems biologic analysis of the microbiome and evaluated cognitive changes after treatment with rifaximin (550 mg bid) in 20 cirrhotic patients diagnosed with MHE. Therapy was associated with improved cognitive function and reduced endotoxemia. Moreover, treatment with rifaximin resulted in a modest change in stool microbiota characterized by a reduction in Veillonellaceae and an increase in Eubacteriaceae. Veillonellaceae are gram negative cocci that are more abundant in the stool of patients with cirrhosis compared to healthy individuals.
      • Chen Y.
      • Yang F.
      • Lu H.
      • et al.
      Characterization of fecal microbial communities in patients with liver cirrhosis.
      The initial studies for rifaximin demonstrated its efficacy in the management of OHE. Compared to lactulose, rifaximin is more effective in the treatment of OHE.
      • Jiang Q.
      • Jiang X.H.
      • Zheng M.H.
      • Jiang L.M.
      • Chen Y.P.
      • Wang L.
      Rifaximin versus nonabsorbable disaccharides in the management of hepatic encephalopathy: a meta-analysis.
      In a randomized double-blind placebo controlled trial (total, N = 299 patients) over a 6-month-period, rifaximin (550 mg twice daily) reduced the risk of an episode of OHE and the time to first hospitalization, with no serious adverse events.
      • Bass N.M.
      • Mullen K.D.
      • Sanyal A.
      • et al.
      Rifaximin treatment in hepatic encephalopathy.
      Moreover, Neff et al recently showed that rifaximin use for greater than 6 months proved to be effective in the management of HE, especially in patients with MELD ≤20.
      • Neff G.W.
      • Jones M.
      • Broda T.
      • et al.
      Durability of rifaximin response in hepatic encephalopathy.
      Because of its documented safety and efficacy in patients with OHE, the investigation of rifaximin in the management of MHE has been a natural progression. A recent randomized double-blinded crossover study demonstrated that rifaximin significantly improved psychometric tests (PHES) and reduced intestinal ammonia production.
      • Grande L.J.M.
      • Fobelo M.
      • Figueruela B.
      • et al.
      Double-blinded crossover trial analyzing the usefulness of Rifaximin in the treatment of minimal hepatic encephalopathy (MHE): an interin analysis.
      Further, the RIME trial demonstrated the benefit of rifaximin in the management of MHE. Patients were randomized to rifaximin (1200 mg/day, N = 49) or placebo for 8 weeks with the primary end points being reversal of MHE symptoms and effect on HRQoL.
      • Sidhu S.S.
      • Goyal O.
      • Mishra B.P.
      • Sood A.
      • Chhina R.S.
      • Soni R.K.
      Rifaximin improves psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (the RIME Trial).
      Intention to treat analysis revealed that at 2 weeks (57.1% (28/49) vs 17.8% (8/45), P < 0.0001) and 8 weeks (75.5% (37/49) vs 20% (9/45), P < 0.0001) rifaximin significantly reversed MHE compared to placebo, respectively. Treatment further resulted in a significant improvement in both the semi-quantitative (mean reduction in abnormal neuropsychometric tests) and quantitative cognitive scores (reduction in mean Z-scores). HRQoL was concomitantly improved in the rifaximin group compared to placebo (P < 0.001) and strongly correlated with improved neuropsychologic scores (r = 0.376, P < 0.01). Therefore, improvement in cognitive function was associated with better HRQoL. Interestingly, no significant difference was noted in progression to OHE between the two groups. Overall, rifaximin was well-tolerated with no significant adverse events. The results of the RIME trial showed that the benefits of rifaximin could be extended to patients with MHE.
      These findings were furthered by Bajaj et al in a randomized double-blind placebo controlled trial assessing the effect of rifaximin on driving performance. Driving and navigations skills are important because they require attention, working memory, and consolidation of various inputs; the very cognitive domains affected in MHE.
      • Bajaj J.S.
      • Heuman D.M.
      • Wade J.B.
      • et al.
      Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy.
      Cirrhotic patients diagnosed with MHE received rifaximin or placebo twice daily for 8 weeks. Treatment significantly reduced total driving related errors, specifically speeding tickets and navigation of illegal turns [(total errors, 76% vs 33%, P = 0.013); (speeding tickets, 81% vs 33%; P = 0.005); (illegal turns, 62% vs 19%; P = 0.01)]. Baseline cognitive function significantly improved in the rifaximin group compared to placebo (Z-scores: 1.13 ± 0.2 vs 0.42 ± 0.2; respectively, P = 0.02), and there was a negative correlation between improvement in mean cognitive scores, total driving errors (r = −0.3, P = 0.05), and speeding tickets (r = −0.4, P = 0.01). This suggests that improved cognitive performance resulted in reduced driving related errors. While overall HRQoL at week 8 was not different, there was significant improvement in the psychosocial dimension of the Sickness Impact Profile compared to placebo (P = 0.04).
      Rifaximin is considered to be safe and well-tolerated. Adherence to rifaximin during treatment is high (greater than 90%), and demonstrates no difference in the most common adverse events—headache, flatulence, and abdominal pain compared to placebo.
      • Bajaj J.S.
      • Heuman D.M.
      • Wade J.B.
      • et al.
      Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy.
      Overall, the efficacy of rifaximin in the management of MHE is well documented, with its safety/tolerability profile making it an ideal candidate for therapy. While the cost of rifaximin therapy remains a limiting factor, progression to OHE has further significant long-term financial implications. One study showed that OHE patients had a shorter hospital stay and lower per patient hospitalization cost when prescribed rifaximin. Future therapy will depend on the cost effectiveness of maintenance rifaximin therapy
      • Leevy C.B.
      • Phillips J.A.
      Hospitalizations during the use of rifaximin versus lactulose for the treatment of hepatic encephalopathy.
      ; and whether these savings can be expanded to patients with CHE.

      Probiotics

      Probiotics are live microorganisms that alter the balance of intestinal microflora, and synbiotics are probiotics with the addition of fermentable fiber. While their mechanism of action remains uncertain, it is presumed that reducing intestinal bacterial urease activity decreases absorption of ammonia and other gut derived toxins that result in oxidative stress/inflammation. Probiotics are not only efficacious in the treatment of OHE, but demonstrate benefit for MHE.
      • Bajaj J.S.
      • Saeian K.
      • Christensen K.M.
      • et al.
      Probiotic yogurt for the treatment of minimal hepatic encephalopathy.
      • Liu Q.
      • Duan Z.P.
      • Ha D.K.
      • Bengmark S.
      • Kurtovic J.
      • Riordan S.M.
      Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis.
      • Malaguarnera M.
      • Greco F.
      • Barone G.
      • Gargante M.P.
      • Malaguarnera M.
      • Toscano M.A.
      Bifidobacterium longum with fructo-oligosaccharide (FOS) treatment in minimal hepatic encephalopathy: a randomized, double-blind, placebo-controlled study.
      • Sharma P.
      • Sharma B.C.
      • Puri V.
      • Sarin S.K.
      An open-label randomized controlled trial of lactulose and probiotics in the treatment of minimal hepatic encephalopathy.
      In a placebo controlled trial, synbiotic treatment for 30 days resulted in a decrease in intestinal pH, blood ammonia levels, and reversal of MHE compared to placebo (50.0% vs 13.3%, respectively; P < 0.05). Moreover, none of the patients developed OHE in this study.
      • Liu Q.
      • Duan Z.P.
      • Ha D.K.
      • Bengmark S.
      • Kurtovic J.
      • Riordan S.M.
      Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis.
      Bajaj et al further reported that probiotic yogurt treatment lead to a reversal of MHE in 71% of patients with non-alcoholic cirrhosis with no progression to OHE.
      • Bajaj J.S.
      • Saeian K.
      • Christensen K.M.
      • et al.
      Probiotic yogurt for the treatment of minimal hepatic encephalopathy.
      Consistent with prior findings, patients with MHE in this study had lower baseline HRQoL as determined by 36 item Short Form Health Survey (SF-36). However, probiotic treatment did not convey a significant difference from baseline HRQoL scores and this was likely related to the lack of sensitivity of the SF-36 in assessing HRQoL in patients with MHE.
      • Bajaj J.S.
      • Saeian K.
      • Christensen K.M.
      • et al.
      Probiotic yogurt for the treatment of minimal hepatic encephalopathy.
      In another study, cirrhotic patients with MHE received either probiotic, lactulose, or combination of both agents for a period of one month. There was significant improvement from baseline in all neuropsychometric scores and MHE for all three treatment groups (P ≤ 0.05).
      • Sharma P.
      • Sharma B.C.
      • Puri V.
      • Sarin S.K.
      An open-label randomized controlled trial of lactulose and probiotics in the treatment of minimal hepatic encephalopathy.
      In a 2011 Cochrane Review of 7 trials, probiotics were efficacious in the treatment of HE, including quality of life, all cause mortality, and the number of adverse events compared to placebo. Congruent with these findings, a subsequent meta-analysis of 9 studies showed a 50% reduction in the relative risk of no improvement in MHE with probiotic treatment.
      • Shukla S.
      • Shukla A.
      • Mehboob S.
      • Guha S.
      Meta-analysis: the effects of gut flora modulation using prebiotics, probiotics and synbiotics on minimal hepatic encephalopathy.
      Specific limitations with this data include the lack of consensus on the diagnosis of MHE and the small number of patients included in the trials; thereby limiting the strength of analysis.
      • Holte K.
      • Krag A.
      • Gluud L.L.
      Systematic review and meta-analysis of randomized trials on probiotics for hepatic encephalopathy.
      Recently, in an open labeled randomized controlled trial, a total 42 patients diagnosed with MHE were treated with VSL # 3 (3 capsules daily—108 CFU) with a mean follow-up to treatment of roughly 39 weeks. There was 23% absolute risk reduction and 50% reduction in progression to OHE with probiotic use compared to placebo.
      • Lunia M.K.
      • B. S.
      • Sachdeva
      • et al.
      An open label randomized controlled trial of probiotics for primary prophylaxsis of hepatic encephalopathy in patients with cirrhosis.
      Not all studies have shown a benefit from probiotic treatment. In a randomized double-blind placebo controlled trial involving 4 weeks of probiotic therapy, Saji et al showed no improvement in MHE compared with placebo treatment.
      • Saji S.
      • Kumar S.
      • Thomas V.
      A randomized double blind placebo controlled trial of probiotics in minimal hepatic encephalopathy.
      The results of this study must be interpreted with caution as MHE was not defined according to consensus guidelines. Probiotics are widely available, with no reported adverse effects, and may represent a long-term treatment option in the management of MHE. Unfortunately, strain specific evidence is lacking with different probiotics used in each trial, making it difficult to generalize recommendations. Therefore, larger studies with a longer duration of follow-up are required with standardization of probiotic formulations.

      LOLA (l-ornithine-l-aspartate)

      l-ornithine-l-aspartate has been shown to reduce ammonia levels
      • Kircheis G.
      • Nilius R.
      • Held C.
      • et al.
      Therapeutic efficacy of l-ornithine-l-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study.
      • Poo J.L.
      • Gongora J.
      • Sanchez-Avila F.
      • et al.
      Efficacy of oral l-ornithine-l-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study.
      by upregulating glutamine synthetase and urea cycle activity.
      • Bai M.
      • Yang Z.
      • Qi X.
      • Fan D.
      • Han G.
      l-ornithine-l-aspartate for hepatic encephalopathy in patients with cirrhosis: a meta-analysis of randomized controlled trials.
      l-ornithine and l-aspartate are separately metabolized to form glutamate, which combined with ammonia, results in the formation of glutamine. Therefore, LOLA lowers plasma ammonia concentrations by enhancing metabolism of ammonia to glutamine.
      • Bai M.
      • Yang Z.
      • Qi X.
      • Fan D.
      • Han G.
      l-ornithine-l-aspartate for hepatic encephalopathy in patients with cirrhosis: a meta-analysis of randomized controlled trials.
      In a meta-analysis, Bai et al evaluated 8 randomized controlled trials (total, N = 646 patients—46% diagnosed with MHE) assessing the efficacy of LOLA compared to placebo in patients with cirrhosis. Treatment with LOLA demonstrated a significant improvement in MHE, diminished serum ammonia levels, and no increase in adverse reactions.
      • Bai M.
      • Yang Z.
      • Qi X.
      • Fan D.
      • Han G.
      l-ornithine-l-aspartate for hepatic encephalopathy in patients with cirrhosis: a meta-analysis of randomized controlled trials.
      Analysis of individual studies revealed a reduction in abnormal neuropsychological testing and increased HRQoL. Further, Ndhara et al reported the effect of LOLA administration on the nutritional status of patients diagnosed with MHE.
      • Ndraha S.
      • Hasan I.
      • Simadibrata M.
      The effect of l-ornithine l-aspartate and branch chain amino acids on encephalopathy and nutritional status in liver cirrhosis with malnutrition.
      All study subjects were provided information regarding appropriate caloric/protein intake. Those receiving LOLA showed a significant decrease in abnormal psychometric testing, but there was no difference in the improvement of nutritional status (measured by pre-albumin) between the groups. In another randomized trial involving 160 patients diagnosed with MHE, 40 patients were treated with LOLA over a 3-month-period. Treatment revealed a significant improvement in reversal of MHE and HRQoL.
      • Mittal V.V.
      • Sharma B.C.
      • Sharma P.
      • Sarin S.K.
      A randomized controlled trial comparing lactulose, probiotics, and l-ornithine l-aspartate in treatment of minimal hepatic encephalopathy.
      Recently, in a randomized trial, cirrhotic patients diagnosed with MHE were treated with LOLA vs. placebo over a 6-month-period. Matched for age, Child's score and MELD, patients receiving LOLA showed an improvement in number connection tests B (NCT-B) (3.4 ± 3.4 vs 1.5 ± 2.3, P = 0.01), critical flicker frequency (CFF) (42.2 ± 5.8 vs 45.2 ± 5.8, P = 0.02), and progression to OHE ( 5% vs 37.9%, P = 0.016).
      • Alvares-da-Silva M.R.
      • de Araujo A.
      • Vicenzi J.R.
      • et al.
      Oral l-ornithine-l-aspartate in minimal hepatic encephalopathy: a randomized, double-blind, placebo-controlled trial.
      Of significance, there was no difference in the whole psychometric battery evaluation between patients treated with LOLA and placebo.
      Generally, administration of LOLA is safe with the most common side effects being nausea, cough, muscle cramps, and less frequently diarrhea.
      • Schmid M.
      • Peck-Radosavljevic M.
      • Konig F.
      • Mittermaier C.
      • Gangl A.
      • Ferenci P.
      A double-blind, randomized, placebo-controlled trial of intravenous l-ornithine-l-aspartate on postural control in patients with cirrhosis.
      Given the small sample size of studies evaluating LOLA, there is a risk of publication bias; therefore the role of LOLA in the management of CHE should be interpreted with caution.

      Management Guidelines for Covert Hepatic Encephalopathy

      While significant progress has been made in understanding the importance CHE, to date there is no standardized algorithm for diagnosis and treatment. Once patients with cirrhosis develop MHE, they are at a substantial risk of progression to OHE, resulting in a significant burden to the healthcare system and an increased risk of mortality.
      • Bustamante J.
      • Rimola A.
      • Ventura P.J.
      • et al.
      Prognostic significance of hepatic encephalopathy in patients with cirrhosis.
      • Fichet J.
      • Mercier E.
      • Genee O.
      • et al.
      Prognosis and 1-year mortality of intensive care unit patients with severe hepatic encephalopathy.
      Studies have consistently shown that patients with MHE have a diminished quality of life, cognitive function, daily function, and driving impairment.
      • Arguedas M.R.
      • DeLawrence T.G.
      • McGuire B.M.
      Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis.
      • Bajaj J.S.
      • Hafeezullah M.
      • Hoffmann R.G.
      • Saeian K.
      Minimal hepatic encephalopathy: a vehicle for accidents and traffic violations.
      • Bajaj J.S.
      • Saeian K.
      • Schubert C.M.
      • et al.
      Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test.
      • Bianchi G.
      • Giovagnoli M.
      • Sasdelli A.S.
      • Marchesini G.
      Hepatic encephalopathy and health-related quality of life.
      • Groeneweg M.
      • Quero J.C.
      • De Bruijn I.
      • et al.
      Subclinical hepatic encephalopathy impairs daily functioning.
      • Roman E.
      • Cordoba J.
      • Torrens M.
      • et al.
      Minimal hepatic encephalopathy is associated with falls.
      • Schomerus H.
      • Hamster W.
      Quality of life in cirrhotics with minimal hepatic encephalopathy.
      • Wein C.
      • Koch H.
      • Popp B.
      • Oehler G.
      • Schauder P.
      Minimal hepatic encephalopathy impairs fitness to drive.
      While it was once thought that cognitive impairment with CHE or OHE was reversible, data from studies evaluating medical treatment or liver transplantation suggest that the associated cognitive changes may not be totally reversible.
      • Bajaj J.S.
      • Schubert C.M.
      • Heuman D.M.
      • et al.
      Persistence of cognitive impairment after resolution of overt hepatic encephalopathy.
      • Campagna F.
      • Biancardi A.
      • Montagnese S.
      • et al.
      Incomplete reversal of cognitive dysfunction after liver transplantation in individuals who had overt hepatic encephalopathy before liver transplantation.
      • Riggio O.
      • Ridola L.
      • Pasquale C.
      • et al.
      Evidence of persistent cognitive impairment after resolution of overt hepatic encephalopathy.
      Moreover, it has been demonstrated that even after therapy and improvement to normal mental status, a single episode of OHE may continue to have residual negative effects on cognitive function.
      • Bajaj J.S.
      • Schubert C.M.
      • Heuman D.M.
      • et al.
      Persistence of cognitive impairment after resolution of overt hepatic encephalopathy.
      Therefore, it would only seem logical to consider prophylactic treatment for HE in patients with cirrhosis. Currently, there are no consensus guidelines regarding screening for CHE and there is debate as to the utility of testing all cirrhotic patients as opposed to a limited testing strategy for those patients with evidence of cognitive impairment.
      • Bajaj J.S.
      Management options for minimal hepatic encephalopathy.
      • Quero Guillen J.C.
      • Groeneweg M.
      • Jimenez Saenz M.
      • Schalm S.W.
      • Herrerias Gutierrez J.M.
      Is it a medical error if we do not screen cirrhotic patients for minimal hepatic encephalopathy?.
      There is also a paucity of data regarding the role of prophylaxis in CHE. A recent analysis using motor vehicle accidents as an end point to compare five treatment strategies for MHE suggested that therapy with lactulose was cost-effective and rifaximin was not.
      • Bajaj J.S.
      • Pinkerton S.D.
      • Sanyal A.J.
      • Heuman D.M.
      Diagnosis and treatment of minimal hepatic encephalopathy to prevent motor vehicle accidents: a cost-effectiveness analysis.
      The study limited cost/benefit analysis to an end point of motor vehicle accidents; therefore further research is required. Guidelines by the Practice Parameters Committee of the American College of Gastroenterology for MHE were last published in 2001. Over the last decade, there is compelling evidence that MHE has a negative impact on quality of life and patient well being.
      • Arguedas M.R.
      • DeLawrence T.G.
      • McGuire B.M.
      Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis.
      • Bajaj J.S.
      • Hafeezullah M.
      • Hoffmann R.G.
      • Saeian K.
      Minimal hepatic encephalopathy: a vehicle for accidents and traffic violations.
      • Bajaj J.S.
      • Saeian K.
      • Schubert C.M.
      • et al.
      Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test.
      • Bianchi G.
      • Giovagnoli M.
      • Sasdelli A.S.
      • Marchesini G.
      Hepatic encephalopathy and health-related quality of life.
      • Groeneweg M.
      • Quero J.C.
      • De Bruijn I.
      • et al.
      Subclinical hepatic encephalopathy impairs daily functioning.
      • Roman E.
      • Cordoba J.
      • Torrens M.
      • et al.
      Minimal hepatic encephalopathy is associated with falls.
      • Schomerus H.
      • Hamster W.
      Quality of life in cirrhotics with minimal hepatic encephalopathy.
      • Wein C.
      • Koch H.
      • Popp B.
      • Oehler G.
      • Schauder P.
      Minimal hepatic encephalopathy impairs fitness to drive.
      However, the natural history of CHE and the effect of treatment on the overall prognosis of CHE requires further long-term studies.
      Given the side effects of therapies such as lactulose and cost of rifaximin, research into alternative treatment only seems logical. Probiotics and LOLA appear to have benefit in CHE although their role in therapy is not clearly defined. Other treatment options such as branched amino acid (BCAA) or flumazenil have been used to treat HE with limited success.
      • Gluud L.L.
      • Dam G.
      • Borre M.
      • et al.
      Lactulose, rifaximin or branched chain amino acids for hepatic encephalopathy: what is the evidence?.
      • Als-Nielsen B.
      • Kjaergard L.L.
      • Gluud C.
      Benzodiazepine receptor antagonists for acute and chronic hepatic encephalopathy.
      Overall larger randomized trials are necessary to define the best therapeutic option for CHE treatment.

      Conflicts of interest

      All authors have none to declare.

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