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The Current Hepatic Encephalopathy Pipeline

Published:February 08, 2020DOI:https://doi.org/10.1016/j.jceh.2020.01.001
      Hepatic encephalopathy (HE) is a complication of acute or chronic liver failure; its mechanism is complex, involving multiple organ systems, and is still being elucidated. The standard of care, lactulose, has remained generally unchanged for decades. However, in recent years, better understanding of the pathophysiology has yielded new therapeutic targets for this reversible condition. These novel treatments act both on traditional pathways established in the ammonia hypothesis and through more recently discovered mechanisms. Here, we review contemporary investigational therapies for HE. We used narrative reviews and searched ClinicalTrials.gov database for the condition “hepatic encephalopathy” through August 29, 2019. Our review yielded six key areas of therapeutic focus: (1) antibiotics against urease-producing gut bacteria, (2) intravenous ammonia scavengers, (3) modified synthetic probiotics, (4) fecal microbiota transplant, (5) brain steroid–modulating agents, and 6) nonlactulose laxatives. Active trials are ongoing in each of these therapeutic areas.

      Keywords

      Abbreviations:

      CHESS (clinical hepatic encephalopathy staging scale), FMT (fecal microbiota transplant), HE (hepatic encephalopathy), HESA (hepatic encephalopathy scoring algorithm), MAD (multiple-ascending dose), MES (modified encephalopathy scale), ORT (object recognition test), PEG (polyethylene glycol-3350), SAD (single-ascending dose), SEV (saccadic eye velocity)
      Hepatic encephalopathy (HE) was likely first described by Hippocrates, over two millennia ago, when he noted the association between jaundice and acute behavioral abnormalities.
      • Amodio P.
      Hepatic encephalopathy: historical remarks.
      In subsequent centuries, further research into the pathophysiology of HE has elucidated some of the disease's mediators, although it is likely that others remain to be discovered. In addition to ammonia, these mediators may include neurosteroids, endogenous benzodiazepines, manganese, short-chain fatty acids, mercaptans, and inflammatory cytokines.
      • Frederick R.T.
      Current concepts in the pathophysiology and management of hepatic encephalopathy.
      • Bismuth M.
      • Funakoshi N.
      • Cadranel J.-F.
      • Blanc P.
      Hepatic encephalopathy.
      • Tapper E.B.
      • Jiang Z.G.
      • Patwardhan V.R.
      Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy.
      • Wijdicks E.F.M.
      Hepatic encephalopathy.
      Current understanding suggests that many of these mediators ultimately contribute to astrocyte dysfunction or directly to neuronal dysfunction in producing the phenotype of HE.
      • Frederick R.T.
      Current concepts in the pathophysiology and management of hepatic encephalopathy.
      ,
      • Tapper E.B.
      • Jiang Z.G.
      • Patwardhan V.R.
      Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy.
      ,
      • Wijdicks E.F.M.
      Hepatic encephalopathy.
      Presently, lactulose, a nonabsorbable disaccharide, is the mainstay of HE treatment, working by expelling ammonia (and achieving acidification) in the stool, as it generally has been since its first trials in the 1960s.
      • Müller J.B.
      • Guggenheim P.
      • UP Haemmerli
      Treatment OF chronic portal-systemic encephalopathy with lactulose.
      ,
      • Elkington S.G.
      • Floch M.H.
      • Conn H.O.
      Lactulose in the treatment of chronic portal-systemic encephalopathy.
      Thereby, improved understanding of the multiple pathways contributing to HE has yielded novel experimental therapies targeting new organs in recent years. Most treatments focus on modulating circulating ammonia levels, as this remains the best-understood and most influential mediator in creating the HE syndrome.
      • Bismuth M.
      • Funakoshi N.
      • Cadranel J.-F.
      • Blanc P.
      Hepatic encephalopathy.
      • Tapper E.B.
      • Jiang Z.G.
      • Patwardhan V.R.
      Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy.
      • Wijdicks E.F.M.
      Hepatic encephalopathy.
      Presently, we note six key areas of emerging investigation regarding novel HE therapies, which we describe in this manuscript.

      ANTIBIOTICS AGAINST UREASE-PRODUCING GUT BACTERIA

      Antibiotics have been a recognized component of HE treatment for most of the condition's history. Antibiotics are presumed to exert effects by decreasing colonic populations of urease-producing bacteria. Over time, prescribing trends evolved from chlortetracycline in the 1950's to neomycin and others now, with antibiotics generally falling out of favor for some time because of severe side effects.
      • Elkington S.G.
      • Floch M.H.
      • Conn H.O.
      Lactulose in the treatment of chronic portal-systemic encephalopathy.
      • Stormont J.M.
      • Mackie J.E.
      • Davidson C.S.
      Observations on antibiotics in the treatment of hepatic coma and on factors contributing to prognosis.
      • Morgan M.H.
      • Read A.E.
      Treatment of hepatic encephalopathy with metronidazole.
      • Conn H.O.
      • Leevy C.M.
      • Vlahcevic Z.
      • et al.
      Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy: a double blind controlled trial.
      • Als-Nielsen B.
      • Gluud L.L.
      • Gluud C.
      Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials.
      In 2010, influential evidence emerged supporting the use of rifaximin, a broad-spectrum antibiotic with minimal systemic absorption.
      • Bass N.M.
      • Mullen K.D.
      • Sanyal A.
      • et al.
      Rifaximin treatment in hepatic encephalopathy.
      Rifaximin showed superior efficacy relative to placebo with regards to end points of time to overt HE and time to HE-related hospitalization. Ninety percent of enrolled patients across control and intervention groups were concurrently using lactulose therapy. Side effects were reduced relative to previous antibiotic options.
      • Bass N.M.
      • Mullen K.D.
      • Sanyal A.
      • et al.
      Rifaximin treatment in hepatic encephalopathy.
      Subsequently, the use of rifaximin was incorporated into the latest guidelines for HE management (i.e., United States Food and Drug Administration (FDA) approved after failure of initial lactulose monotherapy resulting in readmission for HE), alongside lactulose.
      • Singh Bajaj J.
      Hepatic encephalopathy: classification and treatment AFFECTED PATIENTS DISEASED SKELETAL MUSCLE CIRRHOSIS-UNRELATED FACTORS: • medications • dementia • sleep apnea • cognitive reserve HEPATIC ENCEPHALOPATHY WEST HAVEN CRITERIA CONSEQUENCES OF HE normal mi.
      A newer agent currently in clinical trials is nitazoxanide, a broad spectrum antibiotic and antiparasitic agent, with activity against gut anaerobes.

      National Center for Biotechnology Information. Nitazoxanide CID=41684. PubChem Compound Database.

      Nitazoxanide was first explored as a treatment for HE in 2008 in a pilot study using combination therapy with nitazoxanide and lactulose.
      • Basu P.
      • Rayapudi K.
      • Esteves J.
      • Brown R.
      A pilot study utilizing nitazoxanide for hepatic encephalopathy in chronic liver failure: 392.
      Results from the first randomized, double-blind clinical trial comparing nitazoxanide and lactulose to lactulose alone were recently published, with favorable findings for the efficacy and tolerability of nitazoxanide.
      • Abd-Elsalam S.
      • El-Kalla F.
      • Elwan N.
      • et al.
      A randomized controlled trial comparing nitazoxanide plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy.
      This study enrolled 120 patients with cirrhosis with overt HE and randomized them to treatment with nitazoxanide and lactulose, or placebo and lactulose. The primary end point was the time to total reversal of HE, while the secondary end point was any treatment-related adverse effects. The primary end point was evaluated using the Clinical Hepatic Encephalopathy Staging Scale (CHESS). Nitazoxanide was administered once daily at a dose of 500 mg while lactulose was dosed to a goal of two to three bowel movements per day. The study found statistically significant difference in posttreatment CHESS scores, favoring the nitazoxanide group, and a statistically significant decrease in the time to total recovery from HE. The absolute difference in CHESS score improvement was 1.28 points, although the fact that all intervention patients achieved a perfect postintervention CHESS score of zero may be somewhat suspected. The absolute difference in time to full recovery was 0.34 days. Adverse effects were not statistically inferior for the nitazoxanide group. Further studies are anticipated and will hopefully address the question of whether nitazoxanide may be a more effective adjunctive treatment to lactulose as compared with rifaximin.

      INTRAVENOUS AMINO ACIDS FOR AMMONIA SCAVENGING

      Another area of recent interest has been the development of intravenous ammonia-scavenging molecules to treat HE by lowering circulating ammonia. Historically, this therapeutic area has relied on targeting various metabolites within the tricarboxylic acid cycle and urea cycle to sequester nitrogen and thereby decrease ammonia formation, with mixed laboratory and clinic results over time.
      • Shioya A.
      • Kuraishi K.
      • Kakimoto M.
      • Tamama Y.
      Pharmacological study on L-ornithine L-aspartate.
      • Rose C.
      • Michalak A.
      • Rao K.V.
      • Quack G.
      • Kircheis G.
      • Butterworth R.F.
      L-Ornithine-L-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure.
      • Staedt U.
      • Leweling H.
      • Gladisch R.
      • Kortsik C.
      • Hagmüller E.
      • Holm E.
      Effects of ornithine aspartate on plasma ammonia and plasma amino acids in patients with cirrhosis. A double-blind, randomized study using a four-fold crossover design.
      • Kircheis G.
      • Nilius R.
      • Held C.
      • et al.
      Therapeutic efficacy ofL-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study.
      • Zieve L.
      • Lyftogt C.
      • Raphael D.
      Ammonia toxicity: comparative protective effect of various arginine and ornithine derivatives, aspartate, benzoate, and carbamyl glutamate.
      • Rahimi R.
      • Rockey D.
      Hepatic encephalopathy: pharmacological therapies targeting ammonia.
      • Misel M.L.
      • Gish R.G.
      • Patton H.
      • Mendler M.
      Sodium benzoate for treatment of hepatic encephalopathy.
      • Ventura-Cots M.
      • Concepción M.
      • Arranz J.A.
      • et al.
      Impact of ornithine phenylacetate (OCR-002) in lowering plasma ammonia after upper gastrointestinal bleeding in cirrhotic patients.
      Recently, the focus of therapeutic ammonia scavenging research has centered on compounds which bind ammonia-precursor amino acids, namely glutamine and glycine, to form renally excreted compounds.
      • Rahimi R.S.
      • Rockey D.C.
      Novel ammonia-lowering agents for hepatic encephalopathy.
      ,
      • Hadjihambi A.
      • Jalan R.
      Hepatic encephalopathy: new treatments.
      The most recently explored such compound is ornithine phenylacetate, first described as a potential therapy for HE in 2007.
      • Jalan R.
      • Wright G.
      • Davies N.A.
      Hodges SJ. l-Ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy.
      Clinically, this drug appears targeted to address the issues of slow onset of action and difficulty of administration (i.e., nonadherence) encountered with lactulose. Commercial development of this molecule was pursued through phase 2b trials where statistical significance was not achieved for the primary end point, although a dose-response trend was observed.
      • Hassanein T.
      • Kittrelle J.P.
      • Cato J.
      • Fischer L.
      • Anderson K.E.
      Sa1016 OCR-002 (Ornithine Phenylacetate) a Novel Ammonia Scavenger for the Treatment of He via Pagn Production: Impact of Liver Function on Metabolism and Urinary Excretion of Pagn.
      • Ocera Therapeutics
      Ocera Announces Top-Line Results for Phase 2b Study in Hepatic Encephalopathy Nasdaq:OCRX. GlobalNewswire.
      • Safadi R.
      • Rahimi R.S.
      • DiLiberti C.E.
      • et al.
      OCR-002 (ornithine phenylacetate) is a potent ammonia scavenger as demonstrated in phase 2b STOP-HE study (Abstract).
      Methods and results of completed trials are summarized in Table 1. Currently, a phase 2a, open-label trial comparing ornithine phenylacetate with rifaximin is underway, with a targeted enrollment of 48 participants, a primary outcome of area under the plasma concentration time curve for ammonia at 24 h, and secondary outcomes of maximum plasma concentrations of phenylacetic acid, and any hyperammonemic crisis within five days.
      Mallinckrodt Pharmacodynamics
      Safety and pharmacokinetics of the oral administration MNK6106 (L-ornithine phenylacetate) vs rifaximin in participants with hepatic cirrhosis and a history of prior episodes of hepatic encephalopathy - full text view - ClinicalTrials.go. ClinicalTrials.gov.
      A developing phase 3 study of ornithine phenylacetate will start recruitment in the first quarter of 2020.
      • Alsahhar J.S.
      • Rahimi R.S.
      Updates on the pathophysiology and therapeutic targets for hepatic encephalopathy.
      Pending further data regarding the efficacy of ornithine phenylacetate, this agent could potentially become another additive treatment option for overt HE, specifically providing a different mechanism of action (i.e., elimination of ammonia via the kidneys) while treating concurrently with lactulose (i.e., elimination of ammonia via the gut).
      Table 1Summary of Cited Human Trials.
      StudyNTherapyControlStudy typePrimary end pointsResults summary and limitations
      Basu PP, Rayapudi K, Esteves J and Brown R. Am J Gastroenterol. 2008
      • Basu P.
      • Rayapudi K.
      • Esteves J.
      • Brown R.
      A pilot study utilizing nitazoxanide for hepatic encephalopathy in chronic liver failure: 392.
      20Nitazoxanide with lactuloseN/ASingle-arm tolerability and efficacy pilotTolerability, improvement on MES
      MES, modified encephalopathy scale.
      and ORT
      ORT, object recognition test.
      after 2 weeks or therapy.
      19 of 20 patients completed the study. 79% and 63% of patients demonstrated improvement on MES and ORT scores, respectively
      Abd-Elsalam S, El-Kalla F, Elwan N, et al. J Clin Gastroenterol. 2019
      • Abd-Elsalam S.
      • El-Kalla F.
      • Elwan N.
      • et al.
      A randomized controlled trial comparing nitazoxanide plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy.
      120Nitazoxanide with lactuloseLactulosePhase 1–2 randomized controlled trialImprovement in CHESS
      CHESS, clinical hepatic encephalopathy staging scale.
      score at 1 week
      Nitazoxanide group improved from CHESS 4.15 to 0.00, compared with improvement of 4.96 to 1.28 for controls (P < 0.001)
      Hassanein T, Kittrelle JP, Cato J, et al. Gastroenterol.(abstract) 2012
      • Hassanein T.
      • Kittrelle J.P.
      • Cato J.
      • Fischer L.
      • Anderson K.E.
      Sa1016 OCR-002 (Ornithine Phenylacetate) a Novel Ammonia Scavenger for the Treatment of He via Pagn Production: Impact of Liver Function on Metabolism and Urinary Excretion of Pagn.
      91Ornithine phenylacetate infusionPlaceboPhase 2a randomized open-label trialSafety, tolerability, and quantification of urinary phenylacetylglutamine (PAGN)Well tolerated; one time doses from 3 to 10 g led to significantly increased urine PAGN output.
      Safadi R, Rahimi RS, DiLiberti CE et al. Hepatology. (abstract) 2017
      • Safadi R.
      • Rahimi R.S.
      • DiLiberti C.E.
      • et al.
      OCR-002 (ornithine phenylacetate) is a potent ammonia scavenger as demonstrated in phase 2b STOP-HE study (Abstract).
      231Ornithine phenylacetate infusionPlaceboPhase 2b randomized controlled trialClinical improvement in HE symptomsNonsignificant reduction in time to improvement of HE symptoms among those in treatment group (P = 0.129). However, dose response was demonstrated, in a post-hoc analysis excluding patients with normal baseline ammonia levels with statistical significance (P = 0.034).
      Kurtz CB, Millet YA, Puurunen MK, et al. Sci Tansl Med. 2019
      • Kurtz C.B.
      • Millet Y.A.
      • Puurunen M.K.
      • et al.
      An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans.
      52SYNB1020PlaceboPhase 1 randomized controlled trialSafety, tolerability, increase in urinary and plasma15N-nitrate levelsWell tolerated; dose-dependent increase in15N-nitrate levels among healthy subjects
      Synlogic. Unpublished
      • Synlogic I.
      Synlogic Discontinues Development of SYNB1020 to Treat Hyperammonemia - Synlogic.
      23SYNB1020PlaceboPhase 1b/2aSafety and tolerability, lowering of blood ammonia levelWell tolerated but no significant decrease in blood ammonia levels among patients with cirrhosis with hyperammonemia; development has been discontinued.
      Bajaj JS, Kassam Z, Fagan A, et al. Hepatology. 2017
      • Bajaj J.S.
      • Kassam Z.
      • Fagan A.
      • et al.
      Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial.
      20Fecal microbiota transplant enemaLactulose with rifaximinOpen-label randomized trialSafety, tolerabilitySafe, well tolerated; secondary clinical outcome demonstrated decrease in subsequent HE episodes over 150 days
      Johansson M, Mansson M, Lins L-E, et al. Psychopharmacology. 2018
      • Johansson M.
      • Månsson M.
      • Lins L.-E.
      • Scharschmidt B.
      • Doverskog M.
      • Bäckström T.
      GR3027 reversal of neurosteroid-induced, GABA-A receptor-mediated inhibition of human brain function: an allopregnanolone challenge study.
      90GR3027N/APhase 1–2 randomized controlled trialSafety, tolerability, inhibition of allopregnanolone and tetrahydrodeoxycorticosterone effect on SEV
      SEV, saccadic eye velocity.
      and sedation
      Safe, well tolerated; significant reduction in SEV with highest dose GR3027, no significant effects on sedation in predefined analyses. No dose response observed with respect to adverse effects.
      Rahimi RS, Singal AG, Cuthbert JA and Rockey DC. JAMA Intern Med. 2014
      • Rahimi R.S.
      • Singal A.G.
      • Cuthbert J.A.
      • Rockey D.C.
      Lactulose vs polyethylene glycol 3350-electrolyte solution for treatment of overt hepatic encephalopathy.
      50PEG-3350LactuloseOpen-label randomized trialImprovement of HESA
      HESA, hepatic encephalopathy scoring algorithm.
      score by at least 1 grade in 24 h
      Significantly more patients receiving PEG3350 achieved the primary end point relative to control (91% vs 52%, P < 0.01). No difference in length of stay.
      Shehata HH, Elfert AA, Abdin AA, et al. Eur J Gastroenterol Hepatol. 2018
      • Shehata H.H.
      • Elfert A.A.
      • Abdin A.A.
      • et al.
      Randomized controlled trial of polyethylene glycol versus lactulose for the treatment of overt hepatic encephalopathy.
      100PEG-3350LactuloseOpen-label randomized trialImprovement of HESA score by at least 1 grade in 24 hSignificantly more patients receiving PEG3350 achieved the primary end point relative to control (94% vs 72%, P < 0.05). Significantly shorter length of stay with PEG3350 as well.
      Naderian M, Akbari H, Saeedi M, and Sohrabpour AA. Middle East J Dig Dis. 2017
      • Naderian M.
      • Akbari H.
      • Saeedi M.
      • Sohrabpour A.A.
      Polyethylene glycol and lactulose versus lactulose alone in the treatment of hepatic encephalopathy in patients with cirrhosis: a non-inferiority randomized controlled trial.
      40PEG-3350 with lactuloseLactuloseOpen-label randomized trialImprovement of HESA score by at least 1 grade in 24 hSignificantly more patients receiving PEG3350 achieved the primary end point relative to control (95% vs 74%, P = 0.04). Significantly shorter length of stay with PEG3350 as well.
      PEG, polyethylene glycol; HE, hepatic encephalopathy.
      a MES, modified encephalopathy scale.
      b ORT, object recognition test.
      c CHESS, clinical hepatic encephalopathy staging scale.
      d HESA, hepatic encephalopathy scoring algorithm.
      e SEV, saccadic eye velocity.
      Of concern, a notable critique applicable to all intravenous ammonia scavenger therapies was published in 2017. This study used a canine model of liver failure and hyperammonemia and ultimately demonstrated that while benzoate and phenylacetate compound did indeed increase urinary excretion of the intended amino acid complexes, a similar reduction in circulating ammonia was seen with saline infusion. The study's authors concluded that reductions in circulating ammonia levels may therefore be due simply to circulating volume expansion or forced diuresis rather than the previously attributed drug mechanisms.
      • van Straten G.
      • de Sain-van der Velden M.G.M.
      • van Geijlswijk I.M.
      • et al.
      Saline is as effective as nitrogen scavengers for treatment of hyperammonemia.
      Notably, although in canine models, the volume or concentration of treatments was not disclosed.

      MODIFIED SYNTHETIC BACTERIA TO DECREASE GUT AMMONIA PRODUCTION

      Based on the ammonia hypothesis, the concept of modifying gut flora via exogenous probiotics is an approach to HE treatment that has been explored over decades. The first such therapeutic attempt dates back to 1965 in which two patients were treated with neomycin to decimate existing gut flora, followed by lactobacillus acidophilus-inoculated milk.
      E. coli Nissle 1917 is another probiotic species which has shown promise for the treatment of HE.
      • Lata J.
      • Juránková J.
      • Príbramská V.
      • et al.
      [Effect of administration of Escherichia coli Nissle (Mutaflor) on intestinal colonisation, endo-toxemia, liver function and minimal hepatic encephalopathy in patients with liver cirrhosis].
      This particular strain of E. coli, known for its robustness and lack of pathogenicity, has been characterized extensively since its discovery in 1917 by Alfred Nissle, who isolated the strain from the stool of a German soldier who seemed immune to the Salmonella outbreak affecting his compatriots.
      • Sonnenborn U.
      Escherichia coli strain Nissle 1917—from bench to bedside and back: history of a special Escherichia coli strain with probiotic properties.
      One investigational approach to decreasing gut production of ammonia is the synthesis of a modified E. coli strain designed to consume ammonia in the gut. This phase 1b/2a trial used a proprietary, genetically modified strain of Escherichia coli Nissle 1917. Specifically, this engineered strain contains modifications to upregulate the production of arginine, thus increasing ammonia consumption.
      • Tucker A.
      • Kotula J.
      • Isabella V.
      • et al.
      Modulating arginine biosynthesis in E. coli nissle to consume ammonia in a mouse model of hyperammonemia | 2016 synthetic biology: engineering, evolution & design (SEED). Synthetic biology: engineering, evolution & design (SEED).
      E. coli Nissle 1917, in its wild-type form, has an established history of use as a probiotic, in that it colonizes and persists in the human intestine, and is intended to confer health benefits.
      • Zyrek A.A.
      • Cichon C.
      • Helms S.
      • Enders C.
      • Sonnenborn U.
      • Schmidt M.A.
      Molecular mechanisms underlying the probiotic effects of Escherichia coli Nissle 1917 involve ZO-2 and PKC? redistribution resulting in tight junction and epithelial barrier repair.
      • Schultz M.
      Clinical use of E. coli Nissle 1917 in inflammatory bowel disease.
      • Kruis W.
      • Fric P.
      • Pokrotnieks J.
      • et al.
      Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine.
      • Ciorba M.A.
      A gastroenterologist's guide to probiotics.
      E. coli Nissle 1917, as well as other probiotics and synbiotics are also supported by randomized controlled trial data documenting modest efficacy.
      • 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.
      • 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.
      The use of a probiotic to prevent and treat HE would presumably benefit patients by providing a convenient and easily tolerated therapy that addresses the early pathogenesis of HE.
      A phase 1 trial, in combination with preclinical data, was recently published regarding genetically engineered E. coli Nissle 1917.
      • Kurtz C.B.
      • Millet Y.A.
      • Puurunen M.K.
      • et al.
      An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans.
      The synthesized strain of E. coli Nissle 1917 was modified to increase its activity in converting ammonia to l-arginine. Although this compound demonstrated promising preclinical results and acceptable safety and tolerability, a phase 1b/2a trial did not demonstrate clinical efficacy and thus development was discontinued.
      • Synlogic I.
      Synlogic Discontinues Development of SYNB1020 to Treat Hyperammonemia - Synlogic.
      ,
      • Synlogic
      Safety, tolerability and pharmacodynamics of SYNB1020 - full text view - ClinicalTrials.gov. ClinicalTrials.gov.
      The results of relevant trials are summarized in Table 1.

      FECAL MICROBIOTA TRANSPLANT

      The role of the colonic microbiome in HE pathogenesis has been long recognized under the ammonia hypothesis.
      • Amodio P.
      Hepatic encephalopathy: historical remarks.
      ,
      • Tapper E.B.
      • Jiang Z.G.
      • Patwardhan V.R.
      Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy.
      ,
      • McDermott W.V.
      • Victor M.
      • Point W.W.
      Exclusion of the colon in the treatment of hepatic encephalopathy.
      ,
      • Macbeth W.A.G.
      • Kass E.
      • Mcdermott W.
      Treatment OF hepatic encephalopathy BY alteration OF intestinal flora with lactobacillus acidophilus.
      Fecal microbiota transplant (FMT) first gained widespread recognition as a treatment for recurrent clostridium difficile infection in 2013, after the decreased gut microbiome diversity was a recognized contributor to disease.
      • van Nood E.
      • Vrieze A.
      • Nieuwdorp M.
      • et al.
      Duodenal infusion of donor feces for recurrent Clostridium difficile.
      • Quraishi M.N.
      • Widlak M.
      • Bhala N.
      • et al.
      Systematic review with meta-analysis: the efficacy of faecal microbiota transplantation for the treatment of recurrent and refractory Clostridium difficile infection.
      • Chang J.Y.
      • Antonopoulos D.A.
      • Kalra A.
      • et al.
      Decreased diversity of the fecal microbiome in recurrent Clostridium difficile –associated diarrhea.
      Derangement of gut microbiota has also been documented via ribonucleic acid sequencing in patients with cirrhosis relative to healthy subjects.
      • Chen Y.
      • Yang F.
      • Lu H.
      • et al.
      Characterization of fecal microbial communities in patients with liver cirrhosis.
      Subsequent work demonstrated that the degree of microbiome derangement correlated with the development of HE among patients with cirrhosis.
      • Bajaj J.S.
      • Ridlon J.M.
      • Hylemon P.B.
      • et al.
      Linkage of gut microbiome with cognition in hepatic encephalopathy.
      Early animal data and case reports of FMT for HE emerged in 2015.
      • Kao D.
      • Roach B.
      • Park H.
      • et al.
      Fecal microbiota transplantation in the management of hepatic encephalopathy.
      ,
      • Shen T.-C.D.
      • Albenberg L.
      • Bittinger K.
      • et al.
      Engineering the gut microbiota to treat hyperammonemia.
      A safety and efficacy trial of FMT via enema for HE began enrollment in 2015.
      • Bajaj J.
      Fecal transplant in recurrent hepatic encephalopathy - full text view - ClinicalTrials.gov. ClinicalTrials.gov.
      Results were subsequently published in 2017, with positive findings for safety, tolerability, and secondary clinical outcomes.
      • Bajaj J.S.
      • Kassam Z.
      • Fagan A.
      • et al.
      Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial.
      Specifically, in this open-label randomized trial, 20 adult patients with recurrent HE and Model for End-Stage Liver Disease (MELD) <17 were randomized to treatment with lactulose and rifaximin versus FMT, consisting of broad-spectrum antibiotic pretreatment followed by one-time transplant enema with stool from a single donor. Interestingly, this donor was selected on the basis of having abundant lachnospiraceae and ruminococcaceae species, both of which are reduced in patients with HE. Patients were then followed for 150 days; the primary outcome was serious adverse events and secondary outcomes included adverse events, further HE episodes, and microbiome changes, as measured by 16s rRNA sequencing. Ultimately, patients receiving FMT therapy experienced significantly fewer serious adverse events (SAEs), notably with no SAEs attributable to FMT therapy. In addition, there was a significant decrease in subsequent episodes of HE among those receiving FMT. As expected, gut microbiota diversity decreased in the FMT after antibiotic administration but then increased to preantibiotic levels after FMT. Microbiota diversity was not compared across the two treatment arms. Interestingly, the authors noted that those who underwent FMT subsequently had microbiota enriched in Ruminococcaceae compared with their prior baseline.
      • Bajaj J.S.
      • Kassam Z.
      • Fagan A.
      • et al.
      Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial.
      Presently, there are four active trials, in phases 1 and 2, of FMT for HE; transplants in these trials are administered by oral capsule or by colonoscopy.
      • Kao D.
      • University of Alberta
      Fecal microbiota transplantation (FMT) in the management of hepatic encephalopathy (HE): a pilot study - full text view - ClinicalTrials.gov. ClinicalTrials.gov.
      • University of Alberta
      Fecal transplant for hepatic encephalopathy - full text view - ClinicalTrials.gov. ClinicalTrials.gov.
      • Chung R.T.
      • Hospital M.G.
      Fecal microbiota transplant as treatment of hepatic encephalopathy.
      • Commonwealth University Virginia
      Oral fecal transplant in cirrhosis - full text view - ClinicalTrials.gov. ClinicalTrials.gov.
      A prospective study in Hong Kong recently began enrolling to examine the safety and efficacy of FMT across a variety of infectious, inflammatory, and functional gastrointestinal disorders, including HE. This study will not use randomization or a placebo control and seeks to enroll 450 participants.
      • NG S.C.
      Safety and efficacy of fecal microbiota transplantation. ClinicalTrials.gov.
      In the future, FMT in HE could potentially be used for the treatment of refractory or recurrent HE cases, in a controlled setting, if continued safety data show benefit in this high-risk population.

      BRAIN STEROID–MODULATING AGENTS

      The role of neurosteroids, produced in and acting on the central nervous system, has become a recognized contributor to the HE phenotype.
      • Ahboucha S.
      • Butterworth R.F.
      The neurosteroid system: implication in the pathophysiology of hepatic encephalopathy.
      The mechanism of this is likely via increased gamma aminobutyric acid (GABA)ergic tone.
      • Prakash R.
      • Mullen K.D.
      Mechanisms, diagnosis and management of hepatic encephalopathy.
      Early therapeutic development in this area focused on benzodiazepine receptor antagonists, but more recent work has focused on neurosteroids acting on the GABA-A receptor complex.
      • Ahboucha S.
      • Butterworth R.F.
      The neurosteroid system: implication in the pathophysiology of hepatic encephalopathy.
      ,
      • Prakash R.
      • Mullen K.D.
      Mechanisms, diagnosis and management of hepatic encephalopathy.
      The main steroids implicated thus far have been allopregnanolone and tetrahydrodeoxycorticosterone.
      • Ahboucha S.
      • Butterworth R.F.
      The neurosteroid system: implication in the pathophysiology of hepatic encephalopathy.
      ,
      • Butterworth R.F.
      Neurosteroids in hepatic encephalopathy: novel insights and new therapeutic opportunities.
      A novel compound of interest, GR3027, has emerged targeting this pathway. GR3027 selectively antagonizes the enhanced activation of the GABA-A receptor complex by neurosteroids, including allopregnanolone and tetrahydrodeoxycorticosterone.
      • Johansson M.
      • Agusti A.
      • Llansola M.
      • et al.
      GR3027 antagonizes GABA A receptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy.
      Data generated thus far regarding GR3027 have demonstrated improvement in rat cognitive function in liver failure and hyperammonemia models, as well as acceptable tolerability and evidence of allopregnanolone effect antagonism in humans.
      • Johansson M.
      • Agusti A.
      • Llansola M.
      • et al.
      GR3027 antagonizes GABA A receptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy.
      ,
      • Johansson M.
      • Månsson M.
      • Lins L.-E.
      • Scharschmidt B.
      • Doverskog M.
      • Bäckström T.
      GR3027 reversal of neurosteroid-induced, GABA-A receptor-mediated inhibition of human brain function: an allopregnanolone challenge study.
      A phase 1 trial demonstrated promising safety and tolerability, with the highest dose demonstrating improvement in saccadic eye velocity. The details of this trial are summarized in Table 1. Currently, a phase 2a trial of GR3027 in HE is underway and enrolling subjects as of February, 2019.
      • Cognition Umecrine
      Umecrine Cognition announces first patient included in part D in clinical Phase 2a study with GR3027 in patients with liver cirrhosis and hepatic encephalopathy.
      Further study of clinical outcomes will be needed to determine whether GR3027 can function as a stand-alone treatment or whether it should be used as an adjunct to existing therapies.

      ALTERNATIVE LAXATIVES TO LACTULOSE

      Recently, there has been increased interest in bowel purgatives as alternative to lactulose, as the efficacy and presumed mechanism of action have come under scrutiny.
      • Rahimi R.
      • Rockey D.
      Hepatic encephalopathy: pharmacological therapies targeting ammonia.
      ,
      • Rahimi R.S.
      • Singal A.G.
      • Cuthbert J.A.
      • Rockey D.C.
      Lactulose vs polyethylene glycol 3350-electrolyte solution for treatment of overt hepatic encephalopathy.
      Indeed, case reports dating back to the 1950s suggested that purgative agents alone had some treatment effect in HE.
      • Manning R.T.
      • Delp M.
      Management of hepatocerebral intoxication.
      In particular, polyethylene glycol-3350 (PEG) solution, commonly used for colonoscopy preparation or general constipation, has been studied. In 2014, a randomized clinical trial comparing treatment of HE with either lactulose or PEG-3350 solution demonstrated quicker resolution of HE with PEG-3350 relative to lactulose, overall with excellent tolerability and safety. This study included 50 patients admitted for HE with cirrhosis who were then randomized to either standard of care with lactulose or a single dose of 4 L PEG-3350, in a single-blinded fashion (as the intrinsic amount of bowel movements reported between the two groups lead to unblinding). The primary outcome in this study was an improvement in HE scoring algorithm (HESA) at 24 h; secondary outcomes included duration of hospitalization and time to HE resolution. Ultimately there were 25 participants in the control arm and 23 in the intervention arm, as one patient was discharged early and one refused participation, as both patients had complete resolution of their HE. The study findings appeared to support the use of PEG-3350 in treating HE, with a significant improvement in the rate of HESA score improvement at 24 h (i.e., at least ≥1 HE grade improvement) and time to HE resolution, while the overall length of stay was not significantly different. Notably, subjects were quite comparable between the two groups, with no significant differences in MELD score, age, or etiology of cirrhosis. Reassuringly, the authors also confirmed that there was no significant difference in the rate at which patients required a nasogastric tube to complete their treatment.
      • Rahimi R.S.
      • Singal A.G.
      • Cuthbert J.A.
      • Rockey D.C.
      Lactulose vs polyethylene glycol 3350-electrolyte solution for treatment of overt hepatic encephalopathy.
      A similarly designed trial was recently reported, also comparing the efficacy of PEG-3350 with lactulose in cases of overt HE. Published in 2018, this study randomized 100 patients to treatment with either oral lactulose (20–30 ml spread across 24 h), or combined with lactulose enema (200 ml once) and tap water enema, or oral PEG-3350 (192–256 g depending on patient weight).
      • Shehata H.H.
      • Elfert A.A.
      • Abdin A.A.
      • et al.
      Randomized controlled trial of polyethylene glycol versus lactulose for the treatment of overt hepatic encephalopathy.
      The primary outcome was also improvement in the HESA score; secondary outcomes were length of hospital stay and adverse effects. Interestingly, this trial found that from similar baseline HESA scores, PEG-3350 led to a greater proportion of patients demonstrating improvement in the first 24 h but no significant change by the time of discharge. However, the study did demonstrate a significantly larger proportion of patients demonstrating improvement in HESA score by 1 or more grades in the PEG-3350 group. Length of stay was significantly shorter in the PEG-3350 group, as was time to resolution of HE, apparently performed as a post-hoc analysis. Side effects were not mild and not significantly different between the groups, although the number of bowel movements in the first 24 h, reported as a side effect, was significantly greater in the PEG-3350 group. Baseline age, laboratory and HE characteristics in both groups appeared similar. Overall, these studies suggest that PEG-3350 may be at least as efficacious as lactulose in the treatment of HE, with perhaps a quicker clinical response. A smaller study than the prior ones previously mentioned also demonstrated similar findings with improvement in HE compared with lactulose, with a decrease in length of stay (LOS).
      • Naderian M.
      • Akbari H.
      • Saeedi M.
      • Sohrabpour A.A.
      Polyethylene glycol and lactulose versus lactulose alone in the treatment of hepatic encephalopathy in patients with cirrhosis: a non-inferiority randomized controlled trial.
      At least one further trial comparing the safety and efficacy of PEG-3350 to lactulose is underway.
      • Abd-Elsalam S.
      PEG (polyethylene Glycol)Versus lactulose for treatment of overt hepatic encephalopathy - full text view - ClinicalTrials.gov. ClinicalTrials.gov.
      ,
      • Institute of Liver of Biliary Sciences
      To compare efficacy and safety of lactulose versus polyethylene glycol for treatment of overt hepatic encephalopathy in cirrhotics. - full text view - ClinicalTrials.gov. ClinicalTrials.gov.
      Considering the favorable evidence for PEG-3350, 2–4 L administration could be considered as an off-label first-line therapy for overt HE, especially in severe cases (i.e., grade 3 and coma). Further treatment consideration can be cautiously used particularly in patients for whom the taste or side effects of lactulose are intolerable. The data supporting PEG-3350 in HE also raise the question of what other laxatives might be as effective when compared with lactulose.
      In summary, the options for the treatment of HE are evolving and there is room for optimism. As our understanding of disease mechanisms have progressed, so too have available therapies targeting multiple implicated pathways. Table 1 summarizes the findings of all human trials referenced in this review. Figure 1 summarizes anatomic sites of action of emerging compounds. While the majority of treatments are still based on the ammonia hypothesis, other pathways for treatment have been elucidated. Novel means for modulating systemic ammonia also continue to emerge. Figure 2 demonstrates a hypothetical clinical algorithm for the use of current and emerging HE treatment options. Optimism is bolstered by the volume of innovation and research in this area. However, we note that most emerging therapies lack data on relevant clinical outcomes, and there is a lack of consistency among the research outcomes selected for studies of these therapies, making comparisons challenging.
      Figure 1
      Figure 1Sites of action of hepatic encephalopathy pipeline compounds.
      Figure 2
      Figure 2Hypothetical flow chart of future HE treatment. HE, hepatic encephalopathy.

      Conflicts of interest

      R.S.R. served on advisory boards for Mallinckrodt and has received research support from Valeant and Mallinckrodt (formerly Ocera Therapeutics). M.L.D. and A.J.R. have nothing to disclose.

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