v
Search
Advanced

Publications > Journals > Journal of Clinical and Translational Hepatology > Article Full Text

  • Review Article
  • OPEN ACCESS

Novel Agents in the Management of Hepatic Encephalopathy: A Review

  • Leen Z. Hasan*  and
  • George Y. Wu
 Author information  Cite
Journal of Clinical and Translational Hepatology   2021;9(5):749-759

doi: 10.14218/JCTH.2021.00102

Abstract

Hepatic encephalopathy is an often devastating complication of chronic liver disease, associated with high mortality and increased burden on patients and healthcare systems. Current agents (such as nonabsorbable disaccharides and oral antibiotics) are often only partially effective and associated with unpleasant side effects. With our improved understanding of the pathophysiology of hepatic encephalopathy, multiple treatment modalities have emerged with promising results when used alone or as an adjunct to standard medications. The mechanisms of these agents vary greatly, and include the manipulation of gut microbial composition, reduction of oxidative stress, inhibition of inflammatory mediators, protection of endothelial integrity, modulation of neurotransmitter release and function, and other novel methods to reduce blood ammonia and neurotoxins. Despite their promising results, the studies assessing these treatment modalities are often limited by study design, sample size, outcome assessment heterogeneity, and paucity of data regarding their safety profiles. In this article, we discuss these novel agents in depth and provide the best evidence supporting their use, along with a critical look at their limitations and future directions.

Keywords

Hepatic encephalopathy, Liver cirrhosis, Ammonia

Introduction

Hepatic encephalopathy (HE) is a serious and common complication of liver dysfunction, encompassing a broad spectrum of neurocognitive and psychomotor dysfunction ranging from disorientation to coma.1 It is classified into three major subtypes, based on the underlaying etiology, as follows: type A, resulting from acute liver failure; type B, resulting from portosystemic shunt; and type C, resulting from liver cirrhosis.2 HE, especially due to liver cirrhosis, is associated with significant mortality, reaching up to 64% at 1 year.3 In addition to the high mortality rate, HE imposes a great burden on various aspects of patient lives and healthcare systems.4 The management of HE starts with identifying and treating any precipitating cause, especially in patients with chronic liver diseases who may develop acute HE secondary to infection, bleeding, etc. Currently, several medications are utilized to treat HE, with a primary focus on decreasing ammonia production and absorption, such as by lactulose and rifaximin. Newer therapies are emerging and currently under study for the management of HE targeting traditional mechanisms of ammonia clearance in addition to novel mechanisms related to altering gut microbiome, reducing inflammation and oxidative stress, protecting endothelial integrity, and modifying neuronal responses (Fig. 1). In this article, we aim to review the management of HE, starting with the efficacy and limitations of traditional agents with a focus on the evidence supporting newer therapies in HE (Table 1).

Postulated mechanisms of medications used or being studied for treatment of hepatic encephalopathy.
Fig. 1  Postulated mechanisms of medications used or being studied for treatment of hepatic encephalopathy.

*These agents are approved by the U.S. Food and Drug Administration for the treatment of hepatic encephalopathy

Table 1

Characteristics of novel agents for the treatment of HE

AgentMechanism of actionCurrent stage of researchRoute and dose used in clinical studiesMethods of assessing neuropsychiatric outcomes used in clinical trialsEffect shown in clinical studiesMain limitations of published trialsExamples of ongoing trials in HEΩ
FMTAltering gut microbiome by replacing potentially pathogenic taxa with beneficial, SCFA-producing taxaTwo phase 1 RCTs90 cc enema once in one trial, and 15 FMT tablets once in the other trialPHES, EncephalApp StroopNo serious adverse events associated with the use of enema FMT, including no bacterial infections. - Enema FMT was associated with a reduced number of hospitalizations due to liver-related complications. Also, improvement in cognitive outcomes between baseline and post-treatment in the enema FMT group but none among those undergoing SOC. Oral FMT safe and well-tolerated, associated with enhanced microbial diversity, and favorable changes in antimicrobial protein expression and intestinal inflammatory markers, along with improved performance on cognitive scoresEnema FMT: small sample size; confounding effect of pre-FMT antibiotics; the control arm being SOC instead of placebo antibiotics or autologous FMT; short-term follow up; no significant change in microbiome diversity. Oral FMT: small sample design; single-blind design; low power to assess efficacyNCT03420482, NCT03796598, NCT04014413
ProbioticsReduction of ammonia-producing bacteria, and decreasing ammonia absorption in the gut21 RCTs; 1 Cochrane systematic review and meta-analysisOral; variableWHS, PHES, TMT, NCT, SDT, MRS, BAERCompared to placebo, probiotics improve recovery and may lead to improvements in overt hepatic encephalopathy, quality of life, and plasma ammonia concentrations. No effect on all-cause mortality. No difference in adverse events. Compared to lactulose, benefit is uncertain due to limitationsHigh risk of bias. Outcome heterogeneity. Different types of probiotics used in different trialsNCT04787276, NCT04243148, NCT04175392, NCT03863730
AlbuminNeutralizes reactive oxygen species, inhibits inflammatory mediators and reduces endothelial dysfunction and vasodilation4 RCTs, meta-analysis of cohort and RCTShort-term: 1-1.5 g/kg/day for 1-10 days. Long-term: 40 g twice weekly for 2 weeks, and then 40 g weekly for up to 18 months. Other: 20% albumin infusion up to 14 days or discharge to raise albumin level to ≥30 g/LWHSInitial trials and meta-analysis showed reduction in mortality, incidence of HE, HE recovery, hospital length of stay compared to placebo or standard of care. Recent trial (reference 54) showed no benefit of albumin over SOC when targeting albumin level ≥30 g/LOpen-label randomized trials. Most RCTs have small sample size. Non-blinding of outcome assessment. Cost effectiveness. Some trials with short-term follow-upNCT03585257, NCT02401490
AST-120Reduction of blood ammonia and oxidative stress by limiting absorption of neurotoxins and hepatotoxins2 RCTsVaried per trial; 6-12 (oral) sachets per day divided in 2-4 dosesWHS, HESA; RBANS, PHES, CGA-HEReduction of serum ammonia compared to placebo, reduction of diarrhea and flatulence compared to placebo. No difference on neurocognitive outcomesSmall number of patients. Study design allowed for improvement of neurocognitive outcomes even prior to randomization limiting its ability to detect true differencesNone
Acetyl-L-carnitineReduction of serum ammonia by increasing ureagenesis; enhancement of neurotransmitter, protein and phospholipid synthesis5 RCTs; 1 Cochrane systematic review and meta-analysis2 g (oral) twice dailyTMT, SDMT, AVL, MMSE, EEG, BDI, STAI, VOT, Digit Cancellation Time, EMQ, COWAT, EEG, NPTIndividual studies showed improving neurological findings; reduction of serum ammonia level and improvement in performance on neuropsychological testing; improvement in energy levels, general functioning and well-being, and reduction of anxiety and depression; reduction of physical and mental “fatigue”; and improvement of cognitive deficits and EEG findings. Meta-analysis showed a reduction of blood ammonia among participants receiving acetyl-L-carnitine; however, the certainty of this finding was low due to limitationsSmall number of participants, high risk of bias, and low power for detection of meaningful differences between the treatment groups; no reporting of mortality or serious adverse events between the groupsNone
GPBIncreased urinary excretion of ammonia1 pilot study; 1 phase 2 RCT6 mL (oral) twice dailyWHSGPB reduced the number of patients with HE events, time to first event, total events, HE hospitalizations, and blood ammonia levels. Benefit was sustained after controlling for rifaximin use. No difference in serious adverse events between the two groupsSmall sample size. More patients in the GPB group exited the study prematurely. 1/3 patients were taking rifaximin at the time of randomizationNone
FlumazenilNeurotransmitter modulation through competitive inhibition of GABA-A receptors12 RCTs; 1 Cochrane systematic review and meta-analysisVaried per trial; intravenous flumazenil at a total daily dose 0.2-6.5 mgNCT, BAER, GCS, EEG, NPTNo on all-cause mortality, no difference in serious adverse events. Flumazenil was associated with improvement of HESmall sample size in individual studies. High risk of bias
Cross-over design; relapse rate not assessable. Short-term follow up		None
PEGReduce ammonia absorption by exerting a cathartic effect and reducing transit time3 RCTs4 LHESA, WHSPEG (alone or in combination with lactulose) is more effective than lactulose at improving HE at 24 h and associated with decreased length of stay. No difference in blood ammonia levels. No difference in serious adverse eventsSmall sample size. Single-center experiences. Non-blinding. Short-term follow upNCT04436601, NCT03987893

ΩClinicaltrials.gov website was searched for clinical trials relevant to hepatic encephalopathy and the agent of interest. AVL, auditory verbal learning test; BAER, brain-auditory evoked response; BDI, Beck depression inventory; COWAT, controlled oral word association test; EEG, electroencephalogram; EMQ, everyday memory questionnaire; MMSE, mini mental state examination; NCT, number connection test; NPT, neuropsychiatric test; SDMT, symbol digit modalities test; SDT, serial dotting test; STI, state trait anxiety inventory; TMT, trails making test; VOT, Hooper visual organization test.

Efficacy and limitations of traditional agents in management of HE

Lactulose and lactitol

Lactulose (beta-galactosidofructose) and lactitol (beta-galactosidosorbitol) are synthetic nonabsorbable disaccharides (NADs) that are given orally or rectally in patients with HE, in order to trap ammonia in the gut, thereby limiting intestinal absorption. Lactulose and lactitol are not absorbed due to the absence of a hydrolytic disaccharidase in the small intestine. This permits entry into the colon, where they undergo bacterial fermentation by colonic flora, resulting in an acidification of the luminal contents. Because of this acidity, ammonia (NH3) is converted to ammonium (NH4+) which cannot be absorbed, thus trapping ammonia within the colon and resulting in excretion in feces.5,6 In addition, the hyperosmolar properties of lactulose and lactitol exert cathartic effects which reduce gastrointestinal transit time available for ammonia absorption.7 Other potential mechanisms that have been described include increasing total fecal nitrogen excretion due to increased stool mass8 and reducing the formation of toxic fatty acids and ammonia in the colon.9 However, the most commonly used NADs to treat and prevent HE have been reported to have variable efficacy in randomized-controlled trials (RCTs).

In a recent systematic review and meta-analysis of RCTs (2016), treatment with NADs compared to placebo or no intervention was associated with improvement in HE in ∼1/3 of patients (relative risk [RR]: 0.63, 95% confidence interval [CI]: 0.53-0.74, number needed to treat [NNT]: 4), and reduced mortality by half (RR: 0.49, 95% CI: 0.23-1.05, NNT: 100). These benefits were more pronounced in overt HE compared to minimal HE.10 Studies comparing lactulose to lactitol showed no differences in HE outcomes.11,12 Despite the consistent results showing benefit of NADs in reducing HE and its related mortality, these RCTs did not assess the confounding effect of factors precipitating HE since strategies directed at management of precipitating factors may improve HE with or without NADs. In addition, none of the prevention RCTs reported data on quality of life. Furthermore, the use of NADs was associated with increased risk of nonserious adverse events, such as bloating, diarrhea and nausea.10 These adverse events are likely to affect patient tolerability and compliance.13,14 In addition, the treatment effects on HE improvement (RR: 0.63) and mortality (RR: 0.49) from this meta-analysis indicate that a large proportion of patients with HE did improve despite treatment with NADs.10 Lactulose is Food and Drug Administration-approved and guideline-recommended (American Association for the Study of Liver Diseases [AASLD] 2014) for treatment and prevention of HE.

Oral antibiotics

Rifaximin is the most common oral antibiotic used to treat and prevent HE, usually as an adjunct therapy added to NADs. Because rifaximin is minimally absorbed, it is concentrated in the gastrointestinal tract, which in turn alters gut microbiota composition and function, affects bile acid levels and composition, and exerts anti-inflammatory action and alters neurotoxin levels, all of which are implicated in the pathogenesis of cirrhosis complications.15 The efficacy of rifaximin was evaluated in a meta-analysis of five RCTs comparing rifaximin and NADs for treatment of HE. In that study, rifaximin had similar efficacy to NADs but with better tolerability.16 A subsequent placebo-controlled RCT evaluated the efficacy of rifaximin in prevention of future episodes of HE among patients with history of HE who were in remission. Compared to placebo, rifaximin reduced the incidence of breakthrough HE and future hospitalization involving HE by more than half.17 In that trial, however, more than 90% of patients received concomitant lactulose. A subsequent trial compared the efficacy of rifaximin plus lactulose vs. lactulose alone in resolution of overt HE. The combination therapy was more effective in reversal of HE (76% vs. 50.8%, p<0.004) and resulted in significant reduction of mortality (23.8% vs. 49.1%, p<0.05) and length of hospital stay (5.8±3.4 vs. 8.2±4.6 days, p=0.001). A subsequent, more recent meta-analysis confirmed the benefit of rifaximin in treatment and prevention of HE in addition to its benefit on mortality reduction.18 The 2014 Practice Guideline by the AASLD and the European Association for the Study of the Liver (EASL) recommended the use of rifaximin as an add-on therapy to lactulose for prevention of HE recurrence.19

There are multiple problems with the trials assessing the use of rifaximin,20 such as confounding effects of transjugular intrahepatic portosystemic shunt (TIPS) and surgical portosystemic shunts,17 randomization imbalance,21,22 lack of benefit in high risk populations (such as in prevention of HE in those undergoing TIPS),23 and absence of objective HE scales in outcome assessment in some of the studies.17 Despite these limitations, rifaximin is believed to be the best agent for use in combination with lactulose to maintain remission in patients with recurrent HE.19 Other antibiotics have been studied in management of HE; such as neomycin, metronidazole and vancomycin.24–27 Their use is limited by inconsistent data and concerns regarding toxicity and adverse effects.19 Rifaximin is Food and Drug Administration-approved and guideline-recommended (AASLD 2014) for treatment and prevention of HE.

L-ornithine L-aspartate (LOLA)

Ammonia detoxification is achieved by two main pathways in periportal hepatocytes: 1) urea synthesis in zone 1 and 2) glutamine synthesis in zone 3.28 LOLA is a combination of endogenous amino acids that are metabolized in periportal and perivenous hepatocytes, where L-ornithine is utilized as a substrate in the urea cycle and acts as an activator of carbamoyl phosphate synthetase, the rate limiting enzyme of the urea cycle. Ammonia is also incorporated with glutamate to form glutamine catalyzed by glutamine synthase. The latter process also takes places in skeletal myocytes.28 Multiple RCTs have studied the efficacy of intravenous and oral LOLA compared to placebo for treatment of HE (such as lactulose). Meta-analyses of these trials showed consistent reductions in ammonia levels and clinical improvement of HE.29 Clinical trials assessing the efficacy of LOLA showed that it is at least comparable (sometimes superior) to other interventions (such as lactulose or oral antibiotics), in addition to being well-tolerated and associated with improvement in quality of life.29,30 Despite these benefits, the trials assessing the efficacy of LOLA suffer from several biases related to inadequate blinding, incomplete data, selective reporting, and pharmaceutical funding.31 In addition, there is no evidence to support the use of LOLA in patients with acute liver failure.32 LOLA is available and used routinely for management of HE in Europe. However, it is not available in the USA. Intravenous LOLA is not Food and Drug Administration-approved but is recommended by the guideline (AASLD 2014) as an alternative or additional agent for HE not responsive to conventional therapy.

Other therapies of HE

Mechanism of actions and critique of the evidence

Fecal microbiota transplantation (FMT)

It has been shown that the gut microbial profile of cirrhotic patients with HE is different from those without HE or normal controls. Although this difference in the gut microbiome is in part driven by standard of therapy used in treatment of cirrhosis and HE (such as oral antibiotics, NADs, and acid suppressants) which can affect the gut microbiome composition,33 cross-sectional data of stool metagenomics have revealed that certain metagenomic species are overexpressed or underexpressed in decompensated compared to compensated cirrhosis.33 Additionally, gut dysbiosis has been shown to predict poor outcomes in HE.34 Specifically, HE patients were found to have a lower prevalence of short-chain fatty acid (SCFA)-producing families, such as Lachnospiraceae and Ruminococcaceae, and increased prevalence of potentially pathogenic Enterobacteriaceae.34,35

Using this microbial profile, Bajaj and colleagues36 were able to obtain stool specimens from a single healthy donor with the highest relative abundance of Lachnospiraceae and Ruminococcaceae. Frozen-then-thawed FMT units prepared from the single donor were instilled by enema and retained for 30 m in patients with HE after a 5-day course of broad spectrum antibiotics (metronidazole, ciprofloxacin, and amoxicillin) aimed to decrease host bacterial burden and make the colonic environment more receptive to colonization from the donor microbiota. In this safety and open-label RCT involving 20 patients with cirrhosis and recurrent HE, who were randomized 1:1 to either FMT or standard-of-care (including lactulose and rifaximin), there was no serious adverse event associated with the use of FMT, including no bacterial infections. Additionally, the FMT was associated with a reduced number of hospitalizations due to liver-related complications, and there was a significant improvement in cognitive outcomes between baseline and post-treatment in the FMT group but none among those undergoing standard of care (SOC). This trial had several limitations, including a small sample size, confounding effect of pre-FMT antibiotics, control arm being SOC instead of placebo antibiotics or autologous FMT, and short-term follow up (up to 20 days). Additionally, there was no significant change in microbiome diversity, as assessed by 16S rRNA sequencing.36

In another phase 1, randomized, single-blind, placebo-controlled safety trial, Bajaj and colleagues37 studied the use of oral FMT capsules in patients with cirrhosis and recurrent HE. FMT capsules were prepared from the same healthy donor with the relative high abundance of Lachnospiraceae and Ruminococcaceae used in their previous enema trial, and were given at a dose of 15 capsules at one time. This trial was unique because all subjects underwent esophagogastroduodenoscopy and sigmoidoscopy for mucosal biopsies before and after FMT treatment. Twenty patients already on lactulose/rifaximin were enrolled (randomized 1:1 to either FMT capsules or placebo capsules); FMT appeared to be safe, well-tolerated and associated with enhanced microbial diversity, and to provide favorable changes in antimicrobial protein expression and intestinal inflammatory markers, along with improved performance on cognitive scores. Another, ongoing phase 2 RCT is underway to further investigate the safety and benefit of aggressive gut microbial manipulation using FMT oral capsules.38 At this time, FMT is not Food and Drug Administration-approved nor mentioned by the guidelines (AASLD 2014) yet as a treatment in HE.

Probiotics

A probiotic is conventionally defined as “a preparation of or a product containing viable, defined microorganisms in sufficient numbers, which alter the microflora (by implantation or colonization) in a compartment of the host and by that exert beneficial health effects in this host”.39,40 Although probiotics are often bacterial microorganisms, most commonly Lactobacillus or Bifidobacterium, yeasts are also used. Because of the variety of microorganisms in probiotics, various species or strains may confer a variety of health benefits, and disease-specific probiotics exist. In HE, as discussed above, it has been shown that the alteration of gut microbiome plays an important role in neurocognitive outcomes in patients with cirrhosis. Probiotics are hypothesized to benefit patients with HE through reduction of harmful, ammonia-producing bacteria, and decreasing ammonia absorption in the gut by affecting different aspects of the gastrointestinal environment (including enzymatic composition, epithelial permeability, acidic environment and nutritional status of the gut).41

Evidence supporting the use of probiotics in HE comes from a comprehensive Cochrane systematic review and meta-analysis of 21 trials published prior to June, 2016 involving 1,420 patients comparing a probiotic to either placebo (14 trials) or lactulose (7 trials). When probiotics were compared to placebo or no treatment, this review found no effect in all-cause mortality. However, there was moderate-quality evidence that probiotics improve recovery and may lead to improvements in overt HE, quality of life, and plasma ammonia concentrations. When antibiotics were compared to lactulose, the benefits were uncertain because of the very low-quality evidence. Importantly, no reports of septicemia related to the use of probiotics were found.41 The review highlighted several limitations in the included trials, including high risk of bias, outcome heterogeneity, and different types of probiotics used.41 In these studies, VSL#3 (containing four species of Lactobacilli, three of Bifidobacteria and Streptococcus thermophilus) was the most commonly used probiotic product in the clinical trials. Probiotics use in HE remains under study and multiple clinical trials assessing other strains are underway to investigate its benefits in patients with cirrhosis.42–45 At this time, probiotics are not Food and Drug Administration-approved nor guideline-recommended (AASLD 2014) for the treatment of HE, though they are mentioned as possible alternative therapy pending further study.

Albumin

Synthesized in the liver, albumin is known to decrease in patients with progressive liver disease and cirrhosis. Intravenous albumin administration has been shown in experimental studies to neutralize oxygen-reactive species, inhibit inflammatory mediators and reduce endothelial dysfunction and vasodilation in patients with liver cirrhosis, in addition to its oncotic, volume-expanding effect on the circulation46–48 in patients with cirrhosis. Albumin has been shown to improve response to diuretics, prevent circulatory dysfunction after large-volume paracentesis and to have a role in prevention and treatment of hepatorenal syndrome.49 The benefit of albumin administration in the prevention and treatment of HE was studied in few clinical trials with promising results.

A multicenter, double-blind small RCT involving 56 cirrhotic patients with acute HE who had been randomized to receive intravenous albumin (1.5 g/kg on day 1 and 1.0 g/kg on day 3) vs. isotonic saline, in addition to usual treatment (laxatives and oral antibiotics), showed that there was no significant differences in the percentage of patients with short-term resolution of HE (at day 4). However, there was a significant reduction in mortality at day 90 (69.2% vs. 40%, p=0.02).50 In 2017, Sharma and colleagues51 randomized 120 patients with overt HE to receive lactulose (30–60 mL three times a day; goal 2–3 semisoft stools per day) plus albumin (1.5 g/kg/day) or lactulose alone, and treatment was continued until recovery of HE or for a maximum of 10 days. The combination therapy resulted in more patients achieving complete recovery of HE by day 10, as assessed by West Haven scale (WHS) (75% vs. 53.3%, p=0.03), shorter hospital stay 6.4±3.4 vs. 8.6±4.3 days, p=0.01), lower mortality (18.3% vs. 31.6%, p=0.04), in addition to significant reductions in levels of IL-6, IL-18, TNF-alpha and endotoxins but not levels of arterial ammonia. There was no difference in side effects related to drug therapy. The main limitations of that study included the small sample size, open-label design, and absence of concomitant rifaximin use, which is known to reduce short-term mortality.

The value of long-term albumin administration was investigated in the ANSWER study, a multicenter, randomized, open-label trial that assigned 440 patients with cirrhosis and uncomplicated ascites resistant to diuretic therapy to receive either standard medical therapy or standard medical therapy plus albumin (40 g twice weekly for 2 weeks, and then 40 g weekly) for up to 18 months. Although HE assessment was not the main goal in that study, it was assessed as a secondary end point. At the study completion, 18-month survival was higher in the standard medical therapy plus albumin group (77% vs. 66%, p=0.028), and there was decreased incidence in grade 3–4 HE (odds ratio: 0.48, 95% CI: 0.37–0.63, p<0.001). In addition, albumin treatment decreased the future need for therapeutic paracentesis, renal dysfunction, hyponatremia, hyperkalemia, bacterial infections, hepato-renal syndrome, and hospital length of stay.52 Given the concerns regarding costs of albumin administration, cost-effective analysis in that study showed a favorable cost-effective ratio, likely attributed to better quality of life and fewer hospital admissions in the albumin group. Despite its impressive results, the study had several limitations, the main being its open-label design, which may have led to patients receiving albumin to be seen more frequently than patients in the other group. Additionally, although outcome assessors were from an independent non-profit consortium, they were not blinded to the treatment allocations and may have introduced bias. A more recent, single-center retrospective propensity-matched analysis involving 2,868 patients and meta-analysis of nine cohort and prospective trials showed that albumin administration was associated with reduced incidence and improvement of overt HE in addition to lowering in-hospital mortality.53

Another recent, randomized, multicenter, open-label trial was conducted in the UK and studied whether targeting an albumin serum level ≥30 g/L would reduce the risk of infections, renal dysfunction and death in patients with decompensated cirrhosis.54 In that study, 777 patients hospitalized with decompensated cirrhosis (∼20% of which admitted for HE) and serum albumin <30 g/L were randomized to receive daily infusions of 20% albumin for 14 days or until discharge (whichever comes first) vs. SOC; patients in the SOC group were allowed to receive albumin infusions when indicated (such as hepatorenal syndrome, peritonitis or large-volume paracentesis). At the conclusion of the trial, the primary end-point (new infection, kidney dysfunction, or death between days 3 and 15 after the initiation of treatment) did not differ significantly between the groups (adjusted odds ratio: 0.98; 95% CI 0.71–1.33). Furthermore, subgroup analysis of the primary outcome in those hospitalized for HE did not reveal significant benefit (adjusted OR 0.91; 95% CI 0.44–1.86). The study concluded that targeting albumin level ≥30 g/L is not beneficial compared to SOC in patients with decompensated cirrhosis, and called into question the utility of albumin in patients with decompensated cirrhosis; however, it was limited mainly by its open-label design and short-term follow up. Albumin is currently being evaluated in other ongoing trials.55–57 At this time, albumin is not Food and Drug Administration-approved nor guideline-recommended (AASLD 2014) for the treatment of HE, though it is mentioned as possible alternative therapy pending further study.

AST-120

AST-120 is a synthetic activated carbon microsphere that has a large surface area with a high nonspecific adsorptive capacity. AST-120 has limited gastrointestinal absorption, which adds to its ability to trap neurotoxins and hepatotoxins in the gut.58 The ability of AST-120 to reduce blood ammonia levels and reduce oxidative stress has been shown previously in rat models of cirrhosis58,59 and renal failure.60 AST-120 was studied in a phase-2, multicenter RCT that evaluated the efficacy and safety of AST-120 in the treatment of low-grade HE. The study included 41 patients who were randomized to receive either AST-120 (2 g sachets four-times per day) or lactulose (titrated to 2–3 soft stools per day) for 4 weeks. The primary end-point was defined as ≥1-point reduction in the WHS of HE over 4 weeks. Secondary endpoints were changes in the Hepatic Encephalopathy Scoring Algorithm (HESA), venous ammonia, and tolerability. At the study completion, the primary endpoint at week 4 was similar between treatment groups (38.1% vs. 35.0%, AST-120 vs. lactulose); secondary endpoints were also similar. However, diarrhea and flatulence occurred less frequently in the AST-120 group.61,62 One of the major limitations of this study was the low number of patients and the absence of a placebo arm, prompting a placebo-controlled “AST-120 Used to Treat Mild Hepatic Encephalopathy” (ASTUTE) clinical trial,63 a multicenter, double-blind RCT that randomized 148 patients with compensated cirrhosis to receive either dose-ranging oral AST-120 (2 or 4 g three times per day) vs. placebo.64 The primary endpoint was neurocognitive improvement defined as a change in the global summary score of Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) at 8 weeks compared to baseline; secondary endpoints included Psychometric HE-score (PHES), Clinical Global Assessment of HE (CGA-HE), and frequency of occurrences of overt HE and hospitalization. At study completion, there was no difference in RBANS scores between baseline and 8 weeks for all groups, and there were no differences in secondary endpoints. However, all groups had improvement in RBANS score between the time of screening and baseline visits (at 1 week), even before randomization. Thus, the study was strongly confounded by its design, allowing for improvement in neurocognitive scores prior to randomization. Interestingly, venous ammonia levels significantly improved in treatment groups (but not in placebo) independently of neurocognitive changes.63,64

At the time of this article preparation, there are no known ongoing clinical trials evaluating the use of AST-120 for the treatment of HE. AST-120 is currently being used and actively studied in treatment of progressive of chronic kidney disease.65 At this time, AST-120 is not Food and Drug Administration-approved nor guideline-recommended (AASLD 2014) for the treatment of HE.

Acetyl-L-carnitine

Carnitine is an essential nutrient that is important for fatty acid transfer across the inner mitochondrial membrane, especially in hepatocytes.66 The metabolism of carnitine has been shown to be impaired (and serum carnitine levels reduced) in patients with chronic liver diseases. Acetyl-L-carnitine is an ester of carnitine that is endogenously produced within mitochondria and peroxisomes in the liver, brain and kidney by the enzyme acetyl-L-carnitine transferase.67 The role of acetyl-L-carnitine in the treatment of HE is postulated to be related to reduction of serum ammonia by increasing ureagenesis67 in addition to enhancing the production of acetylcholine in the brain (by facilitating the uptake of acetyl-coenzyme A) and stimulating protein and phospholipid synthesis, all of which increase cellular energy production and reduce neuronal toxicity in patients with HE.66,67

Most of the data on the use of acetyl-L-carnitine comes from small RCTs; although, the individual RCTs suggested a benefit of acetyl-L-carnitine compared to placebo in improving neurological findings.68 Reduction of serum ammonia level and improvement in performance on neuropsychological testing,69 improvement in energy levels, general functioning and well-being, and reduction of anxiety and depression,70 reduction of physical and mental “fatigue”,71 and improvement of cognitive deficits and EEG findings71 in these studies were limited by small number of participants, high risk of bias, and low power for detection of meaningful differences between the treatment groups. A recent Cochrane systematic review and meta-analysis assessing these five RCTs that collectively randomized 398 participants to oral or intravenous acetyl-L-carnitine vs. placebo concluded the studies to be underpowered for the treatment effect, with a high risk of bias.72 Meta-analysis of these trials showed a reduction of blood ammonia among participants receiving acetyl-L-carnitine. However, the certainty of this finding was low due to limitations in study design and execution of the trials. Importantly, none of these trials assessed all-cause mortality and differences in serious adverse events. Adverse events of acetyl-L-carnitine were poorly reported, making the potential harms of acetyl-L-carnitine remain currently unknown.72 More highly powered and adequately designed clinical trials are needed to assess the efficacy and safety of acetyl-L-carnitine compared to placebo and current standard of therapy prior to the implementation of its widespread use. At this time, acetyl-L-carnitine is not Food and Drug Administration-approved nor guideline-recommended (AASLD 2014) for the treatment of HE.

Glycerol phenylbutyrate (GPB)

GPB is a nitrogen-binding agent consisting of three phenylbutyric acid (PBA) molecules joined to glycerol by an ester linkage. It is currently approved in the USA and Europe for use in urea cycle disorders in patients with chronic hyperammonemia who cannot be managed by dietary protein restriction and/or amino acid supplementation alone.73–76 Phenylacetic acid (PAA), the major metabolite of PBA, is conjugated with glutamine (which contains two molecules of nitrogen) by acetylation in the liver and kidneys to form phenylacetylglutamine (PAGN) which is easily excreted by the kidneys, providing an alternate vehicle for nitrogen waste excretion and reducing blood ammonia level.74,76,77 A pilot, open-label dose-ranging study involving 15 patients with cirrhosis and HE patients showed that oral GPB (6 mL) twice a day was tolerated and resulted in significant lowering of blood ammonia concentrations.78 This study was followed by a phase 2, randomized, double-blind trial enrolling 178 cirrhosis patients with history of recurrent HE who received either GPB (6 mL twice daily for 16 weeks) vs. placebo (1:1 randomization). Compared to placebo, GPB reduced the number of patients with HE events (21% vs. 36%, p=0.02), time to first event (hazard ratio [HR] = 0.56, p<0.05), total events (35 vs. 57, p=0.04), HE hospitalizations (13 vs. 25, p=0.06), and blood ammonia levels (p=0.04).79 There was no difference in serious adverse events between the two groups. The study was limited by small sample size, and more patients in the GPB group exited the study prematurely, which could result in a lower HE event rate in the treatment arm. However, the authors showed that the treatment effect remained in a time-to-event survival analysis performed to account for dropouts.79 Additionally, 59 patients (33%) were taking rifaximin at the time of randomization, likely indicating more refractory disease. However, the treatment benefit was sustained after controlling for rifaximin use. At this time, GPB is not Food and Drug Administration-approved nor guideline-recommended (AASLD 2014) for the treatment of HE, though it is mentioned as possible alternative therapy pending further study.

Flumazenil

Flumazenil is a competitive inhibitor at the benzodiazepine binding site on the gamma aminobutyric acid (GABA)-A receptor. It is most commonly used in benzodiazepine overdose and reversal of anesthesia.80 Several studies have shown that patients with HE have an up-regulation of GABA-A receptors and increased GABAergic tone.81,82 Because GABA is the main inhibitory neurotransmitter in the central nervous system, this upregulation of GABAergic neurons is postulated to be responsible, at least in part, for the neurocognitive manifestations of HE. A number of clinical trials assessed the effects of flumazenil in patients with HE. However, these trials were individually relatively small and included cross-over designs that limited the interpretability of clinically meaningful outcomes.83 A Cochrane systematic review and meta-analysis of 12 RCTs involving 842 patients comparing flumazenil vs. placebo reported that there was no effect of flumazenil on all-cause mortality. However, flumazenil was associated with an improvement of HE, and with no difference in serious adverse events. The main limitation of these studies was the short follow-up time which ranged from a few minutes to 2 weeks in these trials. However, follow up was less than 1 day in the majority of the studies, limiting any overreaching conclusions about the benefit of flumazenil on long-term cognitive outcomes.83 Other limitations include high risk of bias in the majority of the studies, and cross-over designs in individual studies limiting the ability to estimate the risk of HE relapse.83 Because of this limited duration of action and no effect on mortality, flumazenil is not routinely used for the treatment of HE until warranted by further trial data. At this time, flumazenil is not Food and Drug Administration-approved nor guideline-recommended (AASLD 2014) for the treatment of HE, though it is mentioned as possible therapy in select cases pending further study.

Polyethylene glycol

Polyethylene glycol 3350-electrolyte solution (PEG) is a cathartic agent postulated to improve outcomes in HE by reducing gastrointestinal transit time available for ammonia absorption. This cathartic effect is somewhat similar to that exerted by NADs due to their unabsorbed hyperosmolar characteristics. However, unlike lactulose and lactitol, PEG does not have the carbohydrate load that reduces stool pH and is not metabolized by colonic bacteria.84 Published in 2014, the HELP study (Hepatic Encephalopathy: Lactulose vs. Polyethylene Glycol 3350-Electrolyte Solution) was the first RCT to compare PEG (4-L dose) vs. lactulose in 50 patients with cirrhosis admitted for HE. PEG was found to be associated with a higher incidence of HE improvement assessed by improvement in HESA scores at 24 h (91% vs. 52%, p<0.01), and with a shorter median time to improvement in HE (1 vs. 2 days, p=0.01). There was no difference in serious adverse events, although the PEG group experienced more diarrhea and the lactulose group experienced more bloating.85 Ammonia levels in that study did not correlate with improvement in HE scores.

A more recent RCT similarly compared PEG with lactulose for treatment of overt HE in 100 patients with post-hepatitis C cirrhosis admitted for HE. At study completion, PEG was associated with a higher incidence of HE improvement on HESA scores compared to lactulose (94% vs. 72%), along with a reduced time needed for HE resolution and length of hospital stay, and no differences in serious adverse events.86 Combining lactulose with PEG might be helpful, which was assessed in a non-inferiority trial that randomized 40 patients with cirrhosis and HE to receive either lactulose alone (20–30 g orally or 200 g enema) or a similar dose of lactulose plus PEG (280 g in 4 L of water orally as a single dose in 30–120 m). Combination therapy (PEG plus lactulose) was more effective than lactulose alone in improving HESA scores at 24 h and was associated with reduced length of hospital stay and with no significant differences in blood ammonia levels or serious adverse events.87 The main limitations of these trials include the small sample size, being limited to single-center experiences, non-blinding of the studies, and absence of long-term outcomes. There are multiple ongoing trials assessing the benefit of PEG in HE.88,89 At this time, polyethylene glycol is not Food and Drug Administration-approved nor guideline-recommended (AASLD 2014) for the treatment of HE, though it is mentioned as possible alternative therapy pending further study.

Agents such as L-ornithine phenyl acetate, sodium benzoate, and zinc have been studied but lack sufficient evidence of efficacy to be recommended.90–92

Conclusions

The management of HE is complex and requires clinicians to be updated on the most recent advances in prevention and treatment. Older therapies (such as NADs and oral antibiotics) remain the first line of treatment according to current guidelines. However, multiple new agents have been developed and are being used for the treatment of HE. These agents are in various stages of research and some require further study prior to routine use in clinical practice. Because of several limitations in the existing literature, future research should focus on large-scale clinical trials with adequate design, sample size, elimination of biases, reporting of adverse events, and standardization of treatment outcomes.

Abbreviations

AASLD: 

American Association for the Study of Liver Diseases

CGA-HE: 

Clinical Global Assessment of Hepatic Encephalopathy

CI: 

confidence interval

EASL: 

European Association for the Study of the Liver

FMT: 

fecal microbiota transplantation

GABA: 

gamma aminobutyric acid

GPB: 

glycerol phenylbutyrate

HAS: 

hepatic encephalopathy scoring algorithm

HE: 

hepatic encephalopathy

HR: 

hazard ratio

LOLA: 

L-ornithine L-aspartate

NAD: 

non-absorbable disaccharides

NNT: 

number needed to treat

OR: 

odds ratio

PAA: 

phenylacetic acid

PBA: 

phenylbutyric acid

PEG: 

polyethylene glycol

PHES: 

Psychometric HE-score

RBANS: 

Repeatable Battery for the Assessment of Neuropsychological Status

RCT: 

randomized clinical trial

RR: 

relative risk

SCFA: 

short-chain fatty acid

SOC: 

standard of care

TIPS: 

transjugular intrahepatic portosystemic shunt

WHS: 

West Haven scale

Declarations

Acknowledgement

This work was made possible by the Herman Lopata Chair in Hepatitis Research.

Funding

None to declare.

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Proposal of concept for review and revision of the manuscript (GYW), and writing of the manuscript (LZH).

References

  1. Weissenborn K. Hepatic encephalopathy: definition, clinical grading and diagnostic principles. Drugs 2019;79:5-9 View Article
  2. Butterworth RF. Hepatic encephalopathy in cirrhosis: pathology and pathophysiology. Drugs 2019;79:17-21 View Article
  3. Jepsen P, Ott P, Andersen PK, Sørensen HT, Vilstrup H. Clinical course of alcoholic liver cirrhosis: a danish population-based cohort study. Hepatology 2010;51:1675-1682 View Article
  4. Yanny B, Winters A, Boutros S, Saab S. Hepatic encephalopathy challenges, burden, and diagnostic and therapeutic approach. Clin Liver Dis 2019;23(4):607-623 View Article
  5. Patil DH, Westaby D, Mahida YR, Palmer KR, Rees R, Clark ML, et al. Comparative modes of action of lactitol and lactulose in the treatment of hepatic encephalopathy. Gut 1987;28:255-259 View Article
  6. Clausen MR, Mortensen PB. Lactulose, disaccharides and colonic flora. Clinical consequences. Drugs 1997;53:930-942 View Article
  7. Hadjihambi A, Arias N, Sheikh M, Jalan R. Hepatic encephalopathy: a critical current review. Hepatol Int 2018;12:135-147 View Article
  8. Mortensen PB. The effect of oral-administered lactulose on colonic nitrogen metabolism and excretion. Hepatology 1992;16:1350-1356 View Article
  9. Mortensen PB, Holtug K, Bonnén H, Clausen MR. The degradation of amino acids, proteins, and blood to short-chain fatty acids in colon is prevented by lactulose. Gastroenterology 1990;98:353-360 View Article
  10. Gluud LL, Vilstrup H, Morgan MY. Nonabsorbable disaccharides for hepatic encephalopathy: a systematic review and meta-analysis. Hepatology 2016;64:908-922 View Article
  11. Cammà C, Fiorello F, Tinè F, Marchesini G, Fabbri A, Pagliaro L. Lactitol in treatment of chronic hepatic encephalopathy - a meta-analysis. Dig Dis Sci 1993;38:916-922 View Article
  12. Morgan MY, Hawley KE. Lactitol vs. lactulose in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double-blind, randomized trial. Hepatology 1987;7:1278-1284 View Article
  13. Hayward KL, Valery PC, Martin JH, Karmakar A, Patel PJ, Horsfall LU, et al. Medication beliefs predict medication adherence in ambulatory patients with decompensated cirrhosis. World J Gastroenterol 2017;23:7321-7331 View Article
  14. Hudson M, Schuchmann M. Long-term management of hepatic encephalopathy with lactulose and/or rifaximin: a review of the evidence. Eur J Gastroenterol Hepatol 2019;31:434-450 View Article
  15. Bajaj JS. Review article: potential mechanisms of action of rifaximin in the management of hepatic encephalopathy and other complications of cirrhosis. Aliment Pharmacol Ther 2016;43:11-26 View Article
  16. Jiang Q, Jiang XH, Zheng MH, Jiang LM, Chen YP, Wang L. Rifaximin versus nonabsorbable disaccharides in the management of hepatic encephalopathy: a meta-analysis. Eur J Gastroenterol Hepatol 2008;20:1064-70 View Article
  17. Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010;362:1071-1081 View Article
  18. Kimer N, Krag A, Møller S, Bendtsen F, Gluud LL. Systematic review with meta-analysis: the effects of rifaximin in hepatic encephalopathy. Aliment Pharmacol Ther 2014;40:123-132 View Article
  19. Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the european association for the study of the liver and the American association for the study of liver diseases. J Hepatol 2014;61:642-659 View Article
  20. Zullo A. Rifaximin therapy and hepatic encephalopathy: pros and cons. World J Gastrointest Pharmacol Ther 2012;3:62 View Article
  21. Sidhu SS, Goyal O, Mishra BP, Sood A, Chhina RS, Soni RK. Rifaximin improves psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (the RIME trial). Am J Gastroenterol 2011;106:307-316 View Article
  22. Zullo A, Hassan C, Lorenzetti R. Rifaximin therapy in minimal hepatic encephalopathy cirrhotics. Am J Gastroenterol 2011;106:2041 View Article
  23. Riggio O, Masini A, Efrati C, Nicolao F, Angeloni S, Salvatori FM, et al. Pharmacological prophylaxis of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled study. J Hepatol 2005;42:674-679 View Article
  24. Conn H, Leevy C, Vlahcevic Z, Rodgers J, Maddrey W, Seeff L LL. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. a double blind controlled trial. Gastroenterology 1977;72(4 Pt 1):573-583
  25. Strauss E, Tramote R, Silva E, Caly W, Honain N, Maffei R, et al. Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy. Hepatogastroenterology 1992;39:542-545
  26. Tarao K, Ikeda T, Hayashi K, Sakurai A, Okada T, Ito T, et al. Successful use of vancomycin hydrochloride in the treatment of lactulose resistant chronic hepatic encephalopathy. Gut 1990;31:702-706 View Article
  27. Morgan MH, Read AE, Speller DCE. Treatment of hepatic encephalopathy with metronidazole. Gut 1982;23:1-7 View Article
  28. Khungar V, Poordad F. Hepatic encephalopathy. Clin Liver Dis 2012;16:301-320 View Article
  29. Butterworth RF, McPhail MJW. l-Ornithine l-Aspartate (LOLA) for hepatic encephalopathy in cirrhosis: results of randomized controlled trials and meta-analyses. Drugs 2019;79:31-37 View Article
  30. Ong JP, Oehler G, Krüger-Jansen C, Lambert-Baumann J, Younossi ZM. Oral L-ornithine-L-aspartate improves health-related quality of life in cirrhotic patients with hepatic encephalopathy: an open-label, prospective, multicentre observational study. Clin Drug Investig 2011;31:213-220 View Article
  31. Goh ET, Stokes CS, Sidhu SS, Vilstrup H, Gluud LL, Morgan MY. L-ornithine L-aspartate for prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev 2018 View Article
  32. Acharya SK, Bhatia V, Sreenivas V, Khanal S, Panda SK. Efficacy of L-Ornithine L-Aspartate in acute liver failure: a double-blind, randomized, placebo-controlled study. Gastroenterology 2009;136:2159-2168 View Article
  33. Bajaj JS, Betrapally NS, Gillevet PM. Decompensated cirrhosis and microbiome interpretation. Nature 2015;525:E1-2 View Article
  34. Bajaj JS, Heuman DM, Hylemon PB, Sanyal AJ, White MB, Monteith P, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 2014;60:940-947 View Article
  35. Chen Y, Yang F, Lu H, Wang B, Chen Y, Lei D, et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011;54:562-572 View Article
  36. Bajaj JS, Kassam Z, Fagan A, Gavis EA, Liu E, Cox IJ, et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial. Hepatology 2017;66:1727-1738 View Article
  37. Bajaj JS, Salzman NH, Acharya C, Sterling RK, White MB, Gavis EA, et al. Fecal microbial transplant capsules are safe in hepatic encephalopathy: a phase 1, randomized, placebo-controlled trial. Hepatology 2019;70:1690-1703 View Article
  38. Fecal Microbiota Transplant as Treatment of Hepatic Encephalopathy - ClinicalTrials.gov n.d. Available from: https://clinicaltrials.gov/ct2/show/NCT03420482
  39. Schrezenmeir J, de Vrese M. Probiotics, prebiotics, and synbiotics—approaching a definition. Am J Clin Nutr 2001;73:361s-364s View Article
  40. Salminen S, Deighton M, Gorbach S. Lactic acid bacteria in health and disease. Lact Acid Bact 1993:199-225
  41. Dalal R, McGee RG, Riordan SM, Webster AC. Probiotics for people with hepatic encephalopathy. Cochrane Database Syst Rev 2017;2(2):CD008716 View Article
  42. Efficacy and Safety of E.Coli Nissle 1917 in Patients With Mild (Stage 1-2) or Minimal Hepatic Encephalopathy -ClinicalTrials.gov n.d. Available from: https://clinicaltrials.gov/ct2/show/NCT04787276?term=probiotic&cond=Hepatic+Encephalopathy&draw=2&rank=7
  43. Frailty in Patients With Cirrhosis: Prognostic Value of the Phase Angle in Hospitalized Patients and Effect of Multifactorial Intervention - ClinicalTrials.gov n.d. Available from: https://clinicaltrials.gov/ct2/show/NCT04243148?term=probiotic&cond=Cirrhosis&draw=2&rank=8
  44. Effect of Probiotics in Non-alcoholic Fatty Liver Disease and Steatohepatitis -ClinicalTrials.gov n.d. Available from: https://clinicaltrials.gov/ct2/show/NCT04175392?term=probiotic&cond=Cirrhosis&draw=3&rank=13
  45. Profermin®: Prevention of Progression in Alcoholic Liver Disease by Modulating Dysbiotic Microbiota - ClinicalTrials.gov n.d. Available from: https://clinicaltrials.gov/ct2/show/NCT03863730?term=probiotic&cond=Cirrhosis&draw=3&rank=19
  46. Bortoluzzi A, Ceolotto G, Gola E, Sticca A, Bova S, Morando F, et al. Positive cardiac inotropic effect of albumin infusion in rodents with cirrhosis and ascites: molecular mechanisms. Hepatology 2013;57:266-276 View Article
  47. Artigas A, Wernerman J, Arroyo V, Vincent JL, Levy M. Role of albumin in diseases associated with severe systemic inflammation: Pathophysiologic and clinical evidence in sepsis and in decompensated cirrhosis. J Crit Care 2016;33:62-70 View Article
  48. Bernardi M, Angeli P, Claria J, Moreau R, Gines P, Jalan R, et al. Albumin in decompensated cirrhosis: new concepts and perspectives. Gut 2020;69:1127-1138 View Article
  49. Wong F. Drug insight: the role of albumin in the management of chronic liver disease. Nat Clin Pract Gastroenterol Hepatol 2007;4:43-51 View Article
  50. Simón-Talero M, García-Martínez R, Torrens M, Augustin S, Gómez S, Pereira G, et al. Effects of intravenous albumin in patients with cirrhosis and episodic hepatic encephalopathy: a randomized double-blind study. J Hepatol 2013;59:1184-1192 View Article
  51. Sharma BC, Singh J, Srivastava S, Sangam A, Mantri AK, Trehanpati N, et al. Randomized controlled trial comparing lactulose plus albumin versus lactulose alone for treatment of hepatic encephalopathy. J Gastroenterol Hepatol 2017;32:1234-1239 View Article
  52. Caraceni P, Riggio O, Angeli P, Alessandria C, Neri S, Foschi FG, et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial. Lancet 2018;391:2417-2429 View Article
  53. Bai Z, Bernardi M, Yoshida EM, Li H, Guo X, Méndez-Sánchez N, et al. Albumin infusion may decrease the incidence and severity of overt hepatic encephalopathy in liver cirrhosis. Aging (Albany NY) 2019;11:8502-8525 View Article
  54. China L, Freemantle N, Forrest E, Kallis Y, Ryder SD, Wright G, et al. A randomized trial of albumin infusions in hospitalized patients with cirrhosis. N Engl J Med 2021;384:808-817 View Article
  55. HEAL STUDY (Hepatic Encephalopathy and Albumin Study) - ClinicalTrials.gov n.d. Available from: https://clinicaltrials.gov/ct2/show/NCT03585257?term=albumin&cond=Hepatic+Encephalopathy&draw=2&rank=2
  56. Albumin Infusion Effects in Mortality in Patients With Cirrhosis and Hepatic Encephalopathy - ClinicalTrials.gov n.d. Available from: https://clinicaltrials.gov/ct2/show/NCT02401490?term=albumin&cond=Hepatic+Encephalopathy&draw=2&rank=4
  57. Search of: albumin | Cirrhosis - ClinicalTrials.gov n.d. Available from: https://clinicaltrials.gov/ct2/results?cond=Cirrhosis&term=albumin&cntry=&state=&city=&dist=&Search=Search
  58. Bosoi CR, Parent-Robitaille C, Anderson K, Tremblay M, Rose CF. AST-120 (spherical carbon adsorbent) lowers ammonia levels and attenuates brain edema in bile duct-ligated rats. Hepatology 2011;53:1995-2002 View Article
  59. Hiraishi M. The effect of oral adsorbent on surgically induced hepatic failure. Jpn J Surg 1987;17:517-527 View Article
  60. Owada S, Maeba T, Sugano Y, Hirayama A, Ueda A, Nagase S, et al. Spherical carbon adsorbent (AST-120) protects deterioration of renal function in chronic kidney disease rats through inhibition of reactive oxygen species production from mitochondria and reduction of serum lipid peroxidation. Nephron - Exp Nephrol 2010;115(4):e101-e111 View Article
  61. Pockros P, Hassanein T, Vierling J, Heuman D, Hillebrand D, Chojkier M. Phase 2, multicenter, randomized study of AST-120 (spherical carbon adsorbent) vs. Lactulose in the treatment of low-grade hepatic encephalopathy (HE). J Hepatol 2009;50(Suppl 1):S43 View Article
  62. Safety and Efficacy of AST-120 Compared to Lactulose in Patients With Hepatic Encephalopathy - Full Text View - ClinicalTrials.gov n.d. Available from: https://clinicaltrials.gov/ct2/show/NCT00558038
  63. AST-120 Used to Treat Mild Hepatic Encephalopathy - ClinicalTrials.gov n.d. Available from: https://clinicaltrials.gov/ct2/show/NCT00867698
  64. Bajaj JS, Sheikh MY, Chojkier M, Balart L, Sherker AH, Vemuru R, et al. ST-120 (spherical carbon adsorbent) in covert hepatic encephalopathy: results of the Astute trial. J Hepatol 2013;58(5):S84 View Article
  65. Asai M, Kumakura S, Kikuchi M. Review of the efficacy of AST-120 (KREMEZIN®) on renal function in chronic kidney disease patients. Ren Fail 2019;41:47-56 View Article
  66. Malaguarnera M. Carnitine derivatives: clinical usefulness. Curr Opin Gastroenterol 2012;28:166-176 View Article
  67. Malaguarnera M. Acetyl-L-carnitine in hepatic encephalopathy. Metab Brain Dis 2013;28(2):193-199 View Article
  68. Malaguarnera M, Pistone G, Astuto M, Vecchio I, Raffaele R, Lo Giudice E, et al. Effects of L-Acetylcarnitine on cirrhotic patients with hepatic coma: Randomized double-blind, placebo-controlled trial. Dig Dis Sci 2006;51:2242-2247 View Article
  69. Malaguarnera M, Gargante MP, Cristaldi E, Vacante M, Risino C, Cammalleri L, et al. Acetyl-L-carnitine treatment in minimal hepatic encephalopathy. Dig Dis Sci 2008;53:3018-3025 View Article
  70. Malaguarnera M, Bella R, Vacante M, Giordano M, Malaguarnera G, Gargante MP, et al. Acetyl-l-carnitine reduces depression and improves quality of life in patients with minimal hepatic encephalopathy. Scand J Gastroenterol 2011;46:750-759 View Article
  71. Malaguarnera M, Vacante M, Giordano M, Pennisi G, Bella R, Rampello L, et al. Oral acetyl-L-carnitine therapy reduces fatigue in overt hepatic encephalopathy: a randomized, double-blind, placebo-controlled study. Am J Clin Nutr 2011;93:799-808 View Article
  72. Martí-Carvajal AJ, Gluud C, Arevalo-Rodriguez I, Martí-Amarista CE. Acetyl-L-carnitine for patients with hepatic encephalopathy. Cochrane Database Syst Rev 2019;1(1):CD011451 View Article
  73. Lee B, Rhead W, Diaz GA, Scharschmidt BF, Mian A, Shchelochkov O, et al. Phase 2 comparison of a novel ammonia scavenging agent with sodium phenylbutyrate in patients with urea cycle disorders: safety, pharmacokinetics and ammonia control. Mol Genet Metab 2010;100:221-228 View Article
  74. Diaz GA, Krivitzky LS, Mokhtarani M, Rhead W, Bartley J, Feigenbaum A, et al. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology 2013;57:2171-2179 View Article
  75. Lichter-Konecki U, Diaz GA, Merritt JL, Feigenbaum A, Jomphe C, Marier JF, et al. Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate. Mol Genet Metab 2011;103:323-329 View Article
  76. Hyperion Therapeutics. Ravicti (glycerol phenylbutyrate). U.S. Food and Drug Administration website. n.d. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203284s000lbl.pdf
  77. Monteleone JPR, Mokhtarani M, Diaz GA, Rhead W, Lichter-Konecki U, Berry SA, et al. Population pharmacokinetic modeling and dosing simulations of nitrogen-scavenging compounds: disposition of glycerol phenylbutyrate and sodium phenylbutyrate in adult and pediatric patients with urea cycle disorders. J Clin Pharmacol 2013;53:699-710 View Article
  78. Ghabril M, Zupanets IA, Vierling J, Mantry P, Rockey D, Wolf D, et al. Glycerol phenylbutyrate in patients with cirrhosis and episodic hepatic encephalopathy: a pilot study of safety and effect on venous ammonia concentration. Clin Pharmacol Drug Dev 2013;2:278-284 View Article
  79. Rockey DC, Vierling JM, Mantry P, Ghabril M, Brown RS, Alexeeva O, et al. Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy. Hepatology 2014;59:1073-1083 View Article
  80. Aein R, Leishman B, Bentzinger C, Roncari G. Flumazenil in benzodiazepine antagonism: actions and clinical use in intoxications and anaesthesiology. Med Toxicol Adverse Drug Exp 1987;2:411-429 View Article
  81. Bakti G, Fisch HU, Karlaganis G, Minder C, Bircher J. Mechanism of the excessive sedative response of cirrhotics to benzodiazepines: model experiments with triazolam. Hepatology 1987;7:629-638 View Article
  82. Ahboucha S, Butterworth RF. The neurosteroid system: implication in the pathophysiology of hepatic encephalopathy. Neurochem Int 2008;52:575-587 View Article
  83. Goh ET, Andersen ML, Morgan MY, Gluud LL. Flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy. Cochrane Database Syst Rev 2017;8(8):CD002798 View Article
  84. Hammer HF, Santa Ana CA, Schiller LR, Fordtran JS. Studies of osmotic diarrhea induced in normal subjects by ingestion of polyethylene glycol and lactulose. J Clin Invest 1989;84:1056-1062 View Article
  85. Rahimi RS, Singal AG, Cuthbert JA, Rockey DC. Lactulose vs polyethylene glycol 3350-electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial. JAMA Intern Med 2014;174:1727-1733 View Article
  86. Shehata HH, Elfert AA, Abdin AA, Soliman SM, Elkhouly RA, Hawash NI, et al. Randomized controlled trial of polyethylene glycol versus lactulose for the treatment of overt hepatic encephalopathy. Eur J Gastroenterol Hepatol 2018;30:1476-1481 View Article
  87. Naderian M, Akbari H, Saeedi M, Sohrabpour AA. Olyethylene glycol and lactulose versus lactulose alone in the treatment of hepatic encephalopathy in patients with cirrhosis: a non-inferiority randomized controlled trial. Middle East J Dig Dis 2017;9:12-19 View Article
  88. Polyethylene Glycol Versus Lactulose on Hepatic Encephalopathy in Patients With Cirrhosis;(PEGHE Trial) - ClinicalTrials.gov n.d. Available from: https://clinicaltrials.gov/ct2/show/NCT04436601?term=polyethylene+glycol&cond=Hepatic+Encephalopathy&draw=2&rank=1
  89. PEG3350 in ACLF With Hepatic Encephalopathy - ClinicalTrials.gov n.d. Available from: https://clinicaltrials.gov/ct2/show/NCT03987893?term=polyethylene+glycol&cond=Hepatic+Encephalopathy&draw=1&rank=6
  90. Rahimi RS, Safadi R, Thabut D, Bhamidimarri KR, Pyrsopoulos N, Potthoff A, et al. Efficacy and safety of ornithine phenylacetate for treating overt hepatic encephalopathy in a randomized trial. Clin Gastroenterol Hepatol 2020;S1542-3565(20):31432-31434 View Article
  91. Misel ML, Gish RG, Patton H, Mendler M. Sodium benzoate for treatment of hepatic encephalopathy. Gastroenterol Hepatol (N Y) 2013;9(4):219-227
  92. Chavez-Tapia NC, Cesar-Arce A, Barrientos-Gutiérrez T, Villegas-López FA, Méndez-Sanchez N, Uribe M. A systematic review and meta-analysis of the use of oral zinc in the treatment of hepatic encephalopathy. Nutr J 2013;12:74 View Article
Copyright © 2021 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

Article Options

Metrics

Cite this Article

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 2748319
  • Visits today : 2022
Back to Top

Novel Agents in the Management of Hepatic Encephalopathy: A Review

Leen Z. Hasan, George Y. Wu
  • Reset Zoom
  • Download TIFF