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. Author manuscript; available in PMC: 2025 May 1.
Published in final edited form as: Clin Liver Dis. 2024 May;28(2):331–344. doi: 10.1016/j.cld.2024.02.002

Future Therapies of Hepatic Encephalopathy

Adam P Buckholz 1, Robert S Brown Jr 2,*
PMCID: PMC10987054  NIHMSID: NIHMS1966663  PMID: 38548443

Introduction

Hepatic Encephalopathy (HE) is a spectrum of neuropsychiatric disturbances that is a common and highly morbid complication of chronic liver disease. It confers significant reduction in health-related quality of life1 and is associated with increased mortality overall.2 Additionally, while classically thought to be reversible, emerging evidence suggests that HE has lasting effects on cognition and wellbeing even after correction of an acute episode.

The classification and varying presentation of HE is beyond the scope of this review; however, it should be noted that HE can arise from various diseases including acute and chronic liver disease and portosystemic shunting. Likewise, HE can be episodic or persistent and exist in a spectrum of severity from subtle changes (termed covert encephalopathy) to coma (overt encephalopathy), graded according to the West Haven Criteria.3 HE is most commonly seen in chronic liver disease, where up to 40% will eventually develop overt disease and the prevalence of covert HE is >50%.4 A significant portion of HE is precipitated by an acute destabilizing event, especially in those with cirrhosis; such events include infection, bleed, electrolyte abnormality, constipation, renal failure, sedating medication or treatment non-adherence.

HE is now felt to have persistent cognitive damage, potentially due to astrocyte senescence, with research demonstrating that those with HE have worse 1- and 5-year outcomes even after transplant.5 Early detection and appropriate therapy is therefore crucial, but treatment options remain limited for clinicians. This review will briefly discuss the few approved options, before expanding on emerging therapeutics and how they relate to HE pathophysiology.

The pathophysiology of HE is complex and incompletely understood, but the broad overview offered here contextualizes current and proposed therapeutics for HE. Ammonia has long been understood to be a critically important neurotoxic agent in the development of HE.6 A common inorganic nitrogenous waste, it is produced both by human tissue such as muscle and intestine, and especially by urease expressing bacteria in the gut.7 Reduced hepatic metabolism and shunting due to portal hypertension lead to drastically increased systemic exposure to ammonia. This ammonia crosses the blood brain border where it is metabolized by combination with glutamate to glutamine in astrocytes8 creating an osmotic gradient with subsequent astrocyte swelling and neuroinflammation.9 Ammonia and other toxins also potentiate neuroinhibitory cascades and have direct neurotoxic effect on synaptic transmission.10,11 In cirrhosis, progressive frailty and reduced muscle mass also deprives patients of an alternative route for ammonia detoxification, and reduced branch chain amino acids in cirrhosis reduce capacity for peripheral glutamine synthesis from ammonia.12 In addition, systemic inflammation and oxidative stress present in cirrhosis are recognized as significant factors in the pathogenesis of HE. This review will focus on current and emerging treatment options for HE, with a focus on how disease pathophysiology is being addressed by experimental therapeutics (Figure 1).

Figure 1.

Figure 1.

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Nitrogen metabolism in the form of ammonia is a multiorgan process, and increased ammonia exposure in the brain in the setting of cirrhosis and portal hypertension is a major factor in the development of HE. This simplified schematic demonstrates how many experimental therapeutics favor reduced cerebral hyperammonemia and may help treat hepatic encephalopathy.

Current Therapeutics

The nonabsorbable disaccharides lactulose and lactitol have long formed the backbone of HE management.13 They are metabolized into a short-chain acidic form by gut bacteria, and exert their protective effects in multiple ways. First, they increase osmolality of colonic contents, with a laxative effect which decreases colonic transit time and reduces burden of ammonia-genic bacteria. Additionally, they reduce the pH of the colonic lumen, promoting conversion of ammonia into the non-absorbed positively charged ammonium state. The lowering of colonic pH also helps to reduce proliferation of pathogenic bacteria. Usage is most often limited by side effects including flatulence, abdominal bloating and diarrhea; non-adherence to lactulose is a key factor in recurrent HE.14

The non-absorbable antibiotic rifaximin inhibits bacterial RNA synthesis15 and likely has multimodal action in HE improvement. It selectively modulates ammonia production by acting on pathogenic colonic bacteria to reduce efficacy of the ribonucleic acid polymerase without altering microbiome diversity.16 It also may help improve gut barrier function, reducing endotoxemia and systemic inflammation.17 A poorly absorbed antibiotic, it has fewer systemic side effects than other antibiotics which have been previously used in HE, making it a useful agent, especially in recurrent HE.18 However, its high cost sometimes limits availability.

Finally, standard of care management in acute HE entails identifying and correcting underlying exogenous factors such as infection, bleeding, or electrolyte imbalance. Identifying and correcting such factors may result in up to 90% resolution rate in an acute episode.19 Similarly, patients with large portosystemic shunts (either spontaneous20 or surgical21) may benefit from modification, closure or obliteration.

Discussion on Emerging and Experimental Therapeutics

Albumin

Albumin has established utility in the management of renal insufficiency, overdiuresis, and infection in cirrhosis, all of which can be precipitants of hepatic encephalopathy. However, because of its known anti-inflammatory properties, as well as studies suggesting that albumin may lower serum ammonia, colloid therapy with albumin has been investigated as a possible treatment or prevention tool in HE. The RELIEF trial demonstrated no improvement in overall outcomes with albumin dialysis, but a trend towards improved HE.22 When added to lactulose, treatment with albumin improved serum ammonia, inflammatory markers and proportion of patients with complete HE reversal in a small randomized study by Sharma et al.23 While another study by Simon et al failed to find a clear benefit,24 a meta-analysis of 12 pooled studies suggested that albumin was associated with decreased risk of HE both among those without prior HE (OR 0.53 95% CI 0.32,0.86) or prior HE (OR 0.43, 95% CI 0.27,0.68).25 Finally, a recent randomized double blind placebo controlled study of weekly infusions albumin in outpatients with a history of HE showed reduced cognitive impairment and inflammatory markers with albumin treatment.26 Despite this, well controlled studies are lacking at this time, especially to help adjudicate whether the benefit in HE is in fact simply by reversing predisposing factors.

Urea Cycle Modulators

In liver failure and with shunting of portal flow into systemic circulation, the hepatic urea cycle is underutilized. The urea cycle converts ammonia to urea, primarily in the liver, for excretion in the kidneys and is the primary source of ammonia disposal in the healthy state.27 The reduced utilization of the urea cycle due to hepatic dysfunction and portosystemic shunting results in higher levels of systemic ammonia exposure.

L-ornithine and L-aspartate (LOLA) has been proposed as a method to augment the urea cycle. A mixture of two amino acids, LOLA stimulates urea synthesis in periportal hepatocytes and glutamine synthesis in skeletal muscle. A randomized blinded study of 193 patients with acute OHE suggested that LOLA reduced recovery time (1.92 vs 2.50 days, p=0.002) and ammonia levels relative to lactulose and ceftriaxone.28 In one large Cochrane review and meta-analysis of 36 clinical trials with 2377 participants, LOLA was associated with reduced mortality (RR 0.42 95% CI 0.24,0.72) but this beneficial effect was not statistically significant when excluding trials with a high risk of bias.29 This meta-analysis, did, however find that LOLA appeared safe relative to standard of care management. The authors concluded that while it appears LOLA may have a mortality benefit and improve outcomes, higher quality randomized data is needed prior to supporting its use, and it remains unavailable in the United States.

Zinc is an important cofactor in the urea cycle, zinc metabolism impairment and subsequent deficiency is common in cirrhosis.30 For this reason and its widespread availability and low expense, supplementation has long been of interest in the management of HE. Unfortunately, small trials such as a crossover study of 15 participants31 and a subsequent meta-analysis have failed to find clear clinical benefit.32 For this reason, it’s not currently considered useful in HE management.

Urinary Ammonia Excretion

The kidneys have net positive ammonia production, with regulation of ammonia excretion a key factor in acid-base homeostasis.33 In settings of increased acidemia or high ammonia load, healthy kidneys can rapidly upregulate ammonia excretion,34 and this method of non-urea urinary ammonia excretion takes outsized importance in chronic liver disease. In conditions of hypokalemia and acidosis in chronic liver disease, the kidney also uses glutamine preferentially for potassium recovery in the renal tubules and proton disposal, respectively.35

Ornithine phenylacetate is a proposed ammonia scavenger that increases urinary excretion of glutamine in the form of phenylacetylglutamine, preventing it from being utilized by the kidneys for formation of new ammonia.36 While preliminary data suggested that ornithine was effective in lowering serum ammonia,37 a recent randomized trial failed to demonstrate a statistically significant improvement in time to clinical response, meaning further studies are needed prior to clinical utilization.38

Glycerol phenylbutyrate acts similarly to ornithine phenylacetate, by trapping glutamine for urinary excretion. Already used in genetic urea cycle disorders, it’s been shown to reduce serum ammonia levels in small studies.39 A double-blinded randomized controlled trial of 178 patients with cirrhosis found a reduction in proportion of first time HE events (21 vs 36%, p=0.02) and total events (35 vs 57, p=0.04). As a phase II trial, it was somewhat underpowered but represents promise if studied further.40

Antibiotics

Nitazoxanide is an antiprotozoal agent FDA approved for management of diarrheal illnesses. A small head-to-head study comparing twice daily nitazoxanide with twice daily rifaximin demonstrated prolonged remission (137 vs 67 days on average, p<0.01).41 Despite the promising results, this study conducted in Egypt must be followed by larger controlled studies, with one study currently recruiting (NCT04161053).

Rifaximin soluble solid dispersion (SSD) tablets are a novel preparation to improve delivery and pharmoacokinetics of rifaximin therapy. Because of reduced bile acid concentrations in cirrhosis, the largely water-insoluble standard rifaximin formulation may have reduced efficacy compared to a water-soluble formulation (SSD).42 A recent phase II study of rifaximin SSD in various formulations did not meet its primary endpoint relative to placebo for increased time to hospitalization or all-cause mortality, but in a second trial an immediate release formulation reduced time to OHE recovery.43 A phase III study is currently planned (NCT05071716).

Microbiome Modulation with ‘Biotics (Pre-, Pro- and Post-)

Endotoxemia and systemic inflammation are integral to development and progression of HE. It is increasingly clear that altered microbiome in those with worsening liver disease contributes to a pro-inflammatory state.44 It is widely accepted that the gut microbiome is altered in those with cirrhosis. Subsequent gut translocation potentiates systemic inflammation and is also felt to be a driver of HE development.45 A lower intestinal pH is unfavorable to the survival of several bacteria known to produce urease, thus increasing ammonia production, including Klebsiella and Proteus.

Severity of dysbiosis is directly related to severity of liver dysfunction.46 For this reason, further refinement of microbiome targeted therapies is a key development opportunity for HE management (Figure 2). Such therapies could either target reduced inflammation or reduced ammonia load produced by gut bacteria by modulation of relative gut microbial composition. A key study previously demonstrated that reduction of relative Escherichia coli and Staphylococcal populations in favor of non-urease producing Lactobacillus using probiotics and a prebiotic improved systemic inflammation and CHE symptoms.47

Figure 2.

Figure 2.

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Progressive dysbiosis and gut membrane dysfunction is now clearly recognized in the pathophysiology of HE. Several experimental therapies in HE address either gut microbial composition or the gut metabolic environment to favor reduced systemic ammonia absorption and gut induced inflammation.

Prebiotics are non-digestible food products intended to favorably stimulate fermentation and growth of beneficial microorganisms. Lactulose itself is a pre-biotic, and its ability to safely modulate ammonia production in the gut has been attractive for HE research. One prebiotic, Gelsectan, is derived of mucosal protective agents such as xyloglucan with polysaccharides that are thought to promote commensal bacteria, and may increase mucosal integrity.48 It has demonstrated some promise in irritable bowel syndrome and a clinical trial has been registered to evaluate it in HE (NCT05189834).

Probiotics, which are live micro-organisms generally ingested, are a commonly used way to manipulate the microbial composition of the gut. Several strains have been noted in controlled studies to reduce ammonia levels and incidence of overt disease in those with HE. Lactobacillus supplementation, specifically, has been repeatedly demonstrated to be effective at reducing ammonia levels and improving cognitive function, either as an isolated strain or in combination with other bacterial formulations such as in the VSL #3/Visbiome (VSL Pharmaceuticals, Inc./ExeGI Pharma). In one unblinded randomized study, use of VSL #3 reduced the incidence of overt HE episodes in those with cirrhosis.49 Similar results have been found in other studies and using different strains.

Research thus far has been relatively limited, and a legal dispute between the developer of VSL #3 and the subsequent ownership over a unilateral change in strain composition speaks to the somewhat ephemeral and variable nature of the various brands and strains. A Cochrane review published in 2017 asserted that while probiotics (either in combination with or instead of lactulose) may improve recovery and prevent disease progression, there is no clear impact on mortality.50 Additionally, extant research in this field was felt to be possibly affected by bias and random error. Another limitation to the current use of probiotics is that the exact target population is unclear. In one small study, VSL #3 was found to have more profound protective inflammatory changes in patients with alcohol or metabolic liver disease than in those with cirrhosis due to hepatitis C.51 There also may be resistance to long term colonization and durable uptake of strains not already adapted to the gut environment, limiting use.52

One additional limitation of probiotic therapy is that it does not change the host environment (metabolites, gut milieu) that perpetuates dysbiosis in those with cirrhosis. For example, bile acids are an important modulator of the gut microbiome and have decreased concentration in those with advanced liver disease.53 Potentially by influencing primary and secondary bile acid concentration in the gut, indirect influence on microbial populations could lead to reduced inflammatory markers and improved outcomes in HE.54

Other such microbial derived metabolites, often called “postbiotics” may eventually have clinical utility either independent of or in combination with classical HE treatment options. These include tryptophan derivatives, short chain fatty acids, and choline compounds.55

Microbial-based therapy is not only confined to the hindgut, as periodontal treatment has been demonstrated to reduce salivary dysbiosis and improve cognition in those with HE by decreasing endotoxemia and salivary inflammation.56

One future avenue for probiotic therapy in HE is the use of engineered bacteria, potentially to consume a toxic metabolite such as ammonia, converting it to a non-toxic biproduct such as L-arginine.57 However, the first in-human randomized trial failed to show effective lowering of serum ammonia, making any clinical application some distance away.58

Stool Derived Therapies

Fecal microbiota transplant has been demonstrated to improve outcomes in other conditions of significant gut dysbiosis such as recurrent Clostridium difficile infection.7 FMT involves the transfer of a complete community of gut microorganisms from a donor, with significantly increased diversity over the limited number of strains in a probiotic. This potentially leads to a more comprehensive restoration of gut microbial balance. They also incorporate enzymes and metabolites from the donor stool, above and beyond the transplanted organisms, which may also affect the urea/ammonia cycle. In a seminal study of those with recurrent HE, FMT using a donor specifically selected for high levels of short chain fatty acid producing bacteria such as Lachnospiraceae resulted in improved cognition and reduced hospitalization at 30 days.59 Interestingly, follow up in the same group of patients suggested that the population of Lachnospiraceae returned to pre-FMT levels, but cognition remained better in the FMT group and HE hospitalizations remained lower.60 One limitation to FMT therapy at this juncture is that donor stool characteristics have been shown to influence outcomes, making standardization difficult.61 Future research will need to better elucidate the appropriate donor profile, as well as the recipients most likely to benefit. An FMT study by Bloom et al in HE demonstrated that the relative concentration of short chain fatty acid producing bacteria in donor stool influenced recipient outcome.62 Finally, the promise of FMT must be balanced with the understood risk of inducing an infection, potentially with a drug resistant organism, in patients with known immune dysfunction.63

This risk of infection and the variability of donor profiles may limit broad uptake of FMT in clinical practice. One ongoing clinical trial (NCT04899115) is evaluating the use of VE303, a group of 5 strains of commensal, non-pathogenic Clostridia species. These strains are derived from donor stool and manufactured from clonal cell banks to increase standardization and reduce risk of resistant strain infection.64 A phase II study in VE303 recently demonstrated efficacy in prevention of recurrent C. difficile.65

Similarly, RBX7455 is a standardized donor-derived live therapeutic bacterial product which has been lyophilized (“freeze dried”) after being obtained in large aliquots from a single donor and tested for viable bacterial content. It has the added benefit of room temperature stability for storage and being available in a pH resistant capsule. Early studies have been promising in C. difficile infection,66 with an early-stage trial enrolling for HE (NCT04155099).

Gut Adsorbants

AST-120 and Yaq-001 are synthetic carbon-based ingestible microspheres which have been developed to adsorb gut toxins such as ammonia and, because they are not absorbed systemically, reduce systemic ammonia levels and inflammation. While promising data was found in rat models67, the largest randomized study of AST-120 found no clinical benefit.68 A clinical trial of Yaq-001 was terminated due to COVID-19,69 suggesting it will be some time before this potential therapeutic is ready for routine use in HE.

Neurotransmitter modulation

The influx of toxins, especially ammonia, through the blood brain barrier leads to increased neuroinflammation mediated by reactive oxidative species, a critical step in the development of HE. For this reason, modulation at the level of the brain is an attractive target for treatment. Neuroinflammation leads to neurosteroid induced potentiation of the GABA-A system, which is neuroinhibitory and has negative effects on memory, cognition, vigilance and sleep.70 A recently developed GABA-A receptor antagonist, golexanolone (GR3027) is under investigation for possible cognitive benefits in HE. In a small randomized trial of 45 patients with cirrhosis, golexanolone improved vigilance and some cognitive markets, although further studies will be needed to evaluate its possible use to improve outcomes.71

L-carnitine crosses the blood brain barrier, where it facilitates mitochondrial uptake of acetyl Co-A and stimulates phospholipid synthesis while serving as substrate for cerebral energy production.72 It also has been postulated to be protective against neuroinflammation by reducing free radical production.73 In a small randomized double blinded placebo controlled trial, L-carnitine supplementation improved quality of life and reduced serum ammonia concentration.74 Unfortunately, a subsequent Cochrane systematic review found that all 5 trials with 398 patients evaluating L-carnitine use were conducted by the same research group with high potential for bias, with no clear clinical benefit.75 No clinical trials appear to be currently recruiting.

Flumazenil is a synthetic benzodiazepine antagonist hypothesized to have utility in HE through its modulation of inhibitory GABA-A complex receptors, given the posited increased GABAnergic “tone” in those with HE as a result of ammonia and manganese upregulation.76 In a randomized, double-blinded placebo-controlled trial of flumazenil vs placebo in patients hospitalized with severe HE, flumazenil improved neurologic score in more patients (14.7% vs 3.8%, p<0.01).77 A follow up meta-analysis, however, found that most of the 14 studies evaluated had significant risk of bias but overall suggested a possible short-term benefit for flumazenil in severe HE without a mortality benefit.78 Its short-half life and need for intravenous administration limits it to use only in hospitalized patients.

Skeletal muscle metabolism

Muscle is an important alternate source of ammonia metabolism, especially in the presence of hepatic dysfunction. In portal hypertension, muscular glutamine synthetase conversion of glutamate and ammonia into glutamine helps compensate for reduced hepatic metabolism.

Branched chain amino acids (BCAAs), typically derived from dietary protein, are important metabolic precursors of glutamate, which as above is crucial for subsequent ammonia metabolism.79 Transamination in the liver of BCAAs results in glutamate, but a combination of portal hypertension and malnutrition result in relative depletion.80 Reduced relative BCAA concentration (compared to aromatic amino acids) is also felt to negatively affect neurotransmission in the brain. Accordingly, supplementation with either oral81 or intravenous82 BCAAs may be beneficial in HE, especially in those with sarcopenia or nutrition deficiency. Across 16 clinical trials, a Cochrane systematic review and meta-analysis concluded that insufficient evidence was present for mortality benefit, but an overall beneficial effect on HE (RR 0.76, 95% CI 0.63 to 0.92) when combining oral and parenteral studies.83 Unfortunately, they have not been extensively studied in comparison, or as an adjunct therapy, with standard of care in controlled settings. Several early phase studies are currently evaluating BCAAs in acute on chronic liver failure with HE (e.g. NCT05700695), but a published abstract suggested mixed results with early but not sustained improvement.84 The amino acid mixture AXA1655, a combination of BCAAs and LOLA, was studied, demonstrating increased relative BCAA concentration and reduced ammonia in a small trial (n=40);85 however, a follow up Phase II clinical trial was recently terminated by the sponsoring company (NCT04816916). An additional ongoing study (NCT04096014) is evaluating the use of timed protein supplementation with Ensure in the evenings in mornings and its effect on muscle mass and HE.

Conclusion

As the pathophysiology, predisposing factors, and various clinical presentations of HE become better understood, the need for better and more precise therapeutic options grows. As previously posited,86 an ideal treatment regimen would take into account individual patient characteristics and directly address the multifactorial nature of HE. In general, our current armamentarium of lactulose and rifaximin addresses only a limited scope of the problem, is not uniformly effective, and may not be right for every situation especially when considering toxicity and cost. Given the vast array of potential alternatives that have been tested or are being studied, the future of HE management is potentially bright. It’s critically important that well controlled prospective studies be funded in these areas in order to improve outcomes while considering additional factors such as muscle, renal and neurologic drivers of disease.

Key Points:

  • Hepatic Encephalopathy remains a common and highly morbid complication of chronic liver disease

  • There are few current therapies, which are limited especially by patient tolerance and cost.

  • As the pathophysiology of Encephalopathy becomes better understood, there are multiple promising potential targets for therapeutics

  • This review provides an overview of the emerging therapeutics for Hepatic Encephalopathy and their relation to pathways of disease.

Synopsis.

Hepatic encephalopathy, either covert or over, affects more than half of patients with cirrhosis and has lasting effects even after portal hypertension is corrected. Unfortunately, the current therapeutic options still result in high rates of relapse and progression, in part due to cost barriers and side effects leading to poor adherence. This review summarizes emerging treatment options, which may be able to take advantage of alternative disease pathways to improve future care of those with hepatic encephalopathy

Footnotes

Disclosure Statement:

The Authors have nothing to disclose

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Contributor Information

Adam P. Buckholz, Gastroenterology and Hepatology, Division of Gastroenterology and Hepatology, NewYork/Presbyterian-Weill Cornell Medical College, 1305 York Ave, 4th Floor New York, NY 10021.

Robert S. Brown, Jr., Vincent Astor Distinguished Professor of Medicine and Division Chief, Division of Gastroenterology and Hepatology, NewYork/Presbyterian-Weill Cornell Medical College, 1305 York Ave, 4th Floor New York, NY 10021.

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