Paradigm shifts in hepatic encephalopathy: Review of recent therapeutic breakthroughs

Abstract

Hepatic encephalopathy (HE) remains a significant neuropsychiatric complication of liver disease, characterized by a spectrum of cognitive, behavioral, and motor impairments. Recent advances in the understanding of its pathophysiology have identified inflammation and gut-liver-brain axis interactions along with conventional theories on ammonia toxicity. Rifaximin and lactulose continue to be the first-line therapies. However, novel approaches like ammonia-lowering agents such as glycerol phenylbutyrate, ornithine phenylacetate, zinc and L-ornithine L-aspartate, gut microbiota modulation by probiotics, fecal microbiota transplantation, and anti-inflammatory drugs like rifamycin and its analogs started showing promising results in clinical trials. This review emphasizes the importance of a multidisciplinary approach in HE management, combining traditional and innovative therapies to enhance the patient’s quality of life and to reduce the healthcare burdens and also highlights the newer treatment strategies for future research and clinical application.

Key Words: Fetal microbiota transplantation; Gut-brain-liver axis; Hepatic encephalopathy; L-ornithine L-aspartate

Core Tip: The review article explores the current approach of using the past and recent articles and studies found and highlighted with the use of Medical Subject Headings terminologies in platforms such as PubMed Central, Google Scholar, Scopus, Web of Science, and Research Gate.

INTRODUCTION

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome occurring due to liver insufficiency and/or portosystemic shunting, with a spectrum of manifestations ranging from subclinical neurological alterations to severe coma. This condition is commonly associated with chronic liver diseases such as alcohol-related liver disease, nonalcoholic fatty liver disease, viral hepatitis, and primary biliary cholangitis[1]. In patients with cirrhosis, this continues to be a major cause of hospitalizations, readmissions, and mortality, resulting in a substantial economic and healthcare burden[2].

HE is classified into three types based on its etiology: Type A (associated with acute liver failure), Type B (caused by portosystemic shunts without underlying liver disease), and Type C (associated with cirrhosis). The condition is further categorized by severity into minimal HE (MHE), overt HE (grades I–IV), and by its time course as episodic, recurrent, or persistent MHE, although subclinical, profoundly impacts quality of life and cognitive function, whereas overt HE serves as a critical indicator of decompensated cirrhosis, often indicating a poor prognosis[3].

Recent advances have significantly deepened our understanding of the pathophysiology of HE, revealing a complex interaction of factors including ammonia toxicity, systemic and neuroinflammation, oxidative stress, blood-brain barrier dysfunction, disruptions in cerebral metabolism, neurotransmission, and cellular communication. Despite its historical classification as a reversible syndrome, emerging evidence suggests that HE episodes can cause irreversible damage due to neuroinflammation and neuronal cell death, which may potentially lead to persistent neurological deficits even after liver transplantation[4].

The treatment landscape of HE has evolved significantly since the publication of the American Association for the Study of Liver Diseases-European Association for the Study of the Liver clinical guidelines in 2014[3]. Ongoing research into interorgan ammonia metabolism and the role of systemic inflammation in HE has identified novel therapeutic targets and strategies. This review provides a comprehensive overview of the recent breakthroughs in HE treatment. By exploring these developments, we shed light on the evolving therapeutic approaches and highlight avenues for future research in managing this challenging condition.

PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY

Ammonia toxicity

Ammonia, a neurotoxic byproduct of bacterial urease activity, protein digestion[5], and amino acid deamination, is normally detoxified by the liver through the urea cycle and conversion to glutamine[6]. In liver diseases like cirrhosis, the liver's ability to detoxify ammonia is reduced, leading to hyperammonemia, which contributes to astrocyte swelling, brain edema, and altered neurotransmission due to increased intracellular glutamine and osmolarity. The body tries to compensate by using skeletal muscles to remove ammonia, which is often insufficient. This cycle of rising ammonia levels and increased glutamine production worsens HE and affects muscle and brain function[7].

Systemic and neuroinflammation

Neuroinflammation is a critical component in the pathogenesis of HE, with brain cell damage acting both as a result and a contributing factor[8]. Astroglial cells during inflammatory conditions release tumor necrosis factor alpha (TNF-α), followed by glutamate, while also initiating microglial activation[9] leading to the proliferation and the release of pro-inflammatory cytokines, including TNF-α, interleukin 1 beta (IL-1β), and IL-6, which collectively contribute to neuronal death in both in vitro and in vivo models[10]. This inflammatory cascade is often triggered by systemic inflammation associated with alterations in the gut-liver-brain axis[9].

Evidence from clinical and experimental studies indicates that hyperammonemia induces HE only in the presence of systemic inflammatory response syndrome[8,10]. The CANONIC study underscores the association among systemic inflammation, HE severity, and mortality in advanced cases[8]. At the cellular level, TNF-α exposure increases the capacity of human cerebrovascular endothelial cells to transport ammonia, while astroglial cells exposed to ammonia and recombinant pro-inflammatory cytokines exhibit upregulated expression of genes implicated in HE[11].

Oxidative stress

Oxidative stress plays a pivotal role in the pathogenesis of HE, driven by an imbalance between reactive oxygen species, reactive nitrogen species and the body's antioxidant defenses[12]. This imbalance, exacerbated by elevated ammonium levels due to liver dysfunction, leads to systemic and central nervous system (CNS) oxidative stress[13]. The resultant neuroinflammation, mitochondrial dysfunction, and oxidative damage to lipids, proteins, and nucleic acids contribute to neuronal and astrocytic injury[14].

Key mechanisms include the depletion of antioxidants such as glutathione and catalase, impaired detoxification processes[15] and additionally, the formation of toxic compounds, like peroxynitrite from the reaction of nitric oxide with superoxide these contributes to cellular and tissue damage, neurotoxicity, and the progression of HE[16].

Dysregulated neurotransmitters

Alterations in neurotransmission systems, particularly the glutamatergic and GABAergic systems, contribute to energy disturbances and neuronal dysfunction[17]. Astrocytes detoxify plasma ammonia via glutamine synthetase, disrupting potassium buffering leading to elevated potassium and ammonium levels[8,17]. Additionally, hyperammonemia impairs hemichannel function and reduces lactate release, further limiting energy supply to neurons[17]. These findings highlight the complex interaction between ammonia detoxification, energy metabolism, and neurotransmitter systems in HE.

Blood-brain barrier dysfunction

Systemic inflammation, oxidative stress, and elevated levels of blood manganese, bile acids, and lactate contribute to pathological changes in HE. These factors disrupt the blood-brain barrier (BBB), allowing an increased influx of molecules like ammonia, which typically do not cross the BBB in significant amounts[1,10,17].

Gut brain liver axis

HE is intrinsically linked to dysfunction of the gut-liver axis, wherein alterations in gut microbiota and impaired intestinal barrier integrity exacerbate the neurotoxic effects on the brain (Figure 1), allowing gut-derived toxins, such as ammonia and endotoxins, to enter the systemic circulation[5,18,19]. Small intestinal bacterial overgrowth frequently accompanies cirrhosis due to factors such as reduced gut motility, gastric acid secretion, luminal immunoglobulin A deficiency, and malnutrition, further compromising intestinal barrier integrity and increasing bacterial translocation from intestine into the liver[20,21].

Figure 1 Flowchart of the role of the gut-brain-liver axis in the pathogenesis of hepatic encephalopathy.

Manganese accumulation

Manganese accumulation has been implicated in the pathogenesis of HE, with elevated plasma levels resulting from impaired hepatic excretion, leading to its deposition in the basal ganglia[1]. Elevated manganese concentrations in blood, cerebrospinal fluid, and basal ganglia tissue of patients with cirrhosis, along with dopaminergic alterations, further emphasize its role[9,10]. Animal studies also suggest that manganese exacerbates ammonia and glutamine accumulation in the brain, highlighting its contribution to HE pathogenesis[8].

Brain energy metabolism

Hyperammonemia in HE induces mitochondrial dysfunction and disrupts cellular bioenergetics, which leads to altered pH levels that contribute to neuronal depolarization and asterixis via increased neuronal resting membrane potential and inhibition of outward chloride pumps[8]. While definitive evidence linking HE primarily to brain energy failure is lacking, positron emission tomography studies indicate decreased glucose uptake in the anterior cingulate cortex of patients with cirrhosis and HE, correlating with psychometric impairments[9]. Furthermore, reduced cerebral oxygen metabolism has been noted in both episodic HE linked to cirrhosis and that associated with acute liver failure[8]. This suggests that hyperammonemia increases GABAergic tone via astrocytic glutamine synthesis, leading to diminished neuronal activity and energy demand, which further aggravates metabolic dysfunction in the brain during HE episodes[17].

Bile acids

Bile acids play a significant role in the pathophysiology of HE, as evidenced by recent studies. Cirrhotic individuals with HE have been shown to exhibit enormous concentrations of bile acids in their cerebrospinal fluid[9]. Animal models further validate this finding; in a study, rats with acute galactosamine-induced liver failure develop regional cerebral edema, indicating a partial loss of the BBB function[22]. Similarly, bile duct ligation models reveal increased circulating bile acids and compromised BBB integrity[23]. Thus, the role of bile acids and bilirubin in the development of HE warrants further research in light of these findings.

CURRENT PHARMACOLOGICAL THERAPIES

Lactulose

Lactulose is a nonabsorbable disaccharide. It is the first-line therapy for managing HE[24]. Its therapeutic effects are based on its ability to reduce ammonia levels in the gastrointestinal tract. Lactulose functions by promoting the excretion of nitrogen-containing substances through its laxative effects, which enhance bowel movements and increase fecal nitrogen excretion[24-26]. Upon reaching the colon, lactulose is metabolized by colonic microbiota into short-chain organic acids, such as lactic and acetic acid[27]. This conversion acidifies the colonic contents, creating an environment unfavorable for ammonia-producing bacteria and facilitates the conversion of ammonia to nonabsorbable ammonium ions[25,27]. Although lactulose has been used for decades, its consistent benefits in comparative studies remain unproven[24,26]. Nonetheless, it is believed to effectively decrease ammonia absorption and production in the intestinal lumen, thereby alleviating symptoms associated with HE[27,28].

Polyethylene glycol

Polyethylene glycol is an effective treatment for HE. It primarily works as an osmotic agent that enhances bowel clearance and thereby reduces the systemic ammonia levels[28].

Rifaximin

Rifaximin is a nonabsorbable antibiotic primarily used in the management of HE[29]. It works by inhibiting urease-producing bacteria in the gut, which reduces the absorption of ammonia thereby improving hyperammonemia and cognitive function in affected patients[30]. Additionally, rifaximin modulates the gut microbiota, enhancing metabolic pathways that could further mitigate HE symptoms without significantly altering the overall diversity of gut bacteria or inducing antimicrobial resistance[31]. However, caution is advised in patients with severe hepatic impairment due to increased systemic exposure[30,32].

Metronidazole

Metronidazole is presented as a potential alternative or adjunctive treatment to neomycin for HE. The rationale behind its use lies in its activity against anaerobic bacteria, which play a significant role in ammonia production in the gut. By targeting these bacteria, metronidazole aims to reduce the endogenous formation of ammonia, a key factor in the pathogenesis of HE. A clinical trial compared the effects of metronidazole and neomycin in patients with varying degrees of HE. The study found that metronidazole was as effective as neomycin in improving clinical and biochemical criteria, including mental state and EEG readings. This suggests that metronidazole's mechanism of action, targeting anaerobic ammonia production, offers a viable approach to managing HE[33].

L-ornithine L-aspartate

L-ornithine L-aspartate (LOLA) is a salt composed of L-ornithine and L-aspartate, utilized in treating HE by effectively lowering blood ammonia levels[34]. Its mechanism of action involves supplying critical substrates for the urea cycle, where L-ornithine acts as an activator of carbamoyl phosphate synthetase, enhancing ammonia detoxification into urea in periportal hepatocytes[35]. Upon administration, LOLA is rapidly absorbed and dissociates into its constituent amino acids, which participate in transamination reactions to form glutamate, a precursor for glutamine synthesis in the liver and other tissues[35]. LOLA's ability to enhance both ureagenesis and glutamine synthesis explains its role in managing hyperammonemia associated with liver dysfunction[36] (Table 1).

Table 1 Summary of the current treatment options for hepatic encephalopathy.

Treatment option	Proposed mechanism of action	Ref.	Year	Title of study	Study details	Effect
Lactulose	Nonabsorbable disaccharide that reduces ammonia levels in the gastrointestinal tract by promoting excretion of nitrogen-containing substances through laxative effects and acidifying colonic contents	Sharma et al[25]	2013	A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy	Randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt HE	Decreases ammonia absorption and production in the intestinal lumen, alleviating symptoms associated with HE
Polyethylene glycol	Osmotic agent that enhances bowel clearance, thereby reducing systemic ammonia levels	Rahimi et al[28]	2014	Lactulose vs polyethylene glycol 3350-electrolyte solution for treatment of overt hepatic encephalopathy: The HELP randomized clinical trial	50 cirrhotic patients with HE 2 groups polyethylene glycol (PEG) 3350-electrolyte solution (n = 25) or standard-of-care lactulose (n = 25)	HELP Study: 91% of PEG-treated patients showed improvement of 1 or more in HE grade at 24 hours compared to only 52% in the lactulose group (P < 0.01)
Rifaximin	Nonabsorbable antibiotic that inhibits urease-producing bacteria in the gut and modulates gut microbiota	Sharma et al[25]	2013	A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy	Randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt HE	Decreases ammonia absorption and production in the intestinal lumen, alleviating symptoms associated with HE
Metronidazole	Reduces ammonia production by inhibiting urease-producing bacteria	Morgan et al[33]	1982	Treatment of hepatic encephalopathy with metronidazole	Randomized trial in 18 patients with cirrhosis comparing metronidazole vs neomycin	Equal effectiveness to neomycin in treating HE
L-ornithine-L-aspartate	Stable salt that dissociates into L-ornithine and L-aspartate amino acids.L-ornithine activates carbamoyl phosphate synthetase (rate-limiting urea cycle enzyme). Both amino acids undergo transamination to glutamate for glutamine synthesis	Blanco Vela et al[34]	2011	Efficacy of oral L-ornithine L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy	Efficacy study in patients with cirrhosis with hyperammonemic HE	Effectively lowers blood ammonia levels through enhanced ureagenesis and glutamine synthesis
Glycerol phenylbutyrate	Nitrogen-binding agent providing alternative pathway for ammonia elimination. Hydrolysed by pancreatic lipases to phenylbutyric acid, which forms phenylacetylglutamine (PAGN) for urinary excretion, bypassing compromised urea cycle	Zacharias et al[37]	2019	Pharmacotherapies that specifically target ammonia for the prevention and treatment of hepatic encephalopathy in adults with cirrhosis	Phase II RCT: 178 patients with cirrhosis with ≥ 2 HE episodes, 6 mL twice daily for 16 weeks	Reduced HE events (21% vs 36%, P = 0.02), decreased hospitalizations (13 vs 25), enhanced efficacy in non-rifaximin patients (10% vs 32% events, P < 0.01). Safety profile similar to placebo
Sodium phenylbutyrate	Provides alternative nitrogen excretion pathway by β-oxidation to phenylacetate, which conjugates with glutamine to form phenylacetylglutamine for urinary elimination. Inhibits LPS-induced pro-inflammatory cytokines	Weiss et al[39]	2019	Treating hepatic encephalopathy in patients with cirrhosis admitted to ICU with sodium phenylbutyrate: A preliminary study	The study suggests that sodium phenylbutyrate may help treat HE in patients with cirrhosis in the ICU, but results are preliminary	Reverses dysfunctional bile acid synthesis, mitigates CNS abnormalities, and lowers ammonia levels through alternative nitrogen elimination while providing anti-inflammatory effects
Sodium benzoate	Conjugation with glycine to form hippuric acid, which is then excreted in urine, thereby reducing the ammonia load	Sushma et al[39], van Zoest et al[44]	1992, 2025	Sodim Benzoate in the Treatment of Acute Hepatic Encephalopathy: A Double-blind Randomized Trial[39]. Sodium benzoate for the treatment of hepatic encephalopathy in humans and animals: A systematic review and meta-analysis[44]	Double-blind randomized trial comparing sodium benzoate (5 g twice daily) vs lactulose in 74 patients with acute HE. Meta-analysis (2025) study: Systematic review of 16 studies including 314 subjects	80% recovery rate with sodium benzoate vs 81% with lactulose (similar efficacy, P > 0.1). Cost was 30 times lower than lactulose. Similar side effect profile. Meta-analysis (2025) study: Standardized mean difference of ammonia-lowering effect was 0.89 (95%CI: 0.27-1.51) in clinical trials, indicating effective ammonia reduction
L-Ornithine Phenylacetate	L-ornithine acts as substrate for glutamine synthesis in skeletal muscle to detoxify ammonia, while phenylacetate facilitates excretion of ornithine-derived glutamine as phenylacetylglutamine in urine	Safadi et al[47]	2022	Pharmacokinetics/pharmacodynamics of L-ornithine phenylacetate in overt hepatic encephalopathy and the effect of plasma ammonia concentration reduction on clinical outcomes	Pharmacokinetics/pharmacodynamics study examining plasma ammonia concentration reduction and clinical outcomes	L-ornithine phenylacetate (OP) significantly reduced plasma ammonia levels at 3 hours post-infusion compared to placebo (P = 0.014) and accelerated the time to achieve normal ammonia levels (P = 0.028). Most importantly, the study established that clinical response based on HE stage was directly associated with greater reduction in mean plasma ammonia levels (P = 0.009), confirming that OP's ammonia-lowering effect translates into meaningful clinical improvements in HE severity
Probiotics	Bacterial adhesion inhibition, mucosal barrier enhancement, immune system modulation, bioactive metabolite secretion, nervous system regulation, improved metabolism of amino acids/vitamins/bile acids, reduced ammonia production	Dalal et al[51]	2017	Probiotics for people with hepatic encephalopathy	Cochrane Systematic Review study analysed 21 randomized clinical trials with 1,420 participants to determine the beneficial and harmful effects of probiotics for HE	Probiotics probably improve recovery and may lead to improvements in the development of overt HE, quality of life, and plasma ammonia concentrations, but may lead to little or no difference in mortality
Zinc	Enhances ornithine transcarbamylase activity (key enzyme in urea cycle) for improved ammonia detoxification. Maintains intestinal barrier integrity to reduce absorption of gut-derived toxins involved in HE pathogenesis	Reding et al[52], Shen et al[53]	1984, 2019	Oral zinc supplementation improves hepatic encephalopathy. Results of a randomised controlled trial[52]. Zinc supplementation in patients with cirrhosis and hepatic encephalopathy: A systematic review and meta-analysis[53]	RCT involving 22 patients with cirrhosis with chronic encephalopathy who received either zinc acetate 600 mg daily or placebo for 7 days. Systematic Review and Meta-Analysis examined the effects of zinc supplementation on HE treatment in patients with cirrhosis including four trials with 247 patients	The study demonstrated significant improvements in HE as measured by trail-making tests on day 8 in the zinc-supplemented group compared to placebo. The meta-analysis revealed that combination treatment of zinc supplementation and lactulose over 3 to 6 months significantly improved performance in the number connection test (SMD: -0.97; 95%CI: -1.75 to -0.19; P = 0.01; moderate certainty) in patients with mild HE
Albumin	Binds and transports toxins (bilirubin, bile acids, ammonia) reducing their concentrations in blood and brain Anti-inflammatory and antioxidant properties	Sharma et al[25]	2017	Randomized controlled trial comparing lactulose plus albumin vs lactulose alone for treatment of HE	Randomized controlled trial comparing lactulose plus albumin vs lactulose alone for treatment of HE consisting of 120 patients	Combination of lactulose plus albumin is more effective than lactulose alone in treatment of overt HE
Flumazenil	Antagonizes the GABA/benzodiazepine receptor complex, which is overactivated in HE	Goh et al[60]	2017	Flumazenil vs placebo or no intervention for people with cirrhosis and HE	Meta analysis study 14 randomized clinical trials with 867 participants	Short-term clinical improvement (RR 0.75, 95%CI: 0.71-0.80); No significant effect on mortality (RR 0.75, 95%CI: 0.48-1.16)
Naloxone	Opioid receptor antagonist that targets elevated levels of opioid peptides in patients with liver disease, which are potentially involved in HE manifestations	Jiang et al[61]	2010	Naloxone in the management of HE	Meta-analysis study, 15 RCT studies involving 1054 patients with HE	Naloxone use was associated with a significant improvement in HE (RR 1.46, 95%CI: 1.27–1.67; P = 0.0005). Subgroup analysis showed that parenteral administration by intermittent or continuous infusion was most effective (RR 1.34, 95%CI: 1.17–1.53; P < 0.0001), and infusion-only trials showed an RR of 1.42 (95%CI: 1.19–1.69; P < 0.0001)
Acetyl L carnitine	Enhances ureagenesis leading to decreased blood and brain ammonia levels	Malaguarnera et al[62]	2011	Oral acetyl-L-carnitine therapy reduces fatigue in overt hepatic encephalopathy: A randomized, double-blind, placebo-controlled study	Randomized, double-blind, placebo-controlled design with 121 patients with overt HE with treatment duration of 90 days	Malaguarnera et al[62] Study showed significant reductions in blood ammonia levels across treatment groups receiving ALC, along with improvements in cognitive functions including attention, learning, psychomotor speed, and visual function-related domains
Branched-chain amino acids (BCAAs)	Improvement of muscle mass, BCAAs compete with aromatic amino acids for transport across the blood-brain barrier, potentially reducing the influx of false neurotransmitters that contribute to HE symptoms	Marrone et al[64]	2023	Branched chain amino acids in hepatic encephalopathy and sarcopenia in liver cirrhosis: Evidence and uncertainties	16 randomized clinical trials, including 827 patients with overt HE (12 trials) or minimal HE (4 trials)	The study shown the restoration of normal amino acid levels with BCAA supplementation may improve the clinical course of HE and sarcopenia with few side effects. BCAA administration alone improves HE manifestation and reduces HE recurrence but has no significant improvement in mortality
Artificial liver support	Remove protein-bound and water-soluble toxins from circulation. Reduction in serum bilirubin levels, decrease in phenolic aromatic amino acids levels, improvement of systemic hemodynamics by removing vasoactive substances, reduction in neurotoxic substances reaching the brain	Kanjo et al[69]	2021	Efficacy and safety of liver support devices in acute and hyperacute liver failure: A systematic review and network meta-analysis	Meta-analysis of 11 randomized controlled trials comparing liver support systems to standard medical therapy, published between 1973 and 2016, including 479 patients in acute and hyperacute liver failure	Shown benefit in HE improvement and decreasing mortality
Golexanolone	GABA-A receptor-modulating steroid antagonist involves reducing the potentiation of GABA-A receptor activation by neurosteroids such as allopregnanolone which is present in higher concentration in the brains of patients with HE.	Montagnese et al[74]	2021	A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy	A pilot study involving 3 weeks dosing with 33 patients to golexanolone (10, 40, or 80 mg BID) or 12 patients to placebo	Golexanolone was well tolerated and associated with improvement in cognitive performance
Embolization	Occlusion of large spontaneous portosystemic shunts thereby reducing the amount of ammonia and other toxins bypassing hepatic filtration.	Ke et al[78]	2024	Safety and efficacy of interventional embolization in cirrhotic patients with refractory hepatic encephalopathy associated with spontaneous portosystemic shunts	Study involves interventional embolization in 123 patients with cirrhosis with refractory HE associated with large spontaneous portosystemic shunts (34 in the embolization group and 89 in the control group)	Interventional embolization was found to be associated with prolonged HE-free survival and improved liver function in cirrhotic patients with refractory HE related to SPSS
Faecal microbiota transplantation	Restoring the gut microbiota balance to reduce ammonia synthesis, improve intestinal barrier integrity, and enhance ammonia clearance by improving liver function	Gao et al[82]	2023	A meta-analysis of microbiome therapies for hepatic encephalopathy	Meta-analysis study comprising 21 randomized controlled trials and 1746 patients with cirrhosis	FMT significantly: Reversed minimal HE (OR: 0.41, 95%CI: 0.19-0.90, P = 0.03); Reduced development of overt HE (OR: 0.41; 95%CI: 0.28-0.61, P < 0.00001). Decreased serious adverse events (OR: 0.14, 95%CI: 0.04-0.47, P = 0.001). Reduced ammonia levels, inflammatory markers, and hospitalization rate

ALC: Acetyl-L-carnitine; BCAA: Branched chain amino acid; BID: Twice a day; CI: Confidence interval; CNS: Central nervous system; FMT: Fecal microbiota transplantation; GABA-A: Gamma aminobutyric acid type A; HE: Hepatic encephalopathy; ICU: Intensive care unit; LPS: Lipopolysaccharide; OP: L-ornithine phenylacetate; OR: Odds ratio; PAGN: Phenylacetylglutamine; RCT: Randomised controlled trial; RR: Relative risk; SMD: Standardized mean difference; SPSS: Spontaneous portosystemic shunts.

NOVEL TREATMENT STRATEGIES

Glycerol phenylbutyrate

Glycerol phenylbutyrate (GPB) is a nitrogen-binding agent indicated for the management of urea cycle disorders[37]. Its mechanism of action involves the hydrolysis of GPB by pancreatic lipases, which releases phenylbutyrate, a prodrug that subsequently undergoes β-oxidation to form phenylacetate (PAA)[38]. PAA then conjugates with glutamine in the liver and kidneys to produce phenylacetylglutamine, an alternative pathway for nitrogen excretion that mimics urea, effectively reducing toxic ammonia levels in the bloodstream. This metabolic conversion has potential in reducing the CNS effects associated with hyperammonemia in HE[37,38].

Sodium phenylbutyrate

Sodium phenylbutyrate (NaPB) has emerged as a potential therapeutic agent, demonstrating the ability to reverse dysfunctional bile acid synthesis and mitigate CNS abnormalities associated with HE[39,40]. Specifically, NaPB has been shown to inhibit lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines such as IL-6, IL-1β, cyclooxygenase-2, and inducible nitric oxide synthase in bovine macrophage models, indicating its anti-inflammatory properties[41]. Understanding the molecular mechanisms by which phenylbutyrate exerts its effects on HE could illuminate novel therapeutic strategies aimed at alleviating both hepatic and neurological complications associated with HE[40,41].

Sodium phenylacetate

Sodium phenylacetate has emerged as a promising novel therapy for HE, targeting the reduction of ammonia levels in the body[40]. This works by conjugating with glutamine to form phenylacetylglutamine, which is then excreted in the urine, effectively removing excess nitrogen from the bloodstream[42]. By enhancing the elimination of conjugated nitrogen, sodium phenylacetate helps to lower blood ammonia levels improving HE[43].

Sodium benzoate

Sodium benzoate has emerged as a promising alternative therapy for HE, offering a novel approach to managing this serious neuropsychiatric complication of liver disease[44,45]. The mechanism of action involves conjugation with glycine to form hippuric acid, which is then excreted in urine, thereby reducing the ammonia load in the body improving HE[40,44,46].

L-ornithine phenylacetate

L-ornithine phenylacetate (OP) helps in HE by its ammonia detoxification potential[47,48]. The mechanism of action of OP involves two key components: L-ornithine acting as a substrate for glutamine synthesis in skeletal muscle, effectively detoxifying ammonia, while phenylacetate facilitates the excretion of ornithine-derived glutamine as phenylacetylglutamine in the urine[48]. This synergistic action results in a sustained reduction of plasma ammonia levels improving the disease condition[47].

Probiotics

Probiotics are a promising novel therapy for HE in patients with liver disorder[49]. These beneficial bacteria, when administered orally, can disrupt the pathogenesis of HE through multiple mechanisms of action like inhibiting bacterial adhesion, enhancing mucosal barrier function, modulating the innate and adaptive immune systems, secreting bioactive metabolites, and regulating the enteric and central nervous systems[50]. These changes in the gut microbiome and metabolome correlate with improvements in amino acid, vitamin, and secondary bile acid metabolism, potentially reducing the production of ammonia and other gut-derived toxins contributing to the therapeutic effects of probiotics in HE[49,50,51].

Zinc

Zinc supplementation is a potential therapy for HE[52,53]. The mechanism of action of zinc in HE is multifaceted: It enhances the activity of ornithine transcarbamylase, a key enzyme in the urea cycle, thereby improving ammonia detoxification[54]. Additionally, zinc plays a crucial role in maintaining the integrity of the intestinal barrier, potentially reducing the absorption of gut-derived toxins involved in HE pathogenesis[55].

Albumin

Albumin has emerged as a promising novel therapy for HE due to its multifaceted mechanisms of action. The primary mechanism of action involves albumin's ability to bind and transport toxins like bilirubin, bile acids, ammonia which are implicated in HE pathogenesis thereby effectively reducing their concentrations in the blood and brain. Additionally, albumin exhibits potent anti-inflammatory and antioxidant properties, which help mitigate the systemic inflammatory state associated with HE[56,57].

Flumazenil

Flumazenil, a benzodiazepine receptor antagonist, has shown potential as a novel therapy for patients with HE. Its mechanism of action involves antagonizing the GABA/benzodiazepine receptor complex, which is overactivated in HE. Studies have demonstrated that flumazenil can induce rapid improvements in mental status and electroencephalographic activity in some patients with HE[58,59]. While flumazenil has shown short-term benefits in improving symptoms, its effects are often transient, lasting only 1-2 hours[59,60].

Naloxone

Elevated levels of opioid peptides in patients with liver disease suggest their potential involvement in HE manifestations. Naloxone, an opioid receptor antagonist, has shown promise in ameliorating HE symptoms in both animal models and some clinical reports. A meta-analysis of randomized controlled trials indicates that naloxone use is associated with a significant improvement in HE, particularly when administered parenterally via intermittent or continuous infusions. These findings suggest naloxone as a potential therapeutic candidate for HE, though further research is needed to confirm its effectiveness and safety[61].

AST-120

AST-120 is a promising novel therapy for HE. It is an oral adsorbent that efficiently adsorbs ammonia in the gastrointestinal tract, thereby lowering circulating ammonia levels and reducing its toxic effects on the brain[40].

Acetyl L carnitine

Acetyl-L-carnitine (ALC) has emerged as a promising novel therapy for HE, demonstrating significant benefits in reducing ammonia levels and improving cognitive functions[62,63]. The mechanism of action of ALC involves enhancing ureagenesis, which leads to decreased blood and brain ammonia levels, thereby addressing a key pathogenic factor in HE[63]. While a meta-analysis by Jiang et al[63] confirmed the efficacy of ALC across multiple studies, highlighting its role as a safe and effective adjunct therapy in HE management, a randomized controlled trial by Malaguarnera et al[62] found that ALC significantly improves cognitive test scores and reduces serum ammonia levels compared to placebo.

Branched chain amino acids

Branched-chain amino acids (BCAAs) have emerged as a promising novel therapy for HE[64-67]. The mechanism of action of BCAAs in HE involves their role in ammonia detoxification, improvement of muscle mass, and modulation of neurotransmitter balance in the brain. BCAAs compete with aromatic amino acids for transport across the blood-brain barrier, potentially reducing the influx of false neurotransmitters that contribute to HE symptoms. Studies have shown that long-term BCAA supplementation can improve minimal HE, enhance cognitive function, and increase mid-arm muscle circumference in patients with cirrhosis and a history of HE[64-68].

Artificial liver support

Artificial liver support systems have emerged as a promising therapy for HE. These systems, particularly albumin dialysis, aim to remove protein-bound and water-soluble toxins[69,70]. Artificial liver support systems, particularly albumin dialysis, demonstrate varying efficacy in toxin removal and management of HE[69,71,72]. These systems consistently achieve significant reductions in serum bilirubin levels and effectively decrease levels of phenolic aromatic amino acids, both of which are implicated in HE[71,73]. However, results for ammonia removal are mixed, with some studies reporting significant reductions while others found no substantial changes[72,74]. The combined effects of toxin removal improved systemic hemodynamics (by removing vasoactive substances), and modulation of inflammatory responses contributes to the observed improvements in HE, likely due to the reduction in neurotoxic substances reaching the brain and enhanced cerebral blood flow[69,71,72].

Golexanolone

Golexanolone is a promising novel therapy for HE, currently under investigation in preclinical and clinical studies. As a GABA-A receptor-modulating steroid antagonist, its mechanism of action involves reducing the potentiation of GABA-A receptor activation by neurosteroids such as allopregnanolone which is present in higher concentration in the brains of patients with HE. This compound has shown efficacy in restoring spatial learning and motor coordination in animal models of HE, as well as mitigating the effects of intravenous allopregnanolone in healthy adults[73,74]. In a pilot study involving patients with cirrhosis and abnormal continuous reaction time, golexanolone demonstrated satisfactory safety and pharmacokinetics, with directionally favourable changes in measures of sleepiness, attention span, and brain wave activity[73]. Furthermore, golexanolone has been found to reduce peripheral inflammation and neuroinflammation in hyperammonemic rats, which are key factors in the pathogenesis of HE[75].

Embolization

Embolization has emerged as a promising novel therapy for HE, particularly those with large spontaneous portosystemic shunts (SPSS)[76-79]. The mechanism of action involves occluding these abnormal vascular connections, which redirect blood flow back to the liver, reducing the amount of ammonia and other toxins bypassing hepatic filtration. This procedure has shown significant efficacy in reducing HE symptoms and recurrence rates[76-79].

Faecal microbiota transplantation

Faecal microbiota transplantation (FMT) has emerged as a promising novel therapy for HE[80]. This is typically performed by delivering a fecal suspension from a healthy donor into the patient's gastrointestinal tract. The delivery methods can include upper gastrointestinal routes such as esophagogastroduodenoscopy, nasogastric or nasojejunal tube, and oral capsules, with the procedure often repeated multiple times to achieve therapeutic success[81]. The mechanism of action of FMT in HE involves altering the gut microbiota composition to reduce ammonia synthesis, improve intestinal barrier integrity, and enhance ammonia clearance by improving liver function. FMT aims to restore gut microbiota balance, addressing factors such as ammonia toxicity, gut-brain communication disruption, and inflammation in HE[80-82].

CHALLENGES IN CLINICAL TRANSLATION

The article outlines several promising approaches to treating HE, yet moving these discoveries from the laboratory into actual patient care presents substantial obstacles. Researchers face a complex web of regulatory requirements, methodological challenges, safety questions, and significant cost considerations leading to practical difficulties of implementing new treatments in real-world clinical settings. What's particularly challenging is that overcoming these barriers requires unprecedented collaboration between research teams, practicing clinicians, regulatory bodies, and pharmaceutical companies. The future success of these therapeutic advances ultimately hinges on our ability to navigate these obstacles while keeping patients and their actual clinical needs at the center of our efforts.

CONCLUSION

HE remains a significant neurological complication of liver dysfunction, with complex pathophysiological mechanisms involving ammonia toxicity, systemic and neuroinflammation, oxidative stress, neurotransmission disturbances, and gut-liver-brain axis dysregulation. Advances in research have deepened our understanding of these mechanisms, revealing that HE is not merely a transient and reversible condition but may lead to persistent neurological deficits. Therapeutic strategies for HE has evolved, with traditional treatments such as lactulose and rifaximin forming the cornerstone of management. However, novel approaches—including nitrogen-scavenging agents, probiotics, zinc supplementation, and artificial liver support systems—offer promising avenues for more targeted and effective intervention. Emerging therapies, such as golexanolone, fecal microbiota transplantation, and embolization, further highlight the potential for personalized and precision medicine in HE management. Despite these advancements, significant gaps remain in optimizing treatment efficacy, predicting disease progression, and mitigating long-term neurological consequences. Future research should focus on refining diagnostic tools, identifying biomarkers for early intervention, and exploring combination therapies to improve patient outcomes. A multidisciplinary approach integrating hepatology, neurology, and microbiome research will be critical in addressing the complexities of HE and improving the quality of life for affected individuals.