Paradigm shifts in hepatic encephalopathy: Review of recent therapeutic breakthroughs

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.