Transjugular intrahepatic portosystemic shunts (TIPSs) are generally used for the management of complications of portal hypertension in patients with decompensated cirrhosis. However, hepatic encephalopathy (HE), which impairs neuropsychiatric function and motor control, remains the primary adverse effect of TIPS, limiting its utility. Prompt prevention and treatment of post-TIPS HE are critical, as they are strongly associated with readmission rates and poor quality of life. This review focuses on the main pathophysiological mechanisms underlying post-TIPS HE, explores advanced biomarkers and predictive tools, and discusses current management strategies and future directions to prevent or reverse HE following TIPS. These strategies include preoperative patient assessment, individualized shunt diameter optimization, spontaneous portosystemic shunt embolization during the TIPS procedure, postoperative preventive and therapeutic measures such as nutrition management, medical therapy, fecal microbiota transplantation, and stent reduction.

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome associated with liver failure and/or portal systemic shunting. Polyethylene glycol (PEG) electrolyte solution is a commonly used for catharsis of gut, which has been demonstrated to relieve HE in a number of randomized controlled trials. The aim of this paper was to evaluate the comparative efficacy and safety of PEG with lactulose for current HE treatment.

PEG electrolyte solution versus lactulose of HE was deeply studied by conducting a systematic search in electronic databases and other sources until December 31, 2020. The PRISMA statement recommended the use of meta-analysis with 95% confidence interval (CI), relative risk (RR), and weighted mean deviation (WMD) as the estimated effect size. A sensitivity analysis was performed comprehensively to present the risk of bias and the source of heterogeneity.

A total of 434 patients were involved in 7 randomized studies. It is found that there was a significant advantage of PEG therapy in the increase of clinical efficacy (RR=1.46; 95% CI: 1.26-1.68; P=0.000; I2=0.0%) and the decrease of hospital stay (WMD=-1.78; 95% CI: -2.72 to 0.85; P=0.000; I2=90.1%). There was no significant difference in the incidence of adverse events (RR=0.75; 95% CI: 0.48-1.19; P=0.222>0.05; I2=7.2%) and the level of serum ammonia (WMD=9.02; 95% CI: -14.39 to 32.43; P=0.45>0.05; I2=84.9%) after 24 hours between the 2 groups.

The results prove that PEG has a beneficial effect on the treatment of HE. Compared with lactulose, PEG can lead to more rapid HE resolution during the first 24 hours and shorten the length of stay without increasing the rate of adverse effects.

Acute liver failure (ALF) is a life-threatening consequence of hepatic function rapid loss without preexisting liver disease. ALF may result in a spectrum of neuropsychiatric symptoms that encompasses cognitive impairment, coma, and often death, collectively defined as acute hepatic encephalopathy. Micro RNAs are small non-coding RNAs that modulate gene expression and are extensively verified as biomarker candidates in various diseases. Our systematic literature review based on the last decade's reports involving a total of 852 ALF patients, determined 205 altered circulating miRNAs, of which 25 miRNAs were altered in the blood, regardless of study design and methodology. Selected 25 miRNAs, emerging predominantly from the analyses of samples obtained from acetaminophen overdosed patients, represent the most promising biomarker candidates for a diagnostic panel for symptomatic ALF. We discussed the role of selected miRNAs in the context of tissue-specific origin and its possible regulatory role for molecular pathways involved in blood-brain barrier function. The defined several common pathways for 15 differently altered miRNAs were relevant to cellular community processes, indicating loss of intercellular, structural, and functional components, which may result in blood-brain barrier impairment and brain dysfunction. However, a causational relationship between circulating miRNAs differential expression, and particular clinical features of ALF, has to be demonstrated in a further study.

Transjugular intrahepatic portosystemic shunt (TIPS) is an established treatment tool in decompensated liver cirrhosis that has been shown to prolong transplant-free survival. Hepatic encephalopathy (HE) is a frequent complication of decompensated cirrhosis, eventually induced and/or aggravated by TIPS, that remains a clinical challenge especially in these patients. Therefore, patient selection for TIPS requires careful assessment of risk factors for HE. TIPS procedural parameters regarding stent size and invasive portosystemic pressure gradient measurements thereby have an important role. Endovascular shunt modification, in combination with a conservative medical approach, often results in a significant reduction of symptoms. This review summarizes HE molecular mechanisms and pathophysiology as well as diagnostic and therapeutic approaches targeting shunt-induced HE.

Hepatic encephalopathy is a common neuropsychiatric complication of serious liver diseases and serves as a marker for worsening of their course and increasing the risk of death. The principal pathogenesis factors of hepatic encephalopathy is the excessive formation of ammonia and its accumulation by astrocytes. A key role in the prevention and treatment of hepatic encephalopathy is played by drugs that prevent hyperammonemia and promote the removal of ammonia from the body, namely lactulose, rifaximin and L-ornithine-L-aspartate. L-ornithine-L-aspartate has proven clinical effectiveness in the treatment of hepatic encephalopathy, prevents the transformation of minimal hepatic encephalopathy into overt forms, increases the tolerability of psychotropic drugs used in the treatment of alcohol dependence, and improves cognitive functions.

Artesunate (ART) is an antimalarial drug with potential anti-inflammatory effect. This study aimed to explore the potential protective role of ART in hepatic encephalopathy (HE), involving its function against ammonia toxicity.

HE rats were induced by the administration of thioacetamide (TAA, 300mg/kg/day). Spatial learning ability was tested in both Morris water and eight-arm radial maze. Rat cerebellar granule neurons (CGNs) were prepared for ammonia treatment in vitro, in line with SH-SY5Y and C6 cells. ART was administrated at 50 or 100mg/kg/day in vivo or added at 50 or 100μM in vitro. Oxidative damages were evaluated by the changes of cell viability, reactive oxygen species (ROS) levels and glutathione (GSH) content, while glutamate uptake and release, and the activities of glutamine synthetase (GS) and Na⁺K⁺-ATPase were measured to indicate the dysfunction of glutamate signaling.

Decreased escape latency and increased numbers of working errors were observed in TAA-induced HE rats, which could be significantly restored by ART at a dosage-dependent manner. Decreased cell viability and GSH content and increased ROS accumulation were detected in ammonia-treated SH-SY5Y and CGNs, while ammonia-treated C6 cells showed reduced glutamate uptake, increased glutamate release, and decrease of GSH content, GS and Na⁺K⁺-ATPase activity. In contrast, ART, especially at 100μM, strongly reversed all changes induced by ammonia, showing a similar dosage-dependent manner in vitro.

This study revealed a new neuroprotective role of ART in the pathogenesis of HE, by protecting neurons and astroglial cells from ammonia-induced damages and dysfunctions.

Interventional treatment for overt hepatic encephalopathy (OHE), includes non-absorbable disaccharides, neomycin, rifaximin, L-ornithine-L-aspartate and branched chain amino acids (BCAA). However, the optimum regimen remains inconclusive.

To compare interventions in terms of patients' adverse events and major clinical outcomes.

Literature search of PubMed, Embase, Scopus, and Cochrane Library studies published up to July 31 2014. RCTs of above interventions in OHE patients were included. Network meta-analysis combined direct and indirect evidence to estimate odds ratios (ORs) and mean difference (MD) between treatments and the probabilities of ranking for treatment based on clinical outcomes.

Twenty eligible RCTs were included. When compared with observation, only L-ornithine-L-aspartate (OR 3.71, P < 0.001) and BCAA (OR 3.37, P < 0.001) improved clinical efficacy significantly. However, when L-ornithine-L-aspartate was compared with BCAA, non-absorbable disaccharides and neomycin, there was a trend suggesting that L-ornithine-L-aspartate may be the most effective intervention with respect to clinical improvement (OR 1.10), rifaximin (OR 1.31), non-absorbable disaccharides (OR 2.75), neomycin (OR 2.22). In addition, L-ornithine-L-aspartate (MD -20.18, 95% CI -40.12 to -0.27) provided a significant reduction in blood ammonia concentration compared with observation. Neomycin appeared to be associated with more adverse events in comparison with non-absorbable disaccharides (OR 10.15), rifaximin (OR 17.31), L-ornithine-L-aspartate (OR 3.16) or BCAA (OR 7.69).

L-ornithine-L-aspartate treatment may show a trend in superiority for clinical efficacy among standard interventions for OHE. Rifaximin shows the greatest reduction in blood ammonia concentration, and treatment with neomycin demonstrates a higher probability in causing adverse effects among the five compared interventions.