Management of hepatic encephalopathy following transjugular intrahepatic portosystemic shunts: Current strategies and future directions

Abstract

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.

Key Words: Cirrhosis; Portal hypertension; Transjugular intrahepatic portosystemic shunt; Hepatic encephalopathy; Pathophysiological mechanisms; Management strategies

Core Tip: Hepatic encephalopathy (HE) is the main complication following transjugular intrahepatic portosystemic shunt (TIPS), significantly impairs patients’ quality of life. Preoperative evaluation is crucial to mitigate the risk of post-TIPS HE. The shunt diameter and embolization of spontaneous portosystemic shunts should be considered according to the portal pressure gradient. Rifaximin is effective for preventing post-TIPS HE. Endovascular shunt reduction is a potential intervention for refractory HE post-TIPS. Sarcopenia is associated with post-TIPS HE, and the impact of nutritional management on HE following TIPS warrants further investigation. The efficacy of fecal microbiota transplantation in post-TIPS HE requires further validation.

INTRODUCTION

Transjugular intrahepatic portosystemic shunt (TIPS) placement is a standard procedure for treating portal hypertension-related complications, which mainly include recurrent ascites and variceal rebleeding. The major drawbacks of TIPS have been shunt dysfunction and the development of hepatic encephalopathy (HE)[1]. With technical progress and the use of polytetrafluoroethylene-covered stents, the rate of shunt dysfunction has dramatically decreased[2]. However, HE, which is induced and exacerbated by TIPS placement, continues to pose a significant clinical challenge in patients with decompensated cirrhosis[3]. The incidence of post-TIPS HE ranges from 35% to 50%, seriously affects the quality of life of patients and their families, increases readmission and is a major cause of health care expenses[4-7].

The diagnosis of overt HE (OHE) is usually straightforward in clinical practice once other known brain diseases are excluded. However, minimal HE (MHE) is characterized by subtle signs and symptoms that can be detected only through specialized psychometric tests. HE can be classified into three types according to its pathogenesis: Type A is found in patients with acute liver failure, type B is found in those with portosystemic shunts, and type C is found in those with cirrhosis[8]. This review focuses mainly on patients with type C HE. HE is classified into two main categories based on severity: Covert HE, including MHE and West Haven grades 0-1; and OHE, which includes grades 2-4. Furthermore, in terms of its temporal evolution, OHE can be classified as episodic, recurrent (more than one episode within a 6-month period) or persistent (no return to normal or baseline neuropsychiatric function between episodes)[8].

Post-TIPS HE is closely associated with patient baseline characteristics, portosystemic shunt diameter, status of spontaneous portosystemic shunt (SPSS) embolization, and postoperative management. It is imperative for clinicians to understand the pathophysiological mechanisms of post-TIPS HE to effectively prevent and manage this complication. Therefore, this review outlines comprehensive strategies for the prevention and treatment of post-TIPS HE based on its underlying mechanisms, encompassing preoperative, intraoperative, and postoperative approaches (Figure 1). We aim to offer practical recommendations for minimizing HE occurrence and improving patient outcomes after TIPS.

Figure 1 Management of hepatic encephalopathy following transjugular intrahepatic portosystemic shunt requires a comprehensive approach, encompassing preoperative, intraoperative, and postoperative interventions. ¹Further studies are needed to confirm these findings. TIPS: Transjugular intrahepatic portosystemic shunt; HE: Hepatic encephalopathy; PPIs: Proton pump inhibitors; FMT: Fecal microbiota transplantation.

PATHOPHYSIOLOGY OF POST-TIPS HE

The pathogenesis of HE in cirrhotic patients primarily involves hyperammonemia, systemic and neuroinflammation, oxidative stress, and dysfunction of the gut-liver-brain axis[9]. Additionally, genetic and epigenetic factors have been implicated in the development of HE[10]. Among these, hyperammonemia is regarded as the central driver of HE[11].

Hyperammonamia

In healthy individuals, ammonia production primarily occurs in the colon due to the activity of the gut microbiota, which converts glutamine into ammonia via enterocytic glutaminase[12]. Ammonia from the gut undergoes the urea cycle within hepatocytes to form urea, which is then excreted by the kidneys. Indeed, muscles also provide alternative pathways for ammonia removal by synthesizing glutamine from glutamate[13] (Figure 2A). In liver cirrhosis, the ability of hepatocytes to remove ammonia before it reaches the systemic circulation is severely impaired, which leads to hyperammonamia[14]. Elevated blood ammonia levels and increased permeability of the blood-brain barrier (BBB) contribute to increased blood ammonia levels in central nervous system, leading to astroglial swelling and the development of HE[15,16]. In addition, 50% to 70% of cirrhotic patients develop sarcopenia, which substantially reduces the capacity of skeletal muscle for ammonia detoxification and increases the incidence of HE[17] in Figure 2B. TIPS is performed by creating an intrahepatic portosystemic shunt that connects the right or main portal vein to the hepatic vein to alleviate portal pressure[18]. Stent placement causes significant changes in hepatic hemodynamics, leading to a further reduction in first-pass hepatic clearance of neurotoxins that originate from the intestine. This reduction allows for greater amounts of unprocessed ammonia to enter the systemic circulation compared with patients with liver cirrhosis who have not undergone TIPS placement. Although one study showed that TIPS may improve sarcopenia, the improvement might not be sufficient to clear ammonia caused by portosystemic shunting and may not significantly reduce the occurrence of HE (Figure 2C)[19]. However, it should be noted that blood ammonia levels are not always proportional to post-TIPS HE, and a thorough clinical assessment is crucial to prevent misdiagnosis[20].

Figure 2 Metabolic profiles of blood ammonia in different populations. A: In the health, gut-derived ammonia is primarily metabolized in the liver via the urea cycle and excreted by the kidneys, maintaining blood ammonia as NH4⁺ and preventing its passage across the blood-brain barrier (BBB); B: In cirrhotic patients, impaired liver function disrupts the urea cycle, reducing ammonia conversion to urea. Combined with sarcopenia, which diminishes muscle ammonia metabolism, excess ammonia crosses the BBB, leading to astrocyte glutamine accumulation, swelling, and hepatic encephalopathy; C: In patients who undergo transjugular intrahepatic portosystemic shunt, sarcopenia may improve compared with non-transjugular intrahepatic portosystemic shunt patients; however, significant hepatic bypass of blood ammonia through the shunt leads to systemic circulation. This elevated ammonia can cross the BBB, increasing the risk of hepatic encephalopathy. Gln: Glutamine; GS: Glutamine synthetase; Glu: Glutamic acid.

Systemic and neuroinflammatory effects

Systemic inflammation plays a pivotal role in the pathogenesis of HE in patients with cirrhosis, contributing to increased BBB permeability and eliciting a neuroinflammatory response via the activation of microglia and brain endothelial cells[21-23]. The abrupt hemodynamic changes induced by TIPS may facilitate the passage of inflammatory cytokines across the dysfunctional BBB, triggering neuroinflammation and increasing the risk of post-TIPS HE. Li et al[24] reported a significant association between preoperative serum interleukin-6 (IL-6) levels and the development of post-TIPS OHE in a prospective cohort study of 125 cirrhosis patients who underwent TIPS placement. Furthermore, toxic substances such as ammonia can activate microglia and cause the secretion of pro-inflammatory cytokines like IL-β and tumor necrosis factor-alpha (TNF-α), which promote the development of HE[25]. Further research is required to explore the role of inflammation in post-TIPS HE and to determine whether preoperative anti-inflammatory strategies can mitigate its occurrence.

Oxidative stress

Oxidative stress, frequently observed in cirrhosis, compromises BBB permeability through the reactivity of reactive oxygen and nitrogen species with lipids, proteins, and DNA, playing a crucial role in the pathogenesis of HE[26]. It induces the release of reactive oxygen species and mitochondrial dysfunction, leading to an increase in GABAergic tone in the central nervous system, thereby contributing to the development of HE[27]. Additionally, elevated ammonia and inflammation further direct oxidative stress in neurons, resulting in reactive oxygen species production and the development of HE[28]. Elevated blood ammonia levels following TIPS may promote the development of HE through this mechanism, and further investigations are needed in future studies to elucidate this relationship. Recent research suggests that antioxidant properties of vitamin D may alleviate oxidative stress in HE, but the role of vitamin D in patients undergoing TIPS procedures should be further explored[29].

Gut-liver-brain axis dysfunction

The functional integrity of the gut barrier and optimal hepatic function are essential for maintaining the homeostasis of the gut-liver-brain axis in a healthy state, effectively preventing the translocation of toxic metabolic products into the brain[30]. However, in patients with liver cirrhosis, the integrity of the gut barrier is compromised, and gut permeability is increased as a result of systemic and local inflammation, as well as bacterial translocation. This disruption facilitates the harmful metabolites into the bloodstream[31]. Compromised hepatic function leads to inadequate detoxification of gut-derived metabolites, facilitating their passage across the BBB and promoting the development of HE. Following TIPS, increased intestinal absorption facilitates the systemic circulation of toxic metabolites, which bypass hepatic detoxification and directly enter the brain, thereby increased the risk of HE. Additionally, in a prospective study of 106 TIPS-treated cirrhotic patients, the post-TIPS HE group presented increased autochthonous taxa and decreased pathogenic taxa relative to the non-HE group[32]. He et al[33] also identified that high baseline phenylethylamine levels, which are derived mainly from Ruminococcus gnavus, are correlated with a sevenfold higher risk of post-TIPS HE. A prospective study revealed no genus-level gut microbiota differences in hepatitis B-related portal hypertension patients with or without pre-TIPS HE, but post-TIPS HE was associated with increased Morganella, a urease-producing bacterium that elevates blood ammonia[34-36]. These findings indicate that post-TIPS HE may be closely associated with gut microbiota dysbiosis, highlighting its potential as a therapeutic and preventive target for HE following TIPS placement.

Genetic and epigenetic factors

HE is intricately linked to genetic and epigenetic mechanisms involving ammonia metabolism, neuroinflammation, and neurotransmitter regulatory pathways. Astrocytic glutamine synthetase (GS) converts glutamate and ammonia into glutamine, contributing to astrocyte swelling[37,38]. Activation of the intestinal GS gene has been linked to an increased risk of HE in cirrhotic patients[39]. Furthermore, the presence of two long alleles in the GS microsatellite promoter region was predominantly observed in HE patients[40]. Myocyte enhancer factor 2C, a key transcription factor in neuronal development and plasticity, is regulated by lnc240 through interaction with miR-1264-5p. In cirrhotic HE mice, lnc240 downregulation enhances the binding of miR-1264-5p binding to myocyte enhancer factor 2C, leading to neuronal dysfunction[41]. Gut barrier integrity is vital for gut-liver-brain axis homeostasis. In decompensated states, defensin and mucin sulfation genes were downregulated, whereas IL-1, IL-6, and TNF-related genes are upregulated in intestinal epithelial cells[42]. RNA sequencing analysis in a HE mouse model revealed that astrocytes upregulated corticoid receptor and oxidative stress signaling, while microglia displayed transcriptome changes associated with immune cell recruitment, highlighting the inflammation and hypoxia pathways in HE pathogenesis[43]. These findings provide critical insights into the pathophysiological mechanisms of HE and offer novel perspectives for precision medicine and targeted therapies. TIPS placement may further activate pathways associated with the development of HE on the aforementioned genetic basis, thereby increasing the incidence of HE, which warrants further validation in future studies.

ADVANCED BIOMARKERS AND PREDICTIVE TOOLS OF POST-TIPS HE

Advanced biomarkers

Specific biomarkers are crucial for pre-TIPS patient selection, significantly reducing the incidence of post-TIPS HE. Beyond traditional hepatic biochemical markers such as albumin, creatinine, and total bilirubin, an increasing number of biomarkers have been identified as associated with post-TIPS HE[44,45]. Elevated preoperative serum IL-6 levels are strongly linked to post-TIPS HE, indicating a higher risk of severe HE in cirrhotic patients[24]. In contrast, Tiede et al[46] reported no associations between systemic inflammatory markers (IL-6, TNF-α, and IL-β) and post-TIPS OHE in a two-year prospective study of 62 patients. Variations in preoperative liver function and patient characteristics likely contribute to these conflicting outcomes. The predictive role of systemic inflammation for post-TIPS HE may be limited due to the intricate and dynamic mechanisms underlying HE in cirrhosis. Furthermore, bile acid levels in the peripheral vein decrease after TIPS, and mass spectrometry analysis reveals an inverse correlation between the abundance of three specific conjugated di- and tri-hydroxylated bile acids and the severity of post-TIPS HE[47]. A prospective study of 106 cirrhotic patients receiving TIPS demonstrated a decrease in Lachnospiraceae abundance in the HE+ group, highlighting the potential of gut microbiota as a predictive target for post-TIPS HE[32]. Skeletal muscle plays a critical role in ammonia metabolism, and sarcopenia has been identified as a significant risk factor for the development of HE following TIPS placement[48].

Advanced predictive tools

Artificial intelligence (AI) algorithms are integral to fields such as biomics and healthcare analytics. In HE management, AI-based analysis of multidimensional data has revolutionized early detection, risk assessment, and tailored therapeutic interventions[49]. AI-based models, such as machine learning and deep learning algorithms, analyze biomarkers and imaging data to identify subtle patterns predictive of HE onset and progression. Yang et al[50] compared various classification methods for HE prediction in cirrhosis, demonstrating that the weighted random forest model is suitable for developing a risk assessment system for HE. Bajaj et al[51] established a 20-microbial species stool signature using machine learning, which was validated in a multicenter cohort, to distinguish HE from non-HE cases and correct misdiagnoses, thereby improving diagnostic precision and risk stratification for HE. Radiomics enhances these approaches by extracting high-dimensional quantitative features from medical imaging, such as magnetic resonance imaging and computed tomography, to identify biomarkers linked to disease severity and neurological outcomes. Chen et al[52] constructed a model (area under the curve = 0.719) to predict post-TIPS OHE via 3D liver and spleen evaluation, optimizing the TIPS candidacy assessment. Models utilizing clinical and hepatic vascular characteristics from computed tomography images (area under the curve = 0.814) showed robust performance in predicting OHE risk, with good calibration[53]. Collectively, these technologies enable more precise diagnosis, enhanced prediction of HE episodes, and personalized therapeutic strategies, ultimately improving patient outcomes. Future research should focus on refining the accuracy of post-TIPS HE prediction.

MANAGEMENT STRATEGIES

Assessment of patients before TIPS placement

Pre-TIPS liver function is significantly correlated with postoperative prognosis, and a Child-Pugh score > 13 or a model for end-stage liver disease score > 19 has been advocated as a contraindication for TIPS[54]. Common factors that affect HE after TIPS include age, a history of HE, the use of proton pump inhibitors (PPIs), serum sodium and creatinine levels, and the presence of sarcopenia[55,56]. Advanced age is a significant risk factor for post-TIPS HE. A meta-analysis revealed that patients over 70 years of age had a significantly greater incidence of HE after TIPS and a marked increase in readmission rates within 30 days[57,58]. This finding may be related to increased BBB permeability and decreased function of neural cells in elderly patients[59]. Moreover, a history of HE increases the incidence of HE following TIPS, and recurrent or persistent OHE has been advocated as a contraindication for TIPS[60]. PPIs are widely used in gastrointestinal diseases such as reflux esophagitis and peptic ulcers. A retrospective study revealed that the duration of preoperative PPI use was positively correlated with the incidence of postoperative HE, and the incidence of HE decreased after the discontinuation of PPIs[61]. This could be associated with PPIs modifying the pH of the gastrointestinal tract, which results in alterations in the gut microbiota that subsequently impact blood ammonia metabolism[62]. However, a study including 397 patients with liver cirrhosis who received TIPS revealed that 59.1% of patients treated with PPIs did not have a clear indication for PPI use[63]. Therefore, it is essential to adhere strictly to appropriate prescribing indications, especially for patients planned for the TIPS procedure. Additionally, preoperative serum sodium levels have also been identified as relevant to HE following TIPS. Merola et al[64] conducted a retrospective chart review and reported that a lower preoperative serum sodium concentration was associated with a greater risk of HE within the first week post-TIPS. Hyponatraemia exacerbates cerebral edema and combines with hyperammonamia to further impair brain cell function[65]. The serum creatinine level, which reflects renal function, is positively correlated with the incidence of HE after TIPS, as renal dysfunction can impede blood ammonia metabolism and affect the elimination of metabolic products[66]. Skeletal muscle is one of the sites of ammonia metabolism; however, most patients with liver cirrhosis have sarcopenia. Other studies have shown that the presence of sarcopenia before TIPS placement is a risk factor for post-TIPS HE, and improvements in sarcopenia reduce the occurrence of post-TIPS HE[48,67]. Furthermore, reduced muscle mass, such as that associated with myosteatosis, also increases the risk of HE occurring after TIPS[68]. The controlling nutritional status score, which consists of the serum albumin level, total cholesterol, and total peripheral lymphocyte count, has emerged as a reliable indicator for assessing the risk of OHE in patients with cirrhosis after the TIPS procedure[69]. Moreover, Liu et al[19] reported that sarcopenia can be improved in cirrhotic patients following TIPS placement. Although these factors increase the risk of post-TIPS HE, they are not absolute contraindications for TIPS placement. A full understanding of patient characteristics is essential to establish more accurate evaluations and effective treatment strategies.

Shunt diameter determination

The selection of the TIPS stent diameter is crucial for the occurrence of HE after TIPS. A stent diameter that is too small can result in insufficient shunting and ineffective reduction of portal pressure, whereas a stent diameter that is too large increases the incidence of postoperative HE. Currently, a uniform recommendation for the selection of the stent diameter is lacking. The use of the smallest possible stent that can effectively control the complications of portal hypertension is generally advised. The 2023 American Association for the Study of Liver Diseases guidelines recommend a stent diameter of 8 mm[70]. The European guidelines do not specify a particular stent diameter[71]. According to the Baveno VII guidelines, a hepatic venous pressure gradient of < 12 mmHg or a reduction in the portal pressure gradient (PPG) of more than 50% from baseline after stent placement can effectively reduce the risk of recurrent variceal bleeding[72].

Several studies have compared the impact of placing stents with different diameters on portal hypertension complications and the incidence of HE. Initially, patients who underwent TIPS were randomly assigned to either the 8-mm diameter stent group or the 10-mm diameter stent group by Riggio et al[73]. They reported that the incidence of portal hypertension complications was greater in the 8-mm diameter stent group, whereas there was no significant difference in HE between the two groups. However, a meta-analysis including 5 studies and 489 patients indicated that, compared with a 10-mm stent, placing an 8-mm diameter stent did not significantly affect variceal rebleeding but did reduce the incidence of HE[74]. A randomized controlled trial (RCT) revealed that, compared with a 10-mm diameter stent, an 8-mm diameter stent not only reduced liver impairment but also halved the risk of HE, with no significant difference in rebleeding rates[75]. Furthermore, Trebicka et al[76] reported that covered stents with an 8 mm diameter may improve survival compared with 10 mm stents. The above studies suggest that an 8-mm diameter stent may be recommended for use in patients to prevent variceal bleeding because it does not increase the risk of rebleeding or liver impairment. However, the most critical factor in selecting the stent diameter is the patient’s baseline characteristics and treatment goals rather than the specific size of the stent. A retrospective study revealed that a 6-mm shunt significantly reduced the incidence of OHE, protected perioperative liver function, and did not affect the rebleeding rate in patients with a small liver volume[77]. For patients with cirrhosis and refractory ascites who are at high risk for postoperative HE, a stent diameter smaller than 8 mm may be more appropriate[18].

Adjustable stents provide a balanced approach for managing post-TIPS HE and complications related to portal hypertension. Monnin-Bares et al[78] introduced a technique using a balloon-expandable stent-graft and a lasso catheter for adjustable shunt diameter reduction, permitting reversible titration via stent-graft dilation or lasso tightening. The use of adjustable stents requires further validation in large-scale studies to confirm their efficacy and safety.

SPSS embolization

SPSS was identified in 71% of patients with medically refractory HE[79]. These shunts develop as a compensatory mechanism to alleviate portal hypertension, allowing blood to flow from the portal vein directly into the systemic circulation via collateral vessels[33]. Spontaneous splenorenal shunts and spontaneous gastrorenal shunts are relatively common types of SPSSs in patients with cirrhosis[80]. The presence of spontaneous shunts allows some of the portal venous blood to bypass the liver and directly enter the systemic circulation, including gut-derived toxins such as ammonia. These toxins can cross the BBB and interfere with the function of neuroglial cells[37]. Once formed, SPSSs tend to persist and do not easily regress. One-third of SPSSs remain even after TIPS normalizes portal pressure, which may be one of the reasons for persistent HE after TIPS[81]. A multicenter study revealed that the total area of the SPSS can independently predict the incidence of HE and mortality in patients with cirrhosis[82]. An RCT revealed that in patients with variceal bleeding, the combination of TIPS and embolization of a large SPSS decreased the incidence of post-TIPS HE without significantly increasing the risk of other complications[83]. Additionally, a meta-analysis conducted by Yang et al[84] involving a total of 4 studies and 1243 patients demonstrated that the prevalence of SPSS is associated with an increased risk of OHE after TIPS and that embolization of the SPSS during TIPS placement reduces the risk of OHE. The North American practice guidelines recommend considering embolization for SPSSs > 6 mm to reduce the risk of HE after TIPS[85]. Commonly used methods for SPSS embolization include balloon-occluded retrograde transvenous obliteration, plug-assisted retrograde transvenous obliteration, and coil-assisted retrograde transvenous obliteration[86]. However, the above studies have certain limitations, such as small sample sizes and the inclusion of patients with cirrhosis, primarily due to hepatitis B virus infection.

HE prophylaxis and treatment after TIPS operation

Nutrition management: Malnutrition is a prevalent issue in patients with liver cirrhosis, affects 20%-50% of this patient population, and poses a risk for the development of post-TIPS HE[48,87]. Although restricted protein intake was previously recommended for patients with HE, more recent research has suggested that protein restriction in patients with HE should be based on the severity of HE and the patient’s current nutritional status[88,89]. The European Association for the Study of the Liver (EASL) clinical practice guidelines also recommend that daily protein and caloric intake for patients with HE should not fall below the general recommendations for cirrhotic patients, with a minimum daily caloric intake of 35 kcal/kg and a minimum daily protein intake of 1.2-1.5 g/kg[90]. The use of vegetables and dairy protein over animal protein is encouraged[91]. An RCT of 120 cirrhotic patients demonstrated that nutritional therapy (30-35 kcal/kg and 1.0-1.5 g of vegetable protein/kg of ideal body weight/day) effectively treats MHE and improves health-related quality of life[92]. Kato et al[93] also reported that 8 weeks of nutritional support improved MHE in 68.4% of patients. A recent retrospective cohort study revealed that nutritional counseling effectively improved mortality and prevented OHE in patients with alcohol-associated liver disease[94].

However, to date, protein intake management has focused primarily on the prevention and treatment of HE in patients with liver cirrhosis. Only one retrospective prospective study reported that early dietary intervention can reduce the incidence of HE after TIPS in patients with cirrhosis[95]. Therefore, guidelines that recommend dietary management for the prevention of HE after TIPS placement are currently lacking. In clinical practice, both nutritional interventions and dietary counseling are essential and cost-effective measures. However, their efficacy is often constrained by patient compliance and variations in dietary habits.

Medical therapy: Lactulose, a nonabsorbable disaccharide metabolized by the colonic microbiota into short-chain organic acids, creates an acidic environment that inhibits NH₃-producing bacteria, promotes beneficial microorganisms, and converts NH₃ to nonabsorbable NH4⁺ to reduce ammonia levels[96]. Wang et al[97] demonstrated that lactulose is a safe and effective treatment for MHE because it decreases the abundance of Pediococcus, Clostridium, and Pseudomonas and increases the abundance of Anaerosinus and Akkermansia. The EASL guidelines recommend lactulose as the first-line treatment for HE, and it is effective for treating covert HE, preventing HE, and providing secondary prophylaxis after the first episode of OHE[90]. A recent clinical trial demonstrated that lactulose plus rifaximin decreased ammonia production in patients with cirrhosis, as quantified by the constant ammonia infusion technique, which measures whole-body ammonia metabolism[98]. In addition, lactulose promotes the elimination of accumulated blood in the gastrointestinal tract of patients with concurrent esophageal variceal bleeding and suppresses the production and absorption of ammonia to prevent HE. However, some studies have also shown that lactulose can lead to complications such as bloating, flatulence, and severe and unpredictable diarrhea, which may result in dehydration[99]. Current studies on the use of lactulose for the treatment and prevention of HE after TIPS are limited. An RCT from 2005 by Riggio et al[100] suggested that lactulose is not effective in the prophylaxis of HE after TIPS compared with no treatment. However, this study only compared the incidence of HE within 1 month after TIPS, so factors including insufficient medication duration cannot be completely excluded. Furthermore, Seifert et al[101] reported that the combination of lactulose and rifaximin is more effective in patients with HE prior to TIPS than in those with no history of HE. Lactulose is effective in the treatment and prevention of HE in patients with cirrhosis who have not received a TIPS. However, most current treatments and preventive measures for HE after TIPS are not significantly different from those used in the control group. This lack of efficacy may be due to insufficient medication time for patients and the impact of preoperative HE episodes. Alternatively, the preventive effect of lactulose through the aforementioned mechanisms may be insufficient to prevent HE in patients with a high risk of HE compared with patients who have not received a TIPS. Further large-scale RCTs are needed to explore the effects of lactulose alone on HE in patients who have undergone TIPS.

Rifaximin, a nonsystemic antibiotic based on rifamycin, has low gastrointestinal absorption and broad-spectrum antibacterial action without ototoxicity or nephrotoxicity[102]. Owing to its minimal absorption, it has high bioavailability within the gastrointestinal tract[99]. Rifaximin can be used to treat HE by improving bacterial translocation and systemic endotoxemia, reducing systemic inflammation, and repairing the intestinal barrier[103,104]. Rifaximin selectively increases the abundance of Bifidobacterium, Faecalibacterium prausnitzii, and Lactobacillus while reducing the abundance of Veillonellaceae without significantly altering the overall composition of the gut microbiota[105]. Furthermore, recent research utilizing human small intestinal organoids has demonstrated that rifaximin exerts direct effects on ammonia clearance within the small intestinal epithelium by enhancing intracellular nitrogen detoxification through mechanisms independent of the pregnane X receptor[106]. Bass et al[99] reported that rifaximin was more effective than placebo in maintaining remission from HE and reducing the risk of hospitalization related to HE over a six-month follow-up period. Furthermore, Wang et al[97] reported that rifaximin is efficacious in the treatment of MHE and can improve the composition of the gut microbiota. A multicenter RCT suggested that rifaximin is efficacious in preventing HE following TIPS by comparing patients who received rifaximin in conjunction with lactulose therapy post-TIPS to those who did not[107]. However, most of the studies evaluating the treatment of HE after TIPS were based on the combination of lactulose and rifaximin. Thus, the therapeutic effect of rifaximin alone on post-TIPS HE could not be comprehensively assessed. To date, only one prospective RCT has evaluated the therapeutic and prophylactic effects of rifaximin alone for OHE within 6 months after TIPS and revealed that rifaximin can prevent the development of post-TIPS OHE. Nonetheless, this study focused mainly on patients with alcoholic cirrhosis and recurrent ascites. As a result, the preventive efficacy of rifaximin in patients with other etiologies and variceal rebleeding remains undetermined[108]. The 2022 EASL guidelines and 2023 American Association for the Study of Liver Diseases practice guidelines suggest that rifaximin can be considered to prevent HE in cirrhotic patients with a history of OHE before TIPS placement[70,71]. However, in clinical practice, several studies have noted that the increasing incidence of Clostridium difficile infection and its relatively high cost limit its widespread use[109,110]. Therefore, the efficacy, safety, and optimal duration of rifaximin treatment for managing post-TIPS HE should be further evaluated in future multicenter RCTs.

Probiotics: HE is linked to an imbalance of in intestinal homeostasis[111]. Probiotics primarily affect the intestine, treating HE by regulating intestinal flora dysbiosis, enhancing intestinal mucosal barrier function, and modulating intestinal immunity and inflammation-related factors[112]. Various probiotics contain different combinations of bacterial species and play different roles in the treatment and prevention of HE. Bajaj et al[113] demonstrated that Lactobacillus GG is associated with reduced endotoxemia and microecological imbalance, whereas Stadlbauer et al[114] reported that Lactobacillus casei Shirota restored neutrophil phagocytic capacity. Yang et al[115] found that ProBiotic-4 (Bifidobacterium lactis, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus acidophilus) alleviated cognitive impairment in aged mice via the suppression of Toll-like receptor 4- and RIG-I-induced nuclear factor-kappa B signaling and inflammation. Most current studies on probiotic treatment for HE include Bifidobacterium longum, Lactobacillus bulgaricus, and Streptococcus thermophilus which are key components of their probiotic formulations[116,117]. Probiotics are as effective as lactulose and rifaximin in reversing MHE and preventing OHE, with the added advantage of having fewer side effects[118]. Xia et al[119] demonstrated the efficacy of probiotics in treating MHE in patients with hepatitis B virus-induced cirrhosis by comparing changes in cognitive function, the gut microbiota, and venous blood ammonia levels after three months of probiotic treatment vs no treatment. Another RCT reported that taking probiotics for three months is effective in preventing the occurrence of HE in patients with liver cirrhosis[120]. Dhiman et al[121] conducted a double-blind RCT and revealed that the oral administration of probiotics for six months can prevent the recurrence of HE and reduce hospitalization rates. Notably, while the aforementioned studies indicate the effectiveness of probiotics in the treatment or prevention of HE, these studies have included populations from different regions, with inconsistent probiotic administration times and varying types of probiotics. Therefore, the optimal duration for probiotic treatment and the generalizability of these probiotics in HE patients are unclear.

However, the role of probiotics in the prevention and treatment of post-TIPS HE remains uncertain. Probiotics reduce ammonia production by modulating the composition of the intestinal flora, thereby reducing the amount of ammonia that enters the BBB and lowering the incidence of HE. Theoretically, although the use of portal-systemic shunts is increased after TIPS, the incidence of post-TIPS HE is reduced if less ammonia is absorbed from the intestine into the blood. This has been demonstrated in our preliminary study on the prophylaxis of HE after TIPS with probiotics (ChiCTR2200062996). Multicenter prospective RCTs are needed to confirm the role of probiotics in the treatment and prevention of HE following TIPS.

L-ornithine-L-aspartate: The main metabolic pathway for ammonia is the synthesis of urea in the liver through the urea cycle, and ornithine and aspartate are essential substrates in the urea cycle. Moreover, in extrahepatic tissues such as the brain and muscles, ammonia is converted into glutamine, a nontoxic transport form, through the action of GS, which is activated by ornithine and aspartate[122]. L-ornithine-L-aspartate (LOLA) is a combination of ornithine and aspartate that plays an important role in reducing blood ammonia levels both within and outside the liver[123].

A double-blind RCT conducted by Jain et al[124], which focused primarily on patients with grade 3 to 4 OHE, revealed that the continuous intravenous infusion of LOLA for 5 days, in addition to lactulose and rifaximin treatment, was more effective in improving HE grades and reducing the time to recovery from HE than lactulose and rifaximin alone were and decreased 28-day mortality. Other studies have shown that, compared with lactulose and probiotics, LOLA has an equivalent therapeutic effect on HE[125]. Whether the effect of LOLA treatment on HE is associated with the different types of HE (acute HE, chronic HE, or MHE) and the route of LOLA administration (oral or intravenous) remains controversial a review of the treatment and prevention of HE in patients with liver cirrhosis indicated that the efficacy of LOLA is not related to different types of HE or the route of administration[126]. Jiang et al[127] reported that the LOLA is effective in the treatment of acute HE and chronic HE but ineffective in the treatment of MHE. A meta-analysis revealed that oral administration of LOLA is more effective than intravenous infusion in the treatment of MHE[128]. Bai et al[113] compared the venous blood ammonia levels of patients who did and did not receive a LOLA infusion and reported a decrease in venous blood ammonia levels in the group that received a LOLA infusion 7 days post-TIPS. Furthermore, the levels of transaminases and bilirubin were significantly lower in the LOLA-treated group than in the control group, indicating that LOLA can improve liver function after TIPS[113]. However, Seifert et al[101] found no significant difference in the prevention of HE after TIPS between patients with previous HE who received LOLA in addition to rifaximin and lactulose treatment and those who did not. Rees et al[129] enrolled 7 patients who received a TIPS and 8 patients who did not undergo TIPS, challenged them with a glutamine load and administered either LOLA or placebo intravenously, finding that the LOLA improved psychometric testing performance in the non-TIPS group, but no significant improvement was observed in the TIPS group. This may be related to the higher baseline blood ammonia levels in patients who underwent TIPS. However, the study included only 15 patients, so it is difficult to exclude selective bias and other nonintervention factors leading to this conclusion. In summary, we can preliminarily conclude that the LOLA can reduce blood ammonia levels after TIPS and improve cognitive function in patients. However, this effect seems to be insignificant in patients with previous HE.

Branched-chain amino acids: The occurrence of HE is related to an imbalance in the ratio of branched-chain amino acids (BCAAs) (valine, leucine, and isoleucine) to aromatic amino acids (AAAs) (phenylalanine, tyrosine, and tryptophan) in the blood[130]. In healthy individuals, BCAAs and AAAs provide energy for the body and participate in protein synthesis and the regulation of various physiological functions through a series of complex biochemical reactions. In patients with cirrhosis, liver function is impaired, which reduces the synthesis of BCAAs and decreases the breakdown of AAAs to ultimately increase the BCAA/AAA ratio. Excess AAAs can cross the BBB and be converted into neurotransmitters within the brain. The abnormal accumulation of these neurotransmitters can lead to neurological dysfunction and interfere with neural signal transmission.

Supplementation with BCAAs can increase the ratio of BCAAs in the blood, restoring amino acid balance and thereby inhibiting the production and release of false neurotransmitters, thus treating HE[131]. In addition, BCAAs decrease the occurrence of HE by regulating the gut microbiota and improving gut barrier function[132]. An RCT revealed that patients with alcoholic cirrhosis and HE who received a combination of antibiotics and BCAAs had faster and more complete recoveries than did those who received antibiotics alone[133]. Additionally, Vidot et al[134] found that the combination of BCAAs and prebiotics was more effective in treating HE than prebiotics alone. However, in an RCT that included 116 patients with cirrhosis and a previous episode of HE, supplementation with BCAAs in the diet did not reduce the recurrence rate of HE but did improve MHE and skeletal muscle mass[135]. Furthermore, an early study suggested that BCAAs reduce the concentration of AAAs in the blood of HE patients but do not improve brain function[136]. Therefore, the EASL clinical practice guidelines state that while BCAAs are beneficial for HE patients, their role in preventing HE recurrence still needs to be further validated by high-quality RCTs[71]. Regarding the treatment and prevention of HE after TIPS placement, further research on the role of BCAAs is still needed.

Fecal microbiota transplantation: The intestinal microbiome, which consists of various bacteria, fungi, viruses, and other organisms, has proinflammatory or anti-inflammatory effects[137]. In healthy individuals, the intestinal microbiota remains in a balanced state. In patients with liver cirrhosis combined with HE, the reduced production of bile acids disrupts this balance, leading to an increase in harmful bacteria and a decrease in beneficial bacteria[111]. The reduced production of short-chain fatty acids leads to an increase in the intestinal pH, allowing urease-producing bacteria to continue to grow and produce ammonia and endotoxins, which results in hyperammonamia, systemic inflammation, and impaired intestinal barrier function[138].

Fecal microbiota transplantation (FMT) involves transferring fecal materials from healthy donors to patients with dysregulated intestinal environments to restore the gut microbiota balance. Administration methods include colonoscopy, enema, nasogastric, or nasojejunal routes[139,140]. The mechanism by which FMT exerts its effects may involve increasing the colonization of beneficial gut bacteria in patients with liver cirrhosis and HE, thereby reducing intestinal edema, mucosal injury, and inflammatory infiltration[141]. Additionally, FMT reduces blood ammonia levels and improves HE by downregulating the expression of proinflammatory cytokines[142]. An RCT divided patients with recurrent HE into a standard treatment (SOC) group and an SOC plus 5 days of broad-spectrum antibiotic treatment followed by the FMT group. This study revealed that FMT did not increase the incidence of serious adverse events in patients. Additionally, the SOC plus 5 days of broad-spectrum antibiotic treatment followed by FMT group presented improved psychometric hepatic encephalopathy scores and increased gut microbiota diversity[143]. However, in this study, the specific SOC regimen was not detailed, and it is unclear whether patients continued to receiving rifaximin treatment after FMT is unclear. Furthermore, patients received 5 days of broad-spectrum antibiotic treatment prior to FMT, which hindered the evaluation of the impact of FMT on changes in the gut microbiota separately. Bajaj et al[144] reported that decompensated cirrhotic patients, including those with HE, presented increased levels of virulence factors (VFs). Compared with the control and pre-FMT methods, FMT was able to reduce VF. The efficacy of FMT is closely related to the selection of both the recipient and the donor. Bloom et al[141] conducted an open-label study based on fecal metagenomic testing before and after FMT. They reported that FMT improved cognitive function in HE patients and that its efficacy varied with changes in donors and recipients. Additionally, the authors noted that FMT did not completely reshape the faecal microbiome; instead, subtle or proximal gut changes may underlie its therapeutic mechanism. A meta-analysis that included twenty-one studies indicated that microbiome therapies, including probiotics, symbiotics, and FMT, were more effective at improving MHE and preventing progression to OHE[145]. However, none of these studies specified the dose of fecal material, dosing frequency, or ideal donor and delivery modality. Additionally, most of the studies included a limited number of patients.

Although changes in the gut microbiota are associated with the occurrence of HE after TIPS, no studies have yet been conducted on the use of FMT for the treatment of HE following TIPS placement has not yet been studied. Li et al[32] conducted a prospective longitudinal study of 106 patients with cirrhosis who had undergone TIPS and reported that gut microbiota dysbiosis was associated with the occurrence of post-TIPS HE. These findings suggest that the gut microbiome is a target for the treatment of post-TIPS HE. Additionally, in the open-label study by Bloom et al[141] mentioned above, four patients (40%) had received a TIPS prior to FMT, and TIPS did not significantly affect the treatment of HE with FMT.

Post-TIPS HE is correlated with gut microbiota shifts. In a study by Li et al[146], two cirrhotic patients with recurrent grade 2-3 HE experienced improved liver function and a significant decline in HE attacks following three FMT treatments. Bloom et al[147] reported in their open-label study that 40% of patients (n = 4) had a history of TIPS before receiving FMT, and TIPS placement did not significantly impact the therapeutic outcomes of FMT for HE. These findings suggest that the gut microbiome could be a potential therapeutic target for post-TIPS HE and that the role of FMT needs further validation through RCTs.

Endovascular techniques for shunt reduction: An episode of OHE occurs in 35% to 50% of patients after TIPS, whereas refractory HE, including recurrent or persistent HE that cannot be controlled by dietary and pharmacological interventions, occurs in approximately 8% of patients[7,148]. For such patients, stent occlusion or diameter reduction represents a potential therapeutic strategy. However, stent occlusion is associated with a marked increase in the incidence of portal hypertension-related complications and is generally not recommended. To date, the primary techniques for stent reduction include the parallel stent method, the hourglass configuration method, and the tapered stent-graft method. Among these methods, the parallel stent method is more widely applied. Moreover, research has indicated that the hourglass configuration method can be utilized to alter the stent graft, efficiently diminishing shunt flow and improving OHE[149]. In an observational study of 12 patients who developed refractory HE after TIPS, shunt reduction was performed via an hourglass-shaped balloon-expandable expanded polytetrafluoroethylene stent-graft inserted into the original shunt. A follow-up at approximately 1 year revealed no recurrence of HE, but there was no improvement in liver dysfunction[150]. Additionally, Rowley et al[151] employed the parallel reduction technique to reduce the stent in 10 patients who developed refractory HE after TIPS. Among them, recurrent HE improved in 8 out of 10 patients, but the survival rate at 1 year without liver transplantation was only 10%. These findings suggest that stent reduction can effectively alleviate refractory HE after TIPS, but it may not improve liver function or the survival rate. Furthermore, the recurrence of portal hypertension-related complications such as ascites and variceal bleeding after stent reduction is also a major issue. Shah et al[152] studied 33 patients who required stent reduction, 14% of whom experienced a recurrence of ascites after the stent reduction procedure. A review highlighted that following TIPS stent reduction, which involves an increase in the PPG from 8 mmHg to 12 mmHg, the recurrence rate of portal hypertension-related symptoms is 29%[153].

Notably, while the abovementioned studies offer insights into managing post-TIPS refractory HE, their small sample sizes and absence of control groups indicate that the observed improvements in HE could be due to factors unrelated to stent reduction. Moreover, comparing the differences in symptoms related to portal hypertension, liver function, and patient survival rates between those who have undergone stent reduction and those who have not is essential to assess the efficacy of stent reduction precisely for patients with refractory HE following TIPS placement.

FUTURE DIRECTIONS

First, early detection and identification of MHE following TIPS is crucial for the timely removal of precipitating factors, thereby preventing the occurrence of OHE. The creation of an efficient predictive model for MHE based on serum biochemical indicators, cognitive assessment systems, and radiomics warrants further investigation. Second, when sarcopenia is targeted as a therapeutic endpoint, comprehensive preoperative and postoperative nutritional assessments for patients who receive a TIPS, along with dietary guidance provided by nutritionists, may represent a nonpharmacological approach to prevent HE after TIPS placement. Third, the optimal size of the shunt channel that should be embolized to increase the prevention efficiency of HE after TIPS creation needs further investigation. Fourth, future research should focus on developing adjustable stents based on PPG and post-TIPS HE. Finally, the efficacy and safety of FMT as a treatment for HE following TIPS placement need to be investigated in the future.

CONCLUSION

This review is based on physiopathology and provides a detailed exposition about the assessment of patients before TIPS placement, the determination of stent diameter during the procedure, the combination of SPSS embolization, and patient diet, medication, FMT and stent reduction management after TIPS placement. Although TIPS increases the risk of HE in patients, most cases of HE can be effectively controlled by dietary intervention and drug management, and only a small number of recurrent or persistent HE cases require stent reduction. An increasing number of management strategies have been shown to be effective in the treatment of post-TIPS HE. A recent study confirmed that post-TIPS HE does not affect patient survival rates[154]. TIPS also decreases the further decompensation rates of complications other than HE[155]. Therefore, we believe that HE should not be a major barrier to the performance of TIPS. Multicenter RCTs are needed to further validate the effectiveness of the aforementioned HE management strategies after TIPS and to explore new therapeutic options in the future.