Risk factors for hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in cirrhotic patients: A comprehensive minireview

Abstract

Transjugular intrahepatic portosystemic shunt (TIPS) is widely used to treat portal hypertension and its complications patients with cirrhosis. However, managing post-TIPS hepatic encephalopathy (HE) remains a major clinical challenge. HE is characterized by a high incidence and a complex pathogenesis, influenced by various factors. Therefore, careful patient assessment and selection for TIPS is essential. While previous studies have identified several factors contributing to the occurrence of post-TIPS HE, there is a gap in the comprehensive integration of surgical procedural parameters and metabolic mechanisms within a multidimensional analysis. This minireview aims to optimize treatment protocols and refine management strategies by conducting a comprehensive analysis of risk factors, ultimately aiming to reduce the incidence of post-TIPS HE.

Key Words: Portosystemic shunt; Transjugular intrahepatic; Hepatic encephalopathy; Cirrhosis; Portal hypertension

Core Tip: The pathogenesis of hepatic encephalopathy (HE) following transjugular intrahepatic portosystemic shunt (TIPS) is complex, involving numerous risk factors. It is essential to recognize that HE is a multifactorial syndrome that necessitates a thorough understanding of various contributing factors. A comprehensive approach that includes preoperative individualized risk assessment, intraoperative management of portosystemic shunting, and postoperative prognostic care can provide evidence-based strategies for optimizing patient selection for TIPS. This approach aims to reduce the risk of HE following TIPS, improving long-term prognosis.

INTRODUCTION

Transjugular intrahepatic portosystemic shunt (TIPS) is a minimally invasive procedure designed to manage the complications of portal hypertension, including variceal bleeding, refractory pleural effusion, and ascites[1,2]. By creating an intrahepatic shunt between the hepatic and portal veins (PVs), TIPS effectively alleviates these complications and has become an essential tool in the management of portal hypertension since its inception in 1971 and subsequent adoption in clinical practice in 1988[3]. The first TIPS procedure in China was performed in 1992[3], marking an important milestone in its global application. Over the past 3 decades, advancements in TIPS techniques have enhanced the efficacy thereof in treating portal hypertension and its associated complications, leading to improved patient outcomes[4,5]. The advantages of this minimally invasive procedure include a significant reduction in portal pressure, which is crucial to prevent variceal hemorrhage—a major cause of morbidity and mortality in patients with cirrhosis—thus leading to good short-term efficacy.

TIPS can reduce the risk of variceal bleeding by up to 90% and improve overall survival rates in patients with portal hypertension. Furthermore, TIPS is increasingly recognized as a potential bridge to liver transplantation, providing critical support for patients awaiting this life-saving procedure. Despite its advantages, the occurrence of hepatic encephalopathy (HE) remains a major post-TIPS complication that limits its broader application. The incidence of HE after TIPS ranges from 10% to 50%, contributing to increased morbidity and mortality among cirrhotic patients[6,7]. HE not only severely impairs patients’ quality of life and cognitive function but also complicates medical management, leading to a greater healthcare burden. Although TIPS techniques have been optimized in recent years, the pathogenesis of HE is not fully understood.

Several risk factors have been identified, including preoperative liver function, procedural details, postoperative management strategies, and individual patient characteristics. Current predictive models, such as the Controlling Nutritional Status score, show promise but require large-scale validation for clinical application. Moreover, TIPS treatment protocols are largely based on clinical experience and general guidelines, lacking personalized strategies. Addressing these challenges is crucial.

Identifying reliable predictive indicators for post-TIPS HE, establishing appropriate risk stratification criteria, and optimizing predictive models are essential steps toward reducing the incidence of HE after TIPS[8]. This study aimed to conduct a minireview of the risk factors associated with TIPS-related HE, providing guidance for clinical practice and ultimately improving the long-term prognosis of patients undergoing TIPS.

CONCEPT AND CLASSIFICATION OF TIPS-RELATED HE

According to the American and European Associations for the Study of Liver Diseases 2014 guidelines, HE is defined as “a spectrum of neuropsychiatric abnormalities ranging from subclinical changes to coma, caused by liver failure and/or portosystemic shunting”[9]. In 1998, the World Congress of Gastroenterology classified HE into three types: (1) Type A, related to acute liver failure; (2) Type B, related to portosystemic shunting without underlying liver disease; and (3) Type C, associated with liver cirrhosis with portosystemic shunting. Type C is the most prevalent form both domestically and internationally and is potentially reversible[10].

TIPS-related HE is defined as central nervous system dysfunction resulting from metabolic disturbances following the establishment of a shunt between the portal and systemic circulation during TIPS, excluding other known brain diseases[11]. Essentially, this aligns with type C HE as previously mentioned. More recently, post-TIPS HE has been classified as type D, which refers to acute-on-chronic liver failure, such as that caused by acetaminophen overdose[12,13]. The Practice Standards Committee of the American Gastroenterological Association[14] further proposed the West-Haven classification, which divides the severity of the condition into grades 0 to 4 (Table 1). This classification method is currently the most widely used. Due to the challenges in distinguishing between grades 0 and 1, the International Society for Hepatic Encephalopathy and Nitrogen Metabolism[15] proposed the SONIC classification, which combines grades 0 and 1 as covert HE (CHE) and grades 2 to 4 as overt HE (OHE). CHE is defined as the presence of neuropsychological and/or neurophysiological abnormalities in cirrhotic patients without disorientation or flapping tremors.

Table 1 West Haven criteria for semi-quantitative grading of hepatic encephalopathy.

Grade	Manifestation
Grade 0	No overt symptoms; mild cognitive impairment detectable only by specialized tests (e.g., neuropsychological tests)
Grade 1	Mild consciousness disturbance; euphoria and/or anxiety; inattention; impaired ability to perform simple addition
Grade 2	Lethargy or apathy; mild disorientation for time or place; subtle personality changes; inappropriate behavior; impaired ability to perform simple subtraction
Grade 3	Somnolence to semi-stupor but responsive to verbal stimuli; confusion; gross disorientation
Grade 4	Coma (unresponsive to verbal or painful stimuli)

The West Haven classification provides a quantitative framework for clinicians to assess the severity of post-TIPS HE. This system not only aids in evaluating disease progression but also guides tailored treatment plans. For example, grades 1 and 2 HE can be managed with dietary modifications or medications such as lactulose or rifaximin, whereas grades 3 and 4 HE require more aggressive interventions. Overall, this grading method helps optimize risk management and improve long-term prognosis in patients with post-TIPS HE.

The pathogenesis of HE following TIPS is not fully understood. It is currently believed to be multifactorial. First, TIPS increases systemic exposure to gut-derived toxins, such as ammonia, which bypass the liver’s first-pass metabolism and directly enter the systemic circulation. Second, TIPS reduces the liver’s performance, including the synthesis of glutamine and urea by diverting portal blood flow. Ammonia can cross the blood–brain barrier, where its elevated levels prompt astrocytes in the brain to synthesize glutamine, which causes osmotic swelling of the astrocytes and disrupts normal brain function.

Studies have reported a strong correlation between shunt diameter and HE incidence[16,17]. In addition, there are other causes of HE in patients with cirrhosis, such as hepatocyte dysfunction, coexisting portosystemic shunt circulation, increased production of intestinal neurotoxins, and increased permeability of the blood–brain barrier, which contribute to post-TIPS HE[18]. In a recent study, researchers constructed a gut–brain module to assess bacterial neurotoxins using metagenomic data, and found that the phenylalanine decarboxylase (PDC) gene, primarily from Ruminococcus gnavus (R. gnavus), was increased approximately 10-fold in cirrhotic patients and even higher in those with HE[19]. Using a cirrhotic mouse model, they demonstrated that targeting PDC or its metabolite phenylethylamine (PEA) could reverse the neurological symptoms caused by R. gnavus. Clinically, elevated baseline levels of PEA have been associated with a seven-fold increased risk of HE following TIPS[19]. These findings expand our understanding of the gut–liver–brain axis and provide new therapeutic and predictive targets for HE.

However, these risk factors do not act in isolation, but rather interact in subtle ways. For instance, dysbiosis of the gut microbiota leads to the proliferation of ammonia-producing bacteria, such as R. gnavus, thereby increasing the production of ammonia in the gut. A larger shunt diameter not only increases systemic exposure to toxins but may also alter intestinal hemodynamics, further affecting the composition and function of the gut microbiota, thereby increasing the risk of HE. Impaired liver function weakens the detoxification of intestinal toxins, while dysbiosis of the gut microbiota, in turn, exacerbates the liver’s burden by producing more toxins, creating a vicious cycle. Toxins produced by gut microbiota dysbiosis, such as PEA, can affect the permeability of the blood–brain barrier, increasing its sensitivity to ammonia and other toxins, thereby exacerbating the occurrence of HE. These interactions highlight that the development of HE is a multifactorial and complex syndrome (Table 2)[20-29].

Table 2 Research on risk factors for hepatic encephalopathy following transjugular intrahepatic portosystemic shunt.

Ref.	Country	Research design, number of patients	Hepatic encephalopathy incidence (%)	Main risk factors	Effective interventions
Li et al[21]	China	Single-center, retrospective, n = 113	28.3	History of HE	Not reported
Zhuo et al[23]	China	Single-center, retrospective, n = 263	22.1	Diabetes, hyponatremia, portal vein pressure gradient > 12 mmHg	Not reported
Yin et al[24]	China	Single-center, retrospective, n = 108	45.4	Sarcopenia, Child–Pugh C, myosteatosis	Not reported
Luo et al[25]	China	Single-center, retrospective, n = 1244	Overall: Left branch group < right branch group	Portal vein puncture site	Left branch puncture reduced HE risk (P < 0.05)
Wang et al[26]	China	Single-center, retrospective, n = 127	8 mm group: 27.0; 10 mm group: 43.0	Stent diameter, advanced age	8 mm stent reduced HE risk (HR = 0.52)
Fonio et al[20]	Italy	Single-center, retrospective, n = 75	6 months: 36.0; 12 months: 27.0	Advanced age, Child–Pugh C, history of HE	Not reported
Casadaban et al[22]	United States	Single-center, retrospective, n = 191	42.0	History of HE, advanced age, low albumin	Not reported
Schepis et al[27]	Italy (Modena and Florence)	Multicenter, prospective, n = 95	Under-dilated stent: 27.0; control: 54.0	Excessive portal decompression (> 60%), Child–Pugh C	Under-dilated stent reduced HE risk
Bureau et al[29]	France	Multicenter, randomized controlled trial, n = 197	Rifaximin: 34.0; Placebo: 53.0	Not screened	Rifaximin prophylaxis reduced HE risk (HR = 0.52)
Kabelitz et al[28]	Hannover, Vienna, Hamburg	Multicenter, prospective, n = 1509	22.7	Portal pressure gradient reduction > 50%, Child–Pugh C, advanced age	Not reported

HE: Hepatic encephalopathy; HR: Hazard ratio.

PATIENT-RELATED FACTORS ASSOCIATED WITH HE AFTER TIPS

Advanced age

Advanced age is an important prognostic factor of poor outcomes following TIPS[30]. As individuals age, gastrointestinal transit time tends to increase, leading to a higher risk of constipation and imbalances in the gut microbiota, which can precipitate HE. The British Association for the Study of the Liver (BASL) has also demonstrated that although age > 65 years is not an absolute contraindication for TIPS, it may increase the risk of HE, warranting careful consideration when determining the eligibility of candidates for elective TIPS procedures[20,31].

Gut microbiota dysbiosis

Gut microbiota-derived metabolites substantially influence brain physiology and pathophysiology[32]. The liver, which is directly connected to the gut via the portal system, plays a vital role in metabolizing gut-derived neurotoxins. This gut–liver–brain axis is particularly important in the development of HE, particularly in the context of gut dysbiosis[33-35]. The accumulation of bacterial toxin metabolites, along with a weakened capacity for detoxification due to impaired liver function, underlies the pathogenesis of HE (Figure 1)[33-35].

Figure 1 Pathogenesis of hepatic encephalopathy. HE: Hepatic encephalopathy; HV: Hepatic vein; PV: Portal vein; SMV: Superior mesenteric vein; SV: Splenic vein; TIPS: Transjugular intrahepatic portosystemic shunt.

A recent study by He et al[19] systematically elucidated the mechanisms by which gut microbiota influences HE via the PDC–PEA axis, employing an integrative multi-omics approach (combining metagenomics, metabolomics, and transcriptomics), as well as validating their findings in animal models and clinical cohorts. They demonstrated that in compensated liver function, PEA derived from the gut microbiota is effectively metabolized by monoamine oxidase-B (MAO-B). However, in a decompensated state, HE development is linked to decreased MAO-B activity, elevated PDC levels in gut bacteria, and impaired PEA degradation.

Bile acids

Studies have reported an increase in certain bile acids, particularly taurocholic acid and glycocholic acid, in the cerebrospinal fluid of cirrhotic patients with HE[36]. Furthermore, a chronic liver injury mouse model demonstrated elevated total bile acid content in brain tissue prior to the onset of HE, suggesting that bile acids may contribute to the pathogenesis of HE[37]. Li et al[21] found that elevated gamma-glutamyl levels may be associated with an increased risk of HE.

History of HE

In China, several factors, including preoperative history of HE, Child–Turcotte–Pugh classification, advanced age, elevated creatinine levels, hyponatremia, and sarcopenia, are significantly associated with the development of HE after TIPS[38]. Trivedi et al[39] identified a prior history of HE as the most reliable risk factor for HE following TIPS. Additionally, in 2020, the BASL strongly recommended that patients undergoing elective TIPS be screened for covert and OHE based on high-quality evidence[31].

Diabetes mellitus

Yin et al[40] reported a correlation between diabetes mellitus (DM) and the occurrence of HE after TIPS. Their multivariate logistic regression analysis of 436 consecutive cirrhotic patients who underwent TIPS from 2008 to 2016 revealed that DM is an independent risk factor for HE after TIPS [odds ratio (OR) = 1.901, 95%CI: 1.131–3.195, P = 0.015]. Subsequent Kaplan–Meier curve analysis indicated that DM significantly increased the incidence of OHE (log-rank P = 0.026). Potential mechanisms linking DM to HE include systemic inflammation, increased proteolysis, and ammonia production[41]. Additionally, increased glutaminase activity in the liver, kidneys, and small intestine is associated with hyperammonemia. Diabetic patients often experience reduced gastrointestinal motility, leading to gut microbiota imbalances and bacterial translocation. Furthermore, impaired immune function in diabetic patients increases their susceptibility to infections, which are significant triggers for HE development post-TIPS[42].

Nutritional status

Sarcopenia: Malnutrition is a common complication of cirrhosis and is associated with the severity of liver disease and its complications, including HE[43]. Sarcopenia, characterized by the general loss of muscle mass and function, is a major aspect of malnutrition[44]. As early as 1964, it was recognized that malnutrition adversely affects the prognosis of cirrhotic patients[45]. A large Italian multicenter prospective study conducted in 1996 confirmed the prognostic significance of sarcopenia in cirrhotic patients[46]. In a large cohort of patients (675 cirrhotic patients enrolled between 2000 and 2014), sarcopenia was found to be associated with a higher risk of OHE[47]. Han et al[48] indicated that sarcopenia is significantly associated with the risk of significant liver fibrosis in patients with chronic hepatitis B.

Liver fibrosis is an early stage and an inevitable pathway to cirrhosis. Skeletal muscle plays an important role in transporting glutamine to the liver and kidneys. Sarcopenia can impair the metabolism of ammonia, potentially increasing the risk of HE after TIPS. Conversely, sarcopenic obesity can disrupt both ammonia and glutamate metabolism, leading to insufficient clearance of glutamate in the brain, which may cause astrocyte edema and disrupt normal nervous system function, thereby triggering HE[49,50]. A recent study involving 64 cirrhotic patients found that sarcopenia, myosteatosis, and previous episodes of HE were independently associated with the development of minimal HE[51].

Myosteatosis: Few studies have analyzed the relationship between myosteatosis and HE. Bhanji et al[47] conducted a retrospective analysis of patients with cirrhosis using computed tomography scans to assess skeletal muscle. They found that myosteatosis was independently associated with a higher risk of HE in a multivariate analysis.

In the first study to investigate the link between muscle fat infiltration and minimal HE, Nardelli et al[51] demonstrated that myosteatosis is closely related to OHE and to minimal HE. This suggests that myosteatosis may reduce the muscle’s capacity to manage ammonia, thereby being independently associated with HE in patients with cirrhosis. Therefore, improving nutritional status in malnourished patients with cirrhosis prior to TIPS may help reduce the occurrence of HE.

Scoring system

Child–Pugh score: The Child–Pugh scoring system is one of the most widely used assessment tools designed to quantify hepatic function in patients with cirrhosis. Initially proposed by Child in 1964, this scoring system predicts liver function and patient prognosis based on five parameters: (1) HE; (2) Ascites; (3) Serum bilirubin; (4) Serum albumin; and (5) Prothrombin time. The severity of liver disease, as indicated by the Child–Pugh score, is closely associated with the occurrence of post-TIPS-related HE[22]. A meta-analysis has shown that Child–Turcotte–Pugh Class C liver function is an independent predictor of post-TIPS-related HE (OR = 4.0, 95%CI: 1.4–11.1)[38].

FIPS score: The FIPS score, which stands for fibrinogen, international normalized ratio (INR), platelet count, and serum bilirubin, is a novel scoring system for predicting survival in patients after TIPS, first reported by Bettinger et al[30]. It incorporates serum total bilirubin, serum creatinine, age, and albumin. A recent multivariate analysis involving 113 patients with cirrhosis who underwent TIPS for bleeding esophagogastric varices found that the FIPS score was an independent predictor of OHE occurrence after TIPS (t = 2.984, P = 0.004).

Model for End-Stage Liver Disease score: The Model for End-Stage Liver Disease (MELD) score is used to assess the severity of chronic liver disease. It includes patients’ serum bilirubin, serum creatinine, and INR to predict short-term survival rates. The MELD score has been extensively applied to forecast the prognosis of cirrhotic patients and serves as a criterion to prioritize organ allocation in liver transplantation. A single-center retrospective study demonstrated that a MELD score greater than 18 was independently associated with the occurrence of post-TIPS HE (58% vs 37%, P = 0.009)[22].

Novel clinical prediction models: The predictive performance of OHE after TIPS was found to be low across all previously mentioned models. Consequently, numerous studies are underway to develop novel predictive models. For instance, a recent study by Zhuo et al[23] employed logistic regression analysis, incorporating factors such as age, history of diabetes, history of hepatitis B, serum ammonia, and Child–Pugh classification to plot the receiver operating characteristic curves. The results indicated that the Child–Pugh classification had the highest area under the curve (AUC) value of 0.680, while the history of diabetes had the lowest AUC value of 0.579. A predictive model that included age, diabetes, hepatitis B infection, serum ammonia levels, and Child–Pugh classification yielded an AUC of 0.841 (Figure 2), with a sensitivity of 92.6% and a specificity of 63.4%. Similarly, a study conducted in 2023 identified the MELD score [hazard ratio (HR) = 1.083, 95%CI: 1.020–1.449, P = 0.009], myosteatosis (HR = 0.930, 95%CI: 0.889–0.974, P = 0.002), and sarcopenia (HR = 0.895, 95%CI: 0.808–0.992, P = 0.035) as independent risk factors for HE after TIPS and constructed a predictive model based on these factors[24].

Figure 2 Key points for the prevention strategy of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt.

PROCEDURE-RELATED FACTORS ASSOCIATED WITH HE AFTER TIPS

Puncture site

Appropriate selection of the puncture site during TIPS is critical to achieve optimal outcomes and minimize the risk of HE. The 2019 Chinese guidelines recommend using the Viatorr stent, along with intraoperative embolization of spontaneous portosystemic shunts and varices, and establishing a shunt from the left branch of the PV to reduce the incidence of HE after TIPS[52]. However, studies by Yao et al[53] and Deng et al[54] found no statistically significant difference in the incidence of post-TIPS HE between procedures using the left vs the right PV. As early as 2002, Chu et al[55] confirmed through animal experiments that blood ammonia concentrations vary within different segments of the portal venous system. The superior mesenteric vein (SMV) exhibited the highest ammonia concentration, followed by the right PV, the left PV and the splenic vein (SV). This suggests that blood flowing from the SV entering the left PV contains fewer bacterial metabolic products, while blood flowing from the mesenteric vein entering the right PV contains a higher bacterial concentration of these products.

Mogicato et al[56] found using angiography and vascular casting in dogs that the blood from the SMV mainly flows to the right branch of the PV, and the blood from the SV mainly flows to the left branch of the PV. However, there is a lack of evidence comparing bacterial metabolic products in the left and right branches of the PV in humans. Also, there are no reports on hemodynamics related to the different blood flow velocities in the PV. Therefore, whether the occurrence of HE after TIPS is related to the left or right branch of the portal venous shunt remains a topic for further investigation. Therefore, future studies should focus on the individualized selection of the PV puncture site and optimizing the TIPS procedure to reduce the incidence of HE.

Stent lumen diameter

The PV primarily receives blood from the SMV, which is rich in ammonia. Therefore, a larger stent diameter results in a greater volume of shunted blood and elevated serum ammonia levels in systemic circulation, thereby increasing the risk of postoperative HE[25]. Teng et al[57] conducted a study comparing metallic covered stents with bare stents for TIPS. In the subgroup analysis of metallic covered stents, the incidence of HE was significantly lower with the 6 mm stent compared to the 7 mm and 8 mm stents (6.4% vs 37.6% vs 45.7%, P < 0.01; Table 3). Moreover, Wang et al[26] found that the 8 mm covered stent reduced the incidence of HE compared to the 10 mm stent, without compromising shunt function. Subsequent studies have confirmed that a stent diameter greater than 8 mm is an independent risk factor for the development of post-TIPS HE, with a positive correlation between stent size and the risk of postoperative HE[16,58].

Table 3 Incidence of hepatic encephalopathy following transjugular intrahepatic portosystemic shunt procedure with various stent diameters, n (%).

Type of stent	Incidence of hepatic encephalopathy
Uncovered stent (n = 130)	56/130 (43.1)
Diameter of stent: 8 mm (n = 47)	17/47 (36.1)
Diameter of stent: 10 mm (n = 83)	39/83 (47.0)
Covered stent (n = 574)	211/574 (36.8)
Diameter of stent: 6 mm (n = 94)	6/94 (6.4)
Diameter of stent: 7 mm (n = 178)	67/178 (37.6)
Diameter of stent: 8 mm (n = 302)	138/302 (45.7)

Intraoperative changes in PV pressure gradient

The occurrence of HE after TIPS may be related to the volume of shunted blood and the PV pressure gradient (PPG), both of which are associated with the stent diameter[27]. Yao et al[59] identified PPG as a significant factor in the development of HE after TIPS. While a greater reduction in PPG after TIPS improves shunt efficacy[60], it also increases the risk of HE. Specifically, for each 1 mmHg decrease in PPG after TIPS, the probability of developing HE increases by a factor of 1.2[61]. A recent study aimed to determine the optimal degree of PPG reduction after TIPS to effectively control ascites while minimizing the risk of OHE[28]. A total of 1509 patients from three European centers (Hannover, Vienna, and Hamburg) who underwent TIPS from 2000 to 2023 were included. Utilizing machine learning (ML) models, the researchers found that a PPG reduction of 60%–80% represents the optimal range. Within this range, patients experienced a significant decrease in liver decompensation events related to ascites, without an increased incidence of OHE. These findings were further validated in a separate cohort.

Due to differences in the etiology of liver cirrhosis and liver size between domestic and international populations, recent studies[62] have indicated that using an 8 mm inner diameter Viatorr stent to create a shunt channel results in a PPG reduction of 12 mmHg or 50% below baseline, and the incidence of HE among these patients varies depending on the etiology of the cirrhosis. The incidence of post-TIPS HE in patients with hepatitis B-related cirrhosis is lower than that in patients with alcoholic cirrhosis and primary biliary cirrhosis. Therefore, achieving a reasonable reduction in PPG after TIPS and making personalized choices may be a promising direction for future research.

Postoperative management and preventive strategies

Based on these potential risk factors, the careful selection of TIPS patients and early intervention may help prevent HE and improve patients’ quality of life. Historically, patients with HE after TIPS have been conservatively treated with a low-protein diet, along with oral antibiotics that have low intestinal absorption, such as rifaximin and disaccharides, to reduce the production and absorption of intestinal neurotoxins. However, this practice is increasingly being questioned[63-65]. The latest Baveno Consensus VII[66] recommends initiating early treatment with L-ornithine L-aspartate within the first week after TIPS, maintaining regular bowel movements with lactulose, and timely monitoring and correction of water and electrolyte levels as needed. In patients with a history of OHE undergoing elective TIPS, a randomized controlled trial found that daily administration of 1.2 g rifaximin significantly reduced HE after TIPS, consistent with findings from subsequent studies[29,67]. In cirrhotic patients, it is essential to promptly rule out bacterial infections and initiate appropriate antibiotic therapy.

Fecal microbiota transplantation (FMT) is increasingly being used in the management of Clostridium difficile infections, and emerging research suggests that FMT may also play an important role in the management of other conditions related to gut microbiota imbalance, including HE[68]. FMT restores the ecological balance of the gut microbiota, thereby reducing the proliferation of ammonia-producing and other pathogenic bacteria. This restoration leads to a decrease in blood ammonia levels and an improvement in gut barrier function. Additionally, FMT has been demonstrated to modulate the metabolic products of gut microbiota, such as short-chain fatty acids and bile acids, which can influence the gut–brain axis, improve neuroinflammation, and enhance cognitive function.

In a first randomized controlled trial, Bajaj et al[68] reported that FMT can reduce the recurrence of HE, decrease hospitalizations, and improve cognitive function compared to current standard treatments (rifaximin/Lactulose). In recent years, numerous studies have explored the potential application of FMT in managing HE, emphasizing the role of gut microbiota dysbiosis in the pathogenesis of HE[69-71]. Despite the challenges and potential risks associated with the clinical application of FMT—such as donor selection, microbiota quality, infection risk, long-term efficacy and safety, and ethical considerations—the application of FMT in managing HE following TIPS appears to hold great promise. Based on these perspectives, a systematic prevention and treatment protocol for HE following TIPS can be formulated. In terms of pharmacological intervention, rifaximin (1.2 g per day, administered in divided doses) and L-ornithine L-aspartate were started within the first week after TIPS. Lactulose was given for the maintenance of regular bowel movements, with dosage adjusted according to the patient tolerance and bowel movements. A high-quality protein (such as lean meat, fish, legumes, and low-fat dairy products) diet was administered. Timely correction of electrolyte imbalances was performed to avoid precipitation of HE. For patients with recurrent HE, especially those unresponsive to conventional therapy, FMT may be considered. Through the aforementioned structured therapeutic regimen, the management of HE following TIPS was enhanced, thereby improving patients’ quality of life and prognosis.

Future directions and challenges

Future research should focus on improving the accuracy of predictive models for post-TIPS HE. The integration of artificial intelligence (AI) and ML technologies holds great promise in this area[72,73]. Predictive models based on ML algorithms can conduct in-depth mining and analysis of big data, integrating a variety of clinical indicators such as the Child–Pugh score, serum albumin levels, and inflammatory markers to enhance the accuracy of predictions[74]. AI and ML have emerged as transformative tools for the prediction and management of HE following TIPS, particularly excelling in imaging analysis and the integration of multimodal data. However, the clinical translation of these technologies faces challenges related to data quality, model interpretability, and ethical considerations[75]. The accuracy and reliability of AI models are contingent upon high-quality data, yet the quality and completeness of current clinical data remain suboptimal. Subsequently, the complexity of AI models may render their decision-making processes opaque, potentially undermining clinician trust and adoption. Moreover, AI technology involves the collection and processing of extensive patient data, raising urgent concerns regarding data privacy and ethical implications. Looking ahead, as real-time monitoring technologies and AI models continue to develop, individualized TIPS treatment is expected to become more refined, ultimately enhancing patient survival and quality of life.

Many existing predictive models have not been validated in sufficiently large cohorts, which limits their applicability across different healthcare settings. For example, some studies have been conducted in single centers with limited sample sizes, which may lead to overfitting of the models and thus affect their generalizability to broader populations. Moreover, patient characteristics may vary across regions and healthcare environments, such as ethnicity and etiology of cirrhosis, which could impact the predictive performance of the models. Validating these predictive models in larger and more diverse cohorts to enhance their accuracy and reliability across different populations may be a direction for our future efforts.

Another important direction for future research is the optimization of TIPS procedures. The selection of the shunt location is a critical factor that influences the occurrence of postoperative HE. Moving beyond the traditional constraints of “left branch or right branch of the PV” and exploring the impact of TIPS puncture location on HE incidence is essential. Moreover, an ideal advancement would involve the use of controllable-diameter TIPS stents, which could adjust the degree of portal-systemic shunting based on different patient needs. For instance, if HE occurs, a controllable TIPS stent could temporarily narrow its diameter to reduce portal-systemic shunting. This would allow for more precise control over the shunting process, potentially reducing the incidence of HE.

The development of novel therapeutic targets based on the gut microbiota represents a promising direction for future research. The mechanisms by which the gut microbiota drives HE via the gut–liver–brain axis have been systematically elucidated for the first time, and PEA has been identified as a new diagnostic and therapeutic target (Figure 3)[19]. Personalized interventions that leverage microbiota modulation—including serum PEA quantification combined with PDC gene abundance analysis for early detection of HE and risk stratification—are promising. These strategies include FMT to suppress ammoniagenic and pathogenic bacterial overgrowth, the use of multi-target small-molecule inhibitors (e.g., PDC inhibitors), and synergistic regimens that combine traditional ammonia-lowering agents (like lactulose) with microbiota modulators (such as rifaximin). Together, these approaches represent transformative strategies for precision medicine. However, translational challenges persist, particularly regarding microbiota heterogeneity, FMT protocol standardization, and long-term safety validation[76-78]. Addressing these limitations requires collaborative efforts across research, clinical, and industrial sectors to advance mechanistic studies and rigorously designed clinical trials. This collaboration is essential for gaining insights into the gut microbiota that will lead to tangible therapeutic breakthroughs for HE patients.

Figure 3 Mechanisms of action of risk factors for hepatic encephalopathy.

This study has some important limitations. We confirmed that the aforementioned risk factors increase the incidence of HE following TIPS, and that effective prevention and postoperative management can reduce the occurrence of HE. However, the studies included in this minireview were mostly single-centered and retrospective analyses, with some having small sample sizes and high heterogeneity in the inclusion criteria (such as the definition of HE and follow-up duration). Future research will require larger, prospective studies with multicenter patient data to verify these findings, thereby reducing the potential bias in patient selection and obtaining more universally applicable results.

CONCLUSION

The pathogenesis of HE following TIPS is complex, involving numerous risk factors. We emphasize that HE is a multifactorial syndrome that necessitates a comprehensive understanding of the various contributing factors. A multifaceted approach that includes preoperative individualized risk assessment, intraoperative regulation of portosystemic shunting, and postoperative patient prognostic management has the potential to provide evidence-based support for optimizing patient selection for TIPS, reducing the risk of HE following TIPS, and improving long-term prognosis.