Management of upper gastrointestinal bleeding in advanced hepatocellular carcinoma with portal hypertension and variceal bleeding during receiving tyrosine kinase inhibitors therapy: Beyond and known frontiers

Hepatocellular carcinoma (HCC) poses a significant global burden, with most patients being diagnosed at an advanced stage, leading to poor prognosis due to the lack of systemic treatment. The approval of oral tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors, and anti‐angiogenic agents has rapidly expanded the treatment prospects for HCC. However, the use of these drugs has also increased the incidence of portal hypertension (PHT) and upper gastrointestinal variceal bleeding in HCC patients. The diagnosis, screening, emergency treatment, and secondary prevention of upper gastrointestinal variceal rebleeding in advanced HCC patients undergoing oral TKIs therapy have become clinically urgent and critical issues. This review provides an overview of the existing understanding regarding the uses and limitations of transjugular intrahepatic portosystemic shunt (TIPS) insertion for managing HCC in cirrhosis patients with PHT and variceal hemorrhage. Additionally, it explores the potential of TIPS in managing acute upper gastrointestinal bleeding and preventing rebleeding in advanced HCC patients undergoing TKIs therapy. The placement of TIPS within the treatment hierarchy is determined by the specific clinical environment and the individual attributes of the patient.


| INTRODUC TI ON
Hepatocellular carcinoma (HCC) ranks as the sixth most prevalent form of cancer and is responsible for the third-highest number of cancer-related fatalities.It is also the second leading factor for early cancer-related fatalities in China. 1 The occurrence and death rates of HCC have declined in certain East Asian nations like Japan, China, and Korea.Nevertheless, in numerous nations that previously had lower occurrence rates, like the United States, Australia, and various others, there has been a rise in the occurrence and death rates of HCC. 2 In the year 2020, approximately 905,700 individuals globally received a diagnosis of HCC, and 830,200 individuals succumbed to it. 3Sadly, a majority of HCC patients are diagnosed during the advanced stages of the illness, leading to a grim prognosis because of the absence of comprehensive treatment. 4e treatment options for patients with advanced HCC, which refers to tumors that have spread beyond the liver and into the hepatic vasculature including lymph node metastases, have recently expanded.This expansion is due to the approval of various oral tyrosine kinase inhibitors (TKIs) like sorafenib, lenvatinib, donafenib, regorafenib, and cabozantinib.[7] Optimal utilization of these medications in clinical practice can delay the progression of HCC and extend the overall survival of patients with advanced HCC. 8,9 However, their use has also increased the occurrence of fatal adverse events, including liver failure and bleeding. 10The administration of TKIs in advanced HCC is linked to an elevated risk of variceal bleeding of all grades, which may cause some advanced HCC patients to miss out on further TKI treatment for their tumors. 8Therefore, managing variceal bleeding is a critically important issue, particularly in preventing rebleeding of portal hypertension (PHT) in advanced HCC patients undergoing TKI therapy.
Different methods are currently used to treat variceal bleeding, such as vasoactive medications, endoscopic procedures, surgery, and transjugular intrahepatic portosystemic shunt (TIPS). 11doscopy serves the purpose of detecting the origin of bleeding and providing hemostatic treatment for ongoing bleeding lesions. 12vertheless, the efficacy of endoscopic intervention in variceal bleeding is restricted due to its inability to effectively diminish portal vein pressure.The use of TIPS can effectively decrease the intracavitary pressure within the portal vein system, which is a suitable method for treating PHT and preventing rebleeding. 13Despite being the established treatment for high-risk acute variceal bleeding (AVB) patients, prophylactic TIPS is not recommended for patients with HCC due to the risk of postoperative liver failure, severe complications, and low survival rates. 14The effectiveness of TIPS compared to endoscopy + β-blocker treatment in preventing rebleeding for advanced HCC patients undergoing TKI therapy, and its impact on the continued use of TKIs and survival benefits, remains uncertain.

| THE PATHOPHYS IOLOGY OF P ORTAL HYPERTEN S I ON AND UPPER G A S TR OIN TE S TINAL VARICE AL B LEEDING
6][17] It is typically defined by the occurrence of ascites, variceal bleeding, or hepatic encephalopathy.The estimation of PHT is typically done using the hepatic venous pressure gradient (HVPG), where an HVPG ≥10 mmHg is considered to be clinically significant or overt PHT (clinically significant PHT [CSPH] or clinically evident PHT) because hepatic decompensation may occur beyond this threshold. 17However, HVPG is not routinely performed in clinical practice, and the presence of oesophageal/ gastric varices and a low platelet count related to splenomegaly is considered an alternative indicator for clinically evident PHT. 18,19sophageal varices are a major complication of PHT.Around half of the patients with cirrhosis can be diagnosed with this condition, and every year, approximately 5-15% of cirrhotic patients experience the progression or aggravation of varices. 20Cirrhosis causes two primary physiological alterations in individuals with PHT: heightened resistance to portal venous flow and elevated portal blood flow. 21e increased resistance can be ascribed to liver fibrosis and alteration of the liver's typical structure, along with vasoactive elements. 22e progression of cirrhosis to HCC involves changes in the structure of liver sinusoids, chronic and progressive injury to liver cells, and the death of cells.Additionally, there is injury to endothelial cells in the sinusoids, causing a loss of these cells.The loss of sinusoidal endothelial cells leads to a 'capillarization' phenotype, which causes an increase in the secretion of vasoactive factors. 22One of these factors is endothelin-1 (ET-1), which is released and activates inactive hepatic stellate cells, transforming them into myofibroblasts.
The acceleration of collagen deposition in the extracellular matrix leads to the development of fibrosis, 23,24 which in turn causes the formation of PHT over several years.In addition to fibrosis, patients progressing to HCC experience two distinct pathogenic changes: parenchymal area loss and pronounced vascular remodeling, leading to sinusoidal collapse and structural distortion. 25The formation of regenerative nodules occurs as hepatocytes proliferate in the areas that were lost. 26The liver also undergoes increased vascular resistance due to vasoconstrictors like ET-1, while the intrahepatic circulation of vasodilators such as nitric oxide decreases, resulting in increased resistance to portal venous blood flow. 27,28Furthermore, PHT is propagated by the dilation of splanchnic arterioles, leading to an increase in blood flow within the portal venous system.PHT

| HEPATOCELLUL AR C ARCINOMA AND UPPER G A S TR OIN TE S TINAL VARICE AL B LEED ING
Both HCC and PHT are major complications of cirrhosis. 29In the case of cirrhosis, PHT occurs as a result of changes in liver sinusoids and the presence of fibrosis, leading to increased resistance in the intrahepatic blood vessels.The opening of collateral vessels and the formation of new blood vessels on the portal side are associated with the production of vascular endothelial growth factor (VEGF) and platelet-derived growth factor. 15,17Elevated levels of VEGF and chronic inflammation also contribute to the occurrence of HCC.Furthermore, people afflicted with PHT encounter a higher probability of acquiring HCC, and the alterations in the structure of liver cells and the infiltration of blood vessels caused by HCC also play a role in the emergence of PHT. 30,31Considering the frequent coexistence of PHT and HCC in patients, the management of PHT and its associated complications, along with the treatment of HCC, becomes increasingly intricate.Indeed, CSPH can impede curative therapies for HCC, like liver resection/ablation, while also obstructing local or systemic treatment in the presence of severe ascites. 29cites and oesophageal varices have been identified as predictors of mortality in HCC patients, independent of the severity of underlying liver disease and HCC stage. 32,33Conversely, the existence of HCC is independently linked to a bleak prognosis in patients with AVB associated with PHT. 34,35Therefore, comprehending the interaction between HCC and PHT is a vital aspect for enhancing the management of such complications and patient prognosis.
Moreover, HCC could potentially be linked to the invasion of the portal and/or its branches by blood vessels, resulting in PHT and posing a risk of AVB for patients.Nevertheless, the assessment of PHT remains challenging, especially for advanced HCC patients. 36e accuracy of the Baveno criteria for PHT assessment may be compromised due to the influence of HCC on platelet levels and the interference of large tumors, particularly in the right lobe, with elastography results. 37Moreover, the accuracy of HVPG measurements can be affected by the presence of portal vein invasion.Hence, the evaluation of PHT is still a significant worry for individuals with advanced HCC, and it is advisable to opt for periodic endoscopic screenings as the primary method for detecting oesophageal varices, particularly in cases of vascular invasion.
The choice of HCC treatment is greatly influenced by CSPH, which serves as a strong indicator of hepatic decompensation and mortality after hepatectomy.The presence of AVB and clinically relevant ascites is linked to unfavorable prognosis in patients with HCC.Notably, there is a correlation between secondary prevention following AVB and improved overall survival, highlighting the advantage of simultaneously addressing PHT and HCC. 34,38In specific instances, the use of TIPS placement to treat CSPH may prove advantageous, as it can enhance overall survival in high-risk AVB patients and improve transplant-free survival in those with stubborn/ recurring ascites. 39,40Moreover, TIPS can provide HCC patients with the opportunity to receive HCC treatment.Nevertheless, because of worries about the spread of HCC and the unfavorable prognosis of these individuals, TIPS placement is generally not recommended. 41,42There is insufficient information available regarding the potential dangers of liver failure after local treatment and the reduced effectiveness of HCC treatment.The uncertainty regarding whether TIPS is a genuinely substantial risk element for elevated toxicity following local treatment persists.
In the case of patients with Milan-In HCC who have cirrhosis, it is important to consider the use of TIPS when necessary, based on its traditional indications (such as salvage, preemptive treatment, failure of secondary prevention, and refractory/recurrent ascites), to enhance survival rates and act as a connection to liver transplantation.It is important to carry out Salvage TIPS whenever necessary for all individuals with cirrhosis.Nevertheless, for all other instances, it is crucial to meticulously choose candidates, and TIPS should be contraindicated for patients with heart failure, severe hepatic encephalopathy, and advanced liver failure (Child-Pugh-Turcotte score > 13 in preemptive AVB). 40Additionally, regarding HCC treatment, whether as a therapeutic alternative or from a perspective of reducing tumor size, preoperative TIPS insertion might be contemplated for patients with clinically significant PHT before liver resection, aiming to address ascites and enable localized treatment.

| SYS TEMI C TRE ATMENT FOR ADVAN CED HEPATOCELLUL AR C ARCINOMA AND UPPER G A S TR OIN TE S TINAL VARICE AL B LEEDING
Decisions concerning systemic treatment are critical for HCC patients who are usually in the intermediate or advanced stages.Earlystage disease can be treated with surgery (including resection and liver transplantation) or certain local treatments (LRT) like ablation.
Advanced and metastatic diseases require other LRT options such as transarterial chemoembolization (TACE), transarterial radioembolization, and systemic treatments.Before 2007, when the Food and Drug Administration approved the use of the multikinase inhibitor sorafenib in treating inoperable HCC, there were no authorised systemic treatment alternatives available.Over the past few years, several novel systemic alternatives, such as molecular targeted treatment and immunotherapy, have surfaced, demonstrating potential in HCC. 43The American Gastroenterological Association suggests that atezolizumab + bevacizumab is a preferable option to sorafenib for HCC patients who have intact liver function but are unsuitable for LRT or resection, or those with metastatic disease.However, it's important to note that bevacizumab is associated with gastrointestinal hemorrhage, a recognized adverse outcome.This necessitates endoscopic assessment and treatment for oesophageal varices before initiating therapy. 44ll TKIs target VEGFR and have the potential to affect the pathophysiology of PHT.Inhibiting VEGF-induced angiogenesis using drugs like sorafenib has been shown to decrease portal vein pressure, portal collateral circulation, and fibrosis in animal models. 45,46is effect was also observed in rodent models treated with lenvatinib. 47meta-analysis of a randomized trial reported that the occurrence of bleeding events of any grade did not exceed 14% (708 cases out of 4934) in patients receiving sorafenib or sunitinib.In contrast, other multitargeted receptor TKIs applicable to various solid tumors had an incidence of 16.7%, with a relative risk of bleeding at 2.0 (95% CI 1.14-3.49,p < 0.015). 48Contrary to sorafenib, lenvatinib, another multitargeted TKI, significantly worsened the congestion index in 28 Child-Pugh-Turcotte A patients with advanced HCC after 2 weeks of treatment. 49Unlike sorafenib, lenvatinib also targets fibroblast growth factor (FGF) receptors.Additional research is needed to investigate the impact of FGF19 and FGF21 on liver regeneration, liver metabolism, potential liver diseases, and their potential role in promoting PHT. 50However, further research is needed to address this.The occurrence of AVB is a significant concern for patients with HCC, and a comparable incidence of complications related to PHT, such as bleeding, was noted in a phase 3 trial involving advancedstage HCC.2][53] Interestingly, AVB was found to be independently associated with tumor portal vein thrombosis in patients treated with sorafenib.Regular screening and appropriate bleeding prevention measures would be advantageous for these individuals. 9In patients with advanced HCC undergoing TKI therapy, the risk of variceal bleeding is heightened.Consequently, some advanced HCC patients may miss out on additional opportunities for tumor treatment. 54ezolizumab, a checkpoint inhibitor targeting PDL1, is intended to enhance the body's natural defense against tumors and potentially aid in removing damage-associated molecular patterns and pathogen-associated molecular patterns.Hence, in theory, both of these compounds have the potential to reduce the incidence of PHT.In the Imbrave 150 trial, the utilization of the bevacizumab and atezolizumab combination was more prevalent in contrast to the sorafenib combination (25.2% vs. 17.3%), with a 7% and 4.5% incidence of gastrointestinal bleeding, and a 2.4% and 0.6% occurrence of variceal bleeding, respectively. 51In a study conducted by Fang et al. patients were carefully chosen, and most patients with well-managed viral hepatitis had notable advantages from effective prevention of PHT.The determination of the effect of bevacizumab and atezolizumab combination therapy on PHT is still pending.In a series of studies on HCC stage II trial patients using bevacizumab, 10% encountered bleeding complications related to PHT, highlighting the need for standardized prophylactic treatment to prevent AVB in such cases. 55deed, even through VEGF facilitates PHT via the process of angiogenesis, this growth factor plays a crucial role in maintaining sinusoidal stability.The inhibition of VEGF can impact the conserved sinusoids in the non-cancerous liver, causing changes in the sinusoidal structure and reducing the delivery of oxygen and nutrients to liver cells.This can result in cell death and the attraction of inflammatory cells, which can worsen liver diseases and PHT.Moreover, the utilization of atezolizumab, which enhances the function of cytotoxic lymphocytes, could potentially lead to an augmentation in the generation of pro-inflammatory cytokines.Activation of both innate immune cells and hepatic stellate cells, along with sinusoidal endothelial cells, by these cytokines could potentially result in liver fibrosis, chronic inflammation, and PHT. 56A study conducted by Riveiro-Barciela et al. reported the occurrence of sinusoidal obstruction syndrome leading to PHT following nivolumab treatment, suggesting that other immunotherapies may have a comparable impact. 57

| D IAG NOS IS AND SCREENING OF G A S TRI C OE SOPHAG E AL VARI CE S IN HEPATOCELLUL AR C ARCINOMA PATIENTS
In general, the occurrence of gastric varices is less common compared to oesophageal varices.Furthermore, the chance of gastric variceal bleeding is approximately 50% lower compared to oesophageal variceal bleeding. 58However, once gastric varices rupture, the need for blood transfusion and mortality rates are higher than in cases of oesophageal variceal bleeding. 59During screening endoscopy, 25% of patients have gastric varices, and 18% of patients have both gastric and oesophageal varices. 60Decompensated diseases, alcoholic cirrhosis, and the presence of red wale markings during the initial endoscopy are the primary factors that increase the risk of developing large varices. 61The annual occurrence of variceal bleeding is 5%-15%, and the likelihood of bleeding rises in patients with larger varices, the presence of red signs, and more severe liver disease. 62riceal wall tension serves as a significant predictor of rupture and is directly proportional to the vessel diameter.Vessels with larger diameters are more likely to rupture compared to smaller-diameter vessels under the same given pressure.The HVPG is correlated with the pressure within the varices, which is another significant determinant of wall tension.Consequently, reducing HVPG can decrease the likelihood of variceal rupture and bleeding. 63In terms of secondary prevention, the risk of variceal bleeding is minimal if HVPG is below 12 mmHg. 64A decrease in HVPG of over 20% from the initial level or a value below 12 mmHg is linked to a reduction in recurring bleeding, ascites, spontaneous bacterial peritonitis, and mortality rates. 65Nevertheless, it is not advised to regularly monitor HVPG alterations.en PHT is initially diagnosed, it is recommended that all HCC patients be screened for GEV.The preferred screening method is esophagogastroduodenoscopy (EGD), although it should be noted that EGD is an invasive procedure and may cause discomfort for patients.Observer variability in diagnosing and classifying varices, particularly small oesophageal and gastric varices, may exist, and the procedure can be quite expensive.If varices are detected during endoscopy, they must be rinsed, captured on camera, and explained as follows: Grade I-varices collapse when the esophagus is inflated; Grade II-varices that do not fall into Grade I or III; Grade III-varices that occupy over 50% of the lumen. 70 present, there are no specific guidelines for screening GEV in patients with HCC.We believe that utilizing endoscopic screening for GEV in individuals with cirrhosis can be advantageous.In other words, individuals with HCC who do not have varices should have a follow-up endoscopy every 6 months to 1 year (if there is no progression of liver cancer).Patients who have been found to have small varices during endoscopic screening should have an endoscopy performed every 3 months (in case there is continuous tumor advancement) or every 6 months (if the tumor advancement is stable, for example, after surgery).

| EMERG EN C Y TRE ATMENT OF UPPER G A S TR OIN TE S TINAL B LEED ING IN HEPATOCELLUL AR C ARCINOMA
Acute upper gastrointestinal bleeding is a medical emergency that requires intensive care.A multidisciplinary approach involving anesthesiology, emergency medicine, intensive care, hepatology/ gastroenterology, hematology, interventional radiology, and specialized support teams is essential.Like with any bleeding patient, the airway should be assessed and protected as a priority, followed by an evaluation of breathing and circulation.To achieve and sustain hemodynamic stability, it is necessary to commence volume resuscitation.An investigation revealed a robust association between Child-Pugh score and HVPG, with more than 80% of individuals classified as Child-Pugh-Turcotte C patients exhibiting HVPG levels exceeding 20 mmHg.Hence, the assessment is a reliable and pragmatic (albeit indirect) approach for categorizing risk in these individuals. 71Several other investigations have validated this correlation, 72  is associated with a 20% 6-week mortality rate. 73Conducting this scoring and risk stratification helps identify patient subgroups at high risk, enabling early consideration of TIPSS after initial stabilization.The primary goals in the management of AVB are as follows: (i) to regulate the hemorrhaging, (ii) to minimize the chances of rebleeding occurring within 5 days, and (iii) to avert complications associated with bleeding, including infection, hepatic encephalopathy, and acute renal injury.
A randomized trial was conducted on patients with gastrointestinal bleeding, which showed a connection between a 'restrictive' approach to packed red blood cell (PRBC) transfusion (starting transfusion when hemoglobin levels reach 7 g/dL and maintaining it between 7 and 9 g/dL.By implementing this approach, the mortality rate was greatly decreased in comparison to a more lenient transfusion strategy (which involved starting PRBC transfusion at a hemoglobin threshold of 9 g/dL and keeping it between 9 and 11 g/dL).
Patients receiving liberal transfusion had an increase in HVPG, but it remained unchanged in patients receiving restrictive transfusion. 74 is important to note that the strategy of restrictive transfusion is only suitable for hemodynamically stable patients.Initiating drug therapy immediately (i.e., vasoactive drugs and antibiotics) is usually safe, both before and after endoscopic examination.A meta-analysis of 12 RCTs showed that early use of prophylactic antibiotics during AVB significantly increased survival (RR = 0.79, 95% CI 0.63-0.98).
These trials also demonstrated that antibiotics can reduce the risk of bacterial infection and early rebleeding. 75A study analyzing 383 patients found that Child-Pugh-Turcotte A patients with AVB who did not receive preventive antibiotics had lower rates of infection and mortality compared to Child-Pugh-Turcotte B and C patients. 76rrent guidelines advise using antibiotics in all AVB cases, regardless of Child-Pugh-Turcotte classification and the presence of confirmed or suspected infectious focus.Nevertheless, the existing studies on antibiotic therapy for AVB primarily focus on individuals with cirrhosis, necessitating further prospective investigations to establish the clinical advantages in patients with HCC.A systematic review of 30 randomized controlled experiments revealed that the utilization of vasopressors (like terlipressin, somatostatin, and octreotide) for treating AVB can decrease the overall mortality rate and the need for transfusions within a week. 77Terlipressin, an artificial vasopressin analog, induces widespread constriction of blood vessels, leading to a decrease in portal blood flow and collateral circulation, ultimately reducing variceal pressure.According to placebo-based experiments, it has been demonstrated that vasoactive drugs can effectively manage hemorrhaging, decrease the need for transfusions, and decrease the mortality rate within 6 weeks. 78nsequently, it is now customary to initiate the administration of vasoactive medications promptly upon suspicion of variceal bleeding.Once hemostasis is achieved through endoscopic variceal ligation (EVL), the effect of terlipressin at 24 h is the same as at 72 h. 79ce patients have achieved stability and received sufficient resuscitation, it is crucial to promptly conduct an upper gastrointestinal endoscopy within a maximum of 12 h from the time of arrival.If variceal bleeding is confirmed, EVL should be performed.The diagnosis of variceal haemorrhage is considered conclusive when there is visible active bleeding from varices or when recent signs of bleeding (such as the presence of a 'white nipple') are identified.When there is blood present in the stomach or endoscopy is conducted 24 h after bleeding, the presence of varices as the sole lesion should indicate variceal bleeding.The ideal timing of endoscopy is a subject of debate, with numerous guidelines recommending its completion within a 12-h window from the initial presentation.However, there is no proof to back this up, and a study that compared urgent and nonurgent endoscopy found no significant benefit to conducting EGD within 12 h. 80The optimal timing is when the patient is adequately resuscitated and vasoactive drugs and antibiotics have been initiated, but it should be performed within 24 h. 81Endoscopy has been well established to be superior to sclerotherapy -a meta-analysis of 7 RCTs demonstrated that, compared to sclerotherapy, endoscopy reduced rebleeding, mortality, and the occurrence of distal oesophageal stricture. 82ughly 20% of individuals diagnosed with AVB can be categorised as high-risk patients, as supported by a substantial amount of evidence.These patients are refractory to standard treatment and have a high mortality rate.The mortality rate is high for these patients who do not respond to conventional treatment.Patients at high risk are characterised as individuals with HVPG greater than 20 mmHg, belonging to Child-Pugh-Turcotte class C (with scores ranging from 10 to 13), and those in Child-Pugh-Turcotte class B who persistently experience ongoing bleeding during endoscopy despite being administered vasoactive medications.To rapidly control bleeding, a 'bridging' therapy might be necessary until more definitive treatment can be performed. 83One option for temporary treatment is balloon tamponade, which has the potential to stop bleeding in approximately 80% of patients.However, it is important to note that balloon tamponade is linked to a high occurrence of severe adverse events, resulting in a mortality rate of nearly 20%. 84For patients at high risk who do not have any contraindications to TIPS, considering an 'early' TIPS procedure within 72 h after EGD/EVL could be advantageous.Patients who do not receive early TIPS should maintain intravenous vasoactive medications for 2-5 days.Following cessation of vasoactive drugs, the initiation of non-selective beta-blockers (NSBB) is recommended.If these patients cannot control bleeding or experience rebleeding after vasoactive drugs+EVL, rescue TIPS is necessary.Once TIPS is effectively executed for patients, they can stop receiving intravenous vasoactive medications. 85

| S ECONDARY PRE VENTION OF VARICE AL REB LEED ING IN PATIENTS WITH HEPATOCELLUL AR C ARCINOMA
The primary objective for patients at low risk of mortality (where variceal bleeding is the only complication of HCC) should be to prevent further complications, such as the recurrence of variceal bleeding.The main goal for patients who are at high risk, like those who have variceal bleeding and other malignant incidents, should be to improve their chances of survival.Individuals in the process of recuperating from their initial variceal hemorrhage encounter a substantial likelihood of experiencing rebleeding (approximately 60% within the initial year) and a notable fatality rate of up to 33%.Hence, it is imperative that these individuals receive treatment to prevent further bleeding, and this treatment should begin before the patient's release from the medical facility. 37r most patients, the first line of treatment typically includes a combination of non-selective beta-blockers such as propranolol or nadolol, in addition to EVL.A meta-analysis conducted a comparison between combination therapy and single therapies that included either endoscopy or medication.According to the findings, the utilization of combination therapy proved to be superior in the prevention of variceal bleeding when compared to the sole use of endoscopy.
Nonetheless, the efficacy of combination therapy was marginally superior to that of monotherapy using medications (NSBBs + nitrates), and monotherapy using medications tented to enhanced survival. 86is implies that medication therapy forms the foundation of combination therapy.Using both NSBBs and low-dose isosorbide mononitrate (ISMN) has a more pronounced impact on reducing PHT in comparison to using NSBBs alone.Nevertheless, as a result of the inclusion of ISMN-associated adverse reactions, notably migraines, and lightheadedness, the amalgamation exhibits an elevated prevalence of side effects.In a meta-analysis, the combined utilization of NSBBs and ISMN showed comparable rates of rebleeding or mortality compared to using NSBBs alone.Nevertheless, there was a higher incidence of adverse effects observed.To avoid the repetition of solitary gastric variceal hemorrhage and manage hepatic encephalopathy caused by portal-systemic shunting, it is recommended to undergo Balloon-occluded retrograde transvenous obliteration. 87 patients with HCC, endoscopic treatment is not the best choice for preventing variceal bleeding in the long term.In the majority of previous research on the prevention of variceal bleeding, the presence of HCC is considered an exclusion factor, or at the very least, only individuals with early-stage HCC are eligible for inclusion.Multiple endoscopic examinations to mitigate the risk of bleeding have been deemed intolerable for these delicate HCC patients with PHT in the field of clinical practice.Moreover, the potential for drug interactions with the physiological process of wound healing implies that repeated endoscopic therapy may hinder antitumor treatment.The use of various endoscopic procedures can result in the development or worsening of ascites, decreased scores, and staging, and decreased adherence to TKIs.According to previous suggestions for the treatment of PHT, it is advised against using TIPS for HCC patients because it may lead to liver failure after surgery, cause significant complications, and decrease survival rates.In an analysis of medical records and imaging studies, D. Bettinger and co-authors examined 40 patients with PHT who had HCC.Indications for TIPS implantation, surgery-related complications, treatment success rate, and overall survival were evaluated.The research showed that TIPS is a successful and secure therapy for PHT in liver cancer. 88In a recent controlled study, 106 consecutive advanced HCC patients who had undergone TKI therapy and prior treatment with vasoactive drugs combined with endoscopic treatment for variceal bleeding were randomly divided into two groups.One group received TIPS (n = 52), while the other group received endoscopic treatment + β-blockers (n = 54) to prevent rebleeding.After randomization, the main outcome measure was the occurrence of variceal rebleeding.
Over 16 months , 14 individuals in the endoscopic + β-blockers category experienced rebleeding, whereas only 3 patients in the TIPS group had rebleeding (p < 0.001).Forty-nine people tragically died, with thirty-eight in the endoscopic plus β-blockers category and eleven in the TIPS group, indicating a notable distinction (p < 0.001).The TIPS group demonstrated survival rates of 95%, 81%, and 73% at 6, 12, and 18 months correspondingly, whereas the endoscopic + β-blockers group exhibited rates of 35%, 21%, and 15% (p < 0.001) in terms of overall survival.Out of the eight patients in the endoscopic + β-blockers group, two unfortunately passed away despite receiving rescue TIPS treatment.In total, 32 people discontinued the use of TKI medication, with 24 individuals from the endoscopic + β-blockers category and 8 patients from the TIPS group (p < 0.001).The study's findings indicated that the use of TIPS had a significant impact on reducing rebleeding, improving adherence to TKI therapy, and prolonging survival in patients with advanced HCC who were receiving TKIs and experiencing variceal bleeding. 54PS is the preferred treatment for patients who fail to prevent rebleeding (NSBBs + EVL) as a first-line treatment (Table 1).
Therefore, if NSBBs are intolerable, TIPS should be considered, especially if the patient has other complications that could benefit from TIPS (such as ascites).Patients who have received TIPS during a sudden episode do not need particular therapy for PHT or varicose veins, but they should be directed for transplantation assessment.Doppler ultrasound should be used to evaluate TIPS patency every 6 months, while also performing ultrasound for HCC screening.Two randomized trials that were published demonstrated that the prompt utilization of TIPS (inserted within 72 h of admission) was linked to notable decreases in treatment failure and mortality rates when compared to treatment involving drugs and endoscopy.However, survival was not the primary endpoint of these two trials. 83,85Another randomized controlled study further demonstrated that early TIPS treatment should be performed in patients without contraindications. 89However, there is limited information regarding the use of TIPS with covered stents in patients who undergo standard endoscopy and receive vasoactive drugs, and antibiotics.72 individuals who experienced initial or subsequent instances of bleeding in the stomach and/or esophagus due to varices, and who had stable hemodynamics following endoscopy, vasoactive medication, and antibiotic therapy, were enrolled in a randomized controlled trial.They were assigned to either long-term EVL or cyanoacrylate injection combined with β-blockers, or TIPS placement.This study confirmed that in patients successfully treated for variceal bleeding with endoscopic hemostasis, in reducing variceal rebleeding, TIPS with coverage was superior to EVL + β-blockers (0% vs. 29%).Nevertheless, TIPS was linked to an increased incidence of early hepatic encephalopathy, as reported in the study. 91e lowest rebleeding rate is observed in secondary prevention patients who respond to HVPG reduction (defined as HVPG decreasing below 12 mmHg or >20% relative to baseline). 64,93erefore, guiding treatment based on HVPG in centers where HVPG measurement is easily accessible would be a reasonable strategy.A randomized controlled trial covering TIPS and HVPGguided treatment (propranolol and ISMN) showed that patients randomized to receive TIPS had a lower rebleeding rate (7% vs. 26%), with no difference in survival rates. 92 A controlled study without randomization showed that the combination of TACE/TAE+125I with TIPS is an effective treatment for MPVTT and its complications, leading to improved quality of life for patients and decreased mortality rates.This study demonstrated these outcomes. 94e importance of preemptive TIPS treatment for oesophageal variceal bleeding is increasingly recognized.Monescillo and colleagues first explored this strategy in a randomized controlled trial, where patients with HVPG of 20 mmHg or higher who received early TIPS treatment (within 24 h of admission) had significantly lower treatment failure rates and mortality compared to patients receiving standard treatment. 83However, the standard treatment used in the control group is not the current standard of care.In a randomized controlled trial conducted across Europe, the following criteria were used to determine the need for preemptive TIPS placement: patients with Child-Pugh-Turcotte B classification and active bleeding observed during endoscopy (present in approximately half of the patients), or patients with Child-Pugh C classification and a score ranging from 10 to 13. 85 A multicentre international observational study indicated that acute-on-chronic liver failure (ACLF) at admission is an independent predictor of rebleeding and mortality in patients with oesophageal variceal bleeding.Patients with ACLF and AVB (rebleeding) benefit from preemptive (early) placement of TIPS through the jugular vein.
'Preemptive TIPS' refers to the insertion of TIPS early (within 24 or 72 hours of admission), but most importantly, it refers to patients who are at high risk of uncontrolled bleeding and bleedingrelated death.The foundation of this idea relies on significant proof indicating the efficacy of TIPS in managing AVB and averting recurrent bleeding.The hypothesis suggests that a notable decrease in pressure within the portal vein could potentially avert the occurrence of organ failure or ACLF, consequently leading to a decrease in mortality associated with bleeding.A series of randomized controlled trials have assessed the efficacy and safety of preemptive TIPS. 90,95Initially, it is necessary to identify the highrisk population, which refers to the specific group targeted for this intervention.An HVPG of 20 mmHg or higher is strongly linked to an elevated risk of inadequate bleeding control or uncontrollable bleeding (for example, a risk that is more than 5 times higher) and aligns with the overall predictive significance of HVPG.An HVPG of 20 mmHg or higher signifies an elevated likelihood of mortality during hospitalization for patients.

| CON CLUS ION
In advanced HCC, the use of TKIs increases the likelihood of variceal bleeding, which can result in some advanced HCC patients being unable to receive additional tumor treatment with

| 129 SONG
et al.arises due to the amalgamation of improved blood circulation and increased blood flow resistance.
During a physical examination, it is important to initially search for particular physical indicators of PHT in the step-by-step diagnostic process.Some examples of these are spider nevi or abdominal collaterals that can be seen.The absence of these signs does not rule out clinically significant PHT.The most frequent abnormality observed in laboratory data related to PH and the presence of CSPH and gastroesophageal varices (GEV) is a decreased number of platelets.Nevertheless, when examined independently, it is inadequate | 131 SONG et al. to precisely diagnose or exclude CSPH or GEV. 66Ultrasonography offers a secure and cost-effective visual confirmation of structural irregularities linked to cirrhosis and PH.The capacity to evaluate liver stiffness (LS) signifies notable progress in this domain.LS is a characteristic of liver tissue that is affected by the presence of liver fibrosis.Studies have shown that LS, as measured by transient elastography (TE; FibroScan), is extremely precise in distinguishing between patients with CSPH and those without CSPH.Based on five studies involving 420 patients, a meta-analysis found that the area under the receiver operating characteristic curve for TE was 0.93, establishing it as a fundamental component in the non-invasive diagnosis of PHT. 67Nevertheless, the majority of the information was gathered from untreated individuals with cirrhosis caused by viruses or alcohol.Further investigation is needed for data specific to HCC patients.The gold standard technique for evaluating the existence of CSPH, characterized by HVPG ≥10 mmHg, is the measurement of HVPG.Non-invasive tests can detect CSPH, either on their own or when combined with platelet count and spleen size, if LS exceeds 20-25 kPa.Diagnosing CSPH can be accomplished solely by identifying portosystemic collaterals on imaging, as indicated by studies.
and the Model for End-Stage Liver Disease (MELD) score model has demonstrated superior accuracy compared to the assessment.A MELD score > 19 In patients with Child-Pugh-Turcotte C or B class who have continuous bleeding during endoscopy, the risk of treatment failure and poor prognosis is high.Early use of TIPS for such patients significantly improves non-transplant survival, reduces failure in bleeding control, rebleeding, and mortality, decreases the occurrence or worsening of ascites, and does not significantly increase the risk of hepatic encephalopathy.The prognosis of liver cancer is significantly impacted by the metastasis of tumor cells from the liver to the portal vein, leading to main portal vein tumor thrombosis (MPVTT), a significant complication of advanced HCC.Treating MPVTT poses the greatest difficulty.Many complications, including ascites and gastrointestinal bleeding, can arise from PHT caused by MPVTT.
TKIs.Currently, studies on PHT combined with oesophageal variceal bleeding in advanced HCC are mainly focused on patients with cirrhosis, with few studies including advanced HCC patients.The treatment approach for patients with cirrhotic PHT may encompass the diagnosis, screening, and prompt or early treatment of PHT along with gastrointestinal bleeding in advanced HCC patients.The use of endoscopy is vital in the prompt or early management of HCC individuals with PHT and oesophageal variceal bleeding.Nevertheless, TIPS can substitute endoscopy in the secondary prevention of upper gastrointestinal bleeding in HCC patients with PHT.This substitution can lead to better rates of preventing rebleeding and improved survival benefits for patients.In patients with advanced HCC who are undergoing TKI therapy and have variceal bleeding, TIPS outperforms the combination of endoscopy and β-blockers in preventing rebleeding from varices, reducing the likelihood of bleeding control failure, TA B L E 1 Comparison of TIPS, Endoscopy, and NSBB treatment in patients with HCC or cirrhosis complicated with AVB.