BRTO: Past, Present, and Future Directions

Abstract

Balloon-occluded retrograde transvenous obliteration (BRTO) has been developed in Japan as a treatment for gastric varices (GV). The technique has spread mainly around Asia, but is now gaining wider recognition in the United States and Europe. BRTO is characterized by high therapeutic efficacy against GV, and a recent study demonstrated that BRTO resulted in improved liver function after the procedure. In addition, BRTO is becoming an effective treatment for the recently proposed concept of “portosystemic shunt syndrome”. In this review, we describe the indications, methods, and modifications of BRTO, and also discuss the indications and current status of BRTO for portosystemic shunt syndrome.

Introduction: About BRTO

Balloon-occluded retrograde transvenous obliteration (BRTO) is often performed as a treatment for gastric varices (GV) and is becoming an established treatment. GV are less common than esophageal varices (EV), but still account for 20% of all varices [1, 2]. Moreover, gastric variceal bleeding is associated with a higher mortality rate ranging from 14% to 55% [1, 3]. BRTO was first developed by Kanagawa et al. for the treatment of GV by inserting a balloon catheter retrogradely into a drainage vein, such as a gastro-renal (GR) shunt [4]. This technique has frequently been performed in Japan and Korea and is gaining recognition in the United States [5-8]. Nowadays, in the American Association for the Study of Liver Diseases guideline, BRTO and transjugular intrahepatic portosystemic shunt (TIPS) or endoscopic cyanoacrylate therapy are recommended as first-line treatments for patients who have recovered from gastric variceal hemorrhage to prevent rebleeding [9]. In Europe, BRTO is considered as a possible alternative to endoscopic treatment or TIPS [10]. A report on the long-term clinical outcomes of BRTO for GV, based on data collected from multiple centers across various countries, was published. BRTO is expected to become a widely adopted treatment worldwide in the future, particularly in the form of modified techniques such as PARTO and CARTO, which are currently more commonly used internationally [11]. BRTO is characterized by high therapeutic efficacy against GV, and a recent study demonstrated improved liver function after BRTO. In addition, BRTO can be performed to embolize portosystemic shunt (PSS). To overcome refractory hepatic encephalopathy (HE) with large PSS, BTRO is now one of the treatment options. In this review, we first describe the conventional method and modifications of BRTO, then the utility of BRTO for GV and ectopic varices. Finally, we discuss retrograde embolization including BRTO for PSS syndrome (PSSS).

Indication of BRTO for GV

GV are generally identified endoscopically. The findings are widely assessed according to the classification described by Sarin et al. [1]. In Japan, the classification of the Japanese Research Society for Portal Hypertension (JSPH) is used for GV classification [12]. A comparison of these two classification systems is shown in Figure 1. GV classified according to the classification of Sarin et al. as Type 2 gastroesophageal varices (GOV)2 or type 1 isolated gastric varices (IGV1), corresponding to Lg-cf and Lg-f in the JSPH classification, are considered feasible for BRTO. Among GV, the most common type is GOV1, representing 70% of all GV, followed by GOV2 in 21%. The highest risk of bleeding is seen with IGV1, followed by GOV2. In Japan, indications for prophylactic treatment of GV include nodular form and red-colored spot lesions, increasing size over time, and hepatic encephalopathy [12]. Soft (not absolute) contraindications are reported to be: 1) severe uncorrected coagulopathy; 2) splenic vein thrombosis; 3) portal vein thrombosis; and 4) uncontrolled esophageal variceal bleeding [13]. Uncontrolled active gastric variceal bleeding was considered to be a contraindication, because BRTO closes the draining vein, which raises variceal pressure. Primary hemostasis must be obtained for ruptured GV by endoscopic treatment, gastric tamponade balloon, or spontaneous hemostasis [14]. In the case of subsequent procedures for gastric variceal bleeding, it is advisable to perform the procedure after confirming adequate hemostasis and with the backup of an endoscopist so that endoscopic hemostasis such as cyanoacrylate injection can be performed in the event of rebleeding. Recently, emergency plug-assisted retrograde transvenous obliteration (PARTO) has been reported to be technically successful in all cases of ruptured gastric varices, with a mean fluoroscopic time of 30.8 minutes [15]. Hemostasis was achieved in 20 out of 21 patients (95.2%) immediately after PARTO, with no recurrent bleeding. This approach could be one of the options for ruptured GV. Waguri et al. defined BRTO as contraindicated for patients with severe hepatic dysfunction (total bilirubin ≥4.0 mg/dL, Child-Pugh score ≥13), renal dysfunction (estimated glomerular filtration rate <30 mL/min/1.73 m²), or other serious diseases with poor prognosis [16].

Figure 1.

Gastric variceal classification based on the JSPH and Sarin classifications.

In the Japanese Research Society for Portal Hypertension (JSPH) classification, gastric varices (GV) are classified into three main groups based on the relationship with the cardiac orifice. a) GV are classified as Lg-c if adjacent to the cardiac orifice, almost equivalent to type 1 gastroesophageal varices (GOV) in the Sarin classification. b) GV are classified as Lg-cf if they extend from the cardiac orifice to the fornix, almost equivalent to type 2 GOV. c) GV are classified as Lg-f if they are localized to the fornix, almost equivalent to type 1 isolated gastric varices (IGV). d) In addition, GV located in the body of the stomach are classified as Lg-b, and those located in the antrum are classified as Lg-a, almost equivalent to type 2 IGV.

Procedure for conventional BRTO

Before the procedure, contrast-enhanced CT should be performed to detect drainage veins from the GV. Previous reports have shown that the main drainage route is GR shunt in 80-85%, the left inferior phrenic vein (LIPV) contiguous with gastrocaval shunt in 10-15% and pericardiac vein (PCV) in 5% (Figure 2) [17]. The intercostal vein (ICV) could also be a main drainage vein. BRTO from the LIPV, PCV, and ICV have been reported [18-20]. If the main drainage vein is a paraesophageal vein, BRTO may be difficult to perform due to forming venous plexus. In this article, we show the BRTO procedure for the most frequent cases in which the drainage vein is a GR shunt. Most procedures can be performed from the femoral vein, using an S-shaped sheath such as the Asato sheath (Medikit, Tokyo, Japan) . If a catheter cannot be placed in the GR shunt via a femoral approach, a transjugular approach is used. If the drainage pathway is the LIPV, a femoral approach should be applied; if the PCV, a left transjugular approach; and if the ICV, a direct puncture route. Balloon catheters are available with diameters of 1-3 cm. This diameter is determined by the diameter of the drainage vein identified from preoperative CT. In Japan, a double coaxial balloon catheter system developed for BRTO is available (CANDIS; Medikit), constructed using a 9-Fr guiding balloon catheter and a 5-Fr balloon catheter. The 5-Fr catheter is highly flexible and can be coaxially inserted into the guiding catheter in advance [21, 22]. The catheter balloons can be inflated to maximum diameters of 2 cm for the guiding catheter and 1 cm for the 5-Fr catheter. Normally, the GR shunt descends straight down the left margin of the vertebral body in the frontal fluoroscopic view. First, the sheath is inserted into the left renal vein and from there into the GR shunt. Once the catheter has been inserted into the GR shunt, Balloon-occluded retrograde transvenous venography (BRTV) is performed. According to the results of BRTV, GV were classified by degree based on progression of GV and the appearance of collateral veins into the five grades proposed by Hirota et al. (Figure 3) [23]. At the time of BRTV, detecting the presence of portopulmonary vein anastomosis (PPVA) is important [24]. Since PPVA is a potential cause of cerebral infarction, selective embolization of the PPVA should be considered if a large PPVA is identified. If the GV are Grade 1 or 2 by the Hirota classification, sclerosing agents can be injected from the same location. If no GV are visualized (Grade 3 or 4 according to the Hirota classification), downgrading is necessary. One method of downgrading is the catheter advancing method. A balloon catheter is carefully advanced through the GR shunt into the GV or into the GR shunt just distal to the varices [25]. A 3-dimensional roadmap has also been reported as useful for advancing the catheter [26]. Coil embolization is a method for embolizing a large collateral vessel using a microcatheter [27]. Stepwise injection of sclerosant is also useful to reduce collaterals [27]. The oblique method is one way to convert the body position of the patient to an oblique position, considering the specific gravity of the contrast media and sclerosing agent (Figure 4). Infusion of 50% glucose before the injection of sclerosant is also reportedly useful to decrease collateral blood flows other than GR shunt and to enable the sclerosant to occupy the GV [28]. According to Kobayakawa et al., ethanolamine oleate-iopamidol (EOI) and polidocanol are used as sclerosing agents in Japan and Korea, while sodium tetradecyl sulfate (STS) is used in Europe and the United States [29]. In the case of 5% EOI, up to 30 ml is injected into the GV. After confirming sufficient stagnation of the sclerosing agent in the GV, the balloon catheter should be left in place for 1 to 24 hours. Typically, the catheter is removed 1 to 24 hours after sclerosant injection; however, same-day removal can be achieved using the modified method described below. To protect renal function, infusion of saline after BRTO is desirable to prevent dehydration due to temporary diarrhea caused by exacerbated portal hypertension. In cases where EOI was used, administration of human haptoglobin (4000 units) may be considered to prevent acute kidney injury secondary to hemolysis caused by EOI [30].

Figure 2.

The main drainage vein of gastric varices.

The main drainage vein of gastric varices is a gastro-renal shunt (GRS) in 80-85% of cases, the left inferior phrenic vein (LIPV) in 10-15% and the pericardiac vein (PCV) in 5%. An intercostal vein (ICV) can also be a main drainage vein.

SPV=splenic vein; LGV=left gastric vein; PGV=posterior gastric vein; SGV=short gastric vein; IVC=inferior vena cava; LRV=left renal vein

Figure 3.

Schema of Hirota’s classification.

a) Grade 1, gastric varices (GV) are well visualized without evidence of collateral veins. b) Grade 2, collateral veins are identified, and GV are visualized. c) Grade 3, collateral veins are medium-sized, and contrast medium only partially fills the GV. d) Grade 4, many collateral veins are large, and GV are not visualized. In Grade 5 (not shown in this figure), BRTV cannot be performed with a balloon catheter because of the large size of the shunt and/or the rapid blood flow.

Figure 4.

Concept of the oblique method for BRTO using ethanolamine oleate-iopamidol (EOI).

In cases using a sclerosant that is lighter than blood, such as a foam, the direction of the oblique is the opposite. a) Example of positioning of the left gastric vein (LGV), gastric varices (GV), and gastro-renal (GR) shunt in the supine position. b) Distribution of contrast medium or heavier-than-blood EOI injected from the GR shunt in the supine position. Flow may not be in the direction of the GV, and the afferent vein (LGV) and portal vein (PV) are visualized. c) Positional relationships after positional change to the right anterior oblique position. Contrast medium or EOI, both of which are heavier than blood, flow easily into the GV, and afferent and portal veins are not visualized.

Modified BRTO

Many modifications of BRTO have recently been developed [31]. The first modification reported was PARTO (Figure 5a) [32]. An Amplatzer vascular plug (AVP) (St. Jude Medical, Saint Paul, MN, U.S.A.) is placed instead of a balloon catheter to stop the flow in GV, then gelatin sponge slurry is injected. The procedure time is shortened because immediate removal of the catheter is achievable with the AVP. In PARTO, the maximum diameter available for the AVP is currently 22 mm. This procedure cannot be applied for GV with a large shunt. Because of the risk of AVP migration to the pulmonary artery, careful size selection is needed to perform [33]. Mukund et al. reported that anatomical factors showing aneurysmal dilatation of the left renal vein, extreme acute/obtuse angulation and extreme anteroposterior orientation of the shunt in relation to the left renal vein were associated with a higher probability of technical failure for PARTO [34]. Lee et al. then introduced coil-assisted retrograde transvenous obliteration (CARTO), using coils instead of an inflated balloon catheter (Figure 5b) [35]. This procedure can be performed in patients with any kind of shunt, due to the availability of a wide variety of coil diameters. In this procedure, two catheters are inserted into the drainage vein and the narrowest portion of the GR shunt. After coil embolization via the catheter into the GR shunt, gelfoam slurry or STS is injected through the other catheter in the GV. The major drawback of this procedure is cost. The mean number of coils has been reported as 11.1 (range, 5-22) [35]. A retrospective study covering a 10-year experience with modified BRTO techniques, including PARTO and CARTO, was recently reported, with participation from the United States, Korea, Canada, China, and Taiwan [11]. In recent years, embolization of GV and PSS has increasingly been performed using these modified techniques, particularly outside of Japan, where they are becoming more widely adopted. A modified CARTO has recently been reported for downgrading GV (Figure 5c) [36]. This method is effective in GV that are difficult to downgrade using conventional methods. As a modification, we have previously reported the CARTO-II method (Figure 5d) [37]. This method uses a relatively small number of coils (reported as 3.36 per procedure), reducing both procedure time and costs [37]. One of the difficulties in BRTO is downgrading, as described above. To overcome this difficulty, Jogo et al. have published the utility of using a mixture of low-dose gelatin sponge particles and 5% EOI in retrograde transvenous obliteration (GERTO) (Figure 5e) [38]. In this method, the collateral veins visualized in BRTV are embolized with a small amount of mixed gelatin sponge, leading to the omission of downgrading in many cases. This method has been reported to reduce the amount of 5% EOI by 49% and embolization time by 45%. In our institute, combining the GERTO and CARTO-II techniques is performed as the standard BRTO (Figures 5f, 6). However, it should be noted that procedures using gelatin sponges (such as GERTO and PARTO) as sclerosing agents may carry risks such as cerebral infarction via a patent PPVA, as well as portal venous embolization and pulmonary embolism secondary to migration of the gelatin sponge [39].

Figure 5.

Schema of Modified BRTO.

a) In plug-assisted retrograde transvenous obliteration (PARTO), an Amplatzer vascular plug is placed instead of a balloon catheter to stop blood flow and obtain statis in the shunt. In the original method, a gelatin sponge (GS) slurry is injected instead of sclerosant. b) In coil-assisted retrograde transvenous obliteration (CARTO), shunt blood flow is blocked using microcells before injection of GS slurry. c) In modified CARTO, instead of downgrading Hirota’s grade by advancing the balloon catheter, embolization is performed using microcoils and sclerosant is injected upstream towards the gastric varices. d) In CARTO-II, sclerosant is injected from a balloon catheter in the same manner as conventional balloon-occluded retrograde transvenous obliteration (BRTO), and a small number of coils are placed just above the balloon before removal of the balloon catheter. e) In a mixture of low-dose GS particles and 5% ethanolamine oleate-iopamidol in retrograde transvenous obliteration (GERTO), sclerosant mixed with a small amount of GS is injected to embolize collaterals in BRTO. f) Combined GERTO and CARTO-II procedures.

Figure 6.

Case of gastric varices (GV) treated by GERTO+CARTO-II.

A woman in her 60s. The patient had alcoholic cirrhosis and nodular-shaped GV, meeting the indications for prophylactic treatment. The draining vein was a gastro-renal shunt. Balloon-occluded retrograde transvenous obliteration was performed via a femoral approach. a) Balloon-occluded retrograde venography (BRTV) was grade 4 according to the Hirota classification, meaning that many collateral veins were large, and GV were not visualized. b) Instead of downgrading, a mixture of low-dose gelatin sponge particles and 5% ethanolamine oleate-iopamidol (EOI) was applied for retrograde transvenous obliteration (GERTO). A total of 14 ml of EOI mixed with a small amount of gelatin sponge was injected without downgrading. Arrow: GV. c) After placement of 13 mm of one metallic coil (AZUR35CX; Terumo, Tokyo, Japan), the balloon catheter was removed 30 minutes after injection of the mixture of EOI and gelatin sponge.

Treatment results of BRTO for varices

BRTO is effective for emergency treatment of ruptured GV after achieving temporary hemostasis [14, 40]. BRTO has been performed as a primary prophylactic treatment as well as for secondary prophylactic treatment of ruptured GV in Japan. The clinical success (defined as no recurrence or rebleeding of GV, or complete obliteration of GV on subsequent imaging) rate was 97.3% in one meta-analysis [41]. In a prospective study conducted in Japan, the rate of complete thrombosis of GV based on contrast-enhanced CT on day 90 was 93.0% (40 of 43 patients) [6]. This good control rate may be due to the use of sclerosing agents, as suggested by Waguri et al. [42]. Gelatin sponge has no direct effect on blood clot formation, while sclerosants have a thrombus-forming effect in small drainage vessels. Using sclerosant leads to embolization of veins by damaging endothelial cells. Sclerosant should be used in BRTO rather than gelatin sponge alone. Actually, in PARTO, a modified method using gelfoam followed by STS has shown better outcomes approaching a 0% recurrence rate [31]. Another reason may be the fact that the injected sclerosing agent in BRTO can obliterate all the potential afferent vessels, leading to permanent eradication without recurrence. Selective BRTO, which embolizes a small proportion of afferent and draining veins, can preserve the major PSS without worsening portal hypertension [12, 43]. However, one report has suggested that selective BRTO results in a relatively higher recurrence rate than conventional BRTO, making this issue controversial [44]. Nevertheless, if liver function allows, occluding the shunt broadly―including potential afferent vessels―may lead to better outcomes [44].

Compared to other treatments, β-blockers are widely used to control GV [10]. BRTO is associated with a lower risk of rebleeding when compared with β-blockers (relative risk (RR) 0.04; 95% confidence interval (CI) 0.01-0.26) in another meta-analysis [45]. As for endoscopic therapy, some studies have shown that endoscopic variceal ligation (EVL) is inferior to some other methods, so this method is not widely used in the treatment for GV [46]. As for endoscopic cyanoacrylate (CA) injection, a prospective study was conducted to compare CA injection and BRTO [47]. GV after rupture were randomized to undergo either CA injection (n = 32) or BRTO (n = 32), with primary outcomes of GV rebleeding or all-cause rebleeding. The probability of gastric variceal rebleeding was higher in the CA group than in the BRTO group (P = 0.024). The probability of remaining free of all-cause rebleeding at 1 year was 77% for CA injection and 96.3% for BRTO (P = 0.004). Survival rates, frequencies of complications, and rates of worsening EV were similar in both groups. BRTO resulted in fewer hospitalizations, shorter inpatient stay, and lower medical costs compared to CA injection. The results of a lower rebleeding rate with BRTO than CA injection has been confirmed in a prospective study and two retrospective studies [48-50]. TIPS is an IR technique that reduces portal pressure and can significantly reduce GV rebleeding compared with pharmacotherapy and endoscopic treatments such as EVL [51, 52]. However, GV rebleeding is common, with a reported frequency of 8-22% [42, 53]. Gimm et al. retrospectively compared patients who received BRTO (n=157) or TIPS (n=19) to control gastric variceal bleeding. They reported a higher 5-year overall survival rate after BRTO than after TIPS [54]. In a meta-analysis comparing TIPS and BRTO for the management of GV, BRTO in patients with gastric variceal bleeding was associated with lower rates of rebleeding and postprocedural hepatic encephalopathy, as well as better survival compared to TIPS [55]. In some cases, portal hypertensive complications (ascites or EV) may be too severe to perform BRTO for GV. TIPS is effective for such cases. TIPS combined with BRTO may be beneficial, as the presence of TIPS has been reported to have a protective effect against the development of post-BRTO ascites or hydrothorax, as well as recurrent hemorrhage [56].

BRTO is effective not only for GV, but also for ectopic varices. Generally, the localization and anatomy are heterogeneous, which makes standardization of treatment difficult. The guideline thus states that evaluation and treatment should be performed on a case-by-case basis according to the vascular anatomy [9]. Duodenal, small intestinal, colonic, and stomal varices can be treated with BRTO [57-60]. The rectum normally has many drainage veins and BRTO is rarely indicated, but is possible in select cases [61, 62]. If the ectopic varices are located at a site of lower gastrointestinal bleeding, colonoscopy is ineffective because of poor visibility [63]. Complete occlusion of varices by BRTO upon delineation of afferent and efferent vessels is generally considered preferable in elective and prophylactic cases [64, 65]. Prophylactic BRTO may be a good treatment option for ectopic varices.

There have been recent reports of transportal BRTO [66]. BRTO was performed via the dilated posterior superior pancreaticoduodenal vein after puncture of the liver for an arteriovenous malformation (AVM) of the pancreas. Transportal BRTO was also performed for the varix due to left-sided portal hypertension [67]. These techniques can expand the possibility of BRTO in the future.

BRTO for PSS

In an analysis of 1729 cirrhotic patients who underwent abdominal CT or MRI, PSS was identified in 60% of patients [68]. Traditionally, PSS has been considered to result from decompression of portal hypertension, preventing development of EV or ascites [69]. The term “portosystemic shunt syndrome (PSSS)” was coined by Kumamoto et al. to describe the gradual worsening of hepatic function as reflected by an increasing Child-Pugh score [70]. This phenomenon was supported by the analysis of 1729 patients mentioned above [68], which showed that patients with PSS also developed a higher frequency of portal hypertension-related complications such as bleeding or ascites than patients without PSS. Moreover, transplantation-free survival was lower among patients with PSS than among patients without. PSS has been reported as an independent factor associated with death or liver transplantation (hazard ratio 1.26, 95%CI 1.06-1.49; P = 0.008) in a multivariate analysis [68]. Saad et al. defined stages to the PSSS as early, late, and end stage (Figure 7) [71]. In end-stage PSSS, patients display HE with a poor prognosis, showing 1- and 3-year overall survival rates after the initial encephalopathy episode of 42% and 23%, respectively [72]. To prevent the progression of PSSS, endovascular treatments such as BRTO should be considered to obliterate the PSS. Kumamoto et al. reported the presence of a large PSS reflected reduced liver function and poorer prognosis [70]. BRTO, which completely obliterates large PSS, inhibited both the reduction in hepatic functional reserve and the worsening of prognosis, indicating a protective role [70].

Figure 7.

Staging of portosystemic shunt syndrome (PSSS) as defined by Saad et al.

PSSS was divided into three stages based on clinical manifestations and imaging findings: 1) early stage, characterized by the absence of hepatic encephalopathy (HE) episodes, a lack of ascites, and preserved liver function; 2) late stage, frequent HE episodes caused by declining liver function and development of portosystemic shunt (PSS), with radiological images showing reduced liver volume and small portal veins; and 3) end stage, persistent HE with many kinds of episodes, large-sized PSS, and advanced liver failure, potentially with portal vein thrombosis (PVT). Hepatic synthetic function is initially preserved, but hepatic failure eventually (in late or end stage) ensues.

HE is one symptom of PSSS. BRTO for HE with large shunts has been reported as an effective option among carefully selected patients (Table 1) [73-82]. The technical success rates have been reported to range from 95.2% to 100%, with clinical success rates ranging from 33% to 100%. Recently, Mukund et al. conducted randomized study to compare cirrhosis patients presenting with recurrent HE and having PSS who had standard medical treatment (SMT group) or shunt occlusion including BRTO (SO group) [82]. In these patients, the mean liver volume increased (baseline 1040 ± 335 ml to 1132 ± 322 ml, 8.8% increase, p < 0.001) and was observed in 16/18 (88.89%) SO group patients. In the SMT group, the liver volume decreased (baseline 988 ± 270 ml to 904 ± 226 ml, 8.6% reduction, p = 0.009) during the same period. Serum albumin increased in SO group, but reduced in SMT group. After SO, the patients showed a reduction in serum-ammonia levels and an improvement in Model for End-Stage Liver Disease - Sodium score (MELD-Na score）and bone density compared to SMT group. Although no studies have reported results for large numbers of patients regarding indications or contraindications, Philips et al. reported a Child-Pugh score >11 as predictive of mortality in patients with HE [76]. In cases of surgical shunt ligation, Child grade C has been reported as a risk factor for postoperative mortality [83]. Rajesh et al. reported that an absolute increase in hepatic venous portal gradient (HVPG) (≥16 mmHg) and a significant elevation in HVPG from baseline (>4 mmHg) were associated with an increased risk of negative outcomes after embolization [84]. Nakano et al. reported that decision to provide shunt embolization including BRTO is based on a wedged hepatic vein pressure of less than 30 mm Hg at the time of balloon test occlusion, taking into account whether the patient is on diuretics, has ascites or not, and whether it is an SR shunt [85]. They also reported that in case total embolization is considered risky, intentional repeated flow reduction by debranching and rough coiling technique for PSS was useful in avoiding the risk of worsening portal hypertension. Also, the technique of simultaneous shunt embolization and TIPS may be useful for patients at risk of worsening portal hypertension after embolization [86]. Similar to the efficacy of BRTO against HE, many reports have described the utility of BRTO against GV, not only eradicating the GV, but also improving liver function (Table 2) [54, 70, 74, 79, 87-96]. Such results suggest that among various markers of liver function (total bilirubin, serum albumin, and prothrombin time [PT]), serum albumin improved in all cases and PT improved in some. These results suggest that serum albumin and PT are likely to be improved by increasing effective hepatopetal portal blood flow. BRTO in the treatment of PSS is thus often considered to be effective for maintaining liver function. Note that PSS diameter was reported to be strongly associated with liver function at baseline and after BRTO and also with changes in HVPG [95]. On the other hand, the most significant complication of embolization for PSS is worsening portal hypertension. Worsening of EV has also been reported, along with worsening of ascites including refractory ascites, and liver failure [54, 80, 83, 97-99]. Improvements in liver function and worsening of portal hypertension are opposing outcomes and require careful patient selection. Di Marco et al. reported that in patients with decompensated liver cirrhosis with EV, there was no significant difference in prognosis between patient with and without sustained virological response [100]. That represented the first report of so-called “point of no return”. Similarly, embolization of GV with BRTO improves liver function in some, but not all, patients [91]. Both Yamamoto et al. and Ishikawa et al. have reported liver stiffness values with cutoffs of liver stiffness measurement (LSM) of 22.9 or 21.6 kPa, respectively (correlating with clinically significant portal hypertension) as measured by transient elastography are linked to improved liver function after BRTO for GV [91, 101]. Yamamoto et al. also reported that the worsening of EV with baseline LSM by Fibroscan ≤ 22.9 kPa were significantly lower than that of > 22.9 kPa. Shirane et al. reported in multivariate analysis, an LSM value of ≥ 25.1 kPa as an independent risk factor of poor prognosis after BRTO [102]. A liver stiffness around 22-25 kPa may present a so-called “point of no return” in embolization for PSSS. In addition, following BRTO, thrombus development occurs in approximately 15% of patients, involving major portal and systemic veins [103]. This complication may exacerbate portal hypertension and therefore requires careful monitoring.

Table 1.

Representative Studies of Embolization for Portosystemic Shunt Iincluding by Balloon-occluded Retrograde Transvenous Obliteration (BRTO) for Hepatic Encephalopathy (HE).

Reference	Year	Number of patients	Procedure/ Sclerosant	Technical success (%)	Efficacy	Complications	Comments
Sakurabayashi et al. [73]	1997	3	CARTO	100%	33% (1/3) effective		Retrospective, single-center study
Fukuda et al. [74]	2001	11(including GV: 43)	BRTO / 5% EOI	100%	HE improved all.	Worsening of EV	Retrospective, single-center study
Laleman et al. [75]	2013	37	CARTO or PARTO	100%	HE improved in 59.4% on 100 days, 48.6% in 2 years	EV bleeding, no ascites, 4 PVT	Retrospective, multi-center study MELD score >11 is a negative predictive factor of HE recurrence
Philips et al. [76]	2017	21	CARTO, PARTO or BRTO, SSO	95.2%	HE improved in 71% on short-term follow-up, 23% on long-term follow-up	3 had worsening of ascites	Retrospective, single-center study
Lee et al. [78]	2018	43	CARTO	100%	81% improved HE 3 / 43 had recurrence	New or worsened ascites in 7 (16.3%) EV in 10 (23.3%)	MST = 465 days after procedure
Ishikawa et al. [79]	2018	18	BRTO/ 5% EOI	100%	Improved liver function markers	Ascites development and aggravated.	Comparison between BRTO for HE group and GVs group
Philips et al. [80]	2020	45	BRTO, CARTO, PARTO, (CAATO) / STS	100%	Recurrence of HE in 4.5% of early embolization group vs. 28.6% of late embolization group	Rrefractory ascites requiring repeated paracentesis in late shunt embolization (23.8%)	Early shunt embolization might be better
Mukund et al. [81]	2020	39	BRTO, CARTO / STS	98%	Clinical success 94.9%	One developed spontaneous bacterial peritonitis	Overall survival rates were 89.7%, 76.9%, 74.4%, and 64.8%, respectively
Mukund et al. [82]	2023	20	PARTO	100%	Two (10%) presentednew HE.	Two (10%) developed new ascites. Four (20%) developed high-risk varices	Prospective randomized study

CARTO = coil-assisted retrograde transvenous obliteration; EOI = ethanolamine oleate-iopamidol; EV = esophageal varices; GV = gastric varices; STS = sodium tetradecyl sulfate; PARTO = plug-assisted retrograde transvenous obliteration; PVT = portal vein thrombosis; MELD = Model for End-Stage Liver Disease; SSO = surgical shunt occlusion; CAATO = coil-assisted antegrade transvenous obliteration

Table 2.

Studies Showing Improvement of Liver Function after Balloon-occluded Retrograde Transvenous Obliteration (BRTO) for Gastric Varices.

Reference	Year	Number of patients	Liver function marker			Comments
			Total- bilirubin	Albumin	Prothrombin time
Akahane et al. (87)	1997	9		Improved
Fukuda et al. (74)	2001	41		Improved
Miyamoto et al. (88)	2003	14		Improved	Improved	Comparison at 4 weeks after BRTO
Kumamoto et al. (70)	2010	20		Improved		Comparison at 6 and 12 months after BRTO
Kasuga et al. (89)	2010	21		Improved		Comparison at 1 year after BRTO
Saad et al. (90)	2013	29	Improved	Improved	Improved	Comparison between 1.5 and 4.0 months after BRTO
Yamamoto et al. (91)	2016	50		Improved		Comparison at 3 months after BRTO
Kako et al. (92)	2017	23		Improved		Comparison at 1 and 3 months after BRTO
Nakazawa et al. (93)	2017	161		Improved		Comparison at 1 month after BRTO
Gimm et al. (54)	2017	157		Improved	Improved	Comparison at 6 and 12 months after BRTO
Ishikawa et al. (79)	2018	27	Improved	Improved	Improved	Comparison at 1 month after BRTO
Waguri et al. (42)	2021	57		Improved		Comparison at 3 years after BRTO
Tatsumi et al. (95)	2022	18		Improved	Improved	Comparison at 6 months after BRTO
Ke et al. (96)	2024	34	Improved	Improved	Improved	Comparison at 12 months after BRTO

In the aforementioned analysis of 1729 cirrhotic patients, patients with PSS and MELD scores of 6-9 (reflecting relatively good liver function) were at higher risk of ascites (40.5% vs 23%; P < 0.001) and bleeding (15% vs 9%; P = 0.038) than patients without PSS and had a lower risk of transplant-free survival (hazard ratio 1.71, 95%CI 1.16-2.51; P = 0.006) [68]. Patients with a MELD score ≥10 did not show any significant difference in transplant-free survival based on the presence or absence of PSS. This result indicated that patients with lower MELD scores may be more likely to benefit from PSS embolization. A recent retrospective study of 45 patients by Philips et al. evaluated the usefulness of embolization in patients who experienced a first HE and in those who became refractory [80]. They reported that early shunt embolization resulted in a reduction in portal hypertension and improved survival compared to no or late embolization. Philips et al. suggested that embolization of the shunt in the early stages may be useful for the management of PSS in cirrhosis. The utility of early shunt occlusion should thus be examined in a larger prospective study.

Conclusion

BRTO for GV is becoming more established as an effective treatment option, and BRTO for PSSS seems promising. Further accumulation of evidence including randomized controlled trials is necessary.

Disclaimer

Dr. Akira Yamamoto, an author of this paper and a member of the Editorial Board of this journal, was not involved in the peer-review or editorial decision-making process.

Conflicts of Interest

There are no conflicts of interest.