Prophylactic embolization of large spontaneous portosystemic shunts with transjugular intrahepatic portosystemic shunt (TIPS): A panacea for post‐TIPS hepatic encephalopathy?
Authors: Dhiraj Tripathi, Christophe Bureau
Journal: Hepatology (2022)

SEE ARTICLE ON PAGE 676 Transjugular intrahepatic portosystemic shunt (TIPS) has revolutionized the management of portal hypertension, with recent guidelines supporting its use, particularly in recurrent ascites and as a preemptive therapy in acute variceal bleeding, due to significant survival benefits.[1] However, a nagging thorn has been the risk of post‐TIPS HE, which can affect more than half of patients.[2] Risk factors include previous episodes of overt HE, age > 65, minimal HE, sarcopenia, and severity of liver disease (Figure 1).[1,3] Guidelines currently recommend screening carefully for overt and minimal HE prior to elective TIPS.[1,4] An important risk factor not always considered is the presence of spontaneous portosystemic shunt (SPSS). The belief that SPSS helps to decompress the portal venous system has not been confirmed, with studies showing that SPSS correlates with liver dysfunction and decompensating events such as HE, varices, and hepatorenal syndrome.[5] Hence, SPSS is an insufficient compensatory mechanism, not allowing for a sufficient reduction of portal pressure, and could result in a decrease of liver perfusion. It is believed that SPSS forms thorough VEGF‐driven angiogenesis and neovascularization,[6] with the most common being splenorenal shunts, gastrorenal shunts, gastrocaval shunts, and recanalized paraumbilical vein. Gastrorenal shunts are evident in up to 85% of patients with cardiofundal gastric varices. SPSSs are best seen on cross‐sectional imaging, and a recent Baveno VI collaborative study showed SPSS in 60% of patients, with large ones (>8 mm) seen in half of the patients.[5] The same group found that even in compensated cirrhosis, SPSSs were seen in up to 55% of patients and that a total surface area >83 mm2 predicted overt HE and mortality.FIGURE 1: Current options to minimize the risk of post‐TIPS HE. *Prior to TIPS implantation. MELD, Model for End‐Stage Liver Disease; TIPS, transjugular intrahepatic portosystemic shuntTherefore, selective embolization of large SPSSs would seem an attractive option. Indeed, studies confirm this, with nearly two thirds of patients remaining free of HE over a 2‐year follow‐up after embolization.[7] While the prevalence of SPSS can reach 60% of patients with cirrhosis, the prevalence of SPSS after TIPS creation has not been extensively studied and is probably influenced by the procedure itself (e.g., diameter of the shunt). In the study by He et al., SPSSs are present after a TIPS in up to a third of patients and are associated with increased risk of rebleeding and HE.[8] Retrospective studies have shown that SPSSs ≥ 6 mm are associated with overt HE and that SPSS embolization reduced the risk of overt HE by nearly 50% with no difference in mortality, shunt dysfunction, and clinical relapse.[8] Similar results were obtained by Leng et al., who evaluated the combination of TIPS and shunt embolization in variceal bleeding.[9] The study by Lv et al. published in this issue is a welcome addition to the literature, being the first randomized controlled trial (RCT) comparing TIPS plus prophylactic embolization of SPSS versus TIPS alone.[10] The single‐center, blinded study randomized 56 patients with cirrhosis due to undergo an elective TIPS for prevention of variceal bleeding. Patients with SPSS diameter/mean platelet volume diameter ratio ≥ 0.5 were included in the study, with all patients having an SPSS diameter ≥ 6 mm. Patients with a history of recurrent spontaneous HE and Child‐Pugh score > 13 were excluded. Covered 8‐mm Fluency stents were used, and embolization using coils was done prior to deployment of TIPS. Importantly, no patients were offered medical prophylaxis against HE. The sample size was based on the assumption that TIPS + embolization reduced overt HE with an absolute difference of 35%. The primary outcome was the development of overt HE (≥ Grade 2 according to the West Haven classification) over a 2‐year follow‐up period. There was a high screen failure rate with just 12% of screened patients recruited, which was mainly due to failing to meet criteria for SPSS size. SPSSs were splenorenal shunts in > 80% of patients. The post‐TIPS portosystemic pressure gradient (PPG) was numerically lower in the TIPS‐only group, although this did not reach statistical significance. The key finding is of 27% absolute risk reduction in overt HE with TIPS + embolization (HR, 0.38; 95% CI, 0.15–0.97; number needed to tread, 4). This result remained robust after controlling for baseline confounders such as previous HE (numerically higher in the TIPS‐only arm) and using competing risk analysis. Significantly more patients required hospital admission for HE in the TIPS group (12 vs. 4). There were no data on patient‐reported outcomes such as quality of life. Refractory HE only occurred in the TIPS group. There was no impact on secondary outcomes of rebleeding, mortality, shunt function, or other liver‐related events. However, it is noteworthy that rebleeding was numerically higher with transjugular intrahepatic portosystemic stent–shunt + embolization (7 vs. 4; p > 0.05, which may reflect a Type II error). It is well accepted that the risk of further decompensation is associated with the etiological treatment (easier for hepatitis B than for NASH or alcohol‐related cirrhosis) and the type of previous decompensation (ascites vs. bleeding). What are the implications for clinical practice of this study? Firstly, it is important to appreciate the demographics of the patients, patient selection, and the procedure. The etiology of cirrhosis was predominantly hepatitis B and does not reflect that of many other parts of the world. The indication for TIPS is secondary prophylaxis against variceal bleeding, which does not align with the recent North American guidelines, where embolization is advised only where TIPS is done electively for ascites or hepatic hydrothorax.[1] Blinding was done only for analysis of results and not the procedure. The embolization was done prior to TIPS, which the authors believe allows for better assessment of collaterals and theoretically reduces the risk of migration of embolization. This is somewhat debatable and assumes that the direction of blood flow is hepatopetal. One could argue that preexisting SPSS may collapse in most patients after TIPS creation with reduction in portal pressure and that any benefit of embolization is negligible. Whether embolization of any shunt or only larger SPSSs after TIPS reduces the risk of post‐TIPS HE requires confirmation. For the present, a case‐by‐case decision would seem logical. Two important developments since the trial started recruitment include the medical prophylaxis against post‐TIPS HE and advances in TIPS technology. A double‐blind, placebo‐controlled RCT showed that rifaximin reduced the risk of overt HE by 52%.[2] Most patients had alcohol‐related liver disease with ascites, and the post‐TIPS PPG was similar to that in this study. It is well known that standard covered stents undergo passive dilatation resulting in further reduction in the PPG, which can contribute to increased shunting and risk of HE. Controlled expansion stents can overcome this passive dilation phenomenon and have been shown to reduce HE and even survival. The combination of medical prophylaxis and controlled expansion stents can benefit all patients undergoing TIPS, whereas only a minority of patients have large SPSSs at TIPS. To their credit, the authors do recognize this limitation but have also introduced a new precision medicine option to address an important and debilitating complication of TIPS. Finally, there is still a matter of debate regarding the definition of SPSS, and we await a consensual definition allowing a comparison of the results across different studies. In conclusion, this well‐conducted RCT has shown that prophylactic embolization of large SPSS at the time of TIPS insertion can reduce the risk of post‐TIPS HE by 62%, without any detrimental impact on other liver‐related outcomes. However, the results need to be interpreted in the context of a predominant viral hepatitis etiology and lack of medical prophylaxis against overt HE. Further larger RCTs comparing prophylactic embolization during TIPS with medical prophylaxis against HE and eventually combined with small‐diameter expansion stents should be undertaken. The question of whether embolization is restricted only to patients in whom the large SPSS persists after the TIPS procedure remains unresolved. CONFLICT OF INTEREST Dr. Tripathi consults and is on the speaker’s bureau for WL Gore & Associates. Dr. Bureau received grants from WL Gore & Associates.