SAGE Open Med
. 2023 Oct 29;11:20503121231208655. doi: 10.1177/20503121231208655

Clinical outcomes related to portal pressures before and after embolization of large portosystemic shunts in cirrhosis

Sasidharan Rajesh

Sasidharan Rajesh

1Interventional Hepatobiliary Radiology, The Liver Institute, Center of Excellence in GI Sciences, Rajagiri Hospital, Chunangamvely, Aluva, Kerala, India
1, Cyriac Abby Philips

Cyriac Abby Philips

2Clinical and Translational Hepatology and Monarch Liver Laboratory, The Liver Institute, Center for Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, Kerala, India
2,✉, Rizwan Ahamed

Rizwan Ahamed

3Gastroenterology and Advanced GI Endoscopy, Center of Excellence in GI Sciences, Rajagiri Hospital, Chunangamvely, Aluva, Kerala, India
3, Shobhit Singh

Shobhit Singh

1Interventional Hepatobiliary Radiology, The Liver Institute, Center of Excellence in GI Sciences, Rajagiri Hospital, Chunangamvely, Aluva, Kerala, India
1, Jinsha K Abduljaleel

Jinsha K Abduljaleel

3Gastroenterology and Advanced GI Endoscopy, Center of Excellence in GI Sciences, Rajagiri Hospital, Chunangamvely, Aluva, Kerala, India
3, Ajit Tharakan

Ajit Tharakan

3Gastroenterology and Advanced GI Endoscopy, Center of Excellence in GI Sciences, Rajagiri Hospital, Chunangamvely, Aluva, Kerala, India
3, Philip Augustine

Philip Augustine

3Gastroenterology and Advanced GI Endoscopy, Center of Excellence in GI Sciences, Rajagiri Hospital, Chunangamvely, Aluva, Kerala, India
3
1Interventional Hepatobiliary Radiology, The Liver Institute, Center of Excellence in GI Sciences, Rajagiri Hospital, Chunangamvely, Aluva, Kerala, India
2Clinical and Translational Hepatology and Monarch Liver Laboratory, The Liver Institute, Center for Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, Kerala, India
3Gastroenterology and Advanced GI Endoscopy, Center of Excellence in GI Sciences, Rajagiri Hospital, Chunangamvely, Aluva, Kerala, India
✉
Cyriac Abby Philips, Department of Clinical and Translational Hepatology, The Liver Institute, Center for Excellence in Gastrointestinal Sciences, Ground Floor, Phase II, Tower-3, Rajagiri Hospital, Aluva, Kerala 683112, India. Email: abbyphilips@theliverinst.in
Received 2023 Feb 25; Accepted 2023 Oct 3;
© The Author(s) 2023
This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
PMC Copyright notice
PMCID: PMC10617273 PMID: 37915841

Abstract

Objectives:

This study aimed to investigate the clinical implications of dynamic changes in hepatic venous pressure gradient (HVPG) before and after the embolization of large portosystemic shunts (PSS) in patients with cirrhosis. While shunt embolization is a recognized treatment for gastric variceal bleeding (GVB) and hepatic encephalopathy (HE), the precise significance of portal pressure alterations on subsequent clinical outcomes and patient prognosis has remained largely unexplored. This research sought to bridge this knowledge gap by correlating HVPG dynamics with a range of clinical events.

Methods:

We conducted a retrospective single-center analysis of 46 patients who underwent embolization for either GVB, HE, or both between January 2018 and October 2020. The study specifically focused on individuals where HVPG measurements were recorded both before and after the embolization procedure, allowing for a comprehensive assessment of dynamic portal pressure changes. These measurements were then meticulously correlated with various patient outcomes to discern any significant associations.

Results:

The study cohort was predominantly male. Lienorenal shunts represented the most common type of PSS. Embolization was performed for HE in 34 patients and for GVB in 11. Survival rates were 86.96% at 12 months and 54.35% at 32 months. Notably, the mean HVPG significantly increased from 13.4 ± 3.2 mm Hg pre-embolization to 16.9 ± 3.7 mm Hg post-occlusion (p < 0.001). Five patients (10.9%) experienced variceal bleeding, and four (9.5%) developed overt HE during follow-up. The occurrence of infections within 100 days and beyond one year post-procedure correlated with mortality at 12 and 32 months, respectively. An HVPG elevation exceeding 4 mm Hg from baseline and an absolute increase to over 16 mm Hg immediately post-procedure significantly predicted the onset of early- and late-onset ascites.

Conclusion:

Our findings underscore the importance of vigilant monitoring for infections and judicious management of beta-blockers and diuretics following shunt embolization. Such measures are crucial for optimizing clinical outcomes in cirrhotic patients. Furthermore, understanding the dynamic changes in portal pressures, particularly HVPG elevation, can help identify patients who might benefit from early liver transplantation, pending validation through prospective studies.

Keywords: HVPG, variceal bleeding, CSPH, portal hypertension, HCC

Introduction

Portosystemic shunt syndrome (PSS) in cirrhosis represents a critical clinical manifestation within the natural progression of liver disease. Large portosystemic shunts (PSs) are frequently implicated in severe complications such as gastric variceal bleeding (GVB) or spontaneous hepatic encephalopathy (HE). These shunts can also contribute to recurrent GVB, failure to control bleeding, and recurring or persistent HE, often leading to repeated hospitalizations and significantly diminishing the quality of life for affected individuals 1,2. While spontaneous PSS (SPSS) was historically considered a "decompressing channel" for portal hypertension in advanced cirrhosis, contemporary evidence refutes this notion, indicating their association with worsening liver disease and increased severity of portal hypertension.

The presence of large shunts, particularly as revealed through contrast cross-sectional imaging, has been consistently linked to higher mortality rates and an increased risk of complications 3,4. Furthermore, the cumulative cross-sectional area of SPSS, rather than the diameter of a single large shunt, has emerged as a more accurate predictor of adverse outcomes, including the development of HE or increased mortality, even in patients with advanced chronic liver disease who exhibit preserved liver function 5. Consequently, the embolization of large PS in cirrhotic patients has been demonstrably effective in controlling GVB and reducing the frequency of overt HE, as evidenced by multiple high-quality studies.

Anecdotal studies further suggest that early occlusion of large PS offers greater benefits compared to no or delayed embolization in patients with cirrhosis experiencing recurrent or refractory HE 6–8. While shunt embolization is generally considered a safe procedure with minimal local complications, some concerns persist regarding its potential to exacerbate portal hypertension and worsen variceal disease. For instance, Tanihata et al. 9 reported that balloon-occluded retrograde transvenous obliteration (BRTO) of gastric varices intensified esophageal varices, correlating with a post-procedure increase in portal pressure systemic gradient exceeding 5 mm Hg.

Conversely, some researchers have proposed that an increase in portal pressures, as reflected by an elevated post-procedure hepatic venous pressure gradient (HVPG), might be associated with improved liver function. Uehara et al. 10 controversially suggested that an HVPG increase greater than 20% from baseline predicted enhanced liver function after shunt embolization. However, Park et al. 11 presented contrasting findings, demonstrating that embolization of large PS led to an increase in HVPG, significantly raising the risk of symptomatic esophageal variceal progression, despite a temporary improvement in liver function over a six-month follow-up.

Existing literature predominantly consists of a limited number of small cohort studies that primarily focus on HVPG-related changes and portal hypertension complications, particularly variceal events following shunt embolization. A significant void exists in published research concerning the assessment of broader clinical outcomes in the context of pre- and post-shunt embolization HVPG changes. Specifically, there is a lack of comprehensive studies evaluating liver-related (e.g., GVB, ascites, HE, shunt recurrence, hepatocellular carcinoma (HCC)) and non-liver related events (e.g., sepsis, short-term and overall mortality) among cirrhotic patients undergoing shunt embolization for GVB, HE, or both. This study aims to address this critical gap by providing a detailed analysis of these associations.

Methods

Patients

This study rigorously included all patients aged 18 years and older diagnosed with cirrhosis and portal hypertension from our tertiary liver disease treatment center in Kochi, Kerala, India. Participants were selected if they underwent shunt embolization for recurrent or persistent HE, recurrent GVB, or GVB unresponsive to control, or a combination of these conditions. A strict protocol mandated HVPG measurement both before and after the procedure at predefined intervals. Patients who underwent embolization but did not consent to per-protocol HVPG measurement were excluded, as were those who underwent both shunt embolization and transjugular intrahepatic portosystemic shunt (TIPS) placement.

To ensure a focused analysis, patients were also excluded if they had received treatment for liver cancer previously, were diagnosed with liver cancer during the shunt syndrome evaluation, or presented with acute-on-chronic liver failure, recurrent or refractory ascites requiring paracentesis, uncontrolled sepsis, refractory septic or hypovolemic shock, multiple organ failure, malignant or non-malignant main portal vein trunk thrombosis, or multiple shunts posing high technical challenges. Only patients who completed a minimum of one year of follow-up, or a maximum of 32 months from the procedure (or until death or liver transplantation, whichever occurred first), were included in the final analysis, providing a robust dataset for outcome assessment.

Statistical analysis

Statistical analyses were conducted using MedCalc Statistical Software (Ostend, Belgium). Data are presented as mean ± standard deviation or as median with interquartile range (IQR) in brackets. One-way analysis of variance was employed to assess differences in baseline means of investigational variables between groups. A p-value of < 0.05 was considered statistically significant. For comparisons of nominal variables, Fisher’s exact test was utilized, particularly for small sample sizes. Continuous variables were evaluated using Mann–Whitney’s U test. Given the relatively small sample size, exact logistic regression with the Cox-Snell R 2 method was applied to identify independent mortality-related parameters 12. The probability of patient survival up to the study endpoints was calculated using the Kaplan–Meier method and visually represented through survival time curves, providing a clear depiction of patient prognosis over the follow-up period.

Primary and secondary outcome measures

In all enrolled patients, HVPG (expressed in mm Hg) was meticulously measured before and after shunt embolization, adhering to standard and validated protocols 9,10. The elevation in HVPG from baseline and the percentage change in HVPG post-shunt embolization were precisely calculated for each individual. Patients were subsequently categorized based on median HVPG values—both pre- and post-shunt embolization, as well as by the degree of HVPG elevation and percentage change—to facilitate comparative analyses. The overarching objective was to investigate the spectrum of clinical events in cirrhotic patients undergoing shunt embolization in relation to these HVPG-related metrics. The primary outcome measure was survival at the end of one year following the procedure, offering a critical short-term prognostic indicator.

Secondary outcome measures extended to encompass survival at 32 months (exceeding two years), progression of esophageal varices, and the incidence of infections necessitating hospital admission within 100 days and beyond 12 months post-procedure. Additionally, the study tracked the new onset of ascites, hepatic encephalopathy (HE), or hepatocellular carcinoma (HCC) following the embolization procedure. This comprehensive set of outcome measures allowed for a multifaceted assessment of the impact of shunt embolization and portal pressure dynamics on both short- and long-term patient health and disease progression, providing valuable insights into the complex interplay between hemodynamic changes and clinical events in this patient population.

Procedures

All procedures were carried out under local anesthesia, following the acquisition of written informed consent from each patient. Initial access was established via the right common femoral vein or internal jugular vein, where a 6F vascular access sheath (Cook, Bloomington, Indiana) was meticulously positioned. HVPG was then accurately measured utilizing the standard balloon wedge technique. Subsequently, the portosystemic shunt (PS) was cannulated using a combination of a 5F angiographic catheter (multipurpose or cobra; Cook) and a 0.035″ hydrophilic J-tipped guidewire (Radifocus; Terumo, Japan). This catheter was then exchanged for a flexible curved sheath (Flexor Check-Flo Introducer with large valve assembly, Mullin design, and Ansel modification, 7F-14F; Cook) advanced over a 260 cm, 0.035″ Amplatz ultra-stiff guidewire (Cook, Inc), ensuring precise and stable access for the procedure.

Venography was subsequently performed through the sheath to comprehensively delineate the shunt anatomy and confirm accurate sheath placement. The specific occluding modality—whether Balloon-Occluded Retrograde Transvenous Obliteration (BRTO), Plug-Assisted Retrograde Transvenous Obliteration (PARTO), or Coil-Assisted Retrograde Transvenous Obliteration (CARTO), with or without glue instillation—was determined by the interventional radiologist. This decision was based on the shunt anatomy observed in pre-procedural imaging and adherence to standardized techniques 6,7. For balloon-assisted shunt occlusion, a compliant oversized balloon catheter (Equaliser, Boston Scientific Corporation, Natick, MA, USA) was strategically placed into the shunt. After confirming no contrast leak around the balloon, a sclerosing agent—prepared by mixing lipiodol, 3% sodium tetradecyl sulfate (STS; SETROL, Samarth Life Sciences, Mumbai, India), and air in a 1:2:3 ratio—was infused to completely fill the shunt. The balloon was kept inflated for four hours to facilitate effective sclerosis and achieve complete shunt occlusion.

For plug-assisted shunt occlusion, an amplatzer vascular plug (AVP-II; St. Jude Medical, Inc., St. Paul, MN, USA or Cera-Vascular plug, Lifetech Scientific, Shenzhen, China; 8–24 mm) with a diameter 30%–50% larger than the narrowest accessible shunt diameter was carefully deployed. Simultaneously, a 2.7 Fr microcatheter (Progreat, Terumo, Japan) was maintained in the shunt, distal to the plug. A venogram was then performed via the microcatheter to exclude any residual contrast leak and identify additional efferent channels requiring embolization. Subsequently, a sclerosant mixture, consisting of 3% STS and contrast (320 mg I/ml; Visipaque, GE Healthcare, Ireland) in a 2:1 ratio, along with small gel foam pieces, was injected under fluoroscopic guidance until complete filling of the shunt was achieved. The plug was then deployed, and the sheath and catheters were meticulously withdrawn. For coil-assisted shunt occlusion, a procedure analogous to the plug method was followed, but oversized detachable coils (Interlock-35 Fibered IDC Occlusion System, Boston Scientific, USA) were used as the primary occluding agent instead of a plug. The HVPG measurement was meticulously repeated the following day, within 24 hours, after confirmation of PS obliteration via contrast-enhanced cross-sectional imaging. The study adhered strictly to the Helsinki Declaration of 1975 (as revised in 2000 and 2008) regarding human rights. The institutional review board of the Liver Institute, Rajagiri Hospital (CoEGIS/TLI/RAJH:83/12/2022), approved the study design and retrospective data collection. The requirement for consent from legally authorized representatives (for deceased patients) was waived by the Institutional Review Board/Ethics Committee, given the retrospective pooled analysis design that precluded individualistic scrutiny of existing clinical data.

Post-procedure protocol and follow-up

Following shunt embolization, all patients were maintained on optimized beta-blocker therapy, typically carvedilol or propranolol, as determined by the treating physician. Patients developing symptomatic ascites of grade ≥2, either pre- or post-procedure, were initiated on a low-sodium diet and diuretics. For those with symptomatic grade 3 ascites, large-volume paracentesis, supplemented by intravenous human albumin infusion as needed, was performed. Patients diagnosed with hepatic encephalopathy (HE) continued on rifaximin (550 mg twice daily) and oral lactulose (titrated to achieve at least two soft stools daily). Those who developed HE post-embolization were promptly initiated on secondary prophylaxis. Notably, no patients received weekly human albumin infusions before or after the procedure.

All patients underwent upper gastrointestinal endoscopy to assess variceal disease between one and three months post-procedure, followed by surveillance every three to six months for the first year, and annually thereafter. Contrast-enhanced computed tomography of the abdomen was performed 24 hours post-procedure to confirm shunt occlusion, with subsequent scans at six months, one year, and two years; the latest imaging report informed this study's imaging-based variables. The follow-up duration for all included patients was a minimum of one year and a maximum of 32 months, or until death or liver transplantation, whichever occurred first. Death or liver transplantation were both considered negative outcomes for the purpose of this study.

Results

Patients inclusion

From January 2018 to October 2020, our center performed shunt embolization on 99 cirrhotic patients with portosystemic shunt syndrome. Of these, 32 patients who also underwent transjugular intrahepatic portosystemic shunt (TIPS) placement and 3 patients with active or prior hepatocellular carcinoma (HCC) were excluded. Among the remaining 64 patients who received shunt embolization as a standalone procedure, 9 did not undergo hepatic venous pressure gradient (HVPG) measurement, 4 had only a single HVPG measurement, and 5 had incomplete documentation or follow-up data. Consequently, 46 patients, including 34 treated for HE, 11 for GVB, and 1 for both, with complete pre- and post-shunt embolization HVPG measurements, were ultimately included in the final analysis (Figure 1).

Figure 1.

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Details of patients included in the study.

Patients characteristics

The patient cohort was predominantly male (N=39, 84.8%), with a mean age of 58.02 ± 8.71 years. Metabolic-dysfunction-associated fatty liver disease was identified as the primary etiology of cirrhosis in the majority (N=35, 76.1%) of patients. Systemic hypertension (N=42, 91.3%) was the most prevalent comorbidity, and a significant proportion (N=37, 80.4%) were classified as overweight or obese. Baseline median Child-Turcotte-Pugh (CTP) and Model for End-Stage Liver Disease (MELD) scores were 7 (IQR 7–9) and 15.5 (IQR 11–19), respectively. A single large portosystemic shunt was observed in 38 patients (82.6%), while dual shunts were present in the remainder. The most common shunt type was lienorenal (N=25, 54.3%), followed by gastrorenal (N=7, 15.2%) and large left coronary vein (N=4, 8.7%) shunts. The median size of the largest shunt was 15.5 mm, ranging from 7 mm to 35 mm.

Of the 11 patients undergoing shunt embolization for gastric variceal bleeding (GVB), gastro-esophageal varix type 2 (GOV2) was present in 10 (90.9%), with one patient having isolated gastric varix type 1. Among the 35 patients treated for hepatic encephalopathy (HE), indications included recurrent HE (N=21, 45.7%), a severe first episode of overt HE (N=10, 21.7%; nine with pre-coma, one with hepatic coma), and persistent HE (N=4, 8.7%). Ten patients (21.7%) presented with radiologically (grade 1 in eight) or clinically detectable (grades 2 and 3 in two) ascites prior to shunt embolization. The overall survival rate at one year post-embolization was 86.96% (N=46; 6 deaths, 13.04%), with a mean survival of 47.43 ± 1.9 weeks. At the 32-month follow-up, 21 patients had died (45.65%), yielding a mean survival of 24.59 ± 1.5 months and a survival proportion of 54.35%. Notably, one patient underwent successful liver transplantation by 12 months, and two by 32 months (Table 1 and Figure 2).

Table 1.

Complete and pertinent clinical and investigational details at baseline and follow-up of cirrhotic patients undergoing shunt embolization.

| **N ** | Minimum | Maximum | Mean | Median | SD | 25–75 P
---|---|---|---|---|---|---|---
Age (years) | 46 | 40 | 80 | 58.02 | 60 | 8.7 | 51–63
Hemoglobin (g/L) | 46 | 6.8 | 14.2 | 10.6 | 10.8 | 1.9 | 9.1–12.1
White cell count (×103 per cubic mm/L) | 46 | 2.4 | 14.2 | 6.2 | 5.9 | | 4.5–8.4
Platelet count (×103 per cubic mm/L) | 46 | 45 | 178 | 103.8 | 96 | 32.4 | 85–124
Total bilirubin (mg/dL) | 46 | 0.5 | 13.1 | 2.1 | 1.9 | | 1.3–3.1
Serum albumin (g/dL) | 46 | 2.2 | 3.8 | 3.02 | 2.9 | 0.4 | 2.8–3.4
International normalized ratio | 46 | 0.9 | 3.6 | 1.5 | 1.4 | | 1.2–1.7
Serum creatinine (mg/dL) | 46 | 0.6 | 3.9 | 0.9 | 0.9 | | 0.7–1.2
Serum sodium (meq/L) | 46 | 127 | 144 | 134.8 | 135 | 4.5 | 130–138
Child Turcotte Pugh score | 46 | 5 | 13 | 8.1 | 7 | 2.1 | 7–9
Model for end-stage liver disease score | 46 | 6 | 29 | 15.8 | 15.5 | 5.7 | 11–19
Arterial ammonia (μmol/L) | 46 | 24 | 301 | 100.03 | 101.3 | | 74–147
Pre-procedure HVPG (mm Hg) | 46 | 9 | 21 | 13.4 | 13 | 3.2 | 11–15
Post-procedure HVPG (mm Hg) | 46 | 12 | 26 | 16.9 | 16 | 3.6 | 14–19
Percentage change in HVPG from baseline | 46 | 5 | 59 | 28.6 | 28.5 | 13.3 | 18–36
Days in ICU | 15 | 1 | 8 | 2.8 | 3 | | 2–3.7
Size of the largest shunt (in mm) | 46 | 7 | 35 | 14.9 | 15.5 | | 12–19
Time to bleed after the procedure | 5 | 34 | 104 | 58.2 | 69 | | 34.8–83.9
Duration of stay during shunt embolization | 46 | 1 | 19 | 3.4 | 3 | | 2–5
Gender | Males— N = 39, 84.8%
Diabetes/systemic hypertension/obese | N = 29, 63%/N = 4, 8.7%/N = 9, 19.6%
Etiology of liver disease | Non-alcoholic steatohepatitis— N = 35, 76.1%
Grade of esophageal varices (baseline) | 0—6.5%, I—47.8%, II—43.5%, III—2.2%
Grade of esophageal varices (last surveillance) | 0—21.7%, I—26.1%, II—41.3%, III—10.9%
Procedure performed for (indication) | GVB, N = 11, 23.9%; encephalopathy, N = 34, 73.9%; both, N = 1, 2.2%
Type of hepatic encephalopathy (N = 35) | Recurrent, N = 21, 45.7%, first severe overt, N = 10, 21.7%, persistent, N = 4, 8.7%
Gastric varices (baseline) | GOV2— N = 10/11, 90.9%
Number of shunts before the procedure | One in 82.6%, two in 17.4%
Type of shunts identified for embolization | LRS, N = 25, 54.3%GRS, N = 7, 15.2%LCV, N = 4, 8.7%PUV, N = 2, 4.3%MCS, N = 1, 2.2%LRS + GRS, N = 2, 4.3%LRS + LCV, N = 2, 4.3%LRS + MCS, N = 1, 2.2%LRS + PUV. N = 1. 2.2%GRS + PUV, N = 1, 2.2%
Procedure performed (N = 46) | PARTO, N = 13 (28.3%)CARTO, N = 12 (26.1%)BRTO, N = 8, 17.4%CAATO, N = 7, 15.2%CARTO + PARTO, N = 4, 8.7%CAATO + glue, N = 2, 4.3%
Bleeding esophageal varices on follow up | N = 5, 10.9%
Recurrence of shunt on protocol imaging | N = 11, 23.9%
Sepsis within 100 days after the procedure | N = 7, 15.2%Bacteremia (N = 2, 28.6%), pneumonia (N = 2, 28.6%), urinary tract infection (N = 2, 28.6%), spontaneous bacterial peritonitis (N = 1, 14.3%)
Causes of death in the first-year post-procedure | Total, N = 6 (13%): septic shock in four, pulmonary embolism and acute variceal bleeding in one
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SD: standard deviation; LRS: lienorenal shunt; GRS: gastrorenal shunt; LCV: left coronary vein shunt; PUV: paraumbilical vein; MCS: mesocaval shunt.

Figure 2.

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Kaplan–Meier analysis shows the proportion of patients surviving at the end of 1 year and long-term follow-up of 32 months after shunt embolization.

Procedure-related characteristics

The most frequently employed shunt embolization technique was Plug-Assisted Retrograde Transvenous Obliteration (PARTO), performed in 13 patients (28.3%), followed by Coil-Assisted Retrograde Transvenous Obliteration (CARTO) in 12 patients (26.1%). Balloon-Occluded Retrograde Transvenous Obliteration (BRTO) was utilized in 8 patients (17.4%), and Coil-Assisted Antegrade Transvenous Occlusion (CAATO) in 7 patients (15.2%). Combination approaches, such as CARTO + PARTO (N=4, 8.7%) and CAATO + glue (N=2, 4.3%), were also implemented. The transjugular route was the primary access method for 37 patients (80.4%), while a percutaneous approach was used in 8 (17.4%), and a combination of both in 1 patient (2.2%).

Post-procedure, 15 patients (32.6%) required monitoring in the intensive care unit (ICU), with a median ICU stay of 3 days (ranging from 1 to 8 days). The overall median hospital stay was also 3 days (ranging from 1 to 19 days), indicating a relatively efficient recovery period for most patients (Figure 3). The hepatic venous pressure gradient (HVPG) measured before shunt embolization averaged 13.4 ± 3.2 mm Hg (median 13, range 9–21). Following shunt occlusion, the HVPG significantly increased to 16.9 ± 3.7 mm Hg (median 16, range 12–26), demonstrating a statistically significant change (Hodges–Lehmann median difference 3.0, p < 0.0001). The mean percentage change in HVPG from baseline was 28.6 ± 13.3%, with a notable range from 5% to 59%.

Figure 3.

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The various shunt-embolization methods performed in the patient cohort. Large gastric varices (arrow, a) and post-embolization disappearance of varices (asterisk, b) with the development of ascites (arrow, b); large lienorenal shunt occluded using a plug (arrows, c); balloon-assisted retrograde transvenous occlusion of a large shunt (arrow, d); a large bunch of gastric varices (arrow, e) and associated shunt (asterisk, e) and complete occlusion of shunt and associated obliteration of gastric varices (arrows, f).

Portal hypertension-related events

Before shunt embolization, low-grade esophageal varices (no or grade 1) were present in 25 patients (54.3%), while high-grade varices (grades 2 and 3) were noted in 21 patients (45.7%). At the one-year follow-up among survivors (N=40), the proportion of low-grade varices decreased to 42.5%, while high-grade varices increased to 57.5%. By the 32-month follow-up, among the 25 surviving patients, low-grade esophageal varices were observed in 40%, and high-grade varices in 60%. Although an aggravation of variceal disease was evident post-shunt embolization, this trend did not achieve statistical significance.

Variceal bleeding after shunt embolization occurred in only five patients (10.9%) throughout the entire follow-up period, with a median time to bleeding event of 69 weeks (range 34 to 104 weeks). Prior to shunt embolization, 10 patients (21.7%) presented with clinically significant ascites (grade 1 in eight, grades 2 and 3 in two). Post-embolization, clinically significant ascites developed in 12 patients (26.1%) within six months and in an additional 5 patients (11.9%) between six and twelve months (data for 4 deceased patients unavailable). Similarly, overt hepatic encephalopathy (HE) was observed in three patients (6.5%) within six months post-embolization and in four additional patients (9.5%) between six and twelve months. Recurrence of portosystemic shunt (PSS) on follow-up imaging was identified in 11 patients (23.9%).

Clinical events and significance related to outcomes

Infections requiring hospital admission within 100 days post-shunt embolization occurred in 7 patients (15.2%), with the overall incidence rising to 14 patients (30.4%) by the 32-month follow-up. The most common infections within the initial 100 days were bacteremia and pneumonia (each affecting 2 patients, 28.6% of those with infection), followed by urinary tract infection (2 patients, 28.6%) and spontaneous bacterial peritonitis (1 patient, 14.3%). Six patients (13%) died within the first year post-procedure; the primary cause was septic shock (4 patients, 66.7%), with one death each attributed to acute variceal bleeding and massive pulmonary embolism. Over the full 32-month follow-up period, a total of 21 patients (45.7%) succumbed after the shunt embolization procedure.

The development of hepatocellular carcinoma (HCC) on overall follow-up, beyond the first year after shunt embolization, was noted in seven patients (15.2%). A significant association was found between infections requiring hospitalization within 100 days post-embolization and one-year mortality (p = 0.003); however, this early infection was not significantly associated with overall mortality at 32 months (p = 0.68). In contrast, infections requiring hospitalization beyond the first year after shunt embolization were strongly and significantly associated with long-term mortality (relative risk 2.7, 95% CI 1.54–4.76, p < 0.001). Multivariable regression analysis further confirmed that only infection beyond 12 months post-embolization was an independent predictor of mortality (p = 0.001, odds ratio 4.1, 95% CI 1.68–9.72). Neither Child-Turcotte-Pugh (CTP) nor Model for End-Stage Liver Disease (MELD) scores demonstrated a significant association with shunt recurrence or long-term overall mortality in this cohort.

Significant HVPG-associated outcomes

Patients were stratified into groups based on hepatic venous pressure gradient (HVPG) cutoffs: ≤13 mm Hg or >13 mm Hg pre-procedure, and ≤16 mm Hg or >16 mm Hg post-procedure, using median values. A post-procedure HVPG exceeding 16 mm Hg was significantly associated with the development of ascites between 1 and 6 months post-procedure (relative risk 1.6, 95% CI 1.1–2.3, p = 0.01). Similarly, an increase in HVPG from baseline by more than 4 mm Hg also significantly predicted the onset of ascites within the same 1 to 6-month post-occlusion period (p = 0.02). However, neither baseline nor post-procedure HVPG cutoffs showed a significant association with ascites development between 6 and 12 months after shunt embolization.

The occurrence of overt hepatic encephalopathy (HE) post-procedure, both within 1–6 months and 6–12 months, was not significantly influenced by either baseline or post-procedure HVPG cutoffs. Similarly, the incidence of sepsis requiring hospitalization within 100 days and beyond 12 months after shunt embolization was not significantly impacted by HVPG thresholds at baseline or following shunt occlusion. While an increased risk for hepatocellular carcinoma (HCC) development beyond the first year post-procedure was observed in patients with a post-procedure HVPG exceeding 16 mm Hg, this trend did not reach statistical significance (relative risk 1.3, 95% CI 0.99–1.67, p = 0.053). Furthermore, the percentage change in HVPG from baseline demonstrated no significant association with any of the investigated outcome measures in this study (Figure 4).

Figure 4.

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The significance of pre- and post-procedure portal pressures measured as the HVPG on various clinical, investigational, and patient outcomes.

Discussion

Large spontaneous portosystemic shunts (PSS) in patients with cirrhosis are unequivocally linked to hepatic encephalopathy (HE) and reduced transplant-free survival, irrespective of liver function, lower Model for End-Stage Liver Disease (MELD) scores, or beta-blocker treatment 3. Early embolization of symptomatic large PSS has been associated with improved clinical outcomes in cirrhosis, demonstrating better control of gastric variceal bleeding and prevention of HE recurrence 13. Limited studies on shunt embolization have explored the full spectrum of clinical and investigational variables influencing outcomes. Previous research indicated that MELD scores >11–15 and Child-Turcotte-Pugh (CTP) scores above 11 correlated with negative outcomes, while liver stiffness values below 21.6 kPa before embolization were associated with improved survival and fewer adverse events. Moreover, shunt embolization performed early in the disease course generally led to enhanced transplant-free survival 14.

Our current study contributes novel insights by elucidating the association between pre- and post-shunt embolization portal pressures and clinical outcomes in a large single-center cohort. This represents the largest series analyzing shunt occlusion with serial hepatic venous pressure gradient (HVPG) measurements, incorporating various advanced embolization techniques. We observed a one-year survival rate of approximately 87% and a remarkable 55% survival beyond 2.5 years. A critical finding was the strong association between the development of infections (sepsis)—both within 100 days and beyond the first year post-embolization—and mortality at 12 and 32 months, respectively. Indeed, requiring hospital admission for infection was identified as the sole independent predictor of long-term mortality in cirrhotic patients undergoing shunt embolization.

Furthermore, our analysis revealed that an HVPG elevation exceeding 4 mm Hg from baseline and an absolute increase to greater than 16 mm Hg immediately post-procedure significantly predicted the development of early and late-onset ascites. An absolute post-shunt embolization HVPG increase above 16 mm Hg also showed a trend towards increasing the incidence of primary liver cancer. Importantly, the percentage change in HVPG from baseline did not demonstrate a significant impact on any clinical outcome. These findings offer a more nuanced understanding of portal pressure dynamics and their tangible effects on patient prognosis.

Comparing our results to existing literature, Tanihata and colleagues 9 reported that an HVPG elevation exceeding 5 mm Hg post-Balloon-Occluded Retrograde Transvenous Obliteration (BRTO) significantly aggravated esophageal varices, particularly in Child-Turcotte-Pugh (CTP) class B patients, with pre-existing varices and higher grades predicting worsening. In our study, while variceal aggravation was evident post-procedure, only 1 in 10 patients experienced bleeding during follow-up. This favorable outcome, despite increased variceal burden, can likely be attributed to two crucial factors: consistent optimization of beta-blocker therapy before and after embolization, and the utilization of superior embolization techniques such as Plug-Assisted Retrograde Transvenous Obliteration (PARTO) and Coil-Assisted Retrograde Transvenous Obliteration (CARTO) with or without glue. These advanced methods ensure more complete occlusion of the variceal complex and its tributaries, effectively mitigating clinical events even in the presence of aggravated variceal disease.

In a study by Uehara et al., a controversial finding suggested that an HVPG increase of ≥20% from baseline improved liver functions, with no significant post-procedure hepatic encephalopathy or bleeding observed after BRTO 10. However, current literature consistently links elevated HVPG to an increased risk of variceal bleeding, ascites, infections, HE, liver disease progression, and the development of hepatocellular carcinoma (HCC) 14,15. The Uehara study’s contradictory results may stem from uncontrolled confounders. Consistent with broader literature, our study found that HVPG elevation by >4 mm Hg from baseline and an absolute increase above 16 mm Hg were associated with a higher incidence of ascites. This aligns with a large Korean multicenter study showing that only CTP class C was linked to rebleeding after shunt embolization, supporting the notion that post-procedure HVPG elevation aggravates portal hypertension events rather than ameliorating liver disease severity 16.

Similarly, Park and colleagues demonstrated 100% technical success for gastric variceal bleeding embolization using PARTO, but 53% of patients experienced worsening varices 11. Their study noted a significant association between HVPG and esophageal variceal aggravation, though details on beta-blocker optimization and other confounding factors were not discussed. Furthermore, liver function improvement post-PARTO was temporary, lasting only six months, and was not significantly correlated with pre- or post-procedure portal pressures, suggesting that other factors, such as etiological control, might have played a larger role in ameliorating liver disease severity. In our cohort, intermediate and long-term outcomes were primarily influenced by the development of post-shunt embolization infections. While a previous study on shunt embolization for HE linked a CTP score above 11 to higher mortality 17, our study, which included patients with less severe disease, did not find this statistical significance.

A retrospective review from the Royal Free Hospital, London, by Privitera et al., revealed that patients who did not improve post-procedure often succumbed to sepsis, with 20% developing severe ascites and approximately 8% experiencing variceal bleeding. Notably, their study found no association between pre-procedural MELD score and outcome, suggesting that MELD >11 might not be an optimal stratification method, and a substantial proportion of embolized patients still developed portal hypertension-related complications. These findings are consistent with our own observations. Privitera et al. advocated for more detailed patient assessments, including portal pressure measurements, to identify subgroups at lower risk of complications 18. Our study, by analyzing clinical outcomes based on pre- and post-shunt embolization HVPG measurements, identified that an absolute HVPG increase of ≥16 mm Hg, a pertinent HVPG elevation of >4 mm Hg from baseline, and the occurrence of post-procedure infections were indeed predictive of negative outcomes, including portal hypertension complications, HCC development, and reduced transplant-free survival.

Our study presents several key strengths, most notably being the largest single-center investigation to date that meticulously analyzes clinical outcomes in cirrhotic patients undergoing shunt embolization for hepatic encephalopathy or gastric variceal bleeding, specifically in the context of pre- and post-procedure portal pressures. This enabled us to precisely identify a subgroup of patients at higher risk of adverse outcomes based on baseline and post-procedure HVPG. The practical implications of our findings are significant: pre- and post-shunt embolization HVPG assessment can serve as a vital tool to identify patients requiring intensified monitoring for infections, to guide the assessment and control of infection risk factors, and to optimize beta-blocker and diuretic therapy for managing inadvertent portal hypertension complications. Such insights also underscore the importance of close surveillance for hepatocellular carcinoma development. Ultimately, for patients with these identified risk factors or emerging complications, early consideration for liver transplantation could substantially improve survival rates (Figure 5, summary infographics).

Figure 5.

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Summary infographics of the study.

Despite its strengths, our retrospective single-center study is subject to limitations that necessitate validation through well-designed prospective investigations. The precise influence of beta-blocker therapy and the efficacy of its targeted optimization require further exploration, ideally through studies incorporating a control group. The development of stringent, well-defined inclusion criteria in future research could also significantly aid in identifying specific clinical and investigational variables associated with improved liver function post-shunt occlusion. Additionally, given the retrospective, cross-sectional design, a formal sample size calculation was not performed, which may limit the generalizability of some findings. Finally, the differential impact of various shunt embolization methods on long-term patient outcomes warrants further clarification through dedicated comparative studies.

Conclusion

This study demonstrates that both baseline and post-procedure hepatic venous pressure gradient (HVPG), along with their dynamic changes, are crucial determinants of intermediate and long-term clinical outcomes in cirrhotic patients undergoing shunt embolization for hepatic encephalopathy or gastric variceal bleeding. Specifically, an HVPG elevation of greater than 4 mm Hg from baseline and an absolute HVPG increase to ⩾16 mm Hg after the procedure were significantly associated with clinically relevant portal hypertension events. Furthermore, post-shunt embolization sepsis emerged as a critical and independent risk factor for long-term post-procedure mortality. These findings underscore the importance of continuous hemodynamic monitoring and proactive management in this patient population.

Footnotes

Author contributions: Sasidharan Rajesh has been involved in conceptualization, methodology, data curation, writing (review and editing), validation; Cyriac Abby Philips has been involved in conceptualization, visualization, methodology, writing (original draft and review), validation; Rizwan Ahamed has been involved in writing (review and editing), validation, supervision; Shobhit Singh has been involved in data curation, writing (review and editing), validation; Jinsha K Abduljaleel has been involved in writing (review and editing), validation, supervision; Ajit Tharakan has been involved in writing (review and editing), validation, supervision; Philip Augustine has been involved in writing (review and editing), validation, and supervision.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethics approval: Ethical approval for this study was obtained from the Institutional Review Board of the Liver Institute, Rajagiri Hospital (CoEGIS/TLI/RAJH:83/12/2022). All authors confirm that they are accountable for all aspects of the work (if applied, including full data access, the integrity of the data, and the accuracy of the data analysis) in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: The requirement of obtaining consent from a legally authorized representative (in the case of deceased patients) was waived off by the Institutional Review Board/Ethics Committee.
Trial registration: Not applicable as this is not a prospective randomized trial.
ORCID iD: Cyriac Abby Philips https://orcid.org/0000-0002-9587-336X

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Original written by from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10617273/