Introduction
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome resulting from metabolic disruptions stemming from acute or chronic hepatic dysfunction or portosystemic shunt, and may manifest varying degrees of severity.1 2 The precise pathogenesis of HE remains incompletely understood, with current focus primarily centred on the theory that ammonia toxicity is the underlying mechanism.3 In patients with decompensated cirrhosis, the incidence of overt HE ranges from 30% to 45%.4 HE represents a critical contributor to the mortality rate among patients with end-stage liver disease.5 Its symptoms frequently exhibit a waxing and waning course with frequent recurrences, resulting in recurrent hospitalisations.6 This not only impacts the quality of life for both patients and their families but also places substantial pressure on community healthcare resources.7
Spontaneous portosystemic shunts (SPSS) represent anomalous vascular channels that develop in response to portal hypertension in cirrhosis.8 These shunts establish a connection between the portal venous system and the systemic circulation, thereby partially relieving portal pressure.9 Nonetheless, this pressure-alleviating effect remains insufficient and, in fact, diminishes intrahepatic portal venous perfusion, subsequently elevating the risk of HE.8 9 In advanced stages of cirrhosis, the presence of SPSS may lead to the emergence of the portosystemic shunt syndrome.10 This syndrome is characterised by a progressive decline in liver function, the development of HE concurrent with portal vein thrombosis, and ultimately, hepatic atrophy, with the portal blood flow becoming disconnected from the liver parenchyma.10 It is important to note that the presence of an SPSS exhibits a significant association with the recurrence of HE.11 12 Current studies have reported the presence of large SPSS in 46% to 71% of patients experiencing recurrent or persistent HE.13 14
Given its significant contribution to the occurrence of recurrent or persistent HE, optimising the management of SPSS is a critical component in the treatment of cirrhotic patients associated with this particular form of HE.15 Studies have indicated that embolisation of SPSS can yield noteworthy improvements in HE symptoms, while concurrently diminishing the rates of HE recurrence and rehospitalisation.16–18 Nonetheless, it is imperative to acknowledge that this therapeutic intervention may give rise to a substantial elevation in portal pressure subsequent to embolisation, thereby exacerbating ascites and oesophagogastric varices in a subset of patients, and potentially precipitating haemorrhage.9 19 Consequently, the global adoption of SPSS embolisation as a standard therapeutic modality remains limited.2 7 Moreover, existing literature predominantly comprises small-sized, retrospective, uncontrolled studies, rendering the evidence basis for this intervention notably weak and warranting further investigation, particularly through prospective controlled studies.
Therefore, in the current study, our objective was to undertake a prospective controlled study to assess the safety and effectiveness of interventional embolisation in managing cirrhotic patients with recurrent or persistent HE related to large SPSS.
Methods and analysis
Study design
Figure 1 provides a comprehensive graphical representation of the study design. This is a single-centre, prospective, non-randomised, controlled study, with the objective of enrolling a total of 82 cirrhotic patients with recurrent or persistent HE related to large SPSS. After signing the informed consent form (online supplemental appendix A), these patients will be allocated into two groups based on voluntary participation: an interventional embolisation group or the standard medical treatment group, each consisting of 41 patients. Patient recruitment was initiated in June 2023, and the study is projected to extend until May 2025.
Supplemental material
Eligibility criteria
Inclusion criteria
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Adults aged between 18 and 75 years, inclusive of either gender.
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Provision of a written informed consent.
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A conclusive diagnosis of liver cirrhosis accompanied by persistent or recurrent HE.
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The presence of an SPSS with a diameter ≥10 mm confirmed through enhanced CT or MRI.
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Recent blood tests showing haemoglobin level ≥80 g/L, absolute neutrophil count ≥1.5×109/L and platelet count ≥50×109/L.
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Life expectancy exceeding 6 months, in the opinion of the investigator.
Exclusion criteria
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Concurrent invasive malignant tumours.
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Medical history of interventions such as splenic artery embolisation, splenectomy, hepatectomy, liver transplantation and surgical shunt procedures.
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History of transjugular intrahepatic portosystemic shunt procedure.
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Child-Pugh score >13.
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Refractory ascites.
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Ongoing active gastrointestinal bleeding.
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Active infections or being in the acute phase of infections.
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Patients with psychiatric or neurological disorders.
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Patients with other severe cardiopulmonary or renal conditions.
Treatment plan
Standard medical treatment (SMT) will be promptly initiated on the definitive diagnosis of HE. Subsequently, patients will be stratified into either the embolisation group or the control (SMT only) group based on their voluntary decision regarding embolisation. The embolisation procedure will be conducted within 1 week of the patients signing the informed consent form for enrolment. Of note, interventional embolisation will not be delayed until the resolution of HE symptoms with SMT or subsequent to its failure; rather, it will be conducted concomitantly.
The SMT regimen involves several components: identification and elimination of potential precipitating factors, oral administration of lactulose or as a retention enema, and oral intake of rifaximin. Notably, the dosage of lactulose is titrated to sustain a frequency of two to three bowel movements per day. Additionally, the medication regimen is individualised by the investigator for each patient, with the treatment objective being the resolution of HE symptoms.
Interventional embolisation techniques comprised percutaneous transhepatic obliteration, balloon-occluded retrograde transvenous obliteration, plug-assisted retrograde transvenous obliteration, coil-assisted retrograde transvenous obliteration and/or splenic vein embolisation. In these procedures, the primary embolic agents that will be employed include Amplatzer vascular plugs, coils or combinations thereof. In cases where the shunt cannot be effectively occluded using the primary embolic materials, a supplementary substance consisting of cyanoacrylic acid N-butyl ester mixed with potassium iodide will be used. The selection of the specific embolisation treatment and materials will be at the discretion of the operator, with intraoperative venography and shunt size serving as the guiding criteria. Additionally, where possible, measurements of hepatic venous pressure gradient (HVPG) or portal pressure gradient will be made, both before and after the embolisation procedure. All patients undergoing embolisation will receive a regimen of rivaroxaban (orally, 10 mg, once daily) starting from the first postoperative day, continued for a duration of 3 months. Additionally, lifelong maintenance therapy with either propranolol (orally, initiated at 10 mg two times per day with subsequent increments to the maximum tolerated dose) or carvedilol (orally, initiated at 6.25 mg and increased to 12.5 mg once daily after 1 week if tolerated) will be provided. The dosages of β-blockers will be adjusted based on the treatment response criteria, which involve achieving a reduction in resting heart rate to 75% of the baseline or within the range of 50 to 60 beats per minute, alongside achieving an HVPG ≤12 mm Hg or a decrease of at least 10% from the baseline value throughout the treatment course.
Definition, diagnosis and classification
The concepts concerning HE in this study will be delineated in accordance with the pertinent European Association for the Study of the Liver (EASL) and Chinese guidelines.1 4 Patients diagnosed with overt HE will be classified as recurrent HE if they encounter more than two episodes within a 6-month duration. Persistent HE is characterised when a patient did not return to their baseline performance level between episodes. Identification of overt HE relied on the apparent symptoms and comprehensive physical assessments, graded based on the West-Haven criteria. Furthermore, cases categorised as West-Haven Grade 3 and above will be further evaluated using the Glasgow Coma Scale. Conversely, the diagnosis and grading of minimal HE and covert HE, which lack evident symptoms, relied on psychometric and neurophysiological assessments. Within these evaluations, the Number Connection Test A, the Digit Symbol Test and the Animal Naming Test will be used in this study, confirming a diagnosis when all three tests exhibit positive results simultaneously.
Evaluation and follow-up
Schedule of assessments is depicted in table 1. Patients will be screened to confirm their compliance with the eligibility criteria. Subsequently, informed consent will be acquired. A comprehensive set of data will be systematically gathered, encompassing demographic characteristics, medical history, medication usage and physical examination results. Additionally, pretreatment parameters including blood counts, hepatic and renal function tests, coagulation profiles, plasma ammonia concentration, serum sodium level, liver stiffness measurements, electrocardiographic analyses, cardiac ultrasonography, abdominal ultrasound investigations and gastroscopy findings will also be collected.
Participants will undergo follow-up period extending to a minimum of 12 months following the end of treatment. This monitoring will commence with the initial follow-up visit occurring 1 month following the conclusion of the treatment and will continue at regular intervals of 2–3 months thereafter, persisting until the participant’s decease or the conclusion of the clinical trial. The follow-up assessments will encompass a range of clinical parameters, including routine blood tests, hepatic and renal function tests, coagulation profiles, quantification of plasma ammonia level, determination of serum sodium concentration, measurements of liver stiffness, abdominal ultrasonography and enhanced abdominal CT scan. Additionally, repeated gastroscopy will be conducted at 3- and 9-month after treatment.
In cases where patients experience a recurrence of HE during the follow-up period, SMT will be promptly initiated. Should diagnostic imaging indicate the emergence of a novel collateral or the recanalisation of a previously embolised shunt, the decision to pursue a second embolisation procedure will be contingent on the patient’s preferences. Additionally, for individuals eligible for liver transplantation, the option of liver transplantation is permissible post enrolment and during the follow-up period, contingent on the availability of a suitable liver source.
Efficacy assessment
The primary endpoints include the assessment of symptomatic relief of HE following embolisation and the monitoring of overt HE recurrence throughout the follow-up period. Secondary endpoints encompass several parameters, which include (1) the duration and frequency of rehospitalisation due to HE, (2) alterations in liver function, as evaluated through the Child-Pugh score and the Model for End-Stage Liver Disease score, (3) measurement of plasma ammonia levels, (4) assessment of liver volume and (5) overall survival rates.
Safety assessment
Safety will be assessed based on the immediate postoperative complications such as bleeding, thromboembolic events, infections, anaphylactic shock and hypotension, among others. Additionally, long-term safety parameters that will be measured include the de novo recurrence or aggravation of pre-existing gastro-oesophageal varices or portal hypertensive gastropathy, with or without associated haemorrhage, as well as the presence of ascites, either requiring peritoneal puncture or not, and the occurrence of spontaneous bacterial peritonitis.
Data management
Data will be entered in duplicate by two data entry staff. Inconsistent items will then be checked item by item for the case report form and corrected. Once the database check is consistent, it will be submitted to the data management manager for data inspection. All documents will remain confidential. All study data, including all patient confirmations (valid check of recorded information, such as study cases), all original signed informed consent forms and detailed original records of drug distribution, will be retained by the study institution for 5 years after the trial ends.
Sample size
The analysis employs the Log-rank test to compare the 1-year recurrence rate of overt HE between patients in the embolisation group and those in the control group. Based on prior literature reports,18 it was estimated that the 1-year recurrence rate of overt HE would be approximately 29.4% in the embolisation group and approximately 59.1% in the control group. The study was designed with a 1-year enrolment period followed by a 1-year follow-up phase, factoring in an overall dropout rate of approximately 10%, which encompasses patient withdrawals and missed visits. Using the PASS V.11 software, it was determined that a total of 82 patients (41 per group) would be necessary to detect a statistically significant difference in the 1-year overt HE recurrence rate between the two groups, with a statistical power of 80%, at a significance level (α) of 0.05 (two-sided).
Statistical methods
This study has been designed as a prospective, non-randomised controlled study. All statistical analyses will strictly adhere to the intention-to-treat principle and will be performed using R software (V.4.3.1). Continuous variables will be presented as mean±SD when they exhibit a normal distribution, and group comparisons will be conducted using the t-test. In cases where the data exhibits a skewed distribution, values will be expressed as the median along with the IQR, and group comparisons will be analysed using the Mann-Whitney U test. Categorical variables will be presented as frequency (percentage), and group comparisons will be assessed using either the χ2 test or Fisher’s exact test. The recurrence rate of overt HE and overall survival will be calculated using the Kaplan-Meier method, and the statistical differences will be evaluated with the Log-rank test. Prognostic factors associated with the recurrence of overt HE and overall survival will be identified through the Cox regression model.
Patient and public involvement
The patients and general public were not involved in the trial design.
Discussion
According to prevailing guidelines, SMT is the current standard approach for treating patients with HE.1 4 However, in cases where SPSS are present, a significant volume of blood bypasses the liver’s detoxification process, entering directly into the systemic circulation. Consequently, in HE patients with SPSS, the efficacy of this treatment modality is frequently suboptimal.1 15 Historically, SPSS has been regarded as a compensatory response to portal hypertension.19 However, recent work has highlighted that SPSS may precipitate complications such as liver failure, liver atrophy, HE, portal vein thrombosis and hepatofugal flow in the portal trunk.10 12 20 Consequently, research attention has shifted towards the embolisation of SPSS as a therapeutic strategy for alleviating HE symptoms associated with SPSS,15 mirroring the established approach of SPSS embolisation for variceal bleeding management.21 As of now, the definitive role of the embolisation of SPSS in the management of cirrhotic patients with recurrent or persistent HE remains inadequately established, primarily owing to the inherent limitations within the existing retrospective studies.9 15 Therefore, it is imperative to conduct prospective controlled studies that comprehensively evaluate both the safety and efficacy of interventional embolisation for this specific patient population.
By conducting this study, we aim to contribute crucial evidence-based medical insights pertaining to the treatment of cirrhotic patients with recurrent or persistent HE related to SPSS. Simultaneously, we aspire to offer a dependable treatment option for this specific patient cohort. Should the study yield promising outcomes, we intend to advocate for the broader implementation of this treatment across multiple healthcare centres and for a larger patient population.
This study presents several noteworthy limitations that warrant consideration. First, the absence of randomisation in patient selection may introduce selection bias, potentially influencing the study’s outcomes. Second, the inclusion of various types of shunts and embolisation modalities in this investigation may have affected the final results. Last, the study’s scope is confined to a single research centre, which may impact the generalisability of the findings. Consequently, the findings of this study should be subject to further validation through subsequent multi-centre, randomised, controlled clinical trials.
Trial status
The trial has been officially registered with ChiCTR.org (Registration number: ChiCTR2300072189; registration date: 6 June 2023; available at https://www.chictr.org.cn/showproj.html?proj=198888). Ongoing recruitment is in progress. The protocol version used in the study is V.1.0, and adherence to the SPIRIT guidelines has been observed in reporting the study protocol.
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