- Research article
- Open Access
- Open Peer Review
The endoscopic ultrasound probe findings in prediction of esophageal variceal recurrence after endoscopic variceal eradication therapies in cirrhotic patients: a cohort prospective study
© The Author(s). 2019
- Received: 21 November 2018
- Accepted: 28 January 2019
- Published: 19 February 2019
The recurrence of esophageal varices remains high in patients with hepatic portal hypertension after the endoscopic esophageal variceal eradication therapies, including endoscopic variceal band ligation (EVL), injection sclerotherapy (EIS) or EVL plus EIS. The aim of this study was to evaluate the endoscopic ultrasound probe examinations (EUP) findings in the prediction of recurrence following esophageal variceal eradication in a prospective cohort.
A total of 206 cirrhotic portal hypertension patients with esophageal variceal eradication, who underwent endoscopic variceal therapy (EVL or EIS or EVL plus EIS) were initially enrolled. All patients were scheduled for a follow-up every 6 months for up to 3 years. EUP was performed to evaluate peri-esophageal collateral veins (peri-ECVs), perforating veins (PFV) and para-esophageal collateral veins (para-ECVs). In addition, computed tomography (CT) were conducted to detect portal vein diameter, portal vein embolus, and major portosystemic collateral shunts. The relationship between esophageal variceal recurrence and EUP findings were analyzed.
We found that as high as 93.5% of patients developed esophageal variceal recurrence in the 3-year follow-up. The time of esophageal variceal recurrence after variceal eradication was 13.4 months (13.4 ± 9.2 months). Furthermore, the median time of recurrence in patients who were undertaken EVL,EIS and EVL plus EIS was 10, 13 and 12 months, respectively. We identified that the risk factors, including EVL (OR 0.23, 95% CI 0.08–0.71, p < 0.01), Child-Pugh score (OR 3.32,95% CI 1.31–35.35, p < 0.05), large peri-ECVs (OR 4.56, 95% CI 2.17–9.58, p < 0.0001), and existence of PFV (OR 2.14, 95% CI 1.44–3.16, p < 0.001), were significantly associated with the recurrence of esophageal varices. The peri-ECVs and PFV showed better ability to predict esophageal variceal recurrence. When cut-off value of peri-ECVs diameter was 3.5 mm, the specificity of prediction 1-year variceal recurrence was 86% and the sensitivity was 45%.
The EUP appears to be very effective, convenient and economical examinations to predict esophageal varices recurrence after variceal eradication by endoscopic therapies. The high Child-pugh score, large peri-ECVs, and PFV are independent risk factors related to esophageal varices recurrence.
- Esophageal varice
- Liver cirrhosis
- Portal hypertension
- Endoscopic ultrasound probe examinations
The esophageal-gastric variceal bleeding (EVB) is considered as one of major fatal complications in patients with hepatic cirrhosis and portal hypertension [1, 2]. Endoscopic variceal ligation (EVL), endoscopic injection-sclerotherapy (EIS), and the two in combination have been recommended by a majority of guidelines for the prevention and treatment of EVB in cirrhotic patients [2, 3]. Notably, the recurrence of esophageal varices is highly prevalent after the endoscopic esophageal variceal eradication therapies in patients with portal hypertension [4, 5]. Although the underlying pathological mechanisms remain to be elucidated, it would be urgent to identify the independent risk factors associated with the recurrence of the esophageal varices as soon as early intervention treatment possible in order to prevent esophageal variceal rebleeding .
The endoscopic untrasonography (EUS) has capability to evaluate the blood vessels around the wall of the esophagus in patients with portal hypertension . Recently, It have been reported that the peri-esophageal collateral veins, perforating veins, and para-esophageal collateral veins found by EUS were related to the variceal recurrence following endoscopic therapies [8, 9]. However, these previous studies had small samples, short follow-up period (ranging from 1 to 3 months) and EUS was frequently performed before endoscopic therapies. Currently, the endoscopic ultrasound probe examinations (EUP) is easy and safe to operate compared with EUS performing [10, 11]. However, It was less knowledge that the EUP findings were as same usefulness as EUS in prediction variceal recurrence following endoscopic therapies. Thus, In this prospective cohort study, we aimed to evaluate the EUP findings after the esophageal variceal eradication by EVL, EIS, or EVL plus EIS to predict the variceal recurrence.
In this prospective cohort, patients who were diagnosed as esophageal varices as well as complicated with liver cirrhosis and portal hypertension were enrolled during the period from January 2012 to December 2014. Of these, a total of 206 patients met the inclusion and exclusion criteria. During follow-up period, 53 individuals were ruled out. Of them, lost or less than 3-year follow-up 23, received TIPS or surgery 9, and died 21. Total 153 patients were enrolled for study. The inclusion criteria were as follows: (1) Age from 18 to 75 years old cirrhotic patients without any treatemt history for portal hypertension, including oral non-selective beta blockers, interventional radiology (such as TIPS), or surgical therapy (splenectomy and devascularization); (2) Esophageal varices were caused by liver cirrhosis with portal hypertension, (3) Esophageal varices were diagnosed by endosopy according to the guidelines , (4) The esophageal varices were individually treated by EVL, EIS, or EVL plus EIS. The following exclusion criteria were used in this study: (1) Endoscopic treatment failed to achieve eradication of esophageal varices, (2) TIPS, surgery or death were identified during the 3-year follow-up period, (3) Gastric varices (type GOV2, GOV3) or isolated gastric varices (IGV), (4) Child-Pugh score more than 14, (5) The function failures in the renal, brain, and heart, (6) Esophageal varices caused by no-cirrhotic portal hypertension.
Endoscopic ultrasound probe examinations(EUP)
Clinical and laboratory data
Symptoms, signs, and adverse events were recorded in the medical record. Serum markers for hepatitis B and C viruses were detected by electrochemiluminescence immunoassay (Roche E170 modular immunoassay analyzer, Roche Diagnostics, Mannheim, Germany). Serum biomarkers for the liver and renal function, including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), albumin, creatinine, and urea nitrogen, were measured on an automatic biochemical analyzer (AU5400, Olympus Company, Tokyo, Japan). Child-Pugh scores was calculated11; MELD (Model for-stage liver disease) is 3.8 × ln[TBiL(mg/dL)] + 11.2 × ln(INR) + 9.6 × ln[creatinine (mg/d1) + 6.4 × (cause of disease: biliary or alcoholic 0; other 1).
The end-points and follow-up protocol
During the follow-up period, endoscopy and clinical data were collected once every six months, while CT images were reviewed once a year. The endpoints of follow-up were recurrence of esophageal varices, or rebleeding from esophageal varices or follow-ups to 3 years, liver transplantion or TIPS, and death. The criteria of recurrence of esophageal varices were defined as moderate esophageal varices, or mild varicose vein with red sign needed to be treated by endoscopy (Fig. 1d-e). The cirrhotic etiology and complications of portal hypertension were treated following the guidelines. Non-selective beta-blockers, however, were not used during follow-up period. Observation period was defined as the time interval between the end of the endoscopic treatment and the time of the endpoint.
IBM SPSS 22 statistical software was used to statistical analysis. The quantitative data were presented as mean ± standard deviation (SD). The student t test and ANOVA for unpaired data were applied to compare differences between groups. The qualitative data were analyzed by the chi-square test or the Fisher’s exact probability test. Multivariate linear regression analysis was conducted to evaluate the correlation between multiple variables. The Kaplan–Meier estimator and log-rank test was used to analyze the survival. A P value less than 0.05 (two-way) was considered statistically significant.
Demographic and clinical characteristics
The demographic and clinical characteristics of the study patients
55.2 ± 11.9(28–75)
Etiology of cirrhosis(n, %)
alcoholic liver disease
nonalcoholic fatty liver disease
autoimmune liver disease
Cirrhosis with liver cancer(n,%)
Child-Pugh class (n,%)
Endoscopic treatment (n,%)
EVL + EIS
Recurrence of EV (n,%)
within 1 year
Mean time of recurrence (months)
From eradication to recurrence
Risk factors associated with recurrence of esophageal varices
The risk factors of recurrence after esophageal variceal eradication by endoscopic therapies
Within 1 year recurrence group
(n = 89)
1–3 years recurrence(n = 54)
Without variceal recurrence group(n = 10)
EVL + EIS(n,%)
1.22 ± 0.31
1.20 ± 0.3
0.9 ± 0.2
Red signs before treatment(Y/N)
Diameter of peri-ECV(mm)
3.7 ± 1.4
2.5 ± 1.1
1.7 ± 0.9
Existence or not of PFV (Y/N)
Diameter of PFV(mm)
1.9 ± 1.6
0.1 ± 0.4
Diameter of para-ECV(mm)
6.5 ± 2.2
5.9 ± 1.9
6.9 ± 3.7
7.3 ± 2.1
6.5 ± 1.4
6.4 ± 0.9
7.1 ± 7.8
6.9 ± 4.9
5.3 ± 2.0
Veins around the esophagus(Y/N)
Veins around fundus (Y/N)
Other collateral vein(Y/N)
Portal vein embolus(Y/N)
With liver cancer/cirrhosis
Etiology of cirrhosis(n, %)
alcoholic liver disease
nonalcoholic fatty liver disease
autoimmune liver disease
Effects of different endoscopic treatments on esophageal varicel recurrence
The effects of endoscopic therapies on variceal recurrence after esophageal variceal eradication
(n = 54)
(n = 80)
EVL + EIS group
(n = 19)
Course number of endoscopic treatment course to variceal eradication
1.9 ± 0.7
3.2 ± 1.2a
3.4 ± 1.6a
Median time of variceal recurrence(month)
diameter of peri-ECV(mm)
2.9 ± 1.4
3.4 ± 1.5
2.9 ± 1.1
diameter of PFV(mm)
1.44 ± 1.5
0.9 ± 1.5
1.0 ± 1.3
existence or not of PFV(Y/N,n)
diameter of para-ECV(mm)
6.2 ± 2.1
6.3 ± 2.3
6.3 ± 2.4
7.2 ± 2.1
6.7 ± 1.7
7.2 ± 1.9
Portal vein embolus(Y/N, n)
With liver cancer (n,%)
Unknown causes for cirrhosis
Comparison of CT angiography and EUP findings
Comparision between CT angiography and EUP findings
Hemorrhage of esophageal varices has been sought to be a serious complication in liver cirrhotic patients with portal hypertension, accounting for 20–40% mortality of cirrhotic patients with EVB within 6 months [12, 13]. Currently, endoscopic treatment is recommended as the first line therapy according to guidelines [2, 14, 15]. The key problems were the high recurrence of esophageal varices after the endoscopic esophageal variceal eradication therapies [16, 17]. However, up to now, it remains unclear about the risk factors associated with the recurrence of esophageal varices after varices were eradicated by endoscopic treatment. This large cohort prospective study has the following main novel findings: (1) A majority of the patients, accounting for 93% of the study subjects, developed recurrent esophageal varices within 3 years following variceal eradication; (2) The patients who underwent EVL were more likely to have recurrent esophageal varices compared to those with other endoscopic treatments; (3) high Child-Pugh score, large peri-ECV, and existence of PFV were identified as independent risk factors significantly correlated with the recurrence of esophageal varices; (4) The peri-ECV and PFV had good ability to predict recurrence of esophageal varices.
CT angiography and EUS were previously used to evaluate the effectiveness of endoscopic therapy for eradication of esophageal varices., as it allows to clearly show diameter of hepatic portal vein and its collateral circulation [18, 19]. It has also been reported that a number of factors were related with esophageal varices bleeding, including the diameter of esophageal varices, red sign, Child-Pugh score, model for end-stage liver disease score(MELD), diameter of portal vein, portal vein embolus, hepatic venous pressure gradient (HVPG) . In fact, the effect of above-mentioned factors, spontaneous spleno-renal shunts or portosystemic collateral veins in liver cirrhosis, on variceal recurrence are still not fully understood . In this study, we confirmed that the C-P classification was associated with variceal recurrences. EUS and CT angiography are usually allowed to be directly observed collateral vascular structures and evaluate the vascular networks connected to esophageal varices In this study, EUP was also applied to probe the blood vessels around the wall of the esophagus, which appeared to be more effective in examination of para-ECVs, peri-ECVs and PFV, whereas CT angiography was unable to detect peri-ECVs and PFV. We also identified that high Child-Pugh score, method of endoscopic treatment were related with esophageal variceal recurrence, whereas the portal vein embolus had no effect on recurrence. There is a possibility that the reduced HVPG by collateral circulation accompanied by reduced recurrences of varicose veins, especially para-ECVs or spontaneous spleno-renal shunts or gastric-renal shunts and portosystemic collateral veins. In this study, however, peri-ECVs and PFV detected by EUP was significantly associated with the recurrence of esophageal varices. Some clinical studies were reporteded that patients who experienced EV recurrence after EVL were more likely to have severe-grade perforating veins before treatment than those without recurrence, severe peri-ECVs and multiple peri-ECVs were significantly associated with the risk of variceal recurrence, but not with para-ECVs or perforating vein [9, 22, 23]. In patients with portal hypertension, in fact, after esophageal varices were eradicated, other collateral circulation veins needed to be established, such as para-ECVs. In this study, no difference of para-ECVs were observed in both recurrent and non recurrent patients. Thus, the key action to preventing esophageal variceal recurrence could be the closure of PFV and peri-ECVs. Notably, in this study, the rate of closed peri-ECV was 46.3, 70.0% and 69.0.% respectively in EVL, EIS and EVL plus EIS group, which may contribute to the recurrence of esophageal varies. It was worthwhile to note in our study that there were significant differences in the recurrence time of esophageal varices following EVL and EIS. The median recurrence times in EVL group (10 months) was significantly shorter than that in the EIS group (13 months), and median recurrence months of EVL plus EIS group (12 months). Although EIS had a longer time of esophageal variceal eradication, the incidence of complications was relatively higher. The incidence rate of esophageal stenosis in the EIS group was 11.3%, whereas non of the EVL and EVL plus EIS group.. Compared with EIS, EVL has shorter recurrent time, but has less severe complication, for which EVL could be considered to safer than EIS. In addition, in comparison with MELD score, Child–Pugh score was more likely to be associated with the recurrence of esophageal varices. HVPG has been sought to be an ideal indicator to reflect portal hypertension, but some studies showed that there was slightly alteration before and after EVL, EIS treatment [24, 25].
Our study has limitations, including non-randomized design, lack of endoscopic ultrasonography before endoscopic treatment. The effect of beta-blockers, sunch as carvedilol or propranolol, combined with EVL or EIS on variceal recurrence deserves further clinical study.
EUP sonography is useful for the evaluation esophageal varices recurrence after variceal eradication by endoscopic therapies. Our results have demonstrated that the high Child-pugh score, large para-ECV, and PFV are independent risk factors in the prediction of esophageal varices recurrence after variceal eradication by endoscopic therapies. The identified risk factors hold potential for clinical application in the future.
This study was supported by the Beijing Natural Science Foundation-Beijing Municipal Committee of Education (No. KZ201810025037), Beijing Municipal Administration of Hospitals Clinical Medicine Development of special funding (No. ZYLX201610), and Beijing Municipal Administration of Hospitals’Ascent Plan (No. DFL20151602). This study was supported by the State Key Projects Specialized on Infectious Diseases(2017ZX10203202–004, 2017ZX10201201–008).
Availability of data and materials
The datasets used and analyzed in the current study are available from the corresponding author on demand.
JZ and LL performed EUP examinations, collected and analyzed data, as well as wrote the manuscript. YZ, PL, SZ were responsible for endoscopic therapies and patients follow-up. YL were responsible for collected data. HD designed the study and performed scientific edits to the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The study proposal was reviewed and approved by the Ethics Committees of Beijing You An Hospital affiliated to the Capital University of Medical Sciences (Beijing, China). Signed informed consent was obtained from each patient for using samples, materials and publication prior to the study. In addition, this prospective study was performed in compliance with the Declaration of Helsinki and other regulations.
Consent for publication
Informed consents for their clinical materials and images to be used in our manuscript were .obtained.
The authors declare that they have no competing interests. In addition, they have substantially contributed to this current study and approved the content of the manuscript. All authors have consented to publish in MBC Gastroenterology.
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