JOURNAL TRANSCRIPT
Gut and Liver, Vol. 11, No. 6, November 2017, pp. 843-851
ORiginal Article
Useful Endoscopic Ultrasonography Parameters and a Predictive Model for the Recurrence of Esophageal Varices and Bleeding after Variceal Ligation Soung Won Jeong1, Hye Soo Kim2, Sang Gyune Kim2, Jeong-Ju Yoo2, Jae Young Jang1, Sae Hwan Lee3, Hong Soo Kim3, Ji Sung Lee4, Young Seok Kim2, and Boo Sung Kim2 1
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, 3 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, and 4Clinical Research Center, Asan Medical Center, Seoul, Korea 2
Background/Aims: To identify the usefulness of endoscopic ultrasonography with a mini-probe (EUM) and to create a predictive model for esophageal variceal (EV) recurrence and bleeding following esophageal variceal ligation (EVL). Methods: A total of 144 patients who received EUM prior to prophylactic EVL and met the inclusion criteria were enrolled. EUM findings, EV diameter, paraesophageal vein diameter, and the number of perforating veins were assessed. Results: EV recurrence was observed in 42 patients (29.2%), 10 of whom experienced EV bleeding. Larger diameter of the paraesophageal vein (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.17 to 1.96; p=0.002) and perforating vein (OR, 3.27; 95% CI, 1.11 to 9.65; p=0.032) were significant predictive factors for EV recurrence. However, the diameter of the paraesophageal vein was the only significant risk factor for EV bleeding (adjusted OR, 1.51; 95% CI, 1.06 to 2.16; p=0.022). The areas under the curves of the predictive model for EV recurrence and bleeding were 0.872 (95% CI, 0.811 to 0.934) and 0.811 (95% CI, 0.630 to 0.992), respectively. Conclusions: The diameter of the paraesophageal vein was a significant predictive factor for EV recurrence and bleeding. The predictive model constructed based on the significant EUM findings exhibited good performance. (Gut Liver 2017;11:843-851) Key Words: Esophageal and gastric varices; Recurrence; Hemorrhage; Endosonography
INTRODUCTION Portal hypertension increases blood flow and engorgement of the collateral vessels surrounding the lower esophagus and proximal stomach, leading to a build-up of the gastroesophageal varices in approximately 50% of patients with cirrhosis.1 Once varices have been diagnosed, variceal bleeding occurs at a yearly rate of 10% to 15%.2 Esophageal variceal (EV) bleeding is associated with high morbidity and mortality in patients with cirrhosis. Treatment to prevent EV bleeding should be performed when large varices are present. Endoscopy should be considered for patients with compensated liver cirrhosis (LC) at every 2 to 3 years, and for patients with decompensated LC at every 1 to 2 years.3 Despite treatment improvements over the last decade, the overall mortality rate is 20% due to bleeding from EV.4 Either nonselective β-blocker or endoscopic band ligation is recommended for the prevention of the first variceal bleeding of medium or large varices. Also, combination of β-blockers and band ligation is the preferred therapy as it results in lower rebleeding compared to either therapy alone.5 However, little is known about which patients are more prone to bleeding from EV or who need close management after EVL. Endoscopic ultrasonography with a mini-probe (EUM) can be used to clearly visualize the vascular network around EV. The venous anatomy of the lower esophagus and upper stomach has been described in four layers, such as the intraepithelial channels, superficial venous plexus, deep venous plexus, and adventitial veins.6,7 The superficial venous plexus communicates with the deep venous plexus peri-esophageal collateral veins (peri-ECVs) and the para-esophageal collateral veins (para-ECVs)
Correspondence to: Sang Gyune Kim Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, 170 Jomaru-ro, Bucheon 14584, Korea Tel: +82-32-621-5079, Fax: +82-32-621-6927, E-mail:
[email protected] Received on September 9, 2016. Revised on January 2, 2017. Accepted on January 12, 2017. Published online June 27, 2017 pISSN 1976-2283 eISSN 2005-1212 https://doi.org/10.5009/gnl16458 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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through the perforating veins. The peri-ECVs are located adjacent to the muscularis externa of the esophagus, and the paraECVs are external to the esophageal wall, with no contact with the muscularis externa. EUM enables accurate measurements of para-ECV and EV sizes and the location of the perforating veins. The collateral deep veins seen on EUM are related to recurrence of EV.8,9 However, the role of EUM for predicting EV recurrence or bleeding after EVL have not yet been established. In this study, we aimed to identify significant EUM findings to construct a predictive model for EV recurrence and bleeding followed by prophylactic EVL.
MATERIALS AND METHODS 1. Study population A total of 144 of 248 patients with EV who were consecutively examined by EUM at the Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University School of Medicine, Bucheon, Korea from December 2008 to December 2014 and met the inclusion criteria were enrolled in this study (Fig. 1). The diagnosis of liver cirrhosis was based on histological or clinical factors. The inclusion criteria were EV grade ≥F2 as a prerequisite and a moderate to severe red color sign, according to the general rules for recording endoscopic findings of EV, proposed by the Japanese Society for Portal Hypertension;10 all EUM parameters could be evaluated, including diameter of EV, diameter of paraesophageal veins, and diameter of portal veins (PVs); and baseline laboratory data available. The exclusion criteria were: failure to eradicate EV or diagnosed or developed hepatocellular carcinoma; presence of peptic ulcer or inflammatory bowel
disease; concomitant main PV thrombosis; received balloonoccluded retrograde transvenous obliteration (BRTO) or transjugular intrahepatic portosystemic shunt (TIPS), EV bleeding history within 2 years prior to prophylactic EVL, death from other illness independent of liver disease, and lost to follow-up. Demographic data, including age, sex, etiology of cirrhosis, use of nonselective β-blocker, and previous episode of EV bleeding were collected. Platelet count, serum bilirubin and albumin, and prothrombin time were also examined. The severity of liver cirrhosis was graded by Child-Turcotte-Pugh (CTP) class and the Model for End-Stage Liver Disease score. Spleen size was examined by abdominal ultrasonography. This study was approved by the Institutional Review Board (IRB) of Soonchunhyang University Bucheon Hospital (IRB number: 2015-07-022-001). 2. Measurement of endoscopic ultrasonographic parameters All patients underwent EUM prior to EVL. The procedures were carried out by an endoscopist (S.G.K.) using a miniature ultrasonic probe (UM-2R, 12 MHz; Olympus, Tokyo, Japan). The endoscopy used for EUM was a GIF-2TQ 260M or a 2T240 (Olympus). The examinations were recorded on videotape so that an independent endoscopist (Y.S.K.) could review the EUM findings to avoid observer bias and discuss the images until they reached agreement. EV diameter, diameter of para-ECVs located external to the esophageal wall, diameter and number of perforating veins, and the presence of gastric varices were assessed as described previously.9 However, peri-ECVs were not evaluated entirely as many peri-ECVs occur in a single patient. The largest para-ECV that connected with EV through a perforating vein was selected as a valid parameter, but all visible
248 Cirrhotic patients with esophageal varices received EUS
104 Patients were excluded: 36 Fail to achieve EV eradication 26 Follow-up loss 10 TIPS or BRTO 9 HCC development 7 Portal vein thrombosis 6 Past EV bleeding within 2 years 5 Discordant data 3 GV bleeding 2 Other cause of death
144 Patients were enrolled
102 No recurrence of EV
42 Recurrence of EV
32 No EV bleeding
10 EV bleeding
Fig. 1. Flow diagram for the study. EUS, endoscopic ultrasonography; EV, esophageal varices; TIPS, transjugular intrahepatic portosystemic shunt; BRTO, balloon-occluded retrograde transvenous obliteration; HCC, hepatocellular carcinoma; GV, gastric varices.
Jeong SW, et al: Esophageal Varices and Endoscopic Ultrasound
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Para-ECVs Perforating vein (connected with peri-ECVs)
Fig. 2. A schematic diagram showing esophageal varices and vascular structures around the esophageal wall using endoscopic ultrasonography with a mini-probe. Long arrow, para-esophageal collateral veins (ECVs); short arrow, peri-ECVs; arrow head, perforating veins.
Peri-ECVs Lumen
Muscular layer Mucosa & submucosal layer
Muscularis externa
perforating veins were reported in terms of number and diameter. Esophageal varices and the vascular structures around the esophageal wall using EUM is shown as a schematic diagram in Fig. 2.
Table 1. Patient Characteristics (n=144) Variable Age, yr Sex
3. EVL procedure and follow-up The EVL indication was based on the Baveno IV consensus.11 The endoscope loaded with a multi-banding device (6-shooter; Wilson-Cook, Limerick, Ireland) was introduced into the esophagus, and each band was consecutively applied from the gastroesophageal junction to the oral side. All visible varices were ligated during each procedure. EVL was repeated at 2-month intervals until EV were eradicated completely. The obliteration of varices was defined as nonvisualization of varices on endoscopy. Prophylactic antibiotics and omeprazole were given to all patients, and a nonselective β-blocker was prescribed to patients with EV (≥F2) who had not bled but had a high risk of hemorrhage (CTP class B/C or variceal red wale markings on endoscopy) to prevent the first variceal hemorrhage if they could tolerate a nonselective β-blocker. Follow-up endoscopy was performed at 6-month intervals for 1 year after obliteration of EV, and variceal bleeding, reappearance of EV (F1), or the presence of the red color sign was regarded as EV recurrence. Among the patients with recurred EV, bleeding was defined as any episode of hematemesis or melena from recurred EV or when endoscopy showed blood from EV. 4. Statistical analysis Among the demographic and clinical parameters, continuous variables are expressed as mean and standard deviation. Differences of these variables between groups were tested with Student t-test or the Wilcoxon rank-sum test, as appropriate, after testing for normality using the Shapiro-Wilk test and for the equal variance assumption using Levene’s test. Categorical variables were expressed as frequencies and percents (%) and compared with the chi-square or Fisher exact test, as appropriate. A univariate logistic regression analysis was performed to examine the associations between the candidate predictors and the presence or absence of EV recurrence and bleeding after EVL. The odds ratio (OR) for the chance of variceal recurrence
Value
Etiology
53.8±10.4 Male Female
30 (20.8)
Alcohol
62 (43.1)
Hepatitis B
65 (45.1)
Hepatitis C CTP class
Splenomegaly
5 (3.5)
Others
12 (8.3)
A
56 (38.9)
B
67 (46.5)
C
21 (14.6)
Absence
17 (11.8)
Presence
127 (88.2)
Platelet, 103/μL Previous history of EV bleeding
114 (79.2)
85.1±46.2 Yes
85 (59.0)
No
59 (41.0)
F2
105 (72.9)
F3
39 (27.1)
Absence
70 (48.6)
Presence
74 (51.4)
Endoscopic findings EV class Gastric varices EUS findings EV size, mm
8.7±2.5
Para-ECV size, mm
7.7±2.2
Perforating vein size, mm
3.2±0.7
Perforating vein number
3.5±0.7
Session of EVL, n Nonselective β-blocker
3 (3–4) Yes No
Recurrence of EV Bleeding of EV
Absence
115 (79.9) 29 (20.1) 102 (70.8)
Presence
42 (29.2)
Absence
134 (93.1)
Presence
10 (6.9)
Data are presented as mean±SD, number (%), median (interquartile range). CTP, Child-Turcotte-Pugh; EV, esophageal varices; EUS, endoscopic ultrasonography; ECV, esophageal collateral veins; EVL, endoscopic variceal ligation.
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and variceal bleeding was calculated for each predictor. Akaike Information Criterion (AIC)-based backward selection was used to drop insignificant variables in the multivariate logistic regression.12 The initial regression model included factors that showed the significance based on the univariate logistic regression and was further refined by the AIC-based backward selection. Multiple collinearity of continuous variables was assessed by the general variance inflation factor.13 After the final model was determined, the probability predicted for each subject was used as input to generate a receiver-operating characteristic (ROC) curve. The area under the ROC curve (AUC) and the 95% confidence interval (CI) of this area was computed to evaluate diagnostic ability. The diagnostic test was considered to have discriminatory potential if the lower limit of the CI for the AUC was >0.5. The best cutoff probability value for each subject to have a recurrence of EV or bleeding after EVL was determined using Youden’s index.14 Sensitivity, specificity, and positive and negative predictive values of the best cutoff value were calcu-
lated. A two-tailed p-value